Surgical resection (open and laparoscopic radical or partial nephrectomy) is the established therapy for localized renal cell carcinoma. When performing a radical nephrectomy, the kidneys, adrenal gland, and perirenal fat (structures bound by Gerota fascia) are removed. Also, limited regional lymph node dissection can be performed for staging purposes. Partial nephrectomy is standard in patients with smaller tumors (eg, < 7 cm) or in whom radical nephrectomy would unacceptably compromise overall renal function.
Because complete resection is the only known cure for renal cell carcinoma, even in locally advanced disease, surgery is considered if the involved adjacent structures can be safely removed. In patients with metastatic renal cell carcinoma, two randomized, controlled trials have shown a survival benefit of 6 months (combined analysis) with a debulking nephrectomy before interferon-α immunotherapy, as compared with immunotherapy alone. However, patients must be carefully selected before the nephrectomy and should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. It is also recommended that patients have a baseline CT or MRI of the brain before undergoing surgery. The ECOG performance status of a patient before treatment is an important determinant of disease-related outcome and should be considered in making treatment decisions. A number of biologics, such as everolimus, sunitinib, and sorafenib, are under study as adjuvant treatment for high-risk resected renal cancer.
Primary radiation therapy. Thermoablative therapies are increasingly used for patients who are not surgical candidates. Alternatively, radiation therapy may be considered for palliation as the primary therapy for renal cell carcinoma in patients whose clinical condition precludes definitive treatment, either because of extensive disease or poor overall condition. A dose of 4,500 cGy is delivered, with consideration of a boost up to 5,580 cGy. Early results with stereotactic body radiation therapy are encouraging; however, this approach remains strictly investigational.
This modality has not been shown to prevent recurrence.
Radiation therapy is commonly used for palliation of metastatic disease, including that affecting the central nervous system.
Metastatic renal cell carcinoma is resistant to chemotherapeutic agents. An extensive review of currently available agents concluded that the overall response rate to chemotherapy is 6%.
There is no standard adjuvant therapy for renal cell carcinoma after surgical resection, regardless of recurrence risk. Multiple agents, including hormone therapy, radiation, immune therapy, and chemotherapy, have been tried, and none has produced benefit in the adjuvant setting. Thus, observation is the current standard of care. There are ongoing trials testing novel targeted agents in the adjuvant setting.
Interleukin-2 (IL-2, aldesleukin). The first US Food and Drug Administration (FDA)-approved treatment for metastatic renal cell carcinoma was high-dose IL-2 (Table 4).
• High-dose regimen—High-dose IL-2 (720,000 IU/kg IV piggyback every 8 hours for 14 doses, repeated once after a 9-day rest) results in a 15% remission rate (7% complete responses, 8% partial responses). The majority of responses to IL-2 are durable, with a median response duration of 54 months.
The major toxicity of high-dose IL-2 is a sepsis-like syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to a “capillary leak.” Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is totally reversible.
• Other doses and schedules—Because of the toxicity of high-dose IL-2, other doses and schedules have been and are being evaluated. Several trials of low-dose IL-2 (3–18 × 106 IU/d), either alone or combined with interferon-α, have reported outcomes similar to those achieved with high-dose IL-2.
Biologic agents. Several oral multikinase inhibitors have been approved by the FDA for the treatment of advanced kidney cancer. In addition, a monoclonal antibody has been tested extensively in treating the disease and, in combination with interferon-α, was FDA-approved to treat metastatic renal cell carcinoma.
• Sorafenib—This agent targets several serine/threonine and receptor tyrosine kinases, especially vascular endothelial growth factor (VEGF), thought to be integral to the biology of renal cell carcinoma. A phase III, placebo-controlled trial was conducted in 769 patients with advanced renal cell carcinoma who had received prior systemic treatment. The recommended oral dose of sorafenib (400 mg twice daily) was used. The median progression-free survival was 5.5 months in the sorafenib group vs 2.8 months in the placebo group. Toxic effects associated with sorafenib included reversible rashes in 40% and hand-foot skin reactions in 30% of patients. Notably, the incidence of treatment-emergent cardiac ischemia/infarction events was higher with sorafenib (2.9% vs 0.4%).
• Sunitinib—This agent targets several receptor tyrosine kinases. Initial phase II trials of sunitinib, given orally at 50 mg once daily for 4 weeks followed by 2 weeks off to 169 patients with metastatic renal cell cancer that failed to respond to prior cytokine-based therapy demonstrated an investigator-assessed objective response rate of 45%, a median duration of response of 11.9 months, and a median progression-free survival of 8.4 months. A phase III trial of sunitinib vs interferon-α in 750 patients with untreated metastatic renal cell cancer demonstrated a significant advantage with sunitinib, in terms of an independently assessed objective response rate (31%; 95% CI, 26%–36% vs 6%; P < .001) and progression-free survival (11 months vs 5 months). Sunitinib-treated patients had a median overall survival of 26.4 months, compared with 21.8 months for interferon-α–treated patients (P = .051).
• Temsirolimus—This agent and bevacizumab were added to the National Comprehensive Cancer Network Kidney Cancer Guidelines as options for first-line treatment of relapsed or medically unresectable stage IV renal cell carcinoma with predominant clear cell histology and, in the case of temsirolimus, non–clear cell histology. The recommendations were based on the results of large randomized trials. Temsirolimus significantly prolonged median overall survival in a phase III trial of 626 patients (P = .0078) and received FDA approval for first-line as well subsequent treatment of advanced renal cell carcinoma.
• Bevacizumab—Two separate, multicenter, international studies have established bevacizumab-based therapy as robust in the front-line setting. One phase III trial randomized 649 untreated patients with metastatic renal cell carcinoma to treatment with interferon α-2a, recombinant plus placebo infusion or to interferon α-2a plus bevacizumab infusion at 10 mg/kg every 2 weeks. A significant advantage for bevacizumab plus interferon α-2a was observed for objective response rate (31% vs 13%, respectively; P < .0001) and progression-free survival (10.2 months vs 5.4 months; P < .0001). The hazard ratio (HR) for progression in the bevacizumab plus interferon α-2a arm was 0.63 (95% CI, 0.52–0.75; P = .0001).
A second multicenter phase III trial conducted in the United States and Canada through the Cancer and Leukemia Group B was nearly identical in design, except that it lacked a placebo infusion and did not require prior nephrectomy. The median progression-free survival was 8.5 months in patients receiving bevacizumab plus interferon α-2a (95% CI, 7.5–9.7) vs 5.2 months for patients using interferon α-2a monotherapy (95% CI, 3.1–5.6; P < .0001). The HR for progression for patients receiving bevacizumab plus interferon α-2a after adjusting for stratification factors was 0.71 (P < .0001). Also, among patients with measurable disease, the objective response rate was higher in patients treated with bevacizumab plus interferon α-2a (25.5%) than for those given interferon α-2a monotherapy (13.1%, P < .0001).
In the AVOREN (Avastin for Renal Cell Cancer) trial, bevacizumab significantly increased progression-free survival (10.2 months vs 5.4 months; P = .0001) of patients with metastatic renal cell carcinoma when administered in combination with interferon α-2a.
• Pazopanib—This agent, a multikinase angiogenesis inhibitor, has been used to treat advanced renal cell cancer. In a phase III study, 435 patients with advanced renal cell carcinoma were randomly assigned to treatment with pazopanib (800 mg/d orally) or placebo. Progression-free survival was significantly better in the pazopanib group than in the placebo group (HR = 0.46; P < .0000001). This benefit was observed for both treatment-naive patients (HR = 0.40; P < .00001) and for those who had previously received one cytokine-based treatment (HR = 0.54; P < .001). The response rate was 30% with pazopanib vs 3% with placebo, and the median duration of response was 58.7 weeks. Most of the adverse events associated with this therapy were grade 1 or 2. The most common laboratory abnormality was an elevation in alanine aminotransferase level. The FDA approved pazopanib for advanced renal cell carcinoma in October 2009. COMPARZ, a large phase III randomized trial, compared the efficacy and safety of pazopanib and sunitinib as first-line therapy in more than 1,100 patients with metastatic renal cell carcinoma. The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib vs sunitinib. Secondary end points included overall survival, safety, and quality of life. Pazopanib was noninferior to sunitinib with respect to progression-free survival (HR for progression of disease or death from any cause, 1.05; 95% CI, 0.90–1.22), meeting the predefined noninferiority margin (upper bound of the 95% CI, < 1.25). Overall survival was similar (HR for death with pazopanib, 0.91; 95% CI, 0.76–1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs 55%), hand-foot syndrome (50% vs 29%), and thrombocytopenia (78% vs 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60% vs 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P < .05 for all 11 comparisons).
• Everolimus—This agent is an oral inhibitor of mammalian target of rapamycin kinase that has shown activity in metastatic renal cell carcinoma in phase II studies. Motzer and colleagues presented results of a planned interim analysis of a phase III study assessing the clinical benefit of everolimus in patients who had progressive metastatic renal cell carcinoma after receiving sunitinib, sorafenib, or both. The primary end point was progression-free survival. A total of 410 patients were randomized in a 2:1 ratio to receive everolimus at 10 mg or placebo, respectively. Prior bevacizumab and/or cytokine treatment was allowed. The results showed a significant improvement in progression-free survival for everolimus compared with placebo (everolimus, 4 months; placebo, 1.9 months; P < .001)
• Axitinib—This agent is a potent, selective, second-generation inhibitor of VEGF receptors 1, 2, and 3 that blocks VEGF receptors at sub-nanomolar drug concentrations. The relative potency of axitinib is 50 to 450 times greater than that of the first-generation VEGF inhibitors. In addition, axitinib does not block other targets, including platelet-derived growth factor receptors, b-RAF, KIT, and FLT-3, thought to be responsible for some of the adverse events associated with other available oral VEGF inhibitors. The activity of axitinib in advanced renal cell cancer was initially demonstrated in two phase II clinical trials of patients with cytokine-refractory disease. The objective response rate and median progression-free survival were 44% and 15.7 months and 55% and 12 months, respectively. A subsequent randomized phase III trial reported by Rini et al, comparing axitinib with sorafenib, led to the regulatory approval of this compound in renal cancer. This trial included 723 patients with advanced renal cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. The median progression-free survival was 6.7 months with axitinib compared with 4.7 months with sorafenib (HR = 0.665; 95% CI, 0.544–0.812; one-sided P < .0001). The objective response rate as assessed by masked independent radiology review committee was 19% for axitinib and 9% for sorafenib (P = .0001), with a median duration of response of 11 months (95% CI, 7.4; not estimable) for axitinib and 10.6 months (8.8–11.5) for sorafenib. The most common adverse events were diarrhea, hypertension, and fatigue in the axitinib arm, and diarrhea, palmar-plantar erythrodysesthesia, and alopecia in the sorafenib arm.
As always, patients should be encouraged to participate in ongoing clinical trials of treatments for metastatic renal cell cancer.