Surgical Management of Renal Cell Carcinoma

Surgical Management of Renal Cell Carcinoma Bradley C. Leibovich and Michael L. Blute Renal cell carcinoma (RCC) is a relatively rare malignancy, although the incidence appears to be increasing. RCC remains resistant to chemotherapy and curative therapy is limited to surgical resection of localized tumors. Recently there has been an expansion of the indications for nephron sparing approaches to patients with localized tumors. Likewise, the management of locally advanced tumors and the indications for cytoreductive surgery in the setting of metastatic RCC have been clarified by recent studies. Herein, we discuss the role of surgery for the management of localized and metastatic RCC. Semin Oncol 33:552-562 © 2006 Elsevier Inc. All rights reserved.

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ancer of the kidney or renal pelvis will afflict an estimated 38,890 US patients in 2006 with 12,840 estimated deaths,1 and these statistics appear to be rising annually.2 The majority (⬎80%) of cancers involving the kidney are renal cell carcinoma (RCC).3 One third of patients diagnosed with kidney cancer have evidence of metastatic disease at the time of diagnosis and up to half of those treated for localized disease eventually relapse.4 RCC occurs twice as often in men as in women and most commonly occurs during the fifth through seventh decades of life, but it has been reported in much younger patients.4 RCC is resistant to traditional cytotoxic chemotherapy. Radiation therapy has limited efficacy for patients with metastases to the brain or the bones. Surgery remains the only effective method of treatment of primary RCC. Herein we will discuss surgical management of localized and metastatic RCC. The specifics of the surgical approach, including the utilization of minimally invasive techniques, are dependent on the surgeon’s training, preference, expertise, and judgment and are beyond the scope of this review. Recently, there have been many changes in the role of nephron-sparing surgery (NSS), the extent of radical nephrectomy (RN), and the role of surgery in metastatic RCC.

Rationale for Expansion of Nephron-Sparing Surgery The objective of any surgical approach to a solid renal mass should be complete excision with adequate surgical margins. Robson described his boundaries for RN in 1962 and in 1969 summarized his initial surgical experience and results show-

Department of Urology, Mayo Medical School, Mayo Clinic, Rochester, MN. Address correspondence to Bradley C. Leibovich, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: [email protected]

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0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2006.06.007

ing an overall 52% five-year survival rate that improved to 66% in patients with localized RCC.5,6 In 1971, Skinner et al updated the Massachusetts General Hospital experience and described a 44% overall survival at 5 years and an improved long-term 10-year survival for those undergoing RN versus simple nephrectomy.7 Improved results of RN were confirmed by some series8 and disputed by others.9 Although the definition varies, RN generally implies early ligation of the renal artery, excision of Gerota’s fascia and its contents, including the kidney and adrenal gland, and lymph node dissection. This historical standard surgical approach accomplishes several objectives: (1) the ipsilateral adrenal gland, which historically was involved in 10% of cases, is excised; (2) lymphatic metastases, which may diffuse through the perirenal fat, are removed; and (3) a more adequate margin away from the tumor is achieved, especially when the tumor invades the perirenal fat. Vermooten described the expansile growth pattern of renal tumors in 1950 and observed that, in most tumors, the normal parenchyma is compressed and the tumor appears encapsulated.10 He advocated local resection of renal tumors with a 1-cm margin of normal parenchyma surrounding the tumor. While RN is still considered standard of care for most renal masses, partial nephrectomy or NSS is now accepted as efficacious and even advantageous in some circumstances.

Imperative Indications for NSS NSS is considered imperative for renal masses that, if removed by RN, would render the patient functionally anephric and dialysis-dependent. Such conditions include patients with a solitary kidney or functionally solitary kidney and patients with bilateral synchronous tumors. Relative indications for NSS include patients with a renal mass and a contralateral kidney that is considered to be at risk due to a history of urolithiasis, hypertension, diabetes, renovascular

Surgical management of RCC

553

Table 1 Results of Imperative NSS First Author

No. of Patients

% Cause-Specific Survival

% Local Recurrence

Mean Follow-up (mo)

Novick116 Smith117 Novick46 Bazeed118 Provet119 Moll120

17 36 33 29 33 47

83 72 85 93 91 94

NR 8 6 7 3 4

NR * 45 36 36 35

Abbreviation: NR, not reported. *Ranged from 3 to 117 months.

disease, obstructive uropathy, infection, renal tumor syndromes including Von Hippel-Lindau and tuberous sclerosis, or any other condition that could threaten eventual renal function. Early reports of imperative NSS for renal tumors demonstrated local recurrence rates between 3% and 8% and cancer-specific survival rates of 72% to 94% (Table 1).

Rationale for Elective NSS Diagnostic Imaging, Incidental Tumors, and Stage Migration In 1981, ultrasound (US) and computed tomography (CT) were recognized as precise tools for imaging renal masses and cysts.11 The introduction and mainstream use of abdominal CT and US has resulted in an increase in the incidental detection of RCC in asymptomatic patients.12,13 With few exceptions,14 the literature suggests that incidental tumors tend to be smaller, lower grade, lower stage cancers that yield better survival outcomes than tumors detected in symptomatic patients.15-17 A recent retrospective review, analyzed 161 patients with the diagnosis of RCC.18 Patients were divided into those with incidental lesions and those with symptomatic masses. The incidentally detected tumors had lower pathologic stages and grades compared with the symptomatic masses. Overall 5-year survivals were 85% for patients with incidentally detected masses versus 53% for patients who were symptomatic. Likewise, Tsui et al reported that 5-year cancer-specific survival rates were found to be significantly higher for patients with incidental tumors (85%) than for those with symptomatic lesions (63%).17 The increase in the number of incidentally discovered renal masses has resulted in improved survival secondary to stage and tumor size migration.19 The increased frequency of small tumors with corresponding low pathologic stages has led to an expansion in the surgical options available to patients with localized tumors. Quality of Life Clark et al reported results of administering validated questionnaires on quality of life and the impact of the stress of cancer to 97 patients who had undergone either RN or NSS for localized RCC.20 The RN and NSS groups were similar in overall quality of life, and both groups were similar to agematched controls who had not undergone surgery for RCC. However, these investigators found that a greater quantity of remaining renal parenchyma was associated with better self-

reported physical health, less daily anxiety regarding cancer, less concern regarding cancer recurrence, and less impact of cancer on overall health. Quality of life after therapy for localized RCC was assessed in 15 RN and 51 NSS cases by Shinohara et al.21 Patients treated with NSS had a significantly higher score on physical function in a standardized quality-of-life questionnaire than patients treated with RN (P ⬍.05). NSS patients were also found to have less postoperative fatigue, sleep disturbance, pain, and constipation than patients who were treated with RN. Preservation of Renal Function Lau et al reported the long-term follow-up of a matched comparison of RN and NSS in patients with single unilateral RCC and a normal contralateral kidney.22 Patients were matched according to pathologic grade, pathologic tumor stage, size of tumor, age, sex, and year of surgery. RN patients (n ⫽ 164) had a significantly higher risk for proteinuria than NSS patients (n ⫽ 164) as defined by a protein/osmolality ratio of 0.12 or higher (55.2% v 34.5%, respectively). The authors also found that RN patients were nearly four times more likely than NSS patients to develop chronic renal insufficiency (risk ratio [RR], 3.7; 95% confidence interval [CI], 1.2% to 11.2; P ⫽ .01). Ten years postoperatively, the cumulative incidences of chronic renal insufficiency for the RN and NSS groups were 22.4% and 11.6%, respectively. McKiernan et al also compared the incidence of newly developed chronic renal insufficiency after NSS and RN for renal masses 4 cm or less in patients with normal contralateral kidneys.23 The study was controlled for known preoperative risk factors for renal insufficiency and there was no difference in the mean preoperative serum creatinine between the RN and NSS groups (1.0 mg/dL and 0.98, respectively). The incidence of risk factors for renal insufficiency did not differ between the two groups. There was a significantly higher mean postoperative serum creatinine in the RN group relative to the NSS group (1.5 mg/dL [range, 0.8 to 3.8] and 1.0 mg/dL [range, 0.5 to 1.9], respectively). Chronic renal insufficiency defined as serum creatinine greater than 2.0 mg/dL was also significantly greater in the RN group. Morbidity Corman et al compared the morbidity and mortality of patients undergoing either RN or NSS.24 For 1,373 patients who underwent RN and 512 patients who underwent NSS, there

B.C. Leibovich and M.L. Blute

554 Table 2 Complications of Nephron-Sparing Surgery

Postoperative bleeding Urine leak Acute renal failure Repeat open surgery Myocardial infarction Death

Lerner34* (n ⴝ 169)

Morgan121 (n ⴝ 104)

Belldegrun122 (n ⴝ 146)

Lau22 (n ⴝ 164)

Duque123 (n ⴝ 64)

0 3 (1.8%) 0 NR 1 (0.5%) 1 (0.5%)

1 (0.9%) 1 (0.9%) NR NR 1 (0.9%) 2 (1.9%)

3 (2.0%) 2 (1.4%) NR 3 (2.0%) 2 (1.4%) 3 (2.0%)

2 (1.2%) 3 (1.8%) 0 1 (0.6%) 1 (0.6%) 0

3 (4.5%) 6 (9.1%) 10 (15.1%)† 2 (3.0%) 0 0

Ghavamian124† (n ⴝ 76) 1 (1.6%) 2 (3.2%) 8 (12.7%) 7 (11.1%) NR 0

Abbreviation: NR, not reported. *For patients who underwent in situ partial nephrectomy. †NSS in patients with solitary kidneys.

were no statistically significant differences in the rates of postoperative progressive renal failure, acute renal failure, urinary tract infection, prolonged ileus, transfusion, deep wound infection, or length of hospitalization. The 30-day mortality rates were 2.0% and 1.6% for patients undergoing RN and NSS, respectively (P ⫽ .58). Table 2 summarizes the frequency of common complications in NSS in several large reported series. Cost of Care Cost of care is an increasingly important variable in determining appropriate therapy. Shekarriz et al compared the costs of RN and NSS in a retrospective case-matched study.25 No significant differences were seen in the length of hospital stay, complication rates, or cost of care between the RN and NSS patients. Uzzo et al compared direct hospital costs and length of hospital stay between RN and NSS patients to determine whether either treatment imparts a specific cost advantage.26 Fifty-two patients at the Cleveland Clinic Foundation underwent NSS and 28 patients had RN for solitary RCC 4 cm or smaller. The investigators found no difference in the postoperative complication rates or cancer-specific survival rates between the two surgical groups. Total direct hospital costs and length of hospital stay were not statistically significantly different between the NSS and RN groups. The type of surgery was not associated with total cost when controlling for all other factors, including age, sex, year of surgery, tumor size, grade, and stage, and postoperative complications. This study demonstrated that elective NSS could be performed with equivalent direct hospital costs and length of hospital stay when compared with patients undergoing RN for small solitary RCC. These data have significant economic implications for the comparison of competing surgical treatment strategies for localized RCC. Risk of Benign Tumors Advances in imaging have resulted in increased frequency of incidentally detected small renal cortical tumors; however, current imaging technology is unable to differentiate malignant from benign renal masses. A recent retrospective review of the Mayo Clinic Nephrectomy Registry documented 26% (88/340) of contemporary patients undergoing NSS had a benign tumor.27 Each 1-cm increase in tumor size was associated with a 22% increase in the odds of a malignant tumor and an 18% increase in the odds of clear cell compared to papillary

RCC. The proportion of benign tumors decreased from 46.3% for tumors less than 1 cm to 6.3% for tumors ⱖ7 cm. Dechet et al addressed the accuracy of frozen section pathology for needle biopsy of renal tumors in a prospective analysis of 106 renal masses.28 Each specimen was examined by two urologic pathologists blinded to final pathology. Interobserver reliability was 83%. Fifteen lesions were considered benign after formal final pathologic review, one pathologist read 3/15 needle biopsies as malignant, while the other read 5/15 needle biopsies as malignant. Ninety-one final pathology reports revealed malignant tumors and each pathologist read 4/91 needle biopsies as benign lesions. The authors of this study have now expanded their analysis to include imaging and permanent section examinations in a new cohort of 100 patients with solid renal masses.29 Final pathologic examination revealed that 85 lesions were malignant and 15 lesions were benign. CT imaging was available for review in 81 cases. Radiologists specializing in genitourinary cross sectional imaging read the scans without knowledge of the final pathology. Sensitivity and specificity of CT imaging were 74% and 20%, respectively. Imaging was considered nondiagnostic in 31% of cases for one radiologist and 23% for the other radiologist. Permanent section of the renal biopsies was considered nondiagnostic in 20% of the cases. Overall accuracy was 72% for one pathologist and 77% for the other. Sensitivity and specificity were 81% and 60% for one pathologist and 83% and 33% for the other. In summary, the results of these two studies from the Mayo Clinic indicate that the accuracy of CT imaging and renal biopsy evaluated by frozen section or permanent section are unreliable for differentiating benign from malignant solid renal masses. Multifocality Kobayashi et al whole-mounted 58 kidneys from patients who underwent RN for RCC to determine the incidence of multifocality.30 Satellite tumor lesions were noted in 27 specimens (47%) and adenomas or dysplastic foci were noted in 19 (33%). At least one of the three types of lesions was noted in 37 specimens (64%). The authors concluded that NSS risks leaving satellite tumor lesions and still must be considered a treatment reserved for patients requiring nephron preservation. Similarly, Schlichter et al reported on 372 patients who underwent RN for RCC.31 The nephrectomy specimens were cut into 3-mm sections to determine local tumor

Surgical management of RCC

555

spread, as well as incidence of multifocality. Cytogenetic and molecular genetic studies were also performed on the primary and secondary tumor sites. A total of 92 multifocal lesions were found in 61 specimens (16.4%). The incidence of multifocality was independent of primary tumor size and nearly one third of all cases demonstrated concordance regarding chromosomal aberrations between the primary and secondary tumors. The clinical implication of these reports is unclear, as the rate of local tumor recurrence after NSS is much lower than the rate of subclinical satellite lesions. Kletscher et al prospectively examined100 RN specimens with localized RCC for multifocality.32 Analysis of each specimen consisted of preoperative CT or magnetic resonance imaging, standard pathologic examination with frozen section, and 3-mm step-sectioning under magnification. Multifocal RCC was found in 16 specimens. Imaging studies suggested multifocal cancer in seven of the 16 cases (44%) found to have multifocal cancer. Standard pathology techniques identified multifocal cancer in 10 of 16 specimens (63%). Papillary and mixed histologic patterns occurred at a significantly increased rate in specimens with multifocal disease (P ⫽ .011). Other parameters, such as stage, tumor size and volume, histologic grade, and deoxyribonucleic acid ploidy were evaluated and did not correlate with the presence or extent of multifocality. The number of secondary tumors per specimen varied from one to 50 (median, two) and was of higher grade in three (19%) and of lower grade in two (12%) when compared with the predominant tumor. The authors conclude that the risk of unknown multifocality in a surgical setting seems to be 6%. This appears to be a more clinically relevant finding as 6% clinically unrecognized multifocality roughly corresponds to the incidence of locally recurrent disease in published large series of NSS. We advocate clearing Gerota’s fascia from the entire surface of the kidney except for areas overlying masses, which should have the adherent fat removed with the specimen. This allows inspection of the entire kidney for lesions that are not large enough to recognize with imaging techniques. In cases where multifocal lesions are suspected, but not readily visible on the surface of the kidney, intraoperative ultrasound with the transducer placed directly on the cleared surface of the kidney should be utilized.

Local Control and Cause-Specific Survival Elective NSS has been show to have cancer-specific survival rates between 89% and 95% and local tumor recurrence rates between 0% and 6% (Table 3). Moll et al reported on 105 patients with a normal contralateral kidney who were treated with NSS for small renal cortical tumors averaging 4 cm in diameter.33 None of the 100 patients being followed at the conclusion of the study period had progressed with a mean follow-up of 3.5 years. In the 1990s, studies at the Cleveland Clinic and Mayo Clinic confirmed the findings of Moll et al and concluded that elective NSS could safely be performed for small renal tumors with similar outcomes to RN.34,35 Licht et al studied 216 patients undergoing NSS for sporadic RCC and demonstrated its safety and efficacy for renal tumors, especially for tumors less than 4 cm.35 Of 34 patients who had recurrent RCC, only three (1.4%) had isolated local tumor recurrences, with the remainder having metastatic disease either with or without local tumor recurrence. Characteristics that favored improved cancer-specific survival included low stage, unilateral renal tumors, and single tumors. The 5-year cancer-specific survival was 100% for this cohort of patients. Lerner et al studied two matched cohorts of patients with low-stage RCC who underwent NSS or RN.34 A total of 185 patients treated with NSS and 209 patients treated with RN were matched for age, sex, and tumor stage and grade. There were no differences observed for cancer-specific survival or metastasis-free survival between the two cohorts. Multivariate analysis demonstrated that tumor size was the most significant predictor of both cancer-specific survival and metastasis-free survival. They concluded that patients with tumors larger than 4 cm and a normal contralateral kidney would best be served with a RN. This concept had been suggested previously by a similar study by Butler et al, in which no differences in survival or operative morbidity were observed in patients undergoing either NSS or RN for solitary renal cortical masses less than 4 cm.36 Lau et al reported a long-term matched comparison of 189 patients who underwent NSS and 1,492 patients who underwent RN for RCC.22 Over the study period, no differences were noted in cancer-specific or metastasis-free survival. Local tumor recurrence-free survival was slightly higher in the

Table 3 Results of Elective Nephron-Sparing Surgery First Author

No. of Patients

Disease-Specific Survival (%)

Local Tumor Recurrence (%)

Mean Follow-up (mo)

Morgan121 Lerner34 Licht125 Hafez37 Belldegrun122 Lee126 Lau22 Total (range)

104 185 216 485 146 79 164 1,379

89 89 90 92 93 95 91 (89–95)

5.8 5.9 2.5 3.2 2.7 0.0 2.4 (0–5.9)

60 44 50 47 74 40 46 (40–74)

556 NSS cohort (5.4% v 0.8%); however, this was not statistically significant (P ⫽ .18).

Tumor Size, Tumor Location, and Tumor Histology Several studies have examined the effect of tumor size on outcome after NSS and RN. Hafez et al evaluated the impact of tumor size on cancer-specific survival and tumor recurrence.37 In this study, 485 patients who were treated with NSS were subdivided into four groups based on tumor size. The investigators found that patients with tumors ⱕ4 cm had a significantly improved cancer-specific survival compared to patients who had tumors larger than 4 cm. They suggested that the 1997 tumor, node, metastases (TNM) staging system failed to stratify patients at risk for disease progression and suggested further subdividing T1 into T1a and T1b based on a 4.0-cm cutoff. This study addressed patients with local tumor recurrence and distant metastases as one group with recurrent cancer. A total of 44 patients (9%) had recurrent RCC by these criteria. However, only eight of the 44 tumor recurrences (18%), or 1.6% (8/485) of the total cohort, had local tumor recurrence without evidence of disease progression (metastases), three (38%) of which had tumors less than 4.0 cm. This study was able to successfully stratify patients into groups with poorer cancer-specific survival and higher risk for cancer progression, but it did not address those patients at risk for local tumor recurrence. Zisman et al studied 661 patients treated with nephrectomy to determine the association of tumor size with survival.38 They reported 4.5 cm to be the optimal cutoff with a hazards ratio 1.7 times that of the 7-cm cutoff used by 1997 TNM staging system. They then replaced the 7-cm cutoff in the 1997 TNM staging system with the new cutoff value and restaged their cohort accordingly. They found no difference in the 5-year cancer-specific survival when comparing tumors greater than 4.5 and ⱕ7.0 cm and tumors greater than 7.0 cm (TNM stage T2). While their findings were similar to those of Hafez et al, Zisman et al suggested that T1 need not be subdivided, but the cutoff for T2 should simply be lowered from 7.0 to 4.5 cm. Local tumor recurrence was not specifically addressed in this study. Lau et al used univariate and multivariate Cox proportional hazard models to assess the features associated with metastasis-free survival and cancer-specific survival in 840 patients who were treated with radical nephrectomy for pT1 tumors.39 This study supported the data from Hafez et al and Zisman et al and demonstrated a transition from low to high risk between 4.5 and 5.0 cm. They proposed that a size cutoff of 5.0 cm most accurately stratifies patients into high- and low-risk categories for disease progression. This study also addressed the importance of the Heidelberg classification system in determining risk of disease progression and cancer death.40,41 RCC was divided into distinct histologic subtypes: clear cell (conventional), papillary, chromophobe, and collecting duct. Lau et al reported that 81.2% had the more aggressive clear cell (conventional) variant of RCC, and 18.4% had either papillary or chromophobe RCC.39 The his-

B.C. Leibovich and M.L. Blute tologic subtype was shown to be a strong predictor of cancerspecific survival. At 10 years, the cancer-specific survivals were 89.1%, 95.5%, and 100.0% for clear cell, papillary, and chromophobe RCC, respectively. When compared to patients with papillary and chromophobe tumors, patients with clear cell RCC had significantly worse cancer-specific (P ⫽ .013) and metastasis-free survivals (P ⫽ .023). Kattan et al included histologic subtype in their postoperative nomogram for RCC, whereby clear cell RCC carried a higher risk of cancer-free survival.42 Hafez et al determined that tumor location (central vs. peripheral) had no impact on 5-year cancer-specific survival (100% v 97%), tumor recurrence (5.7% v 4.5%), or renal function (serum creatinine 1.43 mg/dL in both groups).43 Although NSS is technically more difficult in centrally located lesions, leading to longer ischemia times and increased incidence of collecting system injuries, the authors concluded that there are no inherent, biologic differences between central and peripheral lesions. Cheville et al evaluated pathological features in a large series of stage pT1 conventional RCC cases from the Mayo Clinic and examined the association of these features with cancer-specific survival.44 Multivariate modeling revealed that tumor size, nuclear grade, and histologic tumor necrosis were jointly significantly associated with cancer-specific survival. Of the 4.5-, 5-, and 6-cm tumor size cutoffs examined on univariate analysis, a cutoff of 5 cm or greater was most predictive of cancer-specific survival. We recently conducted a retrospective review of the Mayo Clinic Renal Nephrectomy Registry to examine outcome after NSS (n ⫽ 91) or RN (n ⫽ 841) for tumors 4 to 7 cm.45 This resulted in 91 NSS cases and 841 RN cases for tumors 4 to 7 cm. The 5-year cancer-specific survival rates were 98% and 86% for NSS and RN, respectively. RN for 4- to 7-cm tumors was associated with a higher risk of death from RCC than NSS for 4- to 7-cm tumors (RR, 3.76; 95% CI, 1.20 to 11.81; P ⫽ .023). The 5-year distant metastasis-free survival rates were 94% and 83% for NSS and RN, respectively. Patients who underwent RN for 4- to 7-cm tumors were more likely to metastasize compared to patients with NSS for 4- to 7-cm tumors (RR, 3.44; 95% CI, 1.27 to 9.28; P ⫽ .015). However, after adjusting for tumor stage, regional lymph node status, nuclear grade, histologic tumor necrosis, tumor size, and histologic subtype, in multivariate analysis, there was no statistical difference in metastasis-free survival or cancer-specific survival between the groups. Our findings indicate that careful selection of patients by surgeons with extensive experience can yield excellent results when performing NSS on tumors greater than 4 cm. However, the features controlled for in multivariate modeling are all pathologic variables, which are not available when the clinician must decide if a specific patient should be offered NSS or RN. We therefore analyzed CT scans blinded to surgical procedure performed to determine which features were predictive of good outcome when performing NSS. Patients who had NSS were less likely to have large tumors, infiltrative growth patterns, intrarenal tumors, and involvement of the collecting system than patients who had RN. No other feature

Surgical management of RCC from the CT films was significantly different between patients treated with NSS and RN.

Adequacy of Resection for NSS When assessing a tumor for NSS, urologists often take into consideration the perceived need for a rim of at least 1 cm of normal uninvolved parenchyma. There are little data to support this practice. Novick et al reported a series of 33 enucleations performed for RCC at Mayo Clinic and Cleveland Clinic between 1970 and 1983.46 Their 3-year survival was 90% and local tumor recurrence occurred in only two patients (6%). Lerner et al compared the outcomes of NSS in 185 patients with RN in 209 matched patients in 1996.34 NSS consisted of partial nephrectomy in 82 patients and enucleation in 87 patients. They found no difference in the rate of cancer death or progression to metastases between patients treated by partial nephrectomy versus enucleation. Recently, Sutherland et al directly examined the issue of surgical margins for NSS by quantifying the thickness of uninvolved tissue surrounding the tumor in 44 partial nephrectomy specimens.47 The mean and median sizes of negative margins were 0.25 and 0.2 cm, respectively (range, 0.05 to 0.7 cm) and three patients had positive surgical margins. One patient with positive surgical margins had multiple local and systemic recurrences. None of the other patients had tumor recurrence with a mean follow-up for this series of 49 months. The authors concluded that only a minimal margin of less than 5 mm is required when performing NSS.

Radical Nephrectomy Cases that are inappropriate for NSS are treated with RN. However, the accepted appropriate extent of surgical resection when performing a RN is in evolution. Indications for adrenalectomy and lymphadenectomy, for example, have changed with better imaging and with increased understanding of the biology of RCC. Kletscher et al conducted a review of 100 radical nephrectomy specimens that included an ipsilateral adrenalectomy. Two patients had adrenal metastases and two had benign lesions, all of which were recognized by preoperative imaging.48 Tsui et al conducted a retrospective review of 511 patients who underwent RN with ipsilateral adrenalectomy.49 Despite the fact that their series was skewed towards patients with advanced RCC, only 29 cases (5.7%) were found to have involvement of the adrenal gland. Only 0.6% of cases had adrenal involvement not recognized on imaging. The authors of both studies concluded that routine adrenalectomy is not indicated in patients with normal adrenal glands on preoperative imaging studies. Data regarding the impact of lymphadenectomy on outcome for RCC patients are limited and conflicting,50-54 although a prospective clinical trial addressing this issue may provide some clarification.55 Pantuck et al reviewed the impact of lymphadenectomy on 900 patients.52 In their series, patients receiving immunotherapy for metastatic RCC had a better prognosis if a lymphadenectomy was performed. A

557 study of 167 patients without lymphadenopathy demonstrated no survival benefit to lymph node resection.51 However, this series include more early-stage disease patients than the study by Pantuck et al. We recently examined parameters predictive of lymph node positivity in a series of 1,652 patients treated with RN for nonmetastatic RCC.50 Nuclear grade 3 or 4, presence of sarcomatoid elements, tumor size greater than 10 cm, pT3 or pT4, and the presence of histologic tumor necrosis were associated with nodal status. Patients with two or more of these features had a 10% incidence of positive nodes versus 0.6% positive nodes if none or one feature was present. Terrone et al examined the staging accuracy of lymphadenectomy based on the number of nodes removed and determined that greater than 12 nodes should be examined to accurately assess for nodal metastases.54 Ultimately, the decision to perform a lymphadenectomy is individualized; however, we recommend that a nodal resection at the time of RN should be performed routinely, especially in patients with multiple poor prognostic features in the primary tumor specimen and those destined for systemic therapy.

Surgery for Metatstatic RCC Therapeutic options for patients with metastatic RCC are limited, especially given RCC’s resistance to chemotherapy and radiotherapy. Traditionally, surgery was the mainstay of treatment,56 although the exact indications for and scope of surgical therapy have been controversial and sometimes poorly defined.57 In addition, outcomes were often poor because surgical treatment was inadequate for some disease sites, and poorly selected patients were unable to tolerate the surgical procedures.58 Recent developments, including the emergence of immunotherapy, advances in surgical techniques, and better patient selection, have rekindled interest in the surgical treatment of metastatic RCC.59,60 Indications for surgical intervention in patients with metastatic RCC include palliation of symptoms, as well as improving prognosis. Palliative nephrectomy can be considered in order to relieve pain, control hematuria, or occasionally to ameliorate paraneoplastic phenomena.57,60,61 However, patient selection is critical to avoid possible morbidity and mortality,62 and there is potential for some symptoms being inadequately treated by surgery.63 Embolization is a reasonable alternative to surgery for high-risk patients with symptomatic metastatic RCC.64 Surgery may also be directed at metastases, in order to control local symptoms.65 The most notable examples are the relief of spinal cord compression66 and the fixation of fractures.67 However, palliation of metastatic sites may also be undertaken using less invasive modalities.68 Ultimately, palliative surgical procedures need to be tailored to specific patients’ needs, and no general guidelines can hope to be universal. Factors that need to be considered in the decisionmaking process include the extent and site of symptomatic disease, the patient’s general health and preferences, and the availability, efficacy, and safety of alternative treatments. The 5-year survival for patients with metastatic RCC is 5% to 30%,61 and one significant goal of treatment is to improve

B.C. Leibovich and M.L. Blute

558 Table 4 Rationale for Cytoreductive Nephrectomy Theoretical Rationale

Experimental Evidence

Improvement of performance status, potentially allowing better tolerance of immunotherapy Improved immunologic function due to removal of immunosuppressive or sequestration (“immunologic sink”) effect of primary tumour Debulking of tumor volume Removal of potential source of new metastases Reduction of complications related to primary tumor that may prevent administration of immunotherapy

4 wks postoperatively, 72% of patients had unchanged or improved performance status105 Enhanced function of natural and lymphocyte-activated killer cells106,107 and improved cell-mediated immunity108

on these outcomes. Multimodality therapy, combining nephrectomy with systemic therapy or occasionally with radiotherapy, are currently the most promising approaches for patients with metastatic RCC. In the occasional patient, total surgical clearance of disease is feasible, and may also impact on survival. Resection of a solitary (or a limited number of) metastasis, along with nephrectomy if the primary tumor is still in situ, may lead to long-term survival in more than 30% of such patients.69-71 The best results are obtained if the metastases are pulmonary, metachronous with a long disease-free interval, and completely resected.65 In the case of pulmonary metastases, size and number of metastases and tumor involvement of intrathoracic lymph nodes have been shown to be prognostic variables.72,73 Encouraging results have been reported following the excision of hepatic,74 adrenal,75 brain,76,77 and pancreatic metastases78-80 or of isolated local recurrences in the nephrectomy bed.81-83 The recurrence of RCC in regional lymph nodes following nephrectomy can also be treated by surgical excision of the nodal mass. In the occasional patient, the sequential surgical excision of multiple asynchronous metastases may allow prolonged disease-free survival,84 although in many instances such patients do succumb to their disease despite surgical treatment. In our review of surgically

managed metastatic RCC, patients with completely resected disease had a twofold reduction in cancer-specific mortality, which remained statistically significant even after adjusting for other prognostic features in multivariate analysis.85 The most frequently used systemic therapy modalities for metastatic RCC have been interferon-␣ (IFN-␣) and interleukin-2 (IL-2).59,60 In early studies of immunotherapy, a history of prior nephrectomy seemed to confer an advantage.86-89 These results led to the concept of cytoreductive nephrectomy as being a desirable preliminary step to undertaking immunotherapy. In fact, the differences in outcomes in these early studies may have been explained in part by the fact that a subset of patients were presenting with delayed metachronous disease, and these tumors were biologically different from the tumors in patients presenting with metastases at diagnosis and who proceeded directly to immunotherapy. Nonetheless, there are theoretical arguments, with some supportive evidence, for initial nephrectomy to improve the efficacy of subsequent immunotherapy (Table 4). The availability of tumor pathologic data prior to embarking on immunotherapy may also be of potential benefit.90 The use of adoptive immunotherapy, which is currently experimental,91,92 of course mandates nephrectomy prior to immunotherapy. In such trials, the immunotherapy is delivered in the

Table 5 Nephrectomy and Immunotherapy Series Reference Cleveland Clinic109 Albert Einstein College101 Yale110 UCLA111 New Medical Center112 National Cancer Institute96,102 M.D. Anderson113 UCSF114 UCLA115 Indiana105 SWOG894990† EORTC 3094793†

No of Complications/Mortality Unable to Receive Response Median Patients* (%) of Surgery Immunotherapy (%) Rate (%)* Survival (mo)* 37 (25) 30 58 (26) 62 28 195 (51)

16/2.7 50/17 NR NR/0 NR/3.6 13/1

22 77 NR 11 7.1 38

8 (12) 13.3 NR 34.5 39 18 (6)

12 (14) NR 15.2 (8.9) 22 20.5 NR (13)

66 63 89 32 120 (121) 42 (43)

35/3 14/3.6 NR 19/3 5/1 14/0

18 27 NR 25 NR 19

NR NR NR NR NR 19 (12)

NR 17.8 16.7 NR 11.1 (8.1) 17 (7)

Abbreviations: UCLA, University of California, Los Angeles; UCSF, University of California, San Francisco; SWOG, Southwest Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; NR, not reported. *Figures in parentheses refer to non-nephrectomy group. †Randomized controlled trials.

Surgical management of RCC form of infiltrating lymphocytes harvested from the tumor or tumor antigens are used as an immunogenic vaccine.60 Trials employing nephrectomy and adoptive immunotherapy protocols represent encouraging avenues to be explored further in the future. A number of centers have published series on cytoreductive nephrectomy prior to immunotherapy (Table 5). In general, response rates and survival were better compared to non-nephrectomy patients in these series (where included) or historical controls. However, given that these are retrospective, single-institution studies, the results could easily be explained by selection bias. Thus, the patients who underwent nephrectomy may have had better performance status and more favorable disease burden on average, compared to patients who did not, and these factors could be the real reason for the differences in outcomes. To address this issue, two recent randomized controlled trials have examined the effect of immunotherapy with or without prior nephrectomy in patients with metastatic RCC.90,93 In the larger, Southwest Oncology Group arm of the study,90 246 patients were randomized, and the median survival was 11.1 months in patients who had had nephrectomy, compared to 8.1 months in those who had not. There were more patients in the nephrectomy group with a favorable performance status, and, since better performance status confers a survival benefit, this may be seen as a potential confounding variable. However, in the regression analysis of proportional hazards, there was no interaction between nephrectomy status and performance status, indicating that the results were not explained by the skewed distribution of performance status. The European Organization for Research and Treatment of Cancer (EORTC) used the same protocol but over a shorter duration, accruing 85 patients.93 Although underpowered, the EORTC arm of the study in fact showed a more pronounced improvement in survival, from a median of 7 months in the control group to 17 months in the nephrectomy group, and an improvement in the time to progression in the nephrectomy group compared to control (5 v 3 months). The consistent results between these two studies94 provide the most compelling evidence for a benefit from nephrectomy prior to immunotherapy. It is notable that the survival benefit of 5.8 months (31%) on combined analysis of the trials94 is small, even in what is obviously a very select group of patients, given the strict selection criteria and low accrual numbers. Some centers have tried implementing immunotherapy first, reserving nephrectomy for patients who respond. It is proposed that this approach would allow the surgical intervention to be targeted to those patients who are most likely to benefit, thus containing costs and limiting unjustified morbidity. There are also concerns that the surgery itself may have immunosuppressive effects that may negatively influence subsequent immunotherapy.95 The primary tumor usually shows minimal response to immunotherapy,96-98 and thus patients who respond would require subsequent nephrectomy to consolidate their therapy, while in some series,

559 Table 6 Criteria for the Selection of Patients to Undergo Cytoreductive Nephrectomy112 Resectability such that >75% debulking can be achieved Absence of CNS, bone or liver metastases Adequate cardiopulmonary functional reserve ECOG performance status 0 or 1 (no or minimal impairment of activity, respectively) Predominantly clear cell histology Abbreviations: CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group.

surgical excision of disease at metastatic sites was also undertaken.99,100 Reported results96-100 have been variable, and theoretical arguments as well as the evidence from recent trials would favor cytoreductive nephrectomy. However, further study is required to definitively establish the optimal timing of nephrectomy in relation to immunotherapy. The greatest concern with undertaking nephrectomy prior to immunotherapy is that the morbidity of surgery may prevent patients from receiving immunotherapy, as occurred frequently in some series.101,102 Most series, however, report much lower complication rates, and acceptable rates of enrolment in immunotherapy (Table 5), presumably because of better patient selection. Current best evidence would suggest that nephrectomy followed by immunotherapy in the form of either IFN-␣ or IL-2 is the gold standard for patients with metastatic RCC. However, one study found that only around 20% of such patients may be suitable for this treatment regimen.103 Some patient subgroups that have particularly poor outcomes include those with extensive metastases63 or poor histologic variants,104 while unimpaired performance status leads to favorable outcomes.90 It would seem logical to frame criteria by which patients are selected for cytoreductive nephrectomy prior to immunotherapy (Table 6).

Conclusions and Future Directions RCC remains primarily a surgical disease; however, the surgical management of RCC continues to evolve. For appropriately selected tumors, NSS is equally effective for control of cancer, diminishes the risk of renal failure, and offers superior quality of life with no significant differences in complications or cost. RN should include lymphadenectomy in appropriate cases and adrenalectomy should be included in selected cases only. Aggressive surgical management of RCC likely improves prognosis. Further changes in the role of surgery are inevitable as technology for minimally invasive techniques progresses. Finally, the development of new targeted therapeutics, such as multiple tyrosine kinase inhibitors, recently approved by the US Food and Drug Administration, will certainly result in changes in the surgical management of metastatic RCC and may offer efficacy in the adjuvant setting for clinically localized surgically treated RCC.

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