The Evolving Role of Cytoreductive Surgery for Metastatic Renal Cell Carcinoma

Drs. Uzair Chaudhary and Gerald Hull provide a comprehensive review of the role of cytoreductive surgery in metastatic renal cell carcinoma. This controversial topic has been debated for many years. Metastatic renal cell carcinoma continues to be a chemotherapyresistant tumor with a poor prognosis. About 30% of newly diagnosed patients present with metastatic disease. In the metastatic setting, the most recognized treatment modalities involve the biologic agents interferon- alpha and interleukin-2 (IL-2, Proleukin). They produce an objective response rate of about 10% to 15%, with approximately 5% of patients achieving a durable complete response. Cytoreduction Followed by Immunotherapy
Cytoreduction in the metastatic setting has been discussed since the early 1970s. Initially, proponents used reports of immune-mediated regression of metastatic deposits following angioinfarction of the primary tumor as the proof with which to advocate cytoreduction.[1] Unfortunately, the morbidity and/or mortality of this procedure far exceeded the rate of regression. In the late 1980s, the surgical branch of the National Cancer Institute (NCI) required that all patients entering their high-dose IL-2 clinical trial for metastatic renal cell carcinoma undergo a prior nephrectomy.[2] The result was that nephrectomy followed by immunotherapy became common practice in the setting of metastatic disease. The evidence for this approach was not based on prospective, randomized trials, and the rate of postoperative complications, mortality, and rapidly progressive disease prior to the initiation of high-dose IL-2 therapy was not insignificant. Flanigan et al reported on the Southwest Oncology Group (SWOG) study of nephrectomy followed by interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) compared with interferon alfa-2b alone for metastatic renal cell carcinoma.[3] This was a randomized, prospective trial in 246 patients accrued over 7 years from 80 institutions. Patients were stratified according to SWOG performance status, the presence or absence of lung metastases, and the presence or absence of at least one measurable metastatic lesion. The analysis showed a significant improvement in overall survival (P = .05) favoring the patients assigned to surgery followed by interferon (11.1 vs 8.1 months). The median survival for patients with a performance status of 0 was 17.4 vs 11.7 months, and for those with a performance status of 1, 6.9 vs 4.8 months. The difference in survival was not dependent on performance status, metastatic site, or the presence or absence of measurable disease. One confounding factor in the analysis of the data was the higher number of patients with a performance status of 1 in the arm that received interferon alone (58.1% vs 45%, P = .04). Mickisch et al reported on an identical trial conducted by the European Organization for Research and Treatment of Cancer (EORTC).[4] This trial enrolled 85 patients, and the findings confirmed the results of the SWOG trial. A significant advantage in median survival (17 vs 7 months) and time to progression (5 vs 3 months) favored patients in the surgery- plus-interferon arm. Management Considerations
These pivotal studies have recently led to a shift in the management of metastatic renal cell carcinoma. Many clinicians are calling for cytoreduction followed by immunotherapy to be the standard arm in future studies, but such a sweeping change needs to be approached with caution. Both the SWOG and EORTC studies limited enrollment to patients with a performance status of 0 or 1. Patients with a performance status of 2 were correctly excluded secondary to their poor survival and higher probability of postoperative complications and mortality. The 2-month improvement in survival noted in the group with a performance status of 1 in the SWOG trial argues against the routine use of nephrectomy for all such patients. Patients with a performance status of 0 should be strongly considered for surgery, but if their primary tumor burden is smaller than their overall tumor burden, a nephrectomy would not be advisable despite their performance status. Another major consideration that limits the generalizability of this approach is the operability of the primary lesion. In the SWOG study, an attending surgeon determined operability. As the result of surgery, mortality and morbidity were much lower in the SWOG trial than noted in previous reports. This does not mean that all centers will achieve similar results. The slow rate of accrual for this trial (less than one patient per year from each participating institution) may be explained by the requirement of an operable patient with a high performance status. Conclusions
We would recommend nephrectomy in the setting of metastatic disease only in a few situations. In our opinion, all patients with a performance status of 0 and a low volume of disease should be considered for cytoreduction. Selected patients with a performance status of 1 should be offered the option of cytoreduction. Patients with a performance status of 2 should not undergo cytoreduction prior to systemic therapy. Although the SWOG and EORTC trials were well designed and demonstrated a significant improvement in survival among patients who receive cytoreduction plus interferon alfa-2b, the lack of generalizability to the majority of patients with metastatic renal cell carcinoma limits this approach. At present, the mechanism that mediates the improvement in survival is unknown. Referral to a major center that handles a large volume of cases should strongly be considered to lower surgical complication rates. An unanticipated benefit of this approach is that tumor specimens can be retrieved and analyzed for the genetic and protein patterns that predict outcome.[5]