103Controversies in the Surgical Management of Renal Cell Carcinoma
Case 1: A 63-year-old male is diagnosed with a left renal mass 12 cm in maximal diameter, with extension into the perirenal fat. Staging imaging shows no evidence of lymphatic involvement or distant metastasis. He is scheduled to undergo a left radical nephrectomy.
Question 1: Should this patient additionally undergo a regional lymph node dissection, and if so, to what extent?
While the indications for lymph node dissection (LND) are well established in the treatment of other urologic cancers, the utility of regional LND for renal cell carcinoma (RCC) remains controversial. The incidence of isolated retroperitoneal lymph node (LN) metastases has been cited to be less than 10% (1). The European Organization for Research and Treatment of Cancer (EORTC) 30881 is the only randomized study to date that has addressed the role of regional LND in the setting of radical nephrectomy (RN) for RCC, and 732 patients with preoperative N0M0 tumors were eligible (2). With a median follow-up period of 12.6 years, regional LND did not improve cure or survival in patients that underwent RN for T1 to T3 diseases. In this cohort, regional nodal metastases were present in 1% of palpably normal nodes and 17% of palpably abnormal nodes, and LND did not increase the risk of perioperative complications.
However, certain limitations do exist in the EORTC 30881 trial. In particular, although the trial enrolled 732 patients, given the small proportion of patients with positive LN status, the study was underpowered to conclude that the outcomes were equivalent. In addition, data such as the number of regional LNs resected and the number of positive LNs were also not included or analyzed in the study.
104While the EORTC study concluded that the added benefit of LND is marginal in patients without clinically abnormal LNs, several retrospective studies suggest that patients with N1 RCC may have improved cancer-specific survival (CSS) and response to adjuvant immunotherapy following LND (3). It has been shown that increasing the number of LNs removed by 10 improves CSS in patients with N1 disease by 10% at 5 years (4). Therefore, in patients with a high risk of nodal metastases, a regional LND may be warranted. Patients considered to be high risk include those with ≥2 of the following risk factors: grade 3 to 4, stage T3 to T4, tumor size ≥ 10 cm, tumor necrosis, and sarcomatoid elements (5).
The most common location of nodal involvement is the interaortocaval nodes in right-sided tumors and the para-aortic nodes in left-sided tumors. Dissection templates should extend from the diaphragmatic crus to the common iliac artery and include paracaval and interaortocaval nodes for right-sided tumors and para-aortic and interaortocaval nodes for left-sided tumors (6).
Case 2: A 71-year-old female is diagnosed with a 13.4 cm right renal mass. Staging workup reveals a 2 cm hepatic nodule and several sub-centimeter right-sided pulmonary lesions. The patient is to be treated with six cycles of bevacizumab + IFN-α.
Question 2: Would this patient benefit from a cytoreductive nephrectomy prior to systemic therapy?
The argument for cytoreductive nephrectomy (CN) was originally developed in the era of systemic immunotherapy. Based on the results of two randomized clinical trials Southwest Oncology Group (SWOG) and EORTC, patients with metastatic RCC (mRCC) with resectable primary tumors without brain metastases and who are medically fit (Eastern Cooperative Oncology Group [ECOG] 0–1) appear to demonstrate improvement in time-to-progression and overall survival when treated with CN prior to systemic interferon (IFN). SWOG 8949 demonstrated a median survival increase of 3 months (11.1 vs. 8.1 months) in 246 patients who were randomized to either IFN-α only or CN with postoperative IFN-α. These findings were independent of performance status, metastatic site, or the presence of metastatic lesions. However, a performance status of 0 was associated with a 10-month median increase in overall survival when 105compared to a performance status of 1 within the CN cohort (7). Meanwhile, the EORTC study showed a survival advantage of 10 months overall (17 vs. 7 months) favoring combination therapy over interferon therapy alone (8). The rate of perioperative mortality was also very low at less than 1%. Flanigan et al subsequently performed a combined analysis of these two studies and found a 6-month overall survival benefit (13.6 vs. 7.8 months) favoring combined CN and immunotherapy. In addition, Lara et al reevaluated the SWOG data with 9-year long-term follow-up data and found a consistent 3-month survival benefit, or a 26% reduction in death. On multivariate analysis, performance status (1 vs. 0), elevated alkaline phosphatase, and lung metastasis were independent predictors of overall survival (9).
Question 3: If the above patient was instead being treated with sunitinib, would she benefit from a cytoreductive nephrectomy?
In the era of targeted therapy for RCC with agents such as tyrosine kinase, mechanistic targets of rapamycin, and vascular endothelial growth factor inhibitors (mechanistic target of rapamycin [mTOR], and vascular endothelial growth factor [VEGF] inhibitors), similar prospective studies have yet to be completed. Targeted therapy has proven itself to be significantly superior to cytokine therapy, and this has resulted in some controversy as to whether concomitant CN is beneficial in patients already receiving targeted therapy. You et al retrospectively reported their results comparing outcomes for 78 patients with mRCC who underwent targeted therapy alone or who had CN as well. Although the CN group did have a median overall survival of 21.6 months compared to 13.9 months in the control group, this was not statistically significant according to the authors (10). In contrast, Choueiri et al performed a multi-institutional study that did demonstrate a statistically significant improvement in median overall survival (19.8 vs. 94 months) in mRCC patients with favorable or intermediate prognostic features who underwent CN. These features include performance score (>80), age less than 75 years, more than one site of metastatic disease, and no brain metastasis (11). Patients with poor prognostic features only realized a marginal benefit from CN, indicating that CN should only be reserved for palliative purposes in such cases.
It is critical to point out that nearly all patients enrolled in the original clinical trials that assessed efficacy of the currently 106available targeted agents were completed in the setting of a prior nephrectomy. Therefore, the clinical efficacy of these targeted agents has only been evaluated in the context of a resected primary tumor. The CARMENA phase 3 trial is an ongoing clinical trial that will hopefully provide the much-needed insight into the role of CN in the era of targeted therapy.
Case 3: A 68-year-old male with a solitary left kidney is found to have a 9.7 cm exophytic renal mass. Metastatic workup demonstrates a 1.5 cm left pulmonary nodule and multiple osteolytic bone lesions, and his estimated glomerular filtration rate (eGFR) is greater than 60.
Question 4: What is the role of cytoreductive nephron-sparing surgery in this patient?
The role of nephron-sparing surgery (NSS) for cytoreductive therapy in the setting of mRCC is less well studied. Several retrospective case series have reported the use of NSS in the setting of mRCC, but no high-quality studies exist. As preservation of renal function is important in the context of potentially nephrotoxic drugs used for mRCC, NSS may be a reasonable alternative to CN in patients with underlying renal dysfunction or other imperative reasons for NSS (i.e., solitary kidney or bilateral tumors).
The four largest retrospective studies evaluating the role of NSS in patients with mRCC include between 16 and 70 patients, and have yielded mixed results. The first such study retrospectively identified 16 patients from the Mayo Clinic Nephrectomy Registry, 12 of whom had a solitary kidney, who underwent NSS for pM1 RCC. CSS rates were comparable to patients who had undergone RN for pM1 disease; however, early and late complication rates were higher in the 12 solitary kidney patients (12). Capitanio et al used the Surveillance, Epidemiology, and End Results (SEER) cancer registry to identify 46 patients with mRCC who were treated with RN or NSS, respectively, and found no difference in CSS in matched and unmatched regression analyses (13). In another mRCC study comparing 45 NSS cases to 732 RN cases, RN led to a 1.7-fold and 1.5-fold higher RCC-specific mortality in unmatched and matched analyses, respectively. However, the results were not statistically significant (14). A fourth retrospective study by Hellenthal et al actually found improved CSS in patients undergoing NSS for mRCC. In this 107study, the authors evaluated 8,498 patients with mRCC from the SEER database, of which 2,950 underwent cytoreductive surgery. While the vast majority of patients (98%) underwent cytoreductive RN, 70 patients (with tumors 2–3 cm in size) underwent cytoreductive partial nephrectomy. Although multivariate analysis was utilized to account for preoperative risk factors, those patients undergoing NSS were found to be 0.49 times as likely to die of RCC as those who underwent RN (15).
It is important to note that several of these studies were population based and contained limited information regarding clinical and patient information. Also, due to the small sample sizes in these studies, other prognostic variables on CSS, such as performance status and LN status, were unable to be controlled. Finally, these results may at least partially be attributed to the difference in tumor burden between patients undergoing NSS and RN.
Patients with a solitary kidney and pM1 disease undergoing NSS have been shown to have an increased rate of early and late complications compared to patients undergoing RN; however, this increase may be due to underlying medical conditions such as chronic renal insufficiency that necessitated NSS in this population. In one analysis of 33 patients with mRCC, those who underwent NSS for metachronous contralateral renal masses and a renal mass ≤ 4 cm had longer overall survival compared to those with bilateral synchronous or unilateral renal masses, likely because patients presenting with synchronous renal tumors were more often metastatic at the time of presentation (16). While further research is needed, the primary tumor burden compared to the metastatic burden, and the time lag between the index tumor and subsequent masses may guide the decision to proceed with cytoreductive RN or NSS for mRCC.
Case 4: A 61-year-old female is diagnosed with a right-sided T3aN0M1 renal cell carcinoma. Percutaneous renal mass biopsy demonstrates papillary type II histology, Fuhrman grade III.
Question 5: Should this patient undergo a cytoreductive radical nephrectomy?
While nonclear cell (ncc) histology following nephrectomy for localized disease predicts a favorable prognosis, metastatic nccRCC is characterized by poor prognosis and resistance to 108chemotherapy. Kassouf et al compared outcomes of 92 patients who underwent CN for metastatic nccRCC against 514 patients who underwent CN for metastatic clear cell RCC (ccRCC) (17). The 2-year overall survival rate in patients with nccRCC was 24% compared to 44% in those with clear cell histology. Nodal disease predicted a worse outcome in patients with ccRCC but was not an independent predictor in the nccRCC cohort, despite the higher incidence of node positivity in that group. Due to the paucity of nccRCC compared to clear cell histology, the relative proportion of patients with ncc histology in clinical trials is typically less than 10%. As a result, there is a lack of strong clinical data on the role of RN or NSS for metastatic disease in this subpopulation.
Case 5: A 66-year-old male with diabetes mellitus and chronic kidney disease (CKD) stage IIIB is found to have a 11.4 cm largely exophytic right renal mass with evidence of invasion into the surrounding Gerota’s fat.
Question 6: Is this patient a candidate for a cytoreductive nephrectomy?
While NSS is routinely utilized in patients with primary renal masses less than 7 cm (stage T1), RN has largely remained the treatment of choice for patients with locally advanced disease (stage T2–T4). However, several studies have examined the potential role of NSS in patients with locally advanced RCC. Margulis et al reviewed 26 patients who underwent NSS for clinical T3a or T3b tumors, mostly due to imperative indications such as solitary kidney, atrophic contralateral kidney, or chronic renal insufficiency (18). When adjusted for grade, stage, size, and tumor histology, NSS did not adversely impact disease recurrence or RCC-specific death compared to RN. NSS was associated with higher procedure-related complications, but similar blood loss, transfusion rates, and hospital length of stay compared to RN. The authors did not comment on the differences between the two groups regarding the need for long-term dialysis or the ability to receive systemic therapy. Likewise, Kolla et al showed comparable recurrence-free survival rates in six of seven patients who underwent NSS for T3b disease, without the need for dialysis at a mean follow-up time of 30 months (19). In another study, Angermeier et al retrospectively reviewed nine patients who underwent NSS for 109tumors with venous involvement. Five patients had no evidence of disease at a median follow-up of 33 months and the remaining four died of metastatic disease at a median time of 35.5 months postoperatively (20).
As locally advanced RCC is associated with an increased risk of contralateral tumor development and systemic relapse, select patients with solitary kidneys or chronic renal insufficiency may be suitable candidates for an attempt at NSS. NSS in the setting of locally advanced disease is technically challenging and associated with longer ischemia times and increased likelihood of postoperative renal dysfunction. Thus, careful preoperative planning and intraoperative ultrasound should be stressed in these complicated cases.
Case 6: A 69-year-old female is found to have a 3 cm exophytic right upper pole and a 4 cm exophytic right interpolar renal mass. She has no history of hereditary syndromes associated with renal tumors, her metastatic workup is negative, and her eGFR is 55.
Question 7: Is this patient a candidate for NSS, and if NSS were to be performed, when would one consider converting to a radical nephrectomy?
Although there is some consensus regarding the surgical management of patients with hereditary syndromes such as Von-Hippel Lindau and familial papillary RCC, there are no clear guidelines on the surgical management of patients found to have sporadic multifocal tumors. While patients with hereditary RCC often present with multifocal disease, sporadic cases are multifocal in only 3% to 20% of patients (21,22). Multifocal cases of sporadic RCC are also usually more advanced at the time of diagnosis and have higher recurrence rates than their solitary counterparts. Nonhereditary multifocal cases are traditionally treated with RN due to these factors; however, the role of NSS has been investigated in three large retrospective studies. Two studies performed at a single institution compared outcomes of NSS and RN for sporadic, multiple, ipsilateral renal tumors. The 5-year CSS was comparable between both groups and the recurrence rates with NSS were between 10% and 13% (23,24). Mano et al. analyzed 78 patients who underwent NSS and 45 patients who underwent RN for nonmetastatic, unilateral, synchronous, multifocal renal tumors (25). Five-year 110recurrence-free survival rates were 98% and 85% in the NSS and RN groups, respectively. Of note, however, cases in the RN group had significantly larger primary tumor burden, higher pathologic T stages, and higher RENAL nephrometry scores. The rate of postoperative complications was comparable between the two groups and kidney function was preserved in 75% of NSS patients at 5 years. These data suggest that with careful surgical selection, NSS produces equivalent survival rates for multifocal sporadic tumors as RN. If NSS is to be performed, the surgeon should be prepared to convert to RN in the presence of extensive tumor burden, large resections resulting in inadequate residual kidney, or adverse intraoperative pathology of satellite lesions.