Ca Cervix Trachelectomy Fertility.docx

A. Introduction Cervical cancer is the third most common cancer (after breast and colorectal cancer) in women, with an estimated 500.000 new cases and 275.000 related deaths annually [1]. Almost 85% of the cases occur in undeveloped countries, accounting for 15% of all cancers in women. In developed countries cervical cancer accounts for 3.6% of new cancers, with an incidence of 14 cases per 100.000 women [2]. The median age of cervical cancer diagnosis worldwide is between 40 and 60 years. Cervical cancer is rarely diagnosed in patients older than 75 year, accounting for only 8.6% of new diagnosis of cervical cancer. In the European Union, 20.9% of women are diagnosed with cervical cancer under the age of 40, which often poses a complication regarding pregnancy plans of women. The average age of women who give birth in Europe is 30.1 years [2]. Forty percent of all stage I cervical cancers are diagnosed before the age of 40 [3]. As more women are delaying pregnancy, preservation of fertility and reproductive function is become a major concern. During the last 3 decades, the use of fertility-sparing surgery (FSS) has gained momentum in the management of cervical cancer, whereas standard surgery in early stage disease is based on a radical hysterectomy (and lymph node dissection), thereby depriving patients of subsequent fertility (1–3). The ‘‘cornerstone’’ of conservative surgery is the radical trachelectomy (RT), first introduced 3 decades ago by Daniel Dargent (using a laparoscopic approach to remove the lymph nodes and a vaginal approach to remove the upper part of the vagina, the cervix, and proximal part of parametria) (1). Other treatment modalities or approaches were defined during that period, and at present five different FSS procedures are now available for cervical cancer: conization or a simple trachelectomy, a vaginal RT, an abdominal RT (a laparotomic or a minimally invasive procedure using a pure laparoscopic or a robotassisted laparoscopic RT), and neoadjuvant chemotherapy (NACT) followed by FSS (conizzation/simple trachelectomy or RT).

B. Cervical Cancer 1. Incidence Cervical cancer is the third most common cancer in women, with an estimated 529 828 new cases and 275 128 deaths reported worldwide in 2008. More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers [1]. In developing countries, the age standardized mortality rate is 10/10 000— more than three times higher than in developed countries [2]. It is common knowledge that the most important cause of cervical cancer is persistent papillomavirus infection. The human papillomavirus (HPV) is detected in 99% of cervical tumors, in particular the oncogenic subtypes such as HPV 16 and 18. While Papanicolau smears are used in the classical primary screening technique, HPV DNA testing, introduced in 2008, is well diffused in developed countries and is taking off in developing countries with a potentially significant reduction in the numbers of advanced cervical cancers and deaths [3]. In the HPV vaccination era, we expect that the cervical cancer incidence will be reduced, especially in those developed countries where large-scale immunization has been introduced. Most developed countries have introduced HPV vaccines into routine vaccination programs and more than 60 million doses have already been distributed in 2010, which could guarantee a protection rate of ∼70% [4]. However, cervical cancer still represents a major public health problem even in developed countries: 54 517 new cases of invasive cervical cancer are diagnosed in Europe every year and 24 874 women die of this disease [4].

2. Pathogenesis-Molecular Study HPV has been recognized as the most important etiologic factor in cervical cancer. HPV16/18 account for at least two-thirds of cervical carcinomas in all continents; HPV 31, 33, 35, 45, 52, and 58 are the next most common types in cancers globally. A prophylactic vaccine against HPV16/18 has the potential to prevent more than two-thirds of worldwide cervical carcinomas and half of high-grade squamous intraepithelial lesions. These proportions may be even higher due to cross-protection against other highrisk HPV-type infections.

Squamous cell carcinomas and their precursor, intraepithelial squamous lesions, are related to HPV infection in almost all the cases and the presence of HPV 18 DNA is associated with poor prognosis. Adenocarcinomas encompass a heterogeneous group of tumors. Endocervical adenocarcinoma of usual type and its precursor, the adenocarcinoma in situ, have been shown to be positive for HPV in nearly 90% and 100% of cases. HPV 18 is more common in adenocarcinomas and adenosquamous carcinomas than in squamous cell carcinomas. Unlike endocervical adenocarcinoma of usual type, the other more rare types including clear-cell and mesonephric adenocarcinoma seem to be unrelated to HPV. Several markers identified along the carcinogenetic pathways have been studied. P53 RAS mutations are rare in cervical carcinomas. EGFR, HER2, VEGS, COX-2, and c-myc were tested as prognostic or predictive factors, but the results were not conclusive. Similarly, estrogen and progesterone receptors do not play a significant role; however, they can be useful in differential diagnosis between endocervival type and endometrioid adenocarcinomas, together with vimentine, CEA, and p16.

3. Diagnosis and staging work-up a. Pathology A biopsy is mandatory to establish the diagnosis of cervical cancer. All lesions must be confirmed by histopathological examination. Punch biopsies from the edge of the gross tumour are recommended. Over 90% of cervical cancers are squamous cell carcinoma, followed by about 10% of adenocarcinomas and nearly 1% clear cell (mesonephric) carcinoma. Verrucous carcinoma is a well differentiated variant of squamous cell carcinoma. Other less frequent histopathologic specimens include adenosquamous carcinoma, glassy cell carcinoma, malignant Müllerian mixed tumours, adenoid cystic carcinoma, small cell carcinoma (one third to one half are neuroendocrine markers positive), basaloid (or adenoid-basal) carcinoma, sarcomas and lymphomas [65]. b. Staging Once a histological diagnosis of cervical cancer has been made, the next step is to formulate the most effective therapy for the individual patient. In order to

properly manage a patient with cervical cancer, it is essential to understand the extent of the stage of disease at the time of diagnosis. A major purpose of staging is to determine the extent of disease, so as to provide a method of comparing clinical experience and treatment results among institutions without confusion or ambiguity. Staging systems should be validated by showing a correlation between stage of disease and patient prognosis. They also guide the clinician in both tailoring the treatment and assessing prognosis. Table 1. Comparison of TNM categories and FIGO staging TNM categories

FIGO stages

TX

Primary tumor cannot be assessed.

T0 Tisb T1

I

No evidence of primary tumor. Carcinoma in situ (preinvasive carcinoma). Cervical carcinoma confined to uterus (extension to corpus should be disregarded).

T1ac

IA

T1a1

IA1

T1a2

IA2

Measured stromal invasion >3.0 mm and ≤5.0 mm with a horizontal spread of ≤7.0 mm.

T1b

IB

Clinically visible lesion confined to the cervix or microscopic lesion >T1a/IA2.

T1b1

IB1

Clinically visible lesion ≤4.0 cm in greatest dimension.

T1b2

IB2

Clinically visible lesion >4.0 cm in greatest dimension.

T2

II

Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina.

T2a T2a1 T2a2

IIA IIA IIA2

Tumor without parametrial invasion. Clinically visible lesion ≤4.0 cm in greatest dimension. Clinically visible lesion >4.0 cm in greatest dimension.

T2b T3

IIB III

Tumor with parametrial invasion. Tumor extends to pelvic wall and/or involves lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney.

T3a

IIIA

Tumor involves lower third of vagina, no extension to pelvic wall.

T3b

IIIB

Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney.

T4

IV

The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.

T4a T4b

IVA IVB

Spread of the growth to adjacent organs. Spread to distant organs.

Invasive carcinoma diagnosed only by microscopy. Stromal invasion with a maximum depth of 5.0 mm measured from the base of the epithelium and a horizontal spread of ≤7.0 mm. Vascular space involvement, venous or lymphatic, does not affect classification. Measured stromal invasion ≤3.0 mm in depth and ≤7.0 mm in horizontal spread.

The classification of the International Federation of Gynecology and Obstetrics (FIGO), which is based on tumour size and the extent of the disease in the

pelvis and distant organs, is recommended for the staging of invasive cervical cancer [66]. The extent of cancer is assessed clinically through the history and physical examination, including a careful pelvic examination, supplemented by a limited number of relatively unsophisticated investigations. In many low resource settings, vaginal and rectal examinations are the only feasible approaches to staging. This assessment can be done under general anaesthesia, preferably together with a gynaecologist or gynaecologic oncologist if the conditions for a thorough pelvic examination are suboptimal. In addition, if an examination under anaesthesia is performed, it is recommended to carry out proctoscopy and cystoscopy in patients with advanced stages of the disease (FIGO stage IIB or greater) or when rectal and/or urinary complaints are present. Imaging modalities that provide additional staging and prognostic information are computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/PET-CT [67–71].

-

Clinical staging Clinical staging is based on clinical evaluation, including bimanual vaginal and rectal examinations, imaging studies, and specific procedures. The pelvic examination, preferably under general anaesthesia, must be performed in all cases [66]. FIGO provides a list of additional examinations allowed: endocervical

curettage,

hysteroscopy,

cystoscopy,

proctoscopy or

colonoscopy, intravenous urography (IVU) and chest X ray. Suspected bladder or rectal involvement should be confirmed by biopsy and histological evidence of tumour involvement. For staging purposes, biopsy or conization is regarded as part of the clinical examination and diagnosis [66, 72, 73]. Other diagnostic procedures such as ultrasound (US), CT scans, MRI, PET/PET-CT scans, barium enema X rays and laparoscopy may be used, but results cannot alter the initial clinical stage [72, 74]. Although FIGO recommends using IVU, this has been largely replaced by the abdominal–pelvic CT scan with contrast. The FIGO

staging system does not take into account the radiological findings from CT, MRI or PET/PET-CT. However, the findings from these imaging studies should be recorded using the tumour, node, metastasis (TNM) classification and taken into account for treatment decisions. -

Post-surgical pathologic staging The histopathological findings after a radical surgical procedure do not change the initial FIGO clinical staging and should be documented using the TNM system (see Annexes I and II). Adequate and detailed information should be obtained from the responsible pathologist regarding potential histopathological risk factors that would impact decisions in terms of adjuvant therapy. In order to identify histopathological risk factors,

the

following

information

should

be

included

in

the

histopathological report after hysterectomy: o

Tumour size

o

Histological type

o

Grade of differentiation

o

Depth of stromal invasion — total thickness of cervical stroma

o

Presence of lymphovascular space involvement

o

Status of the margins

o

Parametrial and/or vaginal involvement

o

Presence of associated precancerous lesions

o

Presence of lymph node involvement: 

Number of lymph nodes contained in the surgical specimen;



Number of positive lymph nodes;



Location of nodal regions sampled and positive nodes;



Size of involved lymph nodes;



Presence of extracapsular extension. If an unsuspected invasive carcinoma is found after hysterectomy,

it should be reported separately. Since there was no evidence of disease prior to surgery, it should not be clinically staged. In this case, a complete

histopathological report with the information indicated above should be submitted by the pathologist as well. c.

Diagnostic workup 1.

Recommended baseline workup: 

Complete medical history



Physical examination, including bimanual vaginal and rectal examinations.



Tumour diagram in three dimensions with measurements.



Diagnostic procedure: punch biopsies (edge of gross tumour, four quadrants in preinvasive lesions). All lesions must be confirmed by histopathological examination.



Cystoscopy, proctosigmoidoscopy: recommended in patients with clinical stage IIB or greater disease, presence of vaginal wall infiltration, and when there are rectal or bladder complaints.

2. Laboratory studies:  

Complete blood count test Blood chemistry, including creatinine level; creatinine clearance or glomerular filtration rate from the creatinine in serum (see Annex III) Liver function tests should be obtained and monitored with the renal function tests in those patients who may be receiving extended field radiotherapy



Urine analysis



Pregnancy test in patients of childbearing age



Optional: HIV testing and, if positive, CD4 lymphocytes count

3. Imaging studies: 

Standard: o Chest X ray, anteroposterior (AP) and lateral o IVU or US of the kidneys (not necessary if CT or MRI is performed) o CT of the abdomen and pelvis with and without intravenous and oral contrasts.



Optional: o MRI of the pelvis with and without gadolinium. o 18F-fluorodeoxiglucose (FDG) PET scan or PET/CT scan

4. Management of cervical cancer o Management of local/locoregional disease o Primary Therapy 

Surgery Microinvasive cervical cancer (stage IA1) without LVSI can be

managed with conisation or simple trachelectomy to preserve fertility [I, B] [18]. Simple hysterectomy can be offered if the patient does not wish to preserve fertility. In stage IA1 with LVSI, surgical assessment of pelvic lymph nodes should be discussed with the patient, including the sentinel lymph node. In patients with FIGO stage IA2, IB and IIA, radical hysterectomy with bilateral lymph node dissection (with or without SLN) is standard treatment, if the patient does not wish to preserve fertility [I, B]. This can be carried out either by laparotomy or laparoscopy (which can be robotically assisted). The minimally invasive approach is gaining increasing relevance and is standard in most centres, since it appears to offer similar oncological safety with favourable surgical morbidity [19]. Sentinel lymph node dissection in cervical cancer. SLN dissection (SLND) is standard in the treatment of breast cancer as well as vulvar cancer and increasing evidence also suggests an important role for SLND in cervical cancer. While the evidence is still evolving and guideline recommendations are not yet clearly defined, it should be considered in FIGO stage I patients with tumours of ≤ 4 cm. Some evidence suggests that the detection rate is highest if the tumour is < 2 cm. Tracer is injected directly into the cervix, and blue dye, technetium radiocolloid or fluorescent indocyanine green is used. SLND should be done only in centres with enough expertise and training. Sentinel nodes should be detected on both sides [II, B] [20] Surgical therapy of the uterus. Since radiotherapy (RT) and surgery are equally effective in early stages, surgery should only be considered in patients with earlier stages

(up to FIGO IIA) without risk factors necessitating adjuvant therapy, which results in a multimodal therapy without improvement of survival but increased toxicity [I, A]. It is important to note that the currently established radical hysterectomy with extensive parametrial resection most likely constitutes overtreatment in many patients, especially those with small and locally restricted tumours. Large randomised studies such as the SHAPE study are currently enrolling patients to compare simple hysterectomy with radical hysterectomy in this population [21]. Neoadjuvant chemotherapy to surgery. The rationale for the use of neoadjuvant chemotherapy (NACT) includes: (i) reduction of the primary tumour size, allowing operability; (ii) eradication of micrometastatic disease; and (iii) potential increase in tumour vascularisation and reduction of the number of hypoxic cells [22– 24]. In a meta-analysis, NACT followed by radical surgery showed a highly significant 35% reduction in the risk of death compared with RT alone

[hazard

ratio

(HR) = 0.65;

P = 0.0004],

with

an

absolute

improvement of 14% in survival at 5 years, increasing from 50% to 64% [25]. The analysis included data from 872 patients with LACC enrolled in five different trials. The largest trial included in a second meta-analysis, enrolled 441 FIGO stage IB2–III cervical cancer patients and compared platinum-based NACT followed by radical surgery with conventional RT. The main criticism of this study is related to the suboptimal RT administration; almost 27% of patients did not receive intracavitary RT; 11% of patients received less than 60 Gy of external pelvic beam radiation total dose at point A and the median total dose delivered was 70 Gy, while the optimal treatment is considered to be 80–90 Gy at point A. Moreover, in all of these studies, the control arm, RT alone without concomitant chemotherapy, does not represent the current standard of care

for LACC. In addition, the RT total dose and the median time of RT administration were sometimes suboptimal. There are two randomised phase III trials that have explored the role of NACT followed by surgery versus chemoradiotherapy (CRT), but the results are not yet available (EORTC Protocol 55994 and NCT00193739) [26, 27]. Moreover, a recent meta-analysis comparing NACT followed by surgery versus surgery alone confirmed that patients treated with NACT had higher local control [odds ratio (OR) = 0.67; 95% confidence interval (CI): 0.45–0.99; P = 0.04)] [28]. Exploratory analysis of pathological response showed a significant decrease in adverse pathological findings with NACT (OR = 0.54; P < 0.0001 for lymph node status; OR = 0.58; P = 0.002 for parametrial infiltration). However, a significant percentage of patients will not have surgery because of treatment toxicity or insufficient response. These results indicate that NACT may offer a benefit over surgery alone in cervical cancer patients (borderline LACC, nodes positive, parametrial invasion at MRI), reducing the need for adjuvant RT [I, C]. Chemoradiotherapy in locally advanced cervical cancer CRT has been the standard of care for patients with bulky IB2– IVA disease for almost two decades. The near simultaneous publication of five randomised trials, three in LACC, collectively demonstrating an improvement in both disease-free survival (DFS) and OS with concomitant chemotherapy and RT over standard RT/hydroxyurea (endorsed by the National Cancer Institute) changed clinical practice worldwide [I, A] [29–33]. However, concerns were raised about the applicability of the results in view of patient selection, protracted overall treatment time, the lack of a RT-only control arm and the poor outcome in the control group. An individual patient data meta-analysis was undertaken to address these issues [34]. The authors identified 18

randomised trials with an RT-only control arm from 11 countries with the subsequent analysis limited to 13 trials. The analysis confirmed the benefit of CRT but with a smaller effect. The HR for OS and DFS was 0.81 and 0.78, respectively, which translates into an absolute improvement of 6% and 8% in OS and DFS, respectively. The estimated absolute survival benefit for CRT compared with RT alone was 10% for those with FIGO stage I/II disease, compared with 3% for those with FIGO stage III/IVa. The most commonly used regimen is weekly cisplatin 40 mg/m2, although the meta-analysis also reported significant benefits with non-platinum agents [I, A] [34]. More recently, colleagues in Mexico reported on a large randomised phase III trial comparing standard CRT with a more intensive concomitant approach with gemcitabine/cisplatin followed by an additional two cycles of adjuvant chemotherapy [35]. Yet, despite a reported 9% improvement in progression-free survival (PFS) at 3 years with treatment intensification, this approach has not been widely adopted amid concerns about toxicity [II, C]. Meanwhile two international trials of additional chemotherapy delivered either before (INTERLACE) or after CRT (OUTBACK) are ongoing and will hopefully answer the question as to whether this approach will improve OS further. Technical advances in imaging and in RT planning have facilitated a move towards increased precision in brachytherapy practice. This approach has been championed by groups in Austria, Denmark and France with the dual aim of improving outcome through dose escalation while reducing the toxicity to the surrounding normal tissues [36]. A recently published multicentre cohort study (RetroEMBRACE) demonstrated excellent local control rates of 93% and 79% for patients with FIGO stage IIB and IIIB disease, respectively, at 3 years [37]. However, the 5-year actuarial OS was 65% and, while this is better than historical controls, it remains to be seen whether this truly represents an improvement in survival over standard CRT with lower RT doses.

With a median follow up of 43 months, the actuarial 5-year G3–G5 morbidity was 5%, 7% and 5% to the bladder, gastrointestinal tract and vagina, respectively, confirming that the improved local control was achieved with a low risk of morbidity [I, B]. Given the rarity of small-cell neuroendocrine carcinoma, there are limited data to guide treatment of this type of cervical cancer. Most clinicians favour: the use of combined modality therapy (surgery followed by chemotherapy or combined CRT) for limited-stage potentially resectable disease; definitive CRT for locoregionally advanced unresectable but non-metastatic disease; and palliative chemotherapy alone for those with metastatic disease, using chemotherapy regimens that are typically used for small-cell lung cancer. Neoadjuvant chemotherapy and radiotherapy The concept of delivering chemotherapy before RT (neoadjuvant or induction chemotherapy) has been explored in clinical trials with conflicting results. An individual patient data meta-analysis was undertaken of 18 randomised trials involving over 2000 patients [38]. Heterogeneity in trial design precluded a unified analysis. However, the authors identified cycle length and platinum dose intensity as important factors in determining the impact of NACT on outcome. The trials that delivered short-cycle chemotherapy (≤ 14 days) gave a pooled HR of 0.83, equivalent to an improvement of 7% in 5-year survival. In contrast, the trials with longer chemotherapy cycles (> 14 days) gave a pooled HR of 1.25, equivalent to an absolute detriment in survival of 8% at 5 years. Accelerated repopulation of resistant cancer cells during prolonged intervals (up to 6 weeks in some studies) between NACT and RT may account for the detrimental effect seen in some studies. The ongoing INTERLACE trial, which is randomising patients with LACC between standard CRT alone and 6 weeks of induction chemotherapy followed immediately in week 7 by standard CRT, seeks to address some of these issues by studying the use of a dose-dense schedule,

incorporating a taxane and eliminating the interval between induction chemotherapy and RT. Lymph node staging and radiotherapy In patients with LACC, RT treatment planning relies on accurate staging information. Pelvic MRI and clinical examination is essential to determine the local extent of the tumour for both external beam RT and brachytherapy planning. Information on para-aortic nodal status is also essential for treatment planning, particularly in determining the superior extent of the external beam RT portal. FIGO staging does not take account of the nodal status and this is one of the weaknesses of this system. Surgical series suggest that the incidence of para-aortic nodal involvement increases with stage from about 5% in patients with stage I disease to 25% in those with stage III disease [39]. There is much debate concerning the best way to assess the paraaortic nodes. In some parts of the world, PET/CT is routinely used for staging while elsewhere there is a reliance on surgical exploration of the para-aortic region. It is hoped that the ongoing randomised trials will address this issue further [40]. This is particularly important in the light of the findings from a multicentre, randomised trial demonstrating an excellent outcome in patients with negative PET scans and metastasis ≤ 5 mm detected histologically after surgical removal and subsequently treated with extended-field CRT [41]. Adjuvant treatment Women with risk factors on the pathology specimen should receive adjuvant therapy following hysterectomy (Table 3). Two classes of risk are defined: intermediate- and high-risk patients. However, intermediaterisk factors such as LVSI, large tumour size and deep stromal invasion (DSI) do not significantly increase the recurrence rate alone but, when combined, the risk of recurrence is increased to 15%–20%, similar to that of high-risk factors.

o Management of advanced/metastatic disease Metastatic or recurrent cervical cancer is usually a symptomatic and devastating situation for the patient. Palliative chemotherapy with the aim of relieving symptoms and improving quality of life is indicated if the patient has a performance status (PS) ≤ 2 and no formal contraindications. Cisplatin 50 mg/m2 every 3 weeks was, for two decades, the standard of care. However, the global efficacy was disappointing due to a low response rate (20%), short median PFS (2.8–3.2 months) and OS (6.2–8.0 months). Cisplatin-based doublets with topotecan or paclitaxel have demonstrated superiority to cisplatin monotherapy in terms of response rate and PFS [43, 44]. Cisplatin combined with topotecan showed superior OS compared with cisplatin alone. Both trials also demonstrated that the response rate was clearly inferior in patients previously exposed to CRT. In addition, retrospective pooled analysis suggested that black race, pelvic location rather than non-pelvic, PS 1 or 2 and first relapse within 1 year of diagnosis may also be poor prognostic factors associated with lower response [45]. The three-drug combination of paclitaxel–ifosfamide–cisplatin (TIP) has shown promising responses (overall response rate 62%, with complete response 26%) and is regarded as an active regimen with acceptable toxicity in advanced/relapsed cervical cancer [46]. A large randomised phase III trial (GOG204) comparing four different cisplatin-based doublets with paclitaxel, topotecan, gemcitabine or vinorelbine was unable to demonstrate the superiority of any regimen. Nevertheless, paclitaxel–cisplatin showed the highest response rate (29%), median PFS (5.8 months) and median OS (12.8 months) and was considered the preferred regimen based on the balance between efficacy and toxicity profile [II, B] [47].

Tumour angiogenesis plays a significant role in the progression of cervical cancer and has been associated with a poor prognosis. Bevacizumab prevents tumour angiogenesis by blocking vascular endothelial growth factor and was shown to be active in a phase II study (GOG-227C) in recurrent cervical cancer [48]. Based on this observation, the GOG-240 study explored the addition of bevacizumab to chemotherapy in a randomised phase III trial with a 2 ×2 factorial design in which OS was the primary endpoint. Patients with primary stage IVB or recurrent/persistent, good PS (0 or 1) and measurable disease were randomised to paclitaxel–cisplatin or paclitaxel–topotecan, both with or without bevacizumab. Two main conclusions were obtained from this study: first, the median OS is significantly prolonged by the addition of bevacizumab (16.8 versus 13.3 months; HR 0.765; 95% CI: 0.62–0.95; P = 0.0068) and second, non-platinum doublet is not superior to cisplatin–paclitaxel, even in the population previously treated with cisplatin. Patients treated with bevacizumab had a higher risk of grade ≥ 2 hypertension (25% versus 1.8%), grade ≥ 3 venous thromboembolic events (8.2% versus 1.8%) and grade ≥ 2 fistula (8.6% versus 1%), and these side-effects must be carefully monitored during treatment [49]. The combination of paclitaxel and carboplatin could be considered an alternative for patients that are not candidates for cisplatin. Although a Japanese randomised clinical trial which compared the two regimens showed a similar efficacy, the combination with cisplatin was superior to carboplatin in patients without

previous

exposure

to

cisplatin

[50].

The

combination

of

carboplatin/paclitaxel/bevacizumab is being studied in a multicentre, single-arm, interventional trial (CECILIA), to evaluate the safety and efficacy of the combination in recurrent and/or metastatic cervical cancer (NCT02467907). Paclitaxel and cisplatin combined with bevacizumab is considered the preferred first-line regimen in metastatic or recurrent cervical cancer based on the balance between efficacy and toxicity profile [I, A]. In patients progressing following first-line therapy, different cytostatic agents, including vinorelbine, topotecan, gemcitabine or nanoparticle albuminbound paclitaxel have been evaluated (Table 4). However, response rates are low

and duration of responses is short. Therefore, no recommendation can be given about the most effective second-line treatment (Table 4). Some patients develop small lung metastases only, which do not rapidly progress and can be managed with stereotactic RT and/or a watchful waiting policy, frequently delaying systemic chemotherapy for a significant period of time. RT can play an important role in patients with recurrent disease, in the case of oligometastatic disease and for patients with only nodal metastasis in the pelvic, periaortic and/or supraclavicular regions, as high-dose RT often leads to long-term disease control and a prolonged progression-free interval. Short-course palliative RT is used to treat symptoms from distant metastases. Local recurrence of cervical cancer following radical surgery The therapeutic options for patients who relapse in the pelvis following primary surgery are either radical RT or pelvic exenteration. The reported survival rates range from 6% to 77%; patients with central recurrences have better prognoses than those with pelvic side wall recurrence. Patients with central recurrences had a 10-year survival rate of 77%, for those with no palpable tumour, and a 10-year survival rate of 48% if the recurrence was < 3 cm; there were no long-term survivors among patients with bulky (> 3 cm) central recurrence in one series. The major prognostic factors associated with survival following salvage radiation in patients with recurrent pelvic disease include disease-free interval, site of recurrence (i.e. central versus pelvic side wall), and size. Higher doses of RT can be delivered with brachytherapy and increase the likelihood of local control for patients with small volume central recurrences. Patients with large volume central or pelvic side wall recurrences have poor prognoses, and efforts should be made to detect pelvic recurrences early to increase the chance of long-term survival [51].

5. Follow Up No definitive agreement exists on the best post-treatment surveillance of cervical cancer. At a minimum, follow-up visits with a complete physical examination, including a pelvic–rectal exam and a patient history, should be conducted by a physician experienced in the surveillance of cancer patients. There is little evidence to suggest that vaginal vault cytology adds significantly to the clinical exam in detecting early disease recurrence. Routine use of various other radiological or biological follow-up investigations in asymptomatic patients is not advocated, because the role of those investigations has yet to be evaluated in a definitive manner. CT or PET/CT scan should be carried out as clinically indicated. A reasonable follow-up schedule involves follow-up visits every 3–6 months in the first 2 years and every 6–12 months in years 3–5. Patients should return to annual population-based general physical and pelvic examinations after 5 years of recurrence-free follow-up [III, C].

6. Fertility Preservation in Cervical Cancer To preserve fertility, conservative surgery (with preservation of uterine body) and ovarian transposition are discussed. In patients without children and with initial tumors of the cervix, radical trachelectomy is an alternative employed for some time. This surgery involves removing the cervix, along with parametria, proximal third of the vagina and pelvic lymph nodes. The abdominal approach allows better dissection of the parametria but the vaginal route can be used by trained teams. For lymphadenectomy, laparoscopy is the preferred option. Trachelectomy is considered a safe procedure if the following

selection criteria are used: usual histology (squamous cell carcinoma or adenocarcinoma, but not neuroendocrine tumors), tumor size less than 2 cm (confirmed on physical examination and MRI of the pelvis), no disease beyond the cervix (confirmed by CT, MRI or PET-CT), tumor-free pelvic lymph nodes, and surgical specimen with free margins. 26-28 However, we know that the removal of parametria and proximal third of the vagina affects the future obstetric condition of the patient, with higher frequency of miscarriages and premature births. Thus, in view of the low probability of parametrial involvement in patients with stage IA2 and IB1 (tumor measuring up to 2 cm), conization to obtain clear margins associated with pelvic lymphadenectomy has been studied without parametrectomy and colpectomy in these situations.3,4 Another approach to IB1 tumors is the use of neoadjuvant chemotherapy prior to trachelectomy. For patients with cancer at more advanced stages or for those not eligible for conservative treatment, one option is ovarian transposition, with the purpose of maintaining hormonal function and ovarian reserve. Surgery consists of releasing the tube and ovary from the pelvic infundibulum, attaching them above the edge of the pelvis, which is the cranial limit for pelvic radiotherapy fields. It is suggested placing clips on the new topography of the annexes, in order to identify these structures later on imaging studies. Keep in mind the risk of ovarian metastasis from cervical carcinoma, which is 0.6% for squamous cell carcinomas and 6% for adenocarcinomas, requiring careful evaluation during surgery and removal of suspicious attachments. The success rate is quite variable, and often there is anticipation of menopause in cases treated with transposition.30 Some of this variation is due to concurrent or adjuvant chemotherapy, which implies a high chance of ovarian failure induced by the chemo in patients older than 35 years.31-33 Other approaches to preserve fertility include advanced procedures such as ovulation induction and oocyte retrieval, in vitro fertilization and embryo freezing, and preservation of ovarian tissue for reimplantation.

C. Trachelectomy in fertility preservation for cervical cancer o Trachelectomy surgical techniques

Vaginal radical trachelectomy (VRT) is a modification of the original Schauta-Stockel procedure. VRT should start with laparoscopic pelvic lymphadenectomy (could be combined with detection of SLNs). Eventually, in regions with less-advanced laparoscopic skills, an abdominal approach can be used but the procedure loses its minimal invasivity, which is essential for the future quality of life and excellent cosmetic results. The other part of the procedure consists of a VRT with the resection of the parametria at the level of radical hysterectomy type B. During VRT, the uterine artery is preserved and only the vaginal branch of the artery is transsected. The cervix should be transsected 1 cm above the margin of the tumour while preserving at least 1 cm of cervical stroma caudally from the internal cervical orificium [23]. Adherence to this guideline could be verified by peroperative frozen section examination of the excised cervix but preferably final pathologic examination should be the determining factor [24]. Abdominal Radical Trachelectomy (ART) was first described in 1932 by Romanian gynaecologist Eugen Aburel but prospectively used as a fertilitysparing procedure by Smith. ART is a modification of the radical abdominal hysterectomy approach, which brings an advantage of minimal special surgical experience except of radical abdominal hysterectomy technique. The first step in the procedure involves pelvic lymphadenectomy. Similarly, the detection of a SLN could be implemented. In the majority of surgical schools, the uterine artery is completely resected though modification with preservation and reanastomosis of the artery has been described [25]. Resection of the parametrium could vary in which resection could be performed according to radical hysterectomy type B or C (with or without nerve-sparing techniques) [26]. The cervix is resected completely and the vagina is sutured directly to the remaining stroma. Simple Trachelectomy (ST) as a fertility-sparing procedure was first described by our group in 2007 [27]. The procedure employs a two-step management of the patients to ensure the highest oncological safety. In the first step, laparoscopic pelvic lymphadenectomy is used in combination with SLNM. In the case of negative SLNs after final pathological evaluation, ST is performed approximately

1 week later. If positive SLNs are detected, the fertility-preserving procedure is abandoned. ST involves amputation of the cervix combined with the resection of the remaining endocervical channel by loop excision. Outer cervical edges are sutured with vaginal edges to achieve optimal postoperative results. Cervical cerclage is not performed. Other reports have used deep laser conisation with adjuvant chemotherapy [22] or a similar technique as described by the Prague group [28]. A recent survey conducted among Gynaecologic Cancer Intergroup (GCIG) members revealed that some of the fertility preservation procedures were offered by all centres, while 20.3% offered ART, 47.3% VRT and 58.1% ST [21]. The differences in indications were based mainly on local preferences and experiences rather than based on certain criteria. It was seen that European centres preferred cone biopsy and vaginal trachelectomy compared to the USA or Japanese centres that perform ART more often. Looking at the procedure chosen based on the stage, cone biopsy was performed mainly in IA1 tumours, whereas simple trachelectomy in IA2 tumours and ART or VRT in IB1 smaller than 2 cm.

Figure 1 shows the different radicality of the described surgical techniques. o Complications of trachelectomy The complication rate of VRT is comparable to laparoscopically assisted radical hysterectomy [29]. The most common peroperative com-plication is an injury to the urinary tract. Postoperative complications include dysmenorrhea in 24%, dyspareunia in 20% and menstrual abnormalities in 17% [30]. ART follows similar steps as in open radical hysterectomy and shows a comparable complication rate. Inflam-matory complications occur in 8.6% of the patients [6]. A typical fertilitypreserving complication is a stenosis of the cervical channel, which occurs in approximately 9–10% of the patients regardless of whether the approach is vaginal or abdominal [6, 31]. o Obstetrical outcomes and care after trachelectomy Different publications or reviews then demonstrated that pregnancy could be considered as a ‘‘real option’’ after RT (116). The overall pregnancy rate is 30% for VRT and 15% for ART [30]. For ST, the pregnancy rate is about 50% [37]. It is

clearly seen that the larger the damage to the paracervical tissue caused by the surgery, the lower the chance of conception. Premature labour before the 32nd week and between the 32nd and 37th week of pregnancy has been observed in approximately 12% and 28% in VRT and ART, respectively [30]. The shortening of the cervix plays an important role in the risk of premature delivery here as proven in patients after cone biopsy (RR about 2) [38]. Our systematic review confirms that more than half of the patients who had undergone RT or another FSS procedure, and wished to become pregnant, achieved at least one pregnancy. This rate is significantly lower in patients submitted to a laparatomic RT (44%) compared with other approaches (particularly the widely used vaginal RT) (Table 4). The fertility rate was high in patients who had received NACT (neoadjuvant chemotherapy) before Fertility Sparing Surgery (FSS), but this ‘‘high rate’’ was due to a very recent series that comprised nearly half of the NACT cases reported in the literature and included 36 of 42 patients wishing to become pregnant who had achieved at least one pregnancy (67).

The lower fertility rate after a laparotomic RT could also be related to the fact that this procedure was more recent than its vaginal counterpart, and consequently some of the patients who had undergone this procedure were not ready to conceive at that time. A recent interesting study about the physical and emotional impact on patients undergoing RT showed that 30% of these patients were still not sexually active 6 months after surgery because ‘‘a little afraid’’ or ‘‘somewhat to very afraid’’ to have sex (28, 117). On the other hand, this lower rate, observed after laparotomic RT, could potentially be due to adhesions related to the approach itself and/or to a higher frequency of septic morbidities (abcesses, local peritonitis) observed mainly in patients who had undergone a laparotomy, or potentially due to uterine artery ligation, frequently performed with this approach. Nevertheless, the subgroup analysis we conducted in these patients showed that uterine artery preservation or ligation had no impact on the fertility rate. This shows that the preservation of the infundibulo-pelvic and ovarian vessels in these young patients could be suffi-cient to adequately supply the arterial vascular network of the uterine corpus and thus achieve a pregnancy. Unfortunately, some patients desiring (and trying to achieve) a pregnancy had become infertile as a result of FSS. Some of them were infertile before the treatment of their cervical cancer (7% in the series by Speiser et al. (32)). In the large recent study by Kasuga et al. (78) comprising 172 pa-tients who had undergone an abdominal RT, among 61 preg-nancies achieved, 42 were after infertility treatment. In the series by Kim et al. (91), among 35 patients attempting conception, 18 had recourse to assisted technologies. This rate did not seem to be related to the FSS modality. In a recent Danish study comprising 120 cases of the Dargent procedure, among 72 patients desiring conception, 40 had been referred for fertility treatment (42). In the series by Shepherd et al. (12), among 63 patients wishing to become pregnant, 18 had fertility treatment. In the series by Plante et al. (9), the rate of infertile patients was lower, representing 13.5% of 111 pa-tients attempting to become pregnant. In the recent series by Johansen et al. (109), which reported on robotic RT, among 21 patients, 16 succeeded spontaneously and 5 were infertile (1 before surgery). The main cause of infertility was related to cervical factors (40% in the series by Plante et al. [9]). Two main specific factors could be incriminated: [1] a

lack of cer-vical mucus to facilitate sperm migration and potentially increased latent subclinical endometritis; and [2] cervical ste-nosis (14–16,118,119). The latter complication is the most common after FSS and could be related to the surgical resection itself, the use of a cerclage, and the use or not of antistenosis tools (119). In a recent review by Li et al. (119) concerning cervical stenosis after RT, its average rate was 10.5%. It can be observed even if RT is performed without a cerclage (3%), but its incidence is increased after a prophylactic cerclage (8.6%), even if this difference did not reach statistical significance in the review by Li et al. (119). The use of antistenosis tools (catheter, intrauterine device, Smit sleeves) seems to decrease the complication rate (119). Because it is the first infertility factor, the infertility management most frequently used was cervical dilatation combined or not with IUI (Intrauterine Insemination) or IVF (In Vitro Fertilization) (or both), which yielded good results (9, 41). Other specific IVF strategies were published as case reports, particularly in the case of persistent severe stenosis (120–123). Other infertility factors could arise, namely ovulatory dysfunction, endometriosis, and male factors (9, 42). An integral part of fertility-preserving procedures is encouragement and close counselling with the patient before and throughout pregnancy. Preferably, the ideal arrangement is to follow the patient during pregnancy at the same department in which the surgery was performed. There is no consensus among authors about the interval between surgery and the first attempt to conceive, but a minimum of 3 months seems to be justified. Another issue in regards to postoperative care concerns prophylactic treatment during pregnancy. Our department administers cephalosporin antibiotics at week 16, 20 and 24 and clindamycin vaginal treatment to prevent intraovulary infection at week 16 and 24. Any suspicion of premature labour should be carefully examined and collaboration with a department equipped with a neonatal intensive care unit is obligatory. Other authors prefer prophylactic use of oral metronidazol during week 15–21 and sexual abstinence during the 2nd and 3rd trimester [39].

An issue of preventive cerclage is an unresolved question. Some centres prefer to place a preventative cerclage during oncological surgery [40, 41], whereas other centres prefer that placement to be done during pregnancy [42].

D. Conclusion Currently, in selected sets of patients (tumours smaller than 2 cm without parametrial and nodal involvement) VRT combined with laparoscopic lymphadenectomy is the standard fertility-preserving procedure for treatment. Oncological safety has been confirmed for VRT as well as for ART. Promising results have been reported for ST in terms of oncological results. Positive pregnancy outcomes have been reported in ascending order of ART, VRT and ST. Use of neoadjuvant chemotherapy is an experimental modality for patients who do not fulfil initial indication criteria.

7. A 8. A 9.

A d.