Related Experiment Videos
Criteria for implementation of large and multiagent clinical chemoprevention trials
1Department of Medicine and Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine, Orange 92868, USA. FLMeyske@UCI.edu
Abstract:
If one were to wait for the perfect set of experimental results before launching a multi-agent chemoprevention or large risk reduction study, the trial would never be launched. On the other hand, non-scientific considerations have led to the premature launching of at least three prominent studies (CARET, Carotene and Retinol Efficacy Trial; ATBC, Apha Tocopherol Beta Carotene; PCPT, Prostate Cancer Prevention Trial) and the much delayed start-up of another, BCPT, the Breast Cancer Prevention Trial. Strong epidemiologic data by itself should not be adequate to justify starting a large trial; experimental and/or clinical data should be developed. On the other hand fear of secondary adverse events that are of low incidence should not be enough to delay a trial if the overall health benefit could be high. The development of multiagent chemoprevention trials requires that each agent is active and additively or synergistically so in combination in preclinical models. Additionally, side effects of each agent should be non-overlapping and low to non-existent, preferably a feature determined in formal phase IIa and IIb trials. These principles will be discussed in the context of prior (CARET, ATBC) and ongoing (EUROSCAN, acetylcysteine/retinol), as well as proposed future trials (difluromethyl/sulindac).
Insights
Launching chemoprevention trials requires balancing evidence with potential benefits. Preclinical data and non-overlapping side effects are crucial for successful risk reduction studies.
Area of Science:
- Oncology
- Preventive Medicine
- Clinical Trial Design
Background:
- Launching large-scale chemoprevention trials necessitates careful consideration of scientific evidence and potential risks.
- Past trials like CARET (Carotene and Retinol Efficacy Trial) and ATBC (Alpha Tocopherol Beta Carotene) highlight challenges in trial initiation.
- Strong epidemiological data alone may not suffice; preclinical and clinical evidence are vital for justifying large trials.
Purpose of the Study:
- To establish principles for developing multi-agent chemoprevention trials.
- To guide the initiation of risk reduction studies by evaluating the balance between scientific data and non-scientific factors.
- To discuss the criteria for selecting agents and designing effective chemoprevention studies.
Main Methods:
- Review of principles for multi-agent chemoprevention trial development.
- Analysis of past, ongoing, and proposed chemoprevention trials (e.g., CARET, ATBC, BCPT, EUROSCAN, acetylcysteine/retinol, difluromethyl/sulindac).
- Discussion of the importance of preclinical efficacy (additive/synergistic effects) and non-overlapping, low-incidence side effects.
Main Results:
- Premature trial launches (e.g., CARET, ATBC, PCPT) and delayed starts (e.g., BCPT) underscore the need for robust scientific justification.
- Fear of rare adverse events should not impede trials with high potential overall health benefits.
- Effective multi-agent chemoprevention requires agents with proven preclinical activity and manageable side effect profiles.
Conclusions:
- Multi-agent chemoprevention trials should be initiated based on a combination of strong preclinical and clinical data, not solely epidemiology.
- Agent selection criteria include demonstrated additive or synergistic activity in preclinical models and minimal, non-overlapping toxicity.
- Formal Phase IIa and IIb trials are essential for characterizing agent safety and informing the design of larger risk reduction studies.