WHI Calcium/Vit D Trial:

ATLANTA— Attendees at the 42nd Annual Meeting of the American Society of Clinical Oncology were eager to learn whether calcium and vitamin D supplementation has beneficial effects on breast cancer, mammograms, and arthralgias. They heard from Women's Health Initiative (WHI) researchers that the dietary intervention had little effect on any of the primary endpoints (abstract LBA6).

The attendees also heard experts contend that the WHI outcome may have been partly attributable to weaknesses in the design of this enormous study.

The discussant for the paper, Carole Fabian, MD, of the University of Kansas Medical Center, Kansas City (see Vantage Point), suggested the design suffered from being "too little, too late," meaning the vitamin D dose was probably too low and the population studied may have been too old to benefit from the intervention. "We should start with phase II biomarker-based studies to demonstrate proof of principle before embarking on such large trials," Dr. Fabian said.

WHI lead investigator Rowan T. Chlebowski, MD, of the Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, said that the 38,000 patient, 7-year study showed no significant effects of calcium and vitamin D supplementation on any of the three study endpoints but did produce an intriguing suggestion that cancers were smaller in the women who took the supplements.

"Calcium and vitamin D intake have been associated with reduced breast cancer risk and reduced mammographic breast density in observation studies. However, randomized trial evidence of calcium/vitamin D supplementation for breast cancer primary prevention is lacking. In addition, vitamin D deficiency is associated with increased arthralgias/myalgias in breast cancer patients, suggesting an estrogen/vitamin D interaction," Dr. Chlebowski said.

The WHI researchers set out to determine whether daily supplementation with calcium and vitamin D would lower breast cancer risk. They randomized postmenopausal women without prior breast cancer from 40 clinical centers to a daily dose of 1,000 mg of elemental calcium as calcium carbonate and 400 IU of vitamin D (n = 16,936) or to matching placebo (n = 16,815).

More than half (54%) of these study subjects also had been randomized 1 year previously to a study of hormone replacement therapy (HRT) vs placebo. The primary study endpoint of that study was hip fracture incidence. The secondary endpoints were colorectal cancer and breast cancer incidence.

Dr. Chlebowski reported that at mean follow-up of 7 years, breast cancer incidence did not differ between the calcium/vitamin D and placebo groups (528 vs 546 cases, HR 0.96). SEER stage and abnormal mammogram frequency were similar between groups, but breast cancers were smaller in the supplementation group (1.54 cm vs 1.71, P = .05).

Suggested Hypothesis

Total vitamin D baseline intake was associated with lower breast cancer risk in the placebo group. Dr. Chlebowski said that in 19,115 women not using vitamin D supplements at baseline, 18% fewer tumors were seen with supplementation than with placebo. There was no such effect in the women who were taking vitamin D at baseline, suggesting a hypothesis—namely, that low vitamin D intake is associated with higher breast cancer risk, which can be mitigated by modest supplement use.

More than 72% of patients reported at least mild joint pain at baseline in both groups, and one-third reported joint swelling. "Neither joint pain nor swelling were influenced by calcium/vitamin D," Dr. Chlebowski said.

Scientific Symposium

The WHI study came under scrutiny in a scientific symposium presented at ASCO ("Why the results of observational studies and randomized trials often conflict: Diet and cancer as an example").

John A. Baron, MD, of the Section of Biostatistics and Epidemiology at Dartmouth Medical School, compared the advantages and disadvantages of observational studies and clinical trials. He pointed to confounding as a major problem for observation studies, and drop-outs as a problem in randomized trials. "In real life, subjects are randomized, and then the trouble begins," he said.

With regard to the WHI study, Dr. Baron said, "In an unusual decision, the investigators made no effort to discourage subjects from taking calcium and vitamin D on their own. Remember, this was a study of calcium and vitamin D!" He also considered the intervention vitamin D dose to be "very low."

In defense of his study, Dr. Chlebowski, who was in the audience at the scientific symposium, said that the randomized clinical trial developed out of observational studies and so was an extension of the flows of the observation studies, but with "big public policy implications."