Neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in patients with high-grade upper-tract urothelial carcinoma.
326 Background: Improved safety and response rates of AMVAC over standard MVAC in patients (pts) with metastatic bladder cancer support study of neoadjuvant AMVAC for pts with muscle invasive bladder cancer (MIBC) and prenephroureterectomy (NU) for pts with high-grade upper-tract urothelial cancer (UTUC). We performed a phase II study of neoadjuvant AMVAC in MIBC and UTUC, and herein report the results of the UTUC exploratory subgroup. Methods: Pts with UTUC (ureter or renal pelvis) with high-grade UC on biopsy, or positive urine cytology and mass on cross sectional imaging, N0-N1, CrCl >=50, adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) day 1, pegfilgrastim 6 mg day 2 or 3, every 2 weeks. NU, with lymph node dissection at surgeon discretion, was performed 4-8 weeks after last cycle. Exploratory endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 10 evaluable UTUC pts enrolled at 2 institutions (FCCC, TJU) over 46.5 months. Median age 67 (range 49-83). Of 10 pts, 6 completed all 3 cycles of AMVAC. Four pts received < 3 cycles due to grade 3 acute kidney injury (1), pyelonephritis and grade 3 diverticulitis (1), flare of underlying hepatitis (1), grade 3 fatigue (1). Additional related grade 3 adverse events (AE) were anemia (1) and nausea/vomiting (1), no grade 4 or 5 AE. All pts underwent NU within 8 weeks of last chemotherapy, median 5.5 weeks. Median time from day 1 AMVAC to NU was 9 wks. 1/10 pts had a pCR, 4/10 patients were staged <pT1, 2/10 pT2, and 3/10 >pT3 or N+. An additional 21.5 months of enrollment were needed in this expansion cohort to accrue 10 pts with UTUC, compared to 44 MIBC pts in 25 mos. All pts completed study treatment as of July 2013. Conclusions: In this small sample, neoadjuvant AMVAC prior to NU was clinically active with manageable toxicity. With short duration from start of chemotherapy to NU, 3 neoadjuvant AMVAC cycles should be considered for further study for high-grade UTUC prior to NU in the cooperative group setting. Clinical trial information: NCT01031420.