Active Survillance In Small Renal Masses

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Active Surveillance for Selected Patients With Renal Masses Updated Results With Long-term Follow-up

Tamer Abou Youssif, MD Wassim Kassouf, MD Jordan Steinberg, MD Armen G. Aprikian, MD Micheal P. Laplante, MD Simon Tanguay, MD

BACKGROUND. The objective of the current study was to evaluate the outcome of a surveillance strategy in patients with renal masses.

METHODS. The medical records of patients with renal masses diagnosed between January 1992 and May 2006 were reviewed retrospectively. In all, 45 patients with renal masses under observation were identified. Of these, 35 patients with 44 renal masses measuring <4 cm in dimension at the time of diagnosis and who were followed for at least 6 months were included in the review. Patients elected

Division of Urology, Department of Surgery, McGill University Health Center, Montreal, Quebec, Canada.

observation because of age, comorbidity, solitary kidney, or bilateral renal masses. Medical records were reviewed to determine tumor size and volume changes as well as clinical progression requiring treatment, the development of metastatic disease, or death.

RESULTS. A total of 35 patients (21 men and 14 women) with 44 renal masses were observed for a mean follow-up of 47.6 months. The mean age of these patients was 71.8 years. The majority of the patients (89%) were asymptomatic at the time of diagnosis. The mean and median initial tumor dimension was 2.2 cm and 2.2 cm, respectively (range, 0.5–4 cm). Of the 35 patients, 2 (5.7%) were lost to follow-up, 8 (22.9%) underwent surgical resection, and 9 (25.7%) died of other causes. The mean dimension growth rate was 0.21 cm/year (range, 0.03–1.9 cm/ year). The mean and median volume growth rate was 2.7 cc/year and 1.4 cc/ year, respectively. Progression to metastatic disease was identified in 2 patients (5.7%).

CONCLUSIONS. The majority of renal masses will grow if observed and some may require treatment. Initial tumor size cannot predict the natural history of renal masses. A small but non-negligible risk of developing metastatic disease exists in this patient population. Further research should focus on the role of biopsy and on identification of prognostic parameters allowing more accurate prediction of tumor growth and metastasis. Cancer 2007;110:1010–3.
2007 American Cancer Society.

KEYWORDS: renal neoplasm, surveillance, watchful waiting, natural history, tumor growth rate, progression.

Address for reprints: Simon Tanguay, MD, Division of Urology, Department of Surgery, McGill University Health Center, 1650 Cedar Avenue, L8-318 Montreal, Quebec, H3G 1A4, Canada; Fax: (514) 934-8297; E-mail: simon.Tanguay@ mcgill.ca Received February 13, 2007; revision received April 29, 2007; accepted May 1, 2007.

ª 2007 American Cancer Society

O

ver the past 20 years, the overall incidence of malignant renal tumors has been rising in the U.S.1 This increase appears to be greatest for asymptomatic small renal masses (SRMs). The incidence of tumors measuring 2 to 4 cm in size increased from 1.0 cases per 100,000 in 1983 to 3.3 cases per 100,000 in 2002. During the same period, the incidence of tumors measuring <2 cm in greatest dimension increased from 0.2 to 0.8 cases per 100,000 persons.1 This phenomenon can be attributed in part to the increased use of

DOI 10.1002/cncr.22871 Published online 12 July 2007 in Wiley InterScience (www.interscience.wiley.com).

Natural History of Small Renal Masses/Youssif et al.

abdominal imaging modalities leading to earlier detection and in part to the natural history of these masses.2,3 Several studies investigated the pathologic features of surgically removed SRMs. Vasudevan et al.3 reported a 33% benign histology in 70 renal masses measuring <5 cm. Frank et al.4 reviewed the pathology specimens of 2770 patients and found that each 1-cm increase in tumor size was associated with a 17% increase in the odds of malignancy. This impact of tumor size was also noted in conventional renal cell carcinoma, in which each 1-cm increase in tumor size increased the odds of a high-grade to a low-grade tumor by 32%.4 These observations were also confirmed by Schlomer et al.5 Despite the fact that SRMs have a low metastatic potential, surgical excision remains the standard of care for young and healthy patients.6 However, in elderly patients or patients with significant comorbidities, it might be appropriate to consider an observation strategy, reserving surgical treatment for tumors that exhibit rapid growth. Many studies have evaluated the natural history of SRMs.2,7–12 All published series to date have demonstrated a limited growth rate during the observation period and a low risk of metastasis in the absence of tumor growth. We previously reported our experience in the observation of 24 patients with SRMs. Tumor growth during the surveillance period was demonstrated in 5 patients after an average of 32 months of observation.7 No patients developed metastatic disease during the observation period. The objective of the current study was to update our experience with the observation of patients with SRMs and provide the results of the long-term follow-up of our original published cohort of patients.

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TABLE 1 Patient Demographics, Tumor Characteristics, and Duration of Follow-up No. of males (%) No. of females (%) Mean/median age at presentation (range), y No symptoms (%) Not asymptomatic (%) Tumor Right (%) Left (%) Bilateral (%) No. in the upper pole (%) No. in the mid pole (%) No. in the lower pole (%) Solid (%) Cystic (%) Mean/median dimension at diagnosis, cm Mean/median volume at diagnosis, cc Mean/median follow-up (range), mo

21 (60%) 14 (40%) 71.8/74 (29–90) 4 (11.4%) 31 (88.6%) 16 (45.7%) 13 (37.1%) 6 (17.1%) 13 (29%) 19 (43%) 12 (27%) 38 (86%) 6 (14%) 2.2/2.2 (0.5–4) 6.1/4.4 (0.07–34.1) 47.6/41 (6–160)

included abdominal imaging, chest X-ray, and blood chemistry. Tumor dimensions were obtained with each imaging study. Tumor volume was calculated from tumor size in 1 of 3 ways depending on the number of available dimensions. The formula used to calculate an ellipsoid volume when 3 dimensions were available was (0.5326xyz), the formula 0.5325(x 1 y/2) was used when 2 dimensions were available, and the formula for volume of sphere (0.5326x3) was used when only 1 dimension was recorded by the radiologist.13 Growth rate was calculated based on both tumor volume and dimension. Patients were categorized as free of metastatic disease based on radiologic findings. The end of followup was determined by either surgical intervention or death.

RESULTS MATERIALS AND METHODS The medical records of 45 patients followed in our clinic between January 1992 and May 2006 with SRMs were reviewed. Of those, 35 patients (21 men and 14 women) with 44 renal masses are included in this report. Patients included had renal masses measuring <4 cm in maximum dimension at the time of initial presentation and were followed for at least 6 months. Patients elected a surveillance strategy because of either age, comorbidity, or fear of renal failure associated with surgical resection. All patients were initially evaluated with either computed tomography (CT) or magnetic resonance imaging (MRI). Radiologic evaluation at diagnosis confirmed the absence of metastatic disease. Follow-up evaluations were performed at 3-month to 6-month intervals and

The demographic data of our patient population and the characteristics of the renal masses are summarized in Table 1. Of the 35 patients, only 4 were symptomatic at the time of presentation, 2 with macroscopic hematuria and 2 with flank pain. Six of the 35 masses were Bosniak IV cystic renal masses. The mean and median initial tumor dimension was 2.2 cm and 2.2 cm, respectively. The mean and median tumor volume was 6.1 cc and 4.4 cc, respectively. The average follow-up duration was 47.6 months (median, 41 months; range, 6–160 months). A total of 211 imaging studies were performed, with an average of 6 imaging studies per patient performed during the observation period. Ultrasonography was used in 69.7% of patients, compared with 21.8% and 9.5% undergoing CT scan and MRI,

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respectively. The choice of imaging studies used during the observation period was left to the preference of the different urologists. Although ultrasound may be associated with more interobserver variability, it was found easier for the follow-up of our elderly patient population. During the observation period, the mean and median size growth rates observed were 0.24 cm/ year and 0.17 cm/year, respectively (range, 20.3 to 1.9 cm/year). The mean and median volume growth rates were 2.7 cc/year and 0.83 cc/year, respectively (range, 20.7 to 26.3 cc/year). There was no correlation between initial tumor dimension and size growth rate or initial tumor volume and volume growth rate. Of the 35 patients, 8 underwent surgical excision, 9 died during the observation period without intervention on their renal masses, 2 were lost of followup, and 17 patients were still being followed actively at the time of last follow-up. Of these 17 patients, 1 patient with bilateral renal masses had a partial nephrectomy performed on 1 side and elected to have the mass on the left side observed. All patients who died during the observation period died of unrelated causes. Table 2 compares the follow-up duration, tumor characteristics, and growth patterns observed in the different groups of patients. Surgical interventions were performed in 8 patients. Of the 8 patients, 3 underwent a radical nephrectomy and 5 underwent a partial nephrectomy. In 4 patients, surgery was performed because of rapid tumor growth. The remaining patients elected to undergo surgery because of fear of tumor growth or metastasis. Of these patients, 4 had conventional histology, 2 had papillary renal cancer, and 2 tumors proved to be benign oncocytomas. The pathologic stage was pT3a in 1 patient and pT1a in the remaining 5 patients. The mean duration of postoperative follow-up was 27 months (range, 2–90 months). Progression to metastatic disease was noted in 2 patients in our study group. One patient presented with a 2.7-cm renal mass. After an initial period of observation, the patient was lost to follow-up and presented 40 months after the initial diagnosis with spinal cord compression due to metastatic disease. At the time of the diagnosis of metastasis, the renal mass measured 5.8 cm in greatest dimension. Retrospectively, a growth rate of 0.95 cm/year or 26.3 cc/ year was calculated. Although this patient developed metastatic disease, the outcome could have been different if a strict observation regimen was maintained. The second patient also presented with a 2.7-cm renal mass. A growth rate of 0.9 cm/year and 13 cc/ year was observed. Given the constant size progres-

TABLE 2 Comparison of Tumor Characteristics, Duration of Follow-up, and Growth Pattern Between Different Patient Groups

Variable

Observation N 5 17

Follow-up duration, mo Mean 54 Median 41 Range 8–160 Initial size, cm Mean 2.1 Median 2.2 Range 0.5–4 P Initial volume, cc Mean 6.5 Median 4.5 Range 0.07–34.1 P Size growth rate, cm/y Mean 0.15 Median 0.17 Range 20.3–0.52 P Volume growth rate, cc/y Mean 1.17 Median 0.9 Range 20.7–4.56 P

Surgery N58

Deceased patient group N59

32 27 6–54

53.5 51 8–88

1.9 2 1.2–3 .276

2.1 2 1.2–3 .262

3.5 2.39 0.92–10.4 .155

5.7 3.8 1.2–15.9 .643

0.5 0.31 0–1.9 .084

0.19 0.14 0–1.0.76 .692

5.5 3 0–22.5 .182

1.65 0.56 20.4–9.3 .592

sion, the patient was offered surgical resection. The patient elected to continue observation and after 26 months of follow-up agreed to undergo surgical resection. Tumor size measured 4.5 cm radiologically at the time of surgery. A radical nephrectomy was performed. The pathologic evaluation demonstrated a conventional renal cell carcinoma, stage pT3aN0M0, Fuhrman grade 3. Lung metastasis and malignant pleural effusion occurred 3 months after surgery. The patient died of metastatic disease 9 months after undergoing radical nephrectomy. Progression to metastatic disease was therefore observed in 2.9% of our patients. Six patients in our cohort had tumor growth of >4 cm in greatest dimension during the observation period. Table 3 summarizes the tumor characteristics of these patients. Two of the 6 patients underwent surgical resection. Pathologic evaluation confirmed conventional and papillary renal cell carcinoma (RCC). Two patients died of other causes, 1 patient progressed to metastatic disease after a period of lost follow-up, and the remaining patient refused to undergo surgery. Both patients who progressed to metastatic disease were part of this group.

Natural History of Small Renal Masses/Youssif et al. TABLE 3 Tumor Features of Patients With Renal Masses >4 cm in Greatest Dimension Initial size, cm Duration of follow-up, mo Size growth rate, cm/y Volume growth rate, cc/y

Mean, 2.5; median, 2.7 (range, 2–4) Mean, 54; median, 46 (range, 6–160) Mean, 0.6; median, 0.3 (range, 0.1–1.9) Mean, 9; median, 3.88 (range, 0.36–26.3)

TABLE 4 Features of Patients With Pathologically Proven RCC Age, y Follow-up, mo Initial size, cm Initial volume, cc Size growth rate, cm/y Volume growth rate, cc/y Subtype

Stage Grade Outcome

Mean, 61; median, 69 (range, 29–78) Mean, 33; median, 27 (range, 6–54) Mean, 2.3; median, 2.2 (range, 1.7–3) Mean, 5.1; median, 4.9 (range, 2–10.4) Mean, 0.6; median, 0.4 (range, 0.09–1.9) Mean, 7.3; median, 3.5 (range, 0.24–22.5) Clear cell carcinoma: 4 patients Papillary RCC: 2 patients Uncertain: 1 patient pT1a: 5 patients pT3a: 1 patient Grade 2: 3 patients Grade 3: 1 patient 1 patient developed metastasis 1 died of other cause

RCC indicates renal cell carcinoma.

In our study group we had 7 patients with pathologically proven RCC: 6 by surgical excision and 1 by percutaneous biopsy. Table 4 demonstrates the variables in these patients.

DISCUSSION The increased detection of asymptomatic SRMs in recent years has been associated with a parallel increase in new treatment options. Open partial nephrectomy is the current standard of care, with proven long-term oncologic safety and limited morbidity.14 In an effort to reduce morbidity, laparoscopic partial nephrectomy emerged as a minimally invasive approach, which is technically feasible in experienced hands, with the additional advantages of reduced postoperative narcotic use, earlier hospital discharge, and a shorter convalescence.15 This surgical technique remains often associated with longer warm ischemia time and a higher complication rate. Long-term studies are needed to assess the oncologic efficacy and safety in centers other than large referral and academic centers that have developed and promoted this technique to ensure it can be transposed with acceptable morbidity into centers with a smaller volume of partial nephrectomy cases.15–17

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New ablative technologies such as radiofrequency ablation, cryotherapy, and high-intensity focused ultrasound are also gaining acceptance. The longterm oncologic safety of these treatment modalities remains to be confirmed to offer them as valid alternatives to surgery for all patients with SRMs.18,19 The published experience with conservative management of SRMs remains limited. In a recent meta-analysis, Chawla et al.12 reported on the published experience with 286 SRMs followed conservatively. The mean size at presentation was 2.60 cm (median 2.48 cm). Patients were followed for a mean of 34 months (median, 32 months; range, 26– 39 months). The mean and median growth rates of 0.28 cm/year were observed. Progression to metastatic disease was reported in only 3 patients, representing 1.0% of the entire number of patients followed. The authors concluded that the majority of small enhancing renal masses will grow at a slow rate when observed. Although the development of metastatic disease and cancer-specific death are rare, serial radiographic data alone are insufficient to predict the natural history of these lesions. Observation can be very appealing for patients with SRMs. However, in the absence of curative treatment strategies for patients with metastatic disease, the development of metastasis during or after the observation period remains the most important risk associated with conservative management in these patients. In our cohort of patients, progression to metastatic disease occurred in 2 patients (5.7%). One of these could be attributed to an inadequate observation and the second occurred after surgical resection. In addition to these 2 patients, we have a third patient (not included in the report) who developed metastatic disease after an observation period. This patient had an incidental finding of a renal mass measuring 4.5 cm 3 3.5 cm. Surgery was recommended but because of his age the patient elected to follow a conservative approach and observe the change over time. A growth rate of 0.28 cm/year was noted and 13 months later the patient underwent a laparoscopic radical nephrectomy for a 4.8 cm 3 4.1 cm papillary RCC. Two years later, the patient was found to have a pancreatic mass with retroperitoneal lymph nodes proven to be metastatic papillary carcinoma of renal origin. Although our experience remains limited, it appears that metastatic disease can occur in these patients managed conservatively, reinforcing the importance of proper patient selection. In our cohort, the majority of patients (6 of 8 patients [75%]) who underwent surgical resection

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were found to have malignant disease, confirming the findings of other studies.3,20 Although it is difficult to predict the clinical behavior of SRMs, the findings of the current study suggest that patients with the worst outcome demonstrated a faster growth rate. The renal masses in our 2 patients who developed metastatic disease had a growth rate of 0.95 cm/year and 0.9 cm/year, which is a faster growth rate than the mean of 0.15 cm/year observed in our 17 patients who were being followed actively. In addition, the growth rate observed in our patients who underwent surgical resection was also faster than that of the other patients in our cohort. Although limited recommendation can be drawn from our experience due to its small sample size, it appears that faster tumor growth rate should alert physicians to the potential risk associated with observation of SRMs until good and reliable prognostic markers are formally identified. Observation of SRMs in select patients may become less attractive, particularly in the setting of minimally invasive therapy such as radiofrequency ablation. However, it remains unclear whether such minimally invasive therapy applied to SRMs does indeed interfere with the biology and natural history of these lesions.

Conclusions The majority of SRMs will demonstrate a slow grow rate and may require treatment. A surveillance strategy must be restricted to carefully selected patients because observation of SRMs is not risk free. Initial tumor size is not a reliable parameter with which to fully predict the natural history of renal masses. Further research should focus on the role of renal biopsy and on the identification of prognostic parameters for both tumor growth and progression to metastasis.

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