Original studyLong-Term Efficacy and Safety Outcomes of Modified (Simplified) MVAC (Methotrexate/Vinblastine/Doxorubicin/Cisplatin) as Frontline Therapy for Unresectable or Metastatic Urothelial Cancer
Introduction
Metastatic urothelial cancer (UC) is still a deadly disease, and no major achievements have been recorded in the landscape of therapeutic options over the past 25 to 30 years.1 Historically, MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) improved results in the first-line setting compared with either cisplatin alone or cisplatin combined with cyclophosphamide and doxorubicin (Adriamycin) (CISCA), with a reported 65% to 72% of complete response (CR) or partial response (PR) and a median survival approximating 12 months.2, 3, 4, 5 Another recognized option was the combination cisplatin/gemcitabine (CG), which became a standard of care based on (1) the results of a single phase III trial reporting response and survival rates that were not significantly lower and, likely, (2) its better tolerability and easier administration in an outpatient setting.6, 7 Through the years, trials attempting to improve results of both regimens with dose intensification of MVAC or the addition of novel chemotherapeutic agents to CG failed to achieve the primary endpoints, and progression-free survival (PFS) as well as overall survival (OS) estimates did not markedly differ from the original published series.8, 9, 10 Unfortunately, 2-year PFS is achieved in fewer than 20% of patients, and only a few patients (5%-10%) have the potential to achieve long-term survival, depending on baseline prognostic features.
A reverse trend was applied to clinical research in the field at the authors' center (Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Istituto Nazionale dei Tumori [INT], Milan, Italy), whereby the focus was on reducing the side effects of MVAC (particularly renal and neurologic toxicity) while increasing the activity over the benchmark. Starting from the second half of the 1980s, this center modified the original MVAC regimen within either a phase II proof-of-principle trial or cohorts of consecutive patients. Since then, sequential treatment modifications were prospectively assessed at the Urology Unit of the INT. All patients signed an ad hoc informed consent form in each case. The phase II trial of this series was approved by the institutional review board of the sponsor institution (Protocol No. INT259/90, approved on February 22, 1990). The last regimen described herein is currently the standard first-line therapy for untreated patients with advanced or metastatic UC outside of clinical trials at INT.
Section snippets
Patient Population Under Study
A total of 245 relevant patients were treated at the authors' institution from September 1986 to May 2012. Of them, 88 were excluded from the present analysis: 69 because they were treated in an adjuvant setting for muscle-invasive disease and 19 because of pure nontransitional cell histologies. The remaining 157 were included in the present appraisal.
Treatment Schedules
Modifications to the classic MVAC schedule were provided as follows: 25 patients were enrolled in a phase II trial of a modified MVAC (mMVAC)
Results
Table 1 presents baseline characteristics of patients. The median age was 60 years (interquartile range [IQR], 53-66); 17 patients (10.8%) had an upper tract UC; 39 (24.8%) presented with hydronephrosis; 26 (16.6%) had an ECOG PS of 1 or 2; and 69 (43.9%) had an MSKCC risk group > 0, including 57 (36.3%) having visceral metastases. Patients in the sMVAC2 cohort had poorer prognostic features (64% [n = 38] had a MSKCC score of 1 or 2, and 52% [n = 31] had visceral metastases; P = .002).
Discussion
Outcome results of these single-institution series provided insights into the major limitations of the approach to advanced and metastatic UC. The case of MVAC is paradigmatic: the sobering realization is that despite major changes in the planned dose intensities across different MVAC (classic and modified) schedules, overall survival estimates are mirroring.
Comparing across studies is fraught with difficulties, mainly in relation to the huge time frame and the varying quality of supportive
Conclusion
Based on the present results, the authors favor the use of simplified MVAC as a suitable platform for combinations with targeted agents, particularly in a setting (neoadjuvant therapy) where the highest activity is needed and where CG is not a recognized option. Consistency of results in relation to the sample size provides a compelling argument supporting the INT's current policy as well as a reappraisal of the optimal management of frontline therapy for advanced and metastatic UC.
Disclosure
This work was not supported by any grant funding.
The authors have stated that they have no conflicts of interest.
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