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Gallbladder cancer Article · October 2014 DOI: 10.3978/j.issn.2304-3881.2014.09.03 · Source: PubMed

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Vol 3,  No 5 OCT 2014

HEPATOBILIARY SURGERY AND NUTRITION

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Focused Issue: Dedicated to the 2nd International Congress of Hepatobiliary and Pancreatic Surgery

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Guest Editors: Leonardo Patrlj, Mario Kopljar and Yuman Fong

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ISSN 2304-3881 Vol 3, No 5 OCT 2014

HBSN

ISSN 2304-3881

© AME Publishing Company 2014. All rights reserved. Contact: [email protected]

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Editor-in-Chief Yilei Mao, MD, PhD Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China Editorial Board René Adam, MD, PhD Villejuif, France Stig Bengmark, MD, PhD Lund, Sweden Henri Bismuth, MD, FACS (Hon) Villejuif, France William S. Blaner, PhD New York, USA Ronald W. Busuttil, MD, PhD Los Angeles, USA William C. Chapman, MD, FACS St. Louis, USA Chao-Long Chen, MD, PhD (Hon.) Kaohsiung, Taiwan N. Joseph Espat, MD, MS, FACS Providence, USA Sheung-Tat Fan, MS, MD, PhD Hong Kong SAR, China John Fung, MD, PhD Cleveland, USA Bengt W Jeppsson, MD, PhD Malmö, Sweden Michael D. Kluger, MD, MPH New York, USA

Deputy Editors-in-Chief J. Michael Millis, MD (Liver Transplantation) Chicago, USA Woo-Jung Lee, MD, PhD (Robotic Surgery) Seoul, Korea

Xiang-Dong Wang, MD, PhD (Nutrition and Liver Cancer) Boston, USA Haitao Zhao, MD, PhD (Hepatobiliary Research) Beijing, China

Norihiro Kokudo, MD, PhD, FACS Tokyo, Japan Paul B.S. Lai, MD, BS Hong Kong SAR, China Masatoshi Makuuchi, MD, PhD Tokyo, Japan Jacques Marescaux, MD, FRCS, FJSES Strasbourg, France Robert CG Martin, II, MD, PhD Louisville, USA Jeffrey B. Matthews, MD Chicago, USA Donald N. Reed, Jr., MD, FACS Ft. Wayne, USA Edward Saltzman, MD Boston, USA Helmut K. Seitz, MD, AGAF Heidelberg, Germany Mary Simmerling, PhD New York, USA Robert J Smith, MD Providence, USA

Frank Tacke, MD, PhD Aachen, Germany Tadatoshi Takayama, MD, PhD Tokyo, Japan Wei Tang, MD, PhD Tokyo, Japan Giuliano Testa, MD, FACS, MBA Texas, USA Haibo Wang, MD Hong Kong SAR, China Roger Williams CBE, MD, FRCP, FRCS, FRCPE, FRACP, FMedSci, FRCPI (Hon), FACP (Hon) London, UK Huttaporn Wongsiriroj, PhD Nakhon Pathom, Thailand Sien-Sing Yang, MD Taipei, Taiwan Suh-Ching Yang, PhD Taipei, Taiwan Shou-Xian Zhong, MD, PhD Beijing, China Thomas R. Ziegler, MD Atlanta, USA

Aims and Scope HepatoBiliary Surgery and Nutrition (Print ISSN 2304-3881; Online ISSN 2304-389X; Hepatobiliary Surg Nutr; HBSN) is a bi-monthly peer-reviewed publication that is dedicated to the advancement of hepatobiliary surgery and nutrition. The journal is now indexed in PubMed and PMC. The main focus of the journal is to describe new findings in hepatobiliary diseases, provide current and practical information on diagnosis, prevention and clinical investigations. Specific areas of interest include, but not limited to, multimodality therapy, biomarkers, imaging, biology, pathology, and technical advances related to hepatobiliary diseases. Contributions pertinent to hepatobiliary diseases are also included from related fields such as nutrition, surgery, public health, human genetics, basic sciences, education, sociology, and nursing. Article categories of the journal include original article, review, research highlight, editorial, case report and a special section on nutrition will be featured. The official publication of: Society for Translational Medicine. Editorial Correspondence Eunice X. Xu. HepatoBiliary Surgery and Nutrition. HK office: 9A Gold Shine Tower, 346-348 Queen’s Road Central, Sheung Wan, Hong Kong. Tel: +852 3488 1279; Fax: +852 3488 1279. Email: [email protected]

Timothy M. Pawlik, MD, MPH, MTS, PhD (Hepatobiliary Surgery) Baltimore, USA

Assistant Editor Zhiyong Guo, MD, PhD Guangzhou, China Managing Editor Katherine L. Ji Senior Editors Eunice X. Xu (Corresponding Editor) Grace S. Li Elva S. Zheng Nancy Q. Zhong Science Editors Silvia L. Zhou Helen X. Seliman Executive Copyeditor Benti L. Peng Executive Typesetting Editor Paula P. Pan Production Editor Emily M. Shi

Note to NIH Grantees Pursuant to NIH mandate, HepatoBiliary Surgery and Nutrition (HBSN) journal will post the accepted version of contributions authored by NIH grant-holders to PubMed Central upon acceptance. This accepted version will be made publicly available 2 months after publication. For further information, see www. thehbsn.org Conflict of Interest Policy for Editors The full policy and the Editors’ disclosure statements are available online at: www.thehbsn.org Disclaimer The Publisher and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher and Editors, neither does the publication of advertisements constitute any endorsement by the Publisher and Editors of the products advertised. For submission instruct ions, subscript ion and all ot her information visit www.thehbsn.org © 2014 HepatoBiliary Surgery and Nutrition

Table of Contents

Preface 219 Maturation of HBP surgery: worldwide advances to address worldwide problems Leonardo Patrlj, Mario Kopljar, Yuman Fong

Review Article 221 Gallbladder cancer Mislav Rakić, Leonardo Patrlj, Mario Kopljar, Robert Kliček, Marijan Kolovrat, Bozo Loncar, Zeljko Busic 227 Pre-resectional inflow vascular control: extrafascial dissection of Glissonean pedicle in liver resections Aleksandar Karamarković, Krstina Doklestić 238 Post-hepatectomy liver failure Rondi Kauffmann, Yuman Fong 247 Pancreatic surgery: evolution and current tailored approach Mario Zovak, Dubravka Mužina Mišić, Goran Glavčić 259 Potential use of Doppler perfusion index in detection of occult liver metastases from colorectal cancer Mario Kopljar, Leonardo Patrlj, Željko Bušić, Marijan Kolovrat, Mislav Rakić, Robert Kliček, Marcel Židak, Igor Stipančić 268 Pancreatic fistula and postoperative pancreatitis after pancreatoduodenectomy for pancreatic cancer Miroslav Ryska, Jan Rudis 276 Techniques for prevention of pancreatic leak after pancreatectomy Hans F. Schoellhammer, Yuman Fong, Singh Gagandeep 288 Robotic liver surgery Universe Leung, Yuman Fong 295 “Vanishing liver metastases”—A real challenge for liver surgeons Alex Zendel, Eylon Lahat, Yael Dreznik, Barak Bar Zakai, Rony Eshkenazy, Arie Ariche 303 Small for size liver remnant following resection: prevention and management Rony Eshkenazy, Yael Dreznik, Eylon Lahat, Barak Bar Zakai, Alex Zendel, Arie Ariche 313 The laparoscopic liver resections—an initial experience and the literature review Mislav Rakić, Leonardo Patrlj, Robert Kliček, Mario Kopljar, Antonija Đuzel, Kristijan Čupurdija, Željko Bušić 317 Complications after percutaneous ablation of liver tumors: a systematic review Eylon Lahat, Rony Eshkenazy, Alex Zendel, Barak Bar Zakai, Mayan Maor, Yael Dreznik, Arie Ariche 324 The surgical treatment of patients with colorectal cancer and liver metastases in the setting of the “liver first” approach Leonardo Patrlj, Mario Kopljar, Robert Kliček, Masa Hrelec Patrlj, Marijan Kolovrat, Mislav Rakić, Antonija Đuzel

© Hepatobiliary Surgery and Nutrition. All rights reserved.

HepatoBiliary Surgery and Nutrition, Vol 3, No 5 October 2014

Preface

Maturation of HBP surgery: worldwide advances to address worldwide problems The evolution of hepatobiliary pancreatic surgery in the last two decades has been remarkable. The improvements in technical surgery, anesthesia, and technology now allow extraordinarily safe surgery. Whereas major hepatectomies or pancreatectomies until recently were performed at few centers due to the enormous risk, they are now common place operations being performed even on the elderly patient. Advances in neoadjuvant, adjuvant, and ablative therapies now allow for many more patients to be eligible for life-prolonging surgeries and for better long-term outcome. Cancers such as cholangiocarcinoma, gallbladder cancer, or metastatic colorectal cancer, which were largely incurable only three decades before are now routinely resected and result in long-term survival and possibly cured. This progress and the current state of the treatment for many of the hepatobiliary malignancies are summarized in this issue of the Hepatobiliary Surgery and Nutrition (HBSN) dedicated to the proceedings of the Congress of Hepatobiliary Surgery about to be held in Croatia. The advances in treatment of liver cancer have consequences throughout the world. Due to the high prevalence of viral hepatitis and the associated liver cancers, hepatobiliary malignancies are some of the most common malignancies globally. It is fitting that contributions to the improvement in surgical care of these malignancies have come from surgeons, anesthesiologists, and scientists worldwide. The authorship of this journal issue includes many of the luminary and most innovative investigators in this field, and include international expert surgeons and educators from Europe, Asia, and America. We thank them for their contribution to this Journal, to the Congress, and for their dedication to these patients and to the field. We also look forward to seeing these surgeons and physicians in beautiful Split for a few days of scholarship, of mutual education, and of camaraderie. Few solid tumors can be cured without surgical therapy. Thus, advances that result in safer operations increases potential for cure. In order for this field to have moved so quickly in the last years is due not only to scientists, engineers, and clinicians, but also due to those who have enrolled in the necessary trials. We therefore thank the patients who have contributed to the advances, and whose diseases are the targets that push us to create new solutions. Gratitude also goes to our post-docs, research fellows and colleagues that help us gather data, refine our hypothesis, and design the next tools. We thank the editors and staff of HBSN, but particularly Editor-in-Chief Yilei Mao and Editor Eunice X. Xu for their support. Finally, we thank our families for the patience and support they have given us to do our investigative and clinical work, and for helping us put together this international meeting.

© Hepatobiliary Surgery and Nutrition. All rights reserved.

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Hepatobiliary Surg Nutr 2014;3(5):219-220

Patrlj et al. Advances in HPB surgery

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Leonardo Patrlj. Department of Abdominal

Mario Kopljar, MD, PhD. Department

Yuman Fong. City of Hope Medical Center,

Surgery, University Hospital Dubrava, Av. G.

of Abdominal Surgery, University Hospital

1500 East Duarte Road, Duarte, CA 91010,

Šuška 6, HR-10000 Zagreb, Croatia.

Dubrava, Av. G. Šuška 6, HR-10000 Zagreb,

USA. (Email: [email protected].)

(Email: [email protected].)

Croatia. (Email: [email protected].)

doi: 10.3978/j.issn.2304-3881.2014.09.11 Disclosure: The authors declare no conflict of interest. View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.11

Cite this article as: Patrlj L, Kopljar M, Fong Y. Maturation of HBP surgery: worldwide advances to address worldwide problems. Hepatobiliary Surg Nutr 2014;3(5):219-220. doi: 10.3978/j.issn.2304-3881.2014.09.11

© Hepatobiliary Surgery and Nutrition. All rights reserved.

www.thehbsn.org

Hepatobiliary Surg Nutr 2014;3(5):219-220

Review Article

Gallbladder cancer Mislav Rakić, Leonardo Patrlj, Mario Kopljar, Robert Kliček, Marijan Kolovrat, Bozo Loncar, Zeljko Busic Department of Hepatobiliary Surgery, University Hospital Dubrava, Zagreb, Croatia Correspondence to: Mislav Rakić, MD. Department of Hepatobiliary Surgery, University Hospital Dubrava, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia. Email: [email protected]; [email protected].

Abstract: Gallbladder cancer is the fifth most common cancer involving gastrointestinal tract, but it is the most common malignancy of the biliary tract, accounting for 80-95% of biliary tract cancers. This tumor is a highly lethal disease with an overall 5-year survival of less than 5% and mean survival mere than 6 months. An early diagnosis is essential as this malignancy progresses silently with a late diagnosis. The percentage of patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone disease is 0.5-1.5%. Patients with preoperative suspicion of gallbladder cancer should not be treated by laparoscopy. Epidemiological studies have identified striking geographic and ethnic disparities—inordinately high occurrence in American Indians, elevated in Southeast Asia, yet quite low elsewhere in the Americas and the world. Environmental triggers play a critical role in eliciting cancer developing in the gallbladder, best exemplified by cholelithiasis and chronic inflammation from biliary tract and parasitic infections. Improved imaging modalities and improved radical aggressive surgical approach in the last decade has improved outcomes and helped prolong survival in patients with gallbladder cancer. The overall 5-year survival for patients with gallbladder cancer who underwent R0 curative resection was from 21% to 69%. In the future, the development of potential diagnostic markers for disease will yield screening opportunities for those at risk either with ethnic susceptibility or known anatomic anomalies of the biliary tract. Keywords: Gallbladder carcinoma; gallstones; laparoscopic cholecystectomy; liver resection Submitted Jul 28, 2014. Accepted for publication Sep 02, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.03 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.03

Introduction Biliary tract cancers are invasive adenocarcinomas that arise from the epithelial lining of the gallbladder and intrahepatic and extra hepatic bile ducts. Although anatomically these malignancies are related and have similar metastatic patterns, each has a distinct clinical presentation, molecular pathology, and prognosis (1). Gallbladder cancer is the most common malignancy of the biliary tract, representing 80-95% of biliary tract cancers worldwide (2,3). It ranks fifth among gastrointestinal cancers. The global rates for gallbladder cancer shows differences, reaching epidemic levels for some regions and ethnicities. Gallbladder cancer has a particularly high incidence in Chile, Japan, and northern India (2). The basis for this variance likely resides in differences in

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environmental exposure and intrinsic genetic predisposition to carcinogenesis. For gallbladder cancer, several conditions associated with chronic inflammation are considered risk factors, which include gallstone disease, porcelain gallbladder, gallbladder polyps, chronic Salmonella infection, congenital biliary cysts, and abnormal pancreaticobiliary duct junction (1,2). The percentage of patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone disease is 0.5-1.5% (4-6). In most instances, gallbladder cancer develops over 5 to 15 years, when metaplasia progresses to dysplasia, carcinoma in situ, and then, invasive cancer (1). A satisfactory outcome depends on an early diagnosis and surgical resection. Despite this potential for cure, less than 10% of patients have tumors that are resectable at the time

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of surgery, while nearly 50% have lymph node metastasis (4). Even with surgery, most progress to metastatic disease, highlighting the importance of improving adjuvant therapies (5). This tumour is traditionally regarded as a highly lethal disease with an overall 5-year survival of less than 5% (5). The overall mean survival rate for patients with gallbladder cancer is 6 months (6). Risk factors The identification of risk factors is critical, providing insight into the pathogenetic mechanism that drives geographic and ethnic variance, and yielding strategies for prevention and treatment. Gallbladder cancer rates tend to increase with advancing age. The median age was 67 years in a Memorial SloanKettering report of 435 gallbladder cancer patients (5). Gender differences demonstrate a marked predominance of women over men worldwide (7). Women are affected 2-6 times more often than men (8). There is a widely variable geographic pattern for gallbladder cancer, Asia is a high risk continent, while the United States and most western and Mediterranean European countries (e.g., UK, France, and Norway) represent low risk areas (5,6,9,10). Ethnicity plays a role even in different geographic locations. The Korean people have the highest incidence rate (per 100,000) of gallbladder cancer in Asia. Korean males living in Los Angeles County, California also carry the highest US ethnic incidence rate (10). Gallstones represent a most important association for this malignancy, being present in most (~85%) patients with gallbladder cancer. The incidence of gallbladder cancer in a population with gallstones varies from 0.3% to 3% (11). The higher risk of gallbladder cancer development in larger stones possibly reflects the greater duration and intensity of mucosal irritation causing chronic inflamation (12,13). Prophylactic cholecystectomy would appear reasonable in these individuals (14). Chronic inflammation causing deoxyribonucleic acid (DNA) damage, provoking repeated tissue proliferative attempts at restoration, releasing cytokines and growth factors, and thus, predisposing cells to oncogenic transformation (15). Chronic inflammation can also result in calcium being deposited in the gallbladder wall. When calcium deposits become extensive, the gallbladder acquires a bluish hue and becomes fragile, even brittle—hence the

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term “porcelain gallbladder” (16). The porcelain gallbladder is frequently (average 25%, range, 12-61%) associated with gallbladder cancer (17,18). Chronic bacterial cholangitis poses a clear risk for biliary tract malignancy. The organisms that have been most implicated are Salmonella (e.g., S. typhi and S. paratyphi) and Helicobacter (e.g., H. bilis) spp (19,20). Bacterial colonization may induce hydrolysis of primary bile acids forming. Malignant transformation is further implicated via chronic inflammation itself and alterations of tumor suppressor genes [such as tumor protein 53 (p53)] or proto-oncogenes [such as mutations of Kirsten ras oncogene homolog (K-ras)] (15,21). Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory syndrome linking chronic inflammation to carcinogenesis (22). Facilitating a metaplasia-dysplasiacarcinoma sequence (23,24). Various environmental exposures have been hypothesized to contribute to gallbladder cancer, such as: heavy metals, tobacco, radon (25-28). Obese people have an increased risk of developing gallbladder cancer (29-31). The risk of developing gallbladder cancer in those with diabetes mellitus is increased (32). Almost 5% of adults harbor gallbladder polyps (33,34). Most of them are pseudopolyps, without neoplastic potential (35). Features that predict malignancy are: large polyps (>10 mm), a solitary or sessile mass, associated gallstones, the patient’s age over 50 years old, and most importantly, rapid polyp growth (7,29). Anomalous junction of the pancreaticobiliary duct is a congenital malformation in which the pancreatic duct drains into the biliary tract outside the papilae Vateri. Such a long common channel defeats the gatekeeper function of the sphincter of Oddi, potentially allowing pancreatic secretions to regurgitate into the bile ducts and gallbladder, thus leading to malignant changes in the mucosa (36). Gallbladder cancer seems to result from a combination of genetic predisposition and exposure to environmental risk factors (37). One proposed carcinogenic pathways suggest that: gallstone mediated inflammation → p53 mutation (↓) → K-ras mutation (↑) (21). Diagnosis Clinical presentation is similar to biliary colic or chronic cholecystitis. The most common symptoms are: persistent right upper quadrant pain, jaundice, nausea and weight loss. In some patients palpable mass is present (38,39).

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Imaging can detect malignancy. Transabdominal ultrasound is a useful initial modality for investigating patients with upper abdominal pain and jaundice (40). Endoscopic ultrasound (EUS) is currently the definitive modality for staging gallbladder cancer. EUS also offers sampling via fine needle aspiration (41). Computerized tomography (CT) helps identify any extension to lymph nodes, liver involvement, or distant metastases, performed preoperatively, determines gallbladder resectability with a high accuracy (up to 93%) (42) . Standard magnetic resonance imaging (MRI) is generally less valuable. Magnetic resonance (MR) cholangiography and MR angiography quite accurately detects bile duct or vascular invasion, with sensitivity and specificity approaching 100%. Positron emission computed tomography (PET) scans are useful in differentiating malignant from benign disease, in preoperative staging, and in detecting postoperative residual disease (43). Staging system Gallbladder cancer staging, based on the American Joint Committee on Cancer (AJCC) guidelines, focuses on tumor invasion and the extent of spread (44). Adenocarcinoma is the most frequent histologic type, accounting for 98% of all gallbladder tumors (45). The other histopathologic variants include the papillary, mucinous, squamous, and adenosquamous subtypes. The disease stage determines the treatment options. The best outcomes are reserved for patients who qualify for cholecystectomy. In stage I disease, according to AJCC criteria, tumor invades the lamina propria or the muscle layer. Stage II is designated by the perforation of the serosa and/or involvement of adjacent organs or structures. T1 to T3 tumor invasion with any nodal involvement is automatically classified as stage II. Both stage I and II are potentially resectable with curative intent. Stage III generally indicates locally unresectable disease, as a consequence of vascular invasion or the involvement of multiple adjacent organs. Stage IV represents nonresectability because of distant metastases (46). Surgical management Primary tumor invasion (T) is the most important factor in the AJCC staging criteria; it determines the surgical approach (44). The overall 5-year survival for patients with

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gallbladder cancer who underwent R0 curative resection was reported to range from 21% to 69%, and 0% for patients who did not get R0 resection. So the R0 curative resection is objective of surgical management for gallbader cancer (40). Type of liver resection for carcinoma of the gallbladder varies from atipical resection of segments IVb at V to right hepatectomy. By the Union for internatonal Cancer Control (UICC)/ AJCC are two types of regional lymphadenectomy for gallbladder cancer: N1—lymphnodes of hepatoduodenal ligament (cystic duct, pericholedochal and hilar lymph nodes); N2—peripancreatic, periductal, periportal, common hepatic artery, coeliac and superior mesenteric artery lymph nodes. Laparoscopic cholecystectomy is absolutely contraindicated when gallbladder cancer is known or suspected pre-operatively. Patients with a pre-operative suspicion of gallbladder cancer should undergo open exploration and cholecystectomy after proper pre-operative assessment, or immediately with suspicion made during laparoscopy. If the diagnosis is confirmed on frozen section radical surgical resection should be performed in the same session (5). Incidental gallbladder cancers are detected histologically after the fact in 0.3-3% of laparoscopic cholecystectomies performed for cholelithiasis. For these patients a second radical resection is indicated after adequate diagnostic and treatment preparation, except for Tis and T1a disease. Port-site recurrences can follow laparoscopic cholecystectomies in up to 17% of cases where unsuspected gallbladder cancer is discovered (47). Here, accidental bile spillage implants tumor cells at the trocar or incision site, leading to recurrence so the excision of the port sites are indicated during the radical reoperation. Tis and T1a gallblader cancer (tumor is limited to mucosa) are usually diagnosed after cholecystectomy. There is consensus that simple cholecystectomy is an adequate treatment which offers a surgical cure with 100% 5-year survival (47). In T1b gallbladder cancer (tumor invades the muscular layer) there is still controversy for the optimal management. Reported incidence of occult lymphatic metastasis is 1525% in this stage with 10% incidence of residual disease in liver bed (47,48). Given the frequency of positive lymph nodes and residual disease in this stage, recommended procedure is cholecystectomy with radical resection which encompasses 3 cm of liver parenchyma segment IVb and V,

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plus adequate lymphadenectomy (48,49). The outcome after simple cholecystectomy in this stage is 75% 10-year survival vs. 100% for radical operation. T2 lesions of gallbladder cancer invade perimuscular connective tissue with no extension beyond the serosa or into the liver. The reported 5-year survival for patients with this stage of disease treated with simple cholecystectomy where 10-61% and 54-100% after radical resection. Yamaguchi reported that over 40% of these patients had positive margins after simple cholecystectomy with rate of positive lymph nodes of 19-62%. So radical resection is the method of choice for these patients. This often requires a more formal resection of segments IVb and V (48-50). In T3 disease, the tumor may extend to the serosa, liver, and/or adjacent organs/structures. Under these circumstances, resection becomes more radical, including an extended right hepatectomy with possible caudate lobectomy (47), regional lymphadenectomy, and extirpation of other affected structures (46). Some centers further advocate pancreaticoduodenectomy to improve outcomes (47). There is 45-70% incidence of lymph node dissemination with 36% of residual disease (51). T4 disease is widely disseminated through vascular invasion and/or metastasis. Lesions here are commonly unresectable and it is impossible to achieve R0 resection in this stage. Consequently palliative therapy which includes adequate pain control, surgical or non-surgical biliary drainage is more appropriate in this stage. The goal of surgical intervention is to obtain R0 resection. Surgical resection for advanced gallbaldder cancer is recommended only if a potentially curative R0 resection is technically possible (46,47,52). Adjuvant therapy Patients with gallbladder cancer often present in advanced stage of disease. In these patients adjuvant therapy with palliative therapy is the only way to treat though there is still no effective adjuvant therapy for gallbladder cancer. Three classes of chemotherapeutics may be used: gemcitabine, fluoropyrimidine, and platinum compounds. Monotherapy has limited effect (43). Combination chemotherapy using gemcitabine and cisplatin offers a significant survival advantage for patients with advanced disease (51). Radiotherapy has proven to be marginally useful in the setting of advanced disease. Therapeutic agents, targeting cellular and molecular

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pathways, can impede tumor growth. Targeted therapy against epidermal growth factor receptor (EGFR) has demonstrated an antiproliferative effect in vitro and provides some optimism for a changing treatment paradigm in the future (53). Unfortunately, the data supporting the use of adjuvant or neoadjuvant chemoradiotherapy is largely based on Phase II trials, with no conclusive evidence favoring benefit (46). Prognosis The most important prognostic factors that can predict survival after resection are: T staging of the original lesion; extent of nodal involvement; metastasis; and jaundice (which can signify biliary invasion and possible obstruction) (46). The advent of gallbladder cancer staging has witnessed an improvement in overall 5-year survival rates, what is the merit of radical and successful surgical curing and advances in diagnosis (2). Further improvement in the treatment of this disease is expected from the progress of chemotherapy (53). The AJCC “Cancer Staging Manual” assessed 10,000 patients diagnosed with gallbladder cancer from 1989 to 1996. The 5-year survival rates start at 80% for stage 0, then progressively fall to 50% for stage I, 28% for stage II, 8% for stage IIIa, 7% for stage IIIb, 4% for stage IVa, and finally, 2% for stage IVb (44). Conclusions Gallbladder cancer is the fifth most common cancer involving gastrointestinal tract, but it is the most common malignancy of the biliary tract with a highly variable prevalence in different parts of the world. Histopathological type is almost always adenocarcinoma. This distinctive malignancy has disastrous outcomes with an overall 5-year survival of less than 5% and mean survival mere than 6 months. Chronic inflammation caused with cholelithiasis is the most important risk factor. Diagnosis may come at the time of cholecystectomy for gallstones, although preoperative imaging with transabdominal and EUS, multisliced computed tomography (MSCT) and MR is providing an important advance. Surgery represents the only potential cure. Unfortunately, the usual late presentation means an advanced stage with potential nodal involvement and leads to recurrences despite attempted resection.

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Laparoscopic cholecystectomy is contraindicated when gallbladder cancer is suspected preoperatively. After incidental finding of gallbladder cancer on pathohistological review following cholecystectomy for cholelithiasis, a second radical resection is indicated except for T1a stage. There is still no effective adjuvant therapy for gallbladder cancer so R0 surgical resection is the only treatment with potential cure. Aggressive surgical approach should be based on a balance between the risk of surgery (morbidity, mortality) and the outcome. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Zhu AX, Hong TS, Hezel AF, et al. Current management of gallbladder carcinoma. Oncologist 2010;15:168-81. 2. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol 2014;6:99-109. 3. Lazcano-Ponce EC, Miquel JF, Muñoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001;51:349-64. 4. Sheth S, Bedford A, Chopra S. Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy. Am J Gastroenterol 2000;95:1402-10. 5. Duffy A, Capanu M, Abou-Alfa GK, et al. Gallbladder cancer (GBC): 10-year experience at Memorial SloanKettering Cancer Centre (MSKCC). J Surg Oncol 2008;98:485-9. 6. Lai CH, Lau WY. Gallbladder cancer--a comprehensive review. Surgeon 2008;6:101-10. 7. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 2006;118:1591-602. 8. Konstantinidis IT, Deshpande V, Genevay M, et al. Trends in presentation and survival for gallbladder cancer during a period of more than 4 decades: a single-institution experience. Arch Surg 2009;144:441-7; discussion 447. 9. Curado MP, Edwards B, Shin HR, et al. eds. Cancer incidence in five continents. IX. Lyon: International Agency for Research on Cancer Scientific Publications, 2007. 10. Surveillance, Epidemiology and End-Results Program (SEER). The Four Most Common Cancers for Different Ethnic Populations 2013. Bethesda, MD: National Cancer Institute; 2013. 11. Singh V, Trikha B, Nain C, et al. Epidemiology of

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gallstone disease in Chandigarh: a community-based study. J Gastroenterol Hepatol 2001;16:560-3. 12. Csendes A, Becerra M, Rojas J, et al. Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: a prospective study of 592 cases. J Gastrointest Surg 2000;4:481-5. 13. Mlinarić-Vrbica S, Vrbica Z. Correlation between cholelithiasis and gallbladder carcinoma in surgical and autopsy specimens. Coll Antropol 2009;33:533-7. 14. Le MD, Henson D, Young H, et al. Is gallbladder cancer decreasing in view of increasing laparoscopic cholecystectomy? Ann Hepatol 2011;10:306-14. 15. Rashid A, Ueki T, Gao YT, et al. K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res 2002;8:3156-63. 16. Berk RN, Armbuster TG, Saltzstein SL. Carcinoma in the porcelain gallbladder. Radiology 1973;106:29-31. 17. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 2001;129:699-703. 18. Cunningham SC, Alexander HR. Porcelain gallbladder and cancer: ethnicity explains a discrepant literature? Am J Med 2007;120:e17-8. 19. Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol 2006;93:633-9. 20. Gonzalez-Escobedo G, Marshall JM, Gunn JS. Chronic and acute infection of the gall bladder by Salmonella Typhi: understanding the carrier state. Nat Rev Microbiol 2011;9:9-14. 21. Saetta AA. K-ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer. J Surg Oncol 2006;93:644-9. 22. Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011;54:1842-52. 23. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a MetaplasiaDysplasia-Carcinoma Sequence. Am J Surg Pathol 2007;31:907-13. 24. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660-78. 25. Pandey M. Environmental pollutants in gallbladder carcinogenesis. J Surg Oncol 2006;93:640-3. 26. Lubin JH, Boice JD Jr, Edling C, et al. Lung cancer in radon-exposed miners and estimation of risk from indoor

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Cite this article as: Rakić M, Patrlj L, Kopljar M, Kliček R, Kolovrat M, Loncar B, Busic Z. Gallbladder cancer. Hepatobiliary Surg Nutr 2014;3(5):221-226. doi: 10.3978/ j.issn.2304-3881.2014.09.03

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Review Article

Pre-resectional inflow vascular control: extrafascial dissection of Glissonean pedicle in liver resections Aleksandar Karamarković1,2, Krstina Doklestić1,2 1

Faculty of Medicine, University of Belgrade, Serbia; 2Clinic for Emergency Surgery, Clinical Center of Serbia, Belgrade, Serbia

Correspondence to: Prof. Aleksandar Karamarković, MD, Ph.D. Clinic for Emergency Surgery, Clinical Center of Serbia, Pasteur Str.2, Belgrade 11000, Serbia. Email: [email protected].

Background/aims: We are evaluated technique of anatomic major and minor hepatic resections using suprahilar-extrafascial dissection of Glissonean pedicle with vascular stapling device for transection of hepatic vessels intending to minimize operative time, and blood loss. Methodology: We prospectively analyzed the clinical records of 170 patients who underwent hepatic resection by suprahilar-extrafascial pedicle isolation and stapling technique in our clinic for emergency surgery in Belgrade. Patients who underwent hilar extrahepatic intrafascial dissection were excluded from the study. Results: We performed 102 minor liver resections and 68 major hepatectomies. The minor liver resections were associated with significantly shorter surgery duration (95.1±31.1 vs. 186.6±56.5) and transection time (35.9±14.5 vs. 65.3±17.2) than major hepatectomies (P<0.001 for all). The mean blood loss was 255.6±129.9 mL in minor resection and 385.7±200.1 mL in major resection (P=0.003). The mean blood transfusion requirement was 300.8±99.5 mL for the patients with minor hepatectomy and 450.9±89.6 mL for those with major liver resection (P=0.067). There was no significant difference in morbidity and mortality between the groups (P=0.989; P=0.920). Major as well as minor liver resection were a superior oncologic operation with no significant difference in the 3-year overall survival rates. Conclusions: Extrafascial dissection of Glissonean pedicle with vascular stapling represents both an effective and safe surgical technique of anatomical liver resection. Presented approach allows early and easy ischemic delineation of appropriate anatomical liver territory to be removed (hemiliver, section, segment) with selective inflow vascular control. Also, it is not time consuming and it is very useful in re-resection, as well as oncologically reasonable. Keywords: Liver resection; segmented orientated liver resection; Glissonean approach (GA); Glissonean pedicle stapling; vascular stapler; extrafascial dissection Submitted Aug 02, 2014. Accepted for publication Sep 02, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.09 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.09

Introduction Hepatic resection had an impressive growth, both by broadening the range of its indications and the occurrence of changes and technical tricks in order to reduce postoperative mortality and morbidity (1). Although the criteria for liver tumors resectability are expanded today, hepatectomies are still demanding procedures due to risk of hemorrhage and hepatic failure (2-6). During the last decades surgical techniques for hepatectomy have changed

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dramatically (2-10). All improvements in liver surgery have the same goals, to preserve the maximum amount of liver parenchyma with minimum blood loss (1-10). The blunt liver dissection has been widely replaced by various time-consuming methods, such as the cavitron ultrasonic surgical aspirator (CUSA), followed by the development of tools for safe approach, isolation and transection of vascular and biliary structures during transection of liver parenchyma (8,9).

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Karamarković and Doklestić. Extrafascial Glissonean approach in liver resections

In 1949, Honjo (Kyoto University) and later in 1952, Lortat-Jacob and Robert were performed the first anatomical right hepatectomy with classical intrafascialextrahepatic approach so-called “classic” hilar dissection (HD) of the hepatic artery, portal vein and bile duct in the hepatoduodenal ligament (7,8,10). Nevertheless, the potential disadvantages of this approach are reflected in the cases of extensive scarring due to previous surgery, the risk of incidental lesion of anomalous hepatic vessels or the contralateral biliary duct (11-14). The observations of Glisson and Couinaud that elements of portal triad are contained within a thick connective tissue and are surrounded by a fibrous sheet (Glissonean pedicle) were the basis for the initial proposal by Couinaud in 1957, that suprahilar vascular control of Glissonean pedicle could serve as an important alternative to classical HD for controlling vascular inflow to the liver. This technique includes the extrafascial dissection of the whole sheath of the pedicle and its division “en masse” (15). Anterior intrahepatic extrafascial approach proposed by Couinaud, Thung and Quang, uses anatomical fissures as door’s of the liver. By splitting the liver substance down along the appropriate fissure could be approach to the pedicle of interest (15,16). The extrafascial dissection of left Glissonean pedicle at the hepatic hilus without liver transection, for the left hepatectomy, was previously reported by Couinaud in 1985 and later by Lazorthes in 1993 (17,18). Takasaki in 1986 described the surgical technique called “Glissonean pedicle transection method”. Technique is based on detachment of the hilar plate and extrafascialextrahepatic dissection of the main left and right, as well as both right sectional pedicles, without opening the liver parenchyma (19,20). Galperin in 1989 described a digital “hooking” technique for the isolation of portal pedicles through an extrafascial-intrahepatic approach after division of a substantial amount of the hepatic tissue (21). In 1992 Launois and Jamieson proposed the posterior intrahepatic approach to the appropriate Glissonean pedicle, through the dorsal fissure of the liver, after making proper perihilar hepatotomies (22). Machado’s modifications of the posterior approach include making small incisions around the hilar plate and strictly instrumental isolation of the pedicle (23-25). It has been reported that the Glissonean approach (GA) can reduce the portal triad closure time, expedite the transection of the liver and reduce intraoperative hemorrhage, as well as the risk of injury to the vasculature or the biliary drainage of the contralateral liver (26,27). A step forward in achieving security is the introduction

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of vascular staplers in liver surgery (8,28-31). Vascular staplers offer speed and safety when dividing hepatic veins and portal branches during hepatectomy, which minimizes blood loss (8,31). Previous studies compared classical HD vs. extrahepatic Glissonian stapling of the pedicle for major hepatectomies with acceptable morbidity (7,32). Using technique of the suprahilar-extrafascial Glissonean pedicle dissection, with endo-GIA vascular stapling device transection of the pedicle, and appropriate hepatic vein, we have performed 170 liver resections for malignant and benign tumors, with intent of minimal blood loss. Here we review our experience gained with liver resections and compare the clinical, perioperative and postoperative results (complications, disease-free survival and overall survival) of the patients who have undergone either segmental resection of different volume, or major hepatectomy. Methodology We prospectively analyzed the clinical records of 170 patients who underwent hepatic resection by suprahilarextrafascial pedicle isolation and stapling technique in our clinic for emergency surgery in Belgrade, between January 2007 and December 2011. Patients who underwent hilar extrahepatic intrafascial dissection were excluded from the study. All procedures were performed by the same operating team. The protocol received the approval of the research review board of our hospital, and informed written consent was obtained from each patient before surgery. Before operation, all patients underwent a thorough physical examination, blood tests and radiologic evaluation. Liver function was evaluated by Child-Pugh-Turcotte (CPT) classification using prothrombin time (PT), albumin, bilirubin and clinical findings of ascites and encephalopathy. CPT score was stratified as classes A [5-6], B [7-9], and C [10-15]. Only CPT class C is considered an absolute contraindication for surgical treatment. Liver resections were defined according to the International Hepato-Pancreato-Biliary Association terminology derived from Couinaud’s classification (33). The amount of operative blood lost was measured by the volume (mL) of blood collected in the aspirator container and the ultrasonic dissector and by the weight of the soaked gauzes. Perioperative data were operative duration (min), transection time (min), intraoperative blood loss (mL), transfusion requirement (intraoperative and postoperative within the first 48 h) and intermittent vascular occlusion

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through the catheter with a bilirubin content 2× higher than the plasma levels. Surgical technique

Figure 1 Takasaki’s technique of extrahepatic-extrafascial dissection and isolation of the right main Glissonean (RMP) and both right anterior (RAP) and right posterior (RPP) sectional pedicles.

(IVO) duration (min). Transection time was defined as the duration between the beginning and the end of the liver parenchyma transection. The amount of operative blood lost was measured by the volume (mL) of blood collected in the aspirator container and by the weight of the soaked gauzes (assuming that 1 mL of blood =1 g). The indications for blood transfusion were massive hemorrhage with hematocrit decreasing to approximately <25% or hemoglobin level <70 g/L. Cumulative clamping time was calculated according to cumulative period of vascular occlusion. Postoperative data included postoperative liver injury, ICU and hospital stay (days), morbidity and mortality and disease-free survival and overall survival. The patients were subjected to postoperative follow-up by blood test, ultrasonography or computed tomography (CT) scans. The degree of postoperative hepatic injury was assessed by measuring the postoperative serum values of the aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin, PT and international normalized ratio (INR) on postoperative days 1, 3, 5 and 7. Postoperatively were followed in the outpatient clinic at 1, 3, and every 6 months thereafter with blood biochemistry and spiral CT scans of the abdomen. Post-operative mortality was defined as any death occurring within 30 days after surgery. Postoperative bleeding, liver ischemia, bile leakage, or perihepatic abscess formation were considered surgical complications. Biliary leak was defined as any drainage

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Makuuchi’s “J”-shaped laparotomy was used for all patients. Liver was mobilized using standard technique. Intraoperative ultrasound (IOUS) was performed to redefine tumor localization in relation to major vascular structures and to determine the transection plane. Extra hepatic “outflow” control was performed after dissection and isolation of major hepatic veins above the liver, whenever it was possible. Ischemic preconditioning (IP) was done to minimize ischemic-reperfusion injury of the liver (IRI). The liver tissue was transected under intermittent hepatic inflow vascular occlusion (IVO) which involves periods of inflow clamping for 15 minutes followed by periods of unclamping for five minutes (mode 15/5). In order to minimize bleeding in minor hepatectomies, selective vascular clamping (SVO) was used as the preferred method of inflow occlusion, particularly in patients with underlying chronic liver disease. Central venous pressure (CPV) was maintained at 0-5 mmHg to help reduce back bleeding from hepatic veins. After the transectional line was marked, the liver capsule was divided with diathermy or harmonic scalpel. Transection of the liver tissue was performed using the cavitron ultrasonic dissecting aspirator (“CUSA Excel”; Valleylab Inc., Boulder, CO, USA). During dissection, small vessels/bile ducts were ligated, coagulated or clipped to achieved hemostasis and biliostasis. The major hepatic veins were divided extrahepatically using vascular surgical stapler (Endo GIA Ultra stapler 3.0; Covidien, USA). Suprahilar vascular control of the appropriate Glissonean pedicle was achieved by Machado’s modification of the posterior intrahepatic approach (23,24), or using Takasaki’s technique (19) (Figure 1). Clamping the taped Glissonean pedicle, demonstrated the further demarcation of the appropriate anatomical territory of the liver as well as delineation of resectional plan (Figure 2). Pedicle was divided at the end of the resectional procedure using endo-GIA vascular stapling device (Endo GIA Ultra stapler 3.0; Covidien) (Figure 3). Firm counter traction on the tape was applied during application of the stapler to ensure that the contralateral pedicle was not accidentally ligated. For the right main Glissonean pedicle (RMP) isolation maneuver, after cholecystectomy, “detachment” of the medial section of the liver (S4) was performed, by lowering the hilar plate and small anterior hepatotomy was made

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Figure 2 Mesohepatectomy: resectional plan along the right sagital fissure of the liver with isolated right anterior (RAP) and right posterior (RPP) sectional pedicles. Figure 3 Right hepatectomy: transection of the right main

in front of the hilum. A second incision was performed perpendicular to the hepatic hilum, between segment S7 and caudate lobe (S1). Curved clamp then was inserted through the first hepatotomy with a 30° angle reaching the second incision. Vascular tape was then placed around the RMP. Tape was pulled down and medially to provide better exposure of the intrahepatic pedicle and to retract the left biliary tree and portal vein away from the area to be clamped or stapled. A third incision performed on the right edge of the gallbladder bed permitted access to the right anterior (RAP) and right posterior (RPP) sectional pedicles, by combining the previously mentioned incisions. In short course of the right main pedicle, the RAP and RPP were ligated and divided separately. The further, distal intrahepatic dissection of the isolated sectional pedicles, allowed the parenchymal isolation of the appropriate (S5-S8) segmental pedicle. For the left main Glissonean pedicle (LMP) isolation, the lesser omentum was divided, exposing the Arantius venous ligament, which was then dissected and divided. The proximal stump enabled the infero-posterior approach to the left hepatic vein and common trunk. The caudal stump of the ligament was dissected towards the left portal vein. This maneuver disclosed the posterior aspect of the left Glissonean pedicle. A small anterior incision (4-5 mm) was performed on the left side of the hilum and a curved clamp was introduced behind the caudal stump of the Arantius ligament, allowing the encircling and exposure of the left

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Glissonean pedicle using endo-GIA vascular stapling device.

main pedicle. This approach spared the caudate lobe (S1) portal branches. The round ligament was retracted upward, exposing the umbilical fissure between segments S3 and S4. If a parenchymal bridge connecting these two segments exists, it must be divided. Using the round ligament as a guide, two small incisions are performed on the left and right margins of the round ligament where it is possible to identify the anterior aspect of the Glissonean pedicle for segment S4 on its right side and segment S3 on its left side. With a clamp introduced through the anterior incision in front of the hilum and the basis of the round ligament on the right side, it is possible to isolate the Glissonean pedicle for the left medial section or segment S4. By combining incisions from the caudal stump of the Arantius ligament to the left side of the basis of the round ligament, it is possible to isolate the Glissonean pedicles for the left lateral section (segments S2 and S3). During pedicle clamping, the color of the area changes and the tumor location is confirmed by IOUS. Pedicle is divided at the end of resectional procedure using vascular surgical stapler (Endo GIA Ultra stapler 3.0; Covidien). After completed resection, the monopolar irrigated electrocautery was applied to stop minor oozing. The raw surface of the liver was sealed using fibrin glue. Closed suction drainage was used in all patients.

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Table 1 Type of minor liver resection

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Table 2 Type of major liver resection

Type of liver resection

n (%)

Type of liver resection

n (%)

Segmentectomy 1

2 (1.9)

Extended right hepatectomy

3 (4.4)

Segmentectomy 2

4 (3.9)

Extended left hepatectomy

Segmentectomy 3

6 (5.8)

Right hepatectomy

24 (35.3)

23 (22.5)

Left hepatectomy

27 (39.7)

Left medial sectionectomy (segment 4)

8 (7.8)

Mesohepatectomy

4 (5.8)

Segmentectomy 5

5 (4.9)

Central transversal hepatectomy (S3,S4b,S5)

4 (5.8)

Segmentectomy 6

4 (3.9)

Right inferior transversal hepatectomy (S4b,S5,S6) 5 (7.3)

Segmentectomy 7

4 (3.9)

Total

Left lateral sectionectomy

Segmentectomy 8

15 (14.7)

Right anterior sectionectomy

8 (7.8)

Bisegmentectomy 4b, 5

5 (4.9)

Bisegmentectomy 3, 4b

4 (3.9)

Right cranial bisegmentectomy 7, 8

4 (3.9)

Total

68 (100.0)

2 (1.9)

Right posterior sectionectomy

Right caudal bisegmentectomy 5, 6

1 (1.5)

8 (7.8) 102 (100.0)

Statistical analysis Data were expressed as mean with SD or median with interquartile range, as appropriate. Categorical data are presented by absolute numbers with percentages. Differences between groups were compared with parametric Student’s t-test or nonparametric Mann-Whitney test. Repeated measures of liver function indicated by serum level of bilirubin, AST, ALT, albumin and PT was assessed by general linear model. For qualitative variables, comparisons between groups were performed by the χ2 test or Fisher exact test, when needed. In all tests, P value <0.05 was considered to be statistically significant. All the calculations were performed with the SPSS 17.0 statistical package (SPSS, Inc., Chicago, IL, USA). Results A total of 170 anatomical hepatectomies were performed by suprahilar-extrafascial Glissonean pedicle dissection and stapling technique, including 68 (40.0%) major and 102 (60.0%) minor liver resections (Tables 1 and 2). Demographics and preoperative data for all patients are shown in Table 3. There were no significant differences between the two groups in terms of age, gender, comorbid conditions, Child-Pugh score, indications and number of tumoral lesions (Table 3). Twenty-eight patients in minor

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resection group (27.4%) were classified as CPT class B and 9 (13.2%) patients in major resection group as CPT class B. Indications for minor liver resection were metastases of colorectal carcinoma (CRC) in 50 (49.02%), hepatocellular carcinoma (HCC) in 10 (9.80%), cholangiocellular carcinoma in 4 (3.92%), non-colorectal liver metastases in 8 (7.84%), gall bladder carcinoma in 7 (6.86%), hemangioma hepatis in 13 (12.74%) and adenoma hepatis in 10 (9.80%) patients. Indications for major hepatectomies were colorectal liver metastases (CRC LM) in 33 (48.5%); noncolorectal liver metastases (non-CRC LM) in 7 (10.3%); HCC in 22 (32.3%); gall bladder carcinoma in 3 (4.4%) patients and liver hemangioma in 3 (4.4%). Intraoperative data for those patients undergoing hepatectomy, hospital stay and outcome are provided in Table 4. There were a significant difference in overall operative time, liver transection time and ischemic duration between minor and major resections (P<0.001 for all) (Table 4). Intraoperative blood loss was significantly higher in the major resection group (P=0.003) (Table 4). Intraoperative transfusion was performed in 46 (27.1%) patients of all and there was no significant difference between minor and major resections (P=0.395). The intraoperative blood transfusion is expressed as the amount of blood volume (mL), there was no significant difference between minor and major resections (P=0.067) (Table 4). In 124 (72.9%) patients of all liver resection were performed without any blood transfusion. Degree of liver damage presented by sequential postoperative serum values of AST, ALT, Bilirubin and PT. The changes in postoperative serum values of liver function markers were not significantly different between major and minor resection (P>0.05) Nevertheless, statistical analysis of the total serum AST, ALT, bilirubin, and PT values found significance in the specified period of time. Total AST and ALT values were significantly decreased on the

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Table 3 Clinical characteristics and preoperative biochemical evaluations of patients included in the study Characteristics

Minor resections (n=102)

Major resections (n=68)

P

Male*

62 (60.78%)

36 (52.9%)

0.561

Age (years)**

62.52±15.29

61.65±13.58

0.778

Comorbidity*

54 (52.94%)

35 (51.5%)

0.881

Malignant indications*

79 (77.45%)

58 (85.3%)

0.345

No. of tumours lesions**

1.71±1.10

2.23±1.28

0.053

CPT score A

74 (72.5%)

59 (86.7%)

0.649

Bilirubin (μmol/L)

20.12±12.27

22.73±14.66

>0.05

AST (U/L)

35.89±13.21

33.36±15.81

>0.05

ALT (U/L)

59.04±35.40

49.66±28.54

>0.05

Albumin (g/L)

30.39±6.59

30.49±6.91

>0.05

INR

1.21±0.19

1.24±0.21

>0.05

PT (s)

13.72±1.68

13.22±2.32

>0.05

†

*, characteristics are presented as numbers of patients and percentage, n (%); **, characteristics are presented as mean ± SD, standard deviation; †, international normalized ratio.

Table 4 Perioperative characteristics of patients included in the study Characteristics

Minor resections (n=102)

Major resections (n=68)

P

Operative time, (min)**

95.1±31.1

186.6±56.5

<0.001

Transection time, (min)**

35.9±14.5

65.3±17.2

<0.001

255.6±129.9

385.7±200.1

Ischaemic duration, (min)

15 [15]

30 [30]

<0.001

CVP (0-5 mmHg)†

2.00 [2]

3.00 [2]

0.291

Blood loss, (mL)** †

0.003

Blood transfusion inraop. (mL)**

300.8±99.5

450.9±89.6

0.067

Resection R0, n (%)*

96 (94.1%)

63 (92.6%)

0.833

Hospital stay (days)†

8 [3]

8 [4]

0.745

ICU stay (days)

1.00 [2]

1.00 [3]

0.441

Morbidity*

37 (36.3%)

25 (36.7%)

0.989

Mortality rate*

1 (0.9%)

2 (2.9%)

0.920

Overall survival rates for CRC°

53%

46%

0.744

Overall survival rates for HCC°

60%

69%

0.744

*, characteristics are presented as numbers of patients and percentage, n (%); **, characteristics are presented as mean ± SD; †, characteristics are presented as median (range); °, follow-up 36 months.

third postoperative day (P˂0.001; P˂0.001). Total bilirubin value was significantly lower on the 5th postoperative day (P˂0.001). Total PT value was significantly reduced on the 5th postoperative day (P=0.001). There was no significant difference in ICU stay, hospital stay and complications rate between the groups (Table 4). In minor resection group complications rate was 37 (36.3%). According to Clavien’s classification, grade 1-2

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complications were recorded in 27 (26.5%): 5 (4.9%) had cardiac complication, 10 (9.8%) had pleural effusion, 5 (4.9%) had atelectasis, 6 of them (5.9%) had wound infections and 1 (0.9%) bronchopneumonia. Total of 10 (9.8%) patients experienced grade ≥3 surgery complications: 4 (3.9%) intra-abdominal fluid collection, 2 (1.9%) biliary fistula, and 4 (3.9%) partial wound dehiscence. In major resection group according to Clavien’s classification, grade

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1-2 complications were recorded in 21 (30.9%): 5 (7.3%) had cardiac complication, 11 (16.2%) had respiratory complications and 5 (7.3%) had wound infections. There were 4 (5.9%) grade ≥3 surgery complications: 2 (2.9%) intra-abdominal fluid collection and 2 (2.9%) biliary fistula. The majority of complications were treated conservatively, or radiological intervention/percutaneous drainage and no patients underwent reoperation. In all cases of the biliary fistula there was spontaneous healing Mortality between groups did not reach a significant difference (P=0.920). The hospital morbidity rate in major resection group was 2.9%. All deaths were caused by nonsurgical complications. In both patients there were a history of cardiac disorders, and mortality was caused by an acute myocardial infarction, after the seventh postoperative day in both cases. One patient who treated by minor liver resection died due to thromboembolic complications and pulmonary embolism, on postoperative day 3, despite regular anticoagulant therapy. The 1- and 3-year disease-free survival rates in group with minor resections were 75% for patients with colorectal metastases (74% for patients with HCC) and 46% for patients with colorectal metastases (49% HCC patients), respectively. These results were similar to those observed in group with major resections (76% for CRC patients; 80% for HCC patients) and (50% for CRC patients; 52% HCC patients), respectively. There was no significant difference in the disease-free survival rates between both groups (P=0.066). The overall survival rates after 1 year and 3 years were found to be 81% for patients with colorectal metastases (90% for patients with HCC) and 53% for patients with colorectal metastases (60% for patients with HCC) in group with minor liver resections and 83% for patients with colorectal metastases (92% for patients with HCC) and 49% for patients with colorectal metastases (69% for patients with HCC) in group with major hepatectomies, respectively. There was no significant difference in the overall survival rates between both groups (P=0.744). Discussion Liver resections are complex procedures that requires detailed knowledge of liver anatomy, precise “bloodless” surgical technique and sufficient volume of the remnant liver (1-8,34). Since the late 1970s, when operative mortality was more

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than 20% for major liver resections, much effort has been done to intraoperative control of blood loss and reduce intraoperative hemorrhage (34,35). Excessive blood loss is associated with increased perioperative morbidity and, in cases of colorectal metastases, a shorter disease-free interval (34,36). Technical refinements are focused on minimizing hemorrhage during transection of hepatic parenchyma and safe dissection of the major hepatic veins and pedicles (34-36). The extrafascial dissection of Glissonean pedicle is a very important technique that can be extremely useful in particular circumstances during liver surgery, such as in multi-operated patients or in patients with cirrhotic liver or anomalous vascular and biliary variations. Regarding this technique some terminology confusion still exists (Glissonean approach, extra-Glissonean approach, Glissonean pedicle transection method, posterior intrahepatic approach, suprahilar vascular control, perihilar posterior approach, superficialisation of Glissonean pedicles) (20,37). Nevertheless, despite many titles the main surgical concept is the same, and it’s based on the anatomical fact and observation of Couinaud that portal triad elements inside the liver substance, are enveloped with fibrous Glissonean sheet, thus representing an important structure of internal architecture of the liver (15,17). The extrafascial Glissonean pedicle approach in liver surgery provides new knowledge of the surgical anatomy of the liver and advances the technique of liver surgery (38). Opposite to “classic” intrafascial dissection, this technique includes extrafascial isolation of the whole sheet of Glissonean pedicle and it’s division “en masse”. Glissonean pedicles can be approached intrahepatically or extrahepatically. The use of vascular staplers in this situation allows quick and safe transection of the pedicle, as well as appropriate hepatic vein (39). The second advantage of this technique presents the quick and easy definition of the anatomic territory of the liver to be removed. Selective clamping of the appropriate isolated pedicle demonstrates the further ischemic demarcation of anatomical liver part of interest (hemiliver, section or even segment) as well as delineation of resectional planes (21-25). Recent advances of presented surgical technique includes liver hanging maneuver and some modifications with two tapes to control the main fissure of the liver or various liver resections using hanging maneuver by three Glisson’s pedicles and three hepatic veins (40,41). The first prospective randomized study which compared extrafascial GA vs. “classic” HD in major hepatectomies, was performed by the group of Figueras, showed that “en bloc” stapling transection of the pedicle was safe and faster than “classic” approach (7). The other studies

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have shown similar results for the safety and operative duration (42-46). Also, the aim of our previous study was to analyze the efficiency and safety of the Glissonean pedicle approach vs. classical HD in major hepatectomies (32). The extrafascial dissection was associated with significantly shorter surgery duration, transection time and ischemic duration than intrafascial HD, while amount of blood loss was significantly lower in GA (32). Extrafascial isolation of Glissonean pedicle saves time comparing with difficult and some time hazardous intrafascial HD. Dissection above hepatic hilum significantly reduces the risk of the potentially injury of the contra-laterally sided vasculature and bile ducts (47). Smyrniotis et al. showed that intrahepatic dissection is safe as extrahepatic hilar division in terms of intraoperative blood requirements and morbidity; but biliary complications are more severe in patients undergoing extrahepatic division of the portal pedicle (43). Advantages of anatomic segment orientated resections include prevention of postoperative liver failure especially in elderly or patients with underlying liver disease, reduction of blood loss as well as lower postoperative mortality and morbidity rates. The question, whether to perform a segmental or a major resection if both procedures are technically feasible, is still under debate. The presented surgical technique of suprahilar extrafascial control of the Glissonean pedicle, is very useful in performing of sectionectomies and segmentectomies. Couinaud and, more recently, Takasaki, Galperin and Launois have noted that the Glissonean capsule continues within the liver parenchyma up to the segmental divisions (19-22). Although the intersegmental planes were not visible on the surface of the liver, the segments were defined by occluding the inflow pedicle to that segment. This study describes our experiences with the extrafascial pedicle dissection and stapling technique during major liver resection and minor hepatectomy: vascular staplers were used to divided pedicles and major hepatic veins while parenchyma transection was performed by CUSA, under IPM or selective vascular occlusion (SVO). The study was not designed to demonstrate the superiority of one major hepatic resection over the minor. Rather, it is the authors’ intention to demonstrate the efficiency of the GA in major as well as in minor hepatectomy. In our study, bisegmentectomies occupy the greatest relative share in minor liver resection group, since left lateral sectionectomies dominates. In major liver resection group, right hepatectomy and left hepatectomy had the

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greatest rate. The minor liver resections were associated with significantly shorter surgery duration and transection time than major hepatectomies. Intraoperative transfusion rate was no significant difference between minor and major resections. The changes in postoperative serum values of liver function markers were not significantly different between major and minor resections. There was no significant difference in ICU stay, hospital stay and complications rate between the groups. Major hepatectomy as well as minor liver resection are a superior oncologic operation with no significant difference in the 1- and 3-year disease-free survival rates and overall survival rates between both groups in our study. Stewart registered a significant difference between the groups with extended resections and segmental ones in terms of operative blood loss and post-operative stay as major post-operative complications are less following segmental resection (48). Intermittent Pringle maneuver (IPM) during transection of liver parenchyma is simple and safe technique that may reduce bleeding from hepatic inflow, and the total clamping time can be extended to 120 minutes in normal livers and 60 minutes in pathological livers (30,36). The disadvantage of IPM is that bleeding occurs from the liver transection surface during the unclamping period and, thus, the overall transection time is prolonged as more time is spent in achieving hemostasis. The presented surgical technique allows the use of SVO during parenchymal transection. Selective clamping it is also important from the haemodynamic point of view because there is no splanchnic stasis and low fluid replacement. A previous randomized study demonstrated that the clinical advantages of selective clamping are more significant in patients with chronic liver disease, particularly in very difficult resections in patients in whom lengthy pedicular clamping is anticipated as a result of portal hypertension or in whom very large areas of transection are necessary (49). By contrast, selective clamping or hemihepatic vascular occlusion, as described by Makuuchi et al. does not increase venous portal pressure or cause fluid overload or a consequent increase in CVP (50). Expected, in our study results showed shorter operation time, transection time, ischemic duration and less blood loss for minor hepatectomies compared to major liver resections. However our results showed that major hepatic resections are safe procedures with outcome results non-significantly different from minor resections. Further development of sophisticated techniques and instruments in order to reduce bleeding during liver resection led to the introduction of

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vascular stapler in liver surgery in the last decade of the twentieth century. Recent publications reporting a number of techniques using stapling devices in liver surgery showed them to be extraordinarily useful in the safe ligation of inflow and outflow vessels (51). Application of vascular staplers to selectively divide major intrahepatic blood vessels for hepatic inflow and outflow vascular control during liver resection, has been shown to achieve excellent results, reducing blood loss, warm ischemia time and operative time (24,26,29). However, there are a few of potential dangers in using the stapler. Serious blood loss can theoretically occur when the stapler has sealed only half the diameter of the vessel or after misfire of the devise although we did not experience such a situation. Another potential danger from the use of staplers in the liver is tearing a major hepatic vein or vena cava, while placing the instrument. Usually after encircling of the hepatic vein, the articulated and rotating Endo-GIA vascular stapler is passed gently around the hepatic vein to staple and divide it. The thinner blade of the stapler is inserted in preference to the thicker blade because the space available is limited. As the thinner blade is not on the same axis as the instrument, difficulty may be encountered if the tip of the blade and tearing of the vein may occur. In order to avoid this complication, we used a right-angle clamp to grab the thinner blade and guide its insertion into the space between the liver parenchyma and major vein. This technique is also reported by other centers (28). Morbidity and mortality are correlated with the amount of blood loss during hepatectomy (34,36). Despite all technological advancing for liver resections, an intraoperative hemorrhage rate ranging from 700 to 1,200 mL is reported with a postoperative morbidity rate ranging from 23% to 46% and a surgical death rate ranging from 4% to 5% (34,36). Jarnagin et al. reported of a moderate blood loss of 600 mL and in major hepatectomy their investigations led to a blood loss of more than 1,000 mL; while 700 to 800 mL observed in the cases of stapler hepatectomy (35,52). Specific complications after liver are all associated with high morbidity in terms of sepsis, liver failure, longer hospital stay, as well as postoperative mortality (53,54). Complications such as biliary leaks continue to be reported with incidences in the range of 2.6-15.6%, in our study 1.7% (53,54). Carefully checking the resection line and completing hemo- and bilistasis, even in a modified cirrhotic liver parenchyma, we obtained literature accepted percentages in resection line related complications (biliary

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fistulas, postoperative bleeding). Capussotti et al. published a study on 610 patients with liver resection, where biliary fistulas occurred in 3.6% of cases, and our rate of 2.3% of all being consistent with these data (53). Treatment is not easy and a number of non-surgical strategies have been proposed. However, surgical intervention should be considered for patients in whom non-surgical interventions are either unsuccessful or not feasible. In this study no patients underwent reoperation, all complications treated successfully by non-operative interventional and radiological techniques. In our series, no hemorrhage, ischemic damage or postoperative liver function was observed. Our experience in study of 170 patients who underwent hepatectomy with stapling of the pedicle shows that this technique is applicable in a routine clinical setting based on both its feasibility and safety. Mortality of 1.7% seen in our group is consistent with the data published in the literature. In the present series, both mortality and morbidity were as low as in a recently published large series of non-selected patients who underwent liver resection in other highvolume surgical centers (1,35,52). Conclusions Extrafascial dissection of Glissonean pedicle with vascular stapling represents both an effective and safe surgical technique of anatomical liver resection. Presented approach allows early and easy ischemic delineation of appropriate anatomical liver territory to be removed (hemiliver, section, segment) with selective inflow vascular control. Also, it is not time consuming and it is very useful in reresection. From the oncological point of view technique is reasonable: early initial ligation of Glissonean pedicle avoid dissemination of neoplastic cells, while anatomical concept of resection allows removal of micrometastases at the root of the pedicle with adequate resectional margin. We have demonstrated that segment-orientated liver resections offers disease-free and overall survival rates similar to those after major resection. However, the patients should be judiciously selected. Finally, according to our opinion, extrafascial GA should be a part of knowledge and skills of HPB surgeon. Acknowledgements Funding: This study was supported by funding from the Ministry of Education and Science of the Republic of Serbia (grant no III 45019). Disclosure: The authors declare no conflict of interest.

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Paris: Masson, 1957. 16. Tung TT. Les Résections Majeures et Mineures du Fois. Paris: Masson & Cie, 1957. 17. Couinaud CM. A simplified method for controlled left hepatectomy. Surgery 1985;97:358-61. 18. Lazorthes F, Chiotasso P, Chevreau P, et al. Hepatectomy with initial suprahilar control of intrahepatic portal pedicles. Surgery 1993;113:103-8. 19. Takasaki K. eds. Glissonean pedicle transection method for hepatic resection. Tokyo: Springer, 2007. 20. Takasaki K. Glissonean pedicle transection method for hepatic resection: a new concept of liver segmentation. J Hepatobiliary Pancreat Surg 1998;5:286-91. 21. Galperin EI, Karagiulian SR. A new simplified method of selective exposure of hepatic pedicles for controlled hepatectomies. HPB Surgery 1989;1:119-30. 22. Launois B, Jamieson GG. The importance of Glisson’s capsule and its sheaths in the intrahepatic approach to resection of the liver. Surg Gynecol Obstet 1992;174:7-10. 23. Machado MA, Herman P, Machado MC. A standardized technique for right segmental liver resections. Arch Surg 2003;138:918-20. 24. Machado MA, Herman P, Machado MC. Anatomical resection of left liver segments. Arch Surg 2004;139:1346-9. 25. Machado MA, Herman P, Meirelles RF Jr, et al. How I do it: bi-segmentectomy V-VIII as alternative to right hepatectomy: an intrahepatic approach. J Surg Oncol 2005;90:43-5. 26. Fong Y, Blumgart L. Useful stapling techniques in liver surgery. J Am Coll Surg 1997;185:93-100. 27. Ramacciato G, Aurello P, D’Angelo F, et al. Effective vascular endostapler techniques in hepatic resection. Int Surg 1998;83:317-23. 28. Wang WX, Fan ST. Use of the Endo-GIA vascular stapler for hepatic resection. Asian J Surg 2003;26:193-6. 29. DeMatteo RP, Fong Y, Jarnagin WR, et al. Recent advances in hepatic resection. Semin Surg Oncol 2000;19:200-7. 30. Schemmer P, Friess H, Hinz U, et al. Stapler hepatectomy is a safe dissection technique: analysis of 300 patients. World J Surg 2006;30:419-30. 31. Bagul A, McMahon G, Alam F, et al. Safely dealing with the right hepatic vein during a right hepectomy. Ann R Coll Surg Engl 2010;92:442-3. 32. Karamarković A, Doklestić K, Milić N, et al. Glissonean pedicle approach in major liver resections. Hepatogastroenterology 2012;59:1896-901. 33. Pang YY. The Brisbane 2000 terminology of liver anatomy

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Cite this article as: Karamarković A, Doklestić K. Preresectional inflow vascular control: extrafascial dissection of Glissonean pedicle in liver resections. Hepatobiliary Surg Nutr 2014;3(5):227-237. doi: 10.3978/j.issn.2304-3881.2014.09.09

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Review Article

Post-hepatectomy liver failure Rondi Kauffmann, Yuman Fong Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA Correspondence to: Yuman Fong, MD. Department of Surgery, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010-8113, USA. Email: [email protected].

Abstract: Hepatectomies are among some of the most complex operative interventions performed. Mortality rates after major hepatectomy are as high as 30%, with post-hepatic liver failure (PHLF) representing the major source of morbidity and mortality. We present a review of PHLF, including the current definition, predictive factors, pre-operative risk assessment, techniques to prevent PHLF, identification and management. Despite great improvements in morbidity and mortality, liver surgery continues to demand excellent clinical judgement in selecting patients for surgery. Appropriate choice of pre-operative techniques to improve the functional liver remnant (FLR), fastidious surgical technique, and excellent post-operative management are essential to optimize patient outcomes. Keywords: Post-hepatectomy liver failure (PHLF); prevention of liver failure; predictive factors for liver failure Submitted Aug 01, 2014. Accepted for publication Aug 21, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.01 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.01

Introduction Hepatic resections are among some of the most complex operative interventions performed, and are fraught with risk and the potential for complications. Mortality rates after major hepatic resection have been reported to be as high as 30% (1,2) with post-hepatectomy liver failure (PHLF) representing the major source of morbidity and mortality after liver resection. Despite great improvements in outcomes after major liver resection due to refinements in operative technique and advances in critical care, PHLF remains one of the most serious complications of major liver resection, and occurs in up to 10% of cases (3,4). Several studies report a lower rate of PHLF in East Asian countries (1-2%), but when present, PHLF represents a significant source of morbidity and mortality (5). Definition The definition of PHLF has varied widely among groups, making comparison of rates between studies challenging. Numerous definitions of PHLF exist in the literature, with variations by country and between hospitals within the same country. Many definitions include complicated formulas or

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obscure laboratory tests, such as hepaplastin or hyaluronic acid levels, limiting their utility (6). The Model for EndStage Liver Disease (MELD) score is one such definition that is widely used. The MELD score is calculated using serum creatinine, INR, and bilirubin, but requires a complex mathematical formula computation (7). The ‘50-50 criterion’ (PT <50% and bilirubin >50 µmL/L) have also been proposed as a simple definition for PHLF (8). However, this definition does not account for any clinical parameters, and relies only on two laboratory values. In 2011, the International Study Group of Liver Surgery (ISGLS) proposed a standardized definition and severity of grading of PHLF. After evaluating more than 50 studies on PHLF after hepatic resection, the consensus conference committee defined PHLF as “a post-operatively acquired deterioration in the ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased INR and concomitant hyperbilirubinemia on or after postoperative day 5” (2). While other definitions of PHLF utilizing biochemical or clinical parameters are used by some centers, the ease with which the ISGLS definition can be calculated and used for comparison renders it the definition that ought to be standardized and used. While PHLF is the most feared complication, the

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Table 1 ISGLS definition and grading of PHLF (2) Grade Clinical description Treatment

Diagnosis

Clinical symptoms

Location for care

A

Deterioration in liver None

• UOP >0.5 mL/kg/h

None

Surgical ward

function

• BUN <150 mg/dL

• Ascites

Intermediate unit

• >90% O2 saturation • INR <1.5 B

Deviation from

Non-invasive: fresh frozen

• UOP ≤0.5 mL/kg/h

plasma; albumin; diuretics; • BUN <150 mg/dL • Weight gain non-invasive ventilatory • <90% O2 saturation despite • Mild respiratory without requirement support; abdominal oxygen supplementation • Insufficiency expected post-

or ICU

operative course for invasive

ultrasound; CT scan

procedures C

• INR ≥1.5, <2.0

• Confusion • Encephalopathy

Multi-system failure Invasive: hemodialysis;

• UOP ≤0.5 mL/kg/h

• Renal failure • Hemodynamic Instability

requiring invasive

intubation; extracorporeal

• BUN ≥150 mg/dL

treatment

liver support; salvage

• ≤85% O2 saturation despite • Respiratory failure

hepatectomy; vasopressors; high fraction of inspired

• Large-volume ascites

intravenous glucose for

• Encephalopathy

oxygen support

ICU

hypoglycemia; ICP monitor • INR ≥2.0 ISGLS, International Study Group of Liver Surgery; PHLF, post-hepatectomy liver failure.

Table 2 Predictive factors associated with increased risk of PHLF Patient related Diabetes mellitus Obesity Chemotherapy-associated steatohepatitis Hepatitis B, C Malnutrition Renal insufficiency Hyperbilirubinemia Thrombocytopenia Lung disease Cirrhosis Age >65 years Surgery related EBL >1,200 mL

severity of its clinical manifestation ranges from temporary hepatic insufficiency to fulminant hepatic failure. The ISGLS group advocated a simple grading system of PHLF, in which laboratory values, clinical symptoms, and need for increasingly invasive treatments define severity of PHLF. The mildest grade of PHLF, grade A, represents a minor, temporary deterioration in liver function that does not require invasive treatment or transfer to the intensive care unit. The most severe, grade C, is characterized by severe liver failure with multisystem failure and the requirement for management of multi-system failure in the intensive care unit (2) (Table 1). The peri-operative mortality of patients with grades A, B, and C PHLF as determined by this grading schema is 0%, 12% and 54%, respectively (9).

Intra-operative transfusions

Predictive factors

Need for vascular resection

Patient factors

>50% liver volume resected Major hepatectomy including right lobectomy Skeletonization of hepatoduodenal ligament <25% of liver volume remaining Post-operative management Post-operative hemorrhage Intra-abdominal infection PHLF, post-hepatectomy liver failure.

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Various patient-related factors are associated with increased risk of PHLF (Table 2). Operative mortality in patients with diabetes undergoing curative-intent hepatic resection for treatment of colorectal metastases has been shown to be higher than comparable patients without diabetes mellitus (6). In that series, operative mortality was 8% in diabetics compared to 2% in non-diabetics (P<0.02). Furthermore, 80% of peri-operative deaths in diabetic patients were www.thehbsn.org

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PHLF, with post-operative hemorrhage (15) and occurrence of intra-abdominal infection (16) conferring increased risk (Table 2). Pre-operative risk assessment

Figure 1 CT scan image of steatohepatitis, with liver attenuation lower than that of the spleen.

secondary to PHLF. Excess mortality seen in diabetic patients undergoing major hepatic resection is likely multifactorial, with alterations in liver metabolism, decreased immune function, and hepatic steatosis contributing to post-operative liver dysfunction (10). Chemotherapy-associated steatohepatitis (CASH) is an increasing challenge in the era of novel chemotherapeutic and biologic agents. Many commonly-used chemotherapy agents cause damage to hepatocytes, including 5-fluorouracil, irinotecan, oxaliplatin, cituximab, and bevacizumab (11-14). Additionally, pre-operative malnutrition or renal insufficiency, hyperbilirubinemia, thrombocytopenia, presence of co-morbidities (lung disease), and advanced age are associated with increased risk of PHLF (15-18). Surgical factors In addition to patient-specific factors, the performance of the surgical procedure itself influences risk of PHLF. Factors associated with increased risk are shown in Table 2 and include operative estimated blood loss >1,200 mL (19,20), intra-operative transfusion requirement, need for vena caval or other vascular resection (21), operative time >240 minutes (13), resection of >50% of liver volume, major hepatectomy including right lobe (22), and skeletonization of the hepatoduodenal ligament in cases of biliary malignancy (23). In patients for whom <25% of the pre-operative liver volume is left post-resection, the risk of PHLF is 3 times that of patients with ≥25% of liver volume remaining (24). Post-operative factors Issues of post-operative management influence the risk of © Hepatobiliary Surgery and Nutrition. All rights reserved.

Given the high mortality rate associated with PHLF, there has been great interest in techniques to pre-operatively identify patients at high risk for hepatic dysfunction or failure. CT-based volumetric analysis is an effective tool that utilizes helical CT scans to assess the volume of resection by semi-automated contouring of the liver. A study by Shoup et al. utilized this technique to show that the percentage of remaining liver was closely correlated with increasing prothrombin time (>18 seconds) and bilirubin level (>3 mg/dL) (24). In their analysis, 90% of patients undergoing trisegmentectomy with ≤25% of liver remaining developed hepatic dysfunction, compared to none of the patients who had >25% of liver remaining after the same operation (24). Furthermore, the percentage of remaining liver, as determined by volumetric analysis, was more specific in predicting PHLF than the anatomic extent of resection (24). Careful evaluation of pre-operative CT scan imaging should focus on liver attenuation. Liver attenuation that is lower than that observed in the spleen indicates fatty infiltration indicative of steatohepatitis (11,24,25) (Figure 1). Similarly, splenomegaly, varices, ascites, or consumptive thrombocytopenia should prompt the clinician to suspect underlying cirrhosis (11) (Figure 2A,B). Although ultrasound and 3-dimensional ultrasound has been advocated by some as a means by which to assess the pre-operative volume of the liver, CT or MRI provide more objective data that is less subject to operator-error. Both CT and MRI show excellent accuracy and precise quantification of hepatic volume (26-28), and are particularly useful in estimating the future liver remnant (FLR) (29). Numerous methods have been developed for calculating liver volume, using either CT or MRI images. The first technique involved manual tracing of the outline of the liver (30), but has been criticized its time-intensity. Most recently, automatic or semi-automatic techniques have been developed that utilize mathematical formulas to measure liver volumes obtained from CT scan images, utilizing commercially-available software programming. These software-based programs have been shown to correlate well with manual volume estimation, but are performed in a fraction of the time (31). www.thehbsn.org

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A

B

Figure 2 (A) CT scan demonstrating evidence of cirrhosis, with ascites, small liver, and splenomegaly; (B) CT scan demonstrating evidence of cirrhosis, with ascites, small liver, splenic varices, and splenomegaly.

Although pre-operative estimation of functional liver volume after resection remains the most advanced method for estimating hepatic functional reserve, newer techniques, such as indocyanine green (ICG) clearance and ICG retention rate (ICG R15) have been reported. Under normal conditions, nearly all ICG administered is cleared by the liver. Because the ICG reflects intra-hepatic blood flow, it has long been used to assess liver functional reserve in patients with cirrhosis (32). Only recently, however, have investigations begun into the application of ICG and ICG R15 to estimating functional hepatic reserve after resection of normal livers in the setting of malignancy. In this method, ICG elimination is measured by pulse spectrophotometry (32), and the indocyanine green plasma disappearance rate (ICG PDR) is determined. The study by de Liguori Carino and colleagues reported that when the pre-operative ICG PDR was less than 17.6%/min and the pre-operative serum bilirubin was >17 µmol/L, the positive

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predictive value for post-operative liver dysfunction was 75%, and the negative predictive value was 90% (32). While additional study is needed, this method appears to be a noninvasive tool for prediction of PHLF. There is increasing interest in the use of 99m Tcdiethylenetriamine-pentaacetic acid-galactosyl human serum albumin (GSA) scintigraphy for the pre-operative evaluation of cirrhotic patients. In this technique, the molecule is taken up by the liver, reflecting the volume of functional liver (33). Uptake corresponds to bilirubin level, INR, and ICG clearance (33). In 9-20% of patients, the severity of liver disease is underestimated by ICG clearance testing, and better represented by GSA scintigraphy. This may be due to the fact that GSA scintigraphy is unaffected by hyperbilirubinemia (33). Use of GSA scintigraphy preoperatively allows for highly accurate estimation of FLR (33). Beyond imaging, a number of laboratory parameters have been shown to correlate with risk of PHLF, including prothrombin activity <70% and hyaluronic acid level ≥200 ng/mL. When elevated pre-operatively, these values portend greater risk of PHLF (34), and can be used as indications for or against major hepatectomy (Table 3). Prevention Treatment of PHLF hinges first on its prevention. In patients identified as high-risk by preoperative evaluation of underlying patient factors, presence of cirrhosis, preoperative laboratory values, volume of liver to be resected, or estimated functional liver volume after resection, consideration should be given to techniques to minimize the risk of PHLF. One such technique is portal vein embolization (PVE), which manipulates portal blood flow, by embolizing portal branches in the liver to be resected, directing blood flow to the intended remnant liver, and thereby inducing hypertrophy of the remnant liver before major hepatectomy (35). By increasing the volume of the intended remnant liver, the risk for PHLF is decreased, even after extended liver resection. Furthermore, preoperative PVE minimizes intra-operative hepatocyte injury that would otherwise be caused by the abrupt increase in portal venous pressure at the time of resection (35). Current guidelines recommend PVE for patients with underlying cirrhosis and an anticipated FLR of ≤40%, or patients with normal liver function and intended FLR of <20% (35). This procedure can be performed with minimal morbidity and mortality, and allows for improved safety of extended hepatectomies (36,37). Even when concurrent

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Table 3 Determinants of low vs. high risk for PHLF Risk category Low

Imaging

Number of safe segments

Laboratory data

Patient factors

• Predicted FLR >25%

• Prothrombin activity ≥70%

• No history of cirrhosis

• Normal splenic size, no

• Hyaluronic acid <200 ng/mL • No previous hepato-toxic

vascular collaterals

for resection Up to 6 (80% of functional liver volume)

chemotherapy

• Platelets >300,000/µL

• Indocyanine green plasma • Normal serum bilirubin level disappearance rate ≥17.6%/min High

• Predicted FLR ≤25%

• Prothrombin activity <70%

• History of cirrhosis

No more than 3 (60% of

• Splenomegaly, presence of • Hyaluronic acid ≥200 ng/mL • Previous administration of vascular collaterals • Steatohepatitis

functional liver volume)

hepato-toxic chemotherapy

• Platelets <100,000/µL • Hyperbilirubinemia

• Indocyanine green plasma disappearance rate <17.6%/min PHLF, post-hepatectomy liver failure.

A

B

Figure 3 (A) Pre-portal vein embolization of right lobe of liver to induce hypertrophy of left lobe of liver; (B) six weeks post-portal vein embolization of right lobe of liver to induce hypertrophy of left lobe of liver. Line marks middle hepatic vein, dividing right and left hemilivers.

neoadjuvant chemotherapy is administered, sufficient hepatic hypertrophy occurs after PVE to allow for major liver resection (38). CT volumetry should be performed 3-4 weeks after PVE to assess the degree of hypertrophy (35). A degree of hypertrophy >5% is associated with improved patient outcomes (39) (Figure 3A,B). Access to the portal system for PVE can be performed via transhepatic contralateral or transhepatic ipsilateral approach. The transhepatic contralateral approach accesses the portal system through the intended FLR, and is technically easier than an ipsilateral approach, but risks injury to the FLR. Additionally, access to segment 4 for embolization is technically difficult when performed from a contralateral approach (35). While the transhepatic

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ipsilateral approach spares the FLR from potential injury, acute angulations of the portal branches may render this approach too technically difficult to be feasible (35). If an extended right hepatectomy is planned, segment 4 could be embolized first to minimize risk of dislodgement of embolic substances to the left liver during manipulation of the catheter (35). Because PVE is not always technically feasible and some patients may experience disease progression during the waiting time between PVE and surgery, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure has been advocated by some, particularly for patients requiring trisectionectomy for bilateral liver metastases, or intrahepatic cholangiocarcinoma. In this

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Table 4 Techniques for preventing and minimizing the risk of PHLF Period

Techniques

Pre-operative

Weight loss in obese patients Nutritional supplementation Aggressive management of co-morbid conditions Portal vein embolization to enlarge FLR

Intra-operative

Avoidance of skeletonization of hepatoduodenal ligament unless required for R0 resection Minimize EBL (resection under low CVP conditions) Avoidance of blood transfusions if able Close attention to hemostasis to avoid post-operative hemorrhage

Post-operative

Early recognition and treatment of post-op hemorrhage Early recognition and treatment of biliary obstruction or leak Early recognition and treatment of intra-abdominal infection

PHLF, post-hepatectomy liver failure; FLR, functional liver remnant.

procedure, blood supply to segments 4-8 is diminished by right portal vein branch ligation, combined with parenchymal transaction along the falciform ligament (40). This technique has shown a 74% increase in the volume of the FLR, but with high postoperative morbidity (68%) and mortality (12%) (41). Although there have been promising results in small series, with rapid liver hypertrophy and enlargement of the FLR, this technique requires additional study to refine its indications and place in the repertoire of techniques for minimizing the risk of PHLF (42). Beyond pre-operative techniques to enlarge the FLR, fastidious intra-operative technique and excellent postoperative management contribute greatly to minimizing the risk of PHLF (Table 4). In cases of very heavy disease burden in the liver, when resection of all lesions would result in an FLR too small to avoid PHLF, a combination of resection and ablation may be used to minimize the amount of liver resected. Additionally, wedge resections with minimal tumor-free margins may be used to treat multi-focal disease, leaving sufficient liver intact to avoid PHLF. Identification and management When present, PHLF is manifest by progressive multisystem organ failure, including renal insufficiency, encephalopathy, need for ventilator support, and need for pressor support. As hepatic function worsens, patients develop persistent hyperbilirubinemia and coagulopathy (43). The development of coagulopathy is a particularly poor prognostic indicator (20). Daily measurement of serum C-reactive protein (CRP) may help with the early

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identification of patients who are developing hepatic insufficiency after hepatectomy. A study by Rahman and colleagues showed that patients who developed PHLF had a lower CRP level on post-operative day 1 than patients who did not develop PHLF. A serum CRP <32 g/dL was an independent predictor of PHLF in multivariate regression analysis (44). Other tools for predicting PHLF include the ‘50-50 criteria’, MELD system, and Acute Physiology and Chronic Health Evaluation (APACHE) III. While the MELD system has a sensitivity of 55% for morbidity and 71% for mortality, the ISGLS criteria for PHLF perform particularly well in assessing the risk of increased mortality after hepatectomy (45). The 50-50 criterion allows for early detection of PHLF, but is not a marker for increased morbidity after liver resection (45). T h e A PA C H E I I I s c o r e p r e d i c t s m o r t a l i t y a f t e r hepatectomy, but has only been validated in patients with cholangiocellular carcinoma (46). The most effective treatment for PHLF is liver transplantation, but this is typically reserved for patients who have failed all other supportive therapies (47). Initial treatment of PHLF includes supportive care of failing systems, including intubation, pressors, or dialysis. Treatment includes infusion of albumin, fibrinogen, fresh frozen plasma, blood transfusion, and initiation of nutritional supplementation (20). Intra-hepatic cholestasis is a type of PHLF that warrants particular mention. It is characterized by a continued increase in serum bilirubin, in the absence of biliary obstruction, with preservation of the synthetic function of the liver (48). Biopsy confirming this entity should be

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obtained at 2 weeks post-operatively, if the diagnosis remains uncertain. Although the course is protracted, PHLF nearly always occurs, with mortality rates approaching 90% despite best supportive care. Conclusions PHLF remains a severe complication of hepatic resection, occurring in approximately 8% of patients undergoing major hepatectomy (49). It ranges from mild hepatic insufficiency, characterized by transient hyperbilirubinemia that does not alter the expected post-operative course, to liver failure resulting in multi-system failure requiring invasive treatment in an intensive care unit. Multiple factors increase the risk of PHLF, including obesity, diabetes, neoadjuvant treatment with chemotherapy, underlying cirrhosis, increased age, male gender, need for extended liver resection, and long operation with high intra-operative EBL. Risk of PHLF can be minimized by accurate preoperative assessment of the FLR to be left after resection, and the induction of hypertrophy of the liver remnant via PVE if the expected FLR is <20% in a person with a normal liver, <30% in a patient with steatosis, or <40% in a cirrhotic patient (50). Early recognition and initiation of supportive care is crucial to improving patient survival in the setting of PHLF. Despite great improvements in morbidity and mortality, liver surgery continues to demand excellent clinical judgement in selecting patients for surgery. Appropriate choice of pre-operative techniques to improve the functional liver remnant (FLR), fastidious surgical technique, and excellent post-operative management are essential to optimize patient outcomes. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Ong GB, Lee NW. Hepatic resection. Br J Surg 1975;62:421-30. 2. Rahbari NN, Garden OJ, Padbury R, et al. Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). Surgery 2011;149:713-24. 3. Paugam-Burtz C, Janny S, Delefosse D, et al. Prospective validation of the “fifty-fifty” criteria as an early and accurate predictor of death after liver resection in intensive

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care unit patients. Ann Surg 2009;249:124-8. 4. Jaeck D, Bachellier P, Oussoultzoglou E, et al. Surgical resection of hepatocellular carcinoma. Post-operative outcome and long-term results in Europe: an overview. Liver Transpl 2004;10:S58-63. 5. Ren Z, Xu Y, Zhu S. Indocyanine green retention test avoiding liver failure after hepatectomy for hepatolithiasis. Hepatogastroenterology 2012;59:782-4. 6. Eguchi H, Umeshita K, Sakon M, et al. Presence of active hepatitis associated with liver cirrhosis is a risk factor for mortality caused by posthepatectomy liver failure. Dig Dis Sci 2000;45:1383-8. 7. Yoo HY, Edwin D, Thuluvath PJ. Relationship of the model for end-stage liver disease (MELD) scale to hepatic encephalopathy, as defined by electroencephalography and neuropsychometric testing, and ascites. Am J Gastroenterol 2003;98:1395-9. 8. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg 2005;242:824-8, discussion 828-9. 9. Reissfelder C, Rahbari NN, Koch M, et al. Postoperative course and clinical significance of biochemical blood tests following hepatic resection. Br J Surg 2011;98:836-44. 10. Little SA, Jarnagin WR, DeMatteo RP, et al. Diabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer. J Gastrointest Surg 2002;6:88-94. 11. Fong Y, Bentrem DJ. CASH (Chemotherapy-Associated Steatohepatitis) costs. Ann Surg 2006;243:8-9. 12. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006;243:1-7. 13. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200:845-53. 14. Peppercorn PD, Reznek RH, Wilson P, et al. Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer. Br J Cancer 1998;77:2008-11. 15. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397-406; discussion 406-7. 16. Tzeng CW, Cooper AB, Vauthey JN, et al. Predictors

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of morbidity and mortality after hepatectomy in elderly patients: analysis of 7621 NSQIP patients. HPB (Oxford) 2014;16:459-68. 17. Golse N, Bucur PO, Adam R, et al. New paradigms in post-hepatectomy liver failure. J Gastrointest Surg 2013;17:593-605. 18. Aloia TA, Fahy BN, Fischer CP, et al. Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database. HPB (Oxford) 2009;11:510-5. 19. Tomuş C, Iancu C, Bălă O, et al. Liver resection for benign hepatic lesion: mortality, morbidity and risk factors for postoperative complications. Chirurgia (Bucur) 2009;104:275-80. 20. Jin S, Fu Q, Wuyun G, et al. Management of posthepatectomy complications. World J Gastroenterol 2013;19:7983-91. 21. Melendez J, Ferri E, Zwillman M, et al. Extended hepatic resection: a 6-year retrospective study of risk factors for perioperative mortality. J Am Coll Surg 2001;192:47-53. 22. Nanashima A, Yamaguchi H, Shibasaki S, et al. Comparative analysis of postoperative morbidity according to type and extent of hepatectomy. Hepatogastroenterology 2005;52:844-8. 23. Fujii Y, Shimada H, Endo I, et al. Risk factors of posthepatectomy liver failure after portal vein embolization. J Hepatobiliary Pancreat Surg 2003;10:226-32. 24. Shoup M, Gonen M, D’Angelica M, et al. Volumetric analysis predicts hepatic dysfunction in patients undergoing major liver resection. J Gastrointest Surg 2003;7:325-30. 25. Panicek DM, Giess CS, Schwartz LH. Qualitative assessment of liver for fatty infiltration on contrastenhanced CT: is muscle a better standard of reference than spleen? J Comput Assist Tomogr 1997;21:699-705. 26. D’Onofrio M, De Robertis R, Demozzi E, et al. Liver volumetry: Is imaging reliable? Personal experience and review of the literature. World J Radiol 2014;6:62-71. 27. Tu R, Xia LP, Yu AL, et al. Assessment of hepatic functional reserve by cirrhosis grading and liver volume measurement using CT. World J Gastroenterol 2007;13:3956-61. 28. Torzilli G, Montorsi M, Del Fabbro D, et al. Ultrasonographically guided surgical approach to liver tumours involving the hepatic veins close to the caval confluence. Br J Surg 2006;93:1238-46. 29. Ulla M, Ardiles V, Levy-Yeyati E, et al. New surgical

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Ann Surg 2012;255:405-14. 42. Vennarecci G, Laurenzi A, Levi Sandri GB, et al. The ALPPS procedure for hepatocellular carcinoma. Eur J Surg Oncol 2014;40:982-8. 43. Roberts KJ, Bharathy KG, Lodge JP. Kinetics of liver function tests after a hepatectomy for colorectal liver metastases predict post-operative liver failure as defined by the International Study Group for Liver Surgery. HPB (Oxford) 2013;15:345-51. 44. Rahman SH, Evans J, Toogood GJ, et al. Prognostic utility of postoperative C-reactive protein for posthepatectomy liver failure. Arch Surg 2008;143:247-53; discussion 253. 45. Rahbari NN, Reissfelder C, Koch M, et al. The predictive value of postoperative clinical risk scores for outcome after hepatic resection: a validation analysis in 807 patients. Ann Surg Oncol 2011;18:3640-9. 46. Hamahata N, Nagino M, Nimura Y. APACHE III, unlike APACHE II, predicts posthepatectomy mortality in

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Cite this article as: Kauffmann R, Fong Y. Post-hepatectomy liver failure. Hepatobiliary Surg Nutr 2014;3(5):238-246. doi: 10.3978/j.issn.2304-3881.2014.09.01

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Review Article

Pancreatic surgery: evolution and current tailored approach Mario Zovak, Dubravka Mužina Mišić, Goran Glavčić Department of Surgery, University Clinical Hospital “Sisters of Charity”, Zagreb, Croatia Correspondence to: Dr. Mario Zovak. Department of Surgery, University Clinical Hospital “Sisters of Charity”, Vinogradska 29, Zagreb, Croatia. Email: [email protected].

Abstract: Surgical resection of pancreatic cancer offers the only chance for prolonged survival. Pancretic resections are technically challenging, and are accompanied by a substantial risk for postoperative complications, the most significant complication being a pancreatic fistula. Risk factors for development of pancreatic leakage are now well known, and several prophylactic pharmacological measures, as well as technical interventions have been suggested in prevention of pancreatic fistula. With better postoperative care and improved radiological interventions, most frequently complications can be managed conservatively. This review also attempts to address some of the controversies related to optimal management of the pancreatic remnant after pancreaticoduodenectomy. Keywords: Pancreatic cancer; pancreatic resection; pancreatic fistula; total pancreatectomy; pancreatic anastomosis Submitted Aug 04, 2014. Accepted for publication Aug 21, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.06 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.06

Introduction Pancreatic cancer is an uncommon type of cancer, the incidence of which has been on the rise worldwide, likely correlated with an increased incidence of obesity. Pancreatic cancer rates are highest in North America and Europe, where the frequency of its occurrence puts it in the eighth place (1,2). Although it is not very common, its significance lies in the fact that it is most often diagnosed in the late stage of the disease, it is almost always fatal, surgical treatment is rather complex and there is no adequate adjuvant treatment. Moreover, it is the only type of cancer in Europe of which increased mortality is anticipated in 2014 (3). Five-year survival rate in Europe and North America is around 6%, which makes it the fourth cause of death according to cancer mortality statistics (1,2). However, within the 10% of patients who have been diagnosed in the early, localised stage, the 5-year survival rate rises to 25% (4,5). There has been immense progress in surgical treatment of pancreatic cancer patients since Kausch and the first pancreaticoduodenectomy of periampullary tumor (6), Whipple and his modification of pancreaticoduodenectomy in the 1930’s (7), Priestley and the first successful total

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pancreatectomy reported in 1944 (8), and Traverso and Longmire with pylorus-preserving pancreaticoduodenectomy in 1978 (9) (Table 1). Despite the initially high mortality and morbidity following surgical treatment (12,13), with the development of surgical technique and concentration of patients in high-volume centres, as well as with improvement in perioperative care, the rate of morbidity and mortality following pancreaticoduodenectomy has dropped to acceptable levels. Morbidity and mortality following total pancreatectomy have also become more acceptable, as well as long term outcome with better blood glucose regulation and exocrine insufficiency management which has been made possible by developing novel insulin formulations and pancreatic enzyme supplements. Improved management of endocrine and exocrine insufficiency following total pancreatectomy and the discovery of novel clinical entities, such as IPMN (intraductal papillary mucinous neoplasm), have revived what was once a rare surgery, with an increased number of procedures and widened indications for surgical treatment. Despite its complications, curative resection is the single most important factor determining the outcome in patients with pancreatic adenocarcinoma (14). Surgery remains the

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Zovak et al. Pancreatic surgery: tailored approach

Table 1 History and evolution of pancreaticoduodenectomy 1909: Kausch 2-stage procedure, first cholecystectomy, followed 6 weeks later by resection of the head of pancreas, pylorus, first and second half of duodenum, with gastroenterostomy, closure of common bile duct and anastomosis of pancreas and the third part of duodenum (6) 1935: Whipple 2-stage procedure, first posterior gastroenterostomy, ligation and division of the common bile duct with cholecystogastrostomy, followed by resection of the duodenum and pancreatic head, with closure of pancreatic stump (7) 1940: Whipple completed the procedure in a single stage, in 1942, modification of the procedure with pancreaticojejunostomy (10) 1946: Waugh and Clagett first used pancreaticogastrostomy (11) 1978: Taverso and Longmire reported pylorus preserving pancreaticoduodenectomy (9)

Table 2 Risk factors for pancreatic leak Pancreas related Soft pancreatic parenchyma Small size pancreatic duct Ampullary, duodenal, cystic and bile duct neoplasms Patient related Male sex Age >70 years Cerebrovascular disease Duration of jaundice Procedure related Type of pancreatic anastomosis Use of somatostatin Surgeon’s experience Intraoperative blood loss

principal treatment for pancreatic cancer and offers the only chance for cure (15,16). Complications of pancreaticoduodenectomy Pancreaticoduodenectomy is indicated for patients with neoplasma of the head of the pancreas, ampullary, duodenal and distal bile duct neoplasms. It is also performed for chronic pancreatitis and rarely for trauma. Although high mortality rate approaching 25% and morbidity rates up to 60% (12,13) were initially related to pancreaticoduodenectomy, in the last few decades there has been a significant decline in mortality rates which is now 3-5% in highly specialized centres (17-19). On the other hand, there are still numerous possible postoperative complications related to pancreaticoduodenectomy and morbidity rates are as high as 30-60% (20-24). Most common local complications are delayed gastric emptying with prevalence of 8-45% (25-30), pancreatic fistula with reported rates from 2% to 22%

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(20,23,24,30-34), infectious complications, most commonly intra-abdominal abscesses, with prevalence from 1-17% (30,35) and hemorrhage. Postoperative bleeding occurs in 3-13% of patients (5,17). Hemorrhage within the first 24 hours is result of the inadequate hemostasis at the time of surgery, a slipped ligature, bleeding from an anastomosis or diffuse hemorrhage from the retroperitoneal operation field, most likely caused by underlying coagulopathy, frequently seen in jaundiced patients (36,37). Late hemorrhage, occurring 1-3 weeks after surgery, is often caused by an anastomotic leak with erosion of retroperitoneal vessels (38) with mortality rates from 15%to 58% (39,40). Other causes of late hemorrhage are pseudoaneurysm and bleeding from the pancreaticojejunostomy. Management includes completion pancreatectomy or formation of pancreatic neoanastomosis (36). Other, not so common, complications are cholangitis, colonic and biliary fistulas. Within the systemic complications group, cardiopulmonary and neurological complications prevail (34,36). Over the years the most significant pancreaticoduodenectomy complication was the development of pancreatic leak and fistula (33,41,42) due to its frequency of occurrence and high mortality. However, with the refinement of surgical techniques, improved postoperative intensive care and concentration of patients in high-volume centres decreased mortality, this also resulted in decline of pancreatic fistula incidence. Depending on the definition used, the incidence of pancreatic fistula used to be 10-29% (43). Nowadays, according to the International Study Group Pancreatic Fistula Definition the incidence of pancreatic fistula is from 2% to 10% in the centres of excellence (30,34,41). The seriousness of pancreatic fistula can be seen in its possible consequences, such as septicaemia and hemorrhage, which makes it the leading risk factor for postoperative death, longer hospital stay and increased hospital costs after pancreaticoduodenectomy even today. Risks for developing the fistula can be divided into a few groups (Table 2). The first group is pancreas related. One www.thehbsn.org

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Table 3 Trials of pancreatic management Varibles

Authors

Trials comparing

Büchler et al. 1992 (53)

Number of patients

Pancreatic fistula (%)

outcomes of the use

Friess et al. 1995 (54)

122 vs. 125

12 vs. 28

of somatostatin and

Yeo et al. 2000 (55)

104 vs. 107

11 vs. 9

analogues

Sarr et al. 2003 (56)

135 vs. 140

24 vs. 23

125 somatostatin vs. 121 control

17.6 vs. 38

Suc et al. 2004 (57)

122 vs. 108

17 vs. 19

Trials comparing

Yeo et al. 1995 (58)

73 PG vs. 72 PJ

12 vs. 11

outcomes of PG and PJ

Duffas et al. 2005 (59)

81 vs. 68

16 vs. 20

Bassi et al. 2005 (60)

69 vs. 82

13 vs. 16

Trials comparing

Winter et al. 2006 (61)

outcomes after duct

Poon et al. 2007 (62)

stenting

Pessaux et al. 2011 (63)

Trials comparing

Marcus et al. 1995 (64)

outcomes after different

Bassi et al. 2003 (65)

anastomotic technique

Berger et al. 2009 (66)

115 with stent vs. 119 no stent

11.3 vs. 7.6

60 vs. 60

6.7 vs. 20

77 vs. 81

26 vs. 42

68 duct-to-mucosa vs. 18 invag

4.4 vs. 5.5

144 duct-to-mucosa vs. invag

13 vs. 15

97 duct-to mucosa vs. 100 invag

24 vs. 12

106 binding vs. 111 invag

0 vs. 7.2

Peng et al. 2007 (67)

Table 4 Solutions for pancreatic leak

Prevention of complications

Use of Somatostatin & analogues

A great deal of research has been conducted over the years aimed at decreasing the risk of pancreatic fistula occurrence (Table 3). It has focused on the influence that somatostatin, pancreatic duct stenting and pancreatic occlusion have on the reduction of PF rate. In addition, a number of studies have become available which compare pancreaticogastric anastomosis versus pancreaticojejunal anastomosis and different pancreaticojejunal anastomotic technique and their influence on frequency of PF occurrence (Table 4).

Pancreaticogastrostomy Binding or invaginating pancreaticojejunostomy Pancreatic duct stenting Pancreatic duct occlusion Total pancreatectomy

of the most widely recognized risk factors is texture of the remnant pancreas; the relation between high rates of pancreatic fistula up to 25% (42,44-47) in the presence of soft pancreatic parenchyma has been repeatedly reported. The pancreatic duct size has been implicated as another relevant factor. Pancreatic duct diameter under 3 mm is related to a significantly higher risk of pancreatic fistula development (42,44,46,47). Pancreatic fistula development is also predisposed by pancreatic pathology: ampullary, bile duct, duodenal carcinoma and cystic neoplasms are correlated with an increased risk of pancreatic fistula (48,49). The second group of risk factors are patient related, including male sex, advanced age (older than 70) (48,50), cardiovascular disease probably due to poor blood supply of anastomosis (30), duration of jaundice (51). The last group is procedure related and includes a type of pancreaticodigestive anastomosis, use of somatostatin, surgeon’s experience and increased operative blood loss (20,21,23,24,30,43-47,52).

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Somatostatin and analogues Octreotide is a synthetic long acting analogue of somatostatin, a potent inhibitor of pancreatic endocrine and exocrine secretion, and gastric and enteric secretion as well. Somatostatin and its analogue are administered postoperatively as prophylaxis. The idea behind this is that the decrease of pancreatic secretion would result in the pancreatic fistula prevention. A number of RTC have examined the benefit of somatostatine in pancreatic leakage prevention, but the results were inconsistent (68). In 2005, Connor conducted meta-analyses of ten RTCs which showed benefits of the use of somatostatin and its analog octreotide in reducing the rate of biochemical fistula formation, pancreas-specific complications and total morbidity. The incidence of clinical anastomotic disruption and mortality

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rate was not reduced (69). Cochrane Database Systematic Review from 2013 involved 2,348 patients in 21 trials. Conclusion drawn from it was that there was no significant difference in postoperative mortality, reoperation rate or hospital stay between the group of patients who were administered prophylactic somatostatin or its analogue and the group which received either placebo or nothing at all. In the somatostatin analogue group, the incidence of pancreatic fistula was lower, as was the overall number of patients with postoperative complications. On the other hand, when only patients with clinically significant fistulas were considered, there was no relevant difference between the groups. Based on the current available evidence, somatostatin and its analogues are recommended for routine use in people undergoing pancreatic resection (70). Duct stenting Internal, transanastomotic stent diverts the pancreatic juice from the anastomosis, and enables easier placement of sutures reducing the risk of iatrogenic duct occlusion. Its drawbacks are possibility of migration of the stent and occlusion which may lead to pancreatic fistula formation. There are not enough studies on internal stenting and their results have been contradictory (71,72). RTC from Winter et al. (61), involving 234 patients, demonstrated that internal duct stenting did not reduce the rate or the severity of pancreatic fistulas. The pancreatic fistula rates were 11.3% in patients with internal stent and 7.6% in patients without internal pancreatic stent. External stent has the possibility of a complete diversion of the pancreatic juice away from the pancreaticojejunal anastomosis which prevents the activation of pancreatic enzymes by bile. The RTC by Poon et al., involving 120 patients, showed that the external stent group pancreatic fistula rate was significantly lower (6.7%) compared to the group which did not undergo the same procedure (20%) (62). In prospective multicenter randomized trial from Pessaux et al., it was shown that external drainage reduces pancreatic fistula rate (26% vs. 42%), morbidity and delayed gastric emptying after pancreaticoduodenectomy in high risk patients (soft pancreatic texture and a nondilated pancreatic duct) (63). Cochrane database systematic Review from 2013 involved 656 patients in order to determine the efficacy of pancreatic stents, both external and internal, in preventing pancreatic fistula after pancreaticoduodenectomy. The use of external or internal stents was not associated with a statistically significant change in incidence of pancreatic fistula, re-

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Zovak et al. Pancreatic surgery: tailored approach

operation rate, length of hospital stay, overall complications and in-hospital mortality. In the subgroup analysis, it was found that the use of external stents is associated with lower incidence of pancreatic fistula, the incidence of complications and length of hospital stay. The review concludes that the external stenting can be useful, but further RCTs on the use of stents are recommended (73). Pancreatojejunal anastomosis technique Ever since Whipple modified pancreaticoduodenectomy in 1942 by performing pancreaticojejunostomy instead of occlusion of pancreatic remnant, this type of anastomosis has been most commonly used for a reconstruction of pancreaticodigestive continuity. There have been further modifications over the years. For example, jejunal loop can be positioned in antecolic, retrocolic or retro-mesenteric fashion, or the isolated Roux loop pancreaticojejunostomy can be performed. The anastomosis can be performed as an end-to-end anastomosis with invagination of the pancreatic stump in the jejunum or as an end-to-side anastomosis with or without duct-to-mucosa suturing (Figure 1) (47,65,74,75). In 2002, Poon et al. su compared duct-to-mucosa with invagination anastomosis, and found that the duct-tomucosa anastomosis was safer (49). In 2013, Bai et al. conducted a meta-analysis of randomized controlled trials comparing duct-to-mucosa (467 patients) and invagination pancreaticojejunostomy (235 patients). Pancreatic fistula rate, mortality, morbidity, reoperation and hospital stay were similar between techniques (76). Peng described a binding pancreaticojejunostomy technique with a pancreatic fistula rate of 0%. This was further validated in an RTC demonstrating that the binding pancreaticojejunostomy in comparison with end-to-end pancreaticojejunostomy demonstrated significantly decreased postoperative pancreatic fistula rates, morbidity, mortality and shortened the hospital stay (67,77). However, multiple authors reported better results with binding or invaginating pancreaticojejunostomy technique in patients with soft pancreatic parenchyma and small size duct (42,64). Type of pancreatic anastomosis I n 1 9 4 6 , Wa u g h a n d C l a g e t t f i r s t i n t r o d u c e d pancreaticogastrostomy in clinical practice (11) (Figure 2). There are several advantages of this anastomosis—the proximity of the stomach and the pancreas enables tensionfree anastomosis, the excellent blood supply to the stomach

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A

B

C

Figure 1 Different ways of doing the anastomosis for a pancreaticoduodenectomy. (A) End-to-side pancreaticojejunostomy; (B) oversewing of the pancreatic remnant; (C) end-to-end pancreaticojejunal invagination

Technique of Pancreaticogastrostomy

Figure 2 Pancreaticogastrostomy.

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251

enhances the anastomotic healing, the acidity of the stomach content inactivates pancreatic enzymes, and the lack of enterokinase in the stomach prevents the conversion of trypsinogen to trypsin and subsequent activation of the pancreatic enzymes, which reduces the risk of pancreatic leakage due to anastomosis autodigestion (78). Yeo et al. were first to conduct prospective randomized trial comparing pancreaticojejunostomy and pancreaticogastrostomy, but this trial failed in finding a significant difference in pancreatic fistula incidence (58). Statistically relevant difference regarding pancreatic fistula rates, postoperative complications or mortality has not been found in two RTCs from Duffas et al. (59) and Bassi et al. (60) as well. In 2014 Menahem et al. published their meta-analysis of seven randomized controlled trials, involving 562 patients with pancreaticogastrostomy and 559 patients with pancreaticojejunostomy after pancreaticoduodenectomy. The pancreatic fistula rate was significantly lower in the PG group (11.2%) then in the PJ group (18.7%). The biliary fistula rate was also significantly lower in the PG group (2% vs. 4.8%) (79). Liu et al. dealt with the same RTCs, but focused also on morbidity, mortality, hospital stay, reoperation and haemorrhage and intra-abdominal fluid collection. As well as having lower incidence of pancreatic and biliary fistula, the PG group showed a significantly lower incidence of intra-abdominal fluid collection and shorter hospital stay (80). Duct occlusion In 1935 Whipple reported on the first series of results after pancreaticoduodenectomy, at which time he did not anatomize pancreas with digestive tract. Since there was a high PF incidence rate, he abandoned the aforementioned concept and implemented pancreaticojejunostomy as a standard part of surgical procedure. Where there was suture ligation of the pancreatic duct, without anastomosis, the rates of pancreatic fistulas was as high as 80% (64,81,82). In a randomized controlled trial, conducted by Tran et al., involving 86 patients with duct occlusion and 83 patients with pancreaticojejunostomy, it was revealed that the da ductal occlusion group had a significantly higher pancreatic fistula rate (17% vs. 5%), but it failed to show any relevant difference regarding other postoperative complications, mortality and exocrine insufficiency. After 3 and 12 months, there were significantly more patients with diabetes mellitus in the ductal occlusion group (83). Occlusion of the main pancreatic with fibrin glue was also abandoned (83,84) based on results from several RCTs because of high fistula

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rates and higher incidence of postoperative diabetes mellitus (83,85). Treatment Surgical interventions for complications after pancreatoduodenectomy are nowadays rare, as low as 4% in centers of excellence (33,34) and 85-90% of patients with pancreatic fistula can be treated conservatively by means of fluid management, parenteral nutrition, suspension of oral intake and antibiotics administration. Lower percentage of surgical interventions can also be attributable to more advanced radiologic interventions for intrabdominal fluid collections, fistulas and bleeding. Indications for surgical intervention are clinical deterioration of the patient, disruption of pancreatic anastomosis, signs of spreading peritonitis, abdominal abscess, haemorrhage, and wound dehiscence. Delayed hemorrhage can be managed, if a patient is stable, by angiographic embolization of the bleeding vessel. In the remaining number of cases, emergency surgery is indicated (86,87). The type of surgical procedure depends on the underlying cause, and includes procedures such as peripancreatic drainage, control of hemorrhage, disruption of the pancreatic anastomosis without a new anastomosis or a conversion in another type of pancreatic anastomosis and a completion pancreatectomy (68,78). Completion pancreatectomy has nowadays become a rare procedure, owing to improvements in conservative treatment and radiologic interventions. Completion pancreatectomy is indicated in patients with pancreatic anastomotic leak accompanied by sepsis or bleeding (88). Owing to the seriousness of the patient’s condition, this procedures postoperative mortality is between 38% and 52% (89,90). Total pancreatectomy Total pancreatectomy was first performed in 1943 by Rockey (91), but the patient died soon after it. In 1944 Priestley performed the first successful total pancreatectomy (8). During the 1950’s this procedure was popularised by Ross (92) and Porter (93) who considered it to be safer than pancreatoduodenectomy with pancreatojejunostomy, because pancreatic anastomosis related morbidity and mortality was avoided. Because of high local recurrence rates and poor long-term survival after Whipple operation, combined with the erroneous belief that pancreatic adenocarcinoma is a

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Zovak et al. Pancreatic surgery: tailored approach

multicentric disease, total pancreatectomy was thought to be an oncologically more radical procedure (94,95). Later reports revealed disadvantages of this procedure: long-term survival after total pancreatectomy was similar or lower than after pancreatoduodenectomy (96), morbidity and mortality were as high as 37% (95-97), with obligatory development of brittle diabetes mellitus and exocrine insufficiency. Development of steatohepatitis with progressive liver failure (98) is another potential long-term complication. Without advantages of oncologic radicality and with diabetes mellitus and malabsorption difficult to control, total pancreatectomy was abandoned for treating pancreatic tumors. Number of total pancreatectomy procedures has been on the rise over the last two decades, for which several reasons can be named. Concentrating patients in high-volume centres and enhancements in surgical techniques have resulted in morbidity and mortality decline, the rates of which are now as low as 35% and 5% respectively (99-101) and are comparable to those following pancreatoduodenectomy. The second reason lies in the development of novel insulin formulations and better pancreatic enzyme preparations. While exocrine insufficiency can be relatively easily managed using pancreatic enzyme supplements, the control of endocrine insufficiency demands intensive insulin programmers, extensive patient education and continuing care (102). Total pancreatectomy is followed by not only insulin insufficiency, but also of glucagon and pancreatic polypeptide insufficiency, which leads to development of diabetes mellitus with tendencies to severe hypoglycemia. However, with intensive insulin programmers utilizing multiple daily insulin injections or pumps, and with glucagon rescue therapy, glycemic control can be achieved with satisfactory levels of HBA1c, similar to those in patients with insulin-dependent diabetes from other causes (99,102-104) and quality of life comparable to those of the patients after PPPD (99,100). The third reason is the existence of broader spectre of indications which now include in situ neoplasia with malignant potential such as intraductal papillary mucinous neoplasm and multifocal islet cell neoplasm; hereditary pancreatitis and familiar pancreatic cancer syndromes. Other indications include locally advanced or multicentric pancreatic adenocarcinoma, neuroendocrine tumors, metastases in the pancreas, end-stage chronic pancreatitis with disabling pain, trauma, unsafe pancreatic anastomosis and completion pancreatectomy after dehisced pancreatoenteric anastomosis (98,99,102). Given that the postoperative total pancreatectomy

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morbidity and mortality outcomes do not differ significantly from those after pancreatoduodenectomy (17,33,34,98,99), and the quality of life is fairly acceptable, there are no restrictions for performing total pancreatectomy on patients with indication for total pancreatectomy (99,101). Discussion After decreasing a 30-day mortality rate after pancreaticoduodenectomy to about 5%, surgeons have now focused their efforts on reducing morbidity, which is still as high as 30-60% (17,105-107). This mainly concerns reduction in incidence of pancreatic fistula, which is regarded the main cause of other frequent complications such as delayed gastric emptying, septic complications and intraabdominal haemorrhage. Ever since Whipple’s first pancreaticojejunostomy after pancreatoduodenectomy, surgeons have paid special attention to anastomosis between pancreatic remnant and digestive tract. In highly specialized centres pancreatic fistula incidence is from 0 to 18% (108), with death rate of 5%. Among the reports classifying pancreatic fistulas as A, B or C, following ISGPF grading system, incidence of grade C pancreatic fistulas was 2-5% (109-111). Grade C pancreatic fistulas were associated with sepsis from intrabdominal collections and bleeding, with high reoperation rate, prolonged length of hospital stay and with mortality rates from 35-40%. Soft pancreatic parenchyma is the most widely recognized risk factor for pancreatic fistula (112,113), along with three other relevant factors: duct size smaller than 3 mm, excessive intraoperative blood loss and specific pathology: ampullary, duodenal, cystic or islet cell neoplasms (111). The question is what to do when one or more risk factors for development of pancreatic fistula are present. There are multiple factors that will influence a decision which procedure to perform. First, to preserve a sufficient endocrine pancreatic function, approximately 50% of alpha and beta cells must be preserved (114). Alpha and beta cells are located predominately in the tail of the pancreas (115), so, theoretically, classical pancreaticoduodenectomy procedure should not cause endocrine insufficiency. When a pancreatic duct is occluded, without pancreatic anastomosis, pancreatic exocrine insufficiency will surely develop. Besides exocrine insufficiency, there is a significantly higher incidence of diabetes mellitus in patients with chemical occlusion of pancreatic duct in comparison with patients with a pancreaticojejunostomy (83).

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On the other hand, exocrine insufficiency will also develop in 9-20% of patients after Whipple procedure (116,117). The underlying cause are probably stenosis of pancreatic anastomosis and postoperative inflammation of the pancreas and fibrosis of pancreatic parenchyma (118,119). Other factors include patient’s preexisting diabetes mellitus or exocrine insufficiency, patient’s overall health and performance status and patient’s compliancy. A surgeon has several possibilities. First option is to perform a pancreatoduodenectomy with pancreatogastrojejunostomy, because of the lower incidence of pancreatic fistula with this type of anastomosis (79,80) or pancreatoduodenectomy with invagination pancreaticojejunostomy, recommended by a number of authors in case of soft pancreatic parenchyma and small pancreatic duct (67,113). Second option is also pancreatoduodenectomy, but with occlusion of the pancreatic remnant, either by ligation of the main pancreatic duct or by occlusion of the main pancreatic duct by Neoprene, Ethibloc or fibrin glue injection. This procedure is related to a higher incidence of pancreatic fistula, but with more benign clinical course, because pancreatic enzymes are not activated. The last option is total pancreatectomy for initial treatment of patients with multiple risk factors. With this procedure potential risks of a pancreatic fistula are eliminated, but with establishment of a total pancreatic state. Because of glycemic instability, predisposition for severe, life-threating hypoglycemia, and need for close glucose monitoring and intense insulin programme, patient’s compliance after total pancreatectomy is essential. When a surgeon encounters such a significant problem, the decision about proper surgical management can be difficult to make. Besides purely technical challenges, patients overall health status, existing comorbidities, pancreas pathology and expected survival are crucial in the decision-making process. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Howlader N, Noone AM, Krapcho M, et al. eds. SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD. Available online: http://seer. cancer.gov/csr/1975_2011/ 2. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality worldwide:

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69. Connor S, Alexakis N, Garden OJ, et al. Meta- analysis of the value of somatostatin and its analogues in reducing complications associated with pancreatic surgery. Br J Surg 2005;92:1059-67. 70. Gurusamy KS, Koti R, Fusai G, et al. Somatostatin analogues for pancreatic surgery. Cochrane Database Syst Rev 2013;4:CD008370. 71. Yoshimi F, Ono H, Asato Y, et al. Internal stenting of the hepaticojejunostomy and pancreaticojejunostomy in patients undergoing pancreatoduodenectomy to promote earlier discharge from hospital. Surg Today 1996;26:665-7. 72. Imaizumi T, Hatori T, Tobita K, et al. Pancreaticojejunostomy using duct-to-mucosa anastomosis without a stenting tube. J Hepatobiliary Pancreat Surg 2006;13:194-201. 73. Dong Z, Xu J, Wang Z, et al. Stents for the prevention of pancreatic fistula following pancreaticoduodenectomy. Cochrane Database Syst Rev 2013;6:CD008914. 74. Strasberg SM, Drebin JA, Mokadam NA, et al. Prospective trial of a blood supply-based technique of pancreaticojejunostomy: effect on anastomotic failure in the Whipple procedure. J Am Coll Surg 2002;194:746-58; discussion 759-60. 75. Z’graggen K, Uhl W, Friess H, et al. How to do a safe pancreatic anastomosis. J Hepatobiliary Pancreat Surg 2002;9:733-7. 76. Bai XL, Zhang Q, Masood N, et al. Duct-to-mucosa versus invagination pancreaticojejunostomy after pancreaticoduodenectomy: a meta-analysis. Chin Med J (Engl) 2013;126:4340-7. 77. Peng S, Mou Y, Cai X, et al. Binding pancreaticojejunostomy is a new technique to minimize leakage. Am J Surg 2002;183:283-5. 78. Crippa S, Salvia R, Falconi M, et al. Anastomotic leakage in pancreatic surgery. HPB 2007;9:8-15. 79. Menahem B, Guittet L, Mulliri A, et al. Pancreaticogastrostomy is superior to pancreaticojejunostomy for prevention of pancreatic fistula after pancreaticoduodenectomy: an updated meta-analysis of randomized controlled trails. Ann Surg 2014. [Epub ahead of print]. 80. Liu FB, Chen JM, Geng W, et al. Pancreaticogastrostomy is associated with significantly less pancreatic fistula than pancreaticojejunostomy reconstruction after pancreaticoduodenectomy: a meta- analysis of seven randomized controlled trials. HPB (Oxford) 2014. [Epub ahead of print]. 81. Sakorafas GH, Friess H, Balsiger BM, et al. Problems of

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recontruction during pancreatoduodenectomy. Dig Surg 2001;18:363-9. 82. Papachristou DN, Fortner JG. Pancreatic fistula complicating pancreatectomy for malignant disease. Br J Surg 1981;68:238-40. 83. Yeo CJ, Cameron JL, Maher MM, et al. A prospective randomized trial of pancreaticogastrostomy versus pancreaticojejunostomy after pancreaticoduodenectomy. Ann Surg 1995;222:580-8; discussion 588-92. 84. Suc B, Msika S, Fingerhut A. French association for Research in Surgery. Temporary Fibrin Glue Occlusion of the main pancreatic duct in the prevention of intraabdominal complications after pancreatic resection. Ann Surg 2003;237:57-65. 85. Konishi T, Hiraishi M, Kubota K, et al. Segmental occlusion of the pancreatic duct with prolamine to prevent fistula formation after distal pancreatectomy. Ann Surg 1995;221:165-70. 86. de Castro SM, Kuhlmann KF, Busch OR, et al. Delayed massive hemorrhafe after pancreatic and biliary surgery. Embolization or surgery? Ann Surg 2005;241:85-91. 87. Yekebas EF, Wolfram L, Cataldegirmen G, et al. Postpancreatectomy hemorrhage: diagnosis and treatment: an analysis in 1669 consecutive pancreatic resections. Ann Surg 2007;246:269-80. 88. Tamijmarane A, Ahmed I, Bhati CS, et al. Role of compoletion pancreatectomy as a damage control option for post- pancreatic surgical complications. Dig Surg 2006;23:229-34. 89. Gueroult S, Parc Y, Duron F, et al. Completion pancreatectomy for postoperative peritonitis after pancreaticoduodenectomy: early and late outcome. Arch Surg 2004;139:16-9. 90. Wittmann DH, Schein M, Condon RE. Management of secondary peritonitis. Ann Surg 1996;224:10-8. 91. Rockey EW. Total pancreatectomy for carcinoma. Case report. Ann Surg 1943;118:603-11. 92. Ross DE. Cancer of the pancreas; a plea for total pancreatectomy. Am J Surg 1954;87:20-33. 93. Porter MR. Carcinoma of the pancreatico-duodenal area; operability and choice of procedure. Ann Surg 1958;148:711-23. 94. ReMine WH, Priestley JT, Judd ES, et al. Total pancreatectomy. Ann Surg 1970,172:595-604. 95. Sarr MG, Behrns KE, van Heerden JA. Total pancreatectomy. An objective analysis of its use in pancreatic cancer. Hepatogastroenterology. 1993;40:418-21. 96. Grace PA, Pitt HA, Tompkins RK, et al. Decreased

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morbidity and mortality after pancreaticoduodenectomy. Am J Surg 1986;151:141-9. 97. McAfee MK, van Heerden JA, Adson MA. Is proximal pancreatoduodenectomy with pyloric preservation superior to total pancreatectomy? Surgery 1989;105:347-51. 98. Heidt DG, Burant C, Simeone DM. Total pancreatectomy: Indications, operative technique, and postoperative sequelae. J Gastrointest Surg 2007;11:209-16. 99. Müller MW, Friess H, Kleeff J, et al. Is there still a role for total pancreatectomy? Ann Surg 2007;246:966-74; discussion 974-5. 100. Billings BJ, Christein JD, Harmsen WS, et al. Qualityof-life after total pancreatectomy: is it really that bad on long-term follow-up? J Gastrointest Surg 2005;9:1059-66; discussion 1066-7. 101. Hartwig W, Gluth A, Hinz U, et al. Total pancreatectomy for primary pancreatic neoplasms: Renaissance of an unpopular operation. Ann Surg 2014. [Epub ahead of print]. 102. Parsaik AK, Murad MH, Sathananthan A, et al. Metabolic and target organ outcomes after total pancreatectomy: Mayo Clinic experience and meta-analysis of the literature. Clinical Endocrinology 2010;73:723-31. 103. Jethwa P, Sodergren M, Lala A, et al. Diabetic control after total pancreatectomy. Dig Liver Dis 2006;38:415-9. 104. MacLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabet Med 1993;10:238-45. 105. Neoptolemos JP, Russell RC, Bramhall S, et al. Low mortality following resection for pancreatic and periampullary tumours in 1026 patients: UK survey of specialist pancreatic units. UK Pancreatic Cancer Group. Br J Surg 1997;84:1370-6. 106. Stojadinovic A, Brooks A, Hoos A, et al. An evidencebased approach to the surgical management of resectable pancreatic adenocarcinoma. J Am Coll Surg 2003;196:954-64. 107. Cooperman AM, Schwartz ET, Fader A, et al. Safety, efficacy, and cost of pancreaticoduodenal resection in a specialized center based at a community hospital. Arch Surg 1997;132:744-7; discussion 748. 108. Schäfer M, Müllhaupt B, Clavien PA. Evidence-based pancreatic head resection for pancreatic cancer and chronic pancreatitis. Ann Surg 2002;236:137-48. 109. Fuks D, Piessen G, Huet E, et al. Life-threatening postoperative pancreatic fistula (grade C) after pancreaticoduodenectomy: incidence, prognosis and risk factors. Am J Surg 2009;197:702-9.

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110. Pratt WB, Maithel SK, Vanounou T, et al. Clinical and economic validation of the International Study Group of Pancreatic Fistula (ISGPF) classification scheme. Ann Surg 2007;245:443-51. 111. Callery MP, Wande BP, Kent TS, et al. Prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreaticoduodenectomy. J Am Coll Surg 2013;216:1-14. 112. Mathur A, Pitt HA, Marine M, et al. Fatty pancreas: a factor in postoperative pancreatic fistula. Ann Surg 2007;246:1058-64. 113. Suzuki Y, Fujino Y, Tanioka Y, et al. Selection of pancreaticojejunostomy techniques according to pancreatic texture and duct size. Arch Surg 2002;137:1044-7; discussion 1048. 114. Schrader H, Menge BA, Breuer TGK, et al. Impaired Glucose-Induced Glucagon Suppression after partial

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pancreatectomy. J Clin Endocrinol Metab 2009;94:2857-63. 115. Wittingen J, Frey CF. Islet concentration in the head, body, tail and uncinate process of the pancreas. Ann Surg 1974;179:412-4. 116. Idezuki Y, Goetz FC, Lillehei RC. Late effect of pancreatic duct ligation on beta cell function. Am J Surg 1969;117:33-39. 117. Shankar S, Theis B, Russell RC. Management of the stump of the pancreas after distal pancreatic resection. Br J Surg 1990;77:541-44. 118. Tran TC, van’t Hof G, Kazemier G, et al. Pancreatic fibrosis correlates with exocrine pancreatic insufficiency after pancreatoduodenectomy. Dig Surg 2008;25:311-8. 119. Nordback I, Parviainen M, Piironen A, et al. Obstructed pancreaticojejunostomy partly explains exocrine insufficiency after paancreatic head resection. Scand J Gastroenterol 2007;42:263-70.

Cite this article as: Zovak M, Mužina Mišić D, Glavčić G. Pancreatic surgery: evolution and current tailored approach. Hepatobiliary Surg Nutr 2014;3(5):247-258. doi: 10.3978/ j.issn.2304-3881.2014.09.06

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Review Article

Potential use of Doppler perfusion index in detection of occult liver metastases from colorectal cancer Mario Kopljar, Leonardo Patrlj, Željko Bušić, Marijan Kolovrat, Mislav Rakić, Robert Kliček, Marcel Židak, Igor Stipančić Department of Abdominal Surgery, University Hospital Dubrava, Zagreb, Croatia Correspondence to: Mario Kopljar, MD, PhD. Department of Abdominal Surgery, University Hospital Dubrava, Av. G. Suska 6, HR-10000 Zagreb, Croatia. Email: [email protected].

Abstract: Many clinical and preclinical studies demonstrated that measurements of liver hemodynamic [Doppler perfusion index (DPI)] may be used to accurately diagnose and predict liver metastases from primary colorectal cancer in a research setting. However, Doppler measurements have some serious limitations when applied to general population. Ultrasound is very operator-dependent, and requires skilled examiners. Also, many conditions may limit the use of Doppler ultrasound and ultrasound in general, such as the presence of air in digestive tract, cardiac arrhythmias, vascular anomalies, obesity and other conditions. Therefore, in spite of the results from clinical studies, its value may be limited in everyday practice. On the contrary, scientific research of the DPI in detection of liver metastases is of great importance, since current research speaks strongly for the presence of systemic vasoactive substance responsible for observed hemodynamic changes. Identification of such a systemic vasoactive substance may lead to the development of a simple and reproducible laboratory test that may reliably identify the presence of occult liver metastases and therefore increase the success of adjuvant chemotherapy through better selection of patients. Further research in this subject is therefore of great importance. Keywords: Doppler perfusion index (DPI); liver; colorectal cancer; liver metastases; oncology; surgery; adjuvant chemotherapy; ultrasound; Doppler ultrasound Submitted Aug 10, 2014. Accepted for publication Aug 31, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.04 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.04

Introduction According to epidemiological research, colorectal cancer is the second most common cancer and the second most common cause of death from malignant disease in Europe, causing approximately 400,000 deaths annually worldwide (1-4). The main cause of death of patients with colorectal cancer is liver metastases (5). It is well known that approximately 25% of patients with colorectal cancer already have liver metastases, and another 25% of patients develop liver metastases during follow up, usually within the first 2 years after the diagnosis of the primary colorectal tumor (6). In rectal cancer, preoperative chemoradiotherapy (CRT) significantly reduces the rate of local recurrence (5.3% vs. 14.1%), but patients who were treated with preoperative CRT do not appear to benefit significantly in

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terms of their long-term prognosis (66.2% vs. 67.8%) (7). Also, improvements in surgical technique resulted in less local recurrence (8). Currently there is no reliable method for detecting small, occult liver metastases. Oncologists use various prognostic factors in deciding on adjuvant treatment. A standard prognostic factor that is used routinely in selecting patients for adjuvant treatment is the Dukes classification of the primary colorectal cancer (9-11). The survival of patients with dukes C stage as well as one part of patients with dukes B stage can be improved by the application of adjuvant chemotherapy after potentially curative surgical resection (12,13). Adjuvant chemotherapy (5-fluorouracil with levamisole or 5-fluorouracil with folinic acid) leads to a 40% reduction in the rate of recurrence and metastases,

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and 33% reduction in mortality rates of patients with Dukes C colon cancer (14). Despite that, approximately one third of patients with Dukes C colon cancer will survive 5 years even without adjuvant chemotherapy. On the other hand, approximately one third of patients with Dukes B colon cancer will develop recurrent disease or metastases. However, today there is no clear recommendation for the application of adjuvant chemotherapy in patients with colorectal cancer stage Dukes B (9). Therefore, it is obvious that Dukes classification is insufficient for the selection of patients for the application of adjuvant chemotherapy after potentially curative resection for colorectal cancer (9). Careful selection of patients is crucial to improve the results of chemotherapy by applying it only to patients with the greatest impact on survival and avoiding harmful effects of chemotherapy in patients with no risk off liver metastasis (15). Therefore, the detection of those patients with micrometastases that are not evident at the time of primary tumor treatment still represents a significant challenge (16). Current morphological methods for diagnosing liver metastases from colorectal cancer obviously have the limitation in detecting small focal liver lesions less than a few millimeters in diameter (17). Hepatic perfusion changes in patients with liver metastases It has been known for a while now, that in patients with liver metastasis there is an alteration of blood flow through the liver (18). Alterations of the hepatic flow in tumors were initially observed using dynamic scintigraphy. In 1983 Parkin et al. (19) proved that when malignant tumors are present the arterial hepatic flow is elevated because tumors have a predominantly arterial vascularity. Parkin also proposed the use of the hepatic perfusion index (HPI), which is increased in patients with liver metastases. Several papers consistently demonstrated that a relative blood flow through the common hepatic artery, expressed as a percentage of total hepatic blood flow is significantly increased in patients with hepatic metastases in comparison to patients without liver metastases (9,20,21). For a long time it has been considered that the observed change of blood flow through the liver is exclusively the consequence of increased neovascularization within the metastases themselves. Clinical and experimental studies demonstrated that liver metastases from colorectal cancer establish their blood supply mostly through hepatic artery system (22-24).

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Although some research demonstrated that liver micrometastases indeed do derive some of their blood flow through the portal system, portal vascularization of liver metastasis is generally considered insignificant in comparison to vascularization derived through hepatic artery, especially considering the fact that the with the growth of metastasis there is also an increase in arterial blood supply compared to a portal blood supply (23). In spite of the well-known thinking that only metastasis greater than one millimeter in diameter receive their blood supply through newly formed blood vessels (22), it has been demonstrated that even metastasis with only half a millimeter have a defined vascularization derived predominantly through the system of hepatic artery (23,25). Hepatic neovascularization is a complex process during which the relative contribution of arterial and portal blood flow changes during the growth of liver metastases (24,25). In the earliest stage, liver metastasis depend on perfusion from adjacent issue, until they reach a diameter of approximately 150-200 μm (26). Further growth of the metastasis induces new vessel formation derived from those arterial and portal system. As liver metastasis increases to over two millimeters in size, arterial blood flow becomes dominant (27). Angiographic research demonstrated a great variability in the vascularization of liver metastasis. Some metastasis demonstrate minimal accumulation of contrast (hypovascularized metastases), while others are extremely well vascularized with a marked arterial supply of the entire liver lobe (24). These variations in blood supply of liver metastasis play a significant role in the choice and success of local therapeutic procedures such as locoregional arterial chemotherapy, dearterialization and embolisation. Doppler perfusion index (DPI) This well known change in liver perfusion in patients with liver metastasis was further investigated by Leen and colleagues using Doppler ultrasound. In a series of papers he demonstrated that a Doppler ultrasound is a simple, non-invasive and reliable method in detecting changes in liver perfusion, especially in patients with colorectal cancer liver metastases (9,28-30). Some research demonstrated that DPI enables greater precision to determine the likelihood of the existence of occult metastases in the liver. The analysis of preoperative values of DPI on a sample of 120 patients with colorectal cancer confirmed the statistically significant predictive value of DPI the detection of liver metastasis. The sensitivity,

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Table 1 Doppler perfusion index—how to do it Procedure

How to do it

Prepare the patient

Overnight fasting; supine position

Measure the diameter of the common

In transverse plane, find the celiac trunk and locate the common hepatic artery. Set the

hepatic artery (AHC)

size of the Doppler window to encompass AHC. Set the measurement point so that the Doppler axis is as close as small as possible (should not be greater than 60 degrees to minimize error). Measure the diameter (in centimeters) of the common hepatic artery perpendicular to the longitudinal axis at the selected measurement point

Measure the cross sectional area of the

Use built-in algorithm or calculate from the diameter of the AHC:

common hepatic artery

cross sectional area (S) =

Measure the velocity of blood flow in the At the same measurement point, position the Doppler cursor in the middle of the artery common hepatic artery

and record Doppler waves for at least 3 cardiac cycles (more cycles may be required if patient has arrhythmia). For each cycle determine the peak systolic velocity (PSV), enddiastolic velocity (EDV) and mean velocity (MV) in centimeters per second. Calculate mean PSV, EDV and MV across several cycles

Calculate resistance index (RI)

RI =

Calculate blood flow in the common

Use built-in algorithm or calculate blood flow in mL/s: fAHC = MV*S

hepatic artery (fAHC) Measure the diameter of the portal vein

Locate the portal vein before its bifurcation (adjacent to common hepatic duct). Set the

(PV)

size of the Doppler window to encompass PV. Set the measurement point so that the Doppler axis is as close as small as possible (should not be greater than 60 degrees to minimize error). Measure the diameter (in centimeters) of the portal vein perpendicular to the longitudinal axis at the selected measurement point

Measure the cross sectional area of the

Use built-in algorithm or calculate from the diameter of the PV:

portal vein

cross sectional area (S) =

Measure the velocity of blood flow in the At the same measurement point, position the Doppler cursor in the middle of the portal vein

portal vein and record Doppler waves for at least 3 cardiac cycles (more cycles may be required if patient has arrhythmia). For each cycle determine the mean velocity (MV) in centimeters per second. Calculate mean MV across several cycles (modern ultrasound machines will do that automatically)

Calculate blood flow in the portal vein

Use built-in algorithm or calculate blood flow in mL/s: fPV = MV × S

(fPV) Calculate Doppler perfusion index (DPI)

DPI =

specificity, positive and negative predictive values as well as the accuracy of determining DPI for identification of patients in whom liver metastasis will be diagnosed during follow up was found to be 95%, 69%, 73%, 94% and 81% (9). Five-year follow-up of patients with colorectal cancer demonstrated that the blood flow redistribution through the liver is strongly correlated to the survival (9). In a prospective study, the 5-year follow-up of patients who underwent potentially curative resection of primary colorectal cancer found that patients with normal values of DPI (DPI <30%) had a 5-year rate of disease free survival of 89%, while the

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5-year disease free survival was only 22% in patients with elevated DPI (DPI ≥30%). Overall survival of patients with normal values of DPI was as high as 91% and only 29% in patients with abnormally elevated DPI (9). Measurement of blood flow through blood vessels by color Doppler is extremely dependent on a number of technical parameters, and even small errors in the measurement of the diameter or cross-sectional area of blood vessels or the angle at which the measurements were performed can produce large errors in the calculation of the blood flow through (Table 1) (31,32). Therefore, in most

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Table 2 The equations that may be used for calculating body surface area in order to standardize blood flow Author

Formula

Du Bois and Du Bois (40)

BSA = 0.007184 × H0.725 × W0.425

Gehan and George (41)

BSA = 0.0235 × H0.42246 × W0.51456

Haycock (42)

BSA = 0.024265 × H0.3964 × W0.5378

Mosteller (43)

BSA = Square root [(H × W)/3,600] 2

H, height (cm); W, weight (kg); BSA, body surface area (m ).

clinical studies where Doppler measurements were used to measure blood flow, mean values of several consecutive measurements of diameters or cross sectional areas of blood vessels were used to reduce the risk of errors in measurements (9). Analyzing the maximum speed of blood flow through the vessel in systole [peak systolic velocity (PSV)], the speed of blood flow at the end of diastole [enddiastolic velocity (EDV)] and calculating the resistance index (RI) can more precisely describe the hemodynamic status of the arteries than the calculation of blood flow volume, because the calculation of the above parameters does not necessitate to knowledge the cross-sectional surface of measured vessels. Despite the fact that ultrasonic Doppler technique is dependent on the examiner, technically challenging and often requires significant time to perform, it has confirmed good reproducibility and validity of the measurements among multiple examiners (33,34). Moreover, satisfactory accuracy and reproducibility of measurements of the DPI of the liver was found when the measurements were performed by operators with no classical medical education and after only a few months of training in this specific area (18). In spite of the standardization of measurements, values of blood flow often demonstrate wide dispersion (6). In order to maximize the extent of comparability and reduce the scattering of value, the flow can be expressed in relation to body surface area. In histological examinations, the diameter of coronary arteries has been brought in correlation with age and body surface area off young healthy people (35). Body surface area is also used as a method of standardization of the cross sectional area of different arteries (36). Body surface area is routinely used in research of blood flow through different vessels as well as for liver haemodynamics (37). Therefore, utilizing body surface area and expressing the blood flow through different vessels relative to body surface area is a specially suitable to compare vascular parameters between groups with substantial morphological differences (38). Also,

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body surface area is used to achieve greater comparability of masses of different organs, such as liver, which mass, expressed relatively according to body surface area can be used in different researches (39). There are several formulas that enable the calculation of the body surface area, such as those recommended by Mosteller or DuBois and DuBois (Table 2) (40,43,44). The calculation of body surface area is a common procedure in many clinical and scientific branches of medicine (45), but surprisingly in most research this method of standardization was not used (6). Another possible downfall of determining DPI with the purpose of detection of micrometastasis in the liver in patients with colorectal cancer is the factor that DPI is increased in patients with cirrhotic liver. However, hemodynamic examination of hepatic blood flow demonstrated that in patients with liver cirrhosis there is also an increase in liver congestion index, defined as the ratio of the cross sectional area of the portal vein and portal mean blood flow velocity (30). However, not all authors were able to prove the clinical usefulness off DPI measurement in the detection of liver metastasis. In a clinical study conducted by Roumen et al. (46), 133 patients with different stages of colorectal cancer were examined. Reliable DPI measurements were not possible in 29 patients, mostly due to technical difficulties caused by the presence of air or other contrast media, obesity, scars or other reasons. In their study, they were unable to detect a single cut-off value that could reliably discriminate patients with liver metastases. It has to be noted that in this study no preselection of patients was performed and the focus was placed on the clinical usefulness of Doppler measurements in unselected population of patients. Apart from technical difficulties, Doppler perfusion measurements are characterized by high variability, which has been reported to be as high as 26% (46). Especially important it is the intraobserver variability that is not merely the result of the method or technique but rather a consequence of inherent subject variations. As the Doppler measurements may well prove not to be

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Table 3 Possible etiology of change in flow Main proposed etiology

Studies

Increased hepatic arterial blood flow

Parkin, 1983 (19); Ridge, 1987 (24); Archer, 1989 (25)

Decreased portal blood flow

Nott, 1991 (48); Carter, 1994 (49); Yarmenitis, 2000 (47)

Decreased portal blood flow with compensatory increase in

Kopljar, 2004 (6)

hepatic arterial blood flow

useful in everyday practice, the underlying hypothesis of the existence of a humoral vasoactive substance responsible for hepatic perfusion changes sheds the new light on the clinical and preclinical research directed towards finding an easily and reliably measured systemic factor. Possibility of a humoral vasoactive factor Until now, the cause of this redistribution of hepatic blood flow is not clearly explained. According to one hypothesis, this phenomenon is caused by splanchnic vasoconstriction and a consequent reduction of portal blood flow with a simultaneous increase in common hepatic artery flow as a result of hemodynamic compensation (15). Some experimental and clinical research indeed demonstrated that in patients with liver metastases that are too small to be detected by conventional radiologic methods there is already an alteration in the blood flow through the liver that was shown to be highly sensitive in the detection of small, occult liver metastasis (9,18,20,47). This raises the question on the nature of these haemodynamic changes, since these small, occult metastases are unlikely to be the cause of sufficient neovascularization responsible for significant changes in hepatic perfusion (Table 3). It was therefore hypothesized that the primary cause of hepatic perfusion changes in patients with colorectal cancer liver metastases is a circulating vazoactive factor causing primarily splanchnic vasoconstriction and subsequent reduction in portal inflow to the liver. In order to prove the hypothesis of circulating vasoactive factor as a possible cause of liver hemodynamic changes in patients with colorectal cancer and liver metastasis, a group of researchers conducted a research on animal model (49). In this research, isolated intestinal loop of a healthy animal was perfused with blood from another animal with experimentally induced liver sarcoma (HSN sarcoma) (49). The experiment showed that splanchnic vascular resistance in healthy animals was significantly greater during perfusion with blood from tumor bearing animals [91.6 (SE 21.5), vs. 51.7 (SE 7.41), P=0.036]. The results of this

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experiment suggest that observed hemodynamic changes are at least partly mediated by a circulating agent. Whether this circulating agent is produced by the tumor itself or is an endogenous agent remains unclear (49). In another animal experiment (47), liver metastases were induced in 30 male Wistar rats by inoculating Walker 256 tumor subcutaneously. Hemodynamic changes were observed and correlated to the liver histology at the time of measurement. By measuring the flow through the hepatic artery and portal vein in this animal model of spontaneous liver metastases, Yarmenitis and colleagues have shown a statistically significant increase in blood flow through the common hepatic artery as early as the fourth day after implantation of the primary tumor, when histological examination of the liver demonstrated only single tumor cells or small clusters in the connective tissue of porta hepatis and periportal interlobular space (47). DPI values were significantly increased as early as on the fourth day after implantation of the primary tumor, and did not significantly increase until the fifteenth day, when the histological examination showed metastatic tumors in the liver with the largest diameter of 2 mm. Also, the flow through the portal vein was reduced in animals with metastatic tumors in the liver on the fourth day, but the difference was not statistically significant. Therefore, a statistically significant increase in DPI and blood flow through the hepatic artery was observed only four days after implantation of tumor cells, when the histological analysis of the liver in these animals was not able to demonstrate any vascular component of either the hepatic artery or portal vein. This finding is consistent with the hypothesis of the existence of a humoral vasoactive factor that can lead to hemodynamic changes in the liver in the earliest stages of the development of metastases, and that its effect may manifest both locally, in the liver, as well as in the splanchnic circulation away from metastases (49). Opposite to some other studies (48,49), in the experimental study conducted by Yarmenitis and associates, DPI changes were primarily attributed to a statistically significant increase in

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the flow through the hepatic artery and without significant changes in portal flow (47). In the research conducted by Nott and coworkers (48), the blood flow through the portal vein was significantly reduced in animals with experimentally induced sarcoma of the liver (Walker carcinosarcoma). The results of this study indicate that overt tumor derived from the intraportal inoculation of Walker cells results in an increase in the HPI. The blood supply to the tumor was shown to be derived principally from the hepatic artery. However, hepatic arterial flow did not change in the presence of tumor and the alterations in the HPI were found to be secondary to a reduction in portal venous inflow. Moreover, the presence of overt hepatic tumor was associated with gross derangement of hepatic hemodynamic with a pronounced increase in intrahepatic arteriovenous shunting. It was concluded that hemodynamic changes accompanying the development of overt hepatic tumor are complex and must be taken into account when attempting to potentiate the distribution of cytotoxics to the tumor by regional administration or through manipulation of liver blood flow (48). Other researchers also demonstrated significant reduction of portal flow in experimental models of liver metastasis, with no changes in arterial hepatic flow (50). An experimental and biomolecular research identified some systemic active factors that might, at least in theory, explain the redistribution of blood flow through the liver in patients with colorectal liver metastasis (51). One possible causative agent might be endothelin-1 (15), a potent vasoconstrictor with significant influence on the portal blood flow that is regularly produced by the colorectal cancer. Peeters and coworkers measured the serum level of endothelin-1 in 68 patients with colorectal cancer and 20 healthy volunteers without malignant disease. The sera level of endothelin-1 was statistically significantly higher in patients with colorectal cancer compared to healthy participants. Further subgroup analysis was performed and patients were divided into three groups: those with primary colorectal cancer without metastasis, patients with colorectal cancer that developed metastasis during follow up and patients with colorectal cancer and synchronous liver metastasis. All three subgroups had higher concentrations of endothelin-1 compared to healthy participants. However, no statistically significant difference in preoperative concentration of endothelin-1 was found between healthy participants and patients with liver metastasis from previously resected colorectal cancer (15). Animal models demonstrated that endothelin-1 results

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in increased blood pressure in the portal vein (52,53). Also, it has been determined that endothelin-1 is synthesized and released from several human epithelial carcinomas. Inagaki and coworkers demonstrated the existence of increased quantities of endothelin-1 in the tissue of primary colorectal carcinoma (54). Furthermore, histochemical methods demonstrated the presence of endothelin-1 in the cytoplasm of colorectal cancer cells metastatic to the liver, as well as in cytoplasm of adjacent myofibroblasts. These results indicate that endothelin-1 is not produced only in tumor cells but also in adjacent cells, thereby influencing the growth of the tumor (51). Unfortunately, survival analysis did not demonstrate prognostic value of pre-operative determination of the concentration of endothelin-1 in patients with colorectal cancer (15). In one clinical study (6) results showed that the DPI successively increased in patients with colorectal cancer with no signs of liver metastases and in patients with liver metastases. There was a statistically significant difference in the blood flow through the portal vein between patients with colorectal cancer without signs of metastases in the liver and healthy control patients, but no statistically significant differences in the flow through the common hepatic artery (6). However, the flow through the common hepatic artery and portal vein in patients with primary colorectal cancer with no signs of liver metastases and those with liver metastases, as well as between patients with liver metastases and control subjects showed statistically significant differences in the absolute values of flow through common hepatic artery and portal vein as well as the values of the flow through the same blood vessels expressed relative to body surface area (6). These results suggest that the early hemodynamic changes in patients with liver metastases are associated with a reduction of flow through the portal vein, while the increase in blood flow through the common hepatic artery is associated with the development of tumor neovascularization in larger metastases (6). Furthermore, clinical research demonstrated no statistically significant differences in the blood flow through the superior mesenteric artery between patients with liver metastases and those without metastases, and the difference in RI was marginally statistically significant (6). These findings are certainly at least partly influenced by the difficulties in measuring the cross-sectional area of blood vessels and blood flow in general, which is why the measurements of vascular index have the advantage. The hypothesis of the existence of systematic acting,

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circulating humoral vasoactive factor in patients with liver metastases is further supported by the analysis results obtained by measuring the flow rate and RI of the superior mesenteric artery among the three groups of patients (patients with liver metastases, those with primary colorectal cancer and no detectable metastases and patients with no malignancy). If this hypothesis is correct, and if indeed a humoral vasoactive factors can be found in the bloodstream of patients with metastases in the liver, then its actions should be expressed also on remote vessels, outside of the liver. Indeed, the EDV in the superior mesenteric artery was higher in healthy subjects compared to patients with colorectal cancer and no signs of liver metastases as well as compared to patients with liver metastases, while the difference in end-diastolic velocity in the superior mesenteric artery in patients with colorectal cancer without signs of metastases in the liver and patients with metastases was not statistically significant (6). Statistically significant differences of RI were found among healthy subjects, patients with colorectal cancer without signs of metastases in the liver and patients with metastases (6). These results clearly indicate that even in patients with colorectal cancer without clinical and radiological signs of metastases in the liver, there is a systemic alteration of blood flow, which is reflected in the reduction of the end-diastolic velocity in the superior mesenteric artery. Conclusions In the last three decades, many clinical and preclinical studies demonstrated that DPI measurements may be used to accurately diagnose and predict liver metastases from primary colorectal cancer. However, Doppler measurements have some serious limitations when applied to general population. Ultrasound is very operator-dependent, and requires skilled examiners. Also, many conditions may limit the use of Doppler ultrasound and ultrasound in general, such as the presence of air in digestive tract, cardiac arrhythmias (including rather common atrial fibrillation), vascular anomalies (e.g., the origin of right hepatic artery from superior mesenteric artery), obesity and other conditions (6,46). Therefore, in spite of the results from clinical studies, its value may be limited in everyday practice. On the contrary, scientific research of the DPI in detection of liver metastases is of great importance, since current research speaks strongly for the presence of

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systemic vasoactive substance responsible for observed hemodynamic changes. Identification of such a systemic vasoactive substance may lead to the development of a simple and reproducible laboratory test that may reliably identify the presence of occult liver metastases and therefore increase the success of adjuvant chemotherapy through better selection of patients. Further research in this subject is therefore of great importance. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Boyle P, Langman JS. ABC of colorectal cancer: Epidemiology. BMJ 2000;321:805-8. 2. Jurisić I, Paradzik MT, Jurić D, et al. National program of colorectal carcinoma early detection in Brod-Posavina County (east Croatia). Coll Antropol 2013;37:1223-7. 3. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48) in Osijek-Baranja County from 2001 to 2006, Croatia. Coll Antropol 2013;37:1209-22. 4. Samardzić S, Mihaljević S, Dmitrović B, et al. First six years of implementing colorectal cancer screening in the Osijek-Baranja County, Croatia--can we do better? Coll Antropol 2013;37:913-8. 5. Doko M, Zovak M, Ledinsky M, et al. Safety of simultaneous resections of colorectal cancer and liver metastases. Coll Antropol 2000;24:381-90. 6. Kopljar M, Brkljacic B, Doko M, et al. Nature of Doppler perfusion index changes in patients with colorectal cancer liver metastases. J Ultrasound Med 2004;23:1295-300. 7. Boras Z, Kondza G, Sisljagić V, et al. Prognostic factors of local recurrence and survival after curative rectal cancer surgery: a single institution experience. Coll Antropol 2012;36:1355-61. 8. Krebs B, Kozelj M, Potrc S. Rectal cancer treatment and survival--comparison of two 5-year time intervals. Coll Antropol 2012;36:419-23. 9. Leen E, Goldberg JA, Angerson WJ, et al. Potential role of doppler perfusion index in selection of patients with colorectal cancer for adjuvant chemotherapy. Lancet 2000;355:34-7. 10. Cunningham D, Findlay M. The chemotherapy of colon cancer can no longer be ignored. Eur J Cancer 1993;29A:2077-9. 11. Bosman FT. Prognostic value of pathological

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26. Strohmeyer T, Haugeberg G, Lierse W. Angioarchitecture and blood supply of micro- and macrometastases in human livers. An anatomic-pathological investigation using injection-techniques. J Hepatol 1987;4:181-9. 27. Ackerman NB. Experimental studies on the role of the portal circulation in hepatic tumor vascularity. Cancer 1986;58:1653-7. 28. Leen E, Goldberg JA, Robertson J, et al. The use of duplex sonography in the detection of colorectal hepatic metastases. Br J Cancer 1991;63:323-5. 29. Robertson J, Leen E, Goldberg JA, et al. Flow measurement using duplex Doppler ultrasound: haemodynamic changes in patients with colorectal liver metastases. Clin Phys Physiol Meas 1992;13:299-310. 30. Leen E, Goldberg JA, Anderson JR, et al. Hepatic perfusion changes in patients with liver metastases: comparison with those patients with cirrhosis. Gut 1993;34:554-7. 31. Breyer B. Medicinski ultrazvuk - uvod u fiziku i tehniku. Zagreb: Školska knjiga; 1989. Available online: http://www. skolskaknjiga.hr 32. Burns PN. Physics and instrumentation: doppler. In: Goldberg BB. eds. Textbook of abdominal ultrasound. Baltimore: Williams & Wilkins; 1993, 24-9. Available online: http://www.lww.com 33. Oppo K, Leen E, Angerson WJ, et al. Doppler perfusion index: an interobserver and intraobserver reproducibility study. Radiology 1998;208:453-7. 34. Krüger S, Strobel D, Wehler M, et al. Hepatic Doppler perfusion index--a sensitive screening method for detecting liver metastases? Ultraschall Med 2000;21:206-9. 35. Litovsky SH, Farb A, Burke AP, et al. Effect of age, race, body surface area, heart weight and atherosclerosis on coronary artery dimensions in young males. Atherosclerosis 1996;123:243-50. 36. Huonker M, Schmid A, Schmidt-Trucksass A, et al. Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletes. J Appl Physiol (1985) 2003;95:685-91. 37. Bombelli L, Genitoni V, Biasi S, et al. Liver hemodynamic flow balance by image-directed Doppler ultrasound evaluation in normal subjects. J Clin Ultrasound 1991;19:257-62. 38. Zeppilli P, Vannicelli R, Santini C, et al. Echocardiographic size of conductance vessels in athletes and sedentary people. Int J Sports Med 1995;16:38-44. 39. Kuo PC, Li K, Alfrey EJ, et al. Magnetic resonance imaging and hepatic hemodynamics: correlation with

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Cite this article as: Kopljar M, Patrlj L, Bušić Ž, Kolovrat M, Rakić M, Kliček R, Židak M, Stipančić I. Potential use of Doppler perfusion index in detection of occult liver metastases from colorectal cancer. Hepatobiliary Surg Nutr 2014;3(5):259267. doi: 10.3978/j.issn.2304-3881.2014.09.04

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Review Article

Pancreatic fistula and postoperative pancreatitis after pancreatoduodenectomy for pancreatic cancer Miroslav Ryska, Jan Rudis Department of Surgery, 2nd Faculty of Medicine, Charles University and Central Military Hospital, Prague, Czech Republic Correspondence to: Miroslav Ryska, MD, Ph.D. Surgery Department, 2nd Faculty of Medicine, Charles University and Central Military Hospital, U Vojenske Nemocnice 1200, 160 00 Prague 6, Czech Republic. Email: [email protected].

Abstract: The most serious complication after pancreatoduodenectomy (PD) is pancreatic fistula (PF) type C, either as a consequence or independently from postoperative pancreatitis (PP). Differentiating between these two types of complications is often very difficult, if not impossible. The most significant factor in early diagnosis of PP after PD is an abrupt change in clinical status. In our retrospective study we also observed significantly higher levels of serum concentrations of CRP and AMS comparing to PF without PP. Based on our findings, CT scan is not beneficial in the early diagnosis of PP. Meantime PF type C is indication to operative revision with mostly drainage procedure which is obviously not much technically demanding, there are no definite guidelines on how to proceed in PP. Therefore the surgeon’s experience determines not only whether PP will be diagnosed early enough and will be differentiated from PF without PP, but also whether a completion pancreatectomy will be performed in indicated cases. Keywords: Pancreatoduodenectomy (PD); pancreatic fistula (PF); postoperative pancreatitis (PP); drainage; total pancreatectomy Submitted Aug 06, 2014. Accepted for publication Sep 09, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.05 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.05

Introduction Pancreatoduodenectomy (PD) has its indication of radical intent in the treatment of periampulary malignant tumors as cephalopancreatic neoplasia, distal cholangiocarcinoma or ampuloma. PD managing to provide a 5-year survival of 31.4% for tumors diagnosed in stage I and only 2.8% for stage IV with a median of 24.1 and 4.5 months respectively (1). In patients with unresectable adenocarcinoma 5-year survival reach only 0.6% for stage IV with a median survival of 2.5 months and 3.8% for stage I with a median of 6.8 months. Radical resection is the only chance for patients with this tumor. Unfortunately only 15-20% of them are suitable for it. Mortality of this type of resection has intermediate risk to compare to total pancreatectomy with highest and to distal pancreatectomy with lowest risk. Retrospective review from a prominent high volume cancer center revealed 30-day

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mortality rates of 4.9% in the 1980s, 1.5% in the 1990s and 1.3% in the 2000s (2). By the Nationwide Inpatient Sample for 1994-1999 Birkmeyer et al. demonstrated wide variation in perioperative mortality based on hospital volume: 17.6% for low volume compared to 3.8% for high volume (3). Complications after PD affect a large part of patients and include a variety of clinical entities—internal (as pneumonia, cardiovascular events, infection and others) as well as surgical [bleeding, pancreatic fistula (PF), postoperative pancreatitis (PP), infection-sepsis and others]. The high rate of complications is due to multiple factors as comorbidity, technical complexity of the operation, frail patient population and remains as high as 31-60% (4). The aim of this review is to present the occurrence of PF and PP, the possibilities of their differentiation and some aspects of treatment after PD as well as to present some aspects of the possibilities to differentiate PH and PP in our retrospective study.

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Table 1 New classification of pancreatic anastomosis failure (9) Grade

Classification

1

Any deviation from the normal postoperative course without the need for pharmacologic treatment or surgical, endoscopic, and radiologic interventions. Allowed therapeutic regimens include: drugs as antiemetics, antipyretics, analgetics, diuretics, electrolytes, and physiotherapy. This grade of complication applies to patients with fistula whose only change in management other than use of allowed drugs in maintenance of the drain until the fistula has dried up

2

Requiring pharmacological treatment with drugs other than such allowed for grade 1 complications. Blood transfusions and total parenteral nutrition are also included

3

Requiring surgical, endoscopic, or radiologic (invasive) intervention 3a

Intervention not under general anesthesia

3b

Intervention under general anesthesia

4

5

Life-threatening complication (including CNS complications) requiring IC/ICU management 4a

Single organ dysfunction (including dialysis)

4b

Multiorgan dysfunction Death of a patient with PAF

CNS, central nervous system; IC, intermediate care; ICU, intensive care unit; PAF, pancreatic anastomosis failure.

Pancreatic fistula (PF) PF is the most feared complication after PD, being considered the “Achilles’ heel” of this procedure (5). In spite of previous studies with outstanding results with almost no need for reoperation (6), actual rate of PF grade “C”—severe—(7) requiring operative re-intervention varies between 5% and 20% with mortality rate nearly 40% (8). Definition There is no universally accepted definition of PF. Most of them rely on amylase content of the effluent from intraabdominal drain. International study group of PF (ISGPF) organized by Bassi et al. (7) extended definition to standardizing of postoperative treatment by the adoption and by the modification the definition based on clinical impact on the patient hospital course and the outcome and graded PF into A, B, C. The grading was based on nine clinical criteria: patient’s condition, use of specific treatment, US and/or CT findings, persistent drainage >3 weeks, reoperation, signs of infection, sepsis, readmissions and death. Strasberg et al. proposed intraabdominal collection with hemorrhage and peritonitis are also the result of PF (9) (Table 1). Risk factors for PF Multivariate logistic regression analysis showed that none of

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the general risk factors as age, gender, history of jaundice, preoperative nutrition, type of resection and the length of postoperative stay seemed to be associated with PH (10,11). Two intraoperative risk factors—pancreatic duct size and parenchyma texture of the remnant pancreas—were found to be significantly associated with PF. Pancreatic duct size >3 mm means only 4.88% of PF, and 38.1% in pancreatic duct size <3 mm respectively. PH rate was less than 3% in hard pancreatic tissue meanwhile in soft tissue reached more than 32%. French multicentric retrospective survey on PD for ductal adenocarcinoma found that a soft pancreatic parenchyma, the absence of preoperative diabetes, pancreaticojejunostomy and low volume centers were independent risk factors for PF (12). Although anastomotic technique was not a significant factor, PH rate was much less in cases of duct-to-mucosa pancreaticojejunostomy (10,13,14). On the other hand PH risk score for prediction of clinically-relevant PH after PD reflected intraoperative blood loss (13). There are other factors apart from technical consideration, of which increased intraoperative blood loss—more advanced stages of disease requiring portal or superior mesenteric vein resection, patient obesity, jaundice associated coagulopathy and others (11). Moreover careful consideration should be given to the larger pancreatic stumps, wide pancreatic remnant mobilization, and the duct decentralization on the stump in anteroposterior axis (15).

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Preventive measures Occlusion of pancreatic duct To prevent complications following PD especially the development of PF various techniques of managing the pancreatic remnant have been proposed (11). Occlusion of the pancreatic duct (chemical occlusion or simple duct ligation) compared with pancreaticojejunostomy there is no significant difference found in the postoperative complications, mortality and exocrine insufficiency. Moreover there were significantly more patients with diabetes mellitus in the duct occlusion group. So there is no evidence to show that pancreaticojejunostomy can be replaced by pancreatic duct occlusion (16). Pancreaticogastrostomy Four RCTs comparing pancreaticogastrostomy to pancreaticojejunostomy have failed to show any significant difference regarding to PF ratio, postoperative complications or mortality (17-20). The type of anastomotic fashion plays no role for the risk of PF. Results of one RCT has showed significantly lower rate and severity of PF after pancreaticogastrostomy compared to pancreaticojejunostomy (21). A prospective RCT by Bassi et al. revealed no significant difference in PF ratio between duct-to-mucosa anastomosis and single layer end-to-side pancreaticojejunostomy (22). The use of isolated Roux-en-Y pancreaticojejunostomy cannot prevent the development of PF formation (20,23). Total pancreatectomy Total pancreatectomy allows not only more extensive lympfadenectomy and decreases the risk of positive resection margins but also obviates a leak from pancreatic anastomosis. This type of procedures is however associated with the development of diabetes mellitus, decreasing of immunity and loss of pancreatic exocrine function. So indication for total pancreatectomy is not corresponding to routine treatment of localized ductal adenocarcinoma of the head of pancreas (24). Based on the current evidence it is unclear whether drainage of pancreatic duct with a stent (internal or external) can reduce PF rate (25,26). Pharmacologic prevention There were optimistic results of the multicentric study regarding to the role of Octreotide in the prevention of postoperative complications following pancreatic resection

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Ryska and Rudis. Complication of pancreatoduodenectomy

from the 90’s showing reducing of the occurrence of the typical postoperative complications (27). Current singlecenter, randomized, double-blind trial of perioperative subcutaneous pasireotide in patients undergoing either PD or distal pancreatectomy showed similar results. Authors presented that the perioperative treatment with pasireotide decreased the rate of clinically significant postoperative PF, leak, or abscess (28). According to the actual literature the administration of Octreotide by principle is not recommended but only in the case of low consistency pancreatic parenchyma or when intraoperative handling of the pancreatic stump is more aggressive (10). Somatostatin administration may have reduced the pancreas edema, protected the normal tissues and improved the anastomosis quality, but on a daily basis, the abdominal drainage fluid is not affected without any difference between preoperative and postoperative use (29). Moreover there is no statistical difference in the incidence of PF between the patients who received the prophylactic use of octreotide after surgery and the patients who did not somatostatin therapy (30). Drain removal and other preventions There is no standard regarding to the best time when the intraabdominal drain should be removed. The most surgeons indicate drainage removal once the output of amylase-rich fluid is low (31). Until now, there has been no consensus on the optimal timing of the removal of prophylactic drainage after pancreatic surgery in general. The similar situation is associated with poor or no agreement to the type of nutrition, use of antibiotics, imaging strategy and hospital discharge (32). Treatment approaches The current treatment depends on the grade of PF. It is noteworthy that 70% of PH resolves spontaneously (33). The best strategy for the management of PF is still highly debated. Actual rate of PF grade C requiring a relaparotomy varies between 5-20% even in experienced center with mortality rate as high as 39% (4,8). Different strategies include both preservation of the pancreatic remnant and a completion pancreatectomy (34). Pancreatectomy avoids further PF but leads to complete pancreatic insufficiency and to “brittle” diabetes (35). Preserving approach— debridement and drainage of the pancreatic region or resection the dehiscent jejunal loop followed by the occlusion of the main pancreatic duct—is technically easier

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and has the advantage of maintaining pancreatic function but on the other hand leads to the risk of a persistent PH. Balzano et al. presented better results with completion pancreatectomy with splenectomy in the case of PH grade C with autologous islet transplantation reducing the metabolic consequences of total pancreatectomy (36). Moreover there is experience with other methods—the conversion to pancreaticogastrostomy and the bridging stent technique but without evidence whether drainage of the pancreatic duct with a stent can reduce PF rate after PD (37). Finally there is also the experience with resection of dehiscent jejunal loop and drainage of pancreatic region followed by gastrofistulostomy (38). Acute postoperative pancreatitis (PP) PP is a less frequent but very serious surgical complication with often fatal results. It is most often seen following surgery on the pancreas itself, but in rare cases has also been described after surgical procedures on organs very distant from the pancreas. The occurrence of PP according to Carter from 1956 depends upon the following condition (39): mechanical injury direct to the pancreas and especially to the pancreatic ducts, vascular conditions, spasm of the sphincter of Oddi and stagnation of duodenal contents. The incidence of PP reported in the literature is approximately 8-10%, following PD ranges from 1.9-50% (40). But to analyze PP ratio by literature is difficult: PP is mostly not evaluated as a separate complication of PD but in the range of PH (40). Contrary to acute pancreatitis with 5-15% mortality, the mortality of PP is more than 30% (41). Diagnosis PP is clinically defined as abdominal pain which develops during the postoperative course with a concurrent twoto three-fold increase in the levels of specific pancreatic enzymes in the blood. A non-standard postoperative course accompanied by pain, distension of the abdominal muscles, prolonged paralytic ileus and cloudy, often brownish, discharge from the drains may signify developing PP (26,42,43). Evaluation may however be complicated by the development of benign postoperative hyperamylasemia and the subjective perception of postoperative pain. Clinical symptoms may be hidden, especially if the patient remains under analgosedation, or even on artificial lung ventilation, after a long operation with greater blood loss. The first warning sign of the development of PP may be progressive

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circulatory instability, especially in patients with replenished blood supply (26). Early diagnosis of PP based on clinical and laboratory results is very difficult from standard currently performed examinations, as is the evaluation of preoperative findings during reoperation, especially after a longer interval from the primary operation. Nonetheless a similar condition may also be caused by other postoperative complications. In a study by Wilson et al. (44) which clinically evaluated the postoperative course PP was only diagnosed at autopsy in 10 of 11 cases. Operative findings on revision also do not always correlate with the results of laboratory and imaging examinations. Pancreatic leak from PJA or PGA and peripancreatic abscess may be clinical signs of PP. They may however also develop due to technical error during sewing of the anastomosis, where edge necrosis may occur in an otherwise undisturbed glandular parenchyma. During surgical revision in a postoperatively changed terrain, pathological changes in the remaining pancreas and its surroundings are often difficult to evaluate due to signs of superficial tissue digestion and the presence of necrosis, which develop due to digestion by activated pancreatic juice. Postoperative changes in cases of PF may easily be misinterpreted for signs of PP and vice-versa. Regarding laboratory analysis, in addition to values of amylase, lipase and trypsin levels, Büchler et al. also favors analysis of CRP and calcium levels (45). In recent years, diagnosis of PP has most often been reliant on CRP level along with the result of spiral contrast CT examination, where necrotic changes in the parenchyma are evaluated according to the Balthazar classification (46). In accordance with current literary findings, CRP levels best reflect the development and course of the disease. In contrast, CT examination performed prior to surgical revision has not shown to be beneficial in terms of evaluating changes in the pancreatic gland. Treatment approaches PJA disconnection and drainage procedures during surgical revision after PD in cases of PP are usually insufficient and do not lead to a better prognosis. An appropriate, although risky, solution during early revision with suspicion of PP is a completion pancreatectomy with splenectomy. However, after late revisions in an operating field devastated by pancreatitis, the mortality of patients after completion pancreatectomy nears 100%, according to most authors (47,48). Is it desirable to proceed with the completion

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pancreatectomy soon after the primary procedure (34)? However to perform a completion pancreatectomy in a patient with PF type C may be an unwarranted procedure, unjustifiably risky with subsequent significant worsening of quality of life. Early diagnosis of PP may therefore be a key moment in the treatment of PH type C in patients after PD. Base on the current literature, very few firm statements can be made: the criteria for drain removal, imaging strategy and timing of hospital discharge in patients with PF remain unclear (31). In the case of PP after PD treatment strategy is unclear yet and available standard is lacking. Our own experience We retrospectively evaluated the postoperative clinical course, and radiological and laboratory data of 7/160 patients underwent PD in the period of 2007-2011 in our institution for ductal adenocarcinoma of the head of pancreas and died during primary hospitalization because of PF type C with autopsy findings of PP in four cases (49). We compared this group of 4 (2.5%) patients to the group of 10 (6.25%) patients with only a pancreatic leak type C and 12 (7.5%) patients with an uncomplicated clinical course. None of the patients with PP survived. We found significantly higher levels of serum pancreatic amylase on the 1st postoperative day (POD) in 3 of these patients compared to the other groups. Significantly increasing levels of CRP during the first five POD were observed in 75% of these patients. Retrospectively analyzed contrast CT scans up to the 5th POD did not show PP. Only one patient had findings of PP type E according to Balthazar on CT scan performed on the 9th POD. Results commentary A basic aim of our study was to confirm or rule out a diagnosis of PP in the interval from the primary surgical procedure to the surgical revision, with respect to our standard type of surgical procedure (disconnection and closure of the feature stump and peripancreatic drainage). Our retrospective evaluation showed that we were mistaken in almost half of the patients. Subsequent decision to perform a disconnection of the pancreatojejunostomy with drainage of the resected area with planned external PF did not reflect the current view on treatment of this complication. This error, in both diagnosis and type of surgical revision, has also been presented by other authors, who came to very similar conclusions based on retrospective analyses (50,51). Completion pancreatectomy can be of

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significant benefit when performed as soon as possible after diagnosis of potentially fatal PP (52). The longer the interval between primary operation and surgical revision, the lower the chance of performing completion pancreatectomy without endangering the life of the patient. Due to the gradual postoperative development of inflammatory peripancreatic infiltrate, the procedure becomes intolerable for the patient. In any case, the decision to perform completion pancreatectomy is very difficult for the surgeon. In our set of patients who died in direct association with a serious postoperative pancreatic leak from the pancreaticojejunostomy, PP occurred in 4 out of 7 cases (57%) based on autopsy histological findings. All of these patients were suspected of having PP based on macroscopic findings during revision surgery. If we retrospectively evaluate our patient group and our reaction to the obtained values—markers—of PP, it is necessary to state that we rather underestimated the increasing values and was of the opinion that the values reflect developing pancreatic leak and that we have time and will observe the patient. We evidently missed the opportunity to perform early surgical revision and remove the remaining pancreas. Another discovery was the evaluation of the postoperative finding on the remaining pancreas. We attributed superficial necroses to developing PP; autopsy findings, however, did not confirm PP. Evidently these were superficial changes caused by digestion of pancreatic tissue by activated pancreatic juice from PJA dehiscence. In accordance with other authors, we do not consider feature soft biopsy to be of value. Prior CT examinations did not describe structural changes in the pancreas in any of the four cases of autopsyconfirmed PP, not even on retrospective evaluation. The results of our retrospective study confirmed the following: (I) An abrupt increase in values of serum amylase and CRP from the 1st POD to 5th POD is indicative of the development of PP following PD for ductal adenocarcinoma; (II) CT examination may not be beneficial in diagnosing this complication; (III) When life-threatening PP is diagnosed, a completion pancreatectomy is recommended. The decision depends on the surgeon’s experience; (IV) I n some patients, PP may not be confirmed on biopsy or autopsy; changes on the remaining pancreas may only be superficial, caused by digestion of activated pancreatic juice leaking from dehiscence of the pancreaticojejunostomy.

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Cost of pancreatic fistula (PF) Patients who experience any complications after pancreatic surgery are associated with a three-fold increase in costs over those without complications (53). It is of note that one of the most serious postoperative surgical complications is PF type C either as a consequence or independently from PP. The hospital stay of these patients is significantly longer than that of patients without PF (53). A median total cost of the treatment depends on the type of PF: A, B and C—100%, 170%, 620% respectively. There is no significant difference in total cost between patients without PF and with PF type A (54). Conclusions The most serious complication after PD is PF type C, either as a consequence or independently from PP. Differentiating between these two types of complications is difficult. Meantime PF type C is indication to operative revision with mostly drainage procedure which is obviously not much technically demanding, there are no definite guidelines on how to proceed in PP. Therefore the surgeon’s experience determines not only whether PP will be diagnosed early enough and will be differentiated from PF without PP, but also whether a completion pancreatectomy will be performed in indicated cases. Patients who experience any complications after pancreatic surgery are associated with a three-fold increase in costs over those without complications. Acknowledgements Supported by grant IGA MZCR NT 13 263 and by project of MO1012. Disclosure: The authors declare no conflict of interest.

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Cite this article as: Ryska M, Rudis J. Pancreatic fistula and postoperative pancreatitis after pancreatoduodenectomy for pancreatic cancer. Hepatobiliary Surg Nutr 2014;3(5):268-275. doi: 10.3978/j.issn.2304-3881.2014.09.05

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Review Article

Techniques for prevention of pancreatic leak after pancreatectomy Hans F. Schoellhammer, Yuman Fong, Singh Gagandeep Division of Surgical Oncology, Department of Surgery; City of Hope National Medical Center, Duarte, CA, USA Correspondence to: Singh Gagandeep, MD. Clinical Professor of Surgery; Head, Hepatobiliary and Pancreatic Surgery; Chief, Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Email: [email protected].

Abstract: Pancreatic resections are some of the most technically challenging operations performed by surgeons, and post-operative pancreatic fistula (POPF) are not uncommon, developing in approximately 13% of pancreaticoduodenectomies and 30% of distal pancreatectomies. Multiple trials of various operative techniques in the creation of the pancreatic ductal anastomosis have been conducted throughout the years, and herein we review the literature and outcomes data regarding these techniques, although no one technique of pancreatic ductal anastomosis has been shown to be superior in decreasing rate of POPF. Similarly, we review the literature regarding techniques of pancreatic closure after distal pancreatectomy. Again, no one technique has been shown to be superior in preventing POPF; however the use of buttressing material on the pancreatic staple line in the future may be a successful means of decreasing POPF. We review adjunctive techniques to decrease POPF such as pancreatic ductal stenting, the use of various topical biologic glues, and the use of somatostatin analogue medications. We conclude that future trials will need to be conducted to find optimal techniques to decrease POPF, and meticulous attention to intra-operative details and post-operative care by surgeons is necessary to prevent POPF and optimally care for patients undergoing pancreatic resection. Keywords: Pancreaticoduodenectomy; distal pancreatectomy; pancreatic leak; post-operative pancreatic fistula (POPF); prevention Submitted Aug 08, 2014. Accepted for publication Aug 21, 2014. doi: 10.3978/j.issn.2304-3881.2014.08.08 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.08.08

Introduction Pancreatic resections, whether for benign or malignant disease processes, are some of the most technically challenging operations performed by surgeons. After pancreatic resection the potential for the development of serious complications exists. One of the most serious complications after pancreatic resection is the development of a post-operative pancreatic leak or fistula, whereby digestive pancreatic enzymes leak out of the pancreatic ductal system via an abnormal connection into the peripancreatic space or the peritoneal cavity, with resulting morbidity such as abdominal pain, ileus, fever, and the possibility of abscess, sepsis, and hemorrhage and consequently prolonged hospitalization. Importantly, patients with post-operative pancreatic fistula (POPF),

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leak, or abscess have been found to have a 90-day mortality of 5% in a single-institution report of pancreatectomy outcomes prospectively-collected over a five-year period (1). The magnitude of this complication is not insignificant; in a large worldwide literature search, the incidence of pancreatic fistula after pancreaticoduodenectomy was found to be 12.9% and 13% after distal pancreatectomy (2), and other reports detail fistula rates up to 31% for distal pancreatectomies (3). Given the need to decrease the incidence of POPF as well as the resulting significant morbidity and mortality, various techniques have been attempted to prevent the formation of pancreatic leak and fistula. In this report we review techniques for the prevention of pancreatic leak after pancreatectomy.

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Definition A POPF is any abnormal connection between the pancreatic ductal system and the peri-pancreatic space, the peritoneal cavity or other body cavities, or externally to the skin. Leakage of enzyme-rich pancreatic fluid is typically diagnosed in the post-operative period via percutaneous drainage of a fluid collection that is found to be high in amylase content or via continued drainage of amylaserich fluid through a drain placed at the time of surgery. In the past, varying criteria for what constitutes POPF have been published in the literature; however in an attempt to standardize the definition of POPF an international study group (ISGPF) of pancreatic surgeons convened in 2005 (4). POPF was thus defined as drain output of any volume occurring on or after post-operative day 3 with amylase content at least three times that of serum amylase levels. In order to standardize the reporting of POPF outcomes, the authors also defined three grades of POPF: Grade A is a transient fistula that does not have any clinical impact, does not delay hospital discharge, and is managed by slow removal of peri-pancreatic drains. Grade B POPF requires a change in clinical management, such as making the patient NPO, administering TPN, or re-positioning drains, and leads to a delay in hospital discharge or to a readmission. Grade C POPF is the most severe and requires a major change in clinical management such as ICU-level care, percutaneous drainage of undrained fluid collections, or operative re-exploration for further drainage or attempted anastomotic repair. Grade C POPF causes a major increase in hospitalization time as well as increased rates of complications and the possibility of mortality (4). Techniques to prevent pancreatic leak Multiple trials using various operative techniques and pharmacologic agents have been conducted to evaluate for a decrease in or prevention of POPF. Herein we review the literature on techniques to decrease POPF. Operative anastomotic construction techniques Historical technique: ligation of the pancreatic duct Historically the creation of a pancreatic-enteric anastomosis after pancreaticoduodenectomy was fraught with leak and complications, and thus some authors advocated simply ligating the pancreatic duct without re-creating continuity to the GI tract as a means of fistula prevention. Brunschwig

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reported on three cases of pancreatic duct ligation all without fistula creation in 1952 (5), and in a large report by Goldsmith and colleagues the POPF rate was equivalent between 45 patients treated with pancreatic duct ligation and 34 treated with anastomosis to the jejunum (6). Pancreatic endocrine dysfunction in the form of diabetes may develop after pancreatic duct ligation (7), and since approximately 1975 pancreatic duct ligation has been abandoned in favor of re-establishment of continuity of the pancreatic duct to the intestines (8,9). Pancreaticojejunostomy (PJ) anastomotic techniques Multiple techniques in anastomosing the pancreatic duct to the gastrointestinal (GI) tract after pancreaticoduodenectomy have been described in the literature. Two of the predominant methods of creating a PJ are an end-to-side duct-to-mucosa anastomosis or the invagination technique. Briefly, in the end-to-side duct-to-mucosa anastomotic technique, the jejunal limb is brought into the retroperitoneum adjacent to the pancreas in a retrocolic fashion. A two-layer anastomosis is constructed with interrupted absorbable suture material, beginning with a posterior row of seromuscular sutures securing the jejunum to the pancreas (Figure 1). The pancreatic duct-to-mucosa anastomosis is performed to an enterotomy in the jejunum with a second circumferential layer of interrupted sutures, taking generous amounts of pancreas and the full-thickness of the jejunum, followed by completion of an anterior layer of seromuscular sutures again securing the anterior aspect of the opened jejunum to the capsule of the pancreas. In a report by Z’graggen and colleagues using this technique, POPF was seen in 2.1% of 331 patients who underwent pancreatic head resection (10). The goal of creating an invagination PJ is to invaginate or “dunk” all of the cut edge of the pancreatic parenchyma into the lumen of the jejunum (11). The performance of invagination PJ anastomosis begins with a posterior row of interrupted seromuscular sutures bringing the jejunum into apposition with the pancreatic capsule (Figure 2). The jejunum is opened, and an inner layer of running locking suture is then performed taking full-thickness jejunal bites and large bites of the pancreatic parenchyma and capsule, but not of the pancreatic duct, with the goal of invaginating all of the cut edge of the pancreatic tissue into the jejunum. An anterior layer of seromuscular sutures rolling the jejunum onto the pancreatic capsule is then performed to complete the anastomosis. Berger and colleagues sought to compare rates of

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Schoellhammer et al. Techniques to prevent pancreatic leak

Figure 1 Duct-to-mucosa pancreaticojejunostomy.

Figure 2 Invagination pancreaticojejunostomy.

POPF at the PJ with the use of the invagination technique versus the duct-to-mucosa technique to test the hypothesis that use of the duct-to-mucosa technique would lead to a decreased POPF rate (12). To this end the authors performed a randomized prospective clinical trial at two institutions and randomized 197 patients undergoing pancreaticoduodenectomy to the invagination or the ductto-mucosa technique; patients were stratified in both groups by whether the pancreatic parenchyma was hard or soft. POPF occurred in 17.8% of all patients, with significantly more POPF seen in the duct-to-mucosa group compared with the invagination group (24% vs. 12%, P<0.05) and with

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more POPF in soft glands (27%) than in hard glands (8%). The authors concluded that the pancreatic texture was the greatest determinant in POPF and that further studies are needed to determine the optimal anastomotic technique. Modified duct-to-mucosa PJ One variation of the duct-to-mucosa technique that bears noting is the transpancreatic U-suture technique with a ductto-mucosa anastomosis described by Grobmyer, Blumgart, and colleagues at Memorial Sloan Kettering Cancer Center and originally created by Dr. Leslie Blumgart (13).

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Figure 3 Modified duct-to-mucosa pancreaticojejunostomy—Blumgart anastomosis.

In this technique an outer layer of polyglactin sutures are first inserted full-thickness anterior-to-posterior through the pancreas with subsequent seromuscular horizontal mattress stitches on the jejunum, followed again by a fullthickness posterior-to-anterior bite coming up through the pancreas (Figure 3). Care is taken not to pass the needle through the pancreatic duct. The u-stitches are not tied yet, and a duct-to-mucosa anastomosis is then created with fine polydioxanone interrupted suture. The seromuscular sutures are then tied bringing the jejunum into close apposition anteriorly on the pancreas; however the suture is not yet cut. Lastly, the sutures with the needles still on are used to create an anterior seromuscular bite on the jejunum with the needle being brought through the pancreas under the previous knots. The sutures are then tied again, thus imbricating the jejunum over the entire pancreas. In an audit of 187 patients with PJ anastomoses constructed by this technique, the authors report an overall POPF rate of 20.3%; however most of these were ISPGF Grade A, with only 6.9% of patients with Grade B or C POPF. Soft pancreatic texture was significantly associated with leak, and patients with POPF had significantly smaller diameter pancreatic ducts compared with patients without POPF (3 vs. 4 mm, P=0.008). Kleespies and colleagues published their outcomes data using what they call the “Blumgart anastomosis” after their department began to use this technique for PJ and abandoned the traditional duct-to-mucosa technique (14). They found significantly decreased leak rate with the Blumgart anastomosis (13% vs. 4%, P=0.032), as well as significantly decreased rates of postoperative hemorrhage,

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complications, and length of ICU stay. Proponents of this technique argue that the transpancreatic sutures minimize radial forces on the anastomosis, and that it is relatively quick to construct and easy to teach to trainees. Binding technique for PJ creation Another technique for creating the PJ anastomosis is the socalled “binding” PJ reported by Peng and colleagues (15), in which the distal 3 cm of the jejunal loop to be used for anastomosis are everted and the mucosa ablated either by electrocoagulation or by topical treatment with 10% carbolic acid followed by immediate rinsing in 75% ethanol and normal saline (Figure 4). The proximal 3 cm of the pancreatic stump is then anastomosed to just the mucosa of the jejunum. The treated 3 cm of jejunum are then rolled out and intussuscepted back over the pancreas, sutured into place, and lastly a catgut tie is looped around the entire circumference of the anastomosis 1 cm from the cut edge of the pancreas. The authors reported a 0% POPF rate after the completion of 150 cases using this anastomosis, with an overall morbidity of 31.3% and a mean hospital stay of 19.8±5 days (16). A subsequent prospective trial conducted by Peng and colleagues randomized 217 patients undergoing pancreaticoduodenectomy to traditional PJ anastomosis or binding PJ anastomosis (17). Leak was seen in 8 of 111 (7.2%) conventional PJ patients compared with 0 of 106 binding PJ patients (P=0.014), and complications were reported in 36.9% of conventional PJ patients compared with 24.5% of binding PJ patients (P=0.048), including 6.3%

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A

B

C

Figure 4 Binding pancreaticojejunostomy.

Figure 5 Pancreaticogastrostomy.

perioperative mortality in the conventional group and 2.8% mortality in the binding group (P=NS). Subsequent trials of binding PJ conducted in Europe have not replicated the impressive rate of POPF. A case-control study 22 binding PJ and 25 conventional PJ patients found no difference in the rate of POPF, with longer delay in POPF healing as well as increased postpancreatectomy hemorrhage in the binding group (18). Similarly, a recent prospective twoinstitution trial of 69 binding PJ patients compared to 52 conventional PJ historical control patients demonstrated significantly shorter hospital stay in the conventional PJ patients. Soft pancreatic texture was significantly associated with POPF; however no significant difference in the rate of POPF between binding and conventional PJ anastomoses was seen (19). Binding PJ remains one of many options for creation of the pancreatic-enteric anastomosis. Pancreaticogastrostomy (PG) creation The creation of pancreatic duct anastomosis to the stomach PG instead of to the jejunum has been studied as well, with

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the rationale that a PG anastomosis is easier to perform and that the stomach has a more robust blood supply compared with the jejunum. Additional rationale for PG instead of PJ in the case of pancreatic head resections that extend to the left past the midline is that the increase in distance may put the resulting jejunal limb and jejunal anastomosis under tension, with increased risk for subsequent leak; however after such a resection the stomach will be immediately adjacent to the remnant pancreas with the opportunity to create a tension-free PG anastomosis (Figure 5). In evaluating PG, an earlier report by Delcore and colleagues demonstrated no leaks of the PG anastomosis in 45 cases (20), and a 0% leak rate over 38 cases was also reported by Mason et al. (21). PG was later compared to PJ anastomosis in a prospective randomized trial conducted by Bassi and coworkers, in which 151 patients with soft pancreatic glands were randomized to PG or end-to-side PJ anastomoses (22). Pancreatic fistula occurred in 13% of PG patients and 16% of PJ (P=NS); however post-operative fluid collections, delayed gastric emptying, and biliary fistulae were significantly less in the PG group. A similar trial was conducted by Duffas

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et al. who randomized 81 patients to PG and 68 patients to PJ after pancreaticoduodenectomy and found POPF in 16% of the PG group and 20% of the PJ group (23). The authors concluded that the type of anastomosis does not influence the development of POPF, and a meta-analysis of PG versus PJ trials noted that there was no superiority of either technique and surgeons should continue to use the technique with which they are most familiar (24). Interestingly, a recent prospective randomized multi-center trial by Topal and colleagues from Belgium randomizing 329 patients to PJ or PG after pancreaticoduodenectomy, in which patients were stratified by pancreatic duct diameter (≤3 or >3 mm), reported significantly more POPF in the PJ group than the PG group (19.8% vs. 8%, OR 2.86, 95% CI: 1.38-6.17, P=0.002) (25). The authors concluded that PG should be the preferred anastomosis after pancreaticoduodenectomy, although further data from a multi-center international trial will be needed to confirm this. Pancreatic duct anastomotic stenting Pancreatic duct stenting at the time of anastomosis creation has been proposed as a technique to decrease pancreatic leak and fistula, with the rationale that stenting prevents the accumulation of pancreatic secretions in the pancreatic stump and the pancreatic anastomosis is excluded from direct contact with the pancreatic juice (26). This was examined in a randomized trial by Winter and colleagues who randomized 238 patients undergoing pancreaticoduodenectomy to internal pancreatic duct stent or no-stent with the endpoint of POPF development (27). Patients were stratified by the texture of the pancreatic remnant (soft vs. normal/hard), with 6 cm pediatric feeding tubes were used as stents. In the hard pancreas group 1.7% stent patients and 4.8% non-stent patients developed POPF (P=0.4), and in the soft pancreas group 21.1% stent patients and 10.7% non-stent patients developed POPF (P=0.1) with the conclusion that internal pancreatic duct stenting does not alter the rate of POPF. Pancreatic duct drainage with external rather than stents has also been studied. In a study from Hong Kong in 2007, Poon et al. prospectively randomized 120 patients undergoing pancreaticoduodenectomy with PJ duct-tomucosa anastomosis to an external stent or not (28). Patients in the stented group had a significantly lower pancreatic fistula rate compared with the no stent group (6.7% vs. 20%, P=0.032), and on multivariable analysis absence of stenting was a significant risk factor for POPF. The authors

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hypothesized that use of external drains more completely diverts pancreatic secretions away from the PJ anastomosis with decreased risk for leak formation. A recent Cochrane Review also examined the efficacy of pancreatic stents in preventing POPF after pancreaticoduodenectomy in a review of randomly controlled trials extracted the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Excerpta Medica database (EMBASE), Web of Science, and other major trials databases (29). A total of 655 patients were included in the systematic review, and the authors found that the use of external, but not internal stents was associated with a significant decrease in the incidence of POPF (RR 0.33, 95% CI: 0.11-0.98, P=0.002). These results are echoed by another systematic review of the literature and metaanalysis performed by Xiong and colleagues, who examined the literature from January 1973 to September 2011 and included 1,726 patients from five randomized clinical trials and 11 non-randomized clinical observation studies in their analysis (30). The authors found that placement of internal or external stents in the pancreatic duct after pancreaticoduodenectomy did not reduce the incidence of POPF; however on subgroup analysis placement of external stents significantly reduced the incidence of POPF compared with no stent (OR 0.42, 95% CI: 0.24-0.76, P=0.004 for randomized clinical trials and OR 0.43, 95% CI: 0.27-0.68, P<0.001 for observational studies). These recent data suggest that if one intends to stent the pancreatic anastomosis, an external stent should be considered; however more data are needed to suggest routine use of pancreatic stents, and many centers have moved away from the use of pancreatic duct stents completely. Pancreatic stump closure after distal pancreatectomy Pancreatic leak after distal pancreatectomy occurs in approximately 30% of patients (31,32), which is a rate higher than is seen in pancreaticoduodenectomy. Many studies have been conducted to determine the optimal method for closing the pancreatic stump in order to prevent POPF. The two main techniques for closure of the pancreatic stump after distal pancreatectomy are suture closure of the pancreatic duct or stapled closure of the parenchyma. A previous retrospective report by Bilimoria et al. in which the authors reviewed their institutional data of 126 patients who underwent distal pancreatectomy over a nine year period found that POPF rates in patients

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who underwent suture closure of the pancreatic duct was significantly lower than patients who did not undergo suture closure (9.6% vs. 34%, P<0.001) (33). On multivariable analysis, failure to ligate the duct was significantly associated with pancreatic leak (OR 5, 95% CI: 2-10, P=0.001). The other most prominent technique for pancreatic transection is to use a surgical stapler. A meta-analysis conducted by Knaebel and co-workers in 2005 examined ten articles in the world literature (two randomized trials and eight observational studies) that reported techniques to decrease POPF after distal pancreatectomy (34). Six of the ten studies compared hand-sutured versus stapled pancreatic closure, and in this analysis the authors found a trend towards decreased POPF with the use of staplers; however the results were not statistically significant (OR 0.66, 95% CI: 0.35-1.26, P=0.21). Given this trend towards decreased POPF with stapled closure, Diener and colleagues designed the multicenter prospective DISPACT trial in which patients undergoing distal pancreatectomy were randomized to stapler or hand-sewn closure with the primary outcomes of POPF and mortality at one week; the authors hypothesized that standardized closure with a stapler would lead to decreased POPF (35). Of 450 patients randomized, 352 were included in the final analysis (175 hand-sewn, 177 stapler). The rate of POPF in the stapler group was 32% compared with 28% in the hand-sewn group, without any significant difference between the two groups (OR 0.84, 95% CI: 0.53-1.33, P=0.56). There was one death in the hand-sewn group and none in the stapler group. The authors concluded that stapled closure was not superior to hand-sewn closure for preventing POPF, and indeed the data demonstrate that these methods of closure have equivalent POPF rates. Given this equivalency, other methods to decrease POPF have been investigated. A prospective randomized trial of prophylactic pancreatic duct stenting to decrease POPF was conducted by Frozanpor et al. with the hypothesis that more efficient diversion of pancreatic secretions into the duodenum away from the pancreatic transection line would lead to decreased POPF (36). A total of 58 patients were analyzed (29 distal pancreatectomy only, 29 distal pancreatectomy with stent); the rate of ISGPF Grade B/C POPF was 42.3% in the stent group and 22.2% in the nostent group without a significant difference between the two (OR 2.57, 95% CI: 0.78-8.48, P=0.122). Decreasing resistance across the sphincter of Oddi with stenting does not appear to have a role in decreasing POPF rates. Various methods of reinforcing the staple line after

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Schoellhammer et al. Techniques to prevent pancreatic leak

distal pancreatectomy have been attempted as a means of decreasing leak. In a small non-randomized singleinstitution trial, Jimenez and colleagues reported rates of POPF with stapled pancreatic stump closure reinforced with bioabsorbable buttress sleeves mounted on the stapler and compared a group of 13 patients treated in this manner with 18 historical controls (37). Rates of POPF were 0% in the buttress group versus 39% in the control group (P=0.025). A similar single-institution report from Thaker and others of 40 patients undergoing distal pancreatectomy and bioabsorbable mesh buttress staple line reinforcement with comparison to 40 historical controls of only stapled closure found significantly decreased rate of POPF with mesh reinforcement (3.5%) compared with staple closure only (22%, P=0.04) (38). In a subsequent single-institution randomized prospective trial of stapled pancreatic closure with or without bioabsorbable mesh staple line reinforcement, Hamilton et al. found significantly fewer ISGPF Grade B/C leaks in 1/53 (1.9%) mesh reinforcement patients compared with 11/45 (20%) no-mesh patients (P=0.007) (39). Currently it appears that reinforcement of the pancreatic staple line with a bioabsorbable mesh is a feasible method of decreasing POPF; however the previous single-institution results still require confirmation in the form of multi-institution prospective randomized trials, preferably with international collaboration. Just as the rigorous methodology of the DISPACT trial appears to have provided a definitive answer to the question of stapled or hand-sewn closure, so is there a need for this methodology regarding the question of bioabsorbable mesh reinforcement. Use of fibrin glue and other topical sealant agents The use of fibrin glue and other topical hemostatic agents applied to the pancreato-enteric anastomosis have been proposed as adjuncts to help seal the anastomosis and prevent POPF; however results have been disappointing. In a report from 1991, Kram and colleagues used fibrin glue made from concentrated fibrinogen and clotting factors which was applied topically to pancreatic wounds, staple/ suture lines, and pancreatic anastomoses in both trauma and non-trauma operations; the authors reported no pancreatic fistulae, abscesses, or pseudocysts in their series of 15 patients (40). In an early prospectively randomized trial reported in 1994 by D’Andrea, 97 patients undergoing pancreatectomy for both benign and malignant conditions

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were enrolled and randomized to intraoperative fibrin sealing of the pancreas or to no sealing (41). Pancreatic fistulae developed in 13.9% of the fibrin glue patients and in 11.1% of the non-fibrin glue patients, with no significant difference seen between in two groups. In a larger prospective randomized trial of fibrin glue conducted by Lillemoe et al., the authors randomized 125 patients, who were felt to be at high risk for pancreatic leak after pancreaticoduodenectomy by their operating surgeon, to either topical application of fibrin glue to the PJ anastomosis (59 patients) versus no glue (66 patients) (42). The rate of POPF was 26% in the glue arm versus 30% in the control group (P=NS), and there was no difference in length of hospital stay between the groups as well. The authors concluded that the use of fibrin glue did not decrease the rate of POPF or of other complications following pancreaticoduodenectomy. A recent large metaanalysis evaluating the effectiveness of fibrin sealants in pancreatic surgery systematically evaluated seven studies including 897 patients and found that fibrin sealants had a non-significant impact on the development of POPF (43). The authors concluded that fibrin sealants cannot be recommended routinely in the setting of pancreatic resection. Internal occlusion of the pancreatic duct with absorbable fibrin glue after creation of a pancreatic duct anastomosis has been proposed as a way to allow the anastomosis to heal without being exposed to the enzyme-rich pancreatic fluid, although early prospective non-randomized trials did not demonstrate a decrease in POPF (44). To address this, Suc and colleagues conducted a multi-institution, single-blind, prospective randomized trial in France of pancreatic resection with or without fibrin glue occlusion of the pancreatic duct occlusion (45). The authors report an overall POPF rate of 16% in their trial; however no difference in POPF rate was seen when comparing the fibrin glue to the control group. Fibrin glue occlusion of the pancreatic duct appears to have no impact on the development of POPF. Use of somatostatin analogues The inhibitory peptide hormone somatostatin acts to decrease the output of secretions from the pancreas, GI tract, and biliary tract, although the half-life is short at approximately two minutes (46). Synthetic analogues of somatostatin with longer half-lives, such as octreotide (47), have been developed and have been used in pancreatic surgery

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in an attempt to decrease POPF, with the hypothesis that decreased pancreatic juice secretion will allow for improved healing of pancreatic ductal anastomoses and consequently decreased leak rates. The use of octreotide has been studied in multiple randomized prospective trials in the United States and Europe; however the results have been mixed. Yeo and colleagues conducted a prospective trial in which patients undergoing pancreaticoduodenectomy were randomized to saline control or octreotide 250 μg subcutaneously every eight hours beginning 1-2 hours before surgery and continuing for seven days (48). Ultimately 211 patients made up the entire study cohort; POPF was seen in 9% of control group and 11% of octreotide group. The authors concluded that octreotide does not reduce incidence of POPF and that omission of this treatment may lead to a cost savings for hospitals. Sarr and co-investigators in the Pancreatic Study Group conducted a prospective, randomized, placebo-controlled trial of the long-acting somatostatin analogue vapreotide, hypothesizing that vapreotide would decrease pancreas-related complications; 135 patients received vapreotide and 140 received placebo (49). No significant differences were seen in pancreas-related complications between the two groups (placebo 26.4% vs. vapreotide 30.4%, P=NS), and the authors concluded that vapreotide offers no therapeutic benefit in terms of postoperative complications. Suc et al. conducted a French multi-center prospective randomized trial in 230 patients undergoing pancreatectomy, with 122 patients randomized to octreotide and 108 randomized to the control arm; the primary endpoint was all intra-abdominal complications (50). Intra-abdominal complications were seen in 22% of octreotide patients versus 32% of placebo patients; however this result was not statistically significant and the authors concluded that octreotide cannot be routinely used to decrease intra-abdominal complications in pancreatectomy patients. Recently, Allen and colleagues reported their results of a single-center, prospective, double-blind, placebo controlled trial using the long-acting somatostatin analogue pasireotide, which has a longer half-life than octreotide as well as a broader receptor binding profile (51). Patients undergoing pancreaticoduodenectomy or distal pancreatectomy were randomized to pasireotide 900 μg subcutaneously given twice daily beginning the morning of operation for seven days (152 patients) or to placebo (148 patients). The primary endpoint was incidence of grade 3 pancreatic leak, fistula, or abscess; grade 3 indicating that a radiologic, endoscopic, or surgical intervention was required, and

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Table 1 Selected trials performed to evaluate rates of POPF Study

Trial arm(s)

Berger, 2009

Duct-to-mucosa

Fistula (%)

Conclusion

100

N

12 (12%)

Fewer POPF in invagination group

97

23 (24%)

Pancreaticojejunostomy (PJ) Invagination PJ Grobmyer, 2010 Modified duct-to-mucosa PJ

187

13 (6.7%) Grade B/C

(Blumgart anastomosis) Kleespies, 2009 Duct-to-mucosa PJ

90

12 (13%)

92

4 (4%)

Fewer POPF with use of Blumgart anastomosis

Modified duct-to-mucosa PJ (Blumgart anastomosis) Peng, 2007

Binding PJ

111

0

Fewer POPF in binding group

Invagination PJ

106

8 (7.5%)

Maggiori, 2010

Binding PJ

22

8 (36%)

Invagination PJ

25

7 (28%)

Bassi, 2005

Pancreaticogastrostomy (PG)

69

9 (13%)

PJ

82

13 (16%)

Topal, 2013

PG

167

13 (8%)

PJ

162

33 (19.8%)

Winter, 2006

Pancreatic duct stent

58

Hard pancreas 1.7%,

No stent

63

Hard pancreas 4.8%,

No POPF difference with use of binding PJ No difference in POPF rates PG decreases POPF rate No difference in POPF rates

soft pancreas 21.1% soft pancreas 10.7% Poon, 2007

External pancreatic duct stent

Diener, 2011

Stapled distal pancreatectomy

175

32%

Hand-sewn distal pancreatectomy

177

28%

Yeo, 2000

Octreotide

104

11 (9%)

No octreotide

107

10 (11%)

Allen, 2014

Pasireotide

152

9%

No pasireotide

148

21%

No stent

60

4 (6.7%)

60

12 (20%)

External stent decreases POPF No difference in POPF rates No difference in POPF rates Pasireotide decrease POPF rates

POPF, post-operative pancreatic fistula.

the secondary endpoint was Grade B or C POPF. In total 15% of patients met the primary endpoint; however the primary endpoint was significantly less in the pasireotide group compared with placebo (9% vs. 21%, RR 0.44, 95% CI: 0.24-0.78, P=0.006). In the pasireotide group 7.9% of patients had Grade B POPF, and zero had Grade C, compared with 16.9% Grade B/C in the placebo group, P=0.02; rates of adverse events were similar between the two groups. Pasireotide significantly reduced risk of postoperative fistula/leak/abscess, and may have a role in the prevention of POPF in the future.

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Conclusions Post-operative pancreatic leak and fistula are a major source of morbidity and mortality after pancreatic resection. Many trials have been undertaken to identify techniques to reduce POPF (Table 1); however no one technique has been shown to definitively be the solution to the problem, and indeed one of the major determinants of POPF is a factor over which the surgeon has very little control, i.e., the consistency of the pancreatic parenchyma itself. Surgeons should continue to use the pancreatic duct

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anastomotic technique with which they are most familiar and comfortable, and currently there is no evidence for routine use of stents or topical sealing products. For closure of the pancreatic stump after distal pancreatectomy, a stapled closure in combination with bioabsorbable mesh buttress may represent a reliable technique to decrease POPF; however high-quality data from multi-institutional prospective trials are currently lacking. In the future, novel somatostatin analogues may play a role in decreasing POPF, but without question meticulous surgical technique and attention to detail will remain the cornerstones of decreasing pancreatic leak and patient morbidity/mortality.

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9.

10.

11.

12.

Acknowledgements Disclosure: The authors declare no conflict of interest. 13.

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Schoellhammer et al. Techniques to prevent pancreatic leak

34. Knaebel HP, Diener MK, Wente MN, et al. Systematic review and meta-analysis of technique for closure of the pancreatic remnant after distal pancreatectomy. Br J Surg 2005;92:539-46. 35. Diener MK, Seiler CM, Rossion I, et al. Efficacy of stapler versus hand-sewn closure after distal pancreatectomy (DISPACT): a randomised, controlled multicentre trial. Lancet 2011;377:1514-22. 36. Frozanpor F, Lundell L, Segersvärd R, et al. The effect of prophylactic transpapillary pancreatic stent insertion on clinically significant leak rate following distal pancreatectomy: results of a prospective controlled clinical trial. Ann Surg 2012;255:1032-6. 37. Jimenez RE, Mavanur A, Macaulay WP. Staple line reinforcement reduces postoperative pancreatic stump leak after distal pancreatectomy. J Gastrointest Surg 2007;11:345-9. 38. Thaker RI, Matthews BD, Linehan DC, et al. Absorbable mesh reinforcement of a stapled pancreatic transection line reduces the leak rate with distal pancreatectomy. J Gastrointest Surg 2007;11:59-65. 39. Hamilton NA, Porembka MR, Johnston FM, et al. Mesh reinforcement of pancreatic transection decreases incidence of pancreatic occlusion failure for left pancreatectomy: a single-blinded, randomized controlled trial. Ann Surg 2012;255:1037-42. 40. Kram HB, Clark SR, Ocampo HP, et al. Fibrin glue sealing of pancreatic injuries, resections, and anastomoses. Am J Surg 1991;161:479-81; discussion 482. 41. D’Andrea AA, Costantino V, Sperti C, et al. Human fibrin sealant in pancreatic surgery: it is useful in preventing fistulas? A prospective randomized study. Ital J Gastroenterol 1994;26:283-6. 42. Lillemoe KD, Cameron JL, Kim MP, et al. Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial. J Gastrointest Surg 2004;8:766-72; discussion 772-4. 43. Orci LA, Oldani G, Berney T, et al. Systematic review and meta-analysis of fibrin sealants for patients undergoing pancreatic resection. HPB (Oxford) 2014;16:3-11. 44. Lorenz D, Wolff H, Waclawiczek H. Pancreatic duct occlusion in resection treatment of chronic pancreatitis and cancer of the head of the pancreas. A 3-year follow-up study. Chirurg 1988;59:90-5. 45. Suc B, Msika S, Fingerhut A, et al. Temporary fibrin glue occlusion of the main pancreatic duct in the prevention of intra-abdominal complications after pancreatic resection:

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prospective randomized trial. Ann Surg 2003;237:57-65. 46. Raptis S, Schlegel W, Lehmann E, et al. Effects of somatostatin on the exocrine pancreas and the release of duodenal hormones. Metabolism 1978;27:1321-8. 47. Meier R, Dierdorf R, Gyr K. Somatostatin analog (octreotide) in clinical use: current and potential indications. Schweiz Med Wochenschr 1992;122:957-68. 48. Yeo CJ, Cameron JL, Lillemoe KD, et al. Does prophylactic octreotide decrease the rates of pancreatic fistula and other complications after pancreaticoduodenectomy? Results of a prospective randomized placebo-controlled trial. Ann Surg 2000;232:419-29. 49. Sarr MG, Pancreatic Surgery Group. The potent

somatostatin analogue vapreotide does not decrease pancreas-specific complications after elective pancreatectomy: a prospective, multicenter, doubleblinded, randomized, placebo-controlled trial. J Am Coll Surg 2003;196:556-64; discussion 564-5; author reply 565. 50. Suc B, Msika S, Piccinini M, et al. Octreotide in the prevention of intra-abdominal complications following elective pancreatic resection: a prospective, multicenter randomized controlled trial. Arch Surg 2004;139:288-94; discussion 295. 51. Allen PJ, Gönen M, Brennan MF, et al. Pasireotide for postoperative pancreatic fistula. N Engl J Med 2014;370:2014-22.

Cite this article as: Schoellhammer HF, Fong Y, Gagandeep S. Techniques for prevention of pancreatic leak after pancreatectomy. Hepatobiliary Surg Nutr 2014;3(5):276-287. doi: 10.3978/j.issn.2304-3881.2014.08.08

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Review Article

Robotic liver surgery Universe Leung1, Yuman Fong2 1

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Department of Surgery, City of Hope Medical Center,

Duarte, CA, USA Correspondence to: Dr. Yuman Fong. City of Hope Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Email: [email protected].

Abstract: Robotic surgery is an evolving technology that has been successfully applied to a number of surgical specialties, but its use in liver surgery has so far been limited. In this review article we discuss the challenges of minimally invasive liver surgery, the pros and cons of robotics, the evolution of medical robots, and the potentials in applying this technology to liver surgery. The current data in the literature are also presented. Keywords: Robotics; hepatectomy; minimally invasive surgery Submitted Aug 17, 2014. Accepted for publication Aug 29, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.02 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.02

Overview of minimally invasive liver surgery Liver resection, once regarded as an operation with prohibitively high mortality and morbidity, has now become a routine operation in expert hands. As laparoscopic techniques for other major abdominal operations such as splenectomy, colectomy, and fundoplication have matured, the interest in applying minimally invasive techniques to liver resection also developed. Technical developments such as more sophisticated energy devices and articulated laparoscopic staplers have enabled surgeons to tackle liver resection laparoscopically. Some of the major technical challenges in liver surgery include the difficult access to the vena cava and major hepatic veins, precision required for dissection at the hilum, and propensity for the liver to bleed. These are made more difficult with laparoscopy due to the limitations in depth perception, restricted movement by rigid instruments and fixed fulcrum at the ports, unnatural ergonomics, and difficult suturing particularly in presence of hemorrhage. There is a steep learning curve making its practice outside high-volume centers difficult. As a result, the uptake of minimally invasive hepatectomy has been slow and cautious. But with increasing experience, surgeons have gradually increased the difficulty and complexity of surgery, from staging and deroofing cysts initially, to resecting readily accessible parts of the liver

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such as the lateral sector and wedge resections from the anteroinferior segments, to major hepatectomies (1). However, certain scenarios are still considered prohibitively challenging, such the presence of extensive adhesions, resection of the caudate or posteriorly placed tumors, and bile duct resection and reconstruction. In 2008, a panel of 45 international experts on laparoscopic liver surgery gathered in Louisville, Kentucky to discuss the state of the art. There was a consensus that the best indications for laparoscopic resection are in patients with solitary lesions, 5 cm or less, located in segments 2 to 6 (2). Of note, the participants of this consensus conference recommended against routine laparoscopic resection of segments 7, 8, 1. This is due to difficulties in visualizing and working in these areas of the liver with straight laparoscopic instruments. Single incision laparoscopic surgery (SILS) has been touted as the next stage in minimally invasive surgery with enhanced cosmesis and possibly recovery compared to conventional laparoscopic surgery. Small series of singleport laparoscopic hepatectomy have been published showing its feasibility (3,4). However, limited views, clashing of the surgeons’ hands, “sword-fighting” of instruments and inability to triangulate remain significant limitations. Attempts have been made to reduce collision by creating articulated instruments, however they may need to be used cross-handed, an unnatural and un-ergonomical operating position (5).

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in complex surgery is the shorter learning curve compared with conventional laparoscopy. Port placement is more forgiving as instruments are not completely restricted by a rigid fulcrum. Currently complex laparoscopic liver resections are generally performed by surgeons who are both expert hepatobiliary surgeons and expert laparoscopic surgeons. Open techniques are more readily translated to robotics and thus surgeons who are expert in hepatobiliary but not necessarily advanced laparoscopy may become proficient quickly. An inherent imperfection in surgical training is the need for inexperienced trainees to operate on real patients while overcoming the learning curve of the procedure, thus exposing patients to a degree of risk. Robotic surgery lends itself well to computer based virtual reality training, similar to how pilots train on flight simulators. Such training systems have been developed and validated, such as the dV-Trainer (Mimic Technologies, Inc, Seattle, WA, USA), and the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA, USA). Studies have found that structured training exercises improved simulator performance, although the translation to actual surgical performance has not been well studied (6,7). Figure 1 Typical room setup for a robotic hepatectomy.

Pros of robotic surgery Robotic assistance was developed in part to compensate for some of these limitations. The unfavorable ergonomics of rigid laparoscopic instruments are partially overcome by articulated ones to mimic the dexterity of the human hand. This allows tissue manipulation and suturing in small spaces, at angles not possible with rigid instruments, and facilitates curved transection lines for more complex resections. Tremor is filtered to allow precise suture placement useful for bleeding, and for creating biliary and enteric anastomoses. The surgeon’s motions are scaled so that small, precise movements are effected at the patient’s end. Operating via a console allows the surgeon to work sitting down in a comfortable position, and the 3-dimensional projection of images partially overcomes the lack of depth perception. The surgeon is in control of the camera, which is mounted on a stable platform, avoiding poor camera work due to a tired or inexperienced assistant. Laparoscopic retractors are also controlled by the surgeon and can be locked into position, further avoiding inappropriate or ineffective retraction. One of the big theoretical advantages of robotic assistance

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Cons of robotic surgery There are a number of disadvantages with robotic surgery. The current generation of robots has a large footprint and bulky arms, in addition to the size of the operating console. Spacious operating rooms are required, and dexterity is limited by collision of robotic arms (Figure 1). A skilled assistant is needed for suction, change of instruments, application of argon plasma, and stapling. There is no tactile feedback so the retraction pressure on the liver may be more difficult to gauge, and suture breakage may be more common, although experienced surgeons adjust to it by visually judging the tension on sutures (8). Changing patient position requires the robot to be undocked and redocked, adding time to the procedure and interrupting the flow of the operation. The separation of surgeon and patient potentially leading to delays in managing intraoperative complications and emergent conversion can be a source of anxiety for the operating team. Studies have generally shown that robotic surgery take longer time than their laparoscopic counterparts, in part due to time setting up and docking the robot, and time spent changing instruments (9-11). However, with increasing experience and proficiency this is likely to reduce. The other recent advancements in the field that will improve accessibility of robotic surgery for liver resection

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A

B

Figure 2 Flexibility for multi-field robotic surgery for the Intuitive Xi Robot. Without moving the patient, or table, or robotic tower, the working arms can be turned 180 degrees to swap from right upper quadrant work (A) to pelvic work (B). This will allow combined hepatectomy and rectal resections.

include the range of new instrumentation that is now available, including robotic suction devices, sealers, and staplers. That has eliminated the routine need for accessory ports and necessity of a skilled bedside assistant. The launch of the Intuitive Xi robot has also allowed ease of multi-field surgery, and provides great ease in repositioning and redocking (Figure 2). This robot is attached to a mobile boom that allows full 180 change in orientation of instruments without moving the patient, or table, or the robot. Robot malfunction in a variety of general surgical operations has been reported but appears to be relatively uncommon, and rarely lead to significant consequences. Approximately half of documented malfunction cases were attributed to robotic instruments and were resolved by replacing the instruments. Other sources of malfunction included optical systems, robotic arms, and the console. Agcaoglu et al. reported 10 cases of robotic malfunction in 223 cases (4.5%), with no adverse outcomes (12). Buchs et al. reported 18 cases of malfunction in 526 cases (3.4%), with one conversion to laparoscopy due to light source failure (13). Kim et al. reported 43 malfunctions in 1,797 cases of general and urological operations (2.4%), leading to conversion to open in one patient and to laparoscopy in two patients, all due to robotic arm malfunction (14). One of the major disadvantages of robotic surgery is the high cost. The purchase of a da Vinci robot has been reported to be around US $1.5 million, with annual

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service cost of around $110,000, plus cost of disposable instruments (15). In a systematic review, Turchetti et al. analyzed 11 studies in the English literature which compared the cost of robotic surgery with the laparoscopic approach for various abdominal operations. The cost of the robotic approach was generally higher due to increased operating time (particularly set-up time) and instruments, while the costs of hospital stay were similar (16). However many studies did not include the purchase and maintenance costs which are significant, particularly in lower volume centers. None of the studies in this review evaluated the potential economic benefits of robotics. Evolution of robots Even though robotics in medicine have only recently caught the attention of the public, the technology is not new. One of the first applications of robotics to modern medicine was the Puma 560 in 1985, an industrial robotic arm used by Kwoh et al. to perform stereotactic brain biopsies. In the 1990s, a number of robots were developed, including the PROBOT at the Imperial College of London for transurethral resection of the prostate, the RoboDoc in the USA for femoral coring for hip replacement, and the ARTEMIS in Germany, a precursor to the modern masterslave manipulator system. Subsequently the robots used in modern surgery were developed by two initially competing

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companies (17,18). One company was Computer Motion Inc based in California. They were contracted by NASA to develop the AESOP, a voice-activated camera control system that was compatible with standard 5 and 10 mm endoscopes. Subsequently the ZEUS robotic system was developed and became commercially available in 1998. The system consisted of a control console and table-mounted robotic arms incorporating the AESOP camera. In the 1980s, the Stanford Research Institute conducted research funded by the U.S. Army to develop telesurgery in the battlefield. Interest arose to extend its application to civilian surgery, and in 1995, Intuitive Surgical Inc was founded in California to further develop this technology. In 1999, Intuitive Surgical released the da Vinci robot in Europe, and in 2000 FDA approved its use in the USA. The da Vinci robot consists of three parts: a control console, a 3- or 4-armed surgical cart that is docked against the operating table, and a vision system. Central to the technology are a high-definition 3-dimensional viewer, a footswitch to allow the surgeon to swap between camera, retractors, and instrument control, and the Endowrist instruments, articulated instruments that mimic the seven degrees of motion of the human hand (18,19). In 2003, Intuitive Surgical and Computer Motion were merged. The ZEUS model was phased out and continued development was focused on the da Vinci system, now the only commercially available robotic operating system in the world. The second generation da Vinci S was released in 2006, and in 2009, the third generation Si model was released with dualconsole capability and improved vision. In 2014, the fourth generation da Vinci Xi robot was approved by the FDA, with a redesigned surgical arm cart, smaller, longer arms, and new camera system to allow more flexibility in cart position and port placement (20). Robotic liver surgery The indications for robotic hepatectomy are similar to those for laparoscopic hepatectomy. Both benign and malignant tumors can be resected robotically. Patients must have the physiological reserve to tolerate general anesthesia and a prolonged pneumoperitoneum. General contraindications to laparoscopy such as uncorrected coagulopathy should be observed. Laparoscopic hepatectomy for lesions in the superoposterior segments such as segment VII and VIII are particularly challenging due to their positions and the curved transection

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lines. As a result, laparoscopically lesions in these segments may be more commonly resected via a right hepatectomy, sacrificing a substantial volume of normal liver (21). Robotic hepatectomy helps overcome this problem and some authors have reported success (22). Thus the greatest theoretical advantage of robotic hepatectomy may lie in sectoral, segmental, or subsegmental resections in difficult-to-reach positions, where patients may be spared the large incisions and extensive mobilization required in an open approach. On the other hand, major hepatectomies for malignant conditions where large incisions are required for specimen extraction may be better served by a traditional open approach. Difficult hepatic resections such as those for hilar cholangiocarcinoma requiring caudate lobectomy and bile duct anastomoses are generally not performed laparoscopically but the use of a robot may allow these to be approached in a minimally invasive manner. Image guided surgery is a developing field where preoperative imaging is used to aid intraoperative maneuvers. There is considerable experience in applying this technology to neurosurgery and orthopedic surgery, but there is increasing interest in hepatobiliary surgery (23). Computer models built on CT or MRI are registered onto the real-life organs by matching landmarks, which then allows intra-operative navigation to be guided. The need for a computer console in robotic surgery makes it ideal for integration of image-guidance as an adjunct to intraoperative ultrasound, creating an augmented reality where images are superimposed onto the field of view which may help surgeons anticipate vascular structures and obtain adequate margins. This is particularly suited to accurate probe placement for ablation of small, difficult to localize tumors. Image-guidance technology in hepatobiliary surgery is still in its infancy with a number of technical challenges such as deformation correction, and further work is needed before augmented reality can be realized. Robotic assistance can potentially overcome some of the limitations of SILS, for example by swapping the hand controls to eliminate cross-handed operating. Early experiences with robotic single-port hepatectomy have been reported (24), but the technology will likely have to be modified to adapt to the unique challenges of SILS, particularly the propensity for the robotic arms to clash with each other. In theory, robotic surgery is an ideal platform for telesurgery. Indeed that was one of the driving forces behind the development of the master-slave robotic system. However, the latency between the surgeon’s movement and

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the observed effect due to transmission of data to and back from the patient is a significant limitation. Marescaux et al. reported the first transatlantic robot-assisted telesurgery in 2001, where a robotic cholecystectomy was performed by surgeons in New York, USA, and the patient in Strasbourg, France (25). The authors reported a total time delay of 155 ms; however this was performed on a dedicated highspeed terrestrial optical fibre network. Current satellitebased networks and public-internet based connections are inadequate for the widespread application of telesurgery over long distances, particularly for complex procedures with small margins of error (26). Current data on robotic liver resection Early experiences with using a robot in cholecystectomy were reported by Gagner et al. and Himpens et al. (27,28). Chan et al. reported their experience with 55 robotic HPB procedures, including 27 hepatectomies, 12 pancreatectomies (including 8 Whipple’s), and 16 biliary operations. Their experience with robotic liver resections for HCC was subsequently also published (29). The largest series of robotic hepatectomy to date was a single-surgeon series published by Giulianotti et al. from the University of Illinois, with 70 patients (60% malignant, 40% benign). Major hepatectomy was performed in 27 patients, including 20 right hepatectomy, 5 left hepatectomy, and 2 right trisectionectomy. Of note, lesions in segments VII and VIII were only attempted if a right hepatectomy was performed. Three patients had a bile duct resection with biliary reconstruction, which is considered by most surgeons as a contraindication to laparoscopic hepatectomy because of the added complexity of a bile duct anastomosis. The median operative time was 270 min; for major resection it was 313 min, minor resection 198 min, and for biliary reconstruction 579 min. Major morbidity occurred in four patients, and there were no mortalities. Median surgical margin was 18 mm. No survival or oncological outcomes were reported (30). Lai et al. from Hong Kong reported their experience of 42 patients with HCC and non-cirrhotic liver or ChildPugh class A cirrhosis. The type of surgical operation included wedge resection in 10 patients, segmentectomy in 7, bisegmentectomy in 4, left lateral sectionectomy in 12, right hepatectomy in 7, and left hepatectomy in 3. Mean operating time was 229 min and median blood loss was 413 mL. Three patients developed complications, and there were no perioperative deaths. Mean hospital stay was

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6.2 days. R0 resection was achieved in 40 patients (93%). Follow-up was relatively short at a median of 14 months. Six patients recurred within the liver and the 2-year overall survival was 94% (10). The hepatopancreatobiliary group at Memorial Sloan Kettering Cancer Center has performed over 70 robotic hepatectomies (Kingham P and Fong Y, 2014, unpublished data). Twenty-three percent of patients have had previous abdominal surgery, including 5 re-operative hepatectomies. Median operating time was 164 minutes, estimated blood loss 100 mL, and four patients required conversion to open (6.1%). There were no mortalities and no re-operations for complications. The major conclusion derived from this series is: lesions in segment 1, 7, and 8 can be performed safely. Unlike the prior series where investigators saw the goal of robotic hepatectomy as trying to perform major hepatectomies, these investigators saw the robot as a means to accomplish resection of ill places minor resections. For major resections, it is unlikely that robotic resection will change much the usual outcomes of hospital stay or complications, since the extent of the hepatic resection and not the incision will be the greatest determinant of outcome. For minor resections of ill placed tumors, the incision usually dominates the clinical outcome. These are likely to be those resections where robotic surgery is likely to be proven superior. These are also those cases where expert opinion has recommended against laparoscopic surgery (2). Positioning of patient and the robot has now been improved to facilitate safe robotic resection of tumors in segments 7 and 8 (Figure 3). Few studies have compared robotic to laparoscopic liver resections. Berber et al. found non-different operating time, blood loss, and resection margin (31). Ji et al. found that robotic resections may have longer operating times than laparoscopic or open resections but comparable blood loss and complications (9). Lai et al. found a similar association for patients undergoing minor hepatectomy (<3 segments) only (10). The largest matched comparison between laparoscopic and robotic hepatectomy was published by Tsung et al. and the University of Pittsburgh group (11). In this retrospective study, 57 patients undergoing robotic hepatectomy were matched with 114 patients undergoing laparoscopic hepatectomy on background liver disease, extent of resection, diagnosis, ASA class, age, BMI, and gender. They found that operating times were significantly longer in the robotic group for both major and minor hepatectomies. There were no significant differences in complication rates, length of stay, mortality, and negative margin rates.

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of the technology has been a slow process. In a review article in 2004, Lanfranco et al. outlined the pros and cons of robotic surgery at its relative infancy (18). Ten years later we find ourselves still facing similar limitations. Future directions may include reducing the size of the robot, modifying the arm mechanism to reduce clashing, multi-purpose instruments to reduce the need for frequent instrument exchanges and for an experienced assistant, development of hepatics to allow tactile feedback, and integration of image guidance. There is still skepticism outside the circle of robotic HPB enthusiasts regarding the wide applicability of this technology. For many centers the high cost will be a major deterrent. Despite all its promises, until the benefits are more clearly defined, robotic liver surgery will likely be practiced by a select group of surgeons at high-volume centers. Acknowledgements Disclosure: The authors declare no conflict of interest. References Figure 3 Positioning for robotic hepatectomy for lesions in segment 7 or 8.

There was a trend towards less blood loss in the robotic major hepatectomies compared with laparoscopic major hepatectomies, which the authors attributed to superior inflow and outflow control, as well as magnified optics allowing better identification of vessels during parenchymal transection. Interestingly for the minor resections, the robotic approach was associated with a significantly higher blood loss than laparoscopic approach. The authors also noted that conversion to open rates were comparable, and that patients in the robotic group were more likely to have their surgery performed completely laparoscopically, without hand-assistance or a hybrid laparoscopic-open approach (93% vs. 49% for the laparoscopic group) (11). Conclusions Current data show that with good patient selection and meticulous technique, robotic hepatectomy is a safe and effective operation that is likely to stay. The goal of robotic assistance is to mimic the techniques of open surgery delivered through a minimally invasive approach. The theoretical advantages of robotic surgery are exciting but the evolution

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1. Cherqui D, Husson E, Hammoud R, et al. Laparoscopic liver resections: a feasibility study in 30 patients. Ann Surg 2000;232:753-62. 2. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg 2009;250:825-30. 3. Shetty GS, You YK, Choi HJ, et al. Extending the limitations of liver surgery: outcomes of initial human experience in a high-volume center performing single-port laparoscopic liver resection for hepatocellular carcinoma. Surg Endosc 2012;26:1602-8. 4. Aikawa M, Miyazawa M, Okamoto K, et al. Single-port laparoscopic hepatectomy: technique, safety, and feasibility in a clinical case series. Surg Endosc 2012;26:1696-701. 5. Romanelli JR, Earle DB. Single-port laparoscopic surgery: an overview. Surg Endosc 2009;23:1419-27. 6. Hung AJ, Patil MB, Zehnder P, et al. Concurrent and predictive validation of a novel robotic surgery simulator: a prospective, randomized study. J Urol 2012;187:630-7. 7. Korets R, Mues AC, Graversen JA, et al. Validating the use of the Mimic dV-trainer for robotic surgery skill acquisition among urology residents. Urology 2011;78:1326-30. 8. Giulianotti PC, Coratti A, Angelini M, et al. Robotics in general surgery: personal experience in a large community hospital. Arch Surg 2003;138:777-84.

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9. Ji WB, Wang HG, Zhao ZM, et al. Robotic-assisted laparoscopic anatomic hepatectomy in China: initial experience. Ann Surg 2011;253:342-8. 10. Lai EC, Yang GP, Tang CN. Robot-assisted laparoscopic liver resection for hepatocellular carcinoma: short-term outcome. Am J Surg 2013;205:697-702. 11. Tsung A, Geller DA, Sukato DC, et al. Robotic versus laparoscopic hepatectomy: a matched comparison. Ann Surg 2014;259:549-55. 12. Agcaoglu O, Aliyev S, Taskin HE, et al. Malfunction and failure of robotic systems during general surgical procedures. Surg Endosc 2012;26:3580-3. 13. Buchs NC, Pugin F, Volontl F, et al. Reliability of robotic system during general surgical procedures in a university hospital. Am J Surg 2014;207:84-8. 14. Kim WT, Ham WS, Jeong W, et al. Failure and malfunction of da Vinci Surgical systems during various robotic surgeries: experience from six departments at a single institute. Urology 2009;74:1234-7. 15. Steinberg PL, Merguerian PA, Bihrle W 3rd, et al. A da Vinci robot system can make sense for a mature laparoscopic prostatectomy program. JSLS 2008;12:9-12. 16. Turchetti G, Palla I, Pierotti F, et al. Economic evaluation of da Vinci-assisted robotic surgery: a systematic review. Surg Endosc 2012;26:598-606. 17. Satava RM. Surgical robotics: the early chronicles: a personal historical perspective. Surg Laparosc Endosc Percutan Tech 2002;12:6-16. 18. Lanfranco AR, Castellanos AE, Desai JP, et al. Robotic surgery: a current perspective. Ann Surg 2004;239:14-21. 19. Yates DR, Vaessen C, Roupret M. From Leonardo to da Vinci: the history of robot-assisted surgery in urology. BJU Int 2011;108:1708-13; discussion 1714. 20. Intuitive Surgical. Da Vinci Surgical Si System. Available online: http://www.intuitivesurgical.com/products/

davinci_surgical_system/davinci_surgical_system_si/ 21. Cho JY, Han HS, Yoon YS, et al. Feasibility of laparoscopic liver resection for tumors located in the posterosuperior segments of the liver, with a special reference to overcoming current limitations on tumor location. Surgery 2008;144:32-8. 22. Casciola L, Patriti A, Ceccarelli G, et al. Robot-assisted parenchymal-sparing liver surgery including lesions located in the posterosuperior segments. Surg Endosc 2011;25:3815-24. 23. Kingham TP, Scherer MA, Neese BW, et al. Image-guided liver surgery: intraoperative projection of computed tomography images utilizing tracked ultrasound. HPB (Oxford) 2012;14:594-603. 24. Kandil E, Noureldine SI, Saggi B, et al. Robotic liver resection: initial experience with three-arm robotic and single-port robotic technique. JSLS 2013;17:56-62. 25. Marescaux J, Leroy J, Gagner M, et al.Transatlantic robotassisted telesurgery. Nature 2001;413:379-80. 26. Xu S, Perez M, Yang K, et al. Determination of the latency effects on surgical performance and the acceptable latency levels in telesurgery using the dV-Trainer(®) simulator. Surg Endosc 2014;28:2569-76. 27. Gagner M, Begin E, Hurteau R, et al. Robotic interactive laparoscopic cholecystectomy. Lancet 1994;343:596-7. 28. Himpens J, Leman G, Cadiere GB. Telesurgical laparoscopic cholecystectomy. Surg Endosc 1998;12:1091. 29. Chan OC, Tang CN, Lai EC, et al. Robotic hepatobiliary and pancreatic surgery: a cohort study. J Hepatobiliary Pancreat Sci 2011;18:471-80. 30. Giulianotti PC, Coratti A, Sbrana F, et al. Robotic liver surgery: results for 70 resections. Surgery 2011;149:29-39. 31. Berber E, Akyildiz HY, Aucejo F, et al. Robotic versus laparoscopic resection of liver tumours. HPB (Oxford) 2010;12:583-6.

Cite this article as: Leung U, Fong Y. Robotic liver surgery. Hepatobiliary Surg Nutr 2014;3(5):288-294. doi: 10.3978/ j.issn.2304-3881.2014.09.02

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Review Article

“Vanishing liver metastases”—A real challenge for liver surgeons Alex Zendel1, Eylon Lahat2, Yael Dreznik2, Barak Bar Zakai3, Rony Eshkenazy3, Arie Ariche3 1

Department of Surgery C, 2Department of Surgery B, 3Department of HPB Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School

of Medicine, Tel-Aviv University, Tel-Aviv, Israel Correspondence to: Arie Ariche. Department of HPB Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel. Email: [email protected].

Abstract: Expanded surgical intervention in colorectal liver metastasis (LM) and improved chemotherapy led to increasing problem of disappearing liver metastases (DLM). Treatment of those continues to evolve and poses a real challenge for HPB surgeons. This review discusses a clinical approach to DLM, emphasizing crucial steps in clinical algorithm. Particular issues such as imaging, intraoperative detection and surgical techniques are addressed. A step-by-step algorithm is suggested. Keywords: Disappearing liver metastases (DLM); complete pathological response; liver imaging; contrastenhanced intraoperative ultrasound (CE-IOUS) Submitted Aug 22, 2014. Accepted for publication Sep 16, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.13 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.13

Introduction Colorectal cancer (CRC) is one of the most common cancers in the world. Advances in treatment have led to a decrease in the death rate for CRC over past two decades (1). Despite these advances, approximately half of all patients diagnosed with CRC will develop liver metastasis (LM) during the course of their disease (2-5). When left untreated, colorectal LM is rapidly and uniformly fatal with a median survival measured in months (6,7). Surgical resection provides the best opportunity for long-term survival and even the chance for cure, and so it is the current paradigm of treatment (8-17). Unfortunately, only 10-25% of patients with LM are candidates for surgical resection at the time of presentation (18-20). In patients with unresectable metastases, chemotherapy is the treatment of choice, either as a palliative treatment or in attempt to convert them into surgical candidates (21-24). Chemotherapy can also be administrated as a neoadjuvant strategy for selected cases of colorectal LM (23-25). Thus, an increasing number of patients receive chemotherapy prior to liver resection (26,27). The introduction of new, more effective systemic cytotoxic and biologic agents have been an important advance in the management of CLM. Tumor response has significantly improved with modern combination regimens, with up to 50% response rates for unresectable LM and 20% proceeding to liver resection with curative intent (28). Along with an © Hepatobiliary Surgery and Nutrition. All rights reserved.

improvement in chemotherapy treatment, there has been an increasing evidence of “disappearing” liver metastases (DLM) (27-31). DLM defined as a disappearance of liver metastases on cross-sectional imaging after administration of preoperative chemotherapy, which means a complete radiological response. That phenomenon occurs in 5-38% of patients who undergo preoperative systemic therapy (27,29-32). The logic basis behind the decision-making algorithm for DLM built on understanding of correlation between the complete radiological response and complete pathological response or durable complete clinical response. The complete pathological response defined as an absence of residual tumor in the resection specimen. The durable complete clinical response means no recurrence during a satisfactory period of time, when the site of disappearing lesion in not resected (left in situ). Both are desirable outcomes promising a chance for cure. In this review we propose a decision-making algorithm for management of DLM which discuss step-by-step how to improve a clinical approach to DLM, emphasizing upfront improvements in imaging, intraoperative detection and surgical techniques. DLM prevention—Overtreatment is not advisable The reported risk factors for the occurrence of DLM are: www.thehbsn.org

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small size of LM (<2 cm), initial number of metastasis (over 3) and a prolonged preoperative chemotherapy (26,30). Therefore, for those patients selected to receive neoadjuvant treatment for a resectable disease, preoperative chemotherapy should be given for a fixed short duration. There is no strict evidence for number of cycles to treat. Van Vledder and colleagues showed that patients with DLM received 7.7 cycles of chemotherapy versus 5.5 cycles in patients without DLM (26). In addition, an 18 % increase in chance of DLM with each additional cycle of treatment was noted. The majority of DLMs arose 3-6 months following the start of chemotherapy (25). Based on that evidence, some writers proposed the numbers of 4-6 cycles (32,33). After that initial course the clinician should reevaluate the patient in order to avoid disappearing and to promptly resect it. It is important to remember, that patients that receive chemotherapy for resectable disease do not need to demonstrate objective response, although radiological response is a good prognostic factor. As far as conversion treatment for unresectable disease concerned, it should be continued until the patient has a resectable disease, not until maximum response (28,33). In fact, prolonged chemotherapy can cause liver toxicity, and thus to disturb the management of LM by two mechanisms. First, it leads to decreased ability of preoperative imaging to detect LM, by increased fatty content (26,33,34). Second, it makes the surgery more difficult technically, causing an obvious increase in intra and postoperative morbidity (23). Preoperative imaging—Are the metastases missing indeed? The rate of complete radiological response varies in different series as much as 4% and 38% (25,26,28,33-37). It can be explained by differences in chemotherapy regimens and by the quality and competence of preoperative imaging. Numbers of modalities are in use to image patients with LM. Computed tomography (CT) Since its introduction into clinical practice in the 1970s, the quality and accuracy of CT in detecting LM has continued to improve, with a sensitivity ranging currently between 63% and 90%, and specificity between 85% and 90%, approaching 100% in some series (26,33,34,38,39). Preoperative chemotherapy can induce parenchymal changes to the liver, defined as steatosis or steatohepatitis

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(33,40). In that setting the background liver appears darker, allowing less contrast between the parenchyma and the hypovascular metastases, hindering their detection (34,41,42). Several risk factors have been reported causing an inadequate staging of LM by CT, such as steatosis > 30%, more than 3 LM and lesions smaller than 1 cm (32-34). Based on this evidence, we assume that all missing metastases on triple-phase CT should be confirmed by another imaging modality. PET-FDG and PET-CT That modality shows high sensitivity, up to 97%, for detecting LM in some series (43,44). Other publications reported wider range of sensitivities—51-90% (40,45-48). This data reflects several factors, which reduce the sensitivity of FDG uptake, such as small lesions (especially less than 1 cm) and impaired glucose uptake in tumor cells due to chemotherapy (49,50). Nevertheless, some series emphasized an important role of PET-FDG, changing the treatment plan in up to 30-40%, either by finding an extrahepatic disease or correctly predicting a complete pathological response (51,52). In a prospective study of 104 patients with CRC, PET-CT revealed unsuspected disease in 19%, changed stage in 13.5% and resulted in modified surgery in 11.5% (53). As the likelihood of extrahepatic disease increases along with the degree of liver involvement, PETCT should be considered as a routine examination in staging patients prior to surgical resection (34). This is important when considering extensive surgery to avoid the morbidity of futile laparotomies. In summary, remaining an important tool in primary staging, PET scan is not a good test for looking at viable cancer within the liver after chemotherapy (54). MRI MRI appears to be the best hepatic imaging modality, especially in the setting of chemotherapy-induced steatosis and for small lesions (28,55). Compared with CT, it has better sensitivity and specificity (34). Recent advances in MRI techniques, such as diffusion-weighted imaging (DWI) and hepatobiliary contrast agents even strengthen that superiority. DWI is a measure of the ability of water molecules to diffuse freely between tissues and hence directly correlates with underlying cellular density. Metastases tend to restrict diffusion and the addition of

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DWI to the typical liver MRI protocol improves sensitivity and specificity for lesion detection and characterization (56-60). In addition to DWI, hepatobiliary phase MRI using liver-specific contrasts has demonstrated improved sensitivity to metastasis detection over routine MRI (61-64). Examples of such contrast agents are Gadoxetic acid and super paramagnetic iron oxide (SPIO). These agents help to improve the contrast between hepatocytes and tumor cells during the late hepatobiliary phase, in which peak parenchymal enhancement happens. In summary, MRI is an optimal modality to image LM missing on CT scan. Moreover, in recent study an inability to observe a DLM on MRI was associated with an increased chance for complete pathological or durable clinical response (30). Following adequate imaging—Should we always operate? Since no preoperative imaging modality, including MRI, has a sensitivity of 100%, there is a subset of DLM that will be found only at the time of surgical exploration. In other words, if we do not proceed to surgical exploration in setting of DLM even after performing comprehensive imaging, we may leave the tumor behind. So one should always consider surgical exploration when feasible, especially in presence of DLM risk factors, mentioned previously, such as small and multiple lesions, prolonged chemotherapy and significant chemotherapy induced liver damage. The literature hasn’t faced the difference between per patient versus per metastases approach to exploration. Obviously, a patient with multiple metastases, which only part of them disappeared on imaging, will undergo exploration, demanding resection of remaining lesions in any case. It is less clear how safe is a possibility to avoid surgery in rare patient with completely “clean” post-chemotherapy liver. Such specific cases should be discussed in a multidisciplinary team, taking in consideration favorable prognosis in good treatment responders. That fact promotes an aggressive approach with meticulous intraoperative assessment. Intraoperative assessment—Could we do better? The role of exploratory laparoscopy as a first step in operative approach to DLM is still being controversial. The main importance of laparoscopy in such cases is probably to rule out a disseminated peritoneal disease. The ability of laparoscopy to identify small lesions missing on

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preoperative imaging is significantly limited. Using formal laparotomy, all patients with DLM should undergo a full liver mobilization, visual inspection, palpation and finally intraoperative ultrasonography (IOUS). Systematic examination by IOUS can lead to an increase in the detection of DLM. In the published experience, a macroscopic residual disease was observed in as much as 2745% of the patients with DLM by combination of palpation and IOUS (25,26,36,37). As mentioned previously, that frequency was lowered by the use of preoperative MRI (26,28,36). Contrast-enhanced intraoperative ultrasound (CEIOUS) is a novel technique that was proposed in 2004 for both CLM and hepatocellular carcinoma detection. The preliminary results were inconclusive for CLM (64-66). Further investigations showed that it is capable of detecting a larger proportion of CLM, in comparison with other imaging modalities including IOUS (53,67,68). Arita et al. assessed a usefulness of CE-IOUS in identifying DLM (69). Out of 32 DLM, 4 were identified by IOUS, all confirmed as tumor by pathology. Out of remaining 28, 12 we found by CE-IOUS, all were resected and a vast majority (11 of 12) consisted of malignancy. The authors concluded that CE-IOUS might be necessary for identifying DLM. Possible factors influencing the surgeon ability to discover DLM include the degree of hepatic steatosis, the depth of DLM, the location relative to anatomical landmarks and surgeon skill with IOUS (28,66,70). How to treat missing LM during surgery When a surgeon cannot identify DLM during the operation, he has two options to manage that situation. First is to treat surgically the site of anatomical location of the metastases, and check for complete pathological response in pathology regimen. Second, he can leave it in situ. In that scenario the outcome will be assessed by the followup imaging, looking for recurrence al the site of DLM. The duration of the follow-up to define a complete clinical response is not well defined. According to the fact that the median time of recurrence is 6-8 months, it is makes sense to define a durable clinical response as no recurrence at cross-sectional imaging at 1 year (26,28,30). The literature is not is not convincing when facing the dilemma of resecting the site of metastasis versus leaving it in situ. Several predicting factors for a good correlation between a complete radiological and complete pathological response were described. Most significant of them were

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initial higher number of LM, more metastases with partial response, young patients (<60 years), low initial CEA level (<30) which normalizes during chemotherapy, small lesions (<3 cm) and an absence of lesion on preoperative MRI (26,37). Another independent predicting factor was a use of hepatic artery infusion (HAI) therapy (28,36,37). Proponents of aggressive resection present high rates of recurrence while left in situ (above 70%) and low rates of complete pathological response when resected (20%) (27,28). van Vledder et al. showed a significant advantage in 3-year intrahepatic recurrence-free survival rates for resection versus follow-up group (26). On the other hand, there was no difference in overall survival (26,27). The possible explanation is the fact that about a half of the patients experience recurrence in any other location, different from the DLM sites or even extrahepatic (33). The aggressive biologic nature of disease in those patients may neutralize the local control of disease by DLM sites resection, thus moderating overall survival benefit (25,26,33). From the practical point of view, the decision should be made based on aggressiveness of the disease, the patient condition and operative risk, an ability to treat all sites surgically and predictive factors for true complete pathological response as described above. Advances in surgeon arsenal—From “blind” hepatectomy to NanoKnife When the lesion cannot be identified, incorporation of the original site to hepatectomy or even performing segmental hepatectomy for a DLM site alone should be considered (26). The clear disadvantage of such “blind” hepatectomy technique is an inadequate residual liver volume and increased surgical risk. In fact, performing a major hepatectomy to resect the site of the DLM may not decrease the recurrence rate (27). On the contrary, the prognosis could be worsened by reducing the possibility of second hepatectomy. Along with the general trend of liver sparing in hepatobiliary surgery, in the field of DLM technological improvements allow more precise intervention. The key point is an exact site location. One option is to mark the LM with coils using percutaneous interventional radiology techniques (71). Although discussed in the chapter of operative treatment, its real place in decision-making algorithm is before starting chemotherapy. One can consider that tool, when dealing with an aggressive disease, which requires prolonged therapy, or when mentioned risk factors for DLM exist. Additional aids to assist in surgical planning

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are new software and applications that alleviate determining surgical planes, evaluating FLR and depicting anatomy (34). Radiofrequency ablation (RFA) is a gaining momentum alternative for liver lesion resection (72). The idea of ablating a previously marked site of DLM is promising in avoiding massive resections. It is timely influencing the debate about the necessity of DLM site resection. The problem in analyzing that modality is to compare it to surgical resections. Unlike in surgical resection, an evidence for complete response rates can be collected by looking for recurrence in follow-up imaging. In spite of its widespread use and noted efficacy, RFA has some limitations. Its dependence on heating of the tissue to denature proteins means adjacent thermosensitive structures such as colon, stomach, bile ducts, gallbladder, and hepatic capsule can be damaged resulting in complications, and large vessels within or close to the treatment zone may cause thermal sinks (“heat-sink” effect) that will prevent complete treatment of the target lesion (72,73). Although there are new thermal technologies such as microwave ablation, which may potentially generate a larger ablation zone in a shorter time, they still have the limitations associated with thermal technologies. These limitations have generated interest in other methods of ablation and have forced an integration of irreversible electroporation (IRE) method into treatment options list of hepatic tumors. IRE, commercially available as NanoKnife, is a new ablative technology that uses high-voltage, low-energy DC current to create nanopores in the cell membrane, disrupting the homeostasis mechanism and inducing cell death by initiating apoptosis (74). Its major advantage is the lack of heat-sink effect and the ability to treat zones near vessels, bile ducts, and critical structures. IRE comes with its own share of limitations. Human experiences are still limited, whereas thermal ablative techniques such as RFA have been time-tested for nearly three decades. The procedure has a learning curve because multiple needle placements are required within a prescribed distance, which can be challenging, and parallel placement of the probes may be hindered by issues, such as intervening ribs. In addition, this is a very expensive technology. We doubt a routine use of it when dealing with the lesion that is not even visible and the need for resection is controversial. Computer assisted liver surgery can be an elegant way to locate and ablate the site of DLM. Indeed, the integration of the prechemotherapy imaging to the US imaging along with the navigation system can allow the surgeon to locate and ablate precisely the metastatic site (75).

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Neoadjuvant therapy

Non resectable

Shrinkage

Resectable

Consider MRI as first-line modality

Triple-phase CT DLM

MRI (DWI + HPB) PET-CT – for extrahepatic disease

DLM Surgical exploration: inspection, palpation, IOUS

Metastases

DLM

Consider CE-IOUS Local site treatment

Resection

Ablation/NanoKnife

DLM

Segmental “blind” hepatectomy

Resection

Figure 1 Algorithm for clinical approach to DLM. DLM, disappearing liver metastases.

Summary Our review suggest an algorithm for clinical approach to DLM (Figure 1). The most crucial steps are a comprehensive preoperative imaging, including MRI, careful surgical exploration, using IOUS and possibly CEIOUS, and to be assisted by variety of operative techniques, such as local ablation of previously marked sites. The algorithm might serve as a helpful tool, but it definitely does not replace a multidisciplinary team, which should carry out the treatment of such a complicated patients. As the technology is improving fast, we look forward for the future improvements. The desirable navigation system may give an answer for difficulties to locate previous sites of DLM. Acknowledgements

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67. Torzilli G, Del Fabbro D, Palmisano A, et al. Contrastenhanced intraoperative ultrasonography during hepatectomies for colorectal cancer liver metastases. J Gastrointest Surg 2005;9:1148-53; discussion 1153-4. 68. Takahashi M, Hasegawa K, Arita J, et al. Contrastenhanced intraoperative ultrasonography using perfluorobutane microbubbles for the enumeration of colorectal liver metastases. Br J Surg 2012;99:1271-7. 69. Arita J, Ono Y, Takahashi M, et al. Usefulness of contrastenhanced intraoperative ultrasound in identifying disappearing liver metastases from colorectal carcinoma after chemotherapy. Ann Surg Oncol 2014;21 Suppl 3:S390-7. 70. Takahashi M, Hasegawa K, Arita J, et al. Contrastenhanced intraoperative ultrasonography using perfluorobutane microbubbles for the enumeration of colorectal liver metastases. Br J Surg 2012;99:1271-7. 71. Zalinski S, Abdalla EK, Mahvash A, et al. A marking technique for intraoperative localization of small liver metastases before systemic chemotherapy. Ann Surg Oncol 2009;16:1208-11. 72. Mahvi DM, Lee FT Jr. Radiofrequency ablation of hepatic malignancies: is heat better than cold? Ann Surg 1999;230:9-11. 73. Nahum Goldberg S, Dupuy DE. Image-guided radiofrequency tumor ablation: challenges and opportunities--part I. J Vasc Interv Radiol 2001;12:1021-32. 74. Kingham TP, Karkar AM, D’Angelica MI, et al. Ablation of perivascular hepatic malignant tumors with irreversible electroporation. J Am Coll Surg 2012;215:379-87. 75. Sakamoto T. Roles of universal three-dimensional image analysis devices that assist surgical operations. J Hepatobiliary Pancreat Sci 2014;21:230-4.

Cite this article as: Zendel A, Lahat E, Dreznik Y, Bar Zakai B, Eshkenazy R, Ariche A. “Vanishing liver metastases”— A real challenge for liver surgeons. Hepatobiliary Surg Nutr 2014;3(5):295-302. doi: 10.3978/j.issn.2304-3881.2014.09.13

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Review Article

Small for size liver remnant following resection: prevention and management Rony Eshkenazy1, Yael Dreznik2, Eylon Lahat2, Barak Bar Zakai1, Alex Zendel3, Arie Ariche1 1

Department of HPB Surgery, 2Department of Surgery B, 3Department of Surgery C, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Correspondence to: Dr. Arie Ariche. Department of HPB Surgery, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel. Email: [email protected].

Abstract: In the latest decades an important change was registered in liver surgery, however the management of liver cirrhosis or small size hepatic remnant still remains a challenge. Currently posthepatectomy liver failure (PLF) is the major cause of death after liver resection often associated with sepsis and ischemia-reperfusion injury (IRI). ‘‘Small-for-size’’ syndrome (SFSS) and PFL have similar mechanism presenting reduction of liver mass and portal hyper flow beyond a certain threshold. Few methods are described to prevent both syndromes, in the preoperative, perioperative and postoperative stages. Additionally to portal vein embolization (PVE), radiological examinations (mainly CT and/or MRI), and more recently 3D computed tomography are fundamental to quantify the liver volume (LV) at a preoperative stage. During surgery, in order to limit parenchymal damage and optimize regenerative capacity, some hepatoprotective measures may be employed, among them: intermittent portal clamping and hypothermic liver preservation. Regarding the treatment, since PLF is a quite complex disease, it is required a multi-disciplinary approach, where it management must be undertaken in conjunction with critical care, hepatology, microbiology and radiology services. The size of the liver cannot be considered the main variable in the development of liver dysfunction after extended hepatectomies. Additional characteristics should be taken into account, such as: the future liver remnant; the portal blood flow and pressure and the exploration of the potential effects of regeneration preconditioning are all promising strategies that could help to expand the indications and increase the safety of liver surgery. Keywords: Liver surgery; small for size liver remnant; post-hepatectomy liver failure (PLF); liver resection Submitted Sep 02, 2014. Accepted for publication Sep 09, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.08 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.08

Introduction In the latest decades an important change was registered in liver surgery, related to the progress of surgical techniques, anesthesiology and postoperative treatment, allowing a sharp decrease in mortality and morbidity. However, management of liver cirrhosis or small size hepatic remnant still remains a challenge (1). The liver presents regenerative capacity, allowing performance of repeated resections. In certain cases, when this capacity is impaired, or where extensive resections were performed with small remnant liver, these patients may develop small for size syndrome (SFSS) with the presence of reduced liver mass insufficient to maintain normal liver

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function. The term SFSS was first employed in liver transplantation to describe the development of acute liver failure (ALF) (hyperbilirubinemia, coagulopathy, encephalopathy and refractory ascites) resulted from the transplantation of a donor liver that was too small for a given recipient (2). A similar syndrome, called ‘‘post-hepatectomy liver failure (PLF)’’ was also described in hepatic surgery involving extended resections of liver mass. The last one is characterized by postoperative liver dysfunction, with clinical signs of prolonged cholestasis, coagulopathy, portal hypertension and ascites. PLF is the major cause of death after liver resection often associated with sepsis and ischemia-

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reperfusion injury (IRI) (3). The patho-physiological mechanisms of the SFSS and PLF are very similar, both presenting reduction of liver mass and portal hyper flow beyond a certain threshold (4). The aim of this review is to discuss applicable perioperative methods to prevent the SFSS or PLF and highlight the main treatment types. Pathophysiology The liver should contain minimum amount of parenchymal hepatic cells to assure its functions and the maintenance of its regeneration capacity. The hepatic parenchyma should be able to accommodate the hemodynamic changes that occur after liver resection, avoiding venous congestion. Factors such as decrease of hepatic parenchyma cells, infection and different causes that might jeopardize regeneration should be absent (5). Decrease in parenchymal volume results in a hyper perfusion of the liver, causing dilation of sinusoids, hemorrhagic infiltration, shear stress, centro lobular necrosis, prolonged cholestasis impaired synthetic function and inhibition of cell proliferation (6). Hepatic resections have higher risks of infection (above 50%). The number of Kupffer cells after hepatic resection decreased and thus the liver’s ability to fight against infection as well. The sepsis possesses the ability to complicate or precipitate PLF. A relative increase in the production of endotoxins in the remnant liver is beneficial, once it activates the Kupffer cells, trigging the liver regeneration. This prolonged state may cause Kupffer’s cellular dysfunction, resulting in difficulty of regeneration and even liver necrosis (7). The parenchymal damage occurs following vascular occlusion or after hemorrhagic shock, causing IRI. After a period of ischemia, the complement cascade is triggered, leading to the activation of Kupffer cells, reactive oxygen appearance of species (ROS) and endothelial cell lesion. During reperfusion a release of cytokines, cell adhesion, activation and recruitment of T cell and polymorphonuclear cell occurs, resulting in microvascular lesion, inflammation and cell death (8). Preoperative period-prevention Liver function tests and scores (9) The liver function tests can be divided into three types: Conventional tests, i.e., serum bilirubin, albumin,

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alkaline phosphatase, gamma glutamyl transpeptidase, prothrombin time (PT) and platelet count; Quantitative tests, i.e., aminopyrine breath test, antipyrine clearance, caffeine clearance, lidocaine clearance, methacetin breath test, galactose elimination capacity, low-dose galactose clearance, clearance sorbitol, indocyanine green disappearance, albumin synthesis, urea synthesis and 99mTcGSA; Scores, i.e., Child-Turcotte-Pugh and MELD. One of the best tests today to check liver function before surgery is liver retention of indocyanine green. Widely used since the decade of the 70 in Asian countries, and not yet widespread in the west. Based on the decisional tree [established by Seyama et al. (Figure 1)] identify before the operation which hepatic volume can be resected in cirrhotic patients depending on their liver function (9). Liver volume (LV) manipulation and liver parenchymal protection The ideal volume of the hepatic remnant was exhaustively discussed in the literature and some formulas to calculate it were described (10) (Table 1). The radiological examinations (mainly CT and/or MRI) before surgery are fundamental to quantify the LV. More recently 3D computed tomography reconstructions could define more accurately the hepatic volume allowing preoperative studies. Through this exam, the surgeon can simulate a resection, making possible the planning and the choice of the best way to do the procedure (15,18). Measurement of volume ratios correlated with the etiology and severity of chronic liver disease (CLD) constitute a reliable predictors of patient survival (19). Although, the reliability of this ratio might be compromised by the presence of dilated bile ducts, multiple tumors, undetected lesions. Additionally, due to cholestasis or previous chemotherapy, cholangitis, vascular obstruction, steatosis or cirrhosis, or segmental atrophy and/or hypertrophy from tumor growth, negatively impacts the liver function (16). Values calculated from graft weight-to-recipient body weight ratio (GRBWR), or standardized liver volume (SLV) based on recipient body surface area (BSA) are used to predict minimum adequate graft volume (15). But in presence of steatosis, particularly >30%, graft weight alone is not a suitable guide (10). Extended resection of 80% of functional parenchyma can be performed in the absence of CLD for hepatobiliary

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Figure 1 Decisional tree established by Seyama et al. (9).

Table 1 Formulas to calculate volume of the hepatic remnant 2

LV =706.2× BSA (m ) +2.4 (11) LV =[13 3 height (cm)] + [12 3 weight (kg)] –1530 (12) LV =1072.8× BSA (m2) –345.7 (13) TLV =191.8+18.51× weight (kg) (14) TLV =–794.41+1267.28× BSA (14) VR = (LV from reconstructed CT image/predicted volume) ×100 (12) SFLR = FLR (by CT volumetry) ÷ absolute LV (15) ERFL = FRL ÷ (TLV – tumour volume) (16) ERFL = (resected volume – tumour volume) ÷ (TLV – tumour volume) (16) GRWR = graft weight ÷ recipient body weight (kg) (17)

malignancies (20). Recommended minimal functional remnant LV following extended hepatectomy is 25% in a normal liver, and 40% in a “sick” liver, with moderate to severe steatosis, cholestasis, fibrosis, cirrhosis, or following chemotherapy (15). There are some strategies that allow volume manipulation, such as portal vein embolization (PVE) and two-stage

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hepatectomy (16,21). PVE is usually performed percutaneously by transhepatic PVE, but may also be achieved by surgical ligation and injection of alcohol or others products to prevent the recanalization of the portal vein. PVE increases the functional capacity of the liver remnant and can increase contralateral lobe volume by up to 20 per cent, with the peak in growth occurring within 2-4 weeks (22). Patients, in which the liver does not have a good result after PVE are selected as no good candidates for large resections due to the difficulty of regeneration (22). Patients with bilateral tumors when proceeding PVE may stimulate of neoplastic cell growth in the nonembolized lobes, in this cases surgical treatment or ablation [radiofrequency (23,24), microwave (25) and NanoKnife® (personal experience)] of such lesions prior to the embolization are required (26). Neoadjuvant chemotherapy (27) and intra-arterial chemotherapy (28) also can be used in combination with PVE to control tumour load before resection (20,29). Patients with bilateral liver lesions, where resection is not feasible under one procedure, the two stage hepatectomy is applied, allowing the remaining liver to be resected to achieve the suitable LV at the second stage.

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Intraoperative period-prevention In order to limit parenchymal damage and optimize regenerative capacity, two hepatoprotective measures may be employed: intermittent portal clamping and hypothermic liver preservation. Intermittent portal clamping with intervals allowed for reperfusion is preferred to continuous clamping, usually applying a 15-min clamp-5-min release regimen (30-32). Total vascular exclusion of the liver should be used when we have no choice to do the resection without it. When chosen, we can utilized hepatic vascular exclusion with preservation of the caval flow (33). Hypothermic liver preservation in conjunction with total vascular exclusion attenuates IRI. The future remnant is infused with a preservative fluid and surrounded by crushed ice to maintain the liver at 4 ℃. This approach is a useful adjunct to complex resections when total vascular exclusion and vascular reconstructions are programmed (34). During surgery it is still possible to apply techniques to prevent the SFSS, if other procedures were not considered on the preoperative period. Association liver partition and portal vein ligation (ALPPS) ALPPS, a newer strategy to increase resectability of hepatic malignancies, has been described for the first time in 2010 (35). This method relies on the fact (proved in clinical trials) that any closure of portal branch will be followed by a reactive perfusion through intrahepatic branches and collaterals present between two lobes. Hence, partition of the liver along the falciform ligament line, for example, will enhance regeneration compared to traditional methods. ALPPS has shown high hypertrophy rates compared to PVE/PVL (40% to 80% within a week compared to 8% to 27% within 2 to 60 days by PVL/PVE), however it is associated with high morbidity rates (16-64% of patients) and mortality rates (12-23% of patients), therefore a careful selection of surgical candidates should be done prior to surgery. Further investigation if ALPPS approach accelerates tumor growth is still required (35-37). Recently, a number of comparisons between ALLPS and standard methods (PVE followed by liver resections) have been published (38-40). One of the proposed benefits of ALLPS, for example, is rapid removal of tumor(s), thus preventing patient dropout due to disease progression of existing liver tumors. This assumption, however, failed to achieve clinical relevance in a recent publication that compared right PVE + segment 4 to ALPPS, demonstrating © Hepatobiliary Surgery and Nutrition. All rights reserved.

mainly extra-hepatic location of metastasis in the patient’s drop-out group. In addition, using PVE in this study yielded sufficient growth in 96.5% of the patients, with median hypertrophy of 62%, comparable to the FLR hypertrophy rates associated with the ALLPS approach (38). Although none of the studies published with this technique provide measurements of portal pressure or portal blood flow, the clinical data suggest that the acceleration of the hypertrophy of the residual parenchyma occurs due to the reduction of intra-hepatic communicants, once the in situ split procedure leads to complete portal devascularization of segment 4, preventing formation of collaterals between the left and the right liver that could otherwise undermine the completeness of right portal vein occlusion alone (41). A second and not mutually exclusive explanation would be the ‘‘regenerating liver’’ hypothesis proposed by Nagano et al. (42). Modulation of portal pressure Intraoperative Doppler ultrasonography has been used in combination with hepatic portal inflow modulation to detect and offset hyperperfusion in a small-for-size graft. Importantly, numerous interventions that modulate the portal blood flow have been shown to prevent the development of the SFSS in experimental models, such as: the performance of a portocaval anastomosis (43,44), the ligation of the splenic artery (45), banding of the portal vein (46) or the infusion of adenosine (47), somatostatin (48), pentoxifylline (49) or endothelin-1 (50). It is important to highlight that the role for inflow modulation at the time of major liver resection or as a salvage therapy in humans remains undefined. After all these studies cited above we can conclude that the development of SFSS or PLF are not strictly determined by the ‘‘size’’ of the liver graft or remnant. It is determined by the hemodynamic parameters of the hepatic circulation and, specifically, by a portal blood flow that, when excessive for the volume of the liver parenchyma leads to over-pressure, sinusoidal endothelial denudation and hemorrhage. Perisinusoidal and periportal hemorrhage occurs in the first minutes after an extended hepatic resection as well as after the reperfusion of a small graft, while arterial vasoconstriction and ischemic cholangitis are observed at later stages (6). Also, experimental and clinical studies consistently show that an increased portal blood flow relative to the weight of the liver results in an inverse relationship between portal and arterial blood flows that is known as the arterio-portal www.thehbsn.org

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buffer (51). The arterio-portal buffer occurs when the portal blood flow increases, the adenosine concentration in the space of mall decreases leading to arterial vasoconstriction and decrease of arterial blood flow, which is responsible for the late damage (52). Studies performed in patients undergoing liver transplantation in which the portal and hepatic arterial blood flows were measured intra-operatively have provided further insights into the pathophysiology of the SFSS (6,53,54). A portal blood flow of 300 mL/min/100 g was established by Jiang et al. as the threshold above that the incidence of the SFSS increases significantly (54). In living donor liver transplantations involving grafts with GWRW below 0.8, Troisi et al. showed that the construction of a portal-systemic shunt whenever the portal blood flow exceeded 250 mL/min/100 g was able to prevent the histological alterations characteristic of the SFSS and to improve the overall patient and graft survival (43,54). Several studies indicate that additionally to blood flow, portal pressure can also be considered a good parameter for predicting the failure of the graft. For example, patients with a portal pressure higher than 20 mmHg show a decrease from 85% to 38% in their 6-month survival (55). Yagi et al. also described that a portal pressure above 20 mmHg was associated with the development of ascites, coagulopathy and hyperbilirubinemia as well as with an early hypertrophy of the graft, higher values of hepatocyte growth factor (HGF) and diminished levels of vascular epithelial growth factor (VEGF), suggesting that an increased portal pressure also influences liver regeneration (56). Kaido et al. reported their experience with small grafts (GWRW of 0.6) in combination with portal pressure control (targeting final portal pressures below 15 mmHg), showing that the survival of recipients of small grafts and standard-size grafts was similar and that the portal pressure control strategy resulted in a decreased rate of complications in the donors (57). As in liver transplantation, studies involving extended hepatic resections also indicate that the increased portal blood flow with diminished residual parenchyma are a critical factor determining the development of PLF (47,58,59). The performance of a portocaval anastomosis in a patient with liver cirrhosis undergoing a major hepatectomy effectively prevented the syndrome, probably by reducing shear stress and damage to the sinusoids (60). Post-operative period-treatment (61) PLF is a quite complex disease, that requires a multi-

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disciplinary approach, where it management must be undertaken in conjunction with critical care, hepatology, microbiology and radiology services (1). After liver resection, clinical and laboratory assessment should be proceeded. Normally, the level of serum bilirubin and the INR rises in the first 48-72 h after resection. It is possible to identify liver dysfunction, whenever bilirubin concentration is above 50 µmol/L (3 mg/dL) or INR greater than 1.7 beyond 5 days of surgery (3). The most sensitive variable is serum bilirubin as predictor of outcome in PLF (62). PT and INR are also relevant, but the interpretation may be compromised if patients have received clotting factors. Serum albumin, although an indicator of hepatic synthetic function, will vary in response to inflammation and administration of intravenous fluids (63,64). Increased levels of liver enzymes are common after liver resection and do not predict outcome (3). Ascites and hepatic encephalopathy are important markers for liver failure, although it may be difficult to assess in the immediate postoperative period. The first occurs as a result of surgery (portal hypertension, dissection, gross fluid overload), while the second is a result of mental state as collateral effect of drugs such as opiates (62). Several studies assessed the role of postoperative functional of the liver. This task still consist a challenge, once the ICGR15 is capable to predicts PLF (65), but its value diminishes once liver failure is established, since the changes in hepatic blood flow impacts ICGR15. In the absence of controlled trials for PLF, management relies on data from experience with ALF, secondary to paracetamol toxicity (66-68). The pattern of organ dysfunction that occurs as a result of PLF is similar to that in sepsis (1). Once the following symptoms occur: cardiovascular failure, characterized by reduced systemic vascular resistance and capillary leak; acute lung injury, due to pulmonary edema and acute respiratory distress syndrome may ensue and acute kidney injury can progress rapidly in PLF. In those cases, fluid balance should be managed judiciously with avoidance of salt and water overload (64). Identifying and treating underlying sepsis is key in managing patients with PLF. Sepsis may exacerbate PLF, and bacterial infection is present in 80 per cent of patients with PLF (69) and in 90 per cent of those with ALF (70). Therefore, any acute deterioration should be attributed to sepsis until proven otherwise. Management of sepsis should be in accordance with the surviving sepsis guidelines (71). A trial of prophylactic antibiotics after liver

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resection failed to show a reduction in liver dysfunction or infective complications (72). A study of ALF have shown that prophylactic antibiotics reduce infections, but the impact on a long-term outcome is inconclusive (70). In critically ill patients with PLF, chest radiography and cultures of blood, urine, sputum and drain site/ascitic fluid should be performed (68). Current guidelines for ALF propose that broad-spectrum antibiotics should be administered empirically to patients with progression to grade 3 or 4 of hepatic encephalopathy, renal failure and/ or worsening SIRS parameters (68). Additionally coagulopathy may occur transiently after major resection and is found in all patients with PLF. As in ALF, coagulation parameters can be used to chart the progress of PLF, provided blood products have not been given. In the absence of bleeding it is not necessary to correct clotting abnormalities, except for invasive procedures or when coagulopathy is severe. The level at which a coagulopathy should be corrected before an interventional procedure in ALF has yet to be defined (66,68,73). Vitamin K may be given, but this is not supported by clinical trials (66). Thrombocytopenia may complicate liver failure (74). Indications for platelet transfusion in ALF include bleeding, severe thrombocytopenia (less than 20×10 6 /L), or when an invasive procedure is planned. A platelet count above 70×106/L is deemed safe for interventional procedures (75). Recombinant factor VIIa (rFVIIa) has been used to treat coagulopathy in patients with ALF (76). In a large controlled trial of rFVIIa following major liver resection, no reduction in bleeding events was observed (77). Its role in PLF is yet to be defined. Gastrointestinal hemorrhage is a recognized complication of liver failure. In ALF, H2-receptor blockers and proton pump inhibitors (PPIs) reduce gastrointestinal ill patients ensuring euglycemia improves survival and reduces morbidity (78). The role of imaging in PLF is to assess hepatic blood flow, identify reversible causes of liver failure and locate sites of infection. Hepatic blood flow can be evaluated using non-invasive imaging. Doppler ultrasonography may identify portal vein, hepatic artery and hepatic vein thrombosis. Contrast CT or MRI can be used to establish hepatic blood flow, provide more details of vascular abnormalities and identify sites of infection. If patency of hepatic vessels is still in doubt on cross-sectional imaging, angiography is the “gold standard” (79). Portal vein thrombosis has also been implicated in

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the development of PLF. In these rare cases of inflow and outflow thrombosis with PLF, a decision must be taken regarding the benefit of surgical or radiological thrombectomy or dissolution versus anticoagulation (80,81). The use of terlipressin also can reduce the portal venous pressure helping to hepatic regeneration (82). Cerebral edema and intracranial hypertension may occur as a result of PLF. It is unlikely in patients with grade 1 or 2 of liver encephalopathy. When achieving grade 3 encephalopathy, a head CT should be performed to exclude intracranial hemorrhage or other causes of declining mental status. In patients with established ALF and encephalopathy, enteral lactulose might prevent or treat cerebral edema, although the benefits remain unproven. Progression to grade 3/4 encephalopathy warrants ventilation and may require intracranial pressure monitoring (68). The concept of hepatocyte transplantation has been investigated as a strategy to boost residual liver function. Intrahepatic hepatocyte transplantation (83) has been used successfully to treat patients with metabolic disorders of the liver. However, results in liver failure (including patients with PLF) have been poor due to insufficient delivery of functional cells. The potential for stem cell therapies has yet to be established (84). The use of salvage hepatectomy and orthotopic liver transplantation for PLF has been reported in seven patients who underwent liver resection for cancer (85). Although the indications for transplantation in this study were questionable, overall 1-year (88 per cent) and 5-year (40 per cent) survival rates were promising. Extracorporeal liver support (ELS) devices fall into two categories: artificial and bioartificial systems. Artificial devices use combinations of haemodialysis and adsorption over charcoal or albumin to detoxify plasma. Bioartificial devices use human or xenogenic hepatocytes maintained within a bioreactor to detoxify and provide synthetic function. These systems have not been evaluated extensively in patients with PLF. A recent meta-analysis and systematic review showed that ELS may improve survival in patients with ALF, but not acute-on-chronic liver failure, in comparison with standard medical therapy (86). Conclusions The increased use of small liver grafts and the expansion of indications of curative liver surgery in patients with hepatic tumors allows a step change in the knowledge of the mechanisms responsible for the development of the SFSS

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and PLF. It became evident that the size of the liver cannot be considered the main variable in the development of liver dysfunction after extended hepatectomies. Additional characteristics should be taken into account, such as: the future liver remnant; the portal blood flow and pressure and the exploration of the potential effects of regeneration preconditioning are all promising strategies that could help to expand the indications and increase the safety of liver surgery. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. van den Broek MA, Olde Damink SW, Dejong CH, et al. Liver failure after partial hepatic resection: definition, pathophysiology, risk factors and treatment. Liver Int 2008;28:767-80. 2. Ikegami T, Shimada M, Imura S, et al. Current concept of small-for-size grafts in living donor liver transplantation. Surg Today 2008;38:971-82. 3. Balzan S, Belghiti J, Farges O, et al. The 50-50 Criteria on Postoperative Day 5. Ann Surg 2005;242:824-8, discussion 828-9. 4. Asencio JM, Vaquero J, Olmedilla L, et al. “Small-for-flow” syndrome: shifting the “size” paradigm. Med Hypotheses 2013;80:573-7. 5. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43:S45-53. 6. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic Observations and Histopathologic Recognition of the Portal Hyperperfusion or Small-forsize-syndrome. Am J Surg Pathol 2006;30:986-93. 7. Panis Y, McMullan DM, Emond JC. Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive resection. Surgery 1997;121:142-9. 8. Jaeschke H. Molecular mechanisms of hepatic ischemiareperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003;284:G15-26. 9. Seyama Y, Kokudo N. Assessment of liver function for safe hepatic resection. Hepatol Res 2009;39:107-16. 10. Tucker ON, Heaton N. The “small for size” liver syndrome. Curr Opin Crit Care 2005;11:150-5. 11. Urata K, Kawasaki S, Matsunami H. Calculation of child and adult standard liver volume for liver transplantation.

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Cite this article as: Eshkenazy R, Dreznik Y, Lahat E, Bar Zakai B, Zendel A, Ariche A. Small for size liver remnant following resection: prevention and management. Hepatobiliary Surg Nutr 2014;3(5):303-312. doi: 10.3978/j.issn.2304-3881.2014.09.08

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Review Article

The laparoscopic liver resections—an initial experience and the literature review Mislav Rakić, Leonardo Patrlj, Robert Kliček, Mario Kopljar, Antonija Đuzel, Kristijan Čupurdija, Željko Bušić Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia Correspondence to: Mislav Rakić, MD. Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10000 Zagreb, Croatia. Email: [email protected].

Abstract: The laparoscopic liver resection (LLR) represents a new pathway in hepatic surgery. Several studies have reported its application in both malignant and benign liver diseases. The most common liver resections performed laparoscopically are wedge, segmental resections and metastasectomy; although in large centers the laparoscopic right and left hepatectomies have begun to perform more frequently. We report the initial experience in LLRs at our department including a case of the first laparoscopic left lateral liver bisegmentectomy performed in patient with follicular nodular hyperplasia and the 15 cases of wedge laparoscopic resections of echinococcic liver cysts. According to literature the mortality rate in LLRs is up to 0.3% and morbidity rate up to 10.5%. The most common cause of the death is liver failure, while the most frequent complication is the bile leakage. Advantages for patients include smaller incisions, less blood loss, and shorter lengths of hospital stay. The LLRs in experienced hands were shown to be safe with acceptable morbidity and mortality for both minor and major hepatic resections in benign and malignant diseases. Keywords: Laparoscopic liver resection (LLR); segmental resections; left lateral bisegmentectomy; liver echinococcic cyst laparoscopic treatment Submitted Aug 06, 2014. Accepted for publication Sep 16, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.10 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.10

In general, liver surgery has seen significant advances in the last decades, particularly associated with improvements in anesthesia and critical care as well as surgical techniques. The improved understanding of the vascular anatomy of the liver based on Couinaud segments, has also led to a great reduction in morbidity and mortality associated with liver resection (1). Clearly challenging, the laparoscopic liver resections (LLRs) were not accepted until recently due to the several reasons: the problem of intraoperative bleeding control, the technical difficulties, the learning curve and the fear of gas embolism (2). Since the first reported cases of liver resection in 1991 and 1992 (3,4), more than 3,000 cases have been reported in literature worldwide. In general, LLR is associated with significant advantages: faster recovery, less post-operative pain, less morbidity, easier subsequent surgery and better cosmetic results (5).

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At first the indications limited to easily accessible tumors mostly placed at the peripheral portion of liver, the anterolateral segments (II, III, V, VI and the inferior part of IV liver segment) (6,7). The majority of initial reports suggested that LLR is poorly indicated when the lesion is located in the posterior or superior part of the liver (segments I, VII and VIII, the same as the superior part of segment IV) (8,9). The indications for LLRs widened from solitary, small, easily approachable lesions, to more demanding procedures including the major liver resections such as left and right hepatectomies (10-14). The disease-related indications for LLRs included various conditions of benign, but also the malignant diseases especially the hepatocellular carcinoma and colorectal liver metastases (15-21). In our department the laparoscopic surgical procedures are widespread. The laparoscopic cholecystectomies

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Figure 1 Magnetic resonance imaging (MRI) record of the operated patient with focal nodular hyperplasia (FNH). The tumor located in segments II and III of the liver, shown with black arrows.

reports of laparoscopic operations of the echinococcic cysts performed in our institution (1,10,11). Through this paper we aim to report our initial experience in laparoscopic liver surgery with the emphasis on the first left lateral bisegmentectomy and to show a brief literature review onto the main problems and concems concerning the LLRs. Report of a case

Figure 2 Resected tumor along with the segment II and III of liver.

and appendectomies are performed routinely and have outnumbered the open cholecystectomies and appendectomies that are done only in a narrow spectrum of indications. Apart from that the explorations, the ulcer perforation and hernia repair are performed laparoscopically, as well. During last 10 years the elective splenectomies and colon resections are performed laparoscopically in the high number of cases. On the other hand, more than 100 open liver resections are performed per year. The experience in laparoscopic surgery and open liver surgery encouraged our surgeons to start performing LLRs. There have already been some

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A 29 years old female patient was admitted to hospital for operative therapy of a liver tumor found on a magnetic resonance imaging (MRI) scan preformed as gastroenterological workup for symptoms related to chronic gastritis (Figure 1). There were no co-morbidities other than mild ankylosing spondylitis and the general clinical state was proper to the age of the patient. According to MRI record the tumor was situated at the left hepatic lobe and its diameters were 62×57 mm. There were no other tumors found inside of the abdominal and thoracic cavity. The patient underwent the laparoscopic left lateral bisegmentectomy of the 2nd and 3rd liver segments (Figure 2). The resection was performed throe three skin incisions (Figure 3), using the harmonic scalpel and the vascular structures were ligated by the endoscopic vascular staplers (35 and 45 mm). The operation lasted for an hour. The patient spent a day in intensive care unit (ICU). There were no any early complication found and the patient was released home on the third postoperative day. The pathology of the resected tumor had shown the follicular nodular hyperplasia. The consequent perioperative period passed without complications.

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Figure 3 Postoperative skin incisions.

Report of laparoscopically treated patients with echinococcic liver disease In our institution 15 laparoscopic pericistectomies were performed to date. All patients were pre-operatively treated with albendazole. Total pericystectomy without opening the cyst cavity was performed laparoscopically in seven patients, while the partials pericystectomy was done laparoscopically five patients. In another three patients the procedure started laparoscopically but were converted and completed as an open procedure. The median operative time was 67.5 minutes (range, 60.0-120.0 minutes) and the median hospital stay 5.0 days (range, 4.0-7.0 days). In one patient the echinococcic cyst was situated in 7th liver segment and another three cysts were found intraabdominaly. All of them were removed laparoscopically. There were no complication nor recurrences reported until now in laparoscopically operated patients. During the same period of time 32 patients underwent the open operation of the echinococcic liver cysts. In those patients the operation lasted longer [mean operative time 100.0 minutes (range, 60.0-210.0 minutes)]. On the other hand, the hospital stay was longer in patient that underwent the open surgical procedure [median hospital stay 8.0 days (range, 7.0-14.0 days)]. Also there was one case of recurrence in patient treated with the open procedure 3 years following the operation. There was no mortality reported until now in both groups of patients. Discussion As the experience and technical improvement grow the spectrum of indications expands. According to recently published study the LLR can be performed safely in selected patients with both benign and malignant liver tumors regardless to the dimensions, location or previous operating

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history with comparable morbidity and mortality to those in open surgical procedures (12). LLRs were concluded to be comparable or even better than open liver resection in the context of intraoperative blood loss and the length of hospital stay (13). A similar or lower mortality (0.3%) and morbidity (10.5%) were reported at LLR in comparison to open operative technique of the liver resection (14). There was no significant difference in overall and disease-free 5-year survival rate for hepatocellular carcinoma between open and laparoscopic hepatectomies (15). The conversion rates vary from 8.1% to 17.6% and the reported rate of complications was 3.6% with the postoperative bile leakage rate of 1.1% in 27 analyzed studies that included 619 patients (16). Conclusions In our initial experience of operated patients the performed laparoscopic surgical procedures were found safe and efficient with the acceptable operative time and hospital stay. The data found in literature are encouraging, however the proper surgical training and experience the same as well technically equipped centers are essential for performing LLRs. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Busić Z, Lemac D, Stipancić I, et al. Surgical treatment of liver echinococcosis--the role of laparoscopy. Acta Chir Belg 2006;106:688-91. 2. Cai X, Li Z, Zhang Y, et al. Laparoscopic liver resection and the learning curve: a 14-year, single-center experience. Surg Endosc 2014;28:1334-41. 3. Reich H, McGlynn F, DeCaprio J, et al. Laparoscopic excision of benign liver lesions. Obstet Gynecol 1991;78:956-8. 4. Gagner M, Rheault M, Dubuc J. Laparoscopic partial hepatectomy for liver tumor [abstract]. Surg Endosc 1992;6:99. 5. Tranchart H, Dagher I. Laparoscopic liver resection: a review. J Visc Surg 2014;151:107-15. 6. Gigot JF, Glineur D, Santiago Azagra J, et al. Laparoscopic liver resection for malignant liver tumors: preliminary results of a multicenter European study. Ann Surg 2002;236:90-7.

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7. Kaneko H, Takagi S, Shiba T. Laparoscopic partial hepatectomy and left lateral segmentectomy: technique and results of a clinical series. Surgery 1996;120:468-75. 8. Laurent A, Cherqui D, Lesurtel M, et al. Laparoscopic liver resection for subcapsular hepatocellular carcinoma complicating chronic liver disease. Arch Surg 2003;138:763-9; discussion 769. 9. Dulucq JL, Wintringer P, Stabilini C, et al. Laparoscopic liver resections: a single center experience. Surg Endosc 2005;19:886-91. 10. Busić Z, Cupurdija K, Servis D, et al. Surgical treatment of liver echinococcosis--open or laparoscopic surgery? Coll Antropol 2012;36:1363-6. 11. Busić Z, Lovrić Z, Kolovrat M, et al. Laparoscopic operation of hepatic hydatid cyst with intraabdominal dissemination--a case report and literature review. Coll Antropol 2009;33 Suppl 2:181-3. 12. Han HS, Yoon YS, Cho JY, et al. Laparoscopic liver resection for hepatocellular carcinoma: korean experiences. Liver Cancer 2013;2:25-30. 13. Simillis C, Constantinides VA, Tekkis PP, et al. Laparoscopic versus open hepatic resections for benign and malignant neoplasms--a meta-analysis. Surgery 2007;141:203-11. 14. Nguyen KT, Gamblin TC, Geller DA. World review

of laparoscopic liver resection-2,804 patients. Ann Surg 2009;250:831-41. 15. Kaneko H, Takagi S, Otsuka Y, et al. Laparoscopic liver resection of hepatocellular carcinoma. Am J Surg 2005;189:190-4. 16. Laurence JM, Lam VW, Langcake ME, et al. Laparoscopic hepatectomy, a systematic review. ANZ J Surg 2007;77:948-53. 17. Jurisić I, Paradzik MT, Jurić D, et al. National program of colorectal carcinoma early detection in Brod-Posavina County (east Croatia). Coll Antropol 2013;37:1223-7. 18. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48) in Osijek-Baranja County from 2001 to 2006, Croatia. Coll Antropol 2013;37:1209-22. 19. Samardzić S, Mihaljević S, Dmitrović B, et al. First six years of implementing colorectal cancer screening in the Osijek-Baranja County, Croatia--can we do better? Coll Antropol 2013;37:913-8. 20. Boras Z, Kondza G, Sisljagić V, et al. Prognostic factors of local recurrence and survival after curative rectal cancer surgery: a single institution experience. Coll Antropol 2012;36:1355-61. 21. Krebs B, Kozelj M, Potrc S. Rectal cancer treatment and survival--comparison of two 5-year time intervals. Coll Antropol 2012;36:419-23.

Cite this article as: Rakić M, Patrlj L, Kliček R, Kopljar M, Đuzel A, Čupurdija K, Bušić Ž. The laparoscopic liver resections—an initial experience and the literature review. Hepatobiliary Surg Nutr 2014;3(5):313-316. doi: 10.3978/ j.issn.2304-3881.2014.09.10

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Hepatobiliary Surg Nutr 2014;3(5):313-316

Review Article

Complications after percutaneous ablation of liver tumors: a systematic review Eylon Lahat1, Rony Eshkenazy2, Alex Zendel3, Barak Bar Zakai2, Mayan Maor2, Yael Dreznik1, Arie Ariche2 1

Department of Surgery B, 2Department of HPB Surgery, 3Department of Surgery C, Chaim Sheba Medical Center, Tel-Hashomer, Sackler School

of Medicine, Tel-Aviv University, Tel-Aviv, Israel Correspondence to: Dr. Arie Ariche, MD. Department of HPB Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, 52621, Israel. Email: [email protected].

Background: Although ablation therapy has been accepted as a promising and safe technique for treatment of unrespectable hepatic tumors, investigation of its complications has been limited. A physician who performs ablation treatment of hepatic malignancies should be aware of the broad spectrum of complications. Proper management is possible only if the physician Performing ablation understands the broad spectrum of complications encountered after ablation. Objectives: To systematically review the complications after different ablation modalities: Radiofrequency ablation (RFA), microwave ablation (MWA) and Nano knife for the treatment of liver tumors and analyze possible risk factors that precipitate these complications. Search methods: We performed electronic searches in the following databases: MEDLINE, EMBASE and COCHARNE. Current trials were identified through the Internet (from January 1, 2000 to January 1, 2014). We included only studies who specific mentioned complications after liver ablation therapy (RFA/ MWA/Nano knife). Main results: A total of 2,588 publications were identified, after detailed examination only 32 publications were included in the review. The included studies involved 15,744 participants. According to the type of technique, 13,044 and 2,700 patients were included for RFA and MWA. Analysis showed a pooled mortality of 0.15% for RFA, and 0.23% for MWA. Conclusions: This systematic review gathers information from controlled clinical trials and observational studies which are vulnerable to different types of bias, never the less RFA and MWA can be considered safe techniques for the treatment of liver tumors. Keywords: Liver tumors; liver metastases; percutaneous ablation; systematic review Submitted Sep 04, 2014. Accepted for publication Sep 09, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.07 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.07

Introduction Hepatocellular carcinoma (HCC) and colorectal liver metastases (CLM) are the two most common malignant liver tumors. Hepatic resection (HR) is the only curative option, but only 15-20% of patients with liver metastases from CRC (CRLMs) are suitable for surgical standard treatment (1). For the HCC group, less than 30% of patients with HCC are eligible for surgery, mainly because of the multiplicity

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of the lesions that often occurs in a background of chronic liver disease, bad liver function, and deteriorating general condition (2,3). Several alternative treatments to control and potentially cure have been developed for use in patients with malignant liver tumors, whether primary or metastatic. Interventional therapies, such as percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MWA) and Nano knife has been developed for treating malignant

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liver tumors. RFA has gained wide acceptance by showing superior anticancer effects with low complications and mortality rate. Recently other emerging techniques such as MWA have attracted interest in clinical practice (4). However, these procedures will always entail some risks. Information regarding mortality and complications is absolutely essential for every intervention to permit an accurate assessment of the risks and benefits (5). One of the greatest persistent problems in hepatic ablation has been the inability to establish quality standards in ablation complications, success, local recurrence after ablation, and nonablation hepatic recurrence. Reports from the literature are heterogeneous because of the study design, sample size, different technical approaches, and number of centers reporting complications and non-uniform terms as well as different parameters to calculate the rate of complications (6-9). Major complications were defined as any symptom that developed after ablation and persisted for more than 1 week, or those that delayed hospital discharge, threatened the patient’s life, or led to substantial morbidity and disability (10). Major complication: included death, hemorrhage, RFA needle-track seeding, intra hepatic arterial pseudo aneurysm, RFA lesion abscess, perforation of gastrointestinal viscus, liver failure, biloma, biliary stricture, portal vein thrombosis, and hemothorax or pneumothorax requiring drainage, and minor complications including pain, fever, and asymptomatic pleural effusion. Our goal was to bring the most updated literature regarding current used techniques (“what we really do”). The use of PEI has become less favorable in the face of new modalities such MWA and Nano knife, hence we decided to remove this technique from this review. Ablation can be done either percutaneous or by surgery, in order to minimize bias related to surgery we decided to include only papers with percutaneous technique. Materials and methods

Search strategy A literature search was conducted on PubMed and EMBASE to identify clinical series of RFA, MWA and Nano knife procedures for liver tumours published between January 2000 and January 2014. Letters to the editors, supplements, review articles and case reports were excluded. The titles and abstracts of all potentially relevant trials were screened by one reviewer (LE). The full text articles of potentially relevant studies were obtained. Based on the full text article, another reviewer (HA) independently determined whether the study meets the inclusion/exclusion criteria. Data collection Information extracted from each study included: the number of patients, age and Child-Pugh score. The type of study were categorized as prospective, retrospective, observational or randomized trial and the type of intervention included RFA/MWA, the tumor according to type (HCC or metastasis). We extracted the data type for outcome measure using number of deaths, major complications and the description of the type of percutaneous ablative technique used. Assessment of complications In this study complications were reported in accordance with the guidelines recommended by the Working Group on Image-Guided Tumor Ablation (10). The definition of major complication is an event that leads to substantial morbidity and disability, increasing the level of care, or results in hospital admission or substantially lengthened hospital stay (SIR classifications C-E) (Table 1). This includes any case in which a blood transfusion or interventional drainage procedure is required. All other complications are considered minor. It is important to stress that several complications, such as pneumothorax or tumor seeding, can be either a major or minor complications.

Inclusion criteria Randomized controlled trials (RCTs) and nonrandomized comparative studies assessing HCC or CRLM treated with RFA, MWA or Nano knife treatment were considered for review. Only patients aged over 18 were included. In order to exclude small studies, we only considered studies analyzing more than 50 patients for at least one technique.

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Results The search on Medline and EMBASE databases provided a total of 2,588 citations (Figure 1). After screening title and abstract, 2,461 were discarded. The full text of the remaining 127 citations was examined in more detail, where 95 studies did not meet the inclusion criteria as described.

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Table 1 Procedure-related complication classification Category I No therapy, no consequence or adverse sequelae Category II Requires unplanned increase in level of care to a nominal degree, minimal consequence or adverse sequelae Category III Requires unplanned increase in level of care to intermediate degree, intermediate adverse sequelae, includes overnight admission for observation only and minor hospitalization Category IV Requires unplanned increase in level of care to major degree, major adverse sequelae, prolonged hospitalization (>48 h) Category V Death directly or indirectly related to procedure Print with authorization from publisher: John Wiley and Sons, License number: 3461161445472.

mortality and complications were primary outcomes.

Records identified using PubMed/EMBASE search N=2,588 Excluded records N=32 Records examined in detail for eligibility N=127

Excluded records failing to meet inclusion criteria

Studies included in the

N=32

systematic review N=32

Figure 1 Study flow diagram.

Finally 32 publications were included in the review. Characteristics Study design, participants and interventions Of the 32 studies selected for the review, one was randomized trials and 31 were observational studies (Table 2). All the reports were published after 2000 (n=32). There were 29 studies using RFA only and 2 using MWA only. One observational study evaluated RFA versus MWA. The included studies involved 15,744 participants. According to the type of technique, 13,044 and 2,700 patients were included for RFA and MWA respectively. The average age of patients ranged from 24 to 89 years. Mean tumor size treated ranged from 1.8 to 5.0 cm. In 16 studies,

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Specific outcomes Death and adverse events were assessed as secondary outcomes in 16 studies. Mean follow-up after treatment ranged from 10 to 137 months. For all percutaneous ablative techniques analyzed, mortality ranged from 0% to 0.88% and the pooled proportion was 0.16% (95% CI, 0.10-0.24%) by the random effects model. Individual analysis showed a pooled mortality of 0.15% for RFA, and 0.23% for MWA. Major complication rates were 4.1% and 4.6% for RFA and MWA respectively. The most frequent major complication was hemorrhage i n t r a p e r i t o n e a l , s u b c a p s u l a r, p l e u r a l , b i l i a r y a n d retroperitoneal hemorrhage requiring blood transfusion (Table 3). Meanwhile the minor complication rates were 5.9% and 5.7% for RFA and MWA. There was no statistically significant difference in the mortality rates, major complications, and minor complications between the RFA and MWA groups (P>0.05). Discussion Ablation techniques have gained wide acceptance as a safe alternative to surgery in the management of early HCC and metastatic liver tumors (43,44). The effectiveness of RFA in the treatment of malignant liver tumors has been proven by a number of clinical studies and medical practice reports (45-48). Recently, developments in MWA technology have demonstrated its

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Table 2 Baseline characteristics of studies included First author

Country Year

Patients (N)

Age (years)

Child-Pugh class

Tumor number

Mean tumor

A

B

HCC

Mets.

size (cm)

83

–

1.9

RFA

C

Intervention

Randomised trials Shibata (11)

Japan

2006

74

65 [41-83]

55

19

Observational studies Livraghi (12)

Italy

2000

114

64 [53-86]

100

14

–

126

–

5.4

RFA

Buscarini (13)

Italy

2001

88

68

56

29

1

101

–

NA

RFA

Livraghi (14)

Italy

2003

2,320

NA

NA

NA

NA

NA

–

3.1

RFA

Guglielmi (15)

Italy

2003

53

68 [48-88]

24

29

–

65

–

4

RFA

Rhim (16)

Korea

2003

1,139

NA

NA

NA

NA

1,303

360

NA

RFA

Ruzzenente (17) Italy

2004

87

68 [41-88]

48

39

–

104

–

3.9

RFA

Gillams (18)

Italy

2004

167

57 [34-87]

–

–

–

–

685

3.9

RFA

Chen (19)

China

2004

110

24-78

26

38

5

74

47

4.7

RFA

Lu (20)

US

2005

52

57

19

29

4

87

–

2.5

RFA

Lu (21)

China

2005

102

RFA: 54 [20-74]; 69

33

–

170

–

RFA: 2.6;

RFA;

MWA: 2.5

MWA

Raut (22)

US, Italy 2005

140

39-86

59

46

35

190

–

3

RFA

Chen (23)

China

2005

338

24-87

96

95

13

430

333

NA

RFA

Cabassa (24)

Italy

2006

59

72 [47-88]

51

8

–

68

–

3.1

RFA

Solmi (25)

Italy

2006

56

68 [45-81]

16

37

3

63

–

2.8

RFA

Choi (26)

Korea

2007

102

54 [31-73]

77

10

–

119

–

2

RFA

Poggi (27)

Italy

2007

250

63

NA

NA

NA

NA

NA

2.9

RFA

Choi (28)

Korea

2007

570

58

359

160

–

674

–

2.5

RFA

Livraghi (29)

Italy

2008

218

68

NA

NA

NA

218

–

NA

RFA

Kondo (30)

Japan

2008

2,480

NA

NA

NA

NA

NA

–

NA

RFA

Zavaglia (31)

Italy

2008

63

58

46

13

4

71

–

NA

RFA

Chen (32)

Taiwan

2008

104

58.6 [28-82]

NA

NA

NA

NA

NA

3.9

RFA

Casaril (33)

UK

2008

130

65 [33-85]

70

20

2

145

94

2.7

RFA

Sartori (34)

Italy

2008

181

60 [36-85]

NA

NA

NA

180

181

NA

RFA

Gillams (35)

UK

2008

309

64 [24-92]

–

–

–

–

NA

3.7

RFA

Liang (36)

China

2009

1,136

54 [23-83]

227

852

57

1,385

516

3.3

MWA

Solbiati (37)

Italy

2012

99

65±11.8

NA

NA

NA

–

202

2.2±1.1

–

Yu (38)

China

2011

1,462

55±11.7

447

942

73

1102

331

3.3±1.9

MWA

Kondo (39)

Japan

2010

589

68.4

396

B/C 151

–

–

2.42-2.73

RFA

Chang (40)

Korea

2010

2,630

61

NA

NA

NA

–

–

2.2

RFA

Francica (41)

Italy

2012

365

67±8

277

86

–

–

–

2.3

RFA

Lee (42)

Korea

2012

102

59.3±1

66

36

–

139

–

2.5±0.1

RFA

MWA: 50 [24-74]

Age recorded as mean ± SD or median [range]. NA, not available; RFA, radio frequency ablation; MWA, microwave ablation; HCC, hepatocellular carcinoma.

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Table 3 Major complications of radiofrequency ablation (RFA)

Prospective studies may report more accurately the number of participants lost to follow-up, the timing of collecting complications and the adequate predefined definitions for harms. It is well understood that the risk of complications can be reduced by proficiency in technique and refinement in pretreatment assessments. There are several strategies for decreasing complications after ablation of hepatic tumors (51). The first key strategy is prevention by not to perform ablation in patients at high risk, meticulous pre evaluation of candidates should be performed, especially in regard to coagulopathy, underlying hepatic reserve, and tumor proximity to major structures such as the bile duct or intestine. In a patient with correctable coagulopathy, ablation should be postponed until all parameters are corrected. Early detection cannot reduce the frequency of complications such as infection or bleeding, but it can potentially minimize their clinical magnitude. Thus, the operator and other medical personnel should be knowledgeable about the spectrum of various complications after ablation because complications can be detected even during the procedure in some cases. Close immediate follow-up with clinical and laboratory data is also essential for early detection of complications.

and microwave ablation (MWA) Intra-peritoneal bleeding Portal vein thrombosis Intra-hepatic hematomas Bile leak Biloma Bile duct injury Liver dysfunction Liver abscess Intestinal perforation Diaphragmatic hernia Hemothorax Intractable pleural effusion Tumour implantation

unique advantage (49,50). Although we intended to include Nano knife in our review there are no publications up to now that met our inclusion criteria and a solid conclusion could not be excreted. Post ablation complications such as liver failure, intraperitoneal bleeding, abscess, bile duct injury, tumor seeding are very serious, and can be life threatening (51,52), other complication can prolonged hospitalization and increase morbidity. Being well aware of the complications and the choice of treatment method will lead to a more practical application and enable this procedure to be safer and more effective. The results without heterogeneity show a mortality of 0.15% and 0.23% for RFA and MWA, respectively. The prevalence of major complications in the reported studies ranged from 1.52% to 4.7%, calculated by using a random effects model in the presence of significant heterogeneity, were 4.1% for RFA and 4.6% for MWA. MWA-associated mortality was reported to occur in 0.002% according to a systematic review of this technique (53). Major complication rates have been reported to be higher with MWA than with RFA in a randomized trial. Our results indicated that MWA is a safe technique in terms of mortality and major complication rate. However, the results should be interpreted with caution and more reports including large number of patients are needed to make a solid conclusion. The difference between the reported complication rates can be explained by several factors: single/multicenter studies, prospective/retrospective studies.

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Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Vanagas T, Gulbinas A, Pundzius J, et al. Radiofrequency ablation of liver tumors (I): biological background. Medicina (Kaunas) 2010;46:13-7. 2. Verslype C, Van Cutsem E, Dicato M, et al. The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008. Ann Oncol 2009;20 Suppl 7:vii1-vii6. 3. Zhu AX. Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives. Semin Oncol 2012;39:493-502. 4. Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology 2010;52:762-73. 5. Lencioni R, Crocetti L, De Simone P, et al. Loco-regional interventional treatment of hepatocellular carcinoma: techniques, outcomes, and future prospects. Transpl Int

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2010;23:698-703. 6. Curley SA, Marra P, Beaty K, et al. Early and late complications after radiofrequency ablation of malignant liver tumors in 608 patients. Ann Surg 2004;239:450-8. 7. de Baère T, Risse O, Kuoch V, et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR Am J Roentgenol 2003;181:695-700. 8. Kasugai H, Osaki Y, Oka H, et al. Severe complications of radiofrequency ablation therapy for hepatocellular carcinoma: an analysis of 3,891 ablations in 2,614 patients. Oncology 2007;72 Suppl 1:72-5. 9. Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 2005;103:1201-9. 10. Goldberg SN, Charboneau JW, Dodd GD 3rd, et al. Image-guided tumor ablation: proposal for standardization of terms and reporting criteria. Radiology 2003;228:335-45. 11. Shibata T, Shibata T, Maetani Y, et al. Radiofrequency ablation for small hepatocellular carcinoma: prospective comparison of internally cooled electrode and expandable electrode. Radiology 2006;238:346-53. 12. Livraghi T, Goldberg SN, Lazzaroni S, et al. Hepatocellular carcinoma: radio-frequency ablation of medium and large lesions. Radiology 2000;214:761-8. 13. Buscarini L, Buscarini E, Di Stasi M, et al. Percutaneous radiofrequency ablation of small hepatocellular carcinoma: long-term results. Eur Radiol 2001;11:914-21. 14. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441-51. 15. Guglielmi A, Ruzzenente A, Battocchia A, et al. Radiofrequency ablation of hepatocellular carcinoma in cirrhotic patients. Hepatogastroenterology 2003;50:480-4. 16. Rhim H, Yoon KH, Lee JM, et al. Major complications after radio-frequency thermal ablation of hepatic tumors: spectrum of imaging findings. Radiographics 2003;23:12334; discussion 134-6. 17. Ruzzenente A, Manzoni GD, Molfetta M, et al. Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation. World J Gastroenterol 2004;10:1137-40. 18. Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metastases in 167 patients. Eur Radiol 2004;14:2261-7. 19. Chen MH, Yang W, Yan K, et al. Large liver tumors: protocol for radiofrequency ablation and its clinical

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application in 110 patients--mathematic model, overlapping mode, and electrode placement process. Radiology 2004;232:260-71. 20. Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 2005;41:1130-7. 21. Lu MD, Xu HX, Xie XY, et al. Percutaneous microwave and radiofrequency ablation for hepatocellular carcinoma: a retrospective comparative study. J Gastroenterol 2005;40:1054-60. 22. Raut CP, Izzo F, Marra P, et al. Significant long-term survival after radiofrequency ablation of unresectable hepatocellular carcinoma in patients with cirrhosis. Ann Surg Oncol 2005;12:616-28. 23. Chen MH, Yang W, Yan K, et al. Treatment efficacy of radiofrequency ablation of 338 patients with hepatic malignant tumor and the relevant complications. World J Gastroenterol 2005;11:6395-401. 24. Cabassa P, Donato F, Simeone F, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term experience with expandable needle electrodes. AJR Am J Roentgenol 2006;186:S316-21. 25. Solmi L, Nigro G, Roda E. Therapeutic effectiveness of echo-guided percutaneous radiofrequency ablation therapy with a LeVeen needle electrode in hepatocellular carcinoma. World J Gastroenterol 2006;12:1098-104. 26. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series. Eur Radiol 2007;17:684-92. 27. Poggi G, Riccardi A, Quaretti P, et al. Complications of percutaneous radiofrequency thermal ablation of primary and secondary lesions of the liver. Anticancer Res 2007;27:2911-6. 28. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for recurrent hepatocellular carcinoma after hepatectomy: long-term results and prognostic factors. Ann Surg Oncol 2007;14:2319-29. 29. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 2008;47:82-9. 30. Kondo Y, Yoshida H, Tateishi R, et al. Percutaneous radiofrequency ablation of liver cancer in the hepatic dome using the intrapleural fluid infusion technique. Br J Surg

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2008;95:996-1004. 31. Zavaglia C, Corso R, Rampoldi A, et al. Is percutaneous radiofrequency thermal ablation of hepatocellular carcinoma a safe procedure? Eur J Gastroenterol Hepatol 2008;20:196-201. 32. Chen TM, Huang PT, Lin LF, et al. Major complications of ultrasound-guided percutaneous radiofrequency ablations for liver malignancies: single center experience. J Gastroenterol Hepatol 2008;23:e445-50. 33. Casaril A, Abu Hilal M, Harb A, et al. The safety of radiofrequency thermal ablation in the treatment of liver malignancies. Eur J Surg Oncol 2008;34:668-72. 34. Sartori S, Tombesi P, Macario F, et al. Subcapsular liver tumors treated with percutaneous radiofrequency ablation: a prospective comparison with nonsubcapsular liver tumors for safety and effectiveness. Radiology 2008;248:670-9. 35. Gillams AR, Lees WR. Five-year survival in 309 patients with colorectal liver metastases treated with radiofrequency ablation. Eur Radiol 2009;19:1206-13. 36. Liang P, Wang Y, Yu X, et al. Malignant liver tumors: treatment with percutaneous microwave ablation-complications among cohort of 1136 patients. Radiology 2009;251:933-40. 37. Solbiati L, Ahmed M, Cova L, et al. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology 2012;265:958-68. 38. Yu J, Liang P, Yu XL, et al. Needle track seeding after percutaneous microwave ablation of malignant liver tumors under ultrasound guidance: analysis of 14-year experience with 1462 patients at a single center. Eur J Radiol 2012;81:2495-9. 39. Kondo Y, Shiina S, Tateishi R, et al. Intrahepatic bile duct dilatation after percutaneous radiofrequency ablation for hepatocellular carcinoma: impact on patient’s prognosis. Liver Int 2011;31:197-205. 40. Chang IS, Rhim H, Kim SH, et al. Biloma formation after radiofrequency ablation of hepatocellular carcinoma: incidence, imaging features, and clinical significance. AJR Am J Roentgenol 2010;195:1131-6. 41. Francica G, Saviano A, De Sio I, et al. Long-term effectiveness of radiofrequency ablation for solitary small hepatocellular carcinoma: a retrospective analysis of 363 patients. Dig Liver Dis 2013;45:336-41. 42. Lee HS, Park SY, Kim SK, et al. Thrombocytopenia represents a risk for deterioration of liver function after radiofrequency ablation in patients with hepatocellular

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carcinoma. Clin Mol Hepatol 2012;18:302-8. 43. Khan MR, Poon RT, Ng KK, et al. Comparison of percutaneous and surgical approaches for radiofrequency ablation of small and medium hepatocellular carcinoma. Arch Surg 2007;142:1136-43; discussion 1143. 44. Guglielmi A, Ruzzenente A, Valdegamberi A, et al. Radiofrequency ablation versus surgical resection for the treatment of hepatocellular carcinoma in cirrhosis. J Gastrointest Surg 2008;12:192-8. 45. Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 2009;249:20-25. 46. Yan K, Chen MH, Yang W, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term outcome and prognostic factors. Eur J Radiol 2008;67:336-347. 47. Lencioni R, Crocetti L. Radiofrequency ablation of liver cancer. Tech Vasc Interv Radiol 2007;10:38-46. 48. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243:321-8. 49. Liang P, Wang Y. Microwave ablation of hepatocellular carcinoma. Oncology 2007;72 Suppl 1:124-31. 50. Jones C, Badger SA, Ellis G. The role of microwave ablation in the management of hepatic colorectal metastases. Surgeon 2011;9:33-7. 51. Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441-51. 52. Giorgio A, Tarantino L, de Stefano G, et al. Complications after percutaneous saline-enhanced radiofrequency ablation of liver tumors: 3-year experience with 336 patients at a single center. AJR Am J Roentgenol 2005;184:207-11. 53. Ong SL, Gravante G, Metcalfe MS, et al. Efficacy and safety of microwave ablation for primary and secondary liver malignancies: a systematic review. Eur J Gastroenterol Hepatol 2009;21:599-605.

Cite this article as: Lahat E, Eshkenazy R, Zendel A, Bar Zakai B, Maor M, Dreznik Y, Ariche A. Complications after percutaneous ablation of liver tumors: a systematic review. Hepatobiliary Surg Nutr 2014;3(5):317-323. doi: 10.3978/ j.issn.2304-3881.2014.09.07

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Review Article

The surgical treatment of patients with colorectal cancer and liver metastases in the setting of the “liver first” approach Leonardo Patrlj1, Mario Kopljar1, Robert Kliček1, Masa Hrelec Patrlj2, Marijan Kolovrat1, Mislav Rakić1, Antonija Đuzel1 1

Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10 000 Zagreb, Croatia; 2Department

of Childrens’ Surgery, Clinical Hospital for Childrens’ Disease, Zagreb, Klaićeva, 10 000 Zagreb, Croatia Correspondence to: Robert Kliček, MD, PhD. Department of Abdominal Surgery, Surgical Clinic, Clinical Hospital Dubrava, Zagreb, Avenija Gojka Šuška 6, 10 000 Zagreb, Croatia. Email: [email protected].

Abstract: A surgical resection is the only curative method in the therapy of colorectal carcinoma and liver metastases. Along with the development of interventional radiological techniques the indications for surgery widen. The number of metastases and patients age should not present a contraindication for surgical resection. However, there are still some doubts concerns what to resect first in cases of synchronous colorectal carcinoma and liver metastases and how to ensure the proper remnant liver volume in order to avoid postoperative liver failure and achieve the best results. Through this review the surgical therapy of colorectal carcinoma and liver metastases was revised in the setting of “liver-first” approach and the problem of ensuring of remnant liver volume. Keywords: Colorectal liver metastases; liver resections; remnant volume; “liver-first” approach Submitted Sep 08, 2014. Accepted for publication Sep 16, 2014. doi: 10.3978/j.issn.2304-3881.2014.09.12 View this article at: http://dx.doi.org/10.3978/j.issn.2304-3881.2014.09.12

Introduction Treatment of colorectal cancer and liver metastases are an extremely important clinical issue since that there are nearly a million newly diagnosed cases and nearly half of the million reported deaths worldwide (1). In large number of countries the incidence continue to rise (2), although the standardized prevention national programs of early detection have developed and brought to an earlier detection and diagnosed cases in early stage of tumor (3-5). In Asian countries, such as China, Japan, South Korea, and Singapore, a 2-4-fold increase in the incidence of colorectal cancer in the past few decades is experienced (6). In Western World the colorectal cancer is reported as the third the most frequent cancer and the most frequent cancer in population older than 75 years (7). Approximately 25% of newly diagnosed patients with colorectal cancer will have liver metastases at the time of diagnosis, another 25% will develop liver metastases during the course of the disease and two-thirds of all patients with

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liver metastases will die of them (8). The 10-year survival rate for patients with stage I disease is 90%, but for patients with inoperable stage IV disease, it is currently only 5% (9). For patients with liver metastases, the treatment strategy should be directed toward resectability (10). The multidisciplinary therapeutic approach, consisting of new and more effective chemotherapeutic agents in single or combined therapy, an advanced role of interventional radiology with portal vein embolization (PVE) and tumor ablation and new strategies and techniques for hepatic resections, brought improved resectability rate of metastases to 20-30% of cases and has resulted in 5-year survival of 35-50% for selected cases (11-13). A need has been recognized for a new staging system that acknowledges the improvements in surgical techniques for resectable metastases and the impact of modern chemotherapy on rendering initially unresectable liver metastases from colorectal carcinoma resectable while distinguishing between patients with a chance for cure at presentation and those for whom only palliative treatment is possible (14).

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There have been presented the predictive factors for survival and local recurrence (15,16). Traditionally, a staged approach (colorectal first) has been used in the management of patients with synchronous colorectal cancer and liver metastases. This involves the initial extirpation of the primary tumor. Systemic chemotherapy followed the operation, after which liver-directed operation was performed. The last 2 decades have brought an increased understanding of the biology of colorectal liver metastases, resulting in more effective targeted therapies in addition to decreased mortality after liver-directed operations (17,18). The goal of this review is to focus onto the doubts concerning the operators all around the world in the context of reassuring the proper remnant liver volume and especially what to resect first in the cases of synchronous liver metastases of colorectal carcinoma. The preoperative imaging and planning the surgical resection The R0 resection is the ultimate goal of the surgical therapy. However the proper indication is essential in order to achieve adequate result of resection. Resectability depends onto the multiple factors: the number and location of metastases, the remnant liver volume and quality of the liver tissue that is not infiltrated by tumor. All lesions identified at the initial imaging records (CT or MRI) before any therapy is performed have to be accounted during planning the liver resection in order to predict the total risk and the outcome of surgical procedure. It is recognized that chemotherapy can induce toxic injury of liver tissue, primarily steatohepatitis and sinusoidal injury. Non-contrast CT and MRI could be used to assess steatosis (19-21), but steatohepatitis cannot be diagnosed with imaging. Sinusoidal injury can be judged by indirect signs of portal hypertension, particularly spleen size (22), or by using the liver-specific MRI contrast agent gadoxetic acid (23). The essential three points that are ultimate for complete resection are preservation of liver vascularity, the adequate remnant liver volume with reference to body weight and total liver volume, and that the quality of the remnant liver parenchyma is acceptable (24). The ultrasound (US), especially contrast enhanced ultrasound (CEUS) presents a unique imaging method for intraoperative assessment of unrevealed metastases, and the relation between tumor and vascular and biliar structures (25), sometimes even significantly more sensitive than CT and/or MRI preoperative imaging records (26). For the detection of extra hepatic metastases and local recurrence at the site of the initial colorectal surgery, apart

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from CT the use of FDG-PET is widespread. A high quality CT can detect the majority of extrahepatic disease, however the FDG-PET may reveal additional signs of disease as high metabolic activity. Although some studies showed a change in management in 10-20% of patients according to record of FDG-PET (27,28), some reports lower percentage and even seem to be more suspicious in its cost-effective role (29), especially in the context of FDG-records following the preoperative chemotherapy which reduces its sensitivity. The surgical resection—what to resect first in synchronous metastases? Surgical treatment of colorectal liver metastases remains the only treatment associated with a long survival time in patients with liver metastases from colorectal carcinoma, with a 40% survival at 5 years and almost 25% postoperative survival up to 10 years in specialized centers (30). The very important issue that the liver surgeon has to deal with is to proceed decide what to resect first liver or colon and/or when to undertake simultaneous surgical resections of both. The perfect solution seems to be a single stage colon and liver operation. The advantage of the one stage procedure could be less psychological stress for the patient, lower financial cost and shorter hospitalization time. On the other hand the advantages of the staged procedure are that there is no accumulation of the risks of liver and bowel resections at the same time. Neoadjuvant chemotherapy may be given before liver resection, and an extended hepatectomy or demanding bowel resection could be performed with the full attention of the surgical team focused on the liver or bowel disease, although, the key point for decision-making is the patient’s safety (1). According to the reported initial experience with simultaneous versus staged resections, a French multicenter study showed an operative mortality of 7% for simultaneous 2% for staged surgery (31), while in a single center US study the mortality was 12% for simultaneous and 4% for staged resections (32). Several studies reported simultaneous operations performed without mortality, however patients were selected by experienced hepatobiliary surgeons and the major hepatectomies were avoided in elderly patients the same as in those with demanding colorectal surgery (33-36). In addition, since the surgical mortality rate is significantly higher when surgery of extensive hepatic resections is combined with colorectal resection (37), this approach should be only performed in carefully selected patients. The standard staged operative treatment recommendations

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in the literature suggest resection of the primary tumor followed by chemotherapy for 3-6 months and second stage of surgical treatment that includes liver surgery. The problem with this approach lies in the fact that liver metastases determine survival more intensive than the primary colorectal tumor. Chemotherapy can sometime not be performed after the surgical treatment of the primary tumor, especially when complicated by anastomotic leak or dehiscence, which occurs in 6-12% of patients (38,39). In cases of advanced rectal cancer usually a long term of radio-chemotherapy of 5 weeks is recommended and the second stage of operative treatment is planned 6-10 weeks following the neoadjuvant therapy. Therefore the patients do not receive a therapy of liver metastases for almost 15 weeks, which brings to the progress of liver metastatic disease (40). On the other hand some experimental studies have reported the rapid growth of metastases after removal of primary tumor (41,42). The underlying mechanism for those experimental results could be the loss of primary tumor-induced inhibition of angiogenesis in the metastases, which supports the founding of the increase of vascular density in humans after resection of primary tumor (43). The reverse surgical approach onto the surgical treatment of colorectal liver metastases known as “liver-first” approach is reported as feasible and safe procedure with promising results, although it brings along the risk of bowel obstruction following the growth of primary tumor, which can be avoided by Hartmanns procedure (39,44). Results from the Liver Met Survey, involving 13,334 patients from 330 centers in 58 countries who underwent surgery for liver metastases, reported a better survival outcome in patients who undergo first resection of liver metastases than in those who do not (45). A recent systematic review of studies published in 1999-2010 confirmed these results and revealed 5-year survival rates for patients with liver metastases in the range of 16-74% (median, 38%) after liver resection (46). The main idea of the “liver first” approach was to avoid the time loss between the operative therapy of primary tumor and the oncological therapy. Since the patients with rectal cancer often require a complex oncological therapy (chemotherapy, radiotherapy, and a complex pelvic operation), they could be the most proper candidates for such an approach (47). Despite liver-first patients usually have a greater hepatic disease burden and undergoing major resection more often, the reverse strategy was found safe and had long-term outcomes comparable to those of the other approaches (48).

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How to achieve resectability without chemotherapy? A large number of liver metastases should not be an absolute contraindication to surgery combined with chemotherapy provided that resection can be complete, with preservation of a functioning liver remnant of 25-30% (49). However, the problem is the loss of the proper functioning remnant volume of normal liver tissue, which presents an absolute contraindication for surgical resection. Advances in interventional radiology, particularly PVE in which the hypertrophy of normal liver tissue is provoked in order to ensure the proper remnant volume (50) and radiofrequency thermal ablation (RFA) widened the indications for surgical treatment of patients with colorectal cancer and liver metastases. In patients planned for major hepatectomies and with an otherwise normal liver, preoperative PVE is recommended when the ratio of the remnant liver to total liver volume is estimated to be less than 30%, whereas in patients with neoadjuvant chemotherapy this ratio is considered to be 40% (51,52). PVE is a safe procedure, but manipulation of the embolic material to the main portal vein or into branches that supply the future remnant liver remains a risk (1). RFA was initially anticipated for local treatment of hepatocellular carcinoma but has recently found application for the management of colorectal liver metastases, where its indications are still under doubt. Critical review of the results of RFA shows that it must be restricted in cases with a maximum of 3 lesions with the size of the biggest lesion less than 3 cm (53). Another limitation for the use of RFA in the management of colorectal liver metastases is the anatomic location of the lesion near big vessels, which increases the risk of incomplete ablation due to reduced heat effect that is used (54). A great indication of RFA is actually recurrence after resection, detected as small lesions, so it is possible not to interrupt chemotherapy (55). A novel method in liver surgery that can solve the problem of remnant volume is the associating of liver partition and portal vein ligation (ALPPS) firstly reported 3 years ago (56). In ALPPS approach, the portal vein ligation associated with in situ splitting is able to induce enormously accelerated hypertrophy (57). The neovascularization and persistence of interlobar perfusion are prevented by performing parenchymal dissection and complete devascularization of segment IV (56). The nearly total parenchymal dissection induced a median hypertrophy of 74%, which is markedly above the range that can be achieved by portal vein ligation or PVE alone (58,59).

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Conclusions Surgical R0 resection still remains the only curative therapeutic tool in patients with colorectal cancer and liver metastases. The proper diagnostic algorithm is ultimate. The indications for surgical treatment are enlarged by the progress in neoadjuvant chemotherapy, diagnostic imaging, interventional radiology procedures especially the usage of PVE and radio frequent ablation. On the other hand the surgical techniques still develop producing the new pathways of treatment such as “liver-first approach” in the context of 2-stage operative therapy and ALPPS for the ensuring the remnant liver volume. Simultaneous liver and colorectal operations are feasible at carefully selected patients but should be avoided in cases of major hepatectomies, in elderly patients, and in patients with too complex intraoperative asset of colorectal tumor. The 2-stage hepatectomies as well as the “liver first” approach seem to become the new treatment strategies that improved the prognosis in patients in whom an R0 resection can be achieved with curative intention. The multidisciplinary treatment therapeutic approach in patients with colorectal cancer and liver metastases is essential to make the proper treatment plan and achieve the best results. Acknowledgements Disclosure: The authors declare no conflict of interest. References 1. Dimitroulis D, Nikiteas N, Troupis T, et al. Role of surgery in colorectal liver metastases: too early or too late? World J Gastroenterol 2010;16:3484-90. 2. Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Version 1.2, Cancer Incidence and Mortality Worldwide. IARC Cancer Base No.10. Available online: http:// globocan.iarc.fr. accessed November 23, 2011. 3. Jurisić I, Paradzik MT, Jurić D, et al. National program of colorectal carcinoma early detection in Brod-Posavina County (east Croatia). Coll Antropol 2013;37:1223-7. 4. Milas J, Samardzić S, Miskulin M. Neoplasms (C00-D48) in Osijek-Baranja County from 2001 to 2006, Croatia. Coll Antropol 2013;37:1209-22. 5. Samardzić S, Mihaljević S, Dmitrović B, et al. First six years of implementing colorectal cancer screening in the Osijek-Baranja County, Croatia--can we do better? Coll Antropol 2013;37:913-8.

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Cite this article as: Patrlj L, Kopljar M, Kliček R, Hrelec Patrlj M, Kolovrat M, Rakić M, Đuzel A. The surgical treatment of patients with colorectal cancer and liver metastases in the setting of the “liver first” approach. Hepatobiliary Surg Nutr 2014;3(5):324-329. doi: 10.3978/j.issn.2304-3881.2014.09.12

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