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21st Annual Congress of the European Association of Urology

Paris, France / April 5-8, 2006

According to Dr. Jean-Jacques Patard, Rennes University Hospital, France, urologists already play a pivotal role in many aspects of clinical care of patients with renal cell carcinoma (RCC) in terms of surgical innovations in patients with small tumours, complex surgery in advanced disease, regular follow-up and research into prognostic factors. But urologists are rarely committed to treating metastatic RCC or contributing to clinical trials in the adjuvant or neo-adjuvant setting. This can be expected to change with the new targeted oral anti-angiogenic and anti-tumour cell proliferation agents for advanced RCC which are in development, he told delegates. Once validated in the adjuvant setting, Dr. Patard suggested the use of these new compounds by urologists could become commonplace.

Dual Target Therapy

“One attractive idea is to target tumour cell proliferation and angiogenesis simultaneously,” suggested Dr. Joaquim Bellmunt, Universidad Autonóma de Barcelona, Spain. This involves focusing on the high levels of receptor tyrosine kinases found in patients with RCC. Among them, increased vascular endothelial growth factor (VEGF) leads to angiogenesis which the tumour must have to grow, while high levels of platelet-derived growth factor (PDGF) lead to maturation and survival of the newly formed blood vessels and their supporting tissue. The latter is also associated with tumour progression. Overstimulation of these receptor tyrosine kinases is often caused by mutations in the von Hippel Lindau gene, which Dr. Bellmunt noted is found in 75% of patients with sporadic clear cell carcinoma. Blocking VEGF and PDGF receptors is therefore believed to have a significant impact on tumour development.

Dr. Bellmunt explained, “Sorafenib is an orally available multikinase inhibitor that inhibits the Raf kinase intracellular signal transduction pathway that promotes tumour cell proliferation and survival, and which blocks VEGF and PDGF receptors to impede both tumour cell proliferation and angiogenesis. In a long-term, randomized phase II study of sorafenib [400 mg b.i.d.] vs. placebo in 202 patients with metastatic RCC, the active drug provided statistically significant [P=0.0001] prolongation of progression-free survival: six weeks in the placebo group compared to 24 weeks for patients receiving sorafenib. Moreover, 71% of subjects achieved some degree of tumour shrinkage and clinical benefit. This drug is suitable for long-term administration.”

The antitumour activity demonstrated by those results prompted researchers at the Institut Gustave-Roussy, Paris, France, to evaluate sorafenib in the largest phase III, randomized, placebo-controlled trial ever conducted in patients with advanced RCC. Reporting preliminary results of that ongoing trial, Dr. Bernard Escudier, Chief of Immunotherapy, said 903 classical metastatic RCC patients (77% lung, 26% liver metastasis) were randomized to oral sorafenib 400 mg b.i.d. or placebo with the best supportive care. The majority of the patients had failed a cytokine-based regimen as prior therapy within the previous eight months; a quarter had prior radiation and most were nephrectomized before treatment. The primary end point of the study was overall survival.

“At the time of first analysis, response in terms of Response Evaluation Criteria in Solid Tumours [RECIST] was 10%. However, 84% of patients achieved tumour control when clinical benefit is included, compared to around 50% in the placebo arm,” Dr. Escudier reported. “An impressive 76% of patients in the sorafenib arm had some tumour shrinkage in contrast to 25% of placebo-treated subjects. At my institution, of 42 patients who were subsequently switched over from placebo to sorafenib, 18 attained some degree of tumour shrinkage, including those who were switched over late in the disease. As for the primary study end point, we had not yet reached median survival at the time of first analysis, but the estimated improvement in median overall survival was 39% vs. placebo. Median survival with placebo was 14.7 months at that point in time,” he indicated. “Progression-free survival was doubled from 12 weeks for placebo to 24 weeks with sorafenib, which was statistically significant and evident in all subsets of evaluated patients.”

Dr. Escudier noted that treatment-related adverse events included diarrhea (43%), hand-foot skin reaction (30%) and hypertension (17%). Neither fatigue nor low hemoglobin were problematic and he characterized the active treatment’s safety profile as especially interesting because there was no myelosuppression, which makes it an easy agent to combine with chemotherapy. The Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index was not reduced by sorafenib, suggesting that it did not adversely affect patient quality of life, he noted, adding that respiratory symptoms and the ability to enjoy life were also improved in the active treatment group vs. placebo.

“This drug works like we think it should work, by decreasing the vascularization of the tumour, and this can be confirmed by different imaging methods,” Dr. Escudier concluded. “Patients who had a decrease in tumour blood flow had significantly superior progression-free survival rates and overall survival than those who did not.” Given those characteristics of sorafenib therapy, he suggested the compound might be valuable as adjuvant or neoadjuvant therapy.

Adjuvant Therapy

Dr. Tim Eisen, Royal Marsden Hospital, London, UK, stated that the aim of adjuvant treatment is to reduce the large proportion of patients who have an apparently curative procedure, yet go on to develop metastatic disease which usually proves fatal. Because tyrosine kinase inhibitors have been shown to be active in the majority of patients with RCC and are tolerated well enough to allow for long-term adjuvant treatment, clinical studies to evaluate the potential of multikinase inhibitors as adjuvant therapy for RCC have proceeded to the advanced phase of design.

A phase III, randomized, double-blind controlled study comparing sorafenib with placebo in patients with resected primary RCC at high or intermediate risk of relapse aims to determine whether adjuvant therapy with sorafenib results in prolonged survival, if the duration of such therapy correlates with survival and which biologic markers predict benefit from sorafenib. “We will be looking at genetic epidemiology both in terms of risk of RCC and tolerability of the drug,” Dr. Eisen explained. “The primary outcome measure is metastasis-free survival. Secondaries are RCC-specific survival time, toxicity, biologic characteristics, overexpression of a number of growth factor receptors and signalling molecule activity.”

Two of every eight patients will be randomized to placebo, three will be randomized to active treatment for one year followed by placebo for two years and three will be randomized to active treatment for three years. The design is intended to minimize the number of patients who receive placebo only, he stressed. Recruitment is to start in the autumn of this year.

Summary

Dr. Patard noted that as patients with localized tumours often have micro-metastases, it is important that prognostic factors are used by urologists to help identify patients with the highest risk of disease progression after initial surgery. There is a strong rationale to use anti-angiogenic therapy in those patients to prevent growth of micro-metastases as well as therapy for the primary tumour, he told delegates. In the neoadjuvant setting, he remarked that urologists could play a role in the development of translational research programs. He concluded that the involvement of urologists in the treatment of patients with advanced disease, and in the design and recruitment into active treatment trials of novel adjuvant and neoadjuvant therapies, will be vital to enable these new oral anti-angiogenic agents to be optimally integrated into surgical strategies.