VITAMIN SUPPLEMENTS IN BREAST CANCER

December 30, 2010 — The evidence continues to be unclear as to whether dietary supplements are helpful or harmful during cancer treatment. Many clinicians recommend that vitamin supplements — and in particular, high doses of antioxidants — not be used while therapy is ongoing because of concerns that they might reduce the efficacy of radiation and chemotherapy.

However, a new study finds no evidence that the use of vitamins during first 6 months after a diagnosis of breast cancer adversely affected outcomes. In fact, it found quite the opposite: vitamin use appeared to have a beneficial effect among patients with breast cancer who underwent chemotherapy.

Vitamin use — and the use of vitamins C and E in particular — appeared to be associated with reduced risk for mortality and recurrence.

The study was published online December 21 in Cancer Epidemiology, Biomarkers & Prevention.

Patients who used antioxidants (vitamin E, vitamin C, multivitamins) had an 18% reduction in their mortality risk (hazard ratio (HR), 0.82; 95% confidence interval [CI], 0.65 - 1.02), and the risk for recurrence was decreased by 22% (HR, 0.78; 95% CI, 0.63 - 0.95). This association was observed whether vitamin use was concurrent or nonconcurrent with chemotherapy. However, this benefit was only seen in patients who did not receive radiotherapy.

Although complete information was not available for dosages taken, approximately 85% of vitamin C users took 400 mg/day or less, and 99% of vitamin E users took 400 mg/day or less.

Helpful or Harmful?

"The recommendation to avoid supplements during cancer treatment is based on the concern that antioxidant supplements may protect tumor cells during radiotherapy and chemotherapy, thereby reducing the effectiveness of cancer treatments and potentially increasing risk of mortality and cancer recurrence," said Xiao Ou Shu, MD, MPH, PhD, lead author of the study and a professor of medicine at Vanderbilt University School of Medicine, Nashville, Tennessee.

Dr. Shu pointed out that the evidence to support this concern is largely based on laboratory studies and on 1 randomized controlled clinical trial of 540 patients with head and neck cancer. That randomized trial reported that risk for all-cause mortality was increased among participants who were given supplements and who smoked during radiotherapy.

"On the other hand, there is also evidence that antioxidant supplements may help protect normal cells from oxidative damage that occurs during cancer treatment, and thereby reduce the short- and long-term harmful effects of cancer treatment," Dr. Shu told Medscape Medical News.

A number of studies have evaluated the use of antioxidant supplements in the primary prevention of cancer. As previously reported by Medscape Medical News, 2 studies that examined the use of multivitamins and breast cancer risk came to very different conclusions: One study found that their use decreased the risk for breast cancer, and the other study showed that vitamin supplementation actually increased the risk for breast cancer.

The use of vitamin supplements is common among patients with breast cancer, but very few studies have investigated the role of vitamin supplement use during treatment and prognosis. "To our knowledge, our study is the first large prospective cohort study to investigate whether regular doses of vitamin supplement during cancer treatment influences breast cancer prognosis," Dr. Shu commented. "It should be noted that in our study, most breast cancer patients took a regular dose of vitamin supplement, while the above-mentioned head-neck cancer clinical trial investigated megadose vitamin supplements."

Opens Door for Discussion

This latest study is squarely at the heart of an ongoing controversy in integrative oncology, commented Mary Hardy, MD, medical director of the Simms/Mann University of California–Los Angeles Center for Integrative Oncology. "There are theoretical concerns with antioxidants that they can be harmful, while this paper says that there are beneficial. But even if you read this paper conservatively," she said, "it doesn't appear that antioxidants interfered with outcomes."

In an interview, Dr. Hardy noted that the study does have significant limitations — the primary one being that it is not a randomized trial. The study was also conducted in a population of women in Shanghai, China, so there may be issues such as diet, culture, genetics, and so forth that could affect outcome.

"But the most important aspect of this paper is that it begins to suggest...what a lot of us in integrative oncology have been saying,...that the monolithic absolute rejection of all antioxidants is probably not going to be supported by the literature," said Dr. Hardy.

The risks have always been theoretical, and many patients with cancer are using supplements, she explained. "And in many cases, when physicians would say not to use them, patients would just continue anyway and then not tell their physician."

The current study "allows physicians some degree of comfort, or to better tolerate some things that they may not have been comfortable with," Dr. Hardy told Medscape Medical News. "Patients really don't like absolutes, and this allows doctors to have a much more nuanced discussion about the subject."

However, it remains a complicated issue, and this study does not settle the question, she added.

Dr. Shu agrees. "Results from single observational study are not adequate to change the guidelines of vitamin use during cancer treatment," she said. "However, our study calls for more studies on this particular question, particularly in different settings and populations."

Lower Risk for Mortality and Recurrence

In this study, Dr. Shu and colleagues evaluated the associations of total mortality and breast cancer recurrence with vitamin supplement use in a population-based prospective cohort study of 4877 women diagnosed with invasive breast cancer. The study was conducted in Shanghai, China, between March 2002 and April 2006, and patients were interviewed approximately 6 months after their diagnosis.

At an average of 4.1 years of follow-up (range, 0.5 - 6.2 years), 444 women had died (389 from breast cancer, 55 from other causes). A total of 4325 patients remained disease free during the follow-up period, and 532 experienced a disease recurrence.

Of the breast cancer survivors, approximately 36.4% ever used any type of vitamin supplement after their diagnosis. Vitamin C was the most commonly used (17.5%), followed by B vitamins (16.3%), vitamin E (7.6%), vitamin A (1.7%), and vitamin D (0.4%). In addition, about 11% reported using multivitamins.

Vitamin users tended to have higher levels of education, income, daily intake of cruciferous vegetables, and soy protein and were more likely to have a lower body mass index. They were also more likely to be nonsmokers and to report consumption of tea and regular exercise.

The use of vitamins also did not significantly vary as far as age at diagnosis, joint estrogen receptor and progesterone receptor tumor status, TNM stage, type of cancer treatment (chemotherapy, radiotherapy, tamoxifen use), number of pregnancies, family history of breast cancer, alcohol intake, or meat intake.

Overall, use of vitamins within the first 6 months of cancer diagnosis (including any vitamins, multivitamins, vitamin E alone, vitamin C alone, and any antioxidants) was associated with a lower risk for total mortality and breast cancer recurrence, with the largest risk reduction observed in patients who used vitamins C or E for a longer duration after diagnosis.

More specifically, the authors note, women who used vitamin C for more than 3 months had a 44% decrease in risk for mortality (adjusted HR, 0.56; 95% CI, 0.37 - 0.87) and a 38% decrease in risk for disease recurrence (adjusted HR, 0.62; 95% CI, 0.43 - 0.90).

On a similar note, women who used vitamin E for more than 3 months had a reduced risk for both mortality (adjusted HR, 0.52; 95% CI, 0.27 - 1.01) and recurrence (adjusted HR, 0.57; 95% CI, 0.32 - 1.01), although point estimates were of marginal statistical significance.

Associations With Radiotherapy

The researchers also investigated the effect of radiotherapy (which was used in about one third of women) on the outcomes seen with vitamin use.

Among the women who did not receive radiotherapy (n = 3280), vitamin use was associated with a lower risk for both mortality and recurrence. This association was the strongest observed for use of any antioxidant (adjusted HR for mortality, 0.65; 95% CI, 0.47 - 0.92; adjusted HR for recurrence, 0.63; 95% CI, 0.46 - 0.86).

Patients who used vitamins and did not receive radiotherapy were at reduced risk for mortality (adjusted HR, 0.67; 95% CI, 0.48 - 0.94) and recurrence (adjusted HR, 0.66; 95% CI, 0.49 - 0.89) compared with those who did not receive radiotherapy or use vitamins.

Women who did undergo radiotherapy (n = 1597) showed slightly worse outcomes, but the results were not statistically significant. Women who underwent radiotherapy and who did not take antioxidant vitamins were at nonsignificant increased risk for mortality (adjusted HR, 1.26; 95% CI, 0.92 - 1.72) and recurrence (adjusted HR, 1.26; 95% CI, 1.00 - 1.57).

Similarly, patients treated with radiotherapy and who used antioxidant vitamins also had nonsignificant increased risk for mortality (adjusted HR, 1.27; 95% CI, 0.99 - 1.64) and recurrence (adjusted HR, 1.17; 95% CI, 0.88 - 1.54).

The study was funded by grants from the Department of Defense Breast Cancer Research Program and the National Cancer Institute. The authors have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. Published online December 21, 2010.