ABSTRACT: Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab(Drug information on bevacizumab) (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib(Drug information on sorafenib) (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.
The medical management of metastatic renal cell carcinoma (RCC) has undergone a transformation in recent years. Initial attempts at treatment with hormonal or chemotherapeutic agents produced little success. The historical standard of cytokine immunotherapy, including interleukin (IL)-2 (Proleukin) and interferon (IFN)-alpha, resulted in limited clinical benefit in unselected cohorts. More recently, systemic therapy targeted at the vascular endothelial growth factor (VEGF) protein and related pathway elements has produced robust clinical effects in metastatic RCC, leading to regulatory approval of sorafenib (Nexavar), sunitinib (Sutent), and temsirolimus (CCI-779, Torisel), an inhibitor of the mammalian target of rapamycin (mTOR). Bevacizumab (Avastin) has also demonstrated antitumor activity in metastatic RCC and is awaiting regulatory approval in the United States.
It is useful to review the existing data from each of these approaches to formulate an overall management strategy of metastatic RCC patients. Further, we will discuss ongoing investigative efforts including sequencing, combination therapy and novel agents.
Historical Perspective
Systemic anticancer agents such as medroxyprogesterone(Drug information on medroxyprogesterone) acetate and cytotoxic chemotherapy were initially applied to metastatic RCC patients. These agents produced minimal objective response rates of approximately 2% to 5%.[1-4] While symptom palliation can be observed in some patients, the benefit for the entire cohort of RCC patients is extremely low. Despite combination chemotherapy regimens resulting in slightly higher response rates, such regimens are not in routine use pending further study of novel agents or additional patient selection efforts.
The immunogenic nature of RCC and the lack of benefit from chemotherapy and hormone therapy resulted in the clinical application of immunotherapeutic cytokines. Two phase III randomized trials have examined the benefit of high-dose IL-2 and low-dose cytokine (IL-2 monotherapy or IL-2 plus IFN-alpha) regimens (Table 1).[5,6] Both studies demonstrated an objective response rate advantage for the high-dose IL-2 arms, without any difference in disease-free or overall survival. Taken together, these data suggest that high-dose IL-2 has a higher overall and complete response rate compared with low-dose cytokines, with the majority of benefit realized in patients who experience a durable complete response. The limited benefit, however, precluded demonstration of a disease-free or overall survival advantage with high-dose IL-2 for the entire cohort. Further, the lack of applicability of high-dose IL-2 to the broad RCC population has dampened enthusiasm for this approach.
Summary of Agents and Approaches in Renal Cell Carcinoma
Low-dose IFN-alpha monotherapy has also been investigated (Table 1). A meta-analysis that reviewed 53 randomized controlled trials with IL-2 or IFN-alpha in metastatic RCC provides the most comprehensive view.[7] Four trials (N = 644) randomized patients to IFN-alpha vs a non–IFN-alpha control arm. The weighted median survival improvement with IFN-alpha treatment vs the control group was 3.8 months (P = .007), with an odds ratio for death at 1 year of 0.56 for IFN-alpha (95% confidence interval = 0.40–0.77). The investigators found no evidence of a dose-response relationship and no correlation between response rate and overall survival. Despite multiple attempts, no prospective randomized trial has demonstrated a benefit to adding any additional cytokine/immunotherapeutic or noncytokine agent to cytokine monotherapy, with the notable exception of IFN-alpha plus bevacizumab trials.
The role of cytokine therapy in metastatic RCC is currently evolving and unclear. As noted above, cytokine monotherapy is of modest benefit in unselected populations, but select patients should be considered for high-dose IL-2 therapy, solely on the basis of the small but real chance of a durable complete response. Whether or not this durable complete response benefit is preserved when high-dose IL-2 is given after targeted therapy is not clear at present. Current investigative efforts are appropriately focused on additional patient selection efforts and combination therapy. For example, tumors expressing carbonic anhydrase IX (CAIX, also called G250) have been associated with a higher rate of objective response to IL-2 in retrospective analyses, and further prospective trials are ongoing.[8,9] In addition, based on nonoverlapping mechanisms of action, cytokines are being investigated in combination with targeted therapy, as discussed below.
Targeted Therapy
The premise of targeted therapy in all oncologic endeavors is the fundamental reliance of tumor cells on given biologic pathways that drugs can be designed to disrupt. A growing understanding of the underlying molecular biology of RCC has established the VEGF and mTOR pathways as relevant therapeutic targets.
The pathogenesis of RCC was elucidated by the discovery of the von Hippel-Lindau (VHL) gene, which is named for the familial cancer syndrome in which it is implicated.[10] VHL is a tumor-suppressor gene in which biallelic gene inactivation promotes a tumor phenotype. One allele is inactivated through a deletion (also known as loss of heterozygosity) observed in over 90% of sporadic clear cell RCC cases.[11,12] The remaining VHL allele can be inactivated either through a gene mutation (approximately 50% of clear cell RCC[13,14]) or through gene silencing by methylation (approximately 5% to 10% of cases).[15,16])
Under normal conditions, VHL encodes a protein that targets a crucial transcription factor called hypoxia-inducible factor (HIF) for proteolysis.[17] As a result of the VHL gene inactivation, a defective VHL protein is produced and HIF is not subject to proteolysis and inactivation. Activated HIF then translocates into the nucleus and leads to the transcription of a variety of genes that play a central role in tumor progression. Transcription genes include VEGF,[18] platelet-derived growth factor (PDGF),[19] transforming growth factor (TGF)-alpha,[20] and basic fibroblast growth factor (bFGF). Clinical testing has identified the VEGF protein and its receptor (VEGFR) as the most relevant targets in anti-RCC therapy.
Sunitinib
Sunitinib is a small-molecule inhibitor of the tyrosine kinase portion of VEGFR and related receptors. Updated data from the initial phase II trials of sunitinib in metastatic RCC patients (N = 169) who had failed prior cytokine-based therapy demonstrated an investigator-assessed pooled objective response rate of 45%, a median duration of response of 11.9 months, and median progression-free survival (PFS) of 8.4 months (Table 1).[21]
A phase III trial in untreated, metastatic RCC patients (N = 750) of sunitinib vs IFN-alpha demonstrated a significant advantage in objective response rate (39% vs 8%, P < .000001) and PFS (11 vs 5 months, P < .000001) for sunitinib-treated patients (Table 1).[22] Baseline clinical features predictive of improved PFS at 12 months in sunitinib-treated patients identified Eastern Cooperative Oncology Group (ECOG) performance status 0, time from diagnosis ≥ 1 year and corrected serum calcium ≤ 10 mg/dL as favorable characteristics.[22]
Based on these data, sunitinib has emerged as a front-line standard of care in metastatic RCC. This drug is notable for a superior objective response rate compared to other agents, balanced against toxicity including fatigue, hand-foot syndrome, and diarrhea. Final analysis of the survival data from this trial is pending
Sorafenib
Sorafenib is a small-molecule inhibitor of VEGFR and related receptors in addition to inhibition of an intracellular-signaling enzyme, raf kinase. A phase III trial of sorafenib randomized 900 treatment-refractory metastatic RCC patients to sorafenib at 400 mg twice daily or placebo. A PFS advantage in the treatment arm was observed (5.5 vs 2.8 months, P < .000001; Table 1).[23] Although overall survival was similar between the two arms (17.8 vs 15.2 months, P = .15), a preplanned analysis demonstrated improved survival with sorafenib after the censoring of placebo patients who crossed over to the sorafenib arm (17.8 vs 14.3 months, P = .03).[24]
It is likely for this trial and other phase III trials that patient crossover to active therapy may obscure the overall survival benefit of targeted therapy in a single trial. The phase III data contrast somewhat with the results of a smaller, randomized phase II study of sorafenib vs IFN-alpha in 189 previously untreated metastatic RCC patients. In this smaller trial, median PFS was 5.7 months with sorafenib vs 5.6 months with IFN-alpha.[25] The reason for the lack of significant effect vs IFN-alpha in the front-line setting is not entirely clear but may result from weaker inhibition of VEGFR compared to sunitinib. Although there may be patients in whom sorafenib would be the preferred initial agent, for example, due to toxicity profile, sorafenib use has moved toward second-line and later therapy. Investigators need to identify the phenotype of patients in whom sorafenib is the preferred initial treatment.
