Original study
Long-Term Efficacy and Safety Outcomes of Modified (Simplified) MVAC (Methotrexate/Vinblastine/Doxorubicin/Cisplatin) as Frontline Therapy for Unresectable or Metastatic Urothelial Cancer

Presented at the 2013 Genitourinary Cancers Symposium, February 14-16, 2013, Orlando, FL.
https://doi.org/10.1016/j.clgc.2013.11.022Get rights and content

Abstract

Background

The classic MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) regimen was the first recognized option for untreated patients with locally advanced or metastatic urothelial cancer (UC). Modifying MVAC by reducing side effects may have the potential to improve efficacy.

Patients and Methods

Changes to classic MVAC were provided at the authors' institution: (1) deletion of day 22 and administration of 25 mg/m2 cisplatin on days 2 to 5 (modified [m]MVAC); (2) deletion of day 22 only (simplified [s]MVAC1); and (3) deletion of days 15 and 22 in a 3-week schedule (sMVAC2). A total of 4 to 6 cycles were provided. Multivariate analysis was undertaken for recognized clinical variables.

Results

For the period from September 1986 to May 2012, 157 patients were identified (25 with mMVAC, 72 with sMVAC1, and 60 with sMVAC2). Overall, 43.9% had a Memorial Sloan-Kettering Cancer Center score of 1 or 2, with differences across series (P = .002). Altogether, 65.8% attained a complete (19.1%) or partial response (46.7%), and 24.3% a stable disease, with no difference across regimens. After a median follow-up of 87 months (interquartile range, 37-161), median progression-free survival was 10.2 months (95% CI, 8.4-10.8), and median overall survival (OS) was 19.5 months (95% CI, 16.3-24.1). Responses were mainly seen in nodal metastases or soft tissue relapse (odds ratio, 2.48; 95% CI, 1.12-5.54). Only visceral (hazard ratio [HR], 2.42; 95% CI, 1.37-4.30) and nodal metastases/local relapse (HR, 1.70; 95% CI, 1.07-2.69) were independently associated with OS. Grade 3 or 4 toxicities were similar across regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. Two treatment-related deaths occurred.

Conclusion

Simplifying MVAC may result in improved efficacy and reduced toxicity. The combined results of the original and modified MVAC regimens encourage a reappraisal of the frontline management of advanced UC.

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.

References (18)

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