Clinical trials of cancer prevention

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

The design of prevention trials in normal people is parallel to but significantly different from classical cancer therapeutic trials. For example, during the trials of tamoxifen given as an adjuvant therapy in early breast cancer, it was observed that the incidence of second primary breast cancer in the contralateral breast was lower in women treated with tamoxifen than in those with placebo. This led to the hypothesis that tamoxifen might be a cancer-preventive agent as well a cancer therapy.

There followed a series of trials leading to the landmark publication of the Breast Cancer Prevention Trial (BCPT ) in 1998, which showed that tamoxifen could reduce by half the number of breast cancers observed in women at high risk. However, in two additional trials in different patient populations, no proven benefit was observed.

There remains controversy as to how effective this agent is, and in which healthy women it should be prescribed.

These trials have highlighted problems inherent in chemoprevention studies:

  • Which healthy individuals should be invited to participate in such trials or be offered therapy off study?
  • How should these individuals be identified and contacted?
  • When should the drug be started and for how long should it be continued?
  • Side effects that are quite acceptable in cancer patients may be unacceptable in healthy subjects.
  • If chronic exposure can produce serious illness even rarely, the agent may be unsuitable for chemoprevention (e.g., tamoxifen rarely causes endometrial cancer).

Phase I/II clinical trials

The main objective of early clinical trials of chemopreventive agents is to establish tolerability and side effects of candidate compounds. One major difference from conventional cytotoxic agents is that the duration of administration of the preventive agent will be much longer than for a cytotoxic one, so chronic side effects are at least as important as acute side effects. For phase I studies:

  • A major side effect would include either fatality or problems requiring intervention by a physician or long-term disability.
  • Major side effects would automatically rule out any further development of chemopreventive agents.
  • Minor side effects may preclude chronic dosing with the agent.
  • The route of administration is usually oral, although inhalation and topical modalities are also of interest in some cancers.

A phase II trial will frequently be of longer duration and may have more than one dose level.

  • It may be randomized with a placebo control to clarify toxicities and provide preliminary evidence of efficacy through measurement of an intermediate risk biomarker, if one has been validated for the disease under study.
  • A crucial component in assessment of the agent at this stage is compliance, which may require pharmacokinetic confirmation.
  • Duration may be six months to five years, and the sample size typically ranges from 50 to more than 1000 volunteers or potential patients.

The use of surrogate end points is extremely important for cost-efficient studies, although there are few biomarkers that are of proven value (e.g., development of carcinoma in situ or other precancerous lesion).

Ease of recruitment is important because “high risk” may be clear to a physician but not so clear to a normal individual.

Phase III clinical trials

Randomized placebo-controlled phase III studies of chemopreventive agents need to be large and lengthy because diagnosis of cancer is a relatively rare event. Because it is costly (in terms of time and resources) to test each new agent with the classical phase III design, two solutions are being tested:

  • One is the concentration on high-risk groups of individuals.
  • The other is the development of intermediate biomarkers.


Chemoprevention is in its infancy. New methodologies are being evaluated, and new surrogate end points and novel candidate interventions are emerging rapidly from the revolution in molecular biology and genetics.

It is an extremely promising and exciting branch of oncology.


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