Journal of the National Cancer Institute Advance Access originally published online on October 28, 2008
JNCI Journal of the National Cancer Institute 2008 100(21):1558-1559; doi:10.1093/jnci/djn346
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: Should Supplemental Antioxidant Administration Be Avoided During Chemotherapy and Radiation Therapy?
Affiliation of authors: Simone Protective Cancer Institute, Lawrenceville, NJ
Correspondence to: Charles B. Simone, MD, Simone Protective Cancer Institute, 123 Franklin Corner Road, Lawrenceville, NJ 08648 (e-mail: mail{at}drsimone.com).
Lawenda et al. (1) expressed concerns about our review (2) of antioxidant and nutrient use during chemotherapy or radiation. The authors stated that we reviewed 52 human trials when in fact we discussed only 50. They dismissed the 36 observational studies we reviewed on the basis of study design. Unlike Lawenda et al., however, we included all pertinent peer-reviewed publications, regardless of randomization or sample size, to avoid bias and because observational studies provide valid information and virtually equivalent results as randomized trials, do not overestimate the magnitude of treatment effects, and are less costly than randomized trials (3,4).
Lawenda et al. further discounted 10 randomized trials that we cited because of small sample size. However, only five of nine trials with concurrent radiation and five of 16 trials with chemotherapy that they cited had a sample size more than 66 patients, and five chemotherapeutic trials had a sample size of 20 or fewer patients. Although Lawenda et al. concluded that "high-dose antioxidant supplementation during radiotherapy decreases local tumor control and shortens the survival of cancer patients," the very trials they cited do not substantiate these claims. Lawenda et al. also did not mention the survival benefit demonstrated in a 100-patient study by Lissoni et al. (Table 1), thus biasing their commentary.
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Although most of the trials they cited demonstrated a decrease in side effects and several also showed an increase in treatment response and overall survival, one (5) reported an increase in disease recurrence and second primaries among smokers who received supplements. Although Lawenda et al. stated that "this study is the most important randomized clinical trial, to date, on the use of supplemental antioxidant and radiation therapy," the conclusion drawn by the authors of that study was seriously flawed because they used retrospective capsule counts by patients to assess supplement compliance and never verified compliance by measuring antioxidant serum levels.
Lawenda et al. further stated that "anticancer therapies may lower plasma antioxidant concentrations by altering dietary intakes." Although this is true, we reported that plasma antioxidants are decreased mainly by chemotherapy and radiation due to lipid peroxidation.
Lawenda et al. speculated that "antioxidants can exert their effects on all tissues to some degree, thereby protecting tumor cells as well as healthy ones." However, the four in vitro studies they cited showed that more antioxidants accumulate in cancer cells than normal cells, which we reported (2). Accumulation of excessive antioxidants and nutrients in cancer cells can shut down oxidative reactions necessary for generating energy. Antioxidants also produce biologic effects on cancer cells unrelated to oxidative damage: they increase cancer cell differentiation, apoptosis, and growth inhibition, and they inhibit or enhance gene expression and/or activity of numerous proteins. Antioxidants selectively inhibit repair of radiation damage of cancer cells but protect normal cells when antioxidants are used before, during, and after radiation, and there are no published studies showing that antioxidants protect cancer cells against radiation (6,7).
Lawenda et al. begin their commentary with the maxim "first, do no harm." Studies involving thousands of patients have demonstrated that antioxidants and other nutrients do not interfere with chemotherapy or radiation, but instead decrease toxicity and may improve response rates and overall survival. Perhaps, then, should the first step in doing no harm be to have a discussion with cancer patients about the utility of concurrent antioxidant administration?
REFERENCES
1. Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst (2008) 100(11):773–783.
2. Simone CB II, Simone NL, Simone V, et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med. 2007; 13(1):22–28; Part 2. Altern Ther Health Med. 2007;13(2):40–47.
3. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med (2000) 342(25):1878–1886.
4. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med (2000) 342(25):1887–1892.
5. Bairati I, Meyer F, Jobin E, et al. Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer (2006) 119(9):2221–2224.[CrossRef][Web of Science][Medline]
6. Prasad KN, Cole WC, Kumar B, et al. Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. J Am Coll Nutr (2001) 20(5 suppl):450S–463S.
7. Prasad KN, Cole WC, Kumar B, et al. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev. (2002) 28(2):79–91.[CrossRef][Web of Science][Medline]
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