original reports

Protective Effects of Dietary Intake of

Antioxidants and Treatment-Related Toxicity in
Childhood Leukemia: A Report From the
DALLT Cohort
Elena J. Ladas, PhD, RD1,2,3; Traci M. Blonquist, MS4; Maneka Puligandla, MS4; Manuela Orjuela, MD, ScM1,3; Kristen Stevenson, MS4;
Peter D. Cole, MD5; Uma H. Athale, MD6; Luis A. Clavell, MD7; Jean-Marie Leclerc, MD8; Caroline Laverdiere, MD9; Bruno Michon, MD9;
Marshall A. Schorin, MD10; Jennifer Greene Welch, MD11; Barbara L. Asselin, MD12; Stephen E. Sallan, MD4;
Lewis B. Silverman, MD4; and Kara M. Kelly, MD13
abstract

PURPOSE The benefits and risks of supplementation with antioxidants during cancer therapy have been
a controversial area. Few studies have systematically evaluated dietary intake of antioxidants with toxicity and
survival in childhood cancer. We sought to determine the role of dietary intake of antioxidants on rates of
infections, mucositis, relapse, and disease-free survival during induction and postinduction phases of therapy
among children and adolescents with acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS We enrolled 794 children in a prospective clinical trial for treatment of ALL. Dietary
intake was prospectively evaluated by a food frequency questionnaire. The association between dietary intake of
antioxidants and treatment-related toxicities and survival were evaluated with the Benjamini-Hochberg false
discovery rate (q) and logistic regression and the Kaplan-Meier method, respectively.
RESULTS Dietary surveys were available for analysis from 614 (77%), and 561 (71%) participants at diagnosis
and at end of induction, respectively. Of 513 participants who completed the dietary surveys at both time points,
120 (23%) and 87 (16%) experienced a bacterial infection and 22 (4%) and 55 (10%) experienced mucositis
during the induction or postinduction phases of treatment, respectively. Increased intake of dietary antioxidants
was associated with significantly lower rates of infection and mucositis. No association with relapse or disease-
free survival was observed. Supplementation was not associated with toxicity, relapse, or survival.
CONCLUSION Consumption of antioxidants through dietary intake was associated with reduced rates of infection
or mucositis, with no increased risk of relapse or reduced survival. Dietary counseling on a well-balanced diet
that includes an array of antioxidants from food sources alone may confer a benefit from infections and mucositis
during treatment of childhood ALL.
J Clin Oncol 38. © 2020 by American Society of Clinical Oncology

INTRODUCTION reported that supplementation may interfere with

The effects of intake of antioxidants from either the diet anticancer therapy.6 There is a paucity of data on the
or dietary supplements on disease control or adverse effects of antioxidant intake through diet alone during
ASSOCIATED
CONTENT effects during and after treatment of cancer have been cancer therapy.
Data Supplement controversial. Past estimates of antioxidant supple- Several preclinical studies have found that antioxi-
Author affiliations ments use by patients with cancer have varied con- dants enhance the sensitivity of leukemia cells to
and support siderably, ranging from 13%-87% depending on the chemotherapy or reduce chemotherapy-related tox-
information (if
survey, the type of cancer studied, and a variety of icities.7 For example, pretreatment of leukemia and
applicable) appear
at the end of this demographic variables.1,2 Antioxidants have been lymphoma cell lines with vitamin C conferred a pro-
article. promoted as agents capable of reducing chemother- tective effect from vincristine, doxorubicin, metho-
Accepted on March apy- and radiation-induced toxicities and improving trexate, cisplatin, and imatinib.8 Others have reported
10, 2020 and survival through sequestering harmful free radicals, that the combination of vitamins C and K increased the
published at thereby protecting healthy cells either through enzy- sensitivity of leukemic blasts to barasertib and ever-
ascopubs.org/journal/
jco on April 24, 2020:
matic or nonenzymatic pathways.3 Several preclinical4 olimus.9 Animal studies have found that antioxidant
DOI https://doi.org/10. and clinical studies2,5 have reported a beneficial effect supplementation promotes Wnt/b-catenin signaling
1200/JCO.19.02555 of antioxidant supplementation. However, others have and suppression of proinflammatory cytokines

1
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 Ladas et al

CONTEXT
Key Objective
To determine the association of dietary intake of antioxidants and treatment-related toxicities in childhood ALL.
Knowledge Generated
Dietary intake of select antioxidants was associated with reduced infections and mucositis early on in treatment for
childhood ALL.
Relevance
Proactive dietary counseling on a well-balanced, diverse diet may reduce the development of infections and mucositis in
childhood ALL.

attributed to bone morbidities in pediatric acute lympho-
blastic leukemia (ALL).10 Clinical trial data from high-quality
studies are limited. Among 103 children with ALL, in-
creased dietary intake of antioxidants during treatment of
childhood ALL was associated with a reduced risk of he-
matologic or nonhematologic adverse effects, fewer delays
in the administration of scheduled chemotherapy, and
fewer days spent in the hospital.11
To further understand the risks and benefits of dietary
intake of antioxidants during treatment of childhood ALL,
we examined the association of dietary intake of antioxi-
dants with treatment-related toxicity and disease control. To
test our hypothesis that dietary intake of antioxidants re-
duces treatment-related toxicities, we investigated the as-
sociation of the dietary intake of the antioxidants (vitamins
A, E, and C; zinc; and carotenoids) and the incidence of
bacterial infection, mucositis, remission rates, levels of
minimal residual disease (MRD), and disease-free survival
(DFS) among children and adolescents who were enrolled
on a multicenter phase III clinical trial for treatment of
childhood ALL.
PATIENTS AND METHODS
Participants. Eligible participants for the described study
were children and adolescents ages 1-18 years with newly
diagnosed ALL enrolled in the Dana-Farber Cancer Institute
(DFCI) ALL Consortium protocol 05-001. Consent to the
treatment study was obtained as per the institutional review
board of all participating centers and served as consent to
this companion study. The details of this trial have been
described elsewhere.12,13 The trial was registered with clin-
icaltrials.gov (ClinicalTrials.gov identifier: NCT01523977).
Study Design and Procedures. Details on study respondents
and procedures have been previously published.14 Briefly,
this is a prospective cohort study that collected dietary
intake over the course of a 2-year treatment period for ALL.
For this article, we analyzed dietary intake that was col-
lected at two of the time points during therapy: diagnosis
and end of the induction phase (approximately 32 days
from diagnosis). Reported data reflected dietary intake from
the previous month. The food frequency questionnaire
(FFQ) provided antioxidant intakes from dietary sources
alone as well as intakes from dietary sources and sup-
plementation. Validation of this survey in the pediatric
population and pediatric oncology population has been
previously described.11,15-19
Toxicity was assessed using National Cancer Institute
Common Terminology Criteria for Adverse Events (version
3.0.). We collected data on rates of infections and mucositis
during induction and postinduction through the end of the
consolidation II phase (approximately 8-9 months). All
bacteremias were prospectively reported, and mucositis
was reported if classified as grade $ 3. DFS was defined as
the time from complete remission to the first of relapse
or death.
Statistical Analysis. Antioxidant intake was summarized at
each time point with descriptive statistics. At each time
point, dietary intake distributions across age group and
sex were examined for outliers and non-normality. The
distribution of patients was characterized by median and
interquartile range (IQR), using previously published
methodology.20 Cases that were . 1.5 IQR below the first
quartile or above the third quartile were excluded as out-
liers. Little’s missing completely at random test was also
performed to evaluate the missing data pattern. The
change in micronutrient intake from diagnosis (T1) and end
of induction (T2) was expressed as a ratio. It was possible
for a micronutrient to be 0 or approach 0; therefore,
a constant (c 5 1) was add to the numerator and de-
nominator for all micronutrient ratios. A square root
transformation of the levels taken at T2 and a log2 trans-
formation of the ratios for T2/T1 were taken to normalize all
nutrient data. The proportion of participants receiving
supplementation during induction was determined by
taking the difference between total micronutrient and from
food source only; any patient with a value . 0 was con-
sidered to be supplementing with the antioxidants under
investigation.
Toxicities of interest included bacterial infection and grade
3 or higher mucositis in induction and postinduction (CNS

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 Antioxidants, Toxicities, and Pediatric ALL

phase through end of consolidation II phase). The asso-
ciation between each individual antioxidant and the odds of
developing a bacterial infection, and the odds of developing
mucositis, were modeled univariately with logistic re-
gression. For each toxicity and treatment phase, the
Benjamini-Hochberg false discovery rate (q) was used to
adjust for multiple comparisons; false discovery rate–
adjusted P values (q-value) , .05 were considered sig-
nificant. Because of an association of induction toxicity and
sex, each induction model was also adjusted by sex. As-
sociation between induction toxicity and dietary reference
intakes (DRI) at T1, as well as the change in DRI from T1 to
T2 for vitamin A, C, E, and zinc, were explored with logistic
regression. The association between postinduction toxicity
and DRI at T2 was similarly explored. In addition, intakes
were categorized as under (intake below the recommended
dietary allowance [RDA]), met (intakes within the RDA), or
exceed (intakes exceeding the RDA) and used in logistic
regression models.
The association between reported dietary intake, defined
by DRI, at the end of induction and DFS was explored with
the Kaplan-Meier method and tested between groups with
the log-rank test. DFS was defined in the subset of par-
ticipants achieving a complete remission (CR) at the end of
induction as the time from complete remission to the first of
relapse or death and was censored at the time last know
alive and disease-free. All analyses were performed in SAS
version 9.4 and R version 3.5.1.
RESULTS
A total of 794 eligible patients were enrolled in DFCI 05-
001.12,13 The demographics of the cohort who completed
an FFQ at diagnosis and at the end of induction may be
found in the Data Supplement. As previously reported,21
significant differences between the two groups were re-
flective of changes in clinical research support at two
participating institutions. After removing outlying dietary
data and unbelievable values, dietary intake and use of
dietary supplements were available for analysis from 614
(77%) and 561 (71%) participants at diagnosis (T1) and
end of induction (T2), respectively. The median and IQR of
vitamins A, C, and E, zinc, a- and b-carotene, and total
carotenoid intakes at diagnosis and end of induction are
presented in the Data Supplement. With the exception of
zinc and vitamin E, the majority of intakes were within the
DRI recommended values.21 Eighty (13%) and 88 (16%)
participants reported taking antioxidant supplements at
each of the time points, respectively. The observed values
are lower than previously reported (mean use, 20%-60%)1;
however, the majority of published surveys represent
single-institution surveys rather than data obtained from
multicenter, clinical studies.

TABLE 1. Logistic Regression of Dietary Intake of Antioxidants During Induction and the Odds of Developing a Bacterial Infection and
Grade $ 3 Mucositis During the Induction Phase of Treatment
Nutrient Estimate 95% Lower CL 95% Upper CL P qa
Bacterial infection
a-carotene 0.90 0.82 0.98 .018 .038
b-carotene 0.81 0.70 0.93 .004 .014
b-carotene (diet only) 0.81 0.71 0.94 .005 .014
Carotenoids 0.81 0.70 0.93 .003 .014
Carotenoids (diet only) 0.81 0.71 0.94 .004 .014
Vitamin A 0.77 0.64 0.94 .008 .020
Vitamin A (diet only) 0.73 0.60 0.89 .002 .014
Grade $ 3 mucositis
Vitamin E (diet only) 0.33 0.16 0.67 .002 .017
Zinc (diet only) 0.45 0.25 0.89 .020 .037
a-carotene 0.83 0.70 0.98 .026 .043
b-carotene 0.70 0.55 0.91 .007 .017
b-carotene (diet only) 0.70 0.55 0.90 .006 .017
Carotenoids 0.70 0.54 0.90 .006 .017
Carotenoids (diet only) 0.70 0.54 0.90 .005 .017
Vitamin A 0.71 0.50 1.01 .058 .079
Vitamin A (diet only) 0.64 0.46 0.90 .010 .021

NOTE. Only significant associations shown; adjustment was made overall. Models adjusted for sex.
Abbreviation: CL, confidence limit.
a
False discovery rate–adjusted P value.

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 Ladas et al

Alpha carotene Beta carotene Beta carotene (diet only)

5
2 2

0 0 0

−2 −2
−5
−4 −4

−6 −6
−10

Yes No Yes No Yes No

Carotenoids Carotenoids (diet only) Vitamin A

2.5 2.5
log (T2 = 1)/(T1 + 1)

2.5
0.0 0.0
0.0
−2.5 −2.5
−2.5
−5.0 −5.0
−5.0

Yes No Yes No Yes No

Vitamin A (diet only)

4

−2

−4

−6

Yes No
Bacterial Infection

FIG 1. Change in dietary intake of antioxidants from diagnosis (T1) to end of induction (T2) and incidence of bacterial infection.

Dietary Intake of Antioxidants and Induction Toxicities excessively high intakes of antioxidants from supplemen-
Dietary intake of antioxidants increased twofold in 25% of tation among the cohort.
participants, whereas 43% reported a reduction in dietary We evaluated the association of change in dietary intake of
intake of antioxidants by at least half during the 1-month antioxidants from diagnosis to the end of induction with
induction phase (Data Supplement). Dietary intakes of the episodes of bacterial infection and mucositis during in-
majority of antioxidants with an established DRI did not duction. A total of 513 participants completed the diagnosis
exceed the upper tolerable levels.21 We did not observe and end-of-induction dietary surveys, of whom 120 (23%)
and 22 (4%) experienced a bacterial infection or grade 3 or
TABLE 2. Induction Toxicity: Supplements at T1 Versus No higher mucositis, respectively. No associations between
Supplements sex, age, body mass index, and final risk group were ob-
Toxicity OR 95% CI P served with either toxicity. Antioxidant intake solely from the
Bacterial infection 0.96 0.81 to 1.13 .62 diet (excludes dietary supplements) revealed that higher
intakes of b-carotene, carotenoids, and vitamin A were
Mucositis 1.63 0.46 to 4.57 .39
associated with reduced odds of a bacterial infection,
NOTE. Models are sex adjusted. controlling for sex (Table 1; Fig 1). A similar observation
Abbreviations: OR, odds ratio; T1, diagnosis. was found for a-carotene when intake from diet and

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 Antioxidants, Toxicities, and Pediatric ALL

TABLE 3. Logistic Regression of Dietary Intake of Antioxidants at the End of Induction and the Odds of Grade $ 3 Mucositis During Postinduction
Phase of Therapy
Nutrient Estimate 95% Lower CL 95% Upper CL P qa
Vitamin C 0.880 0.810 0.955 .002 .004
Vitamin C (diet only) 0.866 0.794 0.945 .001 .003
Vitamin E 0.560 0.382 0.820 .003 .004
Vitamin E (diet only) 0.420 0.269 0.657 , .001 .001
Zinc 0.507 0.358 0.717 , .001 .001
Zinc (diet only) 0.488 0.341 0.699 , .001 .001
a-carotene 0.955 0.927 0.985 .003 .004
b-carotene 0.974 0.958 0.991 .003 .004
b-carotene (diet only) 0.975 0.958 0.992 .004 .004
Carotenoids 0.981 0.968 0.993 .003 .004
Carotenoids (diet only) 0.981 0.968 0.993 .003 .004
Vitamin A 0.979 0.967 0.992 .001 .003
Vitamin A (diet only) 0.979 0.967 0.992 .001 .003

NOTE. Models adjusted for sex.

Abbreviation: CL, confidence limit.
a
False discovery rate–adjusted P value.

supplements was evaluated. For mucositis, a benefit was
observed with higher intakes of vitamins A, E, and zinc from
dietary sources alone and reduced odds of developing
mucositis. a-Carotene (diet only), b-carotene, and carot-
enoids (diet and supplementation) were associated with
reduced odds of developing mucositis (Table 1; Data
Supplement). To explore the association of the use of di-
etary supplements on induction toxicities, we evaluated the
odds of developing an infection among participants who
self-reported use of dietary supplements compared with
those who did not supplement. No effect was observed on
rates of bacterial infections or mucositis (Table 2).
No significant associations between dietary intake at the
end of induction and postinduction bacterial infections
were observed (Data Supplement). In contrast, dietary
intake of vitamins A, C, E, zinc, a-carotene, b-carotene,
and carotenoids from the diet alone at the end of in-
duction was significantly associated with lower odds of
subsequently developing mucositis (Table 3; Data Supple-
ment). Supplementation did not significantly alter the
associations observed with intakes solely from the diet
(Table 3). Moreover, no significant differences were ob-
served between users of dietary supplements compared
with nonusers on postinduction toxicities (Table 4).

Dietary Intake of Antioxidants and Postinduction

Comparison of Toxicity by DRI Category
Toxicities
For those antioxidants with a DRI value (Table 3),
To explore the sustained effects of dietary intake of anti-
evaluation of dietary intakes by DRI categories (below,
oxidants, we evaluated the association of dietary intake at
met, and over) at diagnosis did not reveal a significant
the end of induction (T2) on infections and mucositis
association with induction-related infections. In addition,
during the postinduction phase of treatment. Among the
no significant difference in toxicity rates was detected in
549 participants achieving a CR who provided dietary in-
patients who changed DRI categories from diagnosis to
take at the end of induction, 87 (16%) had at least one
the end of induction (Data Supplement). In contrast,
bacterial infection and 55 (10%) experienced mucositis
dietary intake during induction (T2 survey, which re-
during these subsequent phases.
flected intake during induction phase of treatment) of
TABLE 4. Postinduction Toxicity: Supplements at T2 Versus No
vitamin E and zinc was associated with the rate of
Supplements postinduction bacterial infection. Participants with di-
Toxicity OR 95% CI P etary intakes below the DRI for zinc and vitamin E ex-
perienced an increased rate of bacterial infection (P 5
Bacterial infection 0.58 0.26 to 1.14 .14
.025, P 5 .009, respectively). For mucositis, lower intake
Mucositis 1.06 0.47 to 2.16 .88
of vitamins A and C were associated with a higher rate of
NOTE. Models are sex-adjusted. mucositis during the postinduction phase of treatment
Abbreviations: OR, odds ratio; T2, end of induction. (P 5 .002, P 5 .042, respectively).

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 Ladas et al

A B
Disease-Free (proportion)

Disease-Free (proportion)
1.0 1.0

0.8 0.8
Alive and

Alive and
0.6 0.6

0.4 0.4
Under

0.2 Met 0.2 Under

Over Met

0 2 4 6 8 10 0 2 4 6 8 10
Time Since Remission (years) Time Since Remission (years)
No. at risk No. at risk
Under 67 63 51 28 14 2 Under 101 98 81 49 25 6
Met 266 260 215 136 60 10 Met 448 432 357 227 111 17
Over 216 207 172 112 62 11

C D
Disease-Free (proportion)

Disease-Free (proportion)
1.0 1.0

0.8 0.8
Alive and

Alive and
0.6 0.6

0.4 0.4 Under

Under Met
0.2 0.2
Met Over

0 2 4 6 8 10 0 2 4 6 8 10
Time Since Remission (years) Time Since Remission (years)
No. at risk No. at risk
Under 369 357 300 191 90 19 Under 39 39 28 12 6 2
Met 180 173 138 85 46 4 Met 120 112 88 58 27 4
Over 343 333 286 188 97 17

FIG 2. Disease-free survival curves by end of induction dietary reference intakes for (A) zinc, (B) vitamin C, (C) Vitamin E, and (D) Vitamin A.

Dietary Antioxidants, Remission, and Survival
Of the 513 with diagnosis and end-of-induction dietary
information, 504 (98%) achieved a CR of ALL, with 8 (2%)
experienced induction failure; one participant was ineva-
luable for remission status. MRD was measured pro-
spectively at the end of induction in 452 patients with
B-ALL, 37 of whom had high MRD (defined as $ 1023).
There were no significant associations between end-of-
induction MRD and intakes from diet sources or supple-
ments. No associations were observed between DFS and
dietary intake of vitamins A, C, E, and zinc at the end of
induction (Fig 2).
DISCUSSION
Dietary intake of antioxidants during induction was signif-
icantly associated with reduced odds of several common
induction toxicities of ALL treatment, confirming the results
of our pilot work.11,17 Increasing intake of antioxidants
through self-reported supplementation, within the reported
dose ranges, did not confer an enhanced effect on in-
fections or mucositis when compared with antioxidant in-
take from dietary sources alone, underscoring the potential
benefit of a healthy diet during treatment of childhood ALL.
Moreover, we found that dietary intake of antioxidants
obtained from food and supplements, within the reported
dietary intakes, was neither beneficial nor harmful on rates
of high end induction MRD or DFS. The latter finding is
particularly noteworthy in light of the controversy sur-
rounding antioxidant intake from diet and supplements
during cancer therapy. To our knowledge, these results are
the first to suggest that a high-quality diet, rather than
supplementation, during treatment of cancer may be
beneficial in reducing toxicities.
Confirming our hypothesis and that of our pilot work,11,17 we
found that increases in the dietary intakes of vitamin A, a-
and b-carotene, and carotenoids from the time of diagnosis
to end of induction was associated with a reduced in-
cidence of bacterial infection. Low levels of vitamin A have
been associated with increased intestinal permeability and
reduced immune function in children undergoing stem-cell
transplantation, providing a plausible mechanism for the
observed associations with vitamin A.22 The collective
benefit of carotenoids is likely linked to their provitamin A
activity, strong antioxidant ability, and anti-inflammatory

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 Antioxidants, Toxicities, and Pediatric ALL

TABLE 5. Classification of Dietary Intake of Antioxidants by DRI and the Incidence regulate the biologic activities of zinc, a hypothesis that has
of a Toxic Event During the Induction and Postinduction Phase of Treatment been put forth for the prevention of diarrhea. Deficient
Bacterial Infection Mucositis dietary intake of zinc may alter the composition of the
Nutrient No. % P No. % P microbiome, thereby affecting systemic effects through
effects on the metabolome.23 Finally, enteric infection and
Induction
pathogenic bacteria may inhibit absorption of nutrients,
Vitamin C .47 .71
conferring variable associations in the postinduction phase
Under (n 5 46) 13 28.26 1 2.17 of treatment.
Met (n 5 568) 135 23.77 28 4.93
All of the antioxidant nutrients were associated with re-
Vitamin E .37 .36 duced odds of developing mucositis. The observed re-
Under (n 5 472) 118 25.00 20 4.24 lationships may be due to the role of antioxidants, oxidative
Met (n 5 142) 30 21.13 9 6.34 stress, and inflammation in the development of mucositis.24
Zinc .43 .11
Our study did not observe a stronger protective effect when
dietary intake from diet and supplementation was exam-
Under (n 5 38) 8 21.05 2 5.26
ined. Moreover, we did not find a beneficial effect among
Met (n 5 299) 79 26.42 9 3.01 children who used supplements compared with those who
Over (n 5 277) 61 22.02 18 6.50 did not during the induction or postinduction phases of
Vitamin A .19 .25 treatment. This finding was consistent in each of our an-
Under (n 5 20) 4 20.00 2 10.00 alyses and may indicate that a high-quality diet confers
a benefit because of the synergistic activities of nutrients
Met (n 5 111) 34 30.63 3 2.70
found in a diet rich in dietary nutrients. This finding aligns
Over (n 5 483) 110 22.77 24 4.97 with other dietary studies evaluating diet quality and pre-
Postinduction vention of cancer or late effects25,26; subsequent in-
Vitamin C .37 .042 vestigations may consider the role of diet quality for the
Under (n 5 101) 19 18.81 16 15.84 prevention of acute and late toxicities associated with
childhood ALL. Taken together, our study suggests that
Met (n 5 448) 68 15.18 39 8.71
dietary counseling on nutrient-rich foods rather than
Vitamin E .009 .65
supplementation may provide a benefit to reducing
Under (n 5 369) 69 18.70 39 10.57 toxicities.
Met (n 5 180) 18 10.00 16 8.89
Our findings must be interpreted in light of several limi-
Zinc .025 .087 tations as well as the inherent limitations of FFQs and the
Under (n 5 67) 18 26.87 12 17.91 nutrient databases providing nutrient output.16,27,28 Our null
Met (n 5 266) 42 15.79 23 8.65 findings in the postinduction phase of treatment may be
Over (n 5 216) 27 12.50 20 9.26 related to the expected lower frequency of bacterial in-
fections, which may have underpowered our study to detect
Vitamin A .72 .002
an effect. Similarly, for several nutrients (eg, vitamin E), the
Under (n 5 39) 8 20.51 11 28.21 majority of our population was below the minimum dietary
Met (n 5 120) 19 15.83 11 9.17 requirements for age and sex; thus, any potential benefit of
Over (n 5 343) 54 15.74 29 8.45 vitamin E was unlikely to be detected because of the narrow
range of reported intakes. Thus, we were not able to
NOTE. Reported dietary intakes were classified as detailed in the DRI; under
evaluate the effect of very low or very high intakes on the
(intake below the RDA), met (intakes within the RDA), and exceed (intakes
toxicities for most of the nutrients explored. Collection of
exceeding the RDA).
additional FFQs during the postinduction phase of treat-
Abbreviations: DRI, dietary reference intakes; RDA, recommended dietary
allowance. ment (eg, 3 and 6 months postdiagnosis) may have re-
duced misclassification of dietary intakes; however, this
may have been minimized, because our previous report21
found that dietary intake at 15 months postdiagnosis is
properties, each of which is associated with the develop-
reflective of that at diagnosis. Our findings may also be
ment of infections and mucositis.
attributable to the values set by the DRI, which meet the
We found a wide range of intakes of dietary zinc, and nearly minimum intake for 98% of the healthy population and may
a third of patients exceeded the DRI for zinc. Emerging not be sufficient for individuals experiencing a severe ill-
research suggests that zinc’s beneficial effects may func- ness. Dietary intake was collected through FFQs; thus,
tion through the intestinal immune system.23 It is plausible there is an inherent risk of misreporting (eg, inaccurate
that perturbations to the microbiome as a result of che- recall of dietary intake). However, our systematic ap-
motherapy and prophylactic antibiotic therapy may proach to removing outlying data and unbelievable values

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 Ladas et al

minimized this weakness.14 Our collection of mucositis
toxicity was limited to those experiencing grade $ 3
mucositis. Lower grades of mucositis that may affect
quality of life and nutritional status could not be in-
vestigated in this study. Finally, we did not evaluate
serum or plasma levels of antioxidants or other indicators
of oxidative stress. Given the observed associations,
future studies may consider evaluation of intake, nutrient
status, and associated biomarkers to improve our un-
derstanding of underlying mechanisms of antioxidant
nutrients within the context of childhood ALL.
In summary, we demonstrate the potential clinical impor-
tance of maintenance of dietary intake of foods rich in
antioxidants as part of a healthy, balanced diet during
treatment of childhood ALL. Our results do not support any
added benefit of antioxidant supplementation over and above
that gained by dietary intake alone. We are unable to de-
termine the role of supra-dosing of antioxidants in pediatric
ALL. Future studies are underway to explore underlying
mechanisms by which dietary intake may be exerting a benefit
on biologic outcomes and treatment-related toxicities in pe-
diatric ALL (ClinicalTrials.gov identifier: NCT03157323).

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

1
Division of Pediatric Hematology/Oncology/Stem Cell Transplant, INTEREST AND DATA AVAILABILITY STATEMENT
Columbia University Medical Center, New York, NY Disclosures provided by the authors and data availability statement (if
2
Institute of Human Nutrition, Columbia University, New York, NY applicable) are available with this article at DOI https://doi.org/10.1200/
3
Department of Epidemiology, Mailman School of Public Health, JCO.19.02555.
Columbia University Medical Center, New York, NY
4
Dana-Farber Cancer Institute/Boston Children’s Hospital, Boston, MA
5
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
AUTHOR CONTRIBUTIONS
6
Division of Hematology/Oncology, McMaster Children’s Hospital, Conception and design: Elena J. Ladas, Manuela Orjuela, Peter D. Cole,
Hamilton Health Sciences, Hamilton, Ontario, Canada Kara M. Kelly
7
San Jorge Children’s Hospital, San Juan, Puerto Rico Provision of study material or patients: Elena J. Ladas, Peter D. Cole, Uma
8
Hematology-Oncology Division, Charles Bruneau Cancer Center, Sainte- H. Athale, Luis A. Clavell, Jean-Marie Leclerc, Caroline Laverdiere, Bruno
Justine University Hospital, University of Montreal, Montreal, Quebec, Michon, Marshall A. Schorin, Jennifer Greene Welch, Barbara L. Asselin,
Canada Lewis B. Silverman, Kara M. Kelly
9
Centre Hospitalier Universitaire de Quebec, Sainte-Foy, Quebec, Collection and assembly of data: Elena J. Ladas, Manuela Orjuela, Uma H.
Canada Athale, Luis A. Clavell, Caroline Laverdiere, Bruno Michon, Marshall A.
10
Inova Children’s Hospital, Falls Church, VA Schorin, Jennifer Greene Welch, Barbara L. Asselin, Lewis B. Silverman,
11
Division of Pediatric Hematology/Oncology, Hasbro Children’s Kara M. Kelly
Hospital, Brown University, Providence, RI Data analysis and interpretation: Elena J. Ladas, Traci M. Blonquist,
12
Department of Pediatrics, University of Rochester School of Medicine, Maneka Puligandla, Manuela Orjuela, Kristen Stevenson, Peter D. Cole,
Golisano Children’s Hospital at URMC, Rochester, NY Stephen E. Sallan, Kara M. Kelly
13
Department of Pediatrics, Roswell Park Comprehensive Cancer Center Manuscript writing: All authors
and University at Buffalo Jacobs School of Medicine and Biomedical Final approval of manuscript: All authors
Sciences, Buffalo, NY Accountable for all aspects of the work: All authors

CORRESPONDING AUTHOR ACKNOWLEDGMENT

Elena J. Ladas, PhD, RD, Columbia University Medical Center, 3959
Broadway, CHN 10-06A, New York, NY 10032; e-mail: ejd14@
cumc.columbia.edu.
SUPPORT
Supported by the Tamarind Foundation (E.J.L.), Mentored Research
Scholar Grant No. 127000-MRSG-14-157-01-CCE, the American
Cancer Society (E.J.L.), and the American Institute for Cancer Research
Grant No. AICR CU09-1011 (K.M.K.).
We thank the patients, families, physicians, nurses, research
coordinators, and all others who participated in the data collection for this
trial. We also thank Alanna Cabrero, MS, RD, Joelle Karlik, MD, and
Deborah Hughes Ndao, MPH for their contributions. We thank Helaine
Rockett, MS, RD, and Laura Sampson, MS, RD, at the Harvard T.H. Chan
School of Public Health for their contribution in the analysis of the food
frequency questionnaires.

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Journal of Clinical Oncology 9

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 Ladas et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia: A Report from the DALLT Cohort
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Traci M. Blonquist Stephen E. Sallan

Stock and Other Ownership Interests: JNJ, Pfizer Consulting or Advisory Role: Syndax
Travel, Accommodations, Expenses: Syndax
Manuela Orjuela
Honoraria: Atara Biotherapeutics Lewis B. Silverman
Consulting or Advisory Role: Atara Biotherapeutics Consulting or Advisory Role: Adaptive Biotechnologies, Takeda, Servier
Travel, Accommodations, Expenses: Atara Biotherapeutics Research Funding: Baxalta/Shire (Inst), Servier (Inst)
Kristen Stevenson Kara M. Kelly
Patents, Royalties, Other Intellectual Property: In the past year I received Research Funding: Merck (Inst)
royalties for a patent on a gene mutation signature for patients with Travel, Accommodations, Expenses: Bristol-Myers Squibb
myelodysplastic syndrome.
No other potential conflicts of interest were reported.

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