ABSTRACT
Single agents and MVAC era Studies in the 1970s identified the chemosensitivity of urothelial cancer to several agents: cisplatin, methotrexate, adriamycin, vinblastine, and 5-fluorouracil (5FU) were shown to be the most active.2 Although these earlier trials led to a response rate of only 10% to 30% when used in monotherapy and with limited duration of responses, they established the foundation for combination chemotherapeutic trials which characterized the 1980s.3 These trials were mainly cisplatin-based combination regimens such as cisplatin/methotrexate/vinblastine (CMV), cisplatin/adriamycin/ cyclophosphamide (CISCA), and methotrexate/vinblastine/ adriamycin/cisplatin (MVAC).4-6 These combinations were reported initially as single-institution phase II studies with objective response rates as high as 65% to 75%, with approximately 20% to 35% of cases achieving complete remission (CR), and median survival periods increasing from 3-4 months to 12-14 months.3-7
As a consequence, it became apparent that cisplatin was an essential component of combination chemotherapy regimens for patients with adequate renal function. A randomized study conducted in the UK comparing methotrexate and vinblastine (MV) with CMV demonstrated an absolute improvement in 1-year survival of 13% with the treatment containing cisplatin (29% for CMV and 16% for MV). The median survival for CMV was significantly longer than that for MV: 7 months compared with 4.5 months.8 This study demonstrated the significant survival impact of cisplatin and has helped to justify the routine use of cisplatin-based combination chemotherapy. In addition, as more experience was gained with MVAC, it emerged as the preferred cisplatin-based combination therapy (Table 25.1).9-13 In randomized trials, MVAC produced a modest, though significant, survival benefit when compared with cisplatin as a single agent, CISCA, or carboplatin-based regimens.11,13,14
for those with nodal disease appeared more favorable.2,9 Patients with nontransitional-cell histology and poor performance status had a poor prognosis and were unlikely to benefit significantly from MVAC chemotherapy.15 In addition, long-term survival was low, with only 3.7% of patients experiencing more than 6 years of disease-free survival.9,11-15
Due to the toxicity that was reported with MVAC, with up to 25% incidence of neutropenic fever, 50% grade 2-3 stomatitis, and 3% drug-related mortality, the incorporation of granulocyte colonystimulating factor (G-CSF) or granulocyte-macrophage colonystimulating factor (GM-CSF) was added to the schedule. This was done both in an effort to reduce toxicity and to increase the dose density of the combination since, in the majority of patients, cycles were delivered every 5 weeks instead of every 4 weeks.9-13 With the simultaneous use of G-CSF or GM-CSF, these toxicities can be reduced, allowing more patients to receive the dose originally planned in the conventional MVAC treatment, and even an intensified MVAC schedule. Unfortunately, dose intensification of the MVAC regimen has not translated into a clinical benefit in terms of improved survival.16-22 A recent phase III study by the European Organisation for Research and Treatment of Cancer (EORTC), comparing classical MVAC to a high dose (HD) MVAC regimen every 2 weeks with G-CSF support, revealed significant differences in terms of complete response and overall response rates in favor of the HD-MVAC arm (25% and 72%, respectively), compared with the standard MVAC arm (11% and 58%, respectively). However, there was no statistically significant difference between the two treatment arms in terms of the primary endpoint: overall survival with a median survival of 15.5 months for the HD-MVAC arm and 14.1 months for the standard MVAC arm.23
