Get Adobe Flash player
Bladder Cancer After Failure of Prior Chemotherapy – Cytotoxics, Targeted Agents, Immunomodulation – Current Available Data and Potential Synergistic Combinations with Vinflunine Arnulf Stenzl Department of Urology, Eberhard Karls University Tübingen, Germany An overview of evidence on use and development of cytotoxic and targeted agents in the second-line setting after failure of a platinum-based regimen will be presented below. Additional considerations on the possible role of immunotherapy in bladder cancer are also discussed. Combinations of vinflunine with therapeutic agents that are already in use in bladder cancer are known to have potential additive and synergistic effects, which may affect both efficacy or tolerability. Possible combinations of vinflunine include combinations with ‘classic’ cytotoxic agents, vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin (mTOR) inhibitors. Checkpoint Sorafenib was tested in a prospective, randomised, double-blind phase II trial that compared GC plus placebo versus GC plus sorafenib in 85 patients with locally advanced or metastatic urothelial carcinoma in the first-line setting. 4 The trial resulted in a negative outcome, with no significant benefit in progression-free survival (PFS) or overall survival (OS) upon addition of sorafenib (PFS 6.3 months in the GC arm versus 7.2 months with added sorafenib; OS 10.5 months in the GC arm versus 11.3 months in the sorafenib arm). Investigation of sorafenib as a monotherapy also resulted in a negative outcome following a small preliminary phase II trial in 27 patients with advanced urothelial carcinoma in the second-line modulation of T-cell differentiation and vaccination strategies are at a much more theoretical and experimental stage, but also worthy of mention, due to the immunological nature of bladder cancer. 1 setting. 5 The trial observed no objective responses. The 4-month PFS rate was 9.5  % and median OS was 6.8 months. Despite the disappointing outcomes, these studies were nevertheless interesting in terms of planning for future possible combinations. There may be some potential in combining sorafenib with vinflunine. Classic Cytotoxics Vinflunine combined with classic cytotoxic agents, such as gemcitabine or carboplatin, is associated with haematotoxicity (leukopenia, neutropenia, thrombocytopenia and anaemia) and stomatitis. Vinca alcaloid class effects include cardiotoxicity and neurotoxicity, which may be a concern in combination with taxanes. Limited data are available on the potential drug interactions and toxicities that may occur if vinflunine is combined with other agents. Pemetrexed was a promising drug for second-line bladder cancer treatment, but conflicting results led to it falling out of the bladder cancer field. It remains an active drug considered to be an option in bladder cancer, which functions like an improved version of methotrexate. It is approved in the second-line treatment of non-small cell lung cancer (NSCLC). The planned Scandinavian NUCOG2 randomised phase II trial will evaluate vinflunine plus pemetrexed versus vinflunine alone in the second-line setting. Tyrosine Kinase Inhibitors, Vascular Endothelial Growth Factor Inhibitors and Mammalian Target of Rapamycin Inhibitors Several elements from preclinical studies suggest that TKI and mTOR inhibitors may have a role in bladder cancer. Activation of the PI3K/Akt/ mTOR pathway has been shown to correlate with tumour progression and reduced survival in patients with urothelial carcinoma of the bladder. 2 There is evidence for PTEN-independent Akt activation and Akt-independent p27Kip1 expression in advanced bladder cancer, thus supporting further investigation of protein profiling and targeted therapy in bladder cancer. 3 An ongoing phase II trial is exploring the activity and safety of everolimus with or without paclitaxel as first-line therapy for cisplatin- ineligible patients with advanced urothelial carcinoma (NCT01215136). © TO U CH MED ICA L MEDIA 2013 The planned NUCOG3 phase I dose finding, single arm trial will test vinflunine plus sorafenib in the second-line setting. Fixed doses of vinflunine will be administered in two starting dose groups, at 280 mg/ m 2 or 320 mg/m 2 on day 1, followed on day 2 by three dose steps of 400, 600 and 800 mg sorafenib over 21 days. Sunitinib was tested in a phase II study in 77 pre-treated patients with metastatic urothelial carcinoma in the second-line setting did not show promising results. 6 A 50 mg daily sunitinib dose failed to show significant prolongation of PFS and OS. However, partial responses were observed in some patients, identifying antiangiogenesis-targeted therapy as a viable approach for bladder cancer treatment. Other data evaluating sunitinib efficacy as part of combination chemotherapy regimens support this notion. In a preclinical model, sunitinib was active against human urothelial carcinoma and enhanced the activity of cisplatin. 7 Of note, in vivo data in transitional cell carcinoma cell lines have shown that sunitinib can enhance Bacillus Calmette–Guérin (BCG)-mediated cytotoxicity through the apoptosis pathway. 8 Similarly, sunitinib synergistically potentiated the anti-tumour effect of gemcitabine in human bladder cancer cells. 9 These proposed therapeutic combination models may have potential future clinical applications in bladder cancer treatment. Of note is the possibility to combine a systemic drug such as sunitinib or maybe vinflunine with topical application of BCG (immunoinstillation), mitomycin or gemcitabine (chemoinstillation; see below) and thereby achieve a dual method of application synergistic effect. Nevertheless, haematotoxicity profile of sunitinib as well as the fibrosis of the bladder wall should be considered for any such combination therapy. 21