The Null Series — Vitamins for cancer prevention

Good news — that isn’t trying to scare us into doing something, buying something, or eating something — means there’s nothing to sell us. That may explain why good news is considered bad news and studies showing there’s nothing to worry about rarely make headlines. Yet, those unpopular “nothing to fear here” studies, also known as “null studies,” are some of the best kinds. They help us feel less stressed out and enable us to protect ourselves from being taken advantage of.

Sound studies bringing good news about our diets and the big three diseases of aging — cancer, heart disease and Alzheimer’s — have been published so fast and furiously this past month, that they’ve stacked up. So, we’ll mush them together into a brief series we’ll call the Null Series.

Today’s post highlights two major randomized, double-blind, placebo-controlled clinical trials of various vitamins and minerals and cancers.

B Vitamins

The Women’s Antioxidant and Cardiovascular Study (WACS) just published the results of its findings of the effects B vitamins — folic acid, vitamin B₆ and vitamin B₁₂ — on incidences of cancers.

This major clinical trial of more than 8,100 women had begun back in May, 1993 and ran through February of 2006. [Clinicaltrials.gov ID NCT00000541] It was carefully designed to determine whether various antioxidant vitamins were protective against chronic diseases of aging. Since it was reviewed here in detail, we’ll make its latest report brief.

This clinical trial had earlier reported no cardiovascular benefits of antioxidant vitamins C, E or beta-carotene. Those results from WACS had come after some 16 other major clinical trials — including the Heart Outcomes Prevention Evaluation (HOPE), Atherosclerosis Folic Acid Supplementation Trial (ASFAST), and the Norwegian Vitamin Trial (NORVIT) — all firmly demonstrating no benefit of folic acid or vitamin supplementation for heart disease or for that all important clinical endpoint, premature death.

No matter how many clinical trials have consistently failed to support a role of antioxidants for preventing age-related diseases, beliefs in vitamins and phyto-rich fruits and vegetables continue. The free radical theory has not been easily swayed in the hearts and minds of the public. Or in public health officials. One might have thought that the Cochrane Collaborative’s latest systematic review of every clinical trial of antioxidants conducted since 1945 would have finally put the issue to rest. It found no sound evidence that antioxidants decrease mortality or any evidence to support a role of antioxidants for primary or secondary prevention. [Reviewed here.]

So, this new study, published in the Journal of the American Medical Association, might seem redundant, but it may provide women added reassurance about their risks for breast cancer and other cancers. Briefly, in this arm of the WASC trial, 5,442 women health professionals who had at least three risk factors for heart disease had been randomized to receive either folic acid, B₆ and B₁₂ or a placebo. They were then followed for more than 7 years. There were a total of 379 incidences of invasive cancers (187 in the vitamin group and 192 in the placebo group) with a clinically insignificant difference in cancer cases: 1.01% versus 1.04%, respectively.

Calcium and Vitamin D

This next study warrants a more in-depth look, especially because misinformation has been prolific in the media surrounding it and vitamin D. The Women’s Health Initiative just published the results of its randomized, placebo-controlled, blinded clinical trial of calcium and vitamin D supplementation on women’s risks for breast cancer.

As readers may remember, the WHI was launched in 1992 as the largest study on women’s preventive health. [Clinicaltrials.gov ID NCT00000611] It included a massive observational arm, but more importantly, some of the most carefully conducted randomized, placebo-controlled, clinical trials in our country’s history to test preventive health measures for the leading causes of death, disability and impaired quality of life for women. More than 68,000 women participated in the randomized controlled trial, at forty medical centers across the country, that included four interventions. One was the WHI Dietary Modification Trial — one of the largest, longest and most expensive randomized controlled diet clinical trials in the history of our country and was designed to finally put to test the government’s “healthy” eating dietary guidelines for the prevention of obesity and chronic diseases. After eight years of intensive interventions, there were no significant differences in the incidences of more than 30 cancers, heart attacks or strokes, diabetes or weight changes, among the more than 19,000 women who ate a restrictive “healthy” diet and the control group of nearly 30,000 women who ate whatever they chose.

The results of another WHI trial just published in the November issue of the Journal of the National Cancer Institute had enrolled 36,282 postmenopausal women who were cancer-free with no history of breast cancer or any other cancers for a decade. The women’s diets and supplement usage were assessed with food frequency questionnaires at the beginning of the trial, including vitamin D intakes, and they had blood tests to measure their 25-hydroxyvitamin D levels (the biologically active form of Vitamin D, explained here). The women were randomized to receive 1,000mg elemental calcium and 400IU of vitamin D₃ or a placebo.

The intervention group and control group were extremely evenly matched at baseline and throughout the study among an extensive list of potential confounding factors including age, race/ethnicity, education, geographic region, age at menarche, family breast cancer history, oophorectomy, hormone use, use of tamoxifen or raloxifene (only used by 0.06 to 0.11%), BMI, physical activity, alcohol, smoking, aspirin usage, and baseline total calcium and vitamin D intakes (both from dietary sources and supplements). The third of women already taking calcium with vitamin D supplements in both the intervention and control groups were allowed to continue them. But all of the women in the intervention group added the study vitamin D to their usual intakes, increasing their Vitamin D intake by 400 mg, bringing some of the women up to a total of 1,000mg/day. Throughout the trial, the usage of vitamin D supplements remained even between the study arms at every level of usage, with about a 3% annual loss of compliance also even between the groups.

The women were followed for an average of 7 years with annual clinical exams, serial mammograms and breast exams. A total of 528 invasive cancers were diagnosed in the supplement group and 546 in the placebo group; 145 and 152 in-situ cancers; and a total of 23 deaths in each group. No statistical difference. The histologies of their cancers were similar, and they were of similar stages and estrogen receptor status. There was no difference in the cumulative risk for breast cancers among the women taking calcium and vitamin D and the women on the placebo, as strong of a null finding as you'll find:

The authors concluded:

In this randomized, double-blind, placebo-controlled trial, daily supplementation with 1000 mg of elemental calcium combined with 400 IU of vitamin D 3 had no effect on breast cancer incidence. Thus, the main findings do not support a causal relationship between calcium and vitamin D supplement use and reduced breast cancer incidence, despite the association observed in some epidemiological studies.

Here we go again

As they reviewed, claims surrounding vitamin D’s possibly preventive role in cancer come primarily from epidemiological studies, looking for correlations among a group of people, or computer modeling. Although some observational (epidemiological) studies report an inverse association between higher vitamin D and/or higher calcium intakes and lower postmenopausal breast cancers, an equal number of others do not, with quality varying notably. Similar inconsistencies are found in observational studies of 25-hydroxyvitamin D levels and associations with breast cancers.

[Examples of epidemiological studies of vitamin D and/or calcium and correlations to cancers, fractures and overall mortality were looked at here, here and here. Correlations aren’t always tenable and outside chance or statistical error, either, but usually make the news as if they were. The soundest studies show little tenable correlations between calcium intake and hip fractures, and many hip fractures occur in women with particularly low bone densities. Beware those confounding factors behind correlations.]

All studies are not equal, but it has proven difficult to help people understand the scientific process and what makes a fair test of an hypothesis. In an earlier issue of the Journal of the National Cancer Institute, Gary G. Schwartz (with the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, NC) and William J. Blot (at the International Epidemiology Institute in Rockville, MD, and Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center in Nashville, TN) wrote about a large epidemiological data dredge from the Physicians Health Study. It had reported statistically significant lower cancers associated with vitamin D and speculated that most men had suboptimal vitamin D and 25-hydroxyvitamin D levels. Doctors Schwartz and Blot cautioned: “Although the cohort findings are likely to increase enthusiasm for the cancer prevention potential of vitamin D, inherent limitations of observational epidemiologic studies, combined with a history of prior disappointments with other potential chemopreventive agents, suggest caution in their interpretation.”

There is a long history of people jumping behind a vitamin, food, diet or lifestyle based on epidemiological correlations, only to discover later when it was put to test in carefully-conducted clinical trials, the popular belief was disproven. Beta-carotene was thought to prevent cancers, before randomized trials found it might even increase risks. Then there was vitamin E, long publicized for its cancer and heart disease prevention, only to be crushed in multiple randomized clinical trials. Low-fat, wholegrain, fruits and vegetables have gone the same way. Even this same WHI trial reported on the effects of calcium and vitamin D supplements on bone densities and fractures in the New England Journal of Medicine and found that after 7 years, the supplements resulted in a small, statistically significant improvement in hip bone density, but did not reduce hip fractures, while the supplements slightly increased the risks for kidney stones. There was also no reduction in mortality among those taking supplements.

The somber reality is that correlations found in observational studies, no matter how solid, strong, consistent and impressive they might seem, cannot substitute for actual randomized clinical studies on real people.

“The sobering lesson is that trends observed in non-experimental settings, including cohort studies, are not always confirmed experimentally when tested in randomized clinical trials,” wrote doctors Schwartz and Blot. “Science, after all, is a continual process of hypothesis formulation, testing, and refinement.” Epidemiological studies, showing correlations (such as geography and sunshine and cancer, as reviewed here) only provide clues to possible causes, they wrote, “but randomized trials are generally needed to confirm these leads and develop effective disease prevention strategies.”

The WHI authors then exhaustively looked more closely at the data to parse out if there were any other possible relationships. They performed a nested case-control analysis of the 25-hydroxyvitamin D levels among the 1,067 women who got breast cancer and matching controls who were breast cancer free. There was no association between 25-hydroxyvitamin D levels and breast cancer risk, after adjusting for confounding factors (age, race/ethnicity, family history, BMI, physical activity, hormone use, etc.). In fact, there was no linear relationship (dose-response) between 25-hydroxyvitamin D levels (<32.4nmol/L to >67.6nmol/L) and those who went on to develop invasive breast cancer during the study.

Dispelling one popular misconception, the authors found little correlation between the women’s 25-hydroxyvitamin D levels and their vitamin D intakes — or with their geographic location (which in some studies has been used as a correlation with sunshine). There was no interaction between vitamin D intakes and any of the differing 25-hydroxyvitamin D levels. There was considerable overlap in vitamin D intakes at all ranges of 25-hydroxyvitamin D levels. In other words, adding more vitamin D to the diet wasn’t shown to correspondingly raise the biologically active form of vitamin D in the body. This has been supported in 16 prospective trials which have found wide variations between the dose of vitamin D supplements and changes in 25-hydroxyvitamin D levels. As the authors noted:

Such results suggest that factors other than dietary and supplement intake of vitamin D likely influence 25-hydroxyvitamin D levels. In fact, although sunlight exposure is a recognized influence on 25-hydroxyvitamin D levels,a substantial genetic influence on such levels has also been reported…Although this mechanism is speculative, a genetic predisposition to both high 25-hydroxyvitamin D levels and low breast cancer risk could appear as a protective effect of vitamin D on breast cancer.

So, before clinical trials of higher doses of vitamin D for cancer prevention are implemented, they said, researchers would first need to demonstrate that the chosen vitamin D dose could definitively increase the circulating 25-hydroxyvitamin D levels in order to support claims of vitamin D’s causal role.

Another increasingly popular assertion, based on the suggestions from some epidemiological statistical analyses, is that higher doses of vitamin D than were used in this trial would be needed to see a reduction in breast cancer. “However, our findings provide some evidence against that hypothesis,” the authors said. “Because approximately half of the women were taking an additional 400 IU of nonprotocol vitamin D supplement daily, actual vitamin D supplement intake was greater than 800 IU daily for a substantial number of participants in the supplement group.” Still, no effects on risk of breast cancer were observed at any dosage, nor a suggestion of a favorable dose response. Quite the opposite.

Of interest is how meticulously the authors compared each level of total vitamin D intake among these women from both diet and supplements, with and without the usual supplement users, and looking at the supplement users alone, and there were no tenable correlations to breast cancer. In fact, the women with the highest vitamin D intakes at the start of the trial from natural dietary sources and taking supplements (and hence, would also have had the longest and highest levels with the trial drug added) had the highest risks (34%) for breast cancer of any level of vitamin D intake. Those women who’d been consuming the lowest levels (<200mg/day) were associated with the lowest risk (21% lower). Although we’re splitting hairs here among untenable risks, those with the highest baseline vitamin D levels from natural dietary sources only, also had the highest risks, 6%. The point being again, there is no suggestion of a favorable dose response or that higher doses might be beneficial.

“Although further study of relationships among calcium plus vitamin D supplement use and breast cancer can be considered, current evidence does not support their use in any dose to reduce breast cancer risk,” they said.

Another possible issue raised was that the 15% of women in the placebo group who continued to take their regular calcium with vitamin D supplements could be said to cross over into the intervention group among the women who weren’t taking any before the trial began and had increased their intakes to those levels. But the authors pointed out that the difference in calcium and vitamin D dose between the intervention and control groups was enough to show a statistically significantly increase bone mineral density, and their overall findings were strong enough to hold regardless.

Another question that’s been raised is that 7 years might not be long enough to observe a protective role of vitamin D for breast cancer and that cancers can take years to develop and the women hadn’t taken the supplements long enough. The authors quelled this concern by pointing out that the drugs raloxifene and tamoxifen approved by the FDA for use in breast cancer reduction, had shown efficacy in their clinical trials within five years. “Given difficulties in maintaining long-term drug adherence, any putative pharmacologic intervention that requires decades-long and continuous exposure would likely have limited public health implications,” they said.

In summary, calcium and vitamin D supplementation in the dosage provided in this trial did not reduce the incidence of invasive breast cancer in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

The media spin has been quite different, among those who’ve reported this study at all. This study provides reassurance that there is no support for us to worry that we are raising our risks for cancer based on how much calcium and vitamin D we consume. Coming up in the next edition of the Null Series is a look at the latest good news studies on vitamins and fiber for the prevention of heart disease.

© 2008 Sandy Szwarc