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RDBCT in patients with prior adenoma; 35-75 years old

2.0g/day (vs. 3.8g/day ispaghula husk) vs. placebo x 36 months

Adenoma incidence/recurrence, 34% reduction (NS)

Women's Health Initiative92

45,00048,000

Complex factorial, DBRCT in postmenopausal women 50-79 years old

Calcium + vitamin D; hormone replacement therapy; low-fat diet x approximately 9 years

Colorectal cancer incidence (among many others): ongoing

a Number randomized.

bTrial designs: SBRCT, single-blind, randomized, controlled trial; DBRCT, double-blind, randomized, controlled trial; DBRCXT, double-blind, randomized, controlled cross-over trial; RCXT, unblinded, randomized, controlled cross-over trial. c Calcium carbonate unless noted otherwise.

d Proliferation assessed via random biopsies of normal appearing mucosa. NS, nonsignificant. 'Statistically significant result (P < 0.05).

a Number randomized.

bTrial designs: SBRCT, single-blind, randomized, controlled trial; DBRCT, double-blind, randomized, controlled trial; DBRCXT, double-blind, randomized, controlled cross-over trial; RCXT, unblinded, randomized, controlled cross-over trial. c Calcium carbonate unless noted otherwise.

d Proliferation assessed via random biopsies of normal appearing mucosa. NS, nonsignificant. 'Statistically significant result (P < 0.05).

the Western diet alone.89 The challenges rest in how well the Western-style rodent diet is mirrored in the complex arrays of current Western-style human diets and the identification of the windows of human development that are sensitive to their reported dietary modulations.

Case Study VII: Nonsteroidal Antiinflammatory Drugs, Selective Cyclooxygenase 2 Inhibitors, and Cancer Prevention

As a class, nonsteroidal antiinflammatory drugs (NSAIDs) are structurally diverse, yet seem to share several common activities that might be relevant to the prevention of cancer. Anti-neoplastic effects may include modulation of cell cycle, apoptosis, proliferation, and invasion. Although many of these effects are linked to cyclooxygenase (COX) inhibitory activity, a number of COX-independent effects are well established. COX inhibition by NSAIDs is exerted on at least two distinct isoforms: COX-1 and COX-2. COX-1 is constitutively expressed in most tissues, whereas COX-2 is found generally at low levels of expression unless induced by inflammatory factors, growth factors, or tumor promoters. Most NSAIDs, including aspirin or sulindac, suppress the activities of both isozymes. This indiscriminate inhibition causes anticancer effects as well as collateral damage, including gastric ulceration and renal toxicity. COX-2-selective inhibitors (COXIBs), including celecoxib (Celebrex) and rofecoxib (Vioxx), burst on the scene in 1999 with the potential to revolutionize the relief of inflammation and pain arthritis, without the collateral side effects of aspirin and the other nonselective NSAIDs. It was soon discovered that these agents also had tremendous potential as safe and effective chemopreventive agents for some cancers. However, Vioxx was withdrawn from the market on September 30, 2004, because of concern that it increases the risk of heart attacks and strokes in patients taking it longer than 18 months.93 Although recent findings suggest a higher risk of admission for congestive heart failure in users of rofe-coxib but not celecoxib, relative to non-NSAID controls,94 further studies and analyses are imperative to determine if the increased cardiovascular risks are limited to Vioxx or are characteristic of the entire class of COXIBs.

Evidence from Animal Studies

COX-2 is commonly overexpressed in many cancers, including many stages of colorectal carcinogenesis; some studies report overexpression in more than 50% of adenomas and more than 80% of adenocarcinomas, but it is rarely expressed in normal colorectal epithelium. The role of NSAIDs in cancer prevention was first investigated in rodent models in the early 1980s.95 NSAIDs, such as aspirin, indomethacin, piroxicam, and sulindac, exhibited inhibitory effects on tumors of the colon; however, tumor growth often resumed when NSAIDs were discontinued. Overwhelming preclinical data suggest that COX-2 is functionally important for neo-plastic progression, as evidenced by the regression of intestinal polyps in rodent models of colorectal cancer prevention as well as in COX-2-deficient mice. As recently reviewed,96 almost 400 reports in PubMed are published on rodent models of both genetic and carcinogen-induced carcinogenesis that used NSAIDs or their derivatives. The majority of these studies demonstrate NSAIDs are relatively effective against most stages of colon cancer, including aberrant crypt foci; adenoma and adenocarcinoma multiplicity, incidence, and size; metastasis; and survival.

Nine studies of COXIBs—two with NS-398, one with MF tricyclic, two with nimesulide, one with rofecoxib, and three with celecoxib—have proved this class of chemopreventive agents is promising in reducing aberrant crypts and colorec-tal tumors in carcinogen-induced and genetically driven rodent models of intestinal neoplasia.96 COX-2 is overex-pressed at very early stages of colorectal carcinogenesis in animals, as reported by Oshima et al.97 This study also showed that the COX-2-selective agent MF tricyclic was as effective as the nonselective COX inhibitor sulindac. This study further provided direct evidence of the mechanistic importance and significance of COX-2 inhibition, as COX-2 knockout (+/-, and -/-) mice had a reduction in adenomas in a dose-dependent (COX-2 gene) manner.98

Evidence from Epidemiologic Studies and Randomized Clinical Trials

Among 21 retrospective and 9 prospective observational studies, all but 2 reported statistically significant inverse associations between use of NSAIDs or COXIBs and colorectal neoplasia risk.96 Reductions in neoplastic lesions by NSAIDs use ranged from 16% to 92% with an average reduction in adenomas of about 40% to 50%. In contrast, a prospective study of 12,180 individuals for 8.5 years reported an association between daily aspirin use and increased CRC risk for men (RR = 1.38) and women (RR = 1.10).98 A major difference in this from other observational studies is that the median age of participants was 73 years. In a report from the Physicians' Health Trial and Follow-Up Study (n = 22,071 healthy men aged 40-84 years in 1982), aspirin was not associated with risk of colorectal cancer in those randomized to 325 mg every other day for the first 6 years [RR = 1.03 (95% CI = 0.83-1.28)] nor associated with risk in the postrandom-ization interval in men who used aspirin frequently [RR = 1.07 (95% CI = 0.75-1.53)].99 A much larger number of studies show a positive cancer preventive effect of NSAIDs and COXIBs. In nested case-control analysis of a population-based cohort study of 940,000 individuals in the UK, a significant 40% reduction in colorectal cancer risk was reported in long-term aspirin users of 300 mg daily, but no significant benefit appeared in users of 75 or 150mg daily.100

Numerous clinical trials showing protective effects of NSAIDs against colon polyp formation or colon cancer are summarized in Table 23.6. In 2003, three studies reported dramatic findings that reveal aspirin as a major player in the defense against cancer. Two randomized controlled studies considered patients at risk of colorectal cancer. Both studies found a clear reduction in polyp recurrence from aspirin use. In one study, 1,084 patients with a history of polyps were followed with a colonoscopy 3 years after their entry into the study.101 The greatest benefit was observed in the low-dose (81 mg daily) group, who experienced an unadjusted risk ratio of 0.81 (95% CI = 0.69-0.96) whereas those in the high-dose (325mg daily) group experienced a RR of 0.96 (95% CI = 0.81-1.13). When large or malignant polyps were considered separately, the benefits were clearer; risk ratios of 0.59 (95% CI = 0.38-0.92) in the low-dose group, and to some extent in the high-dose group (RR = 0.83; 95% CI = 0.55-1.23). The second study followed 517 patients with previous malignant CRC for a year and reported the RR for new polyps of 0.65 (95% CI = 0.46-0.91) in the 325 mg daily aspirin treatment group.102 Meanwhile, a third study, which combined three earlier case-control studies into a cancer patient base of 965 and 1,779 controls,103 showed a dramatic reduction in the incidence of tumors of the mouth, throat, and esophagus with long-term use of aspirin. After controlling for factors, such as smoking and diet, the incidence of the three types of cancer in people who had taken aspirin regularly for at least 5 years was a third that in nonusers [OR = 0.33 (95% CI = 0.13-0.82)]. Similarly, more than 15 case series and reports have described the benefits of NSAIDs for prevention of prevalent adenomas in persons with familial adenomatous polyposis (FAP).

Selective COX-2 inhibitors (COXIBs) recently approved for treatment and management of pain and arthritis provide a unique opportunity in terms of sparing COX-1 beneficial functions while inhibiting COX-2 in the process. On the basis of preclinical and observational studies just described, COXIBs have now advanced to human clinical trials in cancer prevention. A recent randomized, placebo-controlled trial of celecoxib administered over 6 months to 77 individuals with FAP showed significant regression and reduction in colorec-tal adenoma number and size. As an added benefit, celecoxib treatment also decreased duodenal polyps, suggesting a dualorgan benefit in this cohort. The importance of this study is underscored by FDA's approval of celecoxib to complement the endoscopic surveillance and prophylactic surgery in FAP individuals. Furthermore, based on these preliminary but landmark results, celecoxib is now under study in several clinical trials involving persons at elevated risk for CRC because of either a genetic predisposition or a history of prior sporadic neoplasia.

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Thank you for deciding to learn more about the disorder, Osteoarthritis. Inside these pages, you will learn what it is, who is most at risk for developing it, what causes it, and some treatment plans to help those that do have it feel better. While there is no definitive “cure” for Osteoarthritis, there are ways in which individuals can improve their quality of life and change the discomfort level to one that can be tolerated on a daily basis.

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