Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Cancer Chemoprevention: A review of ongoing clinical studies A. Costa, G. Santoro & G. Assimakopoulos To cite this article: A. Costa, G. Santoro & G. Assimakopoulos (1990) Cancer Chemoprevention: A review of ongoing clinical studies, Acta Oncologica, 29:5, 657-663, DOI: 10.3109/02841869009090071 To link to this article: https://doi.org/10.3109/02841869009090071
Published online: 08 Jul 2009.
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Reviews in Oncology 3 (1990) No. 2 (in Acta Oncologica Vol. 29, Fax. 5)
FROM THE ISTITUTO NAZIONALE TUMORI, MILAN, ITALY.
CANCER CHEMOPREVENTION A review of ongoing clinical studies A. COSTA,G . SANTOROand G . ASSIMAKOPOULOS
Abstract The mass of experimental data on various possibilities of inhibiting the carcinogenic process is growing rapidly. However, the biological complexity of carcinogenesis and the intrinsic limitations of the animal models make it often very difficult to identify the real potentially effective agents among the hundreds currently being proposed. In fact, more than 600 potentially chemopreventive agents have been identified and approximately 30 of them are presently being tested in humans. The great heterogeneity of these compounds (they belong to over 20 different classes of chemicals) might be a positive feature as it indicates that a variety of approaches is possible and that the options for selecting effective compounds will be numerous. In recent years, what could be called ‘clinical chemoprevention’ (that is controlled studies to evaluate in human subjects the efficacy of potentially chemopreventive agents) has developed considerably: according to American estimates 4 chemopreventive agents were tested clinically in 1981, 10 in 1985 and 18 in 1988. The number of reported preclinical investigations was 10 in 1985 and 75 in 1988. This rapid expansion has obviously led to some confusion in terminology and in the evaluation of primary results; at present there is still a need for further investigations to better define clinical chemoprevention and to differentiate it from chemotherapy. Key words: Cancer, chemoprevention, vitamins, selenium, antioxidants, carotenoids, indoles, alkaloids, retinoids, hormones.
Chemoprevention of tumours is increasingly attracting attention among oncologists but it is still far from having reached an established ‘status’ in cancer medicine. Experimental data on various possibilities of inhibiting the carcinogenic process are growing rapidly. Moreover, the biological complexity of carcinogenesis and the intrinsic limitations of animal models often makes it very difficult to identify the real potentially effective agents among the hundreds, currently being proposed. The application of in vitro screening systems will certainly improve the selection process in the future and, at the same time, animal models will be used mainly to delineate organ and site specificity.
New tests will probably help identify population at risk and new guidelines (methodological, statistical, pharmacological) will increase the scientific consistency of what could be called ‘clinical chemoprevention’. In the end controlled clinical trials in humans will always be needed to evaluate the efficacy of defined chemical compounds in preventing the onset of cancer. Clinical chemoprevention faces the problem of administering agents over a long period of time to relatively healthy groups of individuals: for this reason, acute and chronic toxicity must be more than just acceptable, medication must be easy to be taken, the intervention should not be expensive and the follow-up schedule not too heavy. Costs of chemoprevention trials are very high due to the heavy commitment of personnel and the drug supply: it has been reported (1) that the pharmaceutical industry provides agents at no cost for ongoing trials in the US at a value of nearly 5 million dollars per year. Drug companies are often somewhat reluctant to invest in this field of cancer medicine since results are expected to come very late and due to the possible risk of chronic toxicity. The rationale behind the hypothesis of chemoprevention of tumours is rather empirical and quite simple: as thousands of chemical substances found in the environment can induce and/or promote cancer in humans, why should not other compounds, able to inhibit carcinogenesis, exist as well? In fact, the originally proposed definition of chemoprevention (2), strictly refers to the prevention of cancer by the use of pharmacological agents to inhibit or reverse the process of carcinogenesis. This concept differs from that of cancer prevention in general, which refers more to the removal or avoidance of factors such as fat, tobacco or UV radiation, the exposure to which is positively correlated with a risk of cancer (3). It is important to stress that chemoprevention constantly 657
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refers to cancer as an evolving molecular and cellular process: the disease being carcinogenesis not cancer (4). From this point of view, patients with ‘preneoplastic’ or ‘premalignant’ lesions are affected with a disease which is often undetectable and not treatable with conventional therapies, but which certainly has a statisically significant probability of progressing to a lethal endpoint, unless effective preventive treatment is developed. Chemoprevention therefore focusses on the biological importance of tumour promotion and progression as well as on the potent, intrinsic mechanisms by which the tissue disorganisation caused by spontaneous mutation, carcinogens, or promoting agents can be overcome particularly in epithelia (5).
Chemopreventive compounds More than 600 potentially chemopreventive agents have been identified and approximately 30 of them are presently being tested in humans (6). The great heterogeneity of these compounds (they belong to over 20 different classes of chemicals) might be a positive feature as it indicates that a variety of approaches is possible and that the options for selecting effective compounds will be numerous. Chemopreventive agents can be classified according to their mechanism into two broad categories (7) i.e. compounds effective against complete carcinogens and compounds effective against tumour promoters. Some compounds belong to both categories. The inhibitors of carcinogen-induced tumours can be further divided into three major groups according to their different mechanisms of action. The first includes agents which interfere with the metabolic reactions changing precursor compounds into carcinogens. The second comprises agents capable of preventing carcinogens from reaching or reacting with target sites, such as by scavenging the reactive form of carcinogens. The third group includes molecules whose inhibitory action follows exposure to carcinogenic agents and which, for this reason, are called suppressing agents. The preventive activity of tumour promotion inhibitors has been tested mainly in models of epidermal mouse neoplasia induced by topical administration of TPA. Modulators of calcium metabolism, polyamines and cyclic nucleotides strictly refer to this group, whereas other chemical classes (such as retinoids, phenols and protease inhibitors) also inhibit carcinogen-induced tumours. Another classification of chemopreventive compounds, according to their localization in the human environment, has been proposed in 1987 by the Division of Cancer Prevention and Control of the US National Cancer Institute (Table 1). In the following short paragraphs attention will be focussed mainly on chemopreventive agents which have been shown to have a potential clinical application in
Table 1 Potential tumour chemopreventive agents by localization in human environmenl Groups
Compounds
1 Micronutrients
Vitamin A, C, E Selenium, calcium, zinc
2 Intentional food additives
Antioxidants
3 Non-nutritive food molecules
Carotenoids Coumarins lndoles Alkaloids
4 Industrial reagents
Photographic developers Herbicides UV light protectors
5 Pharmaceutical agents
Retinoids Nonsteroideal anti-inflammatories Anti-thrombogenic agents Anti-prostaglandins
6 Hormones and anti-hormones
Dehydroepiandrosterone Tamoxifen
(from DCPC, NCI, NIH 1987 modified)
humans and on compounds whose mechanism of action is rather well known and therefore can be of help for a better understanding of the carcinogenic and anti-carcinogenic processes.
Ascorbic acid and tocopherols
Experimental studies have demonstrated that ascorbic acid or vitamin C can inhibit the formation of nitroso compounds both in vitro and in vivo (8). Moreover, in epidemiological studies of diet in relation to gastric cancer, the most constant finding has been the negative association with intake of fresh fruit and vegetables, suggesting that vitamin C could contribute to the protective action. Alpha-tocopherol, or vitamin E (9), has also been shown to inhibit formation of nitroso compounds (7). Protective effects of vitamin E against radiation-induced DNA damage and mutation and dimethylhydrazineinduced carcinogenesis have also been observed.
Phenols
When administered prior to or at the time of carcinogen exposure, the phenolic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are effective inhibitors of carcinogenesis in several organ systems including the lung, colon, skin, liver and mammary glands of experimental animals.
659
CANCER CHEMOPREVENTION
Zndoks
These compounds occur naturally in a number of edible cruciferous vegetables (Brussels sprouts, cabbage, cauliflower and broccoli) and inhibit formation of tumours in some animal models.
Retinoids
This term includes all natural and synthetic analogues of vitamin A. It has been known from the beginning of this century that retinoids are fundamentally involved in the induction or enhancement of cellular differentiation (10) and that most primary human cancers arise in epithelial tissues which depend upon retinoids for normal cellular differentiation. Two very comprehensive reviews on retinoids were published in 1980 (11) and in 1987 (12). Over the past few years retinoids have been shown to be effective inhibitors of chemical carcinogenesis in skin, mammary gland, oesophagus, respiratory tract, pancreas, and urinary bladder of experimental animals, particularly when administered shortly after the carcinogenic insult. Modification of the basic retinoid structure has produced new molecules with enhanced target organ specificity, resulting in increased inhibitory activity with reduced systemic toxicity. Since the development of cancer is fundamentally a process of loss of cellular differentiation, the chemoprevention of cancer with retinoids represents a physiological rather than cytotoxic approach to arresting or reversing the process of carcinogenesis ( 13).
Nonsteroidal anti-inJammatory agents
The most studied compound of this group is indomethacin, which has been reported to inhibit the induction of tumours in the rat colon, mouse oesophagus, rat mammary gland, mouse skin and methylcholanthrene-induced carcinogenesis in the mouse uterine cervix (2). Hormones and anti-hormones
Hormones of pregnancy are thought to alter the mammary gland so that the epithelial cells are less susceptible to carcinogenic insults and consequently some female sex hormones have been suggested to be involved in mammary carcinogenesis. On the other hand, the potential chemopreventive activity of tamoxifen (inhibition of initiation and growth of DMBA-induced mammary carcinomas) has been presupposed since mid 1970s (15). It has been recently confirmed by experimental animals models ( 16) which may be considered rather similar to the human situation since they are focussed on evaluating the onset of spontaneous tumours rather than chemically-induced neoplasms: when given daily to rats, tamoxifen is shown to reduce the incidence of both mammary fibroadenomas and carcinomas (Figure).
35 40
( N o ) 25 30
2o
f
0 TAMOXIFEN A CONTROL 1 END OF THE TRE4TMfNT
4
1
t SACRIFICE
t
Selenium salts
Together with the retinoids the selenium salts have been extensively studied as suppressing agents and have been found to inhibit a considerable variety of experimental neoplastic systems. Epidemiological data have been interpreted by some investigators as indicating that a low selenium consumption may increase cancer risk in certain human populations (14).
Protease inhibitors
Several studies have indicated that protease inhibitors can be powerful anticarcinogenic agents for animals and cells in culture. Epidemiological data on human population show a negative association between the intake of protease inhibitors (rice, maize, corn, bread, cereals) and the incidence of breast, colon, prostatic, oral and pharyngeal cancers suggesting a protective effects.
0
2
4
6
8
10
12
14
16
18
20
22
Weeks from the start of the exper#rnent
24
26
Mdtoni
28 30 32
u .I..
lW7
Figure. Number of mammary carcinomas in rats treated with tamoxifen and in controls.
Chemoprevention of human tumours In recent years, what could be called ‘clinical chemoprevention’ (i.e. controlled studies to evaluate in human subjects the efficacy of potentially chemopreventive agents) has developed considerably: according to American estimates ( 1) 4 chemopreventive agents were tested clinically in 1981, 10 in 1985 and 18 in 1988. The number of reported preclinical investigations was 10 in 1985 and 75 in 1988. This rapid expansion has obviously led to some confusion in terminology and in the evaluation of primary results; at present there is still a need for a ‘new culture’ to better define clinical chemoprevention and to differentiate it from chemotherapy (Table 2).
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Oral cavity
Table 2 Diflerences between chemotherapy and chemoprevention
Endpoints Target of action Duration Sample size Dosage Toxicity
Chemotherapy
Chemoprevention
Clinical improvement Tumour Months N x lO(0) Maximise (efficacy) Acute
Lack of occurrence Host Years Nx1000 Minimise (safety) Acute/chronic
Prolonged administration of potentially chemopreventive agents is not called ‘treatment’ since the subjects receiving it are by definition at risk of cancer but not affected by it: the appropriate term is ‘intervention’. Intervention studies are controlled clinical trials conducted to evalutate the effectiveness of a given compound to prevent recurrences or new primaries in defined populations. The main target site organs of chemopreventive intervention trials have so far been oral cavity, upper respiratory tract and lung, breast, oesophagus and colon, uterine cervix and skin (Table 3). Table 3 Ongoing chemoprevention intervention studies
Target site organ
Target/risk group
Inhibitory agents
Oral cavity
Oral leukoplakia
Oral cavity Lung Lung Lung Lung Lung Breast Breast Colon
Asian betel nut and tobacco chewers Asbestosis Cigarette smokers Smoking males Asbestos Smokers High risk women Breast cancer patients Familial polyposis
Aromatic retinoid 13-cis, and 4-HPR Beta-carotene, retinol
Colon Colon
Familial polyposis Adenomatous polyps
Colon Liver Cervix Cervix Skin Skin
Adenomatous polyps High risk population Cervical dysplasia Cervical dysplasia Albinos Basal cell carcinoma
Skin Skin Skin
Basal cell carcinoma Actinic keratoses Basal cell carcinoma
Skin Skin
Previous basal cell ca. Head and neck basal cell carcinoma US physicians
All sites
From Malone et al. 1989, modified.
Beta-carotene, retinol Beta-carotene, retinol Beta-carotene Beta-carotene, retinol Beta-carotene Tamoxifen 4-HPR Vitamins C, E, and fiber Calcium Beta-carotene, vitamins C, E Piroxicam Selenium Trans-retinoic acid Folic acid Beta-carotene Beta-carotene, vitamins C, E Beta-carotene Retinol Retinol, 13-cis-retinoic acid Selenium 4-HPR Beta-carotene
Leukoplakia is a fairly frequent precancerous lesion of the oral cavity and is clinically defined as a whitish patch of unknown origin on the mucous membrane. Aromatic retinoids have been tested since 1974 and studies made with more than 120 patients have demonstrated that these drugs may be therapeutically employed (17). The results of an interesting chemoprevention trial sponsored by the National Cancer Institue of Canada were published a few years ago (18) stressing the effectiveness of retinoids in inhibiting the carcinogenic processes in the oral cavity. The population chosen comprised 40 Filipino betel nut and tobacco chewers and the design of the study used a diet supplementation with retinol (100 000 IU/week) and betacarotene (300 000 IU/week): after 3 months of intervention a 3-fold decrease was noted in the frequency of micronuclei in cells scraped from inside the cheek. The number of micronuclei is a measure of chromosome breakage in earlier cell division which is usually increased by carcinogenic stimuli. Encouraging results have been obtained with 13-cis retinoic acid (19). A prospective randomized study is presently being run to evaluate the efficacy of the synthetic retinoid 4-HPR in preventing recurrences, new localizations and carcinomas of oral cavity after C 0 2 laser exeresis of leukoplakia. This analogue of vitamin A, N-(.l-hydroxyphenyl)retinamide, was identified in the late 1970s and shown to be effective in preventing chemically induced mammary cancers in rats (20) and one of the least toxic known retinoids. The tolerability of 4-HPR in humans has proven to be fairly good (21) and its pharmacokinetics, including the relationship with retinol serum levels and RBP, has been recently described (22, 23). Upper respiratory tract and lung
A large cooperative trial, called Euroscan, was recently launched by EORTC to investigate the efficacy of a twoyear intervention with high dose vitamin A and an aminoacid derivative, n-acetylcysteine. The test group are patients already cured of lung or head and neck cancer, who have a 10% to 20% risk of developing a second cancer in the same region within 5 years. A randomized clinical trial was activated at the Milan Tumour Institute in 1985 to evaluate whether retinol palmitate administration after complete resection of stage I non-small cell lung cancer, could reduce the occurrence of cancer relapses and/or the incidence of new primary tumours. Although the difference in disease recurrences failed to reach statistical significance, from the clinical point of view, the data are suggestive of a biological effect of intervention (24). In the US, five studies on lung cancer prevention are presently being conducted with the support of the Chemoprevention Branch of the US National Cancer Institute
CANCER CHEMOPREVENTION
( 1): endpoint of the two trials designed by the University of Texas is the regression of bronchial squamous metaplasia and/or dysplasia following administration of 13-cisretinoic acid in chronic smokers and of beta-carotene and retinol in men exposed to asbestos. In a similar population and with the same chemopreventive agents, the incidence of lung cancer is being evaluated at the University of Washington; the association of beta-carotene and vitamin E is under study at the US National Cancer Institute.
Breast
Despite the great epidemiological importance of breast cancer and the number of experimental studies on mammary carcinogenesis, very few relevant clinical trials are presently being conducted on chemoprevention of these tumours, the main reason being the difficulty of identifying proper high-risk groups in the general population. The capability of tamoxifen to reduce the incidence of contralateral primaries in patients already operated on for one breast cancer has recently been shown (25). To move to the general population the critical problem is identification of the high-risk group who could benefit from a long-term chemopreventive intervention with this drug. One of the first designs which has been proposed for entering a woman into a prevention trial requires the candidate to have three of the following five characteristics: a) nulliparity or first childbirth after age of 28; b) serum SHBG (sex-hormone-binding globulin) levels below the population median; c) Wolfe grades (P2 or DY) at mammography (26); d) family history of breast cancer (mother or sister); e) previous benign ‘fibrocystic’ disease (27). Main limiting factors to a development of this area are potential liver and uterine carcinogenicity of tamoxifen, as it has been suggested by some experimental data, possibly related to the oestrogenic effect of this drug. Chemoprevention pilot trials with very low doses and in hysterectomized women have recently been proposed. Another line of research in breast cancer deals with retinoids. A large randomized clinical trial of breast cancer chemoprevention with 4-HPR has been started by Veronesi et at. at the Milan Tumour Institute in Italy in 1987, with the aim of evaluating the reduction of incidence of contralateral breast cancer in patients already operated on for unilateral lesions. Oesophagus, colon, liver
In contrast to Europe and America where alcohol and tobacco can be related to most oesophageal cancers, the causes of these tumours in China are largely unknown. A random sample of 610 subjects was recently studied in Northern China: half of them received active intervention (retinol, riboflavin and zinc) for 6 months and the other half a placebo. The design of the study included ad-
66 1
ministration of questionnaires on smoking, drinking and dietary habits, and blood samples drawn regurlarly for estimation of riboflavin, retinol, beta-carotene and zinc. Oesophagoscopy with at least two biopsies was also performed in 93% of the participants. No significant difference was reported between the two groups in terms of prevalence of precancerous lesions. However, the investigators stressed that individuals with larger increases in retinol, riboflavin and zinc blood levels were more likely to have a histologically normal oesophagus (28). Two additional studies with beta-carotene and multiple vitamins or minerals are also being conducted at the NCI, Bethesda. Five studies on prevention of colon cancer are now ongoing in the US, the selection factors being either familial polyposis or adenomatous polyps. The studied agents include beta-carotene, vitamin C and E, piroxicam, calcium and fibre. One study combines chemoprevention and diet: one group of participants receives wheat bran along with calcium as part of the intervention. With regard to liver cancer, a study is being conducted with the NCI support on woodchucks to evaluate the efficacy of a Phyllanthus amarus extract in eliminating or decreasing Hepatitis B virus. An intervention trial of primary liver cancer with selenium supplementation is being conducted in more than 20000 subjects at risk by the Chinese Academy of Medical Sciences of Beijing and the Qidong Liver Cancer Institute. Uterine cervix
Participants in chemoprevention studies for cervical cancer are generally selected on the basis of dysplasia on Pap smears. In the US two clinical trials are sponsored by the Chemoprevention Branch of the NCI (6), one involving topical application of retinoids, the other using systemic administration of folic acid. Previous experimental topical treatments of cervical dysplasia with retinoids have failed due to the relatively severe local toxicity, mainly because it is difficult to avoid contact between the drug and the vulvar and vaginal mucosa. Moreover, the complete clinical regression of symptoms is not always associated with histological disappearance of the dysplasia (29). Skin
During the past ten years several retinoids have been used in animals and humans for the treatment and prevention of skin tumours (30). Six studies in skin cancer prevention are presently being supported by the NCI in the US: risk factors used include the presence of previous skin cancers, a precancerous condition (actinic keratosis), or a specific population group at high risk for skin cancer, namely, albinos in equatorial Africa. The spectrum of agents being evaluated
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in these studies includes selenium, beta-carotene ( 3 l), vitamin C and E, retinol and 13-cis-retinoicacid. In Europe, a chemoprevention trial of 4-HPR in basal cell carcinoma of the head and neck is being conducted in Milan with the aim of preventing recurrences and new lesions after radical surgical excision in a region of the body where further surgery would induce irreversible and often unacceptable aesthetic damage. Conclusions
Some of the definitions and criteria of traditional medical oncology (e.g. role of placebo, evaluation of toxicity, etc.) could prove to be not readily adoptable to chemopreventive trials and there is a need for new concepts within this field particularly as far as design of studies, ethics and tolerability are concerned. Sample sizes in clinical chemoprevention are usually great and are generally expressed in terms of thousands of subjects; the duration of intervention and observation may extend for over 10 years; the evaluation of compliance is extremely difficult since there is no verifiable information on participants' adherence to the regimen except pill counting and drug serum concentration testing. Major ethical problems arise when the target population has to be identified in designing a clinical chemoprevention trial and when the investigator is requested to assess the risklbenefit ratio of a medical intervention, the efficacy of which cannot be evaluated without the exposure of large numbers of individuals for a long period of time to a given agent. Tolerability of chemopreventive compounds must of course be extremely high but it is also true that there is no means of knowing in advance the consequences and late effects of long-term administration to humans. When observing the large number of tumours for which chemopreventive agents have been shown to have protective effects in experimental studies it is possible that almost half of all human cancers might ultimately be prevented by chemopreventive interventions. No doubt this goal is worthy of a concerted effort both from the drug industry and scientific institutions. Under these circumstances oncologists and epidemiologists should be extremely careful in designing their studies, considerate of the individuals involved in them and critical in evaluating the results. ACKNOWLEDGEMENT The author is indebted to Dr. Maria Pizzichetta for her support in bibliographic research. Request for reprints: Dr Albert0 Costa, Istituto Nazionale Tumori, Via Venezian, 1, 1-20133 Milan, Italy.
REFERENCES I . Malone WF, Kelloff GJ, Boone C, Nixon DW. Chemoprevention and modern cancer prevention. Prev Med 1989; 18: 2553-6 1.
2. Ramesha Rao A, Hussain SP. Modulation of methylcolantrene-induced carcinogenesis in the uterine cervix of mouse by indomethacin. Cancer Lett 1988; 43: 15-9. 3. Bertram JS, Kolonel LN, Meyskens FJ Jr. Rationale and strategies for chemoprevention of cancer in humans. Cancer Res 1987; 47: 3013-31. 4. Wakefield LM, Sporn MB. Suppression of carcinogenesis: a role for TGF-beta and related molecules in prevention of cancer. In: Klein G, ed. Tumor suppressor genes. New York: Dekker Inc, 1990. 5. Pierce GB, Speers WC. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation. Cancer Res 1988; 48: 1996-2004. 6. Malone WF, Kelloff GJ, Pierson H, Greenwald P. Chemoprevention of bladder cancer. Cancer 1987; 60:650-7. 7. Wattemberg LW. Chemoprevention of cancer. Cancer Res 1985; 45: 1-8. 8. Mirvish SS. Inhibition of the formation of carcinogenic Nnitroso compounds by ascorbic acid and other compounds. In: Burchenal JH, Oettgen HF, eds. Cancer achievements, challenges and prospects for the 1980's. New York: Grune and Stratton, 1981: 557-88. 9. Gerber M, Cavallo F, Marubini E, et al. Liposoluble vitamins and lipid parameters in breast cancer. A joint study in Northern Italy and Southern France. Int J Cancer 1988; 42: 489-94. 10. Wolbach SB, Howe PR. Tissue changes following deprivation of fat soluble A vitamin. J Exp Med 1925; 42: 753-77. I f . Lotan R. Effects of vitamin A and its analogues (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 1980; 605: 33-91. 12. Lippman SM, Kessler JF, Meyskens FL Jr. Retinoids as preventive and therapeutic anticancer agents (part I). Cancer Treat Rep 1987; 71: 391-405. 13. Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc 1979; 38: 2528-34. 14. Clark LC. The epidemiology of selenium and cancer. Fed Proc 1985; 44: 422-5. 15. Jordan VC. Effect of tamoxifen (UCU 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer 1976; 1 2 419-24. 16. Maltoni C, Pinto C, Paladini G. Project of experimental bioassays on chemoprevention agents performed at the Bologna Institute of Oncology: report on tamoxifen control of spontaneous mammary tumours on Sprague-Dawley rats. Cancer Invest 1987; 6 59-74. 17. Koch HF. Effects of retinoids on precancerous lesions of oral mucosa. In: Orfanos CE, et al., eds. Retinoids. Berlin: Springer-Verlag 1981: 307-12. 18. Stich HF, Rosin MP, Vallejera MO. Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betel nut and tobacco chewers. Lancet 1984; 2: 1204-6. 19. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986; 315: 1501-5. 20. Moon RC, Thompson HJ, Becci PJ, et al. N-(4-hydroxyphenil) retinamide, a new retinoid for prevention of breast cancer in the rat. Cancer Res 1979; 3 9 1339-46. 21. Costa A, Malone W, Perloff M, et al. Tolerability of the synthetic retinoid Fenretinide (HPR). Eur J Cancer Clin Oncol 1989; 25: 805-8. 22. Peng YM, Dalton WS, Alberts DS, Xu MJ, Lim H, Meyskens FL Jr. Pharmacokinetics of N-4-hydroxyphenil-retinamide and the effect of its oral administration on plasma retinol concentrations in cancer patients. Int J Cancer 1989; 43: 22-6.
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23. Formelli F, Carsana R, Costa A, et al. Plasma retinol level reduction by the synthetic retinoid fenretinide: a one-year follow-up study of breast cancer patients. Cancer Res 1989; 49: 6149-52. 24. Pastorino U, Soresi E, Clerici M, et al. Lung cancer chemoprevention with retinol palmitate. Preliminary data from a randomized trial on stage Ia non small-cell lung cancer. Acta Oncol 1988; 27: 773-82. 25. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptorpositive tumors. N Engl J Med 1989; 320: 479-84. 26. Wolfe JN. Risk for breast cancer development determined by mammographic parenchymal pattern. Cancer 1976; 37: 2486-92. 27. Cuzick J, Wang DY, Bulbrook RD. The prevention of breast cancer. Lancet 1986; 1: 83-8.
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28. Wahrendorf J, Munoz N, Jian-Bang L, Thurnham DI, Crespi M, Bosch FX. Blood, retinol and zinc riboflavin status in relation to precancerous lesions of the oesophagus: findings from a vitamin intervention trial in the People’s Republic of China. Cancer Res 1988; 48: 2280-3. 29. Meyskens FL Jr, Graham V, Chvapil M, Derr RT, Alberts DS, Surwit AE. A phase I trial of beta all-trans-retinoic acid delivered via a collagen sponge and a cervical cap for mild or moderate intraepithelial cervical neoplasia. J Natl Cancer Inst 1983; 71: 921-5. 30. Peck GL. Therapy and prevention of skin cancer. In: Saurat, ed. Retinoids: New trends in research and therapy. Basel: Karger, 1985: 345-54. 31. Greenberg ER, Baron JA, Stevens MM, et al. The skin cancer prevention study: design of a clinical trial of beta-carotene among persons at high risk for nonmelanoma skin cancer. Controlled Clin Trials 1989; 10: 153-66.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Cancer Chemoprevention: A review of ongoing clinical studies A. Costa, G. Santoro & G. Assimakopoulos To cite this article: A. Costa, G. Santoro & G. Assimakopoulos (1990) Cancer Chemoprevention: A review of ongoing clinical studies, Acta Oncologica, 29:5, 657-663, DOI: 10.3109/02841869009090071 To link to this article: https://doi.org/10.3109/02841869009090071
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 57
View related articles
Citing articles: 5 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20
Reviews in Oncology 3 (1990) No. 2 (in Acta Oncologica Vol. 29, Fax. 5)
FROM THE ISTITUTO NAZIONALE TUMORI, MILAN, ITALY.
CANCER CHEMOPREVENTION A review of ongoing clinical studies A. COSTA,G . SANTOROand G . ASSIMAKOPOULOS
Abstract The mass of experimental data on various possibilities of inhibiting the carcinogenic process is growing rapidly. However, the biological complexity of carcinogenesis and the intrinsic limitations of the animal models make it often very difficult to identify the real potentially effective agents among the hundreds currently being proposed. In fact, more than 600 potentially chemopreventive agents have been identified and approximately 30 of them are presently being tested in humans. The great heterogeneity of these compounds (they belong to over 20 different classes of chemicals) might be a positive feature as it indicates that a variety of approaches is possible and that the options for selecting effective compounds will be numerous. In recent years, what could be called ‘clinical chemoprevention’ (that is controlled studies to evaluate in human subjects the efficacy of potentially chemopreventive agents) has developed considerably: according to American estimates 4 chemopreventive agents were tested clinically in 1981, 10 in 1985 and 18 in 1988. The number of reported preclinical investigations was 10 in 1985 and 75 in 1988. This rapid expansion has obviously led to some confusion in terminology and in the evaluation of primary results; at present there is still a need for further investigations to better define clinical chemoprevention and to differentiate it from chemotherapy. Key words: Cancer, chemoprevention, vitamins, selenium, antioxidants, carotenoids, indoles, alkaloids, retinoids, hormones.
Chemoprevention of tumours is increasingly attracting attention among oncologists but it is still far from having reached an established ‘status’ in cancer medicine. Experimental data on various possibilities of inhibiting the carcinogenic process are growing rapidly. Moreover, the biological complexity of carcinogenesis and the intrinsic limitations of animal models often makes it very difficult to identify the real potentially effective agents among the hundreds, currently being proposed. The application of in vitro screening systems will certainly improve the selection process in the future and, at the same time, animal models will be used mainly to delineate organ and site specificity.
New tests will probably help identify population at risk and new guidelines (methodological, statistical, pharmacological) will increase the scientific consistency of what could be called ‘clinical chemoprevention’. In the end controlled clinical trials in humans will always be needed to evaluate the efficacy of defined chemical compounds in preventing the onset of cancer. Clinical chemoprevention faces the problem of administering agents over a long period of time to relatively healthy groups of individuals: for this reason, acute and chronic toxicity must be more than just acceptable, medication must be easy to be taken, the intervention should not be expensive and the follow-up schedule not too heavy. Costs of chemoprevention trials are very high due to the heavy commitment of personnel and the drug supply: it has been reported (1) that the pharmaceutical industry provides agents at no cost for ongoing trials in the US at a value of nearly 5 million dollars per year. Drug companies are often somewhat reluctant to invest in this field of cancer medicine since results are expected to come very late and due to the possible risk of chronic toxicity. The rationale behind the hypothesis of chemoprevention of tumours is rather empirical and quite simple: as thousands of chemical substances found in the environment can induce and/or promote cancer in humans, why should not other compounds, able to inhibit carcinogenesis, exist as well? In fact, the originally proposed definition of chemoprevention (2), strictly refers to the prevention of cancer by the use of pharmacological agents to inhibit or reverse the process of carcinogenesis. This concept differs from that of cancer prevention in general, which refers more to the removal or avoidance of factors such as fat, tobacco or UV radiation, the exposure to which is positively correlated with a risk of cancer (3). It is important to stress that chemoprevention constantly 657
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refers to cancer as an evolving molecular and cellular process: the disease being carcinogenesis not cancer (4). From this point of view, patients with ‘preneoplastic’ or ‘premalignant’ lesions are affected with a disease which is often undetectable and not treatable with conventional therapies, but which certainly has a statisically significant probability of progressing to a lethal endpoint, unless effective preventive treatment is developed. Chemoprevention therefore focusses on the biological importance of tumour promotion and progression as well as on the potent, intrinsic mechanisms by which the tissue disorganisation caused by spontaneous mutation, carcinogens, or promoting agents can be overcome particularly in epithelia (5).
Chemopreventive compounds More than 600 potentially chemopreventive agents have been identified and approximately 30 of them are presently being tested in humans (6). The great heterogeneity of these compounds (they belong to over 20 different classes of chemicals) might be a positive feature as it indicates that a variety of approaches is possible and that the options for selecting effective compounds will be numerous. Chemopreventive agents can be classified according to their mechanism into two broad categories (7) i.e. compounds effective against complete carcinogens and compounds effective against tumour promoters. Some compounds belong to both categories. The inhibitors of carcinogen-induced tumours can be further divided into three major groups according to their different mechanisms of action. The first includes agents which interfere with the metabolic reactions changing precursor compounds into carcinogens. The second comprises agents capable of preventing carcinogens from reaching or reacting with target sites, such as by scavenging the reactive form of carcinogens. The third group includes molecules whose inhibitory action follows exposure to carcinogenic agents and which, for this reason, are called suppressing agents. The preventive activity of tumour promotion inhibitors has been tested mainly in models of epidermal mouse neoplasia induced by topical administration of TPA. Modulators of calcium metabolism, polyamines and cyclic nucleotides strictly refer to this group, whereas other chemical classes (such as retinoids, phenols and protease inhibitors) also inhibit carcinogen-induced tumours. Another classification of chemopreventive compounds, according to their localization in the human environment, has been proposed in 1987 by the Division of Cancer Prevention and Control of the US National Cancer Institute (Table 1). In the following short paragraphs attention will be focussed mainly on chemopreventive agents which have been shown to have a potential clinical application in
Table 1 Potential tumour chemopreventive agents by localization in human environmenl Groups
Compounds
1 Micronutrients
Vitamin A, C, E Selenium, calcium, zinc
2 Intentional food additives
Antioxidants
3 Non-nutritive food molecules
Carotenoids Coumarins lndoles Alkaloids
4 Industrial reagents
Photographic developers Herbicides UV light protectors
5 Pharmaceutical agents
Retinoids Nonsteroideal anti-inflammatories Anti-thrombogenic agents Anti-prostaglandins
6 Hormones and anti-hormones
Dehydroepiandrosterone Tamoxifen
(from DCPC, NCI, NIH 1987 modified)
humans and on compounds whose mechanism of action is rather well known and therefore can be of help for a better understanding of the carcinogenic and anti-carcinogenic processes.
Ascorbic acid and tocopherols
Experimental studies have demonstrated that ascorbic acid or vitamin C can inhibit the formation of nitroso compounds both in vitro and in vivo (8). Moreover, in epidemiological studies of diet in relation to gastric cancer, the most constant finding has been the negative association with intake of fresh fruit and vegetables, suggesting that vitamin C could contribute to the protective action. Alpha-tocopherol, or vitamin E (9), has also been shown to inhibit formation of nitroso compounds (7). Protective effects of vitamin E against radiation-induced DNA damage and mutation and dimethylhydrazineinduced carcinogenesis have also been observed.
Phenols
When administered prior to or at the time of carcinogen exposure, the phenolic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are effective inhibitors of carcinogenesis in several organ systems including the lung, colon, skin, liver and mammary glands of experimental animals.
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Zndoks
These compounds occur naturally in a number of edible cruciferous vegetables (Brussels sprouts, cabbage, cauliflower and broccoli) and inhibit formation of tumours in some animal models.
Retinoids
This term includes all natural and synthetic analogues of vitamin A. It has been known from the beginning of this century that retinoids are fundamentally involved in the induction or enhancement of cellular differentiation (10) and that most primary human cancers arise in epithelial tissues which depend upon retinoids for normal cellular differentiation. Two very comprehensive reviews on retinoids were published in 1980 (11) and in 1987 (12). Over the past few years retinoids have been shown to be effective inhibitors of chemical carcinogenesis in skin, mammary gland, oesophagus, respiratory tract, pancreas, and urinary bladder of experimental animals, particularly when administered shortly after the carcinogenic insult. Modification of the basic retinoid structure has produced new molecules with enhanced target organ specificity, resulting in increased inhibitory activity with reduced systemic toxicity. Since the development of cancer is fundamentally a process of loss of cellular differentiation, the chemoprevention of cancer with retinoids represents a physiological rather than cytotoxic approach to arresting or reversing the process of carcinogenesis ( 13).
Nonsteroidal anti-inJammatory agents
The most studied compound of this group is indomethacin, which has been reported to inhibit the induction of tumours in the rat colon, mouse oesophagus, rat mammary gland, mouse skin and methylcholanthrene-induced carcinogenesis in the mouse uterine cervix (2). Hormones and anti-hormones
Hormones of pregnancy are thought to alter the mammary gland so that the epithelial cells are less susceptible to carcinogenic insults and consequently some female sex hormones have been suggested to be involved in mammary carcinogenesis. On the other hand, the potential chemopreventive activity of tamoxifen (inhibition of initiation and growth of DMBA-induced mammary carcinomas) has been presupposed since mid 1970s (15). It has been recently confirmed by experimental animals models ( 16) which may be considered rather similar to the human situation since they are focussed on evaluating the onset of spontaneous tumours rather than chemically-induced neoplasms: when given daily to rats, tamoxifen is shown to reduce the incidence of both mammary fibroadenomas and carcinomas (Figure).
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0 TAMOXIFEN A CONTROL 1 END OF THE TRE4TMfNT
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t SACRIFICE
t
Selenium salts
Together with the retinoids the selenium salts have been extensively studied as suppressing agents and have been found to inhibit a considerable variety of experimental neoplastic systems. Epidemiological data have been interpreted by some investigators as indicating that a low selenium consumption may increase cancer risk in certain human populations (14).
Protease inhibitors
Several studies have indicated that protease inhibitors can be powerful anticarcinogenic agents for animals and cells in culture. Epidemiological data on human population show a negative association between the intake of protease inhibitors (rice, maize, corn, bread, cereals) and the incidence of breast, colon, prostatic, oral and pharyngeal cancers suggesting a protective effects.
0
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8
10
12
14
16
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Weeks from the start of the exper#rnent
24
26
Mdtoni
28 30 32
u .I..
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Figure. Number of mammary carcinomas in rats treated with tamoxifen and in controls.
Chemoprevention of human tumours In recent years, what could be called ‘clinical chemoprevention’ (i.e. controlled studies to evaluate in human subjects the efficacy of potentially chemopreventive agents) has developed considerably: according to American estimates ( 1) 4 chemopreventive agents were tested clinically in 1981, 10 in 1985 and 18 in 1988. The number of reported preclinical investigations was 10 in 1985 and 75 in 1988. This rapid expansion has obviously led to some confusion in terminology and in the evaluation of primary results; at present there is still a need for a ‘new culture’ to better define clinical chemoprevention and to differentiate it from chemotherapy (Table 2).
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Oral cavity
Table 2 Diflerences between chemotherapy and chemoprevention
Endpoints Target of action Duration Sample size Dosage Toxicity
Chemotherapy
Chemoprevention
Clinical improvement Tumour Months N x lO(0) Maximise (efficacy) Acute
Lack of occurrence Host Years Nx1000 Minimise (safety) Acute/chronic
Prolonged administration of potentially chemopreventive agents is not called ‘treatment’ since the subjects receiving it are by definition at risk of cancer but not affected by it: the appropriate term is ‘intervention’. Intervention studies are controlled clinical trials conducted to evalutate the effectiveness of a given compound to prevent recurrences or new primaries in defined populations. The main target site organs of chemopreventive intervention trials have so far been oral cavity, upper respiratory tract and lung, breast, oesophagus and colon, uterine cervix and skin (Table 3). Table 3 Ongoing chemoprevention intervention studies
Target site organ
Target/risk group
Inhibitory agents
Oral cavity
Oral leukoplakia
Oral cavity Lung Lung Lung Lung Lung Breast Breast Colon
Asian betel nut and tobacco chewers Asbestosis Cigarette smokers Smoking males Asbestos Smokers High risk women Breast cancer patients Familial polyposis
Aromatic retinoid 13-cis, and 4-HPR Beta-carotene, retinol
Colon Colon
Familial polyposis Adenomatous polyps
Colon Liver Cervix Cervix Skin Skin
Adenomatous polyps High risk population Cervical dysplasia Cervical dysplasia Albinos Basal cell carcinoma
Skin Skin Skin
Basal cell carcinoma Actinic keratoses Basal cell carcinoma
Skin Skin
Previous basal cell ca. Head and neck basal cell carcinoma US physicians
All sites
From Malone et al. 1989, modified.
Beta-carotene, retinol Beta-carotene, retinol Beta-carotene Beta-carotene, retinol Beta-carotene Tamoxifen 4-HPR Vitamins C, E, and fiber Calcium Beta-carotene, vitamins C, E Piroxicam Selenium Trans-retinoic acid Folic acid Beta-carotene Beta-carotene, vitamins C, E Beta-carotene Retinol Retinol, 13-cis-retinoic acid Selenium 4-HPR Beta-carotene
Leukoplakia is a fairly frequent precancerous lesion of the oral cavity and is clinically defined as a whitish patch of unknown origin on the mucous membrane. Aromatic retinoids have been tested since 1974 and studies made with more than 120 patients have demonstrated that these drugs may be therapeutically employed (17). The results of an interesting chemoprevention trial sponsored by the National Cancer Institue of Canada were published a few years ago (18) stressing the effectiveness of retinoids in inhibiting the carcinogenic processes in the oral cavity. The population chosen comprised 40 Filipino betel nut and tobacco chewers and the design of the study used a diet supplementation with retinol (100 000 IU/week) and betacarotene (300 000 IU/week): after 3 months of intervention a 3-fold decrease was noted in the frequency of micronuclei in cells scraped from inside the cheek. The number of micronuclei is a measure of chromosome breakage in earlier cell division which is usually increased by carcinogenic stimuli. Encouraging results have been obtained with 13-cis retinoic acid (19). A prospective randomized study is presently being run to evaluate the efficacy of the synthetic retinoid 4-HPR in preventing recurrences, new localizations and carcinomas of oral cavity after C 0 2 laser exeresis of leukoplakia. This analogue of vitamin A, N-(.l-hydroxyphenyl)retinamide, was identified in the late 1970s and shown to be effective in preventing chemically induced mammary cancers in rats (20) and one of the least toxic known retinoids. The tolerability of 4-HPR in humans has proven to be fairly good (21) and its pharmacokinetics, including the relationship with retinol serum levels and RBP, has been recently described (22, 23). Upper respiratory tract and lung
A large cooperative trial, called Euroscan, was recently launched by EORTC to investigate the efficacy of a twoyear intervention with high dose vitamin A and an aminoacid derivative, n-acetylcysteine. The test group are patients already cured of lung or head and neck cancer, who have a 10% to 20% risk of developing a second cancer in the same region within 5 years. A randomized clinical trial was activated at the Milan Tumour Institute in 1985 to evaluate whether retinol palmitate administration after complete resection of stage I non-small cell lung cancer, could reduce the occurrence of cancer relapses and/or the incidence of new primary tumours. Although the difference in disease recurrences failed to reach statistical significance, from the clinical point of view, the data are suggestive of a biological effect of intervention (24). In the US, five studies on lung cancer prevention are presently being conducted with the support of the Chemoprevention Branch of the US National Cancer Institute
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( 1): endpoint of the two trials designed by the University of Texas is the regression of bronchial squamous metaplasia and/or dysplasia following administration of 13-cisretinoic acid in chronic smokers and of beta-carotene and retinol in men exposed to asbestos. In a similar population and with the same chemopreventive agents, the incidence of lung cancer is being evaluated at the University of Washington; the association of beta-carotene and vitamin E is under study at the US National Cancer Institute.
Breast
Despite the great epidemiological importance of breast cancer and the number of experimental studies on mammary carcinogenesis, very few relevant clinical trials are presently being conducted on chemoprevention of these tumours, the main reason being the difficulty of identifying proper high-risk groups in the general population. The capability of tamoxifen to reduce the incidence of contralateral primaries in patients already operated on for one breast cancer has recently been shown (25). To move to the general population the critical problem is identification of the high-risk group who could benefit from a long-term chemopreventive intervention with this drug. One of the first designs which has been proposed for entering a woman into a prevention trial requires the candidate to have three of the following five characteristics: a) nulliparity or first childbirth after age of 28; b) serum SHBG (sex-hormone-binding globulin) levels below the population median; c) Wolfe grades (P2 or DY) at mammography (26); d) family history of breast cancer (mother or sister); e) previous benign ‘fibrocystic’ disease (27). Main limiting factors to a development of this area are potential liver and uterine carcinogenicity of tamoxifen, as it has been suggested by some experimental data, possibly related to the oestrogenic effect of this drug. Chemoprevention pilot trials with very low doses and in hysterectomized women have recently been proposed. Another line of research in breast cancer deals with retinoids. A large randomized clinical trial of breast cancer chemoprevention with 4-HPR has been started by Veronesi et at. at the Milan Tumour Institute in Italy in 1987, with the aim of evaluating the reduction of incidence of contralateral breast cancer in patients already operated on for unilateral lesions. Oesophagus, colon, liver
In contrast to Europe and America where alcohol and tobacco can be related to most oesophageal cancers, the causes of these tumours in China are largely unknown. A random sample of 610 subjects was recently studied in Northern China: half of them received active intervention (retinol, riboflavin and zinc) for 6 months and the other half a placebo. The design of the study included ad-
66 1
ministration of questionnaires on smoking, drinking and dietary habits, and blood samples drawn regurlarly for estimation of riboflavin, retinol, beta-carotene and zinc. Oesophagoscopy with at least two biopsies was also performed in 93% of the participants. No significant difference was reported between the two groups in terms of prevalence of precancerous lesions. However, the investigators stressed that individuals with larger increases in retinol, riboflavin and zinc blood levels were more likely to have a histologically normal oesophagus (28). Two additional studies with beta-carotene and multiple vitamins or minerals are also being conducted at the NCI, Bethesda. Five studies on prevention of colon cancer are now ongoing in the US, the selection factors being either familial polyposis or adenomatous polyps. The studied agents include beta-carotene, vitamin C and E, piroxicam, calcium and fibre. One study combines chemoprevention and diet: one group of participants receives wheat bran along with calcium as part of the intervention. With regard to liver cancer, a study is being conducted with the NCI support on woodchucks to evaluate the efficacy of a Phyllanthus amarus extract in eliminating or decreasing Hepatitis B virus. An intervention trial of primary liver cancer with selenium supplementation is being conducted in more than 20000 subjects at risk by the Chinese Academy of Medical Sciences of Beijing and the Qidong Liver Cancer Institute. Uterine cervix
Participants in chemoprevention studies for cervical cancer are generally selected on the basis of dysplasia on Pap smears. In the US two clinical trials are sponsored by the Chemoprevention Branch of the NCI (6), one involving topical application of retinoids, the other using systemic administration of folic acid. Previous experimental topical treatments of cervical dysplasia with retinoids have failed due to the relatively severe local toxicity, mainly because it is difficult to avoid contact between the drug and the vulvar and vaginal mucosa. Moreover, the complete clinical regression of symptoms is not always associated with histological disappearance of the dysplasia (29). Skin
During the past ten years several retinoids have been used in animals and humans for the treatment and prevention of skin tumours (30). Six studies in skin cancer prevention are presently being supported by the NCI in the US: risk factors used include the presence of previous skin cancers, a precancerous condition (actinic keratosis), or a specific population group at high risk for skin cancer, namely, albinos in equatorial Africa. The spectrum of agents being evaluated
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in these studies includes selenium, beta-carotene ( 3 l), vitamin C and E, retinol and 13-cis-retinoicacid. In Europe, a chemoprevention trial of 4-HPR in basal cell carcinoma of the head and neck is being conducted in Milan with the aim of preventing recurrences and new lesions after radical surgical excision in a region of the body where further surgery would induce irreversible and often unacceptable aesthetic damage. Conclusions
Some of the definitions and criteria of traditional medical oncology (e.g. role of placebo, evaluation of toxicity, etc.) could prove to be not readily adoptable to chemopreventive trials and there is a need for new concepts within this field particularly as far as design of studies, ethics and tolerability are concerned. Sample sizes in clinical chemoprevention are usually great and are generally expressed in terms of thousands of subjects; the duration of intervention and observation may extend for over 10 years; the evaluation of compliance is extremely difficult since there is no verifiable information on participants' adherence to the regimen except pill counting and drug serum concentration testing. Major ethical problems arise when the target population has to be identified in designing a clinical chemoprevention trial and when the investigator is requested to assess the risklbenefit ratio of a medical intervention, the efficacy of which cannot be evaluated without the exposure of large numbers of individuals for a long period of time to a given agent. Tolerability of chemopreventive compounds must of course be extremely high but it is also true that there is no means of knowing in advance the consequences and late effects of long-term administration to humans. When observing the large number of tumours for which chemopreventive agents have been shown to have protective effects in experimental studies it is possible that almost half of all human cancers might ultimately be prevented by chemopreventive interventions. No doubt this goal is worthy of a concerted effort both from the drug industry and scientific institutions. Under these circumstances oncologists and epidemiologists should be extremely careful in designing their studies, considerate of the individuals involved in them and critical in evaluating the results. ACKNOWLEDGEMENT The author is indebted to Dr. Maria Pizzichetta for her support in bibliographic research. Request for reprints: Dr Albert0 Costa, Istituto Nazionale Tumori, Via Venezian, 1, 1-20133 Milan, Italy.
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