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© 1999 American Society for Clinical Oncology
National Cancer Institute–Supported Cancer Chemoprevention Research: Coming of AgeFrom the Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN; and Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center,Houston, TX. Address reprint requests to Worta McCaskill-Stevens, MD, Division ofCancer Prevention, National Cancer Institute, 6130 Executive Blvd, Rm 300, Bethesda, MD 20892; email wm57{at}nih.gov SEVERAL SUCCESSFULLY completed, large, clinical cancer chemoprevention trials have raised awareness of this important cancer control approach, which provides abundant opportunities for participation of clinical investigators from various disciplines. Although not always easily distinguished from chemotherapy, chemoprevention is defined, at its simplest, as the pharmacologic prevention of cancer by either preventing or treating premalignant lesions.1,2 The scope of the National Cancer Institute (NCI) chemoprevention program comprises all aspects of chemopreventive agent research and development—discovery, efficacy and potency evaluation, safety and pharmacokinetics assessment, strategic planning (eg, identification of patient populations, protocol design, market potential, and cost-benefit), and clinical investigation in phase III trials. Currently, more than 400 agents and agent combinations are being evaluated for chemopreventive potential in tests funded by the Division of Cancer Prevention (DCP) of the NCI. More than 40 of the most promising of these agents are now in clinical trials. The clinical trial network of the NCI includes the Cooperative Group Program, the Cancer Center Program, and the Community Clinical Oncology Program (CCOP). CCOPs were developed in 1983 to provide support, through a cooperative agreement, for the expansion of cancer treatment clinical research into the community setting (Fig 1). In 1986, the program expanded its focus to include cancer prevention and control. Advocated by the general public for decades, the strategy of preventing clinically significant cancer has been implemented by the CCOPs within broad-based populations. Recruiting hundreds or thousands of relatively healthy prevention participants presents complex challenges (vastly different from recruiting/enrolling onto therapy trials) that the CCOPs have met successfully. Major CCOP prevention-trial contributions, comprising diverse community elements, are critical to establishing prevention research and practices within broad-based, large populations (Fig 1, legend).
The organizational structure of the DCP provides support for NCI extramural research in cancer prevention and for career training and development (Fig 2). This structure also supports the coordination of community-based clinical research and the dissemination of prevention practices through a consortium of community clinical and academic centers. Understanding the NCI organizational structure, including the role of the clinical trial network, can provide leads for investigators interested in identifying opportunities to participate in the cancer chemoprevention research program that is summarized below.
RANDOMIZED CANCER CHEMOPREVENTION TRIALS The relatively brief history of cancer chemoprevention encompasses a solid cohort of randomized trials that have successfully addressed many important clinical questions.1,2 Currently, there are three major categories of randomized cancer chemoprevention trials: phase III trials (cancer end point), phase IIb trials (premalignancy end point), and translational models.
Large-Scale Phase III Chemoprevention Trials
Ten of the 12 definitive phase III trials were supported by the NCI and form the backbone of a solid record of NCI-sponsored phase III accomplishments. This record is due in no small part to contributions from the national cooperative oncology trials groups, such as the National Surgical Adjuvant Breast and Bowel Project (NSABP) (Table 1) and the Southwest Oncology Group.
Several large-scale phase III trials have proved the feasibility of accruing to and conducting prevention trials within the NCI-sponsored program of research. Two excellent examples of this success are the NSABP P-1, or Breast Cancer Prevention Trial (BCPT), and the Prostate Cancer Prevention Trial (PCPT). These two trials anchor the NCI's parallel trials programs in breast and prostate primary cancer prevention. Conducted by the NSABP, the BCPT successfully accrued and randomized 13,388 women14 and was forerunner to the recently activated phase III Study of Tamoxifen and Raloxifene (designed for 22,000 women). The NSABP B-24 (tamoxifen in ductal carcinoma-in-situ [DCIS] patients) is another completed, large, phase III trial in breast cancer prevention and accrued and randomized 1,804 patients.13 The Southwest Oncology Group is coordinating the ongoing NCI Intergroup PCPT, which has successfully completed accrual and randomization of 18,882 men (within 3 years, on schedule) and is forerunner to the planned Selenium and Vitamin E Chemoprevention Trial to prevent prostate cancer (designed for 32,400 men). Planned accrual has been completed in two other recent NCI Intergroup trials designed to study preventing second primary tumors associated with either the lung or head and neck cancer15,16; both of these trials are spearheaded by the M.D. Anderson Cancer Center CCOP research base. The NSABP P-1 BCPT. The BCPT was a rigorously designed, multicenter trial with an outstanding infrastructure for recruitment. It provided proof of principle of the NCI cooperative group mechanism for cancer prevention trials, as well as for the chemoprevention approach, ie, that a human cancer can be prevented with a pharmacologic intervention.
The BCPT compared tamoxifen with placebo in preventing breast cancer in 13,388 women at high risk of this disease.14 An aspect of the BCPT with tremendous implications for future chemoprevention research is the close relationship between the rationale for the BCPT's endocrine hypothesis and the trial's final outcome. This rationale had its unique and compelling basis in two areas: (1) secondary analyses of large, phase III, adjuvant studies and (2) the target-specific molecular biology of tamoxifen. No previously completed, phase III, large-scale study has depended on either type of rationale.2 The major high-risk criteria required for BCPT eligibility included age (either At a median follow-up of 54.6 months, respective invasive breast cancer figures for the tamoxifen and placebo groups were as follows: 89 v 175 (49% relative reduction); average annual rates of 3.43 v 6.76 per 1,000 women; and absolute 5-year risk reductions of 1.3% v 2.6%. The relative breast cancer risk reduction was similar for all age groups. Tamoxifen's protective effect was limited to estrogen receptor–positive tumors (Table 1). The relative risk reduction of invasive breast cancer was 56% or 86% for women with a history of LCIS (826 women) or atypical hyperplasia (1,193 women), respectively. Tamoxifen achieved a 50% reduction (35 v 69 cases) in noninvasive breast cancers (DCIS and LCIS). Tamoxifen nonsignificantly reduced overall mortality (19%) and the number of breast cancer deaths (three in the tamoxifen group v six in the placebo group). Beneficial secondary BCPT findings included 19% fewer total fractures in the tamoxifen group. The two major secondary adverse findings associated with tamoxifen were increased numbers of endometrial cancers (36 in the tamoxifen group v 15 in the placebo group; risk ratio [RR] = 2.53) and vascular events (110 in the tamoxifen group v 77 in the placebo group, significant only for pulmonary embolism; RR, 3.01). Tamoxifen increased the risk of cataracts (RR, 1.14; 95% confidence interval [CI], 1.01 to 1.29) and hot flashes (81% overall, 18% severe). Neutral secondary BCPT findings included coronary heart disease and depression. Although testing of the BCPT's primary hypothesis was completed successfully, several key unresolved issues remained, such as the effects on mortality, optimal tamoxifen duration, generalizability of results, and the issue of prevention versus treatment. The United States Food and Drug Administration (FDA) and the American Society of Clinical Oncology now recommend tamoxifen for breast cancer risk reduction in high-risk women.17,18 The FDA recommends 20 mg/d for 5 years for high-risk women (defined in terms of risk required for BCPT eligibility) and warns of tamoxifen-associated risks. Somewhat surprisingly, the FDA also approved and recommended tamoxifen for reducing the incidence of contralateral breast cancers, on the basis of consistent secondary adjuvant data, such as that from the NSABP B-14 trial.19,20 Adverse effects make the use of tamoxifen a complex, highly individualized decision for high-risk women, complicated even further by subjective, but important, patient appraisals of fears and concerns. In general terms, however, three rules of thumb point toward an improved tamoxifen risk-to-benefit ratio: (1) higher breast cancer risk (at any age); (2) lower age (at any breast cancer risk); and (3) hysterectomy (at any breast cancer risk of women > 50 years old). DCIS: NSABP B-24. The NSABP B-24 tested 5 years of tamoxifen (20 mg/d; n = 902) versus placebo (n = 902) as adjuvant therapy after resection and radiation in patients with DCIS.13 At 74 months' median follow-up, 5-year incidences of all breast cancer events (invasive and noninvasive) were 8.2% and 13.4% in the tamoxifen and placebo groups, respectively, representing a 37% relative and 5.2% absolute risk reduction (P = .0009; Table 1). The tamoxifen-associated reductions (v placebo) with respect to all ipsilateral and all contralateral cancers were 30% (P = .04) and 52% (P = .01), respectively. The cumulative incidence at 5 years of all invasive breast cancer events in the tamoxifen group was 4.1% compared with 7.2% in the placebo group, representing a 43% relative and a 3.1% absolute risk reduction (P = .004). European tamoxifen breast cancer prevention trials. Two smaller, negative European (Italian and British) tamoxifen breast cancer prevention trials underscore unsettled issues of tamoxifen use in breast cancer prevention.6,12 The major way both trials differed from the BCPT was in having much lower study powers. With 13,388 women and 368 breast cancer events, the BCPT had approximately two times the sample size and three times the number of events of both European trials combined. Each trial also had individual differences from the BCPT. The key differences in the British trial were a population of younger age, stronger family history of breast cancer, and concurrent use of hormone replacement therapy (26%). The key differences in the Italian trial were a relatively low-risk population (48% had had bilateral oophorectomies), poor compliance (26% dropped out, most in the first year), and premature closure to accrual. Beta-carotene studies. The two significant negative (harmful) trials were the Beta-Carotene and Retinol Efficacy Trial (CARET)3 and the Alpha-Tocopherol Beta-Carotene (ATBC) trial.4 The overall findings of these two trials, with a combined total of over 47,000 subjects, indicate that beta-carotene (20 mg/d in the former trial and 30 mg/d plus retinol 25,000 IU/d in the latter trial) increases lung cancer risk in smokers and asbestos-exposed individuals. No trial, including the Physicians' Health Study (PHS),11 indicates that beta-carotene increases lung cancer risk in people who never smoked or former smokers. These beta-carotene lung data are consistent with recent mechanistic and animal data.21,22 With their definitive beta-carotene results, the ATBC trial and CARET emphasize the necessity of rigorous clinical testing to confirm or refute positive epidemiologic studies.23 Provocative secondary cancer and mortality end point results. There have been 13 negative (neutral) outcomes of definitive, large-scale, phase III cancer chemoprevention trials (Fig 3). A small group of negative trials, including a trial of selenium in the skin,5 the Linxian (China) General Population Trial,8 and the ATBC trial,4 had positive secondary analyses. Other hypothesis-generating phase III trials discussed below (adjuvant tamoxifen trials20 and the Multiple Outcomes of Raloxifene Evaluation [MORE] trial24) are special cases, since they did not have primary cancer prevention end points. Whereas secondary analyses are appropriate for hypothesis generation, they are insufficient for definitive testing, as they raise the statistical issue of multiplicity, eg, increased type I error (false-positive) rates.2,25 Positive secondary findings of negative/neutral cancer chemoprevention trials include the findings of the Linxian trial,8 which show that selenium (50 µg/d in a yeast supplement), beta-carotene (15 mg/d), and alpha-tocopherol (30 mg/d) were associated with lower rates of total mortality (RR, 0.91; 95% CI, 0.84 to 0.99), gastric cancer mortality (RR, 0.79; 95% CI, 0.64 to 0.99), and all-cancer mortality (RR, 0.87; 95% CI, 0.75 to 1.00). In the skin study,5 selenium (200µg/d in brewer's yeast) achieved significant secondary results in reducing the incidences of prostate cancer (RR, 0.37; 95% CI, 0.18 to 0.71), lung cancer (RR, 0.54; 95% CI, 0.3 to 0.98), and colon cancer (RR, 0.42; 95% CI, 0.18 to 0.95) and total cancer mortality (RR, 0.50; 95% CI, 0.31 to 0.80). Positive secondary findings of the ATBC trial were significant reductions in the incidence and mortality of prostate cancer of 32% and 41%, respectively, in subjects receiving alpha-tocopherol (50 mg/d).26 Secondary negative findings include a nonsignificantly 23% higher incidence of prostate cancer in ATBC subjects receiving beta-carotene.26 Randomized and observational PHS analyses indicated that aspirin use was not associated with the incidence of colorectal cancer.27 Special cases of secondary findings include the adjuvant trials of tamoxifen for preventing breast cancer recurrence, which provided the strong rationale for the NSABP P-1 and B-24. The worldwide overview of the Early Breast Cancer Trialists' Cooperative Group (which included > 36,000 early-stage breast cancer patients)20 reported that the subset of 7,427 women on about 5 years of adjuvant tamoxifen had a 47% reduced incidence of contralateral breast cancer (93 v 159 events; P < .00001). The MORE trial has provided strong rationale supporting raloxifene in the Study of Tamoxifen and Raloxifene.24 MORE involved 7,705 postmenopausal, osteoporotic women randomized to receive 3 years of raloxifene (two arms; 60 or 120 mg/d) or placebo. At a median follow-up of 40 months, 40 invasive breast cancers were found (13 in the raloxifene group and 27 in the placebo group; RR, 0.24; 95% CI, 0.13 to 0.44; P < .001). Risk reduction was significant only for estrogen receptor–positive tumors. There was no significant difference in the incidence of noninvasive breast cancer (seven cases in the raloxifene group and five in the placebo group). There was a total of 10 endometrial cancers (raloxifene group: RR, 0.80; 95% CI, 0.2 to 2.7). There was a significant increase in raloxifene-associated vascular events (RR, 3.1; 95% CI, 1.5 to 6.2).
Randomized (Phase IIb) Chemoprevention Trials
Translational Randomized Chemoprevention Trials NCI CHEMOPREVENTIVE AGENT DISCOVERY AND DEVELOPMENT PROGRAM
Mechanistic Studies Most often, agents not previously tested in the NCI's DCP program will be put first into mechanistic assays to determine their potential range of chemopreventive activities43 (antimutagenicity, antiproliferation, and antioxidation). Examples of those in the early stages of investigation are inhibitors of cell cyclins, telomerase, and angiogenesis; peroxisome proliferator-activated receptor agonists; and retinoid X receptor–activating retinoids and cyclooxygenase-2 inhibitors, which showed promise in earlier studies. Structure-activity analyses have shown promise for optimizing some of these leads (eg, involving retinoid and oltipraz analogs). Application of recent technologies, such as combinatorial chemistry, should also contribute to the design of chemopreventive agents. Indeed, gene-based agents such as ONYX-015, which selectively induce apoptosis in cells that have lost normal p53 function, are demonstrating the power of mechanism-based interventions in preventive settings.44 Gene delivery techniques will likely play a significant role in prevention as well.45
Drugs Developed for Other Uses
Preclinical Studies Cell culture/organ culture assays. Cell/organ culture assays measure (1) inhibition of benzo(a)pyrene (B(a)P)-induced morphologic transformation in rat tracheal epithelial cells, (2) inhibition of anchorage independence in human lung tumor (A427) cells, (3) inhibition of 7,12-dimethylbenz(a)anthracene (DMBA)-induced hyperplastic nodule formation in mouse mammary organ cultures (MMOCs), (4) inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced cell transformation in mouse JB6 epidermal cells, and (5) propane sultone–induced calcium tolerance in human foreskin cells. The first three assays—rat tracheal epithelial, A427, and MMOCs—are being used now. Initial criteria for selecting the in vitro assays included (1) efficiency in terms of time and cost, (2) sensitivity and ease of quantitation, (3) controlled test conditions, (4) relevance to organ systems of interest, (5) use of epithelial cells, and (5) if possible, use of human cells. The three current in vitro assays all use epithelial cells. The human lung tumor A427 cell assay primarily detects agents that block postinitiation stages of carcinogenesis, whereas the MMOC can detect both antimutagens and antiproliferatives, depending on the treatment condition (eg, with DMBA alone or with DMBA and TPA). In each assay, the agents are tested over a wide range of concentrations, and 50% inhibitory concentrations are determined. More recently, the in vitro efficacy program has been expanded in order to incorporate new cell and organ culture technologies and newer information on genetic susceptibility to cancer. For example, the use of raft cultures, which allow evaluation of stromal-epithelial interactions, cells from transgenic mice, and cells from subjects carrying known cancer-predisposing genes (eg, Li-Fraumeni syndrome, APC mutations) are being explored. Animals with carcinogen-induced tumors. The carcinogen-induced tumor models currently used most frequently for efficacy screening include azoxymethane-induced rat colon aberrant crypt foci and tumors, DMBA- and N'-methyl-N-nitrosourea–induced rat mammary tumors, B(a)P-induced rat lung tumors, and N-butyl-N-(4-hydroxybutyl)nitrosamine–induced mouse urinary bladder tumors.46 Agents are usually assigned first to colon and mammary gland models for screening. Often, the bioavailability of the test agents is not well known, and activity of poorly absorbed agents is most likely to be detected in the colon. Also, as noted above, the aberrant crypt foci assay is short term and, therefore, efficient compared with the other assays, because the end point is an intermediate biomarker rather than colon cancer. The mammary gland assays are well established and seem to detect a wide spectrum of classes of chemopreventive agents. This model also produces preliminary results relatively quickly; because the tumors are palpable, tumor incidence and multiplicity may be estimated before histopathologic analysis. Certain carcinogen-induced models (eg, NSAIDs/colon [consistent with human sulindac/FAP] and tamoxifen/breast) seem to predict effects in humans. The NCI's current DCP program is also evaluating new assay systems, including new target organs (eg, the prostate, esophagus, pancreas, lymphoma, and brain), carcinogens (eg, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the colon), target, and specific classes of agents (eg, prostaglandin synthesis inhibitors in the colon). Transgenic and gene knockout mice. The evaluation of chemopreventive efficacy benefits from targeted research using animal models that mimic specific characteristics of human carcinogenesis. Transgenic and gene knockout mice that carry well-characterized genetic lesions that predispose to carcinogenesis are appropriate models. For example, mice with multiple intestinal neoplasia and other strains that carry lesions in the Apc gene may be the best-developed models.47,48 Mice with multiple intestinal neoplasia have an Apc mutation qualitatively similar to that in human FAP patients which predisposes the mice to developing colorectal adenomas and carcinomas. Jacoby et al49 have found a strong correlation between inhibition of prostaglandin synthesis and adenoma formation in this strain. Also, an HPV-infected (K14-HPV16 heterozygote), estradiol-treated mouse is showing development of cervical squamous carcinomas that result from progression of cervical intraepithelial neoplasia–like lesions.50 Closer approximations to human carcinogenesis may be possible by development of tissue-specific inducible models and by manipulation of two or more carcinogenesis-associated genes in a single animal. For example, it might be feasible to knock out p53 in an animal that already carries another tumor suppressor defect (eg, Apc or p16). A key contribution to future development of such animal models will be identification of specific cancer-related genes (eg, in the Cancer Gene Anatomy Project) that can be applied to the construction of animal models for evaluating chemopreventive efficacy. Carcinogen-induced transgenic and gene knockout mice. The treatment of transgenic and gene knockout mice with carcinogens may prove to be particularly effective as a strategy for modeling human carcinogenesis at specific cancer targets. For example, the NCI's program is evaluating chemopreventive effects of various agents in p53 mutant and gene knockout mice also treated with carcinogens (eg, B(a)P or N-nitrosonornicotine to induce lung tumors, or dimethylhydrazine to induce colon tumors). Epidemiologic studies. Dietary studies (eg, vitamins, trace minerals, curcumin, soy isoflavones, tea compounds, lycopene, selenium, and garlic), drug-use surveys (eg, aspirin and lovastatin), genetic predisposition (eg, genetic polymorphisms in carcinogen-metabolizing enzymes), and occupational and behavioral studies (eg, smoking and exercise) have all suggested use of agents that are being confirmed in preclinical studies and are being further developed in the clinic. For example, tea polyphenol extracts have undergone extensive NCI-funded testing in the colon and esophagus; standardized preparations of curcumin and soy isoflavones (eg, genistein and daidzein) are in clinical safety testing. The preparation and characterization of optimal standardized mixtures and purification of the active substance are challenges for the development of dietary components. The effort to confirm dietary leads is expected to burgeon over the next few years. For example, the FDA will soon publish guidelines for the identification and evaluation of heterogenous botanicals, such as the tea and isoflavone mixtures, and the number of publications on the chemopreventive effects of characterized dietary components is increasing (eg, tea polyphenols, curcuminoids, selenized garlic/selenomethylcysteine, and broccoli compounds such as sulforaphan).51-53 It is expected that the increasing level of sophistication in the analysis of epidemiologic data will lead to many more new chemopreventive hypotheses regarding dietary components.
NCI Funding Mechanisms for Agent Discovery and Development NCI-sponsored cancer chemoprevention research proceeds robustly on all fronts—from preclinical and clinical to translational phase I, II, and III studies—and, as graphically illustrated by Fig 3, has come of age. Crowned by the positive tamoxifen findings of the BCPT, phase III trials have produced a remarkable record of definitive results for shaping public health policy and recommendations. Although recently focused on tamoxifen in breast cancer prevention, attention was focused not long ago on the ATBC, CARET and PHS, but for very different reasons. These trials (with a total of 70,000 subjects) shocked researchers and the public alike in establishing that beta-carotene was neutral at best and harmful for smokers, in respect to lung cancer risk. Positive and negative phase III definitive trials have been invaluable in evaluating agents for broad-based community cancer prevention. The BCPT and other phase III tamoxifen trials justify the NCI's continued support for large-scale phase III trials. Relatively small phase II trials assessing translational end points (with a recent focus on molecular targets)57 also are an important part of this program. Smaller-scale translational/mechanistic research can strengthen the biologic bases for initiating large phase III trials. Also, the smaller trials can help in developing SEBs for definitive agent testing.58 Promising current directions of the NCI drug discovery/development program include novel gene-based agent and preclinical model development (Table 2). Phase II and III studies can incorporate translational elements. Biorepositories of the large phase III trials facilitate innumerable studiesof correlative SEBs/risk markers, eg, BRCA1/2 studies in the BCPT will benefit from that trial's large population.
Implications of the BCPT and other positive tamoxifen/breast cancer prevention studies are profound for women's health, as well as for the entire field of chemoprevention. Although the BCPT has raised widespread debate on tamoxifen issues of substantial associated risks, it nevertheless has provided proof of the principle of chemoprevention, proving once and for all that chemoprevention can control the incidence of cancer in humans.
ACKNOWLEDGMENTS The authors acknowledge the helpful discussions with Leslie Ford, MD, Associate Director of Clinical Research, and Lori Minasian, MD, Chief, Community Oncology and Prevention Trial Research Group, Division of Cancer Prevention, National Cancer Institute. NOTES Supported by grant no. 35267 (to Metro-Minnesota CCOP) and United States Public Health Service grant no. CA16672 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services (to M.D. Anderson Cancer Center). S.M.L. holds the Margaret and Ben Love Professorship in Clinical Cancer Care. REFERENCES 1. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol12:851-873, 1994[Abstract]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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1,000). These design elements contribute to the ability of a trial to achieve either a statistically significant definitive result (positive/protective or negative/harmful) or a definitive neutral result.
