Chapter 078. Prevention and Early Detection of Cancer (Part 4)

Chemoprevention of Cancers of the Upper Aerodigestive Tract Smoking causes diffuse epithelial injury in the head, neck, esophagus, and lung. Patients cured of squamous cell cancers of the lung, esophagus, head, and neck are at risk (as high as 5% per year) of developing second cancers of the upper aerodigestive tract. Cessation of cigarette smoking does not markedly decrease the cured cancer patients risk of second malignancy, even though it does lower the cancer risk in those who have never developed a malignancy. Smoking cessation may halt the early stages of the carcinogenic process (such as metaplasia), but it...
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Chapter 078. Prevention and Early Detection of Cancer (Part 4) Chapter 078. Prevention and Early Detection of Cancer (Part 4) Chemoprevention of Cancers of the Upper Aerodigestive Tract Smoking causes diffuse epithelial injury in the head, neck, esophagus, andlung. Patients cured of squamous cell cancers of the lung, esophagus, head, andneck are at risk (as high as 5% per year) of developing second cancers of the upperaerodigestive tract. Cessation of cigarette smoking does not markedly decrease thecured cancer patients risk of second malignancy, even though it does lower thecancer risk in those who have never developed a malignancy. Smoking cessationmay halt the early stages of the carcinogenic process (such as metaplasia), but itmay have no effect on late stages of carcinogenesis. This field carcinogenesishypothesis for upper aerodigestive tract cancer has made cured patients animportant population for chemoprevention of second malignancies. Oral leukoplakia, a premalignant lesion commonly found in smokers, hasbeen used as an intermediate marker allowing demonstration of chemopreventiveactivity in smaller shorter duration, randomized, placebo-controlled trials.Response was associated with upregulation of retinoic acid receptor-β (RAR-β).Therapy with high, relatively toxic doses of isoretinoin (13-cis-retinoic acid)causes regression of oral leukoplakia. However, the lesions recur when the therapyis withdrawn, suggesting the need for chronic administration. More tolerable dosesof isoretinoin have not proven beneficial in the prevention of head and neckcancer. Isoretinoin also failed to prevent second malignancies in patients cured ofearly-stage non-small cell lung cancer; mortality rates were actually increased incurrent smokers. Premalignant lesions in the oropharyngeal area have also responded toretinol, α-tocopherol (vitamin E), and selenium. Further study to define theactivity of these drugs is ongoing. Several large-scale trials have assessed agents in the chemoprevention oflung cancer in patients at high risk. In the α-tocopherol/β-carotene (ATBC) LungCancer Prevention Trial participants were male smokers, age 50–69 at entry.Participants had smoked an average of one pack of cigarettes per day for 35.9years. Participants received α-tocopherol, β-carotene, and/or placebo in arandomized, 2 x 2 factorial design. After median follow-up of 6.1 years, lungcancer incidence and mortality were statistically significantly increased in thosereceiving β-carotene. α-Tocopherol had no effect on lung cancer mortality, and noevidence suggested interaction between the two drugs. Patients receiving α-tocopherol had a higher incidence of hemorrhagic stroke. The β-Carotene and Retinol Efficacy Trial (CARET) involved 17,000American smokers and workers with asbestos exposure. Entrants were randomlyassigned to one of four arms and received β-carotene, retinol, and/or placebo in a 2x 2 factorial design. This trial also demonstrated harm from β-carotene: a lungcancer rate of 5 per 1000 subjects per year for those taking placebo and of 6 per1000 subjects per year for those taking β-carotene. The ATBC and CARET results demonstrate the importance of testingchemoprevention hypotheses thoroughly before their widespread implementationas the results contradict a number of observational studies. In the ATBC trial,those taking α-tocopherol had a one-third reduction in the incidence of prostatecancer, compared to those not taking α-tocopherol. The Physicians Health Trialshowed no change in the risk of lung cancer for those taking β-carotene; fewer ofits participants were smokers than those in the ATBC and CARET studies. Chemoprevention of Colon Cancer Many of the current colon cancer prevention trials are based on the premisethat most colorectal cancers develop from adenomatous polyps. These trials useadenoma recurrence or disappearance as a surrogate endpoint for colon cancerprevention. Early clinical trial results suggest that nonsteroidal anti-inflammatorydrugs (NSAIDs), such as piroxicam, sulindac, and aspirin, may prevent adenomaformation or cause regression of adenomatous polyps. The mechanism of action ofNSAIDs is unknown, but they are presumed to work through the cyclooxygenasepathway. In the Physicians Health Trial, aspirin had no effect on colon cancerincidence, although the 6-year assessment period may not have been long enoughto evaluate this endpoint definitively. A number of studies suggest that NSAID useis associated with a lower risk of adenomatous polyps and invasive cancer.However, prospective trials have not shown that NSAIDs prevent colon cancer. Cyclooxygenase-2 (COX-2) inhibitors may be even more effective. In aplacebo- ...