Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer

A phase III trial of the gynecologic cancer intergroup

Michael A. Bookman, Mark F. Brady, William P. McGuire, Peter G. Harper, David S Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M. Fowler, Peter A. Argenta, Koen De Geest, David G. Mutch, Robert A. Burger, Ann Marie Swart, Edward L. Trimble, Chrisann Accario-Winslow, Lawrence M. Roth

Research output: Contribution to journalArticle

468 Citations (Scopus)

Abstract

Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

Original languageEnglish (US)
Pages (from-to)1419-1425
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number9
DOIs
StatePublished - Mar 20 2009
Externally publishedYes

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Platinum
Ovarian Neoplasms
Carboplatin
Paclitaxel
Disease-Free Survival
Survival
Cytotoxins
gemcitabine
Carcinoma
Neoplasms
Topotecan
Residual Neoplasm
Therapeutics
Survival Analysis
Demography
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer : A phase III trial of the gynecologic cancer intergroup. / Bookman, Michael A.; Brady, Mark F.; McGuire, William P.; Harper, Peter G.; Alberts, David S; Friedlander, Michael; Colombo, Nicoletta; Fowler, Jeffrey M.; Argenta, Peter A.; De Geest, Koen; Mutch, David G.; Burger, Robert A.; Swart, Ann Marie; Trimble, Edward L.; Accario-Winslow, Chrisann; Roth, Lawrence M.

In: Journal of Clinical Oncology, Vol. 27, No. 9, 20.03.2009, p. 1419-1425.

Research output: Contribution to journalArticle

Bookman, MA, Brady, MF, McGuire, WP, Harper, PG, Alberts, DS, Friedlander, M, Colombo, N, Fowler, JM, Argenta, PA, De Geest, K, Mutch, DG, Burger, RA, Swart, AM, Trimble, EL, Accario-Winslow, C & Roth, LM 2009, 'Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: A phase III trial of the gynecologic cancer intergroup', Journal of Clinical Oncology, vol. 27, no. 9, pp. 1419-1425. https://doi.org/10.1200/JCO.2008.19.1684
Bookman, Michael A. ; Brady, Mark F. ; McGuire, William P. ; Harper, Peter G. ; Alberts, David S ; Friedlander, Michael ; Colombo, Nicoletta ; Fowler, Jeffrey M. ; Argenta, Peter A. ; De Geest, Koen ; Mutch, David G. ; Burger, Robert A. ; Swart, Ann Marie ; Trimble, Edward L. ; Accario-Winslow, Chrisann ; Roth, Lawrence M. / Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer : A phase III trial of the gynecologic cancer intergroup. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 9. pp. 1419-1425.
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abstract = "Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90{\%} chance of detecting a true hazard ratio of 1.33 that limited type I error to 5{\%} (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79{\%} of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.",
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T1 - Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer

T2 - A phase III trial of the gynecologic cancer intergroup

AU - Bookman, Michael A.

AU - Brady, Mark F.

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AU - Harper, Peter G.

AU - Alberts, David S

AU - Friedlander, Michael

AU - Colombo, Nicoletta

AU - Fowler, Jeffrey M.

AU - Argenta, Peter A.

AU - De Geest, Koen

AU - Mutch, David G.

AU - Burger, Robert A.

AU - Swart, Ann Marie

AU - Trimble, Edward L.

AU - Accario-Winslow, Chrisann

AU - Roth, Lawrence M.

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N2 - Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

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