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Thomas Powles, Siobhan McFaul, Justin Stebbing,Peter Wilson, Tim Oliver, Naomi Tranter, Jonathan ShamashDepartment of Medical Oncology, St Bartholomew’s Hospital, London, United KingdomBackground: Sunitinib is widely used as first-line treatment for metastatic clear cell renal cancer (MCRC). No reports are known of treatment after sunitinib failure. As irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy has been reported to influence MCRC after progression on cytokine therapy, we report on the outcome of 11 patients treated with IPM after sunitinib failure.Patients and methods: Eleven patients with progression of disease on sunitinib therapy were treated with 4, monthly cycles of monthly IPM.Results: Nine out of 11 patients progressed during IPM therapy. The median time to progression was 1.4 months (95% CI: 0.7–2.1 months), while the overall survival was 4.2 months (95% CI: 0.9–2.3). Overall 10 patients have died of progressive renal cancer. One patient had a radiological response to therapy and remains progression free 11 months after treatment. Four of the 10 patients required a dose reduction for grade 3 or 4 toxicities.Conclusions: IPM alone does not appear to benefit patients with MCRC who previously progressed during sunitinib therapy. The median progression-free survival and overall survival for these patients is short.Keywords: renal cancer, chemotherapy, sunitinib

Objectives Androgen-deprivation therapy effectively shrinks hormone-naive prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC). Methods Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC. Results AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3 PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3 PCA3 expression and the length of androgen-ablation therapy. Conclusions Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.

Thomas Powles, Siobhan McFaul, Justin Stebbing,Peter Wilson, Tim Oliver, Naomi Tranter, Jonathan ShamashDepartment of Medical Oncology, St Bartholomew’s Hospital, London, United KingdomBackground: Sunitinib is widely used as first-line treatment for metastatic clear cell renal cancer (MCRC). No reports are known of treatment after sunitinib failure. As irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy has been reported to influence MCRC after progression on cytokine therapy, we report on the outcome of 11 patients treated with IPM after sunitinib failure.Patients and methods: Eleven patients with progression of disease on sunitinib therapy were treated with 4, monthly cycles of monthly IPM.Results: Nine out of 11 patients progressed during IPM therapy. The median time to progression was 1.4 months (95% CI: 0.7–2.1 months), while the overall survival was 4.2 months (95% CI: 0.9–2.3). Overall 10 patients have died of progressive renal cancer. One patient had a radiological response to therapy and remains progression free 11 months after treatment. Four of the 10 patients required a dose reduction for grade 3 or 4 toxicities.Conclusions: IPM alone does not appear to benefit patients with MCRC who previously progressed during sunitinib therapy. The median progression-free survival and overall survival for these patients is short.Keywords: renal cancer, chemotherapy, sunitinib