New chemotherapy drugs for advanced bladder cancer

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J Bellmunt
MD
Head of Uro-oncological Unit
Medical Oncology Service
Hospital General
Universitari Vall d’Hebron
E:[email protected]

S Albiol
Medical Oncologist
Medical Oncology Service
Clinica Quiron
Barcelona
Spain

Bladder cancer is common worldwide, and its incidence continues to increase. Although only 20% of urothelial cancer cases are clinically advanced at presentation, many patients with superficial or locally invasive disease eventually recur or develop metastasis. Thus the management of advanced and metastatic urothelial cancer is a frequent problem in clinical practice.

Urothelial cancers are chemosensitive.(1–8) There are many active single agents against transitional cell carcinoma of the urothelium, including cisplatin, methotrexate, ifosfamide, taxanes and gemcitabine. The evidence for their efficacy is discussed below.

Combination chemotherapy with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) is superior to single-agent chemotherapy, but median survival is only 12–13 months. Newer combinations (gemcitabine/cisplatin, paclitaxel/carboplatin, ITP [ifosfamide, paclitaxel and cisplatin] or TCG [paclitaxel, cisplatin and gemcitabine]) are active and showing promise in phase II studies, and combination regimens will be discussed in greater detail in the next issue.

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Platinum compounds
Based on the activity of cisplatin, other platinum compounds have been evaluated. Carboplatin is the most widely tested, due to its milder toxicity and renal tolerance. Results of phase II studies involving 274 advanced urothelial cancer patients who received single-agent carboplatin showed a response rate of only 14%,(9–13) and this appears slightly inferior to that obtained with cisplatin. In view of the toxicity associated with MVAC, particularly in patients with impaired performance status and/or impaired renal function, carboplatin has been substituted for cisplatin in various combinations to produce a more convenient, less toxic regimen. Small et al treated 23 advanced transitional cell carcinoma patients with methotrexate, vinblastine, mitoxantrone and carboplatin (M-VNCa).(14) The overall response rate was 56.5%, and the median overall survival was 10 months. A randomised phase II study reported by Petrioli compared a regimen of methotrexate, vinblastine, epirubicin and cisplatin (M-VEC) with carboplatin-substituted M-VECa in 57 patients with recurrent or metastatic bladder cancer.(15) The overall response (71% vs 41%) and complete response (25% vs 11%) were significantly in favour of M-VEC. Another randomised phase III trial compared MVAC with a three-drug regimen of methotrexate, carboplatin and vinblastine (M-CAVI) in 47 patients with advanced bladder cancer.(16) The overall response rate was higher in patients treated with M-VAC (52% vs 39%) but was not statistically significant. The MVAC regimen was more toxic but produced a significantly longer median disease-related survival time (16 months vs 9 months). Even though the number of patients included was limited, these two trials seem to suggest that cisplatin cannot be routinely substituted by carboplatin for reasons of toxicity without compromising the outcome of therapy. Carboplatinbased chemotherapy, such as M-CAVI or M-VECa, may be of benefit only to patients whose medical condition precludes the use of cisplatin.(17) Future studies are needed to determine whether the activity of carboplatin is lower than, or equivalent to, that of cisplatin in advanced bladder cancer.

Other platinum compounds have been investigated. Lobaplatin, a third-generation platinum complex, was assessed in previously treated patients with urothelial cancer in an EORTC trial, and a response rate of 10% was reported.(18) Oxaliplatin, another promising platinum complex, has not yet been fully assessed in patients with urothelial cancer, but studies either alone or in combination with gemcitabine are ongoing.

Ifosfamide
Ifosfamide was evaluated in a phase II trial of 56 previously treated patients with advanced urothelial cancer. The response rate in this study was 20%, with complete response in four patients, with central nervous system toxicity, nephrotoxicity and myelosuppression as the dose-limiting toxicities.(19)

Piritrexim
Since methotrexate is active in advanced bladder cancer, other antifolates and antimetabolites have been assessed for this purpose. Witte et al reported a response rate of 17% for trimetrexate in patients who had received prior chemotherapy.(20) Piritrexim, an oral second-generation antimetabolite, was tested in two studies including 50 previously treated patients.(21,22) The median overall response rate reported was 23%. MTA, a novel multitargeted antifolate that inhibits multiple folate-dependent enzymes, was evaluated in 22 chemotherapy-naive patients with bladder cancer.(23) Six patients (33%, 95% confidence interval [CI] 13–59%) had a partial remission.

Paclitaxel
Paclitaxel is a member of the novel family of taxanes, which stabilises microtubules and promotes their assembly, resulting in M-phase cell cycle arrest.(24) In preclinical studies, paclitaxel has proved to be a very active anticancer agent against a broad range of cancer cell lines, including human bladder cancer cells.(25,26) In patients with advanced urothelial carcinoma, firstline chemotherapy with paclitaxel, given at a dose of 250mg/m(2) by 24-hour continuous infusion every three weeks,(27) resulted in a response rate of 42%, including 27% complete responses. Since the kidney only minimally excretes paclitaxel, this agent can be appropriately evaluated in patients with urothelial neoplasms, who, quite frequently, have impaired renal function. Early clinical experience has confirmed the utility of this agent in patients with compromised renal function.(28) Docetaxel, another taxane, has a demonstrable response rate of 13% in previously treated patients with urothelial cancer and 31% in firstline patients.(29,30)

Gemcitabine
Gemcitabine, a novel nucleoside analogue, has also demonstrated promising single-agent activity against urothelial cancer. This drug was initially evaluated in an Italian phase I study conducted in 15 patients with metastatic bladder cancer.(31) The doses ranged from 875–1,370mg/m(2). One complete response and two partial responses were seen in 14 previously treated patients, and one partial response was observed in a chemotherapy-naive patient. The overall response rate was 27% (4.3–49.1%, 95% CI). In two phase II trials in previously treated patients, response rates of 28% and 50% were reported.(32,33) Two trials evaluating gemcitabine in previously untreated patients confirm the high activity of this agent. Stadler et al treated 40 patients with gemcitabine 1,200mg/m(2) once a week for three weeks followed by one week off, repeated every 28 days, and reported an overall response rate of 28% (15–45%, 95% CI).(33) Three complete responses were obtained in patients with liver metastasis. Moore et al reported an overall response rate of 24.3% (12–41%, 95% CI) in 37 assessable patients.(34)

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