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


METHODS
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.
Maitland
Michael L
ML
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA. maitland@uchicago.edu
Hudoba
Christine
C
Snider
Kelly L
KL
Ratain
Mark J
MJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D004526:Efficiency; D006801:Humans; D008495:Medical Oncology / Q000379:methods* / Q000706:statistics & numerical data; D009369:Neoplasms / Q000188:drug therapy* / Q000453:epidemiology; D011643:Publishing; D016896:Treatment Outcome