Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With Pegfilgrastim Support in Muscle-Invasive Urothelial Cancer: Pathologic, Radiologic, and Biomarker Correlates

• Published in: Journal of clinical oncology Vol. 32; no. 18; pp. 1889 - 1894
• Main Authors: Choueiri, Toni K., Jacobus, Susanna, Bellmunt, Joaquim, Qu, Angela, Appleman, Leonard J., Tretter, Christopher, Bubley, Glenn J., Stack, Edward C., Signoretti, Sabina, Walsh, Meghara, Steele, Graeme, Hirsch, Michelle, Sweeney, Christopher J., Taplin, Mary-Ellen, Kibel, Adam S., Krajewski, Katherine M., Kantoff, Philip W., Ross, Robert W., Rosenberg, Jonathan E.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.06.2014
• Subjects: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - analysis; Carcinoma, Transitional Cell - chemistry; Carcinoma, Transitional Cell - diagnostic imaging; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - pathology; Carcinoma, Transitional Cell - surgery; Chemotherapy, Adjuvant; Cisplatin - administration & dosage; Cisplatin - adverse effects; Cystectomy; Disease-Free Survival; DNA-Binding Proteins - analysis; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug Administration Schedule; Endonucleases - analysis; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor - therapeutic use; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Magnetic Resonance Imaging - methods; Male; Medical sciences; Methotrexate - administration & dosage; Methotrexate - adverse effects; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoadjuvant Therapy - methods; Neoplasm Invasiveness; Neoplasm Staging; Nephrology. Urinary tract diseases; ORIGINAL REPORTS; Polyethylene Glycols; Protective Agents - therapeutic use; Radiography; Recombinant Proteins - therapeutic use; Treatment Outcome; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - chemistry; Urinary Bladder Neoplasms - diagnostic imaging; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - surgery; Urinary tract. Prostate gland; Vinblastine - administration & dosage; Vinblastine - adverse effects; Antineoplastic agent; Biological marker; Doxorubicin; Neoadjuvant treatment; Antifolate; Alkaloid; Granulocyte colony stimulating factor; Isomerases; Cancerology; Muscle; Invasive cancer; Pegylated form; Methotrexate; Antimitotic; Dose; Platinum II Complexes; DNA topoisomerase (ATP-hydrolysing); Urothelial cancer; Urinary system disease; Vinblastine; Enzyme; Cytokine; Enzyme inhibitor; Topoisomerase II inhibitor; Urinary tract disease; Malignant tumor; Cisplatin; Immunomodulator; Alkylating agent; Antibiotic; Immunostimulant agent; Pegfilgrastim; Antimetabolic; Anthracyclins; Cancer
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.2013.52.4785

In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC). Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ≤ pT1N0M0, and we concluded this regimen was effective. High-grade (grade ≥ 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival. In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.