Mounting evidence from epidemiological studies and several large randomized controlled trials have shown that calcium supplementation may be an effective strategy for preventing and reducing recurrence of colorectal adenomas. Because most CRCs arise from adenomas, calcium chemoprevention may be a reasonable clinical strategy. Whereas calcium supplementation appears to be quite safe, it is prudent to investigate whether calcium chemoprevention of CRC could constitute an effective or cost-effective strategy before considering it as a public health intervention. In doing so, it is mandatory to consider what the optimum target population might be. Given that the randomized trials have evaluated calcium supplementation in individuals with prior adenoma on colonoscopy, a group at higher risk for recurrence than the average population, we focused our analyses on a hypothetical cohort of individuals found to have an adenoma on screening colonoscopy at age 50 years.
Should physicians be recommending, or even prescribing, calcium supplements to their adenoma-bearing patients after polypectomy? Our analyses suggest that surveillance is likely to be much more effective than calcium chemoprevention alone, and that surveillance remains an acceptable intervention in terms of cost-effectiveness over a wide range of calcium chemopreventive effect and calcium cost. Calcium as an adjunct to surveillance may provide a relatively modest improvement in life-expectancy, but this may be achieved at a very substantial cost per life-year gained.
Surveillance colonoscopy is predicted to be a very effective strategy in persons with a history of adenoma. To compete with surveillance, one might postulate that a chemopreventive agent would have to have efficacy approaching a 75–80 percent risk reduction. To enjoy widespread use, it would probably also require a very low cost. As demonstrated in our base case, inexpensive chemoprevention can carry a very high cost/life-year gained as an adjunct to surveillance if it reduces adenoma recurrence risk by only 20–35 percent.
In our simulation, compared with no surveillance or chemoprevention, calcium supplementation was cost-effective by traditional standards. However, because surveillance was much more effective and was a cost-effective alternative, calcium supplementation cannot be recommended as a substitute for surveillance. For adenoma-bearing individuals who have undergone initial polypectomy but are then unable or unwilling to undergo surveillance colonoscopy, calcium supplementation may be a viable and cost-effective strategy.
Our results are similar to those of cost-effectiveness analyses of other chemopreventive agents, such as aspirin and cyclooxygenase-2 inhibitors (3
). Collectively, no single chemopreventive agent has been shown to be superior to screening or surveillance. However, the promise of chemoprevention still holds. Ongoing trials of chemopreventive agents may provide encouraging evidence regarding effectiveness. For instance, combinations of chemopreventive agents such as calcium plus aspirin (17
) and calcium plus vitamin D (17
) may increase effectiveness. Currently, a national trial of vitamin D and calcium supplementation is under way to evaluate reduction in recurrence of adenomas (http://crisp.cit.nih.gov/crisp/crisp_lib.query
Adherence is an important consideration. The estimates we present are for persons who adhere fully with long-term chemoprevention and/or surveillance. Thus, they are optimistic estimates on a population-wide basis. Nationally, adherence to CRC screening is disappointing, and surveillance adherence is not well characterized. Adherence to calcium supplementation outside of a clinical trial is not known. Reduced adherence to calcium supplementation may yield a disproportionate decrease in its efficacy without decreasing cost as much, and hence, low adherence may further disfavor calcium supplementation.
In our analysis, we modeled the use of supplemental calcium. However, another approach to increasing daily intake of calcium is from dietary sources. In theory, the individual cost could be less if calcium is part of foods that also provide nutrients and calories, such as dairy, fruits, and vegetables. However, widespread dietary changes in the population are very difficult to achieve. Two studies addressing the cost of achieving a target amount of calcium intake found that calcium carbonate supplements, generic or brand name, are the least expensive source of calcium (21
In the current analysis, we have not considered other beneficial effects of calcium on health, such as increasing bone density and preventing fractures, particularly among the elderly, and women, and potentially lowering of blood pressure. The benefit on bone health is supported by data from the Women’s Health Initiative showing that calcium and vitamin D supplementation increase bone mass and decrease risk of fractures in those with good compliance. In other analyses, calcium supplementation has been deemed a cost-effective strategy in prevention of vertebral fractures in postmenopausal women (47
) and women treated with glucocorticoids (10
). In such patients, calcium may have the additional benefit of reducing adenoma recurrence, but our results suggest that surveillance colonoscopy should still be pursued if appropriate.
Strengths of our analysis include the calibration of the natural history model to data from chemoprevention trials and systematic review of the effect of calcium on adenomas. Our model accounts for missed adenomas during colonoscopy, reflecting the reality for surveillance in everyday practice. We used a wide range of values in our sensitivity analysis for all clinical and economic parameters.
Our study has several limitations. Because our model focuses on post-polypectomy surveillance, it applies to individuals who are at higher risk for adenomas adenoma formation and CRC. Our quantitative estimates cannot be applied to average risk individuals, but given the lower adenoma risk in these persons, we anticipate that calcium supplementation is also unlikely to be a reasonable substitute for screening. An important consideration is that our model allows for CRC prevention by calcium through its decrease in adenoma recurrence risk. Epidemiological studies suggest that calcium may reduce the risk of CRC (34
) but a study from the Women’s Health Initiative did not support this conclusion (26
). It remains to be clarified whether the Women’s Health Initiative study could have failed to detect a true effect of long-term calcium use on cancer as an outcome. Our estimates on calcium’s potential effectiveness as a chemopreventive agent rely on the assumption that reduction of adenoma recurrence risk will translate into CRC risk reduction. Our sensitivity analyses were one-way deterministic sensitivity analyses.
In summary, calcium supplementation is unlikely to be a reasonable substitute for surveillance after polypectomy. As an adjunct to surveillance, it may add little in terms of CRC risk reduction or increase in life expectancy. Despite its low cost, it is likely to carry a high cost/life-year gained as an adjunct to surveillance. In those who are unwilling or unable to undergo surveillance, calcium supplementation may be a viable option. In the future, combinations of chemopreventive agents may prove to be viable interventions for CRC prevention if they have reasonable effectiveness at a low cost, with excellent safety and long-term adherence.