Information about the pharmacokinetic behavior of chemo- preventive agents is scarce. It is therefore not yet possible to assess whether the concentrations at which these agents are known to elicit biochemical responses are achieved in vivo after eating foods that contain them. OHO-12(205-220) 11/16/02 11:24 AM Page 215 CANCER CHEMOPREVENTION 215 Clinical cancer chemoprevention The substance under test has to be innocuous from a toxicol ogical standpoint, as it is likely to be administered over a considerable period of time an d to healthy individuals. Foodstuffs are attractive sources of tumor-suppressive substances , as the effects of long-term exposure are well-documented. Currently, more than 60 randomized trials of potential chemo- preventive agents have been r eported. Only a few of these trials con- stituted \200\230de \201nitive trials \200\231. A primary chemopreventive trial with a signi \201cantly positive outcome is the retinol st udy that showed pro- tection against squamous cell skin carcinoma. Tamoxifen has been appro ved in the US to reduce the risk of breast cancer in high-risk women. Two de \201nitive trials of (cid:2)-carotene were signi \201cantly negative. In these tri als lung cancer incidence was studied in 50 000 individuals. The outcome of these trials ma de headlines, suggesting that in high- risk groups of smokers and/or workers occupationally exposed to asbestos. (cid:2)-carotene increases rather than decreases the risk of devel- o ping lung cancer. Subgroup analyzes of these two trials revealed that the risk of lung canc er was highest among those individuals who con- tinued to smoke at least 20 cigarettes per day and those in the highest quartile of alcohol consumption. It is conceivable that (cid:2 )-carotene suppresses tumors only in those individuals from whom the initiat- ing stimulus has been removed, but not in those who continue to be subjected to it. These results underline the importance of understanding how chemopreventive agents exert th eir effects and under which condi- tions they are bene \201cial or indeed detrimental, pri or to extensive clin- ical evaluation. Several trials were \200\230classically \200\231 negative \200\224the investigational agen ts (among them (cid:2)-carotene, 13-cis retinoic acid, retinol, selenium, and (cid:3)-tocop herol) failed to prevent a variety of cancers. Analyzes of sub- sets of populations in some of the trials yielded intriguing positive or negative results. For example, a nutritional supplement of selenium reduced total cancer mortality and incidence of prostate, lung, and colorectal cancer, and recently, (cid:3)-tocopherol was reported to protect against prostat e cancer. Whenever possible, trials of agents for \200\230primary prevention \200\231 should be prec eded by clinical evaluation of their ef \201cacy for \200\230secondary pre- vention \200 \231 of cancer in speci \201c epithelial target sites. These studies are aimed at the reve rsal or arrest of pre-malignant lesions, or the preven- tion of second primary tumors in pa tients cured of an initial cancer. Secondary prevention trials are more cost-effective than large and long-term primary prevention trials. The burden of carcinogenic stimuli on the p atient is high and a meaningful endpoint can be mea- sured in a reasonable time frame in a smaller number of patients. Such OHO-12(205-220) 11/16/02 11:24 AM Page 216 CANCER PREVENTION AND SCREENING 216 trials have furnished important leads concerning the bene \201t of retinoids to prevent pr e-malignant lesions and secondary primary malignancies of the head and neck, lung, skin, an d liver, and of the non-steroidal anti-in \202ammatory drug, sulindac, in the prevention o f the development of tumors in familial adenomatous polyposis. Summary Clinical and laboratory-based research in cancer chemoprevention is expanding in an attempt to prevent or postpone the disease. De \201nitive, clinical, Phase III trials inc lude the current studies of tamoxifen. But equally important are the mechanism of action st udies which will furnish better methods of designing and testing chemo- preventive agents, and the identi \201cation of speci \201c biomarkers of car- cinogenesis that can serve as surrogate endpoint markers. Table 12.1 Mechanisms of tumor suppression and examples of cancer chemopreventive agents Scavenging oxygen radicals Polyphenols (curcumin, genistein), selenium, tocopherol (vitamin E) Inhibition of arachidonic acid metabolism N-acetylcysteine, NSAIDs (sulindac, aspirin), polyphenols, tamoxifen Modulation of signal transduction NSAIDs, retinoids, tamoxifen, genistein, curcumin Modulation of hormonal/growth factor activity NSAIDs, retinoids, curcumin, tamoxifen Inhibition of oncogene activity Genistein, NSAIDs, monoterpenes (D-limonene, perillyl alcohol) Inhibition of polyamine metabolism 2-Di \202uoromethylornithine, retinoids, tamoxifen Induction of terminal differentiation Calcium, retinoids, vitamin D3 Genistein, curcumin, r etinoids, Induction of apoptosis tamoxifen NSAIDs = non-steroidal anti-in \202ammatory drugs OHO-12(205-220) 11/16/02 11:24 AM Page 217 SCREENING FOR CANCER 217 Screening for cancer Introduction The strongest evidence that early detection increases the chance of cure comes from randomized trials of screening, but there is also evi- dence that survival after diag nosis is related to duration of symptoms. This has led to public awareness campaigns to per suade individuals to seek advice regarding suspicious symptoms at an early stage. There is, however, no evidence as yet that this strategy can improve survival. Screening is the process whereby asymptomatic individuals are tested in order to detect a d isease that has yet to declare itself. For this to be effective in a population there are c ertain criteria that must be met by the disease in question, the screening test, and the sc reening program. The disease Its natural history is well understood It has a recognizable \200\230early \200\231 stage (cid:2) (cid:2) (cid:2) Treatment at an early stage is more effective than at a later stage It is suf \201ciently common in the target population to warrant screening (cid:2) The test (cid:2) Sensitive and speci \201c (cid:2) Acceptable (cid:2) Safe Inexpensive (cid:2) The program (cid:2) Adequate facilities for diagnosis in those with a positive test (cid:2) High qualit y of treatment for screen-detected disease (cid:2) Screening repeated at intervals if the d isease is of insidious onset (cid:2) Bene \201t must outweigh physical and psychological h arm (cid:2) Bene \201t must justify \201nancial cost It is crucial that treating the dis ease to be screened at an early stage is more effective than treating at a later stage. To justify a screening pro- gramme one cannot compare the outcome of screen-detected disease w ith that of symptomatic disease, because three biases operate in favor of screen-detected d isease: OHO-12(205-220) 11/16/02 11:24 AM Page 218 CANCER PREVENTION AND SCREENING 218 (cid:2) Lead-time bias arises from the fact that if early diagnosis advances the time of di agnosis of a disease, then the period from diagnosis to death will lengthen irrespective of whether or not treatment has altered the natural history of the disease. Screening will on ly be of value if it shifts the survival curve upwards. (cid:2) Length bias operates as slow-growing tumors are more likely to be detected by scree ning tests when compared to fast-growing tumors which are more likely to present with sympt oms before a screening test can be applied or between tests. Thus, screen-detect- ed tumors will tend to be less aggressive and associated with a relatively good prognosis. (cid:2) Selection bias results from the type of person who accepts an invitation to be scre ened. Such a person is more likely to be health conscious than one who refuses or ignores s creening and is therefore likely to survive longer, irrespective of the disease process. Th ese three biases make patients with screen-detected tumors appear to have a better prognosi s than when tumors present with symptoms. For the true effect of screening to be revealed, screening research must take these biases into account. The only way to do this is to carry out randomized, controlled trials in which mortality from a speci \201c disease is compar ed between a population offered screening (including those who present with symptoms before screening can take place or between screens and those who refuse to be screened) and a pop ulation not offered screening. Such trials have been done in breast and colorectal cancer. Screening In screening it is also important to have a target population to avoid large numb ers of fruitless tests. In screening for the common cancers, where the incidence is highly age-dependent, the age range should be that in which the disease is relatively common and i n which the patients are likely to be \201t enough for treatment. There are other high-risk groups, however, and family history is becoming important in this respect, particularly as it is now possible to detect speci \201c genetic mutations from blood samples and to use these to screen close relatives. Examples of this are mutations in the APC gene in familial adenomatous polyposis, in the DNA mismatch repair genes in heredi tary non-polyposis colorectal cancer, and in the BRCA 1 and 2 genes in familial breast and ovarian cancer. A screening test must be acceptable and safe, so that it will be adopt- ed by the target po pulation. It must also be sensitive and speci \201c. Sensitivity is the proportion of indi viduals with the disease who have a positive test, and speci \201city is the proportion of individuals without the disease who have a negative test. Thus the ideal test would be acc eptable to everyone, have no associated morbidity or mortality, and have 100% sensitivity a nd speci \201city \200\224but this ideal has never OHO-12(205-220) 11/16/02 11:24 AM Page 219 SCREENING FOR CANCER 219 been realized and any screening test has to be a compromise between these factors. Screening program When a screening program is established, it is important that the diagnos tic facilities are adequate \200\224this usually requires additional start-up funding. It i s also essential that the diagnosis is of the highest quality to avoid patient dissatisfact ion and the litigation that can result from missed disease or misdiagnosed benign pathology . Similarly, treatment of early disease must be associated with minimal morbidity and morta lity. It must also be remembered that screening does cause psychological morbidity, and along wit h any physical morbidity caused by investiga- tion and treatment, this represents part of t he cost of screening. The bene \201ts gained must outweigh such morbidity, and society mus t make a decision whether or not the health gain justi \201es the \201nancial cost. Randomized trials have been done in breast and colorectal cancer, and in both instances scr eening has been shown to reduce mortality. In the former condition, the screening test stud ied was the mammo- gram, and ef \201cacy of screening proved highly dependent not only on the quality of the X-rays but also on the quality of the reporting. In colorectal cancer, t he test investigated was the fecal occult blood test, followed by colonoscopy when positive . Here, it is the secondary investigation (i.e. the colonoscopy) where quality control is o f the utmost importance. Breast screening is currently available for all women aged 50 \200\22365 years in the UK, b ut provision of colorectal cancer screening is still under discussion. Cervical cancer scre ening using cervical cytology is established but has never been subjected to a randomized t rial. OHO-12(205-220) 11/16/02 11:24 AM Page 220 CANCER PREVENTION AND SCREENING 220 Further reading Benner, S.E., Lippman, S.M., Hong, W.K. (1994) Chemoprevention of second primary tumors: a model for intervention trials. European Journal of Cancer 30A, No 6, 727 \200\2239. Goodman, G.E. (1992) The clinical evaluation of cancer chemoprevention agents: de \201ning and contrasting phase I, II and III objectives. Cancer Research (Suppl.) 52, 2752 \200\223 7. Kelloff, G.J., Boone, C.W., Steele, Y.E., Crowell, J.A., Lubet, R., and Sigman, Ca.C. (1994) Progress in cancer chemoprevention: perspectives on agent selection and short- term clinical intervention trials. Cancer Research (Suppl.) 54, 2015 \200\22324. Lippman, S.M., Benner, S.E., and Ki Hong, W. (1994) Cancer chemoprevention. Journal of Clinical Oncology 12, No 4 851 \200\22373. Lippman, S.M., Lee, J.J. and Sabichi, A.L. (1998) Cancer chemoprevention: progress and prom ise. Journal of the National Cancer Institute 90, No 20, 1514 \200\22328. Meyskens Jr. F.L. (1992) Biomarker intermediate endpoints and cancer prevention. Journal of the National Cancer Institute Monographs No 13, 177 \200\22381. Nixon, D.W. (1994) Special aspect of cancer prevention trials. Cancer (Suppl.) $474, No 9, 2683 \200\2236. Sporn, M.B. (1993) Chemoprevention of cancer. The Lancet 342, 1211 \200\22312. Stewart, B.W ., McGregor, D., and Kleihues, P. (1996) Principles of chemoprevention. IARC Scienti \201c Publication No 139.