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INTRODUCTION
Breast cancer is the second most common type of cancer in women in the United States.1
One in eight women will be diagnosed breast cancer at some point in her lifetime. It is also the
second leading cause of cancer death in the United States, and the chance that a womans death
will be caused by breast cancer is one in 36.2
outcomes have improved since the 1990s,2 which has allowed a shift in focus of research from
total emphasis on survival to include research on the short and long-term impact of treatment and
quality of life.
The treatment regimen for breast cancer varies upon the patient status, cancer type and
disease progression, but is generally a combination of chemotherapy, surgery and/or radiation.
Chemotherapy can be divided into three major categories. The most common type of
chemotherapy includes anthracyclines (e.g., doxorubicin and epirubicin), taxanes (e.g., paclitaxel
and docetaxel) and other drugs, such as fluorouracil and cyclophosphamide. These drugs work
by interfering with DNA replication and cell reproduction. Targeted therapies, such as
trastuzumab (Herceptin), are for HER2 positive malignancies. Hormone therapies, which
include tamoxifen and aromatase inhibitors, are for estrogen receptor positive malignancies and
act by blocking either estrogen production or estrogen receptors in the body.1
These drugs are often used in combination with one another and can cause a variety of
side effects. Many of these side effects can have a negative impact on the patients food intake
and nutritional status. Since many chemotherapy drugs target cell replication, they affect cells
with high replication rates, namely epithelial cells. Common side effects are mouth sores,
nausea, vomiting, and malabsorption issues due to deterioration of the epithelial cells of the
digestive tract. Chemotherapy drugs can also cause damage to cardiac tissue and function and a
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decrease in both white and red blood cell production. Interruption of the digestive tract lining
and lowered disease resistance due to white blood cell counts are cause for dietary restrictions on
salad bars, raw and rare seafood or meats, and unwashed fruits and vegetables. Other common
side effects that influence nutritional intake include general fatigue and taste changes. In
addition, other medications often taken in conjunction with chemotherapy; such as anti-nausea
medications, steroids and antihistamines, can have a negative impact on the patients appetite and
food intake. Other side effects from chemotherapy that do not directly affect nutritional intake,
but may alter micronutrient needs are neuropathy, cardiotoxicity, hepatotoxicity, nephrotoxicity,
and osteoporosis.(1,2)
REVIEW TOPIC
This review examines research on vitamin and mineral supplements for adult women
undergoing chemotherapy for the treatment of breast cancer. This topic was selected because of
the prevalence of the disease, the importance of the possible implications of research findings
and the authors personal experience with breast cancer.
A womens diagnosis of breast cancer is often her first experience with a potentially life
threatening disease, and the treatment process can require both short term and long term changes
in lifestyle. It is a time that requires a quick education on many issues and there is a need for
reliable and consistent information. It is a very common public viewpoint that vitamin and
mineral supplements are strictly beneficial, especially for those individuals who might be
experiencing dietary restrictions or health issues. Without specific advice from a healthcare
provider, many individuals may assume that use of vitamin and mineral supplements while
undergoing chemotherapy is both safe and beneficial. Contrary to this belief, neither the
American Cancer Society nor the National Cancer Institute currently recommend the use of these
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(Suffolk and Nassau Counties, New York) diagnosed with a first primary invasive or in situ
breast cancer; whereas Zirpolis study was ancillary to an intervention trial of chemotherapy
drugs for patients from several locations across the United States who had been diagnosed Stage
II or II breast cancer and other specific criteria. The results of both studies were based on selfreported responses to questionnaires.
ANTIOXIDANTS
The primary focus of this review and primary controversy is antioxidants. Most
chemotherapy drugs are not cell specific and have a primary mechanism of action of producing
free radicals which lead to damage of cell membranes and DNA, thereby slowing or preventing
cell replication.(5,6,7) Although this method of action is an effective cancer treatment, it also
effects healthy cells; particularly cells that have a high replication rate.
Antioxidants prevent the formation of free radicals. Antioxidant blood levels are
typically lower in cancer patients prior to treatment.(7,8,9) A 5-month randomized controlled
study8 of 40 women with Stage II breast cancer revealed lower antioxidant blood levels (P<
0.001) and increased lipid oxidation and DNA damage (P< 0.001) prior to initiation of treatment
when compared to 40 healthy volunteers. This study compared the antioxidant enzymes levels,
lipid oxidation and DNA damage of supplemented patients post-chemotherapy versus nonsupplemented patients. Post-treatment, antioxidant levels were significantly higher and lipid
oxidation and DNA damage significantly lower (P<001) than the levels in the non-supplemented
patients.
A systemic review of 52 articles on this subject by Ladas et al.9 confirms that the
antioxidant status is lower in cancer patients pre-treatment when compared to healthy subjects.
However, the review found inconsistent results when comparing antioxidant levels pre- and post-
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chemotherapy treatment. It is unclear if the results are due to the ineffectiveness of supplements,
dosage levels or form of supplementation. In addition, the studies included in the review did not
take antioxidant dietary intake levels into consideration.
Proponents for antioxidants supplementation contend that both chemotherapy drugs and
antioxidants have multiple mechanisms of action that are not all understood, thus antioxidant
supplements should not be ruled out solely because of their ability to quench free radicals.
However, since antioxidants do prevent the formation of free radicals, supplementation can
reduce side effects and tissue damage caused by chemotherapy. Antioxidants support the
immune system and contribute to the overall wellbeing of the individual. It is believed that
antioxidant supplements can lower the toxicity of the chemotherapy without affecting efficacy of
the treatment and may possibly even increase the efficacy; enabling a higher tolerance to
chemotherapy drugs, better treatment completion rates, and shorter treatment timeframes;
leading to better overall survival, improved quality of life and decreased long-term medical
costs.
Block et al.(6,7) conducted two systemic reviews on the impact of antioxidant
supplementation on chemotherapeutic efficacy and toxicity. The review on efficacy6 included 19
randomized controlled studies for a total of 1,554 patients. The studies included all types of
cancers and mostly advanced or relapsed patients. The supplements evaluated varied by study,
but were glutathione, melatonin, vitamin A, an antioxidant mixture, vitamin C, n-acetylcysteine,
vitamin e and ellagic acid. The review concluded that there was no significant decrease in
chemotherapy efficacy from using antioxidant supplements. Of the 13 studies that examined
survival rates, all showed either similar or improved survival rates. Of the 17 studies that
examined overall response, 16 reported similar or improved response rates. Of the 17 studies
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that examined general toxicities, 15 showed similar or reduced toxicity rates. Only one study
showed an increase in general toxicities. This study involved high dosages of vitamin A.
The second review by Block et al.7 looked at the impact of antioxidant supplementation
on chemotherapeutic toxicity. There were 33 randomized controlled studies, for a total of 2,446
patients, which met the criteria for this review. The studies included all cancer types and
examined the supplementation of glutathione, melatonin, vitamin E, mixed antioxidants,
selenium, n-acetylcysteine, l-carnitine, vitamin A, ellagic acid and coenzyme Q10. There were
86 reports on toxicities, of which 46 showed the intervention group having less toxicity than the
control group. Of these 46, 84% showed statistically significant differences. Of the remaining
reports, 37 showed no difference in toxicities and three showed an increase in toxicities.
Although the authors recognize that there were a number of limitations to the two reviews;
namely the small size of the studies, majority of subjects in advanced stage of disease, variety of
antioxidant types and dosages and the lack of double-blinding; they concluded that the results of
the two reviews suggest that further research on this topic is warranted.
Other researchers and medical professionals maintain that since antioxidants interfere
with the primary method of action of many chemotherapy drugs, supplements can interfere with
treatment and may also support the growth of tumors. While antioxidants from food sources are
both safe and beneficial, some dosages and forms of antioxidant supplements can be harmful to a
patient already at risk for various toxicities.
Greenlees et al.5 review of 22 studies focused on antioxidant supplements during
treatment specifically for breast cancer. The reviewed concluded that there is not sufficient
evidence of a beneficial effect from the use of antioxidant supplements to warrant routine
recommendation of supplements, and that some studies showed decreased survival and increased
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side effects. The review suggests that well designed trials are needed, but currently there is not
enough data to provide clear guidelines either way. As stated by Lawenda et al.10, due to the
lack of evidence and potential for harm, it is recommended that health care providers take the
stance of do no harm.
CALCIUM AND VITAMIN D
Chemotherapy can lower estrogen levels. Some drugs block estrogen receptors and other
block the production of estrogen. Others damage the tissue of the ovaries, inducing early
menopause. This puts the patient at an increased risk for osteoporosis and so calcium and
vitamin D supplements are often recommended. However, calcium supplements may increase
the risk of cardiovascular disease.
Datta and Schwartz11 conducted a systemic review which examined the effectiveness of
calcium and vitamin D supplements in preventing the loss of bone mineral density in women
undergoing breast cancer therapy. The review found that supplement doses of 200 -1,000 IU of
vitamin D and 500-1,500 mg of calcium per day were not effective in preventing the loss of bone
mineral density in women with breast cancer. Given that chemotherapy and radiation can
damage heart tissue and function and the potential of harmful effects of calcium supplements, the
reviewers recommend that further study is needed on both the safety and efficacy of calcium and
vitamin D supplementation.
CONCLUSION
Current evidence does not support the routine recommendation or prescribing of vitamin
and mineral supplements to the adult female breast cancer patient during chemotherapy
treatment. The potential impact on long and short term side effects, chemotherapeutic dose
tolerance, improved response, increased survival and decreased long term cost; as well as the
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potential negative impact of interference of efficacy, increased toxicities and increased cardiac
issues all make this an important subject worthy of further study.
Problems with the current data include the heterogeneity of supplement type and dosage
and cancer type and progression. Interventional trials to date have been small in size and short in
time. There is a demonstrated need for well-designed, large scale studies to determine the effects
of supplements.
Until more is known about the effects of supplements, the lack of firm data may make
healthcare providers hesitant to discuss the matter with their patients. As a result, many patients
opt to self-educate and self-medicate with nutritional supplements that could potentially interfere
with their treatment or health. It is important that what is known and unknown about the effects
of supplements be discussed with patients so that they can make informed decisions.
APPLICATION TO PRACTICE
The impact of cancer and cancer drugs on the nutritional status of the patient, plus the
possible impact of supplements on both tumor and patient, convey the importance of assessment
and monitoring of nutritional intake and needs during the course of treatment. Patients should
also be monitored for deficiency relate side effects and symptoms in order to limit tissue damage,
maintain optimal health and promote the best possible outcome for the individual patient.
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References
1. American Cancer Society Web site. Available at: http://www.cancer.org. Accessed October
1, 2013.
2. National Cancer Institute Web site. Available at: http://cancer.gov. Accessed October 12,
2013.
3. Greenlee H, Gammon M, Jacobson J, et al. Prevalence and Predictors of Antioxidant
Supplement Use During Breast Cancer Treatment The Long Island Breast Cancer Study
Project. Cancer. 2009;115(14):3271-3282. Available from: Science Citation
Index,
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9. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and
cancer therapy: A systematic review. J Clin Oncol. 2004;22(3):517-528. Available from:
CINAHL Plus. Accessed October 10, 2013.
10. Lawenda B, Kelly K, Ladas E, Sagar S, Vickers A, Blumberg J. Should supplemental
antioxidant administration be avoided during chemotherapy and radiation therapy?. J Natl
Cancer Inst. 2008;100(11):773-783. Available from:
2013; (currently in
2013.