title: Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY. toni_choueiri@dfci.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jacobus
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Angela
authors.initials: A
authors.lastname: Qu
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tretter
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Bubley
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Meghara
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Graeme
authors.initials: G
authors.lastname: Steele
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hirsch
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Krajewski
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ross
authors.affiliation: Toni K. Choueiri, Susanna Jacobus, Joaquim Bellmunt, Angela Qu, Edward C. Stack, Sabina Signoretti, Meghara Walsh, Graeme Steele, Michelle Hirsch, Christopher J. Sweeney, Mary-Ellen Taplin, Adam S. Kibel, Katherine M. Krajewski, Philip W. Kantoff, Robert W. Ross, and Jonathan E. Rosenberg, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Christopher Tretter, Lahey Clinic, Burlington; Glenn J. Bubley, Beth Israel Deaconess Medical Center, Boston, MA; Leonard J. Appleman, University of Pittsburgh, Pittsburgh, PA; and Jonathan E. Rosenberg, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002295:Carcinoma, Transitional Cell / Q000737:chemistry / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D015653:Cystectomy; D004268:DNA-Binding Proteins / Q000032:analysis; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004720:Endonucleases / Q000032:analysis; D005260:Female; D000069585:Filgrastim; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011092:Polyethylene Glycols; D020011:Protective Agents / Q000627:therapeutic use*; D011859:Radiography; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D020011:Protective Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D014747:Vinblastine; D004317:Doxorubicin; C071447:ERCC1 protein, human; D004720:Endonucleases; D000069585:Filgrastim; D002945:Cisplatin; D008727:Methotrexate