REVIEW

Current Evidence and Directions for Intermittent

Fasting During Cancer Chemotherapy
Kelsey Gabel,1 Kate Cares,1 Krista Varady,1 Vijayakrishna Gadi,2,3 and Lisa Tussing-Humphreys1,3

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1 Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA; 2 Department of Medicine, University of Illinois at Chicago,
Chicago, IL, USA; and 3 University of Illinois Cancer Center, Chicago, IL, USA

ABSTRACT
Almost 40% of the adult population in the USA will be diagnosed with cancer in their lifetime. Diet is a modifiable factor which is known to
affect cancer risk and recurrence. Yet, little is known about how diet influences cancer treatment outcomes. Intermittent fasting, characterized
by periods of abstaining from foods and beverages alternated with periods of ad libitum intake, when adopted in the context of chemotherapy,
has shown promise in preclinical models resulting in decreased vomiting, diarrhea, visible discomfort, and improved insulin sensitivity and efficacy
of chemotherapeutic treatment. Although intermittent fasting during receipt of chemotherapy has been well-established in preclinical models,
limited numbers of human studies are now being reported. This review aims to survey the current data examining the effect of intermittent
fasting on chemotherapy efficacy, patient treatment outcomes, patient centered outcomes, and circulating biomarkers associated with cancer.
Available data show that periodic fasting, a form of intermittent fasting, may hold potential to improve the effectiveness of chemotherapy, decrease
treatment-related side effects and cancer-promoting factors such as insulin, while ameliorating treatment-related decreases in quality of life and
daily functioning. Larger controlled periodic fasting trials, including exploration of alternate forms of intermittent fasting, are needed to better
elucidate the effect of intermittent fasting on treatment and patient outcomes during chemotherapy. Adv Nutr 2022;13:667–680.

Statement of Significance: This article reviews the most current data in intermittent fasting during chemotherapy, elucidates current gaps
in clinical research, and introduces future directions for utilizing fasting as adjunct intervention during chemotherapy.

Keywords: intermittent fasting, fasting mimicking diet, short-term fasting, cancer, chemotherapy

Introduction healthy body weight, being physically active, and adopting

It is estimated annually in the USA over 1.8 million people
will receive a new cancer diagnosis and >600,000 will not
survive the disease (1). Almost 40% of men and women
will be diagnosed with cancer at some point in their
lifetime. It is estimated that smoking, excess body weight,
physical inactivity, excess alcohol consumption, and poor
nutrition accounts for ∼18% of new cancer cases and 16%
of cancer deaths annually in the USA (2). Maintaining a
This work was supported by NIH R01CA257807 (LT-H and KV), R01CA250390 (LT-H),
R01CA204808 (LT-H), and R01DK119783 (KV). The content is solely the responsibility of the
authors and does not necessarily represent the official views of the NIH.
Author disclosures: Krista Varady received author fees from Hachette Book Group for "The Every
Other Day Diet".
Address correspondence to KG (e-mail: kdipma2@uic.edu).
Abbreviations used: DSR, differential stress resistance; EORTC QLQ-C30, The European
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FACIT,
Functional Assessment of Chronic Illness Therapy; IGF-1, insulin-like growth factor 1; IGFBP,
insulin-like growth factor binding protein; TRE, time-restricted eating.
a primarily plant-based diet low in red and processed
meats, simple sugars, refined carbohydrates, while limiting
alcohol can positively influence cancer prevention (2–4).
However, there is little evidence on how diet may affect
patient outcomes and chemotherapy efficacy. Yet, diet may
be a key nonpharmacological intervention to improve cancer
treatment efficacy and patient outcomes.
Standard recommendations during chemotherapy from
the European Society for Clinical Nutrition and Metabolism
suggest regular nutrient intake (25–30 kcal/[kg·d] and 1–
1.5 g protein/[kg·d]) for all cancers (5). This current approach
is thought to avoid cancer cachexia, the irreversible loss
of fat and lean tissue, which results in a reduced ability
to fight infection, withstand toxicity of cancer treatment,
and is associated with poor prognosis (6). However, current
standard care may be outdated for specific types of cancers
such as breast, ovarian, and prostate, because these cancers


C The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Adv

Nutr 2022;13:667–680; doi: https://doi.org/10.1093/advances/nmab132. 667


FIGURE 1 Possible treatment effects of intermittent fasting
during chemotherapy. Green circles will potentially increase with
fasting. Red circles will potentially decrease with fasting.
have low risk of cachexia and often result in weight gain
during and after treatment (7, 8). Furthermore, in preclinical
models, a caloric deficit extended longevity, decreased overall
tumor incidence, decreased tumor cell proliferation and
metastasis, and increased tumor cell death in mammary,
prostate, brain, hepatic, and pancreatic cancers by means
of improved glucose regulation and reduced growth factors
(9–12). Thus, nonpharmacological diet management may be
important in improving survivability for some cancers.
Other preclinical evidence suggests that interventions
targeting caloric intake during chemotherapy may influence
treatment outcomes and treatment-related side effects (9,
13–16). These outcomes and side effects, including quality
of life, fatigue, weight gain, glucoregulation, inflammation,
and growth factor biomarkers, are relevant to both prognosis
and survival (Figure 1). Intermittent fasting is an emerging
nonpharmacological diet intervention that combines periods
of caloric fasting with periods of ad libitum eating. Periodic
fasting is one type of intermittent fasting that can be broken
into 2 paradigms: short-term fasting (STF; subjects abstain
from food before and after treatment for a total of 24–
120 h) and the fasting mimicking diet (FMD; very low-
calorie low-protein diet 1-wk per mo). Periodic fasting in
in vitro and in vivo murine models demonstrates that this
type of fasting may protect normal cells from oxidative
stress, while decreasing cancer proliferation and increasing
tumor cell death during chemotherapy treatment (17–24). It
is hypothesized that this protection is due to a phenomenon
termed differential stress resistance (DSR) in which inter-
mittent fasting results in a state of nutrient deprivation
that is thought to suppress tumor growth and proliferation
while enabling an intact “stress response” in healthy cells
(19, 24) (Figure 2). This stress response boosts metabolic
668 Gabel et al.
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FIGURE 2 Differential Stress Resistance model. The possible
mechanisms associated with the differential stress resistance
theory. AKT, protein kinase B; IGF-1, insulin-like growth factor 1;
IGFBP, insulin-like growth factor binding protein; mTOR,
mechanistic target of rapamycin; RAS, rat sarcoma virus.
pathways toward maintenance, decreasing the accumulation
of cellular damage, and enhancing reproductive fitness in
normal healthy cells (24). Cancer cells, however, are unable to
induce the same stress resistance response therein selectively
increasing the effectiveness of chemotherapy (24). The
aim of this review is to examine the state of the science
regarding intermittent fasting as an adjunct intervention
during chemotherapy for various cancer types. Specifically,
we will examine current data on treatment- and patient-
related outcomes, possible underlying mechanisms of effect,
and discuss directions for future research.
Methods
A PubMed search was conducted using the following key
words: “chemotherapy,” “chemotherapy treatment,” “cancer,”
“cancer treatment,” “fasting,” “short-term fasting,” “time
restricted eating,” “time restricted feeding,” “intermittent
fasting,” “fasting mimicking diet,” “periodic fasting,” “alter-
nate day fasting,” “alternate day modified fasting,” “5:2 diet,”
“intermittent energy restriction,” “clinical trial,” “human.”
Inclusion criteria for research articles were as follows:
1) adult male and female participants, 2) fasting during
cancer treatment, 3) endpoints that included changes in
treatment-related outcomes, patient-related outcomes, circu-
lating biomarkers for insulin sensitivity, or cancer-promoting
growth factors. The following exclusion criteria were applied:
1) cohort and observational studies, 2) fasting performed as
a religious practice (Ramadan or Seventh Day Adventist).
Our search revealed 8 human trials (Table 1) in intermittent
fasting as an adjunct to chemotherapy, 2 of these studies
 TABLE 1 Characteristics of current studies examining the effect of intermittent fasting during chemotherapy in patients with cancer1

Sample size and Type of cancer and Fasting treatment and

Author allocation treatment trial design Age, y BMI Menopausal status Adherence
Short-term fasting
Bauersfeld et al., n = 34 female breast or ovarian cancers A. STF (36 h before, 24 A. 49.8 A. <25: 9 A. Pre: 72.2% 102 cycles fasted
2018 (40) block randomization various forms of h after) then B. 53.6 25 to <30: 7 Post: 27.8% 74 cycles
with sealed chemotherapy normocaloric (n = 18) ≥30: 2 B. Pre: 68.7% normocaloric
envelope 6 cycles of chemotherapy B. Normocaloric then ST B. <25: 10 Post: 31.3% 5 patients didn’t
allocation, (n = 16) 25 to <30: 6 want to switch to
allocation randomized crossover ≥30: 0 normocaloric after
nonblinded trial first arm
de Groot et al., 2015 n = 13 female HER2-negative stage II/III A. STF (24 h before and A. 51 A. 25.5 — 2 participants
(41) randomized breast cancer receiving after) (n = 7) B. 52 B. 23.8 dropped out in the
neoadjuvant TAC B. Control (n = 6) STF group due to
(docetaxel/doxorubicin randomized control trial neutropenia and
/cyclophosphamide) pyrosis, did not
dexamethasone use resolve with
normal diet
Dorff et al., 2016 (29) n = 20 male and cancer diagnosis prescribed A. 24 h STF (n = 6) 61 ≥20.5 A. 4/6 compliant
female platinum-based B. 48 h STF (n = 7) B. 5/6 compliant
chemotherapy without C. 72 h STF (48 C. 4/7 compliant
radiation, curative or h before/24 h after)
palliative (n = 7)
dexamethasone use and 5HT3 nonrandomized,
inhibitors feasibility trial, no
control
Riedinger et al., 2020 n = 20 female Gynecologic cancers with ≥6 A. STF (24 h before and A. 59.5 A. 27.69 9% dropout rate in
(30) nonblinded cycles of chemotherapy after) (n = 10) B. 59.0 B. 29.06 the fasting group.
randomized Multiagent chemotherapy B. Control (n = 10) – No compliance
(bevacizumab, carboplatin, balanced, data given.
cisplatin, docetaxel, normocaloric diet Serum glucose
doxorubicin, gemcitabine, Randomized control trial tested to indicate
and paclitaxel), ≥2 adherence
participants neoadjuvant
therapy
Safdie et al., 2009 n = 10 Neoplasia of breast, esophagus, Voluntarily fasted 61 — — —
(23) male and female prostate, lung, uterus, ovary (48–140 h prior to and
5–56 h following
treatment) during
treatment
Case series report

(Continued)

Intermittent fasting during chemotherapy 669

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670
Gabel et al.
TABLE 1 (Continued)

Sample size and Type of cancer and Fasting treatment and

Author allocation treatment trial design Age, y BMI Menopausal status Adherence
Zorn et al., 2020 (36) n = 30 female Breast, endometrial, ovarian, or A. mSTF/NC (n = 7) 54 26 — 41% dropout rate
selectively assigned cervical cancer, first B. NC/mSTF (n = 9) 71.4% of fasting
(nonrandomized) diagnosis/recurrence all C. KD + mSTF/NC (n = 1) participants had
stages, neo or adjuvant D. NC/KD + mSTF physiological
chemotherapy, ≥4 cycles (n = 13) blood ketosis
Crossover2–3 cycles of detected
CTX of intervention “difficult”: 1
and control “quite difficult”: 11
“quite easy” or “easy”:
9
Fasting mimicking diet
de Groot et al., 2020 n = 129 female HER-2 negative stage II/III A. FMD (n = 65) 49 25.7 Pre/peri: 41.5% All cycles: 21.5%
(22) block randomization breast cancer, neoadjuvant B. Control (n = 64) Post: 58.5% 4 cycles: 33.8%
FEC-T or AC-T Diet was 3 d prior to and 2 cycles: 50%
chemotherapy. the day of treatment. First cycle: 81.5%
Dexamethasone dc in FMD Randomized control trial, Used
group observer blind ITT/per-protocol
analysis
Lugtenberg et al., n = 129 female HER-2 negative stage II/III A. FMD (n = 65) 49 25.7 Pre/peri: 58.5% All cycles and
2020 (37) block randomization breast cancer, neoadjuvant B. Control (n = 64) Post: 41.5% surgery: 15.4%
FEC-T or AC-T chemotherapy Randomized control All cycles: 21.5%
trial, observer blind Half of cycles: 33.8%
Diet was 3 d prior to and First cycle: 81.5%
the day of treatment
1
AC-T, Adriamycin Cyclophosphamine Taxol regimen; CTX, Cyclophosphamide; FEC-T, Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel; FMD, fasting mimicking diet; ITT, intention to treat; KD + STF, ketogenic diet combined with short-term
fasting (KD 6 d prior to STF); mSTF, modified short-term fasting (<25% of energy needs); NC, normocaloric diet; STF, short-term fasting; TAC, Taxotere-Adriamycin-Cytoxan regimen

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examined the fasting mimicking diet and 6 examined short-
term fasting. The majority of the studies in this emerging
area are feasibility and pilot studies; as such, we will also
mention a case series report to present the full breadth of
data currently available. Due to the novelty of this area of
research, most of the studies presented are underpowered
to make conclusions about the true effect of fasting during
chemotherapy, therefore, this review aims to present a clear
picture of what is currently known and future directions for
this emerging therapy.
Intermittent Fasting and Efficacy of Cancer
Treatment
In cell culture, neuroblastoma, breast, ovarian, mesothe-
lioma, lung, and colorectal cancers cells exposed to cy-
cles of fasting had delayed growth and progression of
the cancer cells as well as increased effectiveness of the
chemotherapeutic drugs (24, 25). Preclinical in vitro models
reported that fasting had antiproliferative effects, delaying
the progression of tumors, and increasing the effectiveness
of chemotherapeutic drugs in melanoma, glioma, colorectal,
and breast cancers (24, 26). In preclinical murine models
of breast cancer, glioma, and neuroblastoma, healthy cells
were protected from oxidative stress, DNA damage, and
treatment-related endometrial hyperplasia during high-dose
chemotherapy when combined with fasting (24, 26–28).
Additionally, in some in vitro and in vivo mouse models,
when fasting was combined with chemotherapy, sensitivity
to and efficacy of chemotherapeutic drugs in breast cancer
and neuroblastoma cells resulted in increased longer-term
cancer-free survival (17, 24, 26–28).
The effect of short-term fasting on cancer treatment
efficacy has been examined in 2 clinical studies (29, 30)
(Table 2). Dorff et al. (29) aimed to determine the optimal
length of a short-term fasting window for a future larger
scale investigation. Men and women with urothelial, non-
small cell lung cancer, uterine, breast, or ovarian cancer
diagnosis prescribed neoadjuvant or adjuvant platinum-
based chemotherapy, were randomly assigned into 3 different
fasting groups: 1) 24 h prior to treatment, 2) 48 h prior to
treatment, or 3) 72 h surrounding treatment (48 h prior to
and 24 h following). No control group was included. After
completion of the adjunct fasting protocol 2 patients had
complete responses (no cancer cells present), 6 had partial
radiographic responses (>30% decrease in sum of all target
lesions), 3 had stable disease, and 8 were nonevaluable based
on RECIST (Response Evaluation Criteria in Solid Tumors
[31]). However, after the completion of the full treatment
plan, 5 participants had a pathological complete response
of which 4 were from the 72 h fasting group and the other
was from the 48 h fasting group (29). Riedinger et al. (30)
recruited women with gynecologic cancers with a treatment
plan consisting of ≥6 cycles of neoadjuvant or adjuvant
chemotherapy and randomly assigned to a short-term fasting
group (24 h before and 24 h after treatment) or a standard
care control group. There were no differences in partial or
complete response between groups. It is possible that the
cancer type may impact the degree of recovery in these
studies as both gynecological and breast cancer have high
survival rates (65% and 90%, respectively [1, 32]). However,
these are currently the safest sample to examine the effect of
periodic fasting during treatment due to low cancer cachexia
risk. Limitations of these initial clinical studies are small
sample size and a heterogenous group of cancer diagnosis all
with variable clinical outcomes.
One study has evaluated the effect of the fasting mim-
icking diet on treatment efficacy during chemotherapy (22)
(Table 2). The DIRECT (Dietary Restriction as an Adjunct
to Neoadjuvant ChemoTherapy for HER2 Negative Breast
Cancer) trial by de Groot et al. (22) examined the fasting
mimicking diet as an adjunct to neoadjuvant chemotherapy
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in women with HER2-negative stage II/III breast cancer. In
the per-protocol analysis, participants that were adherent
to the fasting mimicking diet protocol had a significantly
increased rate of complete or partial radiological response.
Moreover, a 4/5 Miller and Payne pathological response
(>90% loss of tumor cells/no invasive carcinoma) was also
more likely in those that were adherent to the fasting
mimicking diet than those who were not adherent or the
controls. De Groot et al. (22) also reported a decrease
in chemotherapy-induced DNA damage to normal cells
in the fasting mimicking diet group. Current trials lack
a homogeneous large sample size in order to expound
the effect on treatment outcomes. Therefore, larger studies
controlling for cancer and treatment type, dose intensity, and
adherence to the protocol are needed to determine the true
effect of short-term fasting or the fasting mimicking diet on
chemotherapy.
Intermittent Fasting and Treatment-related
Adverse Effects
Side effects are common in patients receiving chemotherapy
for cancer treatment. A prospective cohort study by Pearce
et al. (33) examined the incidence and severity of self-
reported side effects among 478 patients receiving adjuvant
chemotherapy for breast, colorectal, or lung cancer. The
authors reported that 86% of participants experienced ≥1
adverse effect during the study period with fatigue, diarrhea,
and constipation reported most frequently (33). In murine
models, fasting in the context of chemotherapy is associated
with reduced occurrence of treatment-related side effects
including weight loss, decreased activity, diarrhea, leukope-
nia, and other visible signs of discomfort compared with
nonfasting mice (34, 35). This work indicates an area of
opportunity for the use of fasting to mitigate side effects
related to cancer treatment.
Three studies have examined the effect of short-term
fasting on gastrointestinal and neurological adverse effects
in the context of cancer treatment with chemotherapy (23,
29, 36) (Table 2). In a 2009 case series of cancer patients
who had voluntarily fasted for 48–140 h prior to and 5–
56 h following chemotherapy treatment, gastrointestinal
adverse effects such as nausea, vomiting, diarrhea, abdominal
cramps, and mucositis were nearly absent (23). Furthermore,
Intermittent fasting during chemotherapy 671
672
TABLE 2 Treatment efficacy and side effects of intermittent fasting during chemotherapy in patients with cancer1
Author Subjects
Gabel et al.
Short-term fasting
Bauersfeld et al., n = 34 females with
2018 (40) gynecologic cancers,
various forms of
chemotherapy
de Groot et al., n = 13 HER2-negative stage
2015 (41) II/III breast cancer
(histologically confirmed)
receiving neoadjuvant
TAC
(docetaxel/doxorubicin
/cyclophosphamide)
Dorff et al., 2016 n = 20 males and females
(29) with cancer diagnosis
prescribed
platinum-based
chemotherapy w/out
radiation, curative or
palliative
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Neurological adverse
Treatment and design Treatment efficacy GI adverse effects effects Quality of life
A. Group A: STF (36 h before, A. ↑ FACT-G, FACIT F,
24 h after)/Control FACIT-F TOI
B. Group B: during fasting
control/STFrandomized cycles. ↑QOL
crossover trial, 6 cycles of during fasting
chemotherapy and decreased
during control
cycles
B. Ø between cycles
Ø difference
between fasting
cycles
A. STF (24 h before and Within-group change Ø differences between Ø differences between
after) γ -H2AX intensity groups in grade I/II groups in grade I/II
B. Control (follow healthy ↑CD45 + CD13- or III/IV grade or III/IV grade
nutrition guidelines with myeloid cells toxicities using the toxicities using the
a minimum of 2 pieces of (30 min) in control CTCAE CTCAE
fruit per day) only∗
↑CD45 + CD3 + lym-
phocytes (7 d) in
control only∗
Treatment-related side
effects in STF
↑ FT4∗
↑ Erythrocyte counts
(D7, D21) ∗
↑ Thrombocyte (D7) ∗
A. 24 h STF (n = 6) For all groups after
B. 48 h STF (n = 7) chemotherapy: 2 ↓ grade I/II nausea and
C. 72 h STF (48 h before/24 pathological vomiting (test for
h after) (n = 7) complete response, trend)∗∗
Nonrandomized, no control 6 partial Toxicity graded using
radiographic CTCAE
response, 3 stable
disease
Ø difference in olive
moments (indicating
DNA damage) based
on Comet assay
(Continued)
 TABLE 2 (Continued)

Neurological adverse
Author Subjects Treatment and design Treatment efficacy GI adverse effects effects Quality of life
Riedinger et al., n = 20 females with A. STF (24 h before and Ø difference in Ø difference in Ø difference in Ø difference
2020 (30) gynecologic cancers with after) complete or partial treatment-related treatment-related between groups
≥6 cycles of B. Control response between toxicities via toxicities via in mean
chemotherapy groups∗∗ CTCAE∗∗ CTCAE∗∗ NCCN-FACT
Multiagent chemotherapy Randomized control trial ↑ Platelet count in the FOSI-18 score ∗∗
(bevacizumab, STF group at week ↑ QOL# in fasting
carboplatin, cisplatin, 18∗∗ group from first
docetaxel, doxorubicin, to last cycle in the
gemcitabine, and fasting group
paclitaxel), ≥2 compared to
participants neoadjuvant control
therapy
Zorn et al., 2020 n = 30; females with A. mSTF or KD + mSTFB. Treatment-related side mSTF and KD + mSTF Ø score difference
(36) gynecologic cancers, all Control effects in STF had between group
stages, neo or adjuvant Crossover, 2–3 cycles of CTX ↓MCH∗ ↓frequent grade I/II on
chemotherapy of intervention and ↓MCV∗ stomatitis∗ EORTC QLQ-C30,
control ↓Sodium∗ ↓headaches∗ ∗ EORTC
↑Uric acid∗ ↓total toxicities∗ QLQ-CIPN20 or
↓ fT3∗ measured by CTCAE FACIT-F
↑Ft4∗
Fasting mimicking diet
de Groot et al., n = 129 patients with A. FMD (n = 65) Ø difference in toxicity Ø score difference
2020 (22) HER-2 negative stage II/III B. Control (n = 64) of treatment between group
breast cancer, Diet was 3 d prior to and ↑ radiological on
neoadjuvant FEC-T or the day of treatment. complete or partial EORTC QLQ-C30
AC-T chemotherapy Randomized control trial response in pts
following FMD∗
Miller and Payne 4/5
pathological
response more likely
in those compliant
(per-protocol) FMD
CD45 + CD3 + lym-
phocytes (7 d) ↑ in
control and ↓ in
FMD compliant (per
protocol)∗

(Continued)

Intermittent fasting during chemotherapy 673

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674
Gabel et al.
TABLE 2 (Continued)

Neurological adverse
Author Subjects Treatment and design Treatment efficacy GI adverse effects effects Quality of life
Lugtenberg et al., n = 129 patients with HER-2 A. FMD (n = 65) Ø differences between Ø in QLQ-C30 or
2020 (37) negative stage II/III breast B. Control (n = 64) groups QLQ-BR23
cancer Diet was 3 d prior to and Per-protocol analysis: between groups
the day of treatment. less fatigue, nausea, Per-protocol
Randomized control trial and insomnia in analysis:
those adherent to improved
FMD∗ physical, role,
emotional,
cognitive, and
social functioning
in those adherent
to FMD∗
↓fatigue & dyspnea
# in the FMD

complaint 6 mo
after treatment
1
Ø no change, ∗ Significant change within group, P <0.05; ∗∗ significant difference between groups at endpoint, no time interaction, P <0.05; # significant group × time interaction, P <0.05. AC-T, Adriamuycin Cyclophosphamine Taxol regimen;
CIPN, Chemotherapy-induced peripeheral neuropathy; CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; CTX, Cyclophosphamide; EORTC, European Organisation for Research and Treatment of Cancer; FACIT-F,
Functional assessment of chronic illiness therapy fatigue; FACIT-G, Functional assessment of chronic illiness therapy general; FEC-T, Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel; FMD, fasting mimicking diet; KD + STF, ketogenic diet
combined with short-term fasting (KD 6 d prior to STF); MCH, Mean corpuscular hemoglobin; MCV, mean corpuscular volume; mSTF, modified short-term fasting (<25% of energy needs); NCCN - FACIT FOSI 18, National comprehensive cancer
network functional treatment of cancer therapy, Ovarian cancer symptom index; QOL, quality of life; QLQ, Quality of life questionaire; STF, short-term fasting; TAC, Taxotere-Adriamycin-Cytoxan regimen; TOI, Trial outcome index.

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the investigators reported that patients who both fasted and
followed standard care for their specific malignancy (a diet
to prevent or reverse nutrient deficiency and preserve lean
body mass), reported reduced weakness and fatigue when
fasting (23). However, this evidence is anecdotal at best and
the reduced vomiting and diarrhea could have been a result
of the lack of foodstuffs in the gut. In a feasibility trial by
Dorff et al. (29), all participants in the 24 h group reported
grade 1 or 2 nausea, 87% in the 48 h group, and 43% in the
72 h group. Grade 1 and 2 vomiting was reported by 83% of
the 24 h group, 43% in the 48 h group, and 0% in the 72 h
group (29). Constipation was experienced by 50% of the 24
h group, 28% of the 48 h group, and 43% of the 72 h group.
However, the 24 h group reported 33% grade 1–2 diarrhea,
none was reported in the 48 h group, and 57% reported in the
72 h group. There was only one report of grade 3 diarrhea,
which was in the 48 h group. A trial by Zorn et al. (36)
reported a decrease in frequency and severity of stomatitis,
headaches, weakness, and total toxicities with a 96 h modified
short-term fast (<25% of energy needs daily for 96 h, 72 h
before and 24 h after chemotherapy treatment) in women
with gynecological cancer (36). Additionally, participants in
the trial by Zorn et al. (36) experienced better chemotherapy
tolerance, reflected by fewer chemotherapy postponements
in the modified short-term fasting group.
One study examined the effect of the fasting mimicking
diet on gastrointestinal and neurological adverse effects
associated with chemotherapy treatment (37) (Table 2). In
the per-protocol analysis, Lugtenberg et al. (37) reported
that patients who were adherent to the fasting mimicking
diet had less fatigue over time when compared with the
control and nonadherent group. The per-protocol analysis
also reported a between-group difference between those who
were adherent to the fasting protocol and the control or those
not adherent for self-reported nausea and insomnia (37).
However, the intention-to-treat analysis did not report any
differences between the control and fasting mimicking diet
groups. Due to the high prevalence of treatment-related side
effects associated with chemotherapy, future fully powered
studies should explore if intermittent fasting may ameliorate
common treatment-related side effects.
Intermittent Fasting, Quality of Life, and Daily
Functioning During Cancer Treatment
It is possible that the positive effects of intermittent fasting
on treatment-related side effects translate to improved
patient quality of life and daily functioning while receiving
chemotherapy. Four studies have examined the effect of
short-term fasting or the fasting mimicking diet during
chemotherapy on quality of life. Validated self-report ques-
tionnaires were utilized in all studies presented. Quality of
life and function were measured by validated questionnaires
from The European Organization for Research and Treat-
ment of Cancer Core 30 (EORTC QLQ-30 [38]) or the
Functional Assessment of Chronic Illness Therapy (FACIT
[39]).
Three studies have examined the effect of short-term
fasting on quality of life in those undergoing chemotherapy
for cancer (36, 40) (Table 2) but report conflicting findings.
Zorn et al. (36) reported no improvement in patient-reported
quality of life (EORTC QLQ-C30), chemotherapy-induced
polyneuropathy (EORTC-QLQ-CIPN20), or fatigue scores
(FACIT-f) within the short-term fasting group over time,
when compared with standard care, or when combined with
6 d of a ketogenic diet prior to the fasting period. Bauersfeld
et al. (40) performed a 2 × 2 crossover trial in women with
breast and ovarian cancers. Participants either followed a 60
h short-term fast (36 h prior to and 24 after treatment) or
a normocaloric diet for the first 3 cycles of chemotherapy,
then alternating to the other diet protocol the following 3
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cycles. Group A performed short-term fasting in the first
3 cycles and normocaloric diet the last 3 cycles. Overall
quality of life (FACIT-G) and fatigue (TOI FACIT-F) scores
were statistically higher during the fasting cycles than the
normocaloric cycles in Group A. No differences in quality of
life and fatigue scores were reported between diet protocols
in Group B, which fasted second. Although authors report
no carryover effect, this discrepancy may suggest that order
of intervention or temporal intensity of chemotherapy
may act as confounding variables for quality of life and
fatigue scores. When analyzing all participants together,
independent of diet sequence, significant differences in
quality of life were observed with 60 h short-term fasting
compared with the normocaloric diet, in which the latter
group was observed to have a decrease in quality of life.
Both Groups A and B reported smaller increases in fatigue
from baseline during fasting cycles compared with larger
increases in fatigue during the normocaloric diet period.
Lastly, Riedinger et al. (30) measured a disease-related
symptom profile, treatment side effects, general function,
and well-being using NCCN-FACT-OSI-18 (National
Comprehensive Cancer Network Functional Assessment of
Cancer Therapy, Ovarian Cancer Symptom Index). They
reported no difference in any outcome from the first to the
last cycle when the fasting group was compared with the
control. Adequately powered randomized control trials are
needed to determine if short-term fasting may ameliorate the
decreases in treatment-related quality of life and fatigue while
considering timing of treatment-related adverse effects, the
degree of fasting (both total hours and caloric allowances),
as well as the impact of different chemotherapeutic
drugs.
One study by Lugtenberg et al. (37) examined the effect
of the fasting mimicking diet on quality of life during
chemotherapy treatment of HER-2 negative stage II/III breast
cancer (Table 2). No change in quality of life was reported via
the EORTC QLQ-30 for general cancer patients or EORTC
QLQ-BR23 specifically for breast cancer (37). However, in
the per-protocol analysis, among those who were adherent
to the diet, scores for physical, role, emotional, cognitive,
and social functioning were improved over time (37). Only
fatigue and dyspnea were improved 6 mo after surgery in
those who were adherent to the fasting mimicking diet group
Intermittent fasting during chemotherapy 675
versus the normal diet control over time. Although periodic
fasting does not seem to increase baseline quality of life scores
during treatment, it may ameliorate the decrease in quality
of life and daily functioning during treatment, a common
patient-related outcome. However, more data are needed to
determine how fasting affects quality of life, fatigue, and daily
functioning among cancer patients during chemotherapy
treatment.
Intermittent Fasting and Impact on
Cancer-promoting Biomarkers During
Treatment
The DSR hypothesis (Figure 2) is thought to be driven by
improved glucose control and a decrease in growth factors
such as IGF-1 (insulin-like growth factor). Further, IGFBP
(insulin-like growth factor binding protein) is increased
which aids in the sequestration of these proliferative growth
promoters. In preclinical murine models of liver-specific
IGF-1-deficient mice or hormone receptor positive mice with
breast cancer, short-term fasting and the fasting mimicking
diet reduced glucose, insulin, and IGF-1 significantly (27,
28). Reductions in c-peptide and leptin, associated with
reduced insulin and breast cancer growth, respectively, are
also reported in murine models during 72 h short-term
fasting and the fasting mimicking diet. Furthermore, during
chemotherapy, adiponectin concentrations are increased in
fasted mice which is believed to inhibit cancer cell growth and
metastasis via the activation of the AMP-activated protein
kinase (AMPK) pathway (28).
Glucose regulation
Four studies have examined the effect of short-term fasting
on glucose and/or insulin (29, 30, 36, 41) during chemother-
apy (Table 3). In a study by de Groot et al. (41), the
effect of a 24 h fast before and after chemotherapy infusion
among HER 2-negative stage II/III breast cancer patients was
examined. Glucose increased significantly in both the short-
term fasting and control groups, yet, insulin increased in
the control group only (41). However, at baseline, circulating
insulin concentrations in the control group were extremely
low and increased to within normal range; it is unclear if
this is the result of control treatment or reporting error
(41). Zorn et al. (36) did not measure glucose but did
report a decrease in insulin in the modified short-term
fasting group (participants were permitted 25% or less of
their daily energy needs on the fasting days). Conversely,
Riedinger et al. (30) reported a decrease in glucose but no
change in insulin in the short-term fasting group (24 h
before and after chemotherapy infusion). Dorff et al. (29)
examined the effect of different lengths of fasting during
platinum-based neoadjuvant and adjuvant chemotherapy on
glucose and insulin. Although the 24 h, 48 h, and 72 h
short-term fasting regimens did not alter glucose, fasting
insulin decreased by 56%, 27%, and 42%, respectively, in
the 3 groups. One study examined the effect of the fasting
mimicking diet on glucose and insulin during neoadjuvant
chemotherapy for HER2-negative stage II/III breast cancer.
676 Gabel et al.
In the per-protocol analysis, de Groot et al. (22) reported
a decrease in both fasting glucose and fasting insulin in
participants that were adherent to the diet compared with
those that were nonadherent. There was no change in glucose
or insulin between groups over time in the intention-to-treat
analysis. The efficacy of short-term fasting and the fasting
mimicking diet varies across current pilot data likely due
to the small sample sizes, variation in length of the fasting
period, as well as differences in energy intake during the
fasting period. From these preliminary data, intermittent
fasting may indeed improve circulating insulin and glucose.
However, whether intermittent fasting can improve insulin
sensitivity, supporting the DSR hypothesis, has yet to be
confirmed. Therefore, more research is needed utilizing
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indirect insulin sensitivity markers such as glycosylated
hemoglobin (HbA1C) or HOMA-IR calculation as well as
direct measures of insulin sensitivity such as the Matsuda in-
dex, intravenous glucose tolerance test, or hyperinsulinemic
euglycemic clamp.
Cancer biomarkers
Three studies have examined the effect of short-term fasting
on biomarkers associated with cancer promotion (29, 36,
41) (Table 3). Although IGFBP did not appear to be altered
after short-term fasting compared with standard care, both
de Groot et al. (41) and Zorn et al. (36) reported a significant
decrease in IGF-1 in the short-term fasting group with
no change in the standard care group. Dorff et al. (29)
reported changes in both IGF-1 and IGFBP in cancer
patients prescribed neoadjuvant or adjuvant platinum-based
chemotherapy who were assigned to 24 h, 48 h, or 72 h short-
term fasting. IGF-1 decreased 30% in the 24 h group, 33%
in the 48 h group, and 8% in the 72 h group (29). IGFBP
increased 23% in the 24 h group, 10% in the 48 h group, and
117% in the 72 h group (29). Dorff et al. (29) also measured
the ketone β-hydroxybutyrate, as ketone bodies are elevated
during the absence of food and have been associated with
the inhibition of colon and breast cancer cells (42). They
reported an increase in β-hydroxybutyrate in both the 48 h
and 72 h fasting groups and a decrease in the 24 h group
(29).
One study examined the effect of the fasting mimicking
diet during neoadjuvant chemotherapy on cancer-promoting
biomarkers in women with HER2-negative stage II/III breast
cancer (22) (Table 3). In the per-protocol analysis, de Groot
et al. (22) reported a decrease in IGF-1 in participants
that were adherent to the diet. It is currently unclear if
this decrease was due to the caloric restriction, the low-
protein diet prescription, or both. It is possible that fasting
may either directly decrease growth factors during treatment
or indirectly decrease growth factors by increasing IGFBP,
which sequesters IGF-1. However, low-protein diets, such
as that of the macronutrient distribution of the fasting
mimicking diet, have also been associated with decreases in
IGF-1 and increases in IGFBP. Future studies should consider
the possible confounding effect of nutrient intake during the
eating period of the fasting protocol.
 TABLE 3 Effect of intermittent fasting on circulating biochemical markers during chemotherapy in patients with cancer1

Author Subjects Treatment Glucose Insulin IGF-1 IGFBP

Short-term fasting
de Groot et al., n = 13 HER2-negative stage A. STF (24 h before and after) A. ↑∗ A. Ø A. ↓∗ A. Ø
2015 (41) II/III breast cancer receiving B. Control B. ↑∗ B. ↑∗ B. Ø B. Ø
neoadjuvant TAC
Dorff et al., 2016 n = 20 men and women with A. 24 h STF (n = 6) A. Ø A. ↓ 56% A. ↓ 30% A. ↑23%
(29) cancer diagnosis prescribed B. 48 h STF (n = 7) B. ↓27% B. ↓33% B. ↑10%
platinum-based C. 72 h STF (48 h before/24 C. ↓42% C. ↓8% C. ↑117%
chemotherapy h after) (n = 7) No significant No significant
between-group between-group
differences differences
Riedinger et al., n = 20 women with A. STF (24 h before and after) A. ↓∗∗ at time of NA NA NA
2020 (30) gynecologic cancers with B. Control chemotherapy
≥6 cycles of chemotherapy Randomized control trial
Zorn et al., 2020 n = 30; women with A. mSTF OR KD + mSTFB. NA A. ↓∗∗ A. ↓∗∗ NA
(36) gynecologic cancers, all Control
stages, neo or adjuvant Crossover, 2–3 cycles of CTX of
chemotherapy intervention and control
Fasting mimicking diet
de Groot 2020 (22) n = 129 patients with HER-2 A. FMD (n = 65) Ø differences Ø differences Ø differences
negative stage II/III breast B. Control (n = 64) between groups between groups between groups
cancer Diet was 3 d prior to and the Per-protocol: A. ↓ in Per-protocol:A. ↓ in Per-protocol: A. ↓ in
day of treatment. compliant only∗ compliant only∗ compliant only∗
Randomized control trial
Dexamethasone dc in FMD
group
1
Ø, no; NA, did not measure; ∗ Significant change within group, P <0.05; ∗∗ significant difference between groups at endpoint, no time interaction, P <0.05; # significant group × time interaction, P <0.05. CTX, Cyclophosphamide; FMD, fasting
mimicking diet; IGF-1, insulin like growth factor 1; IGFBP, insulin like growth factor binding protein; KD + STF, ketogenic diet combined with short-term fasting (KD 6 d prior to STF); mSTF, modified short-term fasting (<25% of energy needs); STF,
short-term fasting; TAC, Taxotere-Adriamycin-Cytoxan regimen.
.

Intermittent fasting during chemotherapy 677

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Limitations and Future Directions
Although data is limited, short-term fasting and the fasting
mimicking diet do show promise as an emerging nutrition
therapy during chemotherapy for cancers with a low risk
of cancer cachexia. The most notable limitations for the
adoption of these diets as medical nutrition therapy are
limited efficacy data, a low patient adherence, and high
dropout rate (Table 1) (22, 29, 40). Improvements in
patient and treatment outcomes are dependent on diet
adherence. For instance, de Groot et al. (22) reported
patient adherence to the fasting mimicking diet for each
of the 4 fasting/treatment cycles. In the first round 82%
of participants were adherent to the diet, however, this
decreased rapidly with each subsequent cycle with only 20%
of participants adherent to all 4 cycles (22). In their intention-
to-treat analysis, significant differences between the fasting
mimicking diet group and the standard care group were only
seen for radiological response (22). However, in the per-
protocol analysis, Miller and Payne score, glucose, insulin,
IGF-1, and DNA damage were significantly improved in
participants adherent to the fasting mimicking diet (22). In
a follow-up with 24 participants from a trial by Zorn et al.
(36), 1 participant declared the diet was “too difficult,” 11
declared “quite difficult,” and 9 as “easy” or “quite easy.”
Further, only about half said they would fast again during
chemotherapy (36). An additional limitation of periodic
fasting for treatment during chemotherapy is that nutrition
interventions where food is absent for multiple days increases
the patient burden and may have other untoward adverse side
effects such as weakness, hypoglycemia, hyponatremia, and
hypotension (29, 40). Fully powered studies should continue
to determine if periodic fasting may benefit patients with
cancers with low risk of cachexia and increased risk of weight
gain such as breast, ovarian, and prostate cancer. Further,
the utilization of continuous glucose monitors and at home
blood pressure cuffs could be applied to maximize safety
and monitor possible diet-related adverse effects. It is also
currently unclear what participants ate outside the fasting
window in any of the aforementioned studies. Food intake
data would account for the confounding effect of dietary
intake and quality, outside of fasting, on outcome measures.
Larger clinical trials utilizing both short-term fasting and the
fasting mimicking diet should be examined to assess their
feasibility, acceptability, if these diets can improve patient
quality of life or the effectiveness of chemotherapeutic drugs
despite their current low adherence rates and potential of
increased burden to the patient. Further, all current data
examines the effect of short-term fasting and the fasting
mimicking diet surrounding each chemotherapy infusion,
a follow-up period after treatment has yet to be explored.
Future studies should also examine if periodic fasting
could be adopted during survivorship to impact cancer
recurrence.
As previously stated, most studies were conducted as
pilot studies and thus, sample size was low and statistical
power minimal. However, some studies were able to show
some outcomes with statistical significance (Tables 2 and 3).
678 Gabel et al.
Several studies used rigorous methods to eliminate bias,
randomly assigning participants, sealed envelope allocation,
and blinding when possible (Table 1). Objective outcomes
were often measured using validated questionnaires such as
the FACT (Functional Assessment of Cancer Therapy) and
CTCAE (Common Terminology Criteria for Adverse Events)
for toxicity measures. Overall, there was heterogeneity
among cancer type, stages, and treatment therapy within
the studies, a limitation adequately noted by study authors.
However, in women, breast cancer was well represented
across all studies evaluated, lending a more robust picture to
the fasting interventions at this cancer site.
Time-restricted eating (TRE) is a popular form of in-
termittent fasting where individuals extend the overnight
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fasting period (14–20 h) and shorten the daily eating window
(4–10 h). Prolonged nightly fasting has been associated with
decreased risk of cancer recurrence and decreased inflam-
matory markers, a known risk pathway for several cancers
(43–45). Additionally, although there are no restrictions on
types or quantity of food, TRE appears to naturally decrease
daily energy intake by 20% with current data suggesting a
2–4% decrease in body weight after 12–16 wk of 8–10 h
TRE (46–49). This form of intermittent fasting may hold
the potential to improve treatment efficacy and improve
patient-centered outcomes during chemotherapy treatment
all while maintaining a high adherence. Further, TRE is
accessible with no cost to the patient and unlike periodic
fasting, allows the individual to eat daily. Clinical trials
in healthy adults with overweight and obesity report high
adherence with TRE (47, 50–52) unlike forms of periodic
fasting. Limited data is available for the long-term effects
of TRE on body weight, however, a recent year-long study
in healthy low-income women with obesity resulted in the
same weight change as an isocaloric hypocaloric control (53).
Yet, body fat and waist circumference decreased significantly
in the TRE group when compared with the control diet
group over time (53). Further, Gill and Panda (47) reported
weight loss retention of 4% a year after a 16 wk 10 h
TRE intervention in healthy participants with overweight.
This may be another added benefit of intermittent fasting
as obesity can impair treatment outcomes, increase cancer
recurrence, and weight gain is common during and after
treatment in certain cancers such as breast, ovarian, and
prostate. Additionally, in a crossover study from Jamshed
et al. (54) early TRE (intake between 08:00 and 14:00)
participants (n = 11) with overweight and obesity reduced
mean 24 h glucose concentrations, increased LC3A and
ATG12 expression (genes that may enhance autophagy) over
5 d. Mechanistic target of rapamycin (mTOR), a regulatory
pathway for cell growth, increased in the evening only, which
may be associated with increases in insulin. This increase in
both markers may be due to the completion of the eating
window at 14:00 or as part of the protective effect upregulated
by healthy cells in order to decrease autophagy. Although
both IGF-1 and IGFBP decreased, it was not statistically
significant, however, the study was not powered a priori on
these parameters. TRE offers another alternative form of
intermittent fasting for investigation during chemotherapy
and should be examined in the context of cancer care
(55–57).
Conclusion
Preliminary human studies exploring the potential of inter-
mittent fasting as a nutrition therapy during chemotherapy
to improve treatment and patient outcomes are limited yet
promising. Short-term fasting and the fasting mimicking diet
may decrease treatment-related side effects, improve quality
of life, and decrease insulin compared with the current
standard care. Further, if the changes in insulin promote
improved insulin sensitivity these periods of nutrient depri-
vation may improve the efficacy of chemotherapy treatment.
Fully powered trials of short-term fasting and the fasting
mimicking diet are needed and should be tested within the
context of different medication protocols and within specific
cancer types. Furthermore, other forms of intermittent
fasting such as TRE should be rigorously evaluated as a
possible adjunct intervention during cancer chemotherapy to
improve treatment- and patient-related outcomes.
Acknowledgments
The authors’ responsibilities were as follows—KG and KC:
designed and wrote the manuscript; VG, KV, and LT-H:
wrote the manuscript; and all authors: read and approved
the final manuscript. Graphical Figures 1 and 2 were created
with BioRender.com; Agreement number ZW2399HPRZ
and WF2399HIJN.
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