A brief review of its therapeutic potential in the treatment of renal carcinoma

Renal cell carcinoma accounts for 3% of all adult cancer. Approximately one third of patients have distant metastases at presentation. Twenty five percent to 50% of patients treated by nephrectomy for localized disease develop metastatic disease (Lam et al 2005). Approximately 50% of patients with metastases at presentation will survive less than one year and 10% will survive for over 5 years (Motzer et al 2004). RCC is usually highly resistant to chemotherapy and radiotherapy. Standard first-line treatment for metastatic disease was immunotherapy with interferon-alpha and/or interleukin-2, achieving 6% to 20% response rates (Rohrmann et al 2005).

The most common type of RCC is clear-cell RCC, accounting for 75% of cases (Motzer et al 1996). Phenotypically, RCC is a highly vascular tumor, with increased VEGF level, which growth could be stimulated by factors produced through the HIF-1 pathway. Consequently, the inhibition of VEGF and PDGF signaling pathways may reverse, in part, the physiologic consequences of losing VHL protein function and may inhibit tumor progression.

The recommended dose is 50 mg daily for 4 weeks, followed by two weeks off per 6 weeks.

This observation was the basis of the initiation of a large phase II trial including 63 patients with metastatic RCC who had failed cytokine-based therapy. Patients were treated with sunitinib monotherapy 50 mg daily for 4 weeks, followed by 2 weeks off (Motzer, Michaelson, et al 2006). Only four patients (6%) had achieved objective response to prior cytokine-based therapy. Median duration of treatment with sunitinib was 9 months. Twenty five of 63 patients (40%) achieved partial response and 17 patients (28%) had stable disease lasting more than 3 months (Table 1). Twenty four responders had clear cell histology and one had a papillary cell type. Responding lesions included sites of local recurrence and lymphatic, hepatic, pulmonary, bone, and adrenal metastases. Median time to progression was 8.7 months and median overall survival was 16.4 months. The most commonly reported treatment-related grade 3 adverse events were fatigue (11%), nausea (3%), and diarrhea (3%) (Table 2). However, it is important to note that sunitinib may be considered as a maintenance treatment and that the grading system is designed mainly for chemotherapies that are usually not administered over prolonged periods. Thus the impact of fatigue, stomatitis, and other toxicities may be substantially underestimated. The most frequently reported grade 3 or 4 laboratory abnormalities were transient and asymptomatic elevated lipase (21%), neutropenia (13%), and anaemia (10%). Dose reductions were performed in 22 patients (35%) from 50 mg to 37.5 mg daily, and the dose for two of these patients was further reduced to 25 mg daily. The most common reasons for dose reduction were asymptomatic hyperlipasemia or hyperamylasemia and fatigue. Circulating proteins that may represent potential biomarkers of angiogenic activity were measured. At the end of each cycle, VEGF levels were frequently increased, while sVEGFR-2 (a soluble variant of VEGFR-2) levels usually decreased. A trend was observed towards a larger proport ional increase in VEGF levels and decrease in sVEGFR-2 levels in patients having objective response as compared with those with stable disease or progression (Deprimo et al 2005). The observed median time to progression in this study (8.7 months) compares favorably with the median timesof 2.4 months for treatment in second line therapy at the Memorial Sloan-Kettering Cancer Center (Motzer et al 2004) and 2.5 months for treatment with placebo after cytokin failure in a phase II trial (Yang et al 2003).

These outstanding results have led to a phase III trial comparing sunitinib with interferon-? as first-line therapy in patients with metastatic RCC (Motzer, Hutson, et al 2006). Patients were randomized to receive sunitinib 50 mg daily for 4 weeks, with 2 weeks off (n = 375) or subcutaneous injection 9 MU three times weekly interferon-? (n = 375). Objective response rate in the sunitinib arm and in the interferon-? arm were respectively 31% and 6% (p < 0.000001) (Table 1). Median time to progression was significantly longer in the sunitinib arm (11 vs 5 months) (p < 0.000001), as well as median overall survival (p = 0.02), although median overall survival has not yet been reached in either group. The most commonly reported treatment-related grade 3 or 4 adverse events were fatigue (7% vs 11% with interferon-?), diarrhea (5% vs 0% with interferon-?), and dermatitis (5% vs 0% with interferon-?) (Table 2). The most frequently reported grade 3 or 4 laboratory abnormalities were asymptomatic elevated lipase (4% vs 2% with interferon-?), neutropenia (11% vs 7% with interferon-?), and thrombocytopenia (8% vs 0% with interferon-?). Thirty patients (8%) withdrew from the study due to adverse event on sunitinib arm versus 49 patients (13%) on interferon-? arm. This study is the first phase III trial demonstrating a clearly clinical superiority over immunotherapy, with a favorable toxicity profile. Thus, sunitinib becomes the new standard in first-line treatment in patients with metastatic RCC.

Before sunitinib, other targeted therapies had been studied in metastatic RCC. Sorafenib, an oral multitargeted tyrosine kinase inhibitor, had also been studied in metastatic RCC. Sorafenib was identified as a potent inhibitor of VEGFR-2, VEGFR-3, FLT3, PDGFR?, and KIT. Results with sorafenib are consistent with sunitinib results (Escudier et al 2005; Ratain et al 2005). Interestingly, the partial response rate induced by sorafenib is slightly lower to that of sunitinib, and the stable disease rate is similar. The relatively lower partial response rate associated with sorafenib may be related to the differential binding affinity of tyrosine kinase receptors including VEGFR-2 and PDGFR? that is thought to be weaker for sorafenib as compared with that of sunitinib (Fabian et al 2005). So far, single agent clinical trials in RCC patients with either monoclonal antibodies or single molecules that block EGFR tyrosine kinase activity (eg, with erlotinib) have been disappointing ( Yang et al 2003).