The incidence of renal cell carcinoma in the U.S. has been estimated at approximately 31,000 cases per year. Since 1970, the incidence is increasing in all races and both sexes. Approximately 30% have metastatic disease at the time of diagnosis. Patients presenting with localized disease have a 10 to 70% relapse rate after nephrectomy and face long term risk for development of contralateral renal cell carcinoma.

Primary treatment for localized, non-metastatic renal cell cancer remains radical nephrectomy. There is no role for adjuvant immunotherapy with Interferon or IL-2. The role of oral targeted agents such as Sorafenib and Sunitinib is currently being investigated.

For selected patients with metastatic renal cell cancer, surgical resection of the primary tumor (nephrectomy) followed by systemic therapy with Interferon has been shown to prolong survival. This has been demonstrated in two randomized trials, the EORTC 30947 and SWOG 8949. (1)

For metastatic renal cell cancer, the standard treatment option for patients with good performance status has been IL-2. A randomized trial from the NCI did not show a significant difference in the overall survival between the high dose and low dose IL-2 therapy. The response rates were around 15%, however, complete responses and durable responses were only seen on the high dose IL-2 arm. (2)

Clear cell carcinoma is typically associated with mutations in the Von Hippel Lindau (vHL) gene and this results in overproduction of angiogenic factors such as VEGF, PDGF, and TGF. In addition, EGF is over-expressed in the majority of renal cell cancers. Bevacizumab , humanized antibody that recognizes VEGF target in RCC, was tested in a double blind, randomized placebo controlled study in patients with metastatic clear cell RCC. It produced a 10% partial response but more significantly, prolongation of time to progression at a dose of 10mg/kg of Bevacizumab. Toxicity was modest and included hypertension and asymptomatic proteinuria. A recent phase II trial used Bevacizumab at a dose of 10mg/kg IV q 2 weeks and OSI-774 at 150mg/kg given orally. Treatment was well tolerated with side effects such as hypertension, diarrhea, and rash (2,3). A series of multi-targeted small molecule, tyrosine kinase inhibitors have been in clinical trials and recently two of these compounds were approved by the FDA for treatment of cytokine refractory metastatic RCC. These include Sorafenib (Nexavar) and Sunitinib (Sutent).

Nexavar trial looked at 903 mRCC patients in a Phase III multicenter, randomized, double blind, placebo controlled trial.As compared to placebo, Nexavar prolonged the progression free survival (PFS) to 6.1 mos. Vs. 3 months (p < 0.000001). Objective responses were seen in a minority (2%) of patients and the majority of the patients had stable disease (7,8). Sunitinib (Sutent) was studied in two independent single arm phase II trials in patients with mRCC with a total of 168 patients. Partial responses were seen in 40% of patients in Trial I and 44% in Trial 2. In addition 27% of patients had stable disease respectively. The median TTP was 14.8 mos for responders and 7.9 mos for patients with stable disease (5, 6).

Sunitinib has been studied as first-line therapy for mRCC and the results of the phase III trial comparing Sunitinib vs. IFN-alpha for patients with mRCC were presented by Dr. Motzer et al at the ASCO 2006 meeting. 750 patients were randomized and the results showed ORR of 24.8% vs. 4.9% for Sunitinib. Median PFS was 47.3 weeks for Sunitinib vs. 24.9 weeks for IFN (9), both highly statistically significant differences. Another molecular targeting agent, Temsirolimus (CCI-779), an mTOR inhibitor has also been studied in mRCC and initial phase II data from DFCI. Boston showed responses in poor risk patients. Based upon that, a phase III trial was conducted in patients with poor risk mRCC with randomization between Temsirolimus, alpha interferon, or the combination. The results were presented at 2006 ASCO and Tem single agent prolonged the median overall survival to 10.9 months vs. 7.3 months, p= .0069. (10)

Chemotherapy for renal cell carcinoma shows response rates in the 15-20% range with 5FU/Capecitabine/Gemcitabine based regimens, especially those with non-clear cell histology. (4)

References:

• Mickisch et al. Surgery for metastatic renal cell cancer. Lancet 358: 966-970, 2001; Flannigan et al. NEJM 345: 1655-1659, 2001
• Yang et al. Randomized trial of high dose vs low dose IL-2 for metastatic renal cell cancer. JCO 21: 3127-3132, 2003.
• Hainsworth JD et al. Phase II trial of bevacizumab and erlotinib in patients with metastatic renal cell carcinoma (RCC). Proc Am Soc Clin Oncol 123:381a, 2004 (abstr).
• Stadler et al. PASCO 2004, Abst # 4515.
• Motzer RJ et al. 2005 Proceedings of ASCO, Abstract # 4508, Phase II Trials of SU11248 show antitumor activity in second-line therapy patients with metastatic renal cell carcinoma.
• Motzer RJ, et al. Activity of SU11248, a multitargeted injibitor of VEGFR and PDGFR in patient with mRCCC. JCO 24: 16-24, 2006.
• Escudier B et al. 2005 Proceedings of ASCO, Abst. # 4510, Randomized phase III trial of the RAF kinase and VEGFR inhibitor Sorafenib (BAY 43-9006) in patients with advanced RCC.
• Ratain MJ et al. 2005 PASCO, Abst #4544. Final findings from a phase II, placebo controlled, randomized discontinuation trial of Sorafenib in patient with advanced RCC.
• Motzer et al. Phase III randomized trial of Sunitinib vs. IFN-alpha as first-line systemic therapy for patients with mRCC. LBA-3, 2006 PASCO.
• Hudes et al. A phase III, randomized 3 arm study of Temsirolimus or Interferon or the combination in the treatment of first line poor risk patients with advanced RCC. 2006 ASCO Proceedings, LBA 4.