HD-MVAC vs classic MVAC in advanced urothelial tract tumors

Background

Phase 3 EORTC RCT; N=263 locally advanced or metastatic urothelial carcinoma (bladder, ureter, urethra, renal pelvis); dose-dense (HD) MVAC + G-CSF vs classic MVAC.

Interventions and follow up

Arm A: dd-MVAC (methotrexate 30 mg/m2 d1; vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2 d2; G-CSF 240 µg/m2 d4–10) q14d
Arm B: Classic MVAC (methotrexate 30 mg/m2 d1, d15, d22; vinblastine 3 mg/m2 d2, d15, d22; doxorubicin 30 mg/m2 d2; cisplatin 70 mg/m2 d2) q28d
Primary endpoint: Overall survival
Secondary: PFS, time to progression, response rate
mFollow up: 38 mo

Results

mOS: 15.5 mo vs 14.1 mo, HR 0.80, 95% CI 0.60–1.06, P=.122 (NS).
mPFS: 9.1 mo vs 8.2 mo, HR 0.75, 95% CI 0.58–0.98, P=.037.
ORR: 62% (CR 21%, PR 41%) vs 50% (CR 9%, PR 41%); P=.06 ORR, P=.009 CR.
2yr PFS: 24.7% vs 11.6%.

Adverse events

Hematologic (G≥3, dd-MVAC vs MVAC): leukopenia 20% vs 62%, P<.001; thrombocytopenia 22% vs 17%.
Infectious: neutropenic fever 10% vs 26%, P<.001.
Mucosal/renal: any-grade mucositis less with dd-MVAC, P=.034; no difference in renal toxicity (P=.815); toxic deaths similar (~1–3%).

Conclusions

Dose-dense MVAC with G-CSF did not significantly prolong OS but improved CR rate and PFS with less neutropenic fever and mucositis than classic MVAC, supporting dd-MVAC as the preferred MVAC schedule.

Key Limitations

Primary OS endpoint not met (underpowered); secondary endpoints (PFS, CR) positive but exploratory; pre-immunotherapy era; long-term (7yr) follow-up later showed a survival trend favoring dd-MVAC.

Clinical Context

Established dd-MVAC + G-CSF as the preferred MVAC schedule over classic MVAC due to better tolerability and higher response; ESMO/ASCO recognize dd-MVAC as an accepted cisplatin-based regimen in advanced and perioperative urothelial carcinoma (validated neoadjuvantly in VESPER).

References