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MD Consult: Books: Goldman: Cecil Medicine: CHEMOPREVENTION

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


Chemoprevention is the use of pharmacologic interventions to prevent or treat intraepithelial neoplasia or reduce the risk for cancer, or both. Although high-dose isotretinoin is too toxic for long-term use, a randomized trial provided proof of principle by showing that it prevented second primary cancers in patients after definitive treatment of a first head or neck cancer. A subsequent trial of low-dose isotretinoin unfortunately did not reduce second primary cancers, recurrences, or mortality. Several major chemoprevention trials are summarized in Table 191-1 .

TABLE 191-1   — 

Intervention Cohort N Results
HPV-16 vaccine 16–23-Year-old women 2,392 Reduced HPV-16 infection and HPV-16–related CIN[*]
HPV-16, HPV-18 vaccine 16–26-Year-old women 12,167 Reduced CIN/CCIS[*]
Tamoxifen High-risk women 13,388 Reduced breast cancer[*]
Tamoxifen High-risk women 7,410 Reduced breast cancer[*]
Raloxifene/tamoxifen High-risk women 19,747 Equivalent breast cancer rates
Finasteride ≥55-Year-old men 18,882 Reduced overall PC,[*] increased HG PC[*]
Aspirin Previous adenoma 1,121
  81 mg/day     Reduced adenomas[*]
325 mg/day Reduced adenomas
Aspirin (325 mg/day) Previous CRC 635 Reduced adenomas[*]
Aspirin (100 mg every other day) ≥45-Year-old women 39,876 Negative (CRC, other cancers)
Rofecoxib Previous adenoma 2,586 Reduced adenomas[*]
Celecoxib (200/400 mg bid) Previous adenoma (high risk) 2,035 Reduced adenomas[*]
Celecoxib (400 mg/day) Previous adenoma 1,561 Reduced adenomas but increased cardiovascular events
Calcium Previous adenoma 913 Reduced adenomas[*]
LD isotretinoin Previous stage I/II HNC 1,190 Negative
LD isotretinoin Previous stage I NSCLC 1,166 Negative

CCIS = cervical carcinoma in situ; CIN = cervical intraepithelial neoplasia; CRC = colorectal cancer; HG = high grade; HPV = human papillomavirus; HNC = head and neck cancer; LD = low dose; NSCLC = non–small cell lung cancer; PC = prostate cancer.

* Statistically significant.

Despite consistent data suggesting that β-carotene is associated with a lower risk for lung cancer, β-carotene supplements alone or com-bined with retinyl palmitate increased rates of cancer in randomized trials involving patients at high risk for lung cancer.[5] In randomized trials of persons at average or below average risk for cancer (e.g., nonsmokers), β-carotene had neither benefit nor harm. By comparison, the combination of β-carotene, vitamin E, and selenium significantly reduced the incidence of gastric cancer and all cancers, as well as mortality from cancer in a randomized trial in Linxian, China, possibly because of restoration of healthy nutrient levels in an undernourished population.[6]

For women at a higher than average risk for breast cancer, the selective estrogen receptor modulator (SERM) tamoxifen (20 mg/day) reduces the incidence of invasive and noninvasive breast cancer by 50% in one study and by 32% in another. This reduction in risk was limited to estrogen receptor–positive tumors. Tamoxifen also reduced the risk for osteoporotic fractures but increased the risk for endometrial cancer, thromboembolism, and cataracts. There was no effect on cardiovascular disease or mental function. The U.S. FDA approved tamoxifen (20 mg/day for 5 years) to reduce the risk for breast cancer in women with a 5-year predicted risk of at least 1.66% ( Chapter 208 ). The FDA has also approved tamoxifen to reduce the risk for a second, contralateral breast cancer or invasive tumor in women with ductal carcinoma in situ. Another SERM, raloxifene at 60 mg/day, is equally good for reducing the incidence of invasive breast cancer but with lower rates of uterine cancer, thromboembolic events, and cataracts.[7]

Other promising drugs to prevent breast cancer include the aromatase inhibitors, which are currently being tested in large randomized trials. Combination oral contraceptives containing estrogen and progesterone reduce the risk for endometrial and ovarian cancer by 50%. However, the adverse effects of this therapy—heart disease, stroke, and venous thromboembolism—make it unattractive ( Chapter 262 ).

Finasteride (5 mg/day), which inhibits 5α-reductase, the enzyme that converts testosterone to the more potent androgen dihydrotestosterone, reduced the 7-year cumulative incidence of prostate cancer by 25% and reduced symptoms of benign prostatic hypertrophy in men older than 55 years with a normal digital rectal examination and PSA level, but it also increased the rate of sexual dysfunction and high-grade prostate cancer. A randomized trial of selenium and vitamin E to prevent prostate cancer is ongoing in the United States.

In randomized trials, aspirin significantly (but modestly) reduced recurrent adenomas of the colon. The selective cyclooxygenase-2 inhibitors rofecoxib and celecoxib significantly reduce adenomas but also significantly increase adverse cardiovascular events.[8] No randomized study, however, has shown a reduction in colorectal cancer.

Calcium modestly reduced the risk for sporadic adenomas in two randomized trials but did not reduce colorectal cancer in a large-scale trial of calcium plus vitamin D. The incidence of colorectal cancer was also reduced by 37% in a randomized trial of combined estrogen and progestin therapy, but at the expense of an absolute increase in adverse cardiovascular outcomes.

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