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

Elizabeth R. Plimack, Jean H. Hoffman-Censits, Rosalia Viterbo, Edouard J. Trabulsi, Eric A. Ross, Richard E. Greenberg, David Y T Chen, Costas D. Lallas, Yu Ning Wong, Jianqing Lin, Alexander Kutikov, Efrat Dotan, Timothy A. Brennan, Norma Palma, Essel Dulaimi, Reza Mehrazin, Stephen A. Boorjian, William Kevin Kelly, Robert G. Uzzo, Gary R. Hudes

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Abstract

Purpose: 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. Patients and 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1895-1901
Number of pages7
JournalJournal of Clinical Oncology
Volume32
Issue number18
DOIs
StatePublished - Jun 20 2014

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Neoadjuvant Therapy
Vinblastine
Cystectomy
Urinary Bladder Neoplasms
Methotrexate
Doxorubicin
Cisplatin
Muscles
Drug Therapy
Telomere
Mutation
Standard of Care
Lymph Node Excision
Therapeutics
Neoplasm Metastasis
Kidney
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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. / Plimack, Elizabeth R.; Hoffman-Censits, Jean H.; Viterbo, Rosalia; Trabulsi, Edouard J.; Ross, Eric A.; Greenberg, Richard E.; Chen, David Y T; Lallas, Costas D.; Wong, Yu Ning; Lin, Jianqing; Kutikov, Alexander; Dotan, Efrat; Brennan, Timothy A.; Palma, Norma; Dulaimi, Essel; Mehrazin, Reza; Boorjian, Stephen A.; Kelly, William Kevin; Uzzo, Robert G.; Hudes, Gary R.

In: Journal of Clinical Oncology, Vol. 32, No. 18, 20.06.2014, p. 1895-1901.

Research output: Contribution to journalArticle

Plimack, ER, Hoffman-Censits, JH, Viterbo, R, Trabulsi, EJ, Ross, EA, Greenberg, RE, Chen, DYT, Lallas, CD, Wong, YN, Lin, J, Kutikov, A, Dotan, E, Brennan, TA, Palma, N, Dulaimi, E, Mehrazin, R, Boorjian, SA, Kelly, WK, Uzzo, RG & Hudes, GR 2014, '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', Journal of Clinical Oncology, vol. 32, no. 18, pp. 1895-1901. https://doi.org/10.1200/JCO.2013.53.2465
Plimack, Elizabeth R. ; Hoffman-Censits, Jean H. ; Viterbo, Rosalia ; Trabulsi, Edouard J. ; Ross, Eric A. ; Greenberg, Richard E. ; Chen, David Y T ; Lallas, Costas D. ; Wong, Yu Ning ; Lin, Jianqing ; Kutikov, Alexander ; Dotan, Efrat ; Brennan, Timothy A. ; Palma, Norma ; Dulaimi, Essel ; Mehrazin, Reza ; Boorjian, Stephen A. ; Kelly, William Kevin ; Uzzo, Robert G. ; Hudes, Gary R. / 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. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 18. pp. 1895-1901.
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abstract = "Purpose: 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. Patients and 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. Conclusion: 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.",
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T1 - Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer

T2 - Results of a multicenter phase II study with molecular correlates of response and toxicity

AU - Plimack, Elizabeth R.

AU - Hoffman-Censits, Jean H.

AU - Viterbo, Rosalia

AU - Trabulsi, Edouard J.

AU - Ross, Eric A.

AU - Greenberg, Richard E.

AU - Chen, David Y T

AU - Lallas, Costas D.

AU - Wong, Yu Ning

AU - Lin, Jianqing

AU - Kutikov, Alexander

AU - Dotan, Efrat

AU - Brennan, Timothy A.

AU - Palma, Norma

AU - Dulaimi, Essel

AU - Mehrazin, Reza

AU - Boorjian, Stephen A.

AU - Kelly, William Kevin

AU - Uzzo, Robert G.

AU - Hudes, Gary R.

PY - 2014/6/20

Y1 - 2014/6/20

N2 - Purpose: 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. Patients and 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. Conclusion: 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.

AB - Purpose: 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. Patients and 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. Conclusion: 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.

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