Editorial: Supplements and Chemotherapy-Induced Peripheral Neuropathy: Hope or Hype?

JNCI: Journal of the National Cancer Institute, Dec 2017

Ligibel, Jennifer A

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Editorial: Supplements and Chemotherapy-Induced Peripheral Neuropathy: Hope or Hype?

JNCI J Natl Cancer Inst ( Supplements and Chemotherapy-Induced Peripheral Neuropathy: Hope or Hype? Jennifer A. Ligibel 0 1 0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please 1 Affiliation of author: Dana-Farber Cancer Institute , Boston, MA , USA - Multiple studies demonstrate that the majority of cancer patients and survivors use multivitamins and other dietary supplements ( 1–4 ). A review of 32 studies demonstrated that 64% to 81% of cancer patients and survivors overall, and 67% to 87% of breast cancer patients specifically, used dietary supplements after cancer diagnosis (1). Given widespread usage of dietary supplements in the general US population ( 5 ), some individuals continue prediagnosis supplement use through their cancer therapy. Others initiate supplements after cancer diagnosis; cross-sectional studies of breast cancer patients suggest that 8% to 32% of women initiate dietary supplements after cancer diagnosis ( 1 ), often in hopes of reducing toxicity from cancer therapies or improving cancer outcomes. Studies have shown that supplement use in breast cancer patients and other populations is associated with lower body weight, higher levels of physical activity, younger age, and Caucasian race ( 1,4–7 ). Despite the widespread usage of dietary supplements in breast cancer patients, there is relatively little information regarding the safety or benefits of these products during or after cancer therapy. In this issue of the Journal, Zirpoli et al. report on the association between use of multivitamins and other dietary supplements and the incidence of chemotherapy-induced peripheral neuropathy (CIPN) in the Diet, Exercise Lifestyle and Cancer Prognosis (DELCaP) Study ( 8 ). The DELCaP study is a correlative study designed to examine the relationship between lifestyle factors, especially the use of dietary supplements and treatment outcomes, and was embedded in an adjuvant treatment trial (S0221) comparing different regimens of doxorubicin, cyclophosphamide, and paclitaxel. Participants were asked to report supplement usage at the time of breast cancer diagnosis and again at the end of cancer therapy; approximately 74% of participants receiving paclitaxel in the parent trial participated in DELCaP. At baseline, 46.8% of participants reported usage of multivitamins. Use of other vitamin and mineral supplements ranged from 6.4% (iron) to 32.6% (calcium), and rates of multivitamin and supplement usage remained relatively stable throughout treatment. CIPN was more common in patients who were older, nonwhite, had a higher body mass index, who smoked, and had attained lower levels of education. Of note, many of these factors have been inversely related to supplement use in other studies ( 1,4,6,7 ), but associations between patient factors and supplement use were not reported in DELCaP. Multivariable analyses, adjusted for body mass index, race/ethnicity, smoking, alcohol intake, physical activity, and age, demonstrated that use of multivitamins both at baseline and during treatment was associated with a lower rate of CIPN (odds ratio [OR] ¼ 0.60, 95% confidence interval [CI] ¼ 0.42 to 0.87, at baseline; OR ¼ 0.73, 95% CI ¼ 0.49 to 1.08, during therapy). There were no statistically significant relationships between intake of other supplements, either at baseline or during therapy, and incidence of CIPN; however, patients using iron supplementation, especially during chemotherapy, experienced a trend toward increased risk of CIPN. In contrast to this study, a recent report from the Pathways Study looked at predictors of CIPN in 1237 women with newly diagnosed breast cancer in the Kaiser Permanente Group who received adjuvant taxane-based chemotherapy ( 9 ). Women who initiated antioxidant supplements during chemotherapy were found to be at increased risk of developing CIPN as compared with never-users of antioxidants (OR ¼ 3.81, 95% CI ¼ 1.82 to 8.04). However, the study did not collect information regarding whether women initiated the antioxidants prior to developing CIPN or initiated them in response to CIPN symptoms. In the Pathways Study, there was no difference in rates of CIPN in women who used antioxidants at baseline and continued to use them during treatment (continuous users) as compared with never-users (OR ¼ 1.11, 95% CI ¼ 0.53 to 2.23). Several small randomized trials have tested the impact of dietary supplements, including vitamin E, omega-3 fatty acids, and acetyl-L-carnitine, on the risk of CIPN in patients undergoing chemotherapy for breast and other cancers ( 10–14 ). Many of these trials have randomly assigned patients to supplements vs usual care, making it difficult to rule out a placebo effect. While individual trials have suggested that vitamin E ( 11–13,15,16 ) and omega-3 fatty acids ( 16 ) may reduce rates of CIPN in patients receiving taxane and platinum chemotherapy, larger placebocontrolled trials have not demonstrated a reduced risk of CIPN in patients randomly assigned to dietary supplements ( 14,15 ). Notably, one double-blind randomized trial of acetyl-Lcarnitine supplementation in women undergoing taxanebased chemotherapy for early breast cancer demonstrated an increase in CIPN in women randomly assigned to the acetyl-Lcarnitine arm (15). In light of these mixed data, a recent practice guideline published by the Society of Integrative Oncology ( 17 ) concluded that there was no strong evidence supporting the use of dietary supplements in women with breast cancer for management of therapy-related side effects. So where does this leave us? The DELCap Study suggests that women taking multivitamins before and during cancer treatment may be at lower risk of developing CIPN as compared with nonusers. Given the lack of effective strategies for the prevention of CIPN as well as the widespread availability of dietary supplements, it is tempting to consider recommending multivitamins to patients initiating taxane therapy. However, a note of caution is needed in light of the increased risk of CIPN seen both in patients who initiated supplements after cancer diagnosis in the Pathways Study ( 9 ) and in patients randomly assigned to acetylL-carnitine in one of the few randomized trials of dietary supplements in breast cancer patients ( 15 ). Additionally, although the DELCap Study did not report the relationship between supplement use and other factors known to be related to CIPN, other studies have shown that breast cancer patients who use supplements tend to be younger, more physically active, and leaner ( 1,4,6,7 ). Given that these factors are also related to lower rates of CIPN, it may be difficult to fully adjust for these differences when evaluating risk factors for CIPN, raising concerns for uncontrolled confounding in observational analyses. Thus, despite the perception that interventions such as multivitamin use during chemotherapy are lower risk than therapies requiring prescription, placebo-controlled randomized trials, powered to detect both the benefit and harm of multivitamins and other supplements, are needed to guide the use of these products in preventing CIPN and other toxicities in breast cancer patients. The author has no conflicts of interest to disclose. 1. Velicer CM , Ulrich CM . Vitamin and mineral supplement use among US adults after cancer diagnosis: A systematic review . J Clin Oncol . 2008 ; 26 ( 4 ): 665 - 673 . 2. Neuhouser ML , Smith AW , George SM , et al. Use of complementary and alternative medicine and breast cancer survival in the Health , Eating, Activity, and Lifestyle Study . Breast Cancer Res Treat . 2016 ; 160 ( 3 ): 539 - 546 . 3. Inoue-Choi M , Greenlee H , Oppeneer SJ , Robien K. The association between postdiagnosis dietary supplement use and total mortality differs by diet quality among older female cancer survivors . Cancer Epidemiol Biomarkers Prev . 2014 ; 23 ( 5 ): 865 - 875 . 4. Greenlee H , Gammon MD , Abrahamson PE , 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 . 5. Kantor ED , Rehm CD , Du M , White E , Giovannucci EL . Trends in dietary supplement use among US adults from 1999-2012 . JAMA. 2016 ; 316 ( 14 ): 1464 - 1474 . 6. Foote JA , Murphy SP , Wilkens LR , Hankin JH , Henderson BE , Kolonel LN . Factors associated with dietary supplement use among healthy adults of five ethnicities: The Multiethnic Cohort Study . Am J Epidemiol . 2003 ; 157 ( 10 ): 888 - 897 . 7. Strizich G , Gammon MD , Jacobson JS , et al. Latent class analysis suggests four distinct classes of complementary medicine users among women with breast cancer . BMC Complement Altern Med . 2015 ; 15 : 411 . 8. Zirpoli GR , McCann SE , Sucheston-Campbell LE , et al. Supplement use and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221): The DELCaP Study . J Natl Cancer Inst . 2017 ; 109 ( 12 ): djx098 . 9. Greenlee H , Hershman DL , Shi Z , et al. BMI, lifestyle factors and taxaneinduced neuropathy in breast cancer patients: The Pathways Study . J Natl Cancer Inst . 2017 ; 109 ( 2 ): 1 - 8 . 10. Brami C , Bao T , Deng G . Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: A systematic review . Crit Rev Oncol Hematol . 2016 ; 98 : 325 - 334 . 11. Argyriou AA , Chroni E , Koutras A , et al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: Final results . Support Care Cancer . 2006 ; 14 ( 11 ): 1134 - 1140 . 12. Argyriou AA , Chroni E , Koutras A , et al. Preventing paclitaxel-induced peripheral neuropathy: A phase II trial of vitamin E supplementation . J Pain Symptom Manage . 2006 ; 32 ( 3 ): 237 - 244 . 13. Pace A , Giannarelli D , Galie E , et al. Vitamin E neuroprotection for cisplatin neuropathy: A randomized, placebo-controlled trial . Neurology . 2010 ; 74 ( 9 ): 762 - 766 . 14. Kottschade LA , Sloan JA , Mazurczak MA , et al. The use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: Results of a randomized phase III clinical trial . Support Care Cancer . 2011 ; 19 ( 11 ): 1769 - 1777 . 15. Hershman DL , Unger JM , Crew KD , et al. Randomized double-blind placebocontrolled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy . J Clin Oncol . 2013 ; 31 ( 20 ): 2627 - 2633 . 16. Ghoreishi Z , Esfahani A , Djazayeri A , et al. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: A randomized doubleblind placebo controlled trial . BMC Cancer . 2012 ; 12 : 355 . 17. Greenlee H , DuPont-Reyes MJ , Balneaves LG , et al. Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment . CA Cancer J Clin . 2017 ; 67 ( 3 ): 194 - 232 .

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Ligibel, Jennifer A. Editorial: Supplements and Chemotherapy-Induced Peripheral Neuropathy: Hope or Hype?, JNCI: Journal of the National Cancer Institute, 2017, DOI: 10.1093/jnci/djx138