Cancer Chemoprevention: Successes and Failures Mini-Reviews
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Clinical Chemistry 59:1 94–101 (2013) Mini-Reviews Cancer Chemoprevention: Successes and Failures Sherri L. Patterson,1 Karen Colbert Maresso,1 and Ernest Hawk1* BACKGROUND: Cancer has traditionally been considered chemopreventive agents holds tremendous potential a single disease, but it is now known to be far more for reducing the burden of cancer. complex, with an unfolding etiology. In less than 2 cen- © 2012 American Association for Clinical Chemistry turies, hundreds—if not thousands—of drugs for the treatment of cancer and for palliative care have been developed and tested, with 143 having achieved ap- Stated in the simplest of terms, cancer is the dysregu- proval by the US Food and Drug Administration (Medi- lated proliferation of cells. Causative factors include Lexicon International; “Cancer Drugs & Oncology environmental exposures (e.g., asbestos, ultraviolet ra- Drugs,” http://www.medilexicon.com/drugs-list/cancer. diation), lifestyle choices (tobacco, obesity, physical in- php). Just 13 agents have been approved, however, for activity), infectious agents [e.g., human papillomavirus treating precancerous lesions or for reducing risk. (HPV),2 HIV, hepatitis B virus, Helicobacter pylori], and inherited conditions and mutations [e.g., familial CONTENT: Nonsteroidal antiinflammatory drugs, vita- adenomatous polyposis (FAP), hereditary nonpolypo- 3 mins, food constituents and spice components, antidi- sis colorectal cancer, and the BRCA1 (breast cancer 1, abetic drugs, -3 fatty acids, and fiber are just a few of early onset), and BRCA2 (breast cancer 2, early onset) the many classes of compounds that have been tested genes]. The term “chemoprevention,” the inhibition or reversal of the carcinogenic process through the use of for their cancer-preventive potential. We highlight drugs or other compounds, became part of the cancer some of the agents that have been scrutinized by way of lexicon in the latter half of the 20th century (1). Until randomized clinical trials in humans for their cancer then, most efforts to abate the disease were aimed at prevention potential. We summarize the major defin- surgical, radiologic, or chemotherapeutic interven- itive cancer chemoprevention studies that (a) were suc- tions. With its refined insights into early disease patho- cessful in demonstrating efficacy and ultimately re- genesis, new risk models, successful risk assessments, ceived regulatory approval; (b) were not successful in and enhanced screening modalities, translational sci- demonstrating efficacy or had unacceptable toxicities, ence is leading medicine from disease treatment based but from which the field has learned important lessons; on symptoms and loss of normal function to disease and (c) showed compelling efficacy against surrogate prevention based on cellular and molecular insights. end points but failed to achieve regulatory approval because of a lack of consensus regarding the relevance Critical Decisions in the Design of Clinical of those end points to clinical benefit. Prevention Trials SUMMARY: Chemopreventive studies have provided Before providing any meaningful discussion of the suc- new insights into early disease pathogenesis, stimulated cesses and failures in cancer prevention trials, it is im- new risk assessments and models, fostered important portant to briefly review the most critical elements in research in end point biomarkers, and led to 13 ap- trial design, because these elements markedly influence proved agents. The development of safe and effective 2 Nonstandard abbreviations: HPV, human papillomavirus; FAP, familial adeno- matous polyposis; AK, actinic keratosis; PCPT, Prostate Cancer Prevention Trial; SELECT, Selenium and Vitamin E Cancer Prevention Trial; BCPT, Breast Cancer 1 Division of Cancer Prevention and Population Sciences, University of Texas MD Prevention Trial; CARET, Beta-Carotene and Retinol Efficacy Trial; ATBC, Alpha- Anderson Cancer Center, Houston, TX. Tocopherol, Beta-Carotene Cancer Prevention (trial); NSAID, nonsteroidal anti- * Address correspondence to this author at: Division of Cancer Prevention and inflammatory drug; FDA, US Food and Drug Administration; STAR, Study of Population Sciences, University of Texas MD Anderson Cancer Center, 1515 Tamoxifen against Raloxifene; SERM, selective estrogen receptor–modulating Holcombe Blvd., Unit 1370, Houston, TX 77030. Fax 713-792-0629; e-mail agent; BCG, bacille Calmette–Gue´rin; DFMO, ␣-difluoromethylornithine [email protected]. (eflornithine). Received August 6, 2012; accepted October 8, 2012. 3 Human genes: BRCA1, breast cancer 1, early onset; BRCA2, breast cancer 2, Previously published online at DOI: 10.1373/clinchem.2012.185389 early onset. 94 Cancer Chemoprevention: Successes and Failures Mini-Reviews the ultimate success or failure of a trial. Although the ing frequency and route, attendant risks, and accept- goals in the design of chemoprevention trials are not able toxicities are broader in the therapeutic setting unlike those for therapeutic oncology drugs—i.e., than in the prevention setting. build a scientific premise, establish efficacy, explore and/or confirm safety, and achieve regulatory approval— END POINTS AND ACHIEVING REGULATORY APPROVAL the distinctions to be made between these 2 types of Chemoprevention trials are governed by the same reg- trials are important. ulatory rigor assigned to all clinical studies in humans, but the definition of “clinical benefit” remains a topic COHORTS of some debate. The US Food and Drug Administra- Unlike treatment trials based on patients with a con- tion (FDA) drug-approval standards for therapeutic firmed diagnosis of cancer, prevention trials are oncology agents include reduction in mortality, im- most often conducted with asymptomatic, ostensibly provement in survival, efficacy against an established healthy individuals, therefore necessitating extra vigi- surrogate end point, or, for accelerated approval, effi- lance to avoid harm. Cohorts in prevention trials are cacy against a “reasonably likely” surrogate end point typically stratified into 2 main groups: those consid- (5). The end points or efficacy indicators in cancer pre- ered to be at average risk and those at increased risk vention studies often rely on biomarkers that serve as owing to a genetic predisposition, a personal history of surrogates, and although such short-term impacts as cancer, or evidence of preneoplastic lesions [e.g., colo- reduction in the size and number of colorectal adeno- rectal adenomas or actinic keratosis (AK)]. Trials based mas can be measured, long-term benefits or harms of on average-risk cohorts include the Prostate Cancer an intervention can remain unknown for years. Acces- Prevention Trial (PCPT) and the Selenium and Vita- sibility to the target organ(s) remains an important de- min E Cancer Prevention Trial (SELECT), both of Ն terminant in trial design as well. An assessment of the which enrolled men 50 years of age with normal re- end points in trials that have led to the approval of sults in the digital rectal examination and the prostate- preventive agents reveals that nearly all of the agents specific antigen test. Examples of trials based on have been approved for the treatment of intraepithelial increased-risk cohorts include the landmark Breast neoplasia, particularly in accessible organs, rather than Cancer Prevention Trial (BCPT), which enrolled for cancer prevention per se. women with a Gail model score Ͼ1.67 [indicating a In addition to the choices of cohort, agent(s), and higher risk for breast cancer compared with the average end point, there are a host of other issues that affect woman (2)], and the CARET (Beta-Carotene and Ret- cancer chemoprevention trials, including their high inol Efficacy Trial) and ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) trials in lung cancer costs, difficulties in identifying and recruiting partici- prevention, which enrolled smokers and workers ex- pants, and limited interest and investment from pharma- posed to asbestos (3, 4). The choice of cohort can sub- ceutical companies to develop new agents. Nevertheless, stantially influence the outcome of a trial by affecting 13 agents have achieved regulatory approval for treating timelines, statistical power, and adherence. Studies of precancers or for cancer prevention (Table 1). higher-risk cohorts typically offer more power over a Chemoprevention is a rapidly emerging field fu- shorter time frame, and individuals at increased risk for eled by great promise, but the field is also tempered by a disease are often more tolerant of side effects and have unanticipated disappointments. We outline some of more motivation to adhere to a given intervention. the major successes, as well as studies that demon- strated null or negative results. Of course, negative or AGENTS null trials are not failures, because they have been in- In the context of chemoprevention, “agents” have in- valuable in refining our knowledge and providing crit- cluded nonsteroidal antiinflammatory drugs (NSAIDs) ical information to inform future endeavors in the field (e.g., aspirin, sulindac, celecoxib), vitamins and their of cancer chemoprevention. derivatives (e.g., retinoids, selenium, vitamin E), min- erals (e.g., calcium), and plant extracts (e.g., wheat Demonstrating Efficacy and Achieving Regulatory bran fiber, tea catechins, flavonoids, berry extracts, Approval—Examples of Success curcumin). Before an agent or a combination of agents can be considered for testing in human clinical trials for