(Chest. 2004;125:123S-127S.)
© 2004
American College of Chest Physicians
Human Lung Cancer Chemoprevention Strategies*
Parker B. Francis Lecture
Gilbert S. Omenn, MD, PhD
* From the University of Michigan, Ann Arbor, MI.
Correspondence to: Gilbert S. Omenn, MD, PhD, Professor of Internal Medicine, Human Genetics, and Public Health, A510C MSRB I, University of Michigan, Ann Arbor, MI, 48109-0656; e-mail: gomenn{at}umich.edu
 |
Abstract
|
|---|
Pharmacologic or nutritional prevention of lung cancers is needed, especially for 60 million Americans who are former smokers. A portfolio of large-scale trials of beta-carotene, beta-carotene with and without vitamin E, and beta-carotene plus vitamin A demonstrated no benefit whatsoever from beta-carotene. The 
-Tocopherol/ß-Carotene Trial and the ß-Carotene and Retinol Efficacy Trial found significant increases in lung cancer risk and total mortality. Laboratory research soon identified multiple adverse molecular effects. Nevertheless, chemoprevention remains an active, promising strategy, with new hypotheses and new candidate agents, including many already approved as therapies. The most active area currently is focused on selective inhibition of arachidonic metabolism, both Cox-2 and Lox pathways.
Key Words: arachidonic acid pathways • beta-carotene • chemoprevention • lung cancer
|
Introduction
|
|---|
The American Cancer Society estimates that 172,000 new cases of lung cancer will be diagnosed this year, accounting for 13% of 1.3 million new cancer cases expected (not including carcinomas in situ, except for urinary bladder, or basal and squamous cell cancers of the skin).1 Although the lung cancer incidence rate declined in men from 102 per 100,000 in 1984 to 81 per 100,000 in 1999, the rate in women continued to increase during most of that period before plateauing in 1997–1998 at 52 per 100,000. Regrettably, the 5-year survival for patients with lung cancers remains at approximately 15%, essentially the same as 40 years ago. The American Cancer Society estimates 157,000 deaths for 2003, accounting for 28% of all cancer mortality and 6% of all deaths. Lung cancers are by far the leading cancer causes of death in both men and women. Lung cancer has exceeded breast cancer as the leading cancer cause of death in women since 1987, a fact not well known among women and many health professionals.
One strategy for improving outcomes is earlier diagnosis. Cases diagnosed when the tumor is still localized in the lung have considerably better outcomes; Surveillance, Epidemiology, and End Results data2 suggest 48% 5-year survival with stage 1 cases. Even localized stage 1 adenocarcinomas can be separated into good survival and poor survival subsets with gene-expression profiles. After decades of disappointment with periodic chest radiographs or sputum cytology, there is renewed interest in early diagnosis with spiral CT in the National Lung Cancer Screening Trial with 50,000 high-risk individuals. Panels of biomarkers, which we and others are developing with proteomics methods using serum or plasma, may lead to cost-effective combinations of markers and imaging. Furthermore, the many advances in understanding mechanisms of carcinogenesis may yield new agents for therapy and for prevention, targeted not only at receptors and signaling pathways in neoplastic cells, but also at stromal, fibroblastic, endothelial, or inflammatory cells that are critical components of tumors.3 This article reviews experience gained during the past 20 years with chemoprevention strategies for lung cancers, notes the current portfolio of studies, and concludes with a hopeful focus on newer strategies.
|
The Emergence of Chemoprevention Experiments and Clinical Trials in the 1980s
|
|---|
Sporn et al4 introduced the term chemoprevention in 1976 with retinoids as compelling candidates based on striking evidence in animals that these vitamin A analogues diminished cell proliferation, favored cell differentiation, and notably reduced tumor yields even when administered up to many weeks after exposure to potent carcinogens. In 1981, Peto et al5 brought together sufficient evidence of the potential cancer-preventing benefits of beta-carotene to stimulate direct tests of the hypothesis through randomized clinical trials in human populations. The timing was propitious, as the US National Cancer Institute (NCI) had begun to focus on prevention, to complement its basic biology, early detection, and treatment research programs. Doll and Peto6 also published a now-classic analysis of preventable causes of cancers, deducing that approximately 30% were attributable to cigarette smoking, 35% to multiple other categories of exposures (infectious agents, alcohol, environmental pollution, occupational, geophysical), and the rest, very roughly 35%, to unspecified factors in diets. They stimulated a search for explanations—both favorable and adverse—for the striking differences, especially in migrant populations, attributed to dietary factors. As Peto et al5 wrote, "The possibility that discovering anti-cancer substances that can be prescribed, rather than carcinogens that must be proscribed, is attractive, for more people may be willing to accept prescription than proscription." We know from public health measures of many kinds that people resent or reject being told what not to do. Particularly attractive would be agents that inhibit late stages of the multistage carcinogenic processes, since the benefits could be observable within 5 to 10 years, instead of after a 30- to 40-year latent period if the mechanism depended on interference with the initiation of carcinogenesis.7
Chemoprevention against lung cancers was dominated throughout the 1980s and 1990s by a portfolio of large-scale trials of beta-carotene, beta-carotene with and without vitamin E, and beta-carotene plus vitamin A, plus multiple smaller studies with retinoids. These protocols were based on substantial in vitro and limited animal research supporting the hypotheses that antioxidants might retard late-stage tumor progression, and retinoids would reduce cell proliferation. There was ample observational epidemiologic evidence of the association of higher intake of beta-carotene (or fruits and vegetables) and of higher circulating levels of beta-carotene with lower risk of lung cancers and other epithelial cancers. It was time to put these associations to the test with randomized clinical trials. Animal and cell culture studies provided strong support for a pharmacologic effect, not just overcoming a deficiency state.7 Deciding whether beta-carotene or retinol/retinoids should be the primary candidate for prevention trials and at what doses was speculative.
The results of the randomized clinical trials were stunning. The -Tocopherol/ß-Carotene (ATBC) trial of 29,133 Finnish male smokers, the ß-Carotene and Retinol Efficacy Trial (CARET) of 14,254 male and female heavy smokers and 4,060 men occupationally exposed to asbestos, and the Physicians Health Study (PHS) of 22,071 male US physicians all demonstrated no benefit whatsoever from beta-carotene, either alone or in combination.89101112 The two more informative trials—the ATBC trial and CARET, with 10 times higher lung cancer incidence rates than in the PHS—demonstrated significant increases in lung cancer risk, along with higher risks of cardiovascular and total mortality (Table 1
).13 In the ATBC trial, vitamin E also had no benefit on lung cancer risks. The response to the ATBC trial results in 1994 was muted, due to disbelief and continued reliance on the observational epidemiology. However, when the findings were confirmed by the CARET in January 1996, the widely reported results were immediately applied by stopping addition of beta-carotene in cereals and in many, but not all, multivitamins (within the CARET, 606 participants [3%] decided to stop their capsules, equally divided between the two arms of the trial, in response to our notification on the eve of the ATBC trial publication).
Stimulated by these clinical trials findings, laboratory researchers soon identified a broad array of molecular responses that may account for the adverse effects. These include formation of epoxides and ketones of beta-carotene in oxidizing environments (probably including the lung), which enhance BaP-DNA adduct formation in vitro; increases in c-jun, c-fos, and activator protein 1 (AP-1) levels in smoke-exposed ferrets (which accumulate quite high levels of beta-carotene in serum); and increases in ornithine decarboxylase and cell proliferation in rodents.141516 Other beta-carotene prevention trials also showed no benefit against skin or colon cancer risk or in sputum cytology of long-time asbestos workers.7 Beta-carotene was removed from the Women’s Health Study after 2 years. Meanwhile, 13-cis-retinoic acid was shown to reduce incidence of second primaries in patients with head and neck cancer,17 but no clinically useful, well-tolerated retinoid has emerged in the years since.18 Various agents to prevent second primaries or recurrences have failed as well.19
In retrospect, beta-carotene is not such a potent antioxidant, and it has multiple other actions. "Synthetic" beta-carotene is equivalent with "natural" beta-carotene. Even observational studies20 have been inconsistent. In sum, beta-carotene should be regulated as a human carcinogen.
The clinical trials ought to be seen as representing a triumph of the scientific process rather than a failure of therapy. We now know that ß carotene supplements are not an effective means of lowering the risk of cancer... No one should discount the importance of epidemiologic studies of diet and chronic disease. Persons who eat a relatively large quantity of vegetables, fruits, and grains have a profoundly lower risk of death, particularly from cardiovascular disease and cancer.21
"Take any new reports of disease-preventing vitamins with a grain of salt. When this is all sorted out, it could turn out that we will all have to take 50 or 60 different nutrients to get a real benefit. ‘That’s a possibility’, says Goodman, of the Hutchinson Cancer Research Center. ‘It’s called broccoli!’"22
|
The NCI Chemoprevention Drug Development Program
|
|---|
A multifaceted preclinical and early phase clinical program, complementing the clinical trials, was launched at the NCI. By 1994, a summary listed the following promising agents, by class of effect: (1) blocking carcinogens, (2) antioxidants, and (3) antiproliferation/anti-progression agents (Table 2
).
Currently, the NCI Division of Cancer Prevention Web site lists 44 projects related to lung cancers: - Phase 3 randomized clinical trials: SELECT, testing selenium and vitamin E (primarily against prostate cancer, lung cancer secondary) and follow-up of PHS, Women’s Health Study, and Nutritional Prevention of Cancer trial.
- Phase 1 and 2 randomized clinical trials of isothiocyanates; selenium/oxidant stress; Cox-2 and 5-LOX inhibitors, retinoids and combinations; search for biomarkers and surrogate end points across histologic progression of airway dysplasia and neoplasia (P50s); 9-cis or 13-cis retinoic acid plus vitamin E in former smokers; celecoxib in former smokers; aerosolized retinoids or doxorubicin.
- Epidemiology studies: carotenoids (CARET), selenium (selenium and lung cancer risk in asbestos workers: E. Gottschall, University of Colorado, Denver, CO), plus many biomarker studies.
- In vitro studies, using strains A, BALB/c, transgenic mice; F344 rat; human bronchial epithelium and other cell lines, and/or patient biopsies: curcumin (GST5.8); retinoid signaling (retinoic acid receptor [RAR] and retinoid X receptor [RXR] responses); inhaled retinoids; retinoid induction of IGF-BP6; butylated hydroxyanisole (BHA) induction of phase 2; myo-inositol, epigallocatechin-3-gallate (EGCG), isotretinoin, lovostatin after smoke exposure; budesonide, farnesyl transferase inhibitor; isothiocyanates/myo-inositol; smoke and EGCG on nuclear factor-kB; tea/EGCG on arachidonic acid pathways, AP-1, body fat; Cox/Lox/GPCR peptidomimetic compounds; non-small cell lung cancer overexpression of ErbB1, ErbB2, Her2/neu; genotoxicity of commonly used drugs; freeze-dried berries/resveratrol; phenyl propanoids, flavonoids/catechins (EGCG and ellagic acid).
Many of these studies pursue promising molecular targets.23 An interesting preclinical result involves the combination of aerosolized glucocorticoids and oral myoinositol.24
|
Selenium
|
|---|
The Nutritional Prevention of Cancer trial enrolled 1,312 individuals with previous skin cancers; there was no benefit in prevention of skin cancers. However, incidental findings included a hazard ratio (HR) for lung cancer of 0.56 (CI = 0.31–1.01), based on only 17 cases vs 31 cases.25 A follow-up publication26 had an HR of 0.74 (CI = 0.44–1.24, p = 0.26), with 25 cases vs 35 cases in the control vs selenium arms. The cases were 16 vs 25 in current smokers, 7 vs 10 in former smokers; HRs 0.42, 0.91, and 1.25 for lowest, middle, and highest tertiles of plasma selenium respectively. There was sufficient evidence for lower prostate cancer incidence, combined with an observational study showing inverse association of selenium with prostate cancer, to launch SELECT, the Selenium and Vitamin E Cancer Prevention Trial testing L-selenomethionine with and without vitamin E (the vitamin E based on secondary findings in the ATBC trial) in 32,000 men > 12 years old.18
There are many uncertainties about the most appropriate form of selenium to ensure a safe, yet effective dose and the most relevant mechanisms. Selenium increases apoptosis; both inorganic and organic selenium compounds inhibit Cox-2; organic selenium compounds inhibit methylation. Glutathione peroxidase is often used to monitor selenium sufficiency, but 98% of Americans have plasma selenium > 90 ng/mL, which is known to be sufficient to maximize glutathione peroxidase activity; and there are many other selenoproteins.
|
Retinoids and Rexinoids
|
|---|
Renewed interest in retinoids is based on extensive knowledge about the molecular features of RAR and RXR receptor biology and molecular pharmacology.27 RAR-ß down-regulation or mutation is an early event in lung cancers, suggesting a tumor suppressor role. Histone deacetylation inhibition can reactivate RAR-ß. 9-cis-retinoic acid, docosahexanenoic acid, and other compounds are RXR agonists. Currently, targretin, which predominantly activates RXR receptors, is used in a biomarker modulation trial with pretreatment and posttreatment biopsy specimens in women at high risk for breast cancer.18 These compounds may be good in combination with cytotoxic agents.27
|
Optimism About the Future for Chemoprevention of Lung Cancers
|
|---|
Chemoprevention remains a promising strategy, with new hypotheses and new candidate agents coming to the fore. Among these, the most active area currently is focused on selective inhibition of arachidonic metabolism, both the inducible cyclo-oxygenase (Cox-2) pathway to prostaglandins and thromboxanes and the 12-, 5-, and 8-lipoxygenase (Lox) pathways to leukotrienes and hydroeicosatetraenoic acids. Many agents, including several developed and approved by the FDA for use in patients with arthritis or asthma, have shown efficacy in cell culture, animal models, and early clinical trials, especially in the colon.182829 Cox-2 is up-regulated in carcinomas of the lung. Cox-2 inhibitors may have chemopreventive benefits through direct inhibition of Cox-2, with its many effector systems; reversing these effects makes inhibitors antiangiogenic, antiproliferative, antioxidants, apoptotic, and immunomodulatory. Lipoxygenase inhibitors work on targets with very similar effects. Other articles in this issue will address these promising targets.
Other molecular targets have been highlighted by Willis and Colburn30:
- Genes with altered expression or activity causally related to carcinogenesis, with inhibitors commercially available: Ras mutations/raf kinase I (RKI), integrin-linked kinase, matrilysin (matrix metalloproteinase-7) [three disappointing trials so far with matrix metalloproteinase inhibitors].
- Gene targets with causal relationship but no specific drug yet (p27, protein kinase C-delta, AP-1).
- Causal significance uncertain but drugs available: insulin-like growth factor.
- Known or uncertain targets for dietary components without commercial drugs: monoterpenes, isothiocyanates, myo-inositol (inositol hexaphosphate, IP6), vitamins E, C, selenium, RXR-selective retinoids/rexinoids; isoflavones; curcumin in curry, phytosterols in soybeans, polyphenols in green tea, resveratrol in berries.
|
Strategic Conclusions for Chemoprevention of Lung Cancers
|
|---|
Lung cancer incidence is rising globally. Several key observations can provide useful guidance for future chemoprevention studies: - Drugs developed for therapy have major advantages for chemopreventive drug development, because mechanisms may be known, the toxicology profile has satisfied the FDA, and experience in large clinical populations has accumulated.
- Lung cancers are highly heterogeneous: identify subgroups, expect differing responses; exploit agents which may be effective against more than one organ-site tumor, based on common mechanism.31
- Be skeptical of claims of "effects" from observational epidemiologic studies, when these studies only generate clues from "associations"; differences in diet, for example, may be confounded by many other differences between people who eat 5 to 10 servings of fruits and vegetables per day and those who eat none (extreme quartiles or quintiles).
- Agents effective against other cancers should be tested against lung cancers, especially if there is a mechanistic tie; trials can have multiple end points.
- Many targets are in other cells than the tumor cells themselves: inflammatory, endothelial, or stromal cells.
- Validated molecular markers and surrogate end points are essential to take the many chemopreventive candidates into population trials, once preclinical evidence is sufficient.
- All agents must be suspected of multiple effects, including adverse effects; beware focusing only on one convenient effect (the "lightpost problem").
Investment in chemoprevention can be justified by the potential impact and the wealth of promising findings and candidate agents.
|
Footnotes
|
|---|
Abbreviations: AP-1 = activator protein 1; ATBC = -Tocopherol/ß-Carotene; CARET = ß-Carotene and Retinol Efficacy Trial; EGCG = epigallocatechin-3-gallate; HR = hazard ratio; NCI = National Cancer Institute; PHS = Physicians Health Study; RAR = retinoic acid receptor; RXR = retinoid X receptor
|
References
|
|---|
- . American Cancer Society (2003) Cancer facts and figures 2003 American Cancer Society. Atlanta, GA:
- Beer, DG, Kardia, SLR, Huang, C-C, et al Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 2002;8,816-824[ISI][Medline]
- Hanahan, D, Weinberg, RA The hallmarks of cancer. Cell 2000;100,57-70[CrossRef][ISI][Medline]
- Sporn, MB, Dunlop, NM, Newton, DL, et al Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs [retinoids]. Fed Proc 1976;35,1332-1338[ISI][Medline]
- Peto, R, Doll, R, Buckley, JD, et al Can dietary beta-carotene materially reduce human cancer rates? Nature 1981;290,201-208[CrossRef][Medline]
- Doll, R, Peto, R The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981;66,1193-1308
- Omenn, GS Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health 1998;19,73-99[CrossRef][ISI][Medline]
- Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330,1029-1035[Abstract/Free Full Text]
- Albanes, D, Heinonen, OP, Taylor, PR, et al Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: effects of baseline characteristics and study compliance. J Natl Cancer Inst 1996;88,1560-1570[Abstract/Free Full Text]
- Omenn, GS, Goodman, GE, Thornquist, M, et al Effects of a combination of beta-carotene and vitamin A on lung cancer incidence, total mortality, and cardiovascular mortality in smokers and asbestos-exposed workers. N Engl J Med 1996;334,1150-1155[Abstract/Free Full Text]
- Omenn, GS, Goodman, GE, Thornquist, M, et al Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. J Natl Cancer Inst 1996;88,1550-1559[Abstract/Free Full Text]
- Hennekens, CH, Buring, JE, Manson, JE, et al Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334,1145-1149[Abstract/Free Full Text]
- Van Zandwijk, N, Pastorino, U Chemoprevention of lung cancer: soon daily practice? Expert Rev Anticancer Ther 2003;3,91-98[CrossRef][Medline]
- Salgo, MG, Cueto, R, Winston, GW, et al Beta carotene and its oxidation products have different effects on microsome mediated binding of benzo[a]pyrene to DNA. Free Radic Biol Med 1999;26,162-173[CrossRef][ISI][Medline]
- Liu, C, Wang, X-D, Bronson, RT, et al Effects of physiological versus pharmacological beta-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets. Carcinogenesis 2000;21,2245-2253[Abstract/Free Full Text]
- Lee, BM, Park, K-K Beneficial and adverse effects of chemopreventive agents. Mutat Res 2003;523–524,265-278
- Papadimitrakopoulou, VA, Hong, WK, Lee, JS, et al Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: long-term follow-up. J Natl Cancer Inst 1997;89,257-258[Free Full Text]
- Greenwald, P Cancer prevention clinical trials. J Clin Oncol 2002;20,14s-22s[Abstract/Free Full Text]
- Kelley, MJ, McCrory, DDC Prevention of lung cancer: summary of published evidence. Chest 2003;123,50S-59S[Medline]
- Epstein, KR The role of carotenoids on the risk of lung cancer. Semin Oncol 2003;30,86-93[CrossRef][ISI][Medline]
- Greenberg, ER, Sporn, MB Antioxidant vitamins, cancer, and cardiovascular disease. N Engl J Med 1996;334,1189-1190[Free Full Text]
- Ross, PE Spinach in a pill. Forbes 1996;4,354-355
- Kelloff, GJ, Boone, CW, Steele, VE, et al Mechanistic considerations in chemopreventive drug development. J Cell Biochem Suppl 1994;20,1-24[Medline]
- Wattenberg, LW, Wiedmann, TS, Estensen, RD, et al Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis 2000;21,179-182[Abstract/Free Full Text]
- Clark, LC, Combs, GF, Jr, Turnbull, BW, et al Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA 1996;276,1957-1963[Abstract]
- Reid, ME, Duffield-Lillico, AJ, Garland, L, et al Selenium supplementation and lung cancer incidence: an update of the Nutritional Prevention of Cancer Trial. Cancer Epidemiol Biomarkers Prev 2002;11,1285-1291[Abstract/Free Full Text]
- Zusi, FC, Lorenzi, MV, Vivat-Hannah, V Selective retinoids and rexinoids in cancer therapy and chemoprevention. Drug Discov Today 2002;7,1165-1174[CrossRef][ISI][Medline]
- Subbaramaiah, K, Dannenberg, AJ Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 2003;24,96-102[CrossRef][Medline]
- Steele, VE, Hawk, ET, Viner, JL, et al Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer. Mutat Res 2003;523–524,137-144
- Willis, DB, Colburn, NH Molecular targets for cancer prevention: a meeting review of the Third American Cancer Society-Schilling Research Conference. Cancer Epidemiol Biomarkers Prev 2002;11,972-978[Abstract/Free Full Text]
- Omenn, GS, Motulsky, AG Integration of pharmacogenomics into medical practice. Rothstein, MA eds. Pharmacogenomics: social, ethical, and clinical dimensions 2003,137-162 John Wiley & Sons. New York, NY:
TOP
Abstract
Introduction
