Clear-type renal cell carcinoma (RCC) represents 3% of all new cancer cases, 85% of all renal cancers and by far the most lethal urologic cancer. In 2008 it is estimated that there will be 54,390 new kidney and renal pelvis cancer cases (the majority of which are RCC) with a male to female ratio of 1.56:1 . Renal cell carcinoma occurs more often in individuals aged 50 – 70 years old and it has been associated with several risk factors such as smoking, obesity and hypertension, although smoking probably is the most significant risk factor . Renal cell carcinoma has been extremely resistant to chemotherapy, with disappointing response rates (around 6%) . The only effective treatment until recently was immunotherapy with interferon-α and interleukin-2 with higher response rates around 10–15% [4, 5].
The majority of RCC occurs sporadically but there is a small percentage of 1 – 4% that appears to carry a genetic predisposition . Both sporadic and inherited clear type RCC is strongly associated with mutations in Von Hippel Lindau (VHL) tumor suppressor gene . VHL gene is located on chromosome 3 and has a key role in the hypoxia inducible pathway, inducing hypoxia inducible factor (HIF-1 alpha and beta ) ubiquitinosis in the presence of oxygen. HIF-1α is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex VHL . HIF is a transcriptional complex that mediates the response of human cells to hypoxic environment resulting in the transcription of genes as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α) and erythropoietin . Platelet derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs) play an essential role in tumor angiogenesis and growth . VHL – HIF-1 – VEGF pathway is therefore deregulated in RCC and it represents a reasonable therapeutic target for renal cell carcinoma .
Sunitinib malate (SUTENT®, SU11248; Pfizer Inc; New York, USA) is an oral multitargeted tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, Fms-like tyrosine kinase receptor 3 (FLT3), c-KIT (stem-cell factor [SCF] receptor) and PDGFR [13, 14]. Phase I trials established the safety of 50 mg/day sunitinib (4 weeks on, 2 weeks off) and showed responses in a variety of tumors including RCC and gastrointestinal stromal tumors (GIST) . Phase II trials in cytokine-resistant RCC showed a remarkable efficacy with a disease control rate of 65% and a median time-to-progression of 8.7 months . A large randomized phase III trial comparing sunitinib to interferon-α resulted in statistically significant higher objective response rates (31% vs. 6%, P < 0.001) and a longer progression-free survival (11 vs. 5 months), with a hazard ratio of 0.42 (0.32 to 0.54, P < 0.001) . Sunitinib is already approved for the treatment of metastatic RCC and GIST and clinical trials are ongoing in other indications as well as in the adjuvant RCC treatment.
The majority of sunitinib-treated patients obtain a clinical benefit in the form of either objective response or disease stabilization (31% and 48% respectively in the phase III trial). Furthermore there are patients who obtain a clinical benefit that do not show a response in the beginning of treatment and respond later in the course of treatment (unpublished observation). It is therefore important to recognize this population as RECIST criteria seem to be of less value [18, 19] and PFS is not directly related to response rates, at least in the case of targeted treatments . Soluble forms of pro-angiogenic growth factors such as VEGF-A and receptor sVEGFR2 or PlGF can be measured in the plasma of patients by ELISA and used as surrogate markers for response . In the case of sunitinib treatment for metastatic RCC it has been shown that plasma VEGF levels increase after treatment and the ratio of post-treatment VEGF to the pre-treatment levels is different in patients that respond vs. patients with stable disease or disease progression .
We have evaluated 42 patients with metastatic clear-type renal cell carcinoma that were treated in our department with sunitinib (between June 2006 and August 2008) and their plasma levels of proangiogenic markers. There was a different pattern of VEGF level responses in patients with sunitinib-refractory disease (patients who experienced a disease progression after the first two cycles of treatment) and patients with sunitinib resistance (patients who originally obtained a clinical benefit and later progressed while on treatment). This may have implications in the treatment of these two different patient groups.