Chemoprevention to save our lives

CS20-03 A 17th century physician, Thomas Adams, said, "Prevention is better than healing because it saves the labor of being sick." A major fallacy is that you are healthy until you get cancer. Unfortunately, everyone is subject to DNA mutation and methylation. No body is "perfectly healthy." In fact, if the average latent period from the first initiated cancer cell to death from cancer is 20 years, than approximately 11 million Americans alive today, and supposedly healthy, will die of cancer (based on an expected 570,000 deaths per year). It is well documented that cancer is a multi-step process from the first initiated cell through mild, moderate and severe dysplasia to carcinoma in situ and invasive and metastatic cancer. This process, variably can take up to 20-30 years to complete for the common solid cancers, providing innumerable opportunities to intercede with early detection and prevention strategies. For example, intraepithelial neoplasias, such as colorectal adenomas and ductal carcinoma in situ in the breast, can be identified in up to 10% of the population at 50 years of age. These potentially dangerous precancerous lesions can be eradicated surgically or with chemopreventive drugs, vaccines and/or nutrients. In 1976, Michael Sporn defined chemoprevention as, "The use of specific agents to reverse, suppress or prevent the carcinogenic process to invasive cancer." Since the 1970s, great headway has been made in the development of meaningful chemopreventive strategies for breast, cervix, colon, prostate, and non-melanoma skin cancers, although the ideal chemopreventive agent(s) requires continued, intensive research. Before proceeding into large scale chemopreventive agent trials, it is essential to define the mechanism of action of an agent, assure minimal to no clinical toxicity, and for orally administered agents, obtain high bioavailability. The requirements for initiation of large scale phase III trials of chemopreventive agents must be strict, and include: 1. strong data supporting mechanistic activity; 2. strong epidemiologic data, if considering a nutrient drug; 3. strong preclinical efficacy data in appropriate models; and 4. safety and efficacy in phase IIb clinical trials (i.e. randomized, double blinded, placebo controlled trials). Mandatory phase III chemoprevention trial design features include: 1. a hypothesis based on agent mechanism, epidemiologic data and strong preclinical efficacy; 2. a population at relatively high-risk, assuring adequate numbers of events; 3. intermediate and longer term endpoint evaluations, 4. well-defined primary and secondary analyses; and 5. critical tissue banking to allow for hypothesis-driven translational research, leading to fundamental understanding of chemopreventive agent mechanisms. When we don9t fully understand the mechanisms by which a chemopreventive agent works and/or have not performed well-designed phase I, IIa and IIb clinical trials, the results of phase III trials may be surprising. For example, a relatively high dose beta-carotene intervention in heavy smokers in the alpha-tocopherol/beta-carotene (i.e. ATBC trial) and CARET (i.e. beta-carotene and retinol trial) phase III clinical trials resulted in highly significant, 9% and 17% increases in lung cancer specific mortality rates, respectively. What likely went wrong in these extremely large clinical trials is well described in a 1984 Science publication (Science 224:569-573, 1984) by Burton and Ingold, wherein they stated, "At higher oxygen levels, beta-carotene loses its antioxidant activity and shows an autocatalytic, pro-oxidant effect, particularly at relatively high concentrations. Similar oxygen-pressure dependent behavior may be shown by other compounds containing many conjugated double bonds." Like all areas of oncology, the entire field of chemoprevention is a "work in progress;" however, as the positive results continue to add up, the public health significance of our work multiplies, lending credence to Thomas Adams9 original acclamation that, "Prevention is better than healing because it saves the labor of being sick."