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Analysis of the yield of phase II combination therapy trials in medical oncology.

ABSTRACT: Phase II clinical studies screen for treatment regimens that improve patient care, but screening combination regimens is especially challenging. We hypothesized that recognized flaws of single-arm trials could be magnified in combination treatment studies, leading to many reported positive phase II trials but with a low fraction resulting in practice-changing phase III trials.We searched medline and identified 363 combination chemotherapy clinical trials published in 2001 and 2002. Studies were rated as positive, negative, or inconclusive based on a standardized review of abstract and text. The Web of Science Index (Thomson Reuters, NY, NY) was searched for all articles published between January 2003 and October 2007 that cited at least one of these 363 published trials.Of 363 published phase II combination chemotherapy trials, 262 (72%) were declared to be positive. Among 3,760 unique subsequent citing papers, 20 reported randomized phase III trials of the same combination in the same disease as the source paper, and 10 of these resulted in improved standards of care. Estimating from these data, the likelihood that a published, positive phase II combination chemotherapy trial will result in a subsequent trial showing an improvement in standard of care within five years was 0.038 (95% confidence interval, 0.016-0.064).The contributory value of combination chemotherapy phase II trials done by 2001-2002 standards is low despite the participation of more than 16,000 subjects. Future phase II studies of combination regimens require better methods to screen for treatments most likely to improve standards of care.

SUBMITTER: Maitland ML

PROVIDER: S-EPMC2970723 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Analysis of the yield of phase II combination therapy trials in medical oncology.

Maitland Michael L ML Hudoba Christine C Snider Kelly L KL Ratain Mark J MJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20100913 21

<h4>Purpose</h4>Phase II clinical studies screen for treatment regimens that improve patient care, but screening combination regimens is especially challenging. We hypothesized that recognized flaws of single-arm trials could be magnified in combination treatment studies, leading to many reported positive phase II trials but with a low fraction resulting in practice-changing phase III trials.<h4>Experimental design</h4>We searched medline and identified 363 combination chemotherapy clinical tria ...[more]

PMID: 20837695

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Project description:BackgroundPhase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials.Data sourcesA literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015).Study eligibility criteriaAll articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer.InterventionQuality of reporting was assessed using the Key Methodological Score.Results557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001).LimitationsScreening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate.Conclusions & implications of key findingsThis literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

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Analysis of the yield of phase II combination therapy trials in medical oncology.

Publications

Analysis of the yield of phase II combination therapy trials in medical oncology.

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