Nutritional Supplements and Cancer: Potential Benefits and Proven Harms
Expert guidelines from the American Cancer Society, the World Cancer Research Fund, and the American Institute for Cancer Research advise patients with cancer against the use of supplements and advocate obtaining nutrients from foods wherever possible. Despite this, self-prescribed nutritional supplements use is widespread among patients with cancer. The lack of high-quality evidence of benefıts or harms leads to inconsistent or lack of supplement advice from clinicians. Data collected between 2003 and 2010 within the Intergroup phase III Breast Cancer Chemotherapy trial (S0221) found 48% of patients were taking multivitamins; 20% were taking Vitamin C, D, and n-3 oils; 15% vitamin E, B6, and folic acid; and 34% calcium. Clinicians advised one third to start taking a supplement during treatment, 10% to stop taking one, and 7% to stop all except a multivitamin; 51% received no advice.
MULTIVITAMIN AND MINERAL SUPPLEMENTS
These include a range of multivitamin and mineral supplements often found in amounts comparable to the recommended daily allowance, and are the most popular supplements taken by approximately one-third of the U.S. population and half of patients with cancer.
No randomized trials have assessed the effect of multivitamins on toxicity or survival after diagnosis. Observational data from colorectal and breast cancer cohorts in which 50% to 72% of patients were self-prescribing multivitamins showed neither benefıcial nor harmful effects of these supplements on toxicity or survival. A recent meta-analysis of 21 randomized trials in the general population based on 91,074 people and 8,794 deaths found no overall benefıcial or detrimental effects of multivitamin supplements on either all-cause mortality (relative risk [RR] 0.98 [0.94 to 1.02]), cancer mortality (RR 0.96 [0.88 to 1.04]), or vascular mortality (RR 1.01 [0.93 to 1.09]).7 However, two large-scale, randomized controlled trials have reported reduced cancer incidence among men taking a daily multivitamin versus a placebo. In the Physicians’ Health Study (PHS) II trial (14,641 male U.S. physicians), multivitamins reduced incidence of cancer (hazard ratio [HR] 0.92 [0.86 to 0.998]). Likewise in the French SU.VI.MAX Study, men had a modestly reduced risk of cancer (HR 0.69 [0.53 to 0.91]). Supplementation may be effective in men in these trials as it may be restoring adequate intakes of nutrients that were low in baseline diets. There is insuffıcient evidence to make recommendations for the use of multivitamins and minerals in patients with cancer.
ANTIOXIDANT VITAMINS AND MINERALS
Antioxidants have been studied in patients with cancer fırst as potential anticancer agents to improve outcome and second to reduce oxidative damage from chemotherapy and radiotherapy and hence the dose-limiting toxicities of therapies.
Antioxidants have well-defıned potential anticancer effects, including reduced oxidative damage to DNA, lipids and proteins; reduced proliferation and angiogenesis; and increased apoptosis and therefore possible reduced initiation, promotion, progression, and metastases of cancer. Laboratory fındings and observations of lower antioxidant status among those who develop cancers led to a number of large scale, randomized antioxidant cancer prevention trials. These trials recently summarized by Dolara et al have mainly been negative, with some notable harmful effects. Supplementation with beta-carotene increases risk of lung cancer (RR 1.16 [1.06 to 1.27]) and stomach cancer (RR 1.34 [1.06 to 1.7]), while vitamin E increases prostate cancer (RR 1.17 [1.00 to 1.36]) and colorectal adenoma (RR 1.74 [1.09 to 1.79]). Selenium reduced lung cancer in populations with low selenium status (serum_106 ng/mL), increased rates in those with higher serum levels (serum _ 126 ng/mL), and reduced gastric cancer occurrence (RR 0.59 [0.46 to 0.75]). Antioxidant supplements can increase cardiovascular disease (CVD), diabetes, and mortality in the general population. A recent meta-analysis of randomized trials reported increased overall mortality with beta-carotene (RR 1.05 [1.01 to 1.09]) and vitamin E (RR 1.03 [1.00 to 1.05]) and higher doses of vitamin A. Neither vitamin C (RR 1.02 [0.98 to 1.07]) nor selenium (RR 0.97 [0.91 to 1.03]) were benefıcial, (RR 1.0006 [1.0002 to 1.001] P _ 0.002).
These trials highlight the potential cancer-promoting and adverse effects of antioxidants on overall mortality for patients with cancer. An additional concern for patients with cancer is that although antioxidants may reduce the toxicity of chemotherapy and radiotherapy, this reduced toxicity may be at the cost of reduced treatment effıcacy since radiotherapy and many chemotherapy agents (e.g., alkylating agents, anthracyclines, podophyllin derivatives, platinum complexes, and camptothecins), exert their anticancer effects by production of reactive oxygen species (ROS) and increased apoptosis.
Antioxidant Supplementation during Radiotherapy
Although antioxidants reduce radiotherapy toxicity among patients with head and neck cancer, it comes at the cost of increased overall recurrence and mortality, particularly among those who smoked during radiotherapy treatment. Both smoking and antioxidants may reduce radiation effects. Smoking increases blood carboxyhemoglobin and tissue hypoxia, which may reduce the oxygen dependent effects of radiation therapy. In contrast beta carotene supplements did not reduce outcome among patients with prostate cancer in the PHS. Other trials of antioxidants have produced mixed effects on radiotherapy toxicity.
Antioxidant Supplementation during Chemotherapy
Short-term studies have reported benefıcial effects of antioxidants for some but not all cisplatin toxicities. Vitamin E reduced neuropathy, and selenium reduced hematologic toxicity but did not affect nephrotoxicity or ototoxicity. No benefıts have been reported for vitamin E versus taxane neuropathy, oxaliplatin-induced peripheral neuropathy, anthracycline cardio toxicity, or general carboplatin toxicity. None of these trials have assessed the long-term effects of antioxidant supplementation during chemotherapy on recurrence and survival.
Antioxidant Supplementation in Patients with Cancer Not Receiving or after Chemotherapy or Radiotherapy
Three trials reported no effect of supplementation on outcome. These were trials of selenium among patients with stage I, post-op non-small cell lung cancer (NSCLC), beta-carotene among patients with head and neck cancer after radiotherapy, and vitamin E, selenium, vitamin C, and coenzyme Q10 for patients with untreated progressing prostate cancer. Supplementation with antioxidants decreased the recurrence of colon adenomas among nonsmokers and drinkers (RR 0.56 [0.35 to 0.89]), but it doubled risk among participants who smoked and also drank more than one alcoholic drink per day (RR 2.07 [1.39 to 3.08]; p_ 0.001 for difference from nonsmoker/nondrinker). A recent randomized controlled trial reported reduced recurrence of noninvasive bladder cancer with vitamin E supplementation. Two large-scale, phase III trials in Belgium (SELEBLAST trial; 200 _g selenium, 700 patients, NCT00729287) and the United Kingdom (SELENIB Trial; 200 _g selenium and 15 mg _ tocophorol vitamin E NCT00553345) are studying the benefıts of antioxidants for this population but have not yet reported.
Summary and Future Directions for Antioxidant Research
Antioxidants can have antineoplastic or neoplastic effects among patients with cancer that are a function of (1) the antioxidant (i.e., the specifıc choice of antioxidants, dose, and format used); (2) the phenotype of the patient (i.e., poor nutrition, smoking, or high alcohol intakes may lead to pro-oxidant and other carcinogenic effects of antioxidants); and (3) tumor site and therapy (i.e., antioxidants can act as pro-oxidants in tissues with elevated partial pressures of oxygen). This could partly explain the apparent adverse effects in more oxygenated head and neck cancer cells that were not seen in the prostate. Antioxidants appear to reduce the effıcacy of radiotherapy, but there are no trial data on outcomes with chemotherapy.
Further studies should investigate adjusting dosing schedules of antioxidants at the time of radio- and chemotherapy. Targeting individuals on the basis of polymorphisms that influence antioxidant enzymes may be important. Increased exogenous antioxidants could worsen the already poorer prognosis (three-fold) among patients with polymorphisms, which activate endogenous antioxidant enzymes (i.e., glutathione, manganese superoxide dismutase, and catalase) with already lower levels of ROS.
Consideration should be given to patients with cancer who are prescribed high-dose antioxidants for conditions such as age-related macular degeneration (ARMD). These formulations typically contain vitamin C (500 mg), vitamin E (10_g), beta-carotene (15 mg), zinc (80 mg as zinc oxide), and copper (2 mg as cupric oxide). Although these are being reformulated to include lutein and xanthin, which do not appear to have cancer promoting effects of beta-carotene among patients with ARMD.
Adverse effects have been reported with antioxidant supplements but not high antioxidant intakes derived from food. The Women’s Healthy Eating & Living Study (WHELS) tested a very high fruit and vegetable diet among patients with early breast cancer, which included 12 portions of fruit and vegetables and approximately 80 mg of beta-carotene and 1,000 mg of vitamin C per day. These high intakes had neither a benefıcial nor detrimental effect on outcome. Because this diet was initiated after chemotherapy or radiotherapy treatments, this trial does not inform any potential interactions between high dietary intakes and effıcacy of chemotherapy and radiotherapy. Vitamin E and beta-carotene may reduce toxicity from radiotherapy, but there is an associated increase in recurrence especially among smokers.
Vitamin D and Outcome after Diagnosis
Vitamin D is a fat soluble vitamin mainly acquired through endogenous synthesis via ultraviolet exposure of the skin, with minor contributions from dietary sources such as oily fısh, fısh liver oils, beef, liver, cheese, egg yolks, and fortifıed foods. Endogenously synthesized and ingested vitamin D undergoes fırst and second step hydroxylations in the liver and kidney to produce the active metabolite 1,25(OH)D3 (calcitriol). Calcitriol regulates the expression of genes important in development and progression of cancer and can induce cell differentiation and apoptosis and also inhibit proliferation, angiogenesis, invasivion, inflammation, and metastatic potential. Calcitriol also suppresses aromatase activity leading to reduced estrogen levels and reduced breast cancer risk.
Vitamin D defıciency is relatively common among patients with cancer. Typically 30% of patients have greatly reduced serum 1,25(OH)D (_ 25 nmol/L), and 70% have somewhat reduced serum 1,25(OH)D (25–50 nmol/L).36 Observational studies reviewed by Teleni and Buttigliero have linked low serum 25(OH)D with poorer outcome in some trials, with more consistent links reported for prostate and hematologic cancers and melanoma, inconsistent links with breast and colorectal cancer, and no relationship with lung cancer. Observational data can only infer association and not causality and are likely to be confounded by factors such as age, race, body mass index, and physical activity. Some trials have suggested a U-shaped relationship with greater mortality at lower and higher serum levels.
There are limited randomized data to assess the effects of vitamin D supplementation on outcome after diagnosis. A phase II trial of the active vitamin D metabolite calcitriol showed encouraging results among patients with advanced prostate cancer receiving docetaxel chemotherapy. However, the follow-up, open-labeled, phase III Androgen Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT) trial (953 patients) was prematurely stopped after an interim analysis showed a greater mortality in the supplemented versus placebo arm (36% vs. 29%). This may have been linked to different docetaxel dosing schedules between the supplemented (weekly) and un-supplemented (three weekly) arms.
Ongoing phase III randomized trials registered on the National Institutes of Health (NIH) clinical trials database (www.clinicaltrials.gov) are assessing whether vitamin D3 improves survival in patients with Chronic Lymphoid Leukemia (NCT01518959) and resected stage II Melanoma (NCT01264874).39 A partially randomized phase II trial is testing whether vitamin D3 improves survival in patients who are vitamin D–defıcient with newly diagnosed large B-cell lymphoma, early-stage chronic lymphocytic leukemia, and colorectal or breast cancer (NCT01787409; NCT01516216). There is unlikely to be a universal benefıt from vitamin D supplementation on survival among patients with cancer. Effects will be influenced by baseline vitamin D status, vitamin D receptor polymorphisms—which determine the biologic activity of vitamin D—and variable target effects dependent on the vitamin D receptor status of the tumor.
Effects of Vitamin D on Bone Health Among Cancer Survivors
Clinical practice guidelines recommend vitamin D and calcium supplements for subsets of patients with breast and prostate cancer whose bone density can be compromised by chemotherapy-induced menopause, aromatase inhibitors, and androgen deprivation therapy. Recommended doses range between 10 and 25_g vitamin and 1,000 to 1,500 mg for calcium. The assumption that supplements would benefıt bone health and would not cause harm in patients with cancer was based on practice in the non-cancer setting. However, recent meta-analyses have questioned the benefıts and harms of vitamin D and calcium in the general population and have reported no benefıts for vitamin D supplementation alone for bone density or fracture risk. Benefıts are limited to higher doses of vitamin D (_ 10 _g/day) when combined with calcium (_ 1,000 mg) in free living (no institutionalized) Individuals. Other reviews have linked calcium supplementation to increased risk of CVD, although there is a lack of consensus on these fındings.
The effıcacy, safety, and optimum dosage of vitamin D and calcium supplementation for patients with cancer has not been rigorously tested in randomized trials comparing supplements to a no supplement group. A recent review of 16 trials among patients with breast cancer reported declines in lumbar bone mineral density (BMD; 1.5–7.5% during 12 months of breast cancer treatments) in both pre- and postmenopausal women despite daily supplementation with 5 to 25 _g vitamin D and 500 to 1,500 mg calcium. Likewise, a review of 12 trials among patients with prostate cancer concluded that daily supplementation with 5 to 10_g vitamin D and 500 to 1,000 mg calcium was ineffective in preventing androgen deprivation therapy–related BMD loss. The need for vitamin D and calcium supplementation alongside bisphosphonate therapy for patients with osteoporosis is currently being debated in the non-cancer setting. However, supplementation is indicated in patients with low vitamin D status in whom bisphosphonates can provoke hypocalcaemia. Daily supplements of vitamin D (20–25 _g) improve lower limb strength and balance and reduce falls in older adults in the non-cancer setting who are vitamin D defıcient, but the benefıts of vitamin D on musculoskeletal health of patients with cancer is not proven. Given the potential lack of benefıt and potential adverse effects of vitamin D and calcium supplements, randomized trials are needed to evaluate the safety and effıcacy of calcium and vitamin D on bone and musculoskeletal health and CVD risk and among patients with cancer.
Effects on Cachexia and Performance Status
The potential for EPA and DHA as anticachexia agents was originally demonstrated 20 years ago among patients with cachexic pancreatic cancer by Wilmore et al. N-3 oils down-regulate pro-inflammatory cytokine production and the acute-phase protein response in patients with cancer, which plays a central role in cancer cachexia. Furthermore, EPA may inhibit the ubiquitin proteasome pathway, which induces atrophy of skeletal muscle. A recent review by the European Palliative Care Research Collaboration identifıed only six randomized controlled trials that had directly compared the effects of n-3 fatty acids to standard care without n-3 fatty acids among patients with cancer cachexia. Four out of six high-quality studies found no signifıcant benefıts of n-3 oil on appetite, weight, performance status, and quality of life, whereas one reported statistically signifıcant improved survival, median survival 150 days versus 400 days (p _ 0.025), and one increased physically activity, change in TEE (kcal day 340  versus 68  p _ 0.05). Eight randomized trials reported perioperative n-3 fats reduced postoperative complications. The maximum tolerated dose is 12 g of n-3 oil/day providing 2 g of EPA and 1.5 g DHA. The most common side effects of n-3 oil supplements in these trials are mild abdominal discomfort, flatulence, nausea, steatorrhea, and a fısh aftertaste.
A further large randomized controlled trial of EPA (2.18 g/day) versus megestrol acetate (412 patients) reported reduced weight gain with n-3 oil compared with the megestrol acetate arms: 6% versus 18% gained 10% or more of baseline weight (p + 0.004). Neither survival nor quality of life was signifıcantly different between the groups (p = 0.82). Two recent small trials have reported benefıts of n-3 among patients with advanced NSCLC receiving chemotherapy. A randomized controlled trial of 33 patients receiving daily 510 mg EPA and 340 mg DHA reported weight gains of 3.4 kg versus those receiving the placebo. Although a two-arm, nonrandomized phase II trial of 40 patients found 2.2 g/day EPA had better weight maintenance than placebo (-2.3 (0.9) vs. -0.5 (1.0) kg).52,53 Three ongoing trials are currently assessing the effects of DHA and EPA on chemotherapy-related toxicity or nutritional status (NCT01048463, NCT01025167, NCT01049295).
CONCLUSIONS AND FUTURE PERSPECTIVES
Predictably, administering supplements to unselected patients— often with adequate vitamin status— has not been successful. Identifying and repleting individuals with poor vitamin status may be appropriate and benefıcial (e.g., patients undergoing gastric surgery may require B12, iron, or calcium supplementation, while heavy smokers with high alcohol intakes may have low folate status). Although diffıcult, future research should develop targeted nutritional therapies tailored to background diet, the patients’ genetic makeup, tumor histology, and treatments. A targeted approach may yield benefıts in subsets of patients in the same way that the pharmaceutical industry has developed more effective cancer therapies targeted to variations in the individual and tumor type. This is not a trivial challenge and will require standardized nutritional data collection within ongoing observational and randomized clinical cancer treatment trials, large-scale collaborations, and pooling of results.
Patients remain highly interested in supplements. This desire to take supplements often diverts patients’ attention from pursuing more holistic diet- and exercise-based approaches for maintaining general health and improving outcome after diagnosis. For example, 50% of a breast cancer cohort was taking multivitamins, but 70% of these patients were overweight or obese and 13% were current smokers.
Clinicians should provide appropriate advice for the patient on living a healthy lifestyle, including weight control, a low saturated fat, high fıber, low-refıned carbohydrate, moderate alcohol diet, and nutrition support. Clinicians should openly discuss with patients their interest to self-prescribe nutritional supplements and any potential contraindications. Most patients believe that nutritional supplements can do no harm as they are natural, and they are skeptical of adverse reports from clinical trials, which are perceived to be biased toward a medical model. Clinicians should stay up to date with this fast-moving fıeld of research to advise any potential benefıts and contraindications that may apply to their patients. Supplements advice needs to be individualized to the patient, come from a credible source, and be communicated by the patient’s cancer physician.
Ref: Harvie M, Nutritional supplements and cancer: potential benefits and proven harms, Am Soc Clin Oncol Educ Book. 2014:e478-86.