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Bladder Cancer First-line Systemic Therapy in Patients Ineligible (‘Unfit’) to Receive a Cisplatin-based Regimen – Literature Review, Recommendations and Potential Use of Vinflunine in Combination or as Monotherapy Karim Fizazi Institut Gustave Roussy, Villejuif, France First-line Treatment of Unfit Bladder Cancer Patients – An Overview In the first-line setting treatment of unfit bladder cancer patients, a long list of small phase I, II and III trials investigating various combinations of chemotherapy regimens is available (see Table 1). Most data are on gemcitabine-based combinations, such as GCa, which is probably the best currently available regimen in unfit patients, despite its flaws. For instance, in the European Organisation for Research and Treatment of Cancer (EORTC) phase III 30986 trial, it became apparent from phase II onwards that GCa was superior to carboplatin, methotrexate and vinblastine (M-CAVI). 1,2 Other combination regimens have been tested, including paclitaxel combined with carboplatin or gemcitabine, with or without platinum salts. It remains difficult to say with certainty which regimen should be the reference in unfit patients. At best, overall response rate (ORR) values are approximately 30–40  %, with median overall survival (OS) rarely exceeding 10 months (see Table 1). 3–10 In addition, sequential regimens have been explored in phase II trials (see Table 2). Treatment with doxorubicin plus gemcitabine followed by paclitaxel plus carboplatin was studied by Galsky et al., 11 and a recent trial has explored whether bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), could be safely added to GCa and improve outcomes. 12 It is, however, not known whether anti-angiogenic agents have a role in bladder cancer. The available data for bevacizumab are always on top of other chemotherapy regimens, so it is difficult to single out the specific contribution of these drugs (see Table 2). In terms of the use of single agents in first-line unfit patients ineligible for cisplatin, both gemcitabine and sunitinib have been tested, with modest response rates and survival outcomes (see Table 3). 10,13 Only one phase III study in unfit bladder cancer patients has been conducted, evaluating GCa versus M-CAVI (the EORTC 30986 trial) 1 as discussed. Briefly, in OS or progression-free survival (PFS) the trial showed no significant differences. The only significant difference in efficacy favouring GCa was observed with ORR. Nevertheless, safety clearly favoured GCa versus M-CAVI. The interpretation is that GCa should be favoured in this setting as a reference regimen, although it is not firmly established whether carboplatin has a true role on top of gemcitabine for these unfit patients in the first-line setting. European Guideline Recommendations The European Society for Medical Oncology (ESMO) guideline recommendations for first-line treatment in cisplatin-unfit patients 14 highlight that about 50% of patients are unfit for cisplatin-containing © TO U CH MED ICA L MEDIA 2013 chemotherapy due to a poor performance status (PS), impaired renal function or comorbidity. These patients may be palliated with a carboplatin-based regimen or single-agent taxane or gemcitabine. Based on the EORTC 30986 study, severe acute toxicity was slightly higher on M-CAVI, which makes CGa the preferred and reference treatment in unfit patients. Patients with PS 2 and impaired renal function and unfit patients in Bajorin prognostic group 2 have limited benefit from combination chemotherapy, and new strategies are needed. 14 The European Association of Urology (EAU) guideline recommendations for first-line treatment in patients ineligible or unfit for cisplatin 15 are to use carboplatin-based chemotherapy (preferably GCa), or a single-agent regimen (see Table 4). Depending on the number of adverse factors to qualify patients for the unfit group, the EAU guidelines have devised a treatment algorithm for the management of metastatic urothelial cancer. In patients with PS 2 and impaired renal function (glomerular filtration rate [GFR] <60  ml/ minute), combination chemotherapy is said to provide limited benefit. 15 As a reminder, the proposed consensus definition of unfit patients by Galsky et al. for eligibility in clinical trials included at least one of the following: WHO or Eastern Cooperative Oncology Group (ECOG) PS 2 or Karnofsky performance score (KPS) of 60–70 %, creatinine clearance (CrCl) <60 ml/minute, CTCAE v4 grade audiometric hearing loss of ≥2, peripheral neuropathy of ≥ grade 2 and congestive heart failure (CHF) grade ≥3. 16 Integration of Targeted Agents – Angiogenesis Inhibitors in First-line Unfit Patients There is a rationale for investigating angiogenesis inhibitors in bladder cancer. VEGF overexpression has been shown to correlate with poor prognosis, whereas microvessel density predicts N+ and survival. 17 The first trial that reported a regimen in combination with angiogenesis inhibitors in first-line chemotherapy observed a very high response rate, but also very elevated toxicity. Randomised data are required to draw firm conclusions on whether or not these agents have a role in bladder cancer treatment. Several other agents are being evaluated in ongoing phase I/II trials, including everolimus and eribulin, as part of non- platinum-containing regimens being developed in the first-line treatment of patients ineligible to receive cisplatin (see Table 6). Vinflunine Data and Perspectives Phase I study data evaluating the combination of vinflunine with gemcitabine, carboplatin, doxorubicin, or methotrexate in non-small cell lung cancer (NSCLC), metastatic breast cancer or metastatic squamous cell carcinoma of the head and neck are ongoing or planned. 17