title: Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity.
abstract: OBJECTIVE
  Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls.
  
  
  METHODS
  Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity.
  
  
  RESULTS
  Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non-muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity.
  
  
  CONCLUSIONS
  AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy.
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN. elizabeth.plimack@fccc.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Jean H
authors.initials: JH
authors.lastname: Hoffman-Censits
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Viterbo
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Trabulsi
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ross
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Greenberg
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: David Y T
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Costas D
authors.initials: CD
authors.lastname: Lallas
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Wong
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kutikov
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Efrat
authors.initials: E
authors.lastname: Dotan
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Brennan
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Norma
authors.initials: N
authors.lastname: Palma
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Essel
authors.initials: E
authors.lastname: Dulaimi
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Reza
authors.initials: R
authors.lastname: Mehrazin
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Boorjian
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: William Kevin
authors.initials: WK
authors.lastname: Kelly
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Uzzo
authors.affiliation: Elizabeth R. Plimack, Rosalia Viterbo, Eric A. Ross, Richard E. Greenberg, David Y.T. Chen, Yu-Ning Wong, Alexander Kutikov, Efrat Dotan, Essel Dulaimi, Reza Mehrazin, Robert G. Uzzo, and Gary R. Hudes, Fox Chase Cancer Center, Temple Health; Jean H. Hoffman-Censits, Edouard J. Trabulsi, Costas D. Lallas, Jianqing Lin, and William Kevin Kelly, Thomas Jefferson University Hospital, Philadelphia, PA; Timothy A. Brennan and Norma Palma, Foundation Medicine, Cambridge, MA; and Stephen A. Boorjian, Mayo Clinic, Rochester, MN.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Hudes
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001853:Bone Marrow / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D000069585:Filgrastim; D020869:Gene Expression Profiling; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011092:Polyethylene Glycols; D011446:Prospective Studies; D020011:Protective Agents / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D020011:Protective Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D014747:Vinblastine; D004317:Doxorubicin; D000069585:Filgrastim; D002945:Cisplatin; D008727:Methotrexate