The European Organisation for Research and Treatment of Cancer Group conducted another randomized trial that studied 263 patients with advanced bladder cancer and evaluated the efficacy of a high-dose-intensity M-VAC regimen given every 2 weeks with granulocyte colony-stimulating factor (G-CSF) compared to a classic M-VAC regimen given every 4 weeks. Although there was no significant difference in OS at a median follow-up of 3.2 years (HR, 0.80; 95% CI, 0.60–1.06; P = .122), an update at a median follow-up of 7.3 years reported that the high-dose intensity M-VAC regimen was associated with improved OS (HR, 0.76; 95% CI, 0.58–0.99; P = .042), with a 5-year survival rate of 22%, compared to 14% in patients treated with the classic M-VAC regimen. The high-dose intensity M-VAC regimen was also associated with higher response rates (72% vs. 58%, P = .016), improved median progression-free survival (9.5 months vs. 8.1 months, P = .017), and decreased neutropenic fever (10% vs. 26%, P < .001), though only 19% of patients treated with a classic M-VAC regimen ever received G-CSF.[Level of evidence: 1iiA] An imbalance in baseline prognostic factors (i.e., visceral metastases were found in 37 patients randomly assigned to the high-dose M-VAC regimen and 47 patients assigned to the classic M-VAC regimen) may account, in part, for these results. Ongoing studies are evaluating new chemotherapy combinations.
Chemotherapy for patients not eligible for cisplatin
The only regimens that have shown a survival benefit in randomized controlled trials have been the cisplatin-based multiagent regimens MVAC, high-dose MVAC, and CMV; gemcitabine plus cisplatin is generally accepted as equivalent to MVAC based on the data discussed above.[3,4,10,11,12] Optimal treatment of patients who are not eligible for cisplatin-based chemotherapy caused by renal insufficiency or poor performance status is thus unknown. One common practice has been to substitute carboplatin for cisplatin to reduce nephrotoxicity and gastrointestinal toxicity. Two small, randomized trials comparing cisplatin-based regimens to carboplatin-based regimens have been published.[13,14] One trial reported a lower complete response rate, while the other trial reported shorter disease-specific survival with the carboplatin-based regimen. However, these studies were underpowered, and the one that showed a disease-specific survival difference included an anthracycline in the cisplatin arm but not in the carboplatin arm. If carboplatin-based regimens are less effective than cisplatin regimens, which only prolong survival by several months, then carboplatin-based regimens may have no survival benefit.
Several less nephrotoxic regimens have been studied in clinical trials, but most of these trials have not focused on patients with renal impairment or poor performance status. Published regimens that have been studied in trials limited to patients with a medical contraindication to cisplatin include gemcitabine plus carboplatin, single-agent docetaxel, and single-agent paclitaxel.[15,16,17,18,19,20] In general, outcomes of studies in patients unfit for cisplatin have been inferior to those of cisplatin-based regimens with reported median survival times of less than 1 year. A randomized, phase II/III trial comparing gemcitabine plus carboplatin (GCa) to methotrexate, carboplatin and vinblastine (M-CAVI) reported that in the phase II portion of the trial, the response rate was 42% with GCa compared to 30% with M-CAVI. However, patients with a performance status of 2 and a creatinine clearance less than 60 mL/min had a response rate of only 26% and 20%, respectively and a severe acute toxicity rate of 26% and 25%, respectively. These regimens were judged to be nonbeneficial for patients meeting both those criteria.