Analysis of the yield of phase II combination therapy trials in medical oncology
Michael L Maitland1, Christine Hudoba, Kelly L Snider
1Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. maitland@uchicago.edu
Purpose:
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.
Experimental Design:
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.
Results:
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).
Conclusions:
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.
Insights
Phase II combination chemotherapy trials often yield positive results but rarely lead to improved standards of care. New methods are needed to better screen treatments likely to change clinical practice.
Area of Science:
- Oncology
- Clinical Trials
- Pharmacology
Background:
- Phase II clinical studies are crucial for evaluating new treatment regimens.
- Screening combination therapies presents unique challenges compared to single agents.
- Existing flaws in single-arm trials may be amplified in combination studies.
Purpose of the Study:
- To evaluate the predictive value of early-phase combination chemotherapy trials.
- To assess the rate at which positive Phase II combination trials lead to practice-changing Phase III results.
- To identify limitations in current Phase II trial designs for combination regimens.
Main Methods:
- A systematic review of 363 Phase II combination chemotherapy trials published in 2001-2002.
- Classification of trials as positive, negative, or inconclusive.
- Bibliometric analysis of citations to identify subsequent Phase III trials and their outcomes.
Main Results:
- 72% of published Phase II combination chemotherapy trials were reported as positive.
- Only 20 subsequent Phase III trials were identified from 3,760 citing papers.
- The probability of a positive Phase II trial leading to an improved standard of care within five years was low (3.8%).
Conclusions:
- The current value of Phase II combination chemotherapy trials is limited, despite significant patient participation.
- A high rate of positive Phase II trials does not translate to improved cancer care standards.
- Improved methodologies are essential for future Phase II studies of combination regimens to enhance clinical impact.
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