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
). 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 (
), 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
), 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 (
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 (
). 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
), 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 (
). 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 (
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 (
and omega-3 fatty acids (
) 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 (
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
) 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 (
) and in patients randomly assigned to
acetylL-carnitine in one of the few randomized trials of dietary
supplements in breast cancer patients (
). 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
). 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 .