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Functional Assessment of Chronic Illness Therapy; IGF-1, insulin-like growth factor 1; IGFBP, standard care may be outdated for specific types of cancers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

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

668 Gabel et al.

 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)

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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- cancer type may impact the degree of recovery in these
term fasting. The majority of the studies in this emerging studies as both gynecological and breast cancer have high
area are feasibility and pilot studies; as such, we will also survival rates (65% and 90%, respectively [1, 32]). However,
mention a case series report to present the full breadth of these are currently the safest sample to examine the effect of
data currently available. Due to the novelty of this area of periodic fasting during treatment due to low cancer cachexia
research, most of the studies presented are underpowered risk. Limitations of these initial clinical studies are small
to make conclusions about the true effect of fasting during sample size and a heterogenous group of cancer diagnosis all
chemotherapy, therefore, this review aims to present a clear with variable clinical outcomes.
picture of what is currently known and future directions for One study has evaluated the effect of the fasting mim-
this emerging therapy. icking diet on treatment efficacy during chemotherapy (22)
(Table 2). The DIRECT (Dietary Restriction as an Adjunct
Intermittent Fasting and Efficacy of Cancer to Neoadjuvant ChemoTherapy for HER2 Negative Breast
Treatment Cancer) trial by de Groot et al. (22) examined the fasting
In cell culture, neuroblastoma, breast, ovarian, mesothe- mimicking diet as an adjunct to neoadjuvant chemotherapy

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lioma, lung, and colorectal cancers cells exposed to cy- in women with HER2-negative stage II/III breast cancer. In
cles of fasting had delayed growth and progression of the per-protocol analysis, participants that were adherent
the cancer cells as well as increased effectiveness of the to the fasting mimicking diet protocol had a significantly
chemotherapeutic drugs (24, 25). Preclinical in vitro models increased rate of complete or partial radiological response.
reported that fasting had antiproliferative effects, delaying Moreover, a 4/5 Miller and Payne pathological response
the progression of tumors, and increasing the effectiveness (>90% loss of tumor cells/no invasive carcinoma) was also
of chemotherapeutic drugs in melanoma, glioma, colorectal, more likely in those that were adherent to the fasting
and breast cancers (24, 26). In preclinical murine models mimicking diet than those who were not adherent or the
of breast cancer, glioma, and neuroblastoma, healthy cells controls. De Groot et al. (22) also reported a decrease
were protected from oxidative stress, DNA damage, and in chemotherapy-induced DNA damage to normal cells
treatment-related endometrial hyperplasia during high-dose in the fasting mimicking diet group. Current trials lack
chemotherapy when combined with fasting (24, 26–28). a homogeneous large sample size in order to expound
Additionally, in some in vitro and in vivo mouse models, the effect on treatment outcomes. Therefore, larger studies
when fasting was combined with chemotherapy, sensitivity controlling for cancer and treatment type, dose intensity, and
to and efficacy of chemotherapeutic drugs in breast cancer adherence to the protocol are needed to determine the true
and neuroblastoma cells resulted in increased longer-term effect of short-term fasting or the fasting mimicking diet on
cancer-free survival (17, 24, 26–28). chemotherapy.
The effect of short-term fasting on cancer treatment
efficacy has been examined in 2 clinical studies (29, 30) Intermittent Fasting and Treatment-related
(Table 2). Dorff et al. (29) aimed to determine the optimal Adverse Effects
length of a short-term fasting window for a future larger Side effects are common in patients receiving chemotherapy
scale investigation. Men and women with urothelial, non- for cancer treatment. A prospective cohort study by Pearce
small cell lung cancer, uterine, breast, or ovarian cancer et al. (33) examined the incidence and severity of self-
diagnosis prescribed neoadjuvant or adjuvant platinum- reported side effects among 478 patients receiving adjuvant
based chemotherapy, were randomly assigned into 3 different chemotherapy for breast, colorectal, or lung cancer. The
fasting groups: 1) 24 h prior to treatment, 2) 48 h prior to authors reported that 86% of participants experienced ≥1
treatment, or 3) 72 h surrounding treatment (48 h prior to adverse effect during the study period with fatigue, diarrhea,
and 24 h following). No control group was included. After and constipation reported most frequently (33). In murine
completion of the adjunct fasting protocol 2 patients had models, fasting in the context of chemotherapy is associated
complete responses (no cancer cells present), 6 had partial with reduced occurrence of treatment-related side effects
radiographic responses (>30% decrease in sum of all target including weight loss, decreased activity, diarrhea, leukope-
lesions), 3 had stable disease, and 8 were nonevaluable based nia, and other visible signs of discomfort compared with
on RECIST (Response Evaluation Criteria in Solid Tumors nonfasting mice (34, 35). This work indicates an area of
[31]). However, after the completion of the full treatment opportunity for the use of fasting to mitigate side effects
plan, 5 participants had a pathological complete response related to cancer treatment.
of which 4 were from the 72 h fasting group and the other Three studies have examined the effect of short-term
was from the 48 h fasting group (29). Riedinger et al. (30) fasting on gastrointestinal and neurological adverse effects
recruited women with gynecologic cancers with a treatment in the context of cancer treatment with chemotherapy (23,
plan consisting of ≥6 cycles of neoadjuvant or adjuvant 29, 36) (Table 2). In a 2009 case series of cancer patients
chemotherapy and randomly assigned to a short-term fasting who had voluntarily fasted for 48–140 h prior to and 5–
group (24 h before and 24 h after treatment) or a standard 56 h following chemotherapy treatment, gastrointestinal
care control group. There were no differences in partial or adverse effects such as nausea, vomiting, diarrhea, abdominal
complete response between groups. It is possible that the 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

Neurological adverse
Author Subjects Treatment and design Treatment efficacy GI adverse effects effects Quality of life

Gabel et al.
Short-term fasting
Bauersfeld et al., n = 34 females with A. Group A: STF (36 h before, A. ↑ FACT-G, FACIT F,
2018 (40) gynecologic cancers, 24 h after)/Control FACIT-F TOI
various forms of B. Group B: during fasting
chemotherapy 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
de Groot et al., n = 13 HER2-negative stage A. STF (24 h before and Within-group change Ø differences between Ø differences between
2015 (41) II/III breast cancer after) γ -H2AX intensity groups in grade I/II groups in grade I/II
(histologically confirmed) B. Control (follow healthy ↑CD45 + CD13- or III/IV grade or III/IV grade
receiving neoadjuvant nutrition guidelines with myeloid cells toxicities using the toxicities using the
TAC a minimum of 2 pieces of (30 min) in control CTCAE CTCAE
(docetaxel/doxorubicin fruit per day) only∗
/cyclophosphamide) ↑CD45 + CD3 + lym-
phocytes (7 d) in
control only∗
Treatment-related side
effects in STF
↑ FT4∗
↑ Erythrocyte counts
(D7, D21) ∗
↑ Thrombocyte (D7) ∗
Dorff et al., 2016 n = 20 males and females A. 24 h STF (n = 6) For all groups after
(29) with cancer diagnosis B. 48 h STF (n = 7) chemotherapy: 2 ↓ grade I/II nausea and
prescribed C. 72 h STF (48 h before/24 pathological vomiting (test for
platinum-based h after) (n = 7) complete response, trend)∗∗
chemotherapy w/out Nonrandomized, no control 6 partial Toxicity graded using
radiation, curative or radiographic CTCAE
palliative response, 3 stable
disease
Ø difference in olive
moments (indicating
DNA damage) based
on Comet assay

(Continued)

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 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)

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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 Three studies have examined the effect of short-term
followed standard care for their specific malignancy (a diet fasting on quality of life in those undergoing chemotherapy
to prevent or reverse nutrient deficiency and preserve lean for cancer (36, 40) (Table 2) but report conflicting findings.
body mass), reported reduced weakness and fatigue when Zorn et al. (36) reported no improvement in patient-reported
fasting (23). However, this evidence is anecdotal at best and quality of life (EORTC QLQ-C30), chemotherapy-induced
the reduced vomiting and diarrhea could have been a result polyneuropathy (EORTC-QLQ-CIPN20), or fatigue scores
of the lack of foodstuffs in the gut. In a feasibility trial by (FACIT-f) within the short-term fasting group over time,
Dorff et al. (29), all participants in the 24 h group reported when compared with standard care, or when combined with
grade 1 or 2 nausea, 87% in the 48 h group, and 43% in the 6 d of a ketogenic diet prior to the fasting period. Bauersfeld
72 h group. Grade 1 and 2 vomiting was reported by 83% of et al. (40) performed a 2 × 2 crossover trial in women with
the 24 h group, 43% in the 48 h group, and 0% in the 72 h breast and ovarian cancers. Participants either followed a 60
group (29). Constipation was experienced by 50% of the 24 h short-term fast (36 h prior to and 24 after treatment) or
h group, 28% of the 48 h group, and 43% of the 72 h group. a normocaloric diet for the first 3 cycles of chemotherapy,
However, the 24 h group reported 33% grade 1–2 diarrhea, then alternating to the other diet protocol the following 3

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none was reported in the 48 h group, and 57% reported in the cycles. Group A performed short-term fasting in the first
72 h group. There was only one report of grade 3 diarrhea, 3 cycles and normocaloric diet the last 3 cycles. Overall
which was in the 48 h group. A trial by Zorn et al. (36) quality of life (FACIT-G) and fatigue (TOI FACIT-F) scores
reported a decrease in frequency and severity of stomatitis, were statistically higher during the fasting cycles than the
headaches, weakness, and total toxicities with a 96 h modified normocaloric cycles in Group A. No differences in quality of
short-term fast (<25% of energy needs daily for 96 h, 72 h life and fatigue scores were reported between diet protocols
before and 24 h after chemotherapy treatment) in women in Group B, which fasted second. Although authors report
with gynecological cancer (36). Additionally, participants in no carryover effect, this discrepancy may suggest that order
the trial by Zorn et al. (36) experienced better chemotherapy of intervention or temporal intensity of chemotherapy
tolerance, reflected by fewer chemotherapy postponements may act as confounding variables for quality of life and
in the modified short-term fasting group. fatigue scores. When analyzing all participants together,
One study examined the effect of the fasting mimicking independent of diet sequence, significant differences in
diet on gastrointestinal and neurological adverse effects quality of life were observed with 60 h short-term fasting
associated with chemotherapy treatment (37) (Table 2). In compared with the normocaloric diet, in which the latter
the per-protocol analysis, Lugtenberg et al. (37) reported group was observed to have a decrease in quality of life.
that patients who were adherent to the fasting mimicking Both Groups A and B reported smaller increases in fatigue
diet had less fatigue over time when compared with the from baseline during fasting cycles compared with larger
control and nonadherent group. The per-protocol analysis increases in fatigue during the normocaloric diet period.
also reported a between-group difference between those who Lastly, Riedinger et al. (30) measured a disease-related
were adherent to the fasting protocol and the control or those symptom profile, treatment side effects, general function,
not adherent for self-reported nausea and insomnia (37). and well-being using NCCN-FACT-OSI-18 (National
However, the intention-to-treat analysis did not report any Comprehensive Cancer Network Functional Assessment of
differences between the control and fasting mimicking diet Cancer Therapy, Ovarian Cancer Symptom Index). They
groups. Due to the high prevalence of treatment-related side reported no difference in any outcome from the first to the
effects associated with chemotherapy, future fully powered last cycle when the fasting group was compared with the
studies should explore if intermittent fasting may ameliorate control. Adequately powered randomized control trials are
common treatment-related side effects. 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
Intermittent Fasting, Quality of Life, and Daily degree of fasting (both total hours and caloric allowances),
Functioning During Cancer Treatment as well as the impact of different chemotherapeutic
It is possible that the positive effects of intermittent fasting drugs.
on treatment-related side effects translate to improved One study by Lugtenberg et al. (37) examined the effect
patient quality of life and daily functioning while receiving of the fasting mimicking diet on quality of life during
chemotherapy. Four studies have examined the effect of chemotherapy treatment of HER-2 negative stage II/III breast
short-term fasting or the fasting mimicking diet during cancer (Table 2). No change in quality of life was reported via
chemotherapy on quality of life. Validated self-report ques- the EORTC QLQ-30 for general cancer patients or EORTC
tionnaires were utilized in all studies presented. Quality of QLQ-BR23 specifically for breast cancer (37). However, in
life and function were measured by validated questionnaires the per-protocol analysis, among those who were adherent
from The European Organization for Research and Treat- to the diet, scores for physical, role, emotional, cognitive,
ment of Cancer Core 30 (EORTC QLQ-30 [38]) or the and social functioning were improved over time (37). Only
Functional Assessment of Chronic Illness Therapy (FACIT fatigue and dyspnea were improved 6 mo after surgery in
[39]). those who were adherent to the fasting mimicking diet group

Intermittent fasting during chemotherapy 675

versus the normal diet control over time. Although periodic In the per-protocol analysis, de Groot et al. (22) reported
fasting does not seem to increase baseline quality of life scores a decrease in both fasting glucose and fasting insulin in
during treatment, it may ameliorate the decrease in quality participants that were adherent to the diet compared with
of life and daily functioning during treatment, a common those that were nonadherent. There was no change in glucose
patient-related outcome. However, more data are needed to or insulin between groups over time in the intention-to-treat
determine how fasting affects quality of life, fatigue, and daily analysis. The efficacy of short-term fasting and the fasting
functioning among cancer patients during chemotherapy mimicking diet varies across current pilot data likely due
treatment. to the small sample sizes, variation in length of the fasting
period, as well as differences in energy intake during the
Intermittent Fasting and Impact on fasting period. From these preliminary data, intermittent
Cancer-promoting Biomarkers During fasting may indeed improve circulating insulin and glucose.
Treatment However, whether intermittent fasting can improve insulin
The DSR hypothesis (Figure 2) is thought to be driven by sensitivity, supporting the DSR hypothesis, has yet to be
improved glucose control and a decrease in growth factors confirmed. Therefore, more research is needed utilizing

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such as IGF-1 (insulin-like growth factor). Further, IGFBP indirect insulin sensitivity markers such as glycosylated
(insulin-like growth factor binding protein) is increased hemoglobin (HbA1C) or HOMA-IR calculation as well as
which aids in the sequestration of these proliferative growth direct measures of insulin sensitivity such as the Matsuda in-
promoters. In preclinical murine models of liver-specific dex, intravenous glucose tolerance test, or hyperinsulinemic
IGF-1-deficient mice or hormone receptor positive mice with euglycemic clamp.
breast cancer, short-term fasting and the fasting mimicking
diet reduced glucose, insulin, and IGF-1 significantly (27, Cancer biomarkers
28). Reductions in c-peptide and leptin, associated with Three studies have examined the effect of short-term fasting
reduced insulin and breast cancer growth, respectively, are on biomarkers associated with cancer promotion (29, 36,
also reported in murine models during 72 h short-term 41) (Table 3). Although IGFBP did not appear to be altered
fasting and the fasting mimicking diet. Furthermore, during after short-term fasting compared with standard care, both
chemotherapy, adiponectin concentrations are increased in de Groot et al. (41) and Zorn et al. (36) reported a significant
fasted mice which is believed to inhibit cancer cell growth and decrease in IGF-1 in the short-term fasting group with
metastasis via the activation of the AMP-activated protein no change in the standard care group. Dorff et al. (29)
kinase (AMPK) pathway (28). reported changes in both IGF-1 and IGFBP in cancer
patients prescribed neoadjuvant or adjuvant platinum-based
Glucose regulation chemotherapy who were assigned to 24 h, 48 h, or 72 h short-
Four studies have examined the effect of short-term fasting term fasting. IGF-1 decreased 30% in the 24 h group, 33%
on glucose and/or insulin (29, 30, 36, 41) during chemother- in the 48 h group, and 8% in the 72 h group (29). IGFBP
apy (Table 3). In a study by de Groot et al. (41), the increased 23% in the 24 h group, 10% in the 48 h group, and
effect of a 24 h fast before and after chemotherapy infusion 117% in the 72 h group (29). Dorff et al. (29) also measured
among HER 2-negative stage II/III breast cancer patients was the ketone β-hydroxybutyrate, as ketone bodies are elevated
examined. Glucose increased significantly in both the short- during the absence of food and have been associated with
term fasting and control groups, yet, insulin increased in the inhibition of colon and breast cancer cells (42). They
the control group only (41). However, at baseline, circulating reported an increase in β-hydroxybutyrate in both the 48 h
insulin concentrations in the control group were extremely and 72 h fasting groups and a decrease in the 24 h group
low and increased to within normal range; it is unclear if (29).
this is the result of control treatment or reporting error One study examined the effect of the fasting mimicking
(41). Zorn et al. (36) did not measure glucose but did diet during neoadjuvant chemotherapy on cancer-promoting
report a decrease in insulin in the modified short-term biomarkers in women with HER2-negative stage II/III breast
fasting group (participants were permitted 25% or less of cancer (22) (Table 3). In the per-protocol analysis, de Groot
their daily energy needs on the fasting days). Conversely, et al. (22) reported a decrease in IGF-1 in participants
Riedinger et al. (30) reported a decrease in glucose but no that were adherent to the diet. It is currently unclear if
change in insulin in the short-term fasting group (24 h this decrease was due to the caloric restriction, the low-
before and after chemotherapy infusion). Dorff et al. (29) protein diet prescription, or both. It is possible that fasting
examined the effect of different lengths of fasting during may either directly decrease growth factors during treatment
platinum-based neoadjuvant and adjuvant chemotherapy on or indirectly decrease growth factors by increasing IGFBP,
glucose and insulin. Although the 24 h, 48 h, and 72 h which sequesters IGF-1. However, low-protein diets, such
short-term fasting regimens did not alter glucose, fasting as that of the macronutrient distribution of the fasting
insulin decreased by 56%, 27%, and 42%, respectively, in mimicking diet, have also been associated with decreases in
the 3 groups. One study examined the effect of the fasting IGF-1 and increases in IGFBP. Future studies should consider
mimicking diet on glucose and insulin during neoadjuvant the possible confounding effect of nutrient intake during the
chemotherapy for HER2-negative stage II/III breast cancer. eating period of the fasting protocol.

676 Gabel et al.

 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 Several studies used rigorous methods to eliminate bias,
Although data is limited, short-term fasting and the fasting randomly assigning participants, sealed envelope allocation,
mimicking diet do show promise as an emerging nutrition and blinding when possible (Table 1). Objective outcomes
therapy during chemotherapy for cancers with a low risk were often measured using validated questionnaires such as
of cancer cachexia. The most notable limitations for the the FACT (Functional Assessment of Cancer Therapy) and
adoption of these diets as medical nutrition therapy are CTCAE (Common Terminology Criteria for Adverse Events)
limited efficacy data, a low patient adherence, and high for toxicity measures. Overall, there was heterogeneity
dropout rate (Table 1) (22, 29, 40). Improvements in among cancer type, stages, and treatment therapy within
patient and treatment outcomes are dependent on diet the studies, a limitation adequately noted by study authors.
adherence. For instance, de Groot et al. (22) reported However, in women, breast cancer was well represented
patient adherence to the fasting mimicking diet for each across all studies evaluated, lending a more robust picture to
of the 4 fasting/treatment cycles. In the first round 82% the fasting interventions at this cancer site.
of participants were adherent to the diet, however, this Time-restricted eating (TRE) is a popular form of in-
decreased rapidly with each subsequent cycle with only 20% termittent fasting where individuals extend the overnight

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of participants adherent to all 4 cycles (22). In their intention- fasting period (14–20 h) and shorten the daily eating window
to-treat analysis, significant differences between the fasting (4–10 h). Prolonged nightly fasting has been associated with
mimicking diet group and the standard care group were only decreased risk of cancer recurrence and decreased inflam-
seen for radiological response (22). However, in the per- matory markers, a known risk pathway for several cancers
protocol analysis, Miller and Payne score, glucose, insulin, (43–45). Additionally, although there are no restrictions on
IGF-1, and DNA damage were significantly improved in types or quantity of food, TRE appears to naturally decrease
participants adherent to the fasting mimicking diet (22). In daily energy intake by 20% with current data suggesting a
a follow-up with 24 participants from a trial by Zorn et al. 2–4% decrease in body weight after 12–16 wk of 8–10 h
(36), 1 participant declared the diet was “too difficult,” 11 TRE (46–49). This form of intermittent fasting may hold
declared “quite difficult,” and 9 as “easy” or “quite easy.” the potential to improve treatment efficacy and improve
Further, only about half said they would fast again during patient-centered outcomes during chemotherapy treatment
chemotherapy (36). An additional limitation of periodic all while maintaining a high adherence. Further, TRE is
fasting for treatment during chemotherapy is that nutrition accessible with no cost to the patient and unlike periodic
interventions where food is absent for multiple days increases fasting, allows the individual to eat daily. Clinical trials
the patient burden and may have other untoward adverse side in healthy adults with overweight and obesity report high
effects such as weakness, hypoglycemia, hyponatremia, and adherence with TRE (47, 50–52) unlike forms of periodic
hypotension (29, 40). Fully powered studies should continue fasting. Limited data is available for the long-term effects
to determine if periodic fasting may benefit patients with of TRE on body weight, however, a recent year-long study
cancers with low risk of cachexia and increased risk of weight in healthy low-income women with obesity resulted in the
gain such as breast, ovarian, and prostate cancer. Further, same weight change as an isocaloric hypocaloric control (53).
the utilization of continuous glucose monitors and at home Yet, body fat and waist circumference decreased significantly
blood pressure cuffs could be applied to maximize safety in the TRE group when compared with the control diet
and monitor possible diet-related adverse effects. It is also group over time (53). Further, Gill and Panda (47) reported
currently unclear what participants ate outside the fasting weight loss retention of 4% a year after a 16 wk 10 h
window in any of the aforementioned studies. Food intake TRE intervention in healthy participants with overweight.
data would account for the confounding effect of dietary This may be another added benefit of intermittent fasting
intake and quality, outside of fasting, on outcome measures. as obesity can impair treatment outcomes, increase cancer
Larger clinical trials utilizing both short-term fasting and the recurrence, and weight gain is common during and after
fasting mimicking diet should be examined to assess their treatment in certain cancers such as breast, ovarian, and
feasibility, acceptability, if these diets can improve patient prostate. Additionally, in a crossover study from Jamshed
quality of life or the effectiveness of chemotherapeutic drugs et al. (54) early TRE (intake between 08:00 and 14:00)
despite their current low adherence rates and potential of participants (n = 11) with overweight and obesity reduced
increased burden to the patient. Further, all current data mean 24 h glucose concentrations, increased LC3A and
examines the effect of short-term fasting and the fasting ATG12 expression (genes that may enhance autophagy) over
mimicking diet surrounding each chemotherapy infusion, 5 d. Mechanistic target of rapamycin (mTOR), a regulatory
a follow-up period after treatment has yet to be explored. pathway for cell growth, increased in the evening only, which
Future studies should also examine if periodic fasting may be associated with increases in insulin. This increase in
could be adopted during survivorship to impact cancer both markers may be due to the completion of the eating
recurrence. window at 14:00 or as part of the protective effect upregulated
As previously stated, most studies were conducted as by healthy cells in order to decrease autophagy. Although
pilot studies and thus, sample size was low and statistical both IGF-1 and IGFBP decreased, it was not statistically
power minimal. However, some studies were able to show significant, however, the study was not powered a priori on
some outcomes with statistical significance (Tables 2 and 3). these parameters. TRE offers another alternative form of

678 Gabel et al.

intermittent fasting for investigation during chemotherapy 11. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging
and should be examined in the context of cancer care in mice by dietary restriction: longevity, cancer, immunity and lifetime
energy intake. J Nutr 1986;116(4):641–54.
(55–57).
12. Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction,
ketogenic diet and intermittent fasting during initiation, progression
Conclusion and metastasis of cancer in animal models: a systematic review and
Preliminary human studies exploring the potential of inter- meta-analysis. PLoS One 2014;9(12):e115147.
mittent fasting as a nutrition therapy during chemotherapy 13. Longo VD, Fontana L. Calorie restriction and cancer prevention:
metabolic and molecular mechanisms. Trends Pharmacol Sci
to improve treatment and patient outcomes are limited yet
2010;31(2):89–98.
promising. Short-term fasting and the fasting mimicking diet 14. Cheney KE, Liu RK, Smith GS, Leung RE, Mickey MR, Walford
may decrease treatment-related side effects, improve quality RL. Survival and disease patterns in C57BL/6J mice subjected to
of life, and decrease insulin compared with the current undernutrition. Exp Gerontol 1980;15(4):237–58.
standard care. Further, if the changes in insulin promote 15. Cheney KE, Liu RK, Smith GS, Meredith PJ, Mickey MR, Walford RL.
The effect of dietary restriction of varying duration on survival, tumor
improved insulin sensitivity these periods of nutrient depri-
patterns, immune function, and body temperature in B10C3F1 female
vation may improve the efficacy of chemotherapy treatment.

Downloaded from https://academic.oup.com/advances/article/13/2/667/6425731 by guest on 05 April 2023

mice. J Gerontol 1983;38(4):420–30.
Fully powered trials of short-term fasting and the fasting 16. Klurfeld DM, Welch CB, Davis MJ, Kritchevsky D. Determination
mimicking diet are needed and should be tested within the of degree of energy restriction necessary to reduce DMBA-induced
context of different medication protocols and within specific mammary tumorigenesis in rats during the promotion phase. J Nutr
1989;119(2):286–91.
cancer types. Furthermore, other forms of intermittent
17. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S,
fasting such as TRE should be rigorously evaluated as a Mirisola M, Quinn DI, Dorff TB, et al. Prolonged fasting reduces IGF-
possible adjunct intervention during cancer chemotherapy to 1/PKA to promote hematopoietic-stem-cell-based regeneration
improve treatment- and patient-related outcomes. and reverse immunosuppression. Cell Stem Cell 2014;14(6):
810–23.
18. Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW,
Acknowledgments Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, et al. Fasting
The authors’ responsibilities were as follows—KG and KC: mimicking diet reduces HO-1 to promote T cell-mediated tumor
designed and wrote the manuscript; VG, KV, and LT-H: cytotoxicity. Cancer Cell 2016;30(1):136–46.
wrote the manuscript; and all authors: read and approved 19. Brandhorst S, Harputlugil E, Mitchell JR, Longo VD. Protective effects
the final manuscript. Graphical Figures 1 and 2 were created of short-term dietary restriction in surgical stress and chemotherapy.
with BioRender.com; Agreement number ZW2399HPRZ Ageing Res Rev 2017;39:68–77.
20. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical
and WF2399HIJN. applications. Cell Metab 2014;19(2):181–92.
21. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD.
References Starvation-dependent differential stress resistance protects normal but
1. Institute NC. 27 April, 2018. [Internet]. Available from: https://seer. not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci
cancer.gov/statfacts/html/breast.html(accessed 19 March, 2019). USA 2008;105(24):8215–20.
2. Rock CL, Thomson C, Gansler T, Gapstur SM, McCullough ML, Patel 22. de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk
AV, Andrews KS, Bandera EV, Spees CK, Robien K, et al. American MPG, Smit V, de Graaf H, Heijns JB, Portielje JEA, et al. Fasting
Cancer Society guideline for diet and physical activity for cancer mimicking diet as an adjunct to neoadjuvant chemotherapy for breast
prevention. CA Cancer J Clin 2020;70(4):245–71. cancer in the multicentre randomized phase 2 DIRECT trial. Nat
3. Bail J, Meneses K, Demark-Wahnefried W. Nutritional status and diet Commun 2020;11(1):3083.
in cancer prevention. Semin Oncol Nurs 2016;32(3):206–14. 23. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo
4. Kohler LN, Garcia DO, Harris RB, Oren E, Roe DJ, Jacobs ET. VD. Fasting and cancer treatment in humans: a case series report. Aging
Adherence to diet and physical activity cancer prevention guidelines (Albany NY) 2009;1(12):988–1007.
and cancer outcomes: a systematic review. Cancer Epidemiol 24. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-
Biomarkers Prev 2016;25(7):1018–28. Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, et al. Fasting cycles
5. Muscaritoli M, Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz retard growth of tumors and sensitize a range of cancer cell types to
H, Bozzetti F, Hutterer E, Isenring E, Kaasa S, et al. ESPEN practical chemotherapy. Sci Transl Med 2012;4(124):124ra27.
guideline: clinical nutrition in cancer. Clin Nutr 2021;40(5):2898–913. 25. Shi Y, Felley-Bosco E, Marti TM, Orlowski K, Pruschy M, Stahel RA.
6. Mahan LK, Escott-Stump S, Raymond JL. Krause’s Food and the Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes
Nutrition Care Process. 13 ed. St. Louis, Missouri: Elsevier Saunders, cancer cells to cisplatin. BMC Cancer 2012;12:571.
2012. 26. Caffa I, D’Agostino V, Damonte P, Soncini D, Cea M, Monacelli
7. Harvie MN, Campbell IT, Baildam A, Howell A. Energy balance in early F, Odetti P, Ballestrero A, Provenzani A, Longo VD, et al.
breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Fasting potentiates the anticancer activity of tyrosine kinase
Res Treat 2004;83(3):201–10. inhibitors by strengthening MAPK signaling inhibition. Oncotarget
8. Vance V, Mourtzakis M, McCargar L, Hanning R. Weight gain in breast 2015;6(14):11820–32.
cancer survivors: prevalence, pattern and health consequences. Obes 27. Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, Hwang
Rev 2011;12(4):282–94. D, Cohen P, Bianchi G, Longo VD. Reduced levels of IGF-I mediate
9. Tannenbaum A, Silverstone H. The influence of the degree of caloric differential protection of normal and cancer cells in response to
restriction on the formation of skin tumors and hepatomas in mice. fasting and improve chemotherapeutic index. Cancer Res 2010;70(4):
Cancer Res 1949;9(12):724–7. 1564–72.
10. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, 28. Caffa I, Spagnolo V, Vernieri C, Valdemarin F, Becherini P, Wei M,
Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Brandhorst S, Zucal C, Driehuis E, Ferrando L, et al. Fasting-mimicking
et al. Caloric restriction delays disease onset and mortality in rhesus diet and hormone therapy induce breast cancer regression. Nature
monkeys. Science 2009;325(5937):201–4. 2020;583(7817):620–4.

Intermittent fasting during chemotherapy 679

29. Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, Cheng 42. Cui W, Luo W, Zhou X, Lu Y, Xu W, Zhong S, Feng G, Liang Y, Liang
CW, Brandhorst S, Cohen P, Wei M, et al. Safety and feasibility L, Mo Y, et al. Dysregulation of ketone body metabolism is associated
of fasting in combination with platinum-based chemotherapy. BMC with poor prognosis for clear cell renal cell carcinoma patients. Front
Cancer 2016;16:360. Oncol 2019;9(1422):1422.
30. Riedinger CJ, Kimball KJ, Kilgore LC, Bell CW, Heidel RE, Boone JD. 43. Marinac CR, Nelson SH, Breen CI, Hartman SJ, Natarajan L, Pierce JP,
Water only fasting and its effect on chemotherapy administration Flatt SW, Sears DD, Patterson RE. Prolonged nightly fasting and breast
in gynecologic malignancies. Gynecol Oncol 2020;159(3): cancer prognosis. JAMA Oncol 2016;2(8):1049–55.
799–803. 44. Marinac CR, Natarajan L, Sears DD, Gallo LC, Hartman SJ, Arredondo
31. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, E, Patterson RE. Prolonged nightly fasting and breast cancer risk:
Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian findings from NHANES (2009-2010). Cancer Epidemiol Biomarkers
MC, et al. New guidelines to evaluate the response to treatment in solid Prev 2015;24(5):783–9.
tumors. European Organization for Research and Treatment of Cancer, 45. Marinac CR, Sears DD, Natarajan L, Gallo LC, Breen CI, Patterson RE.
National Cancer Institute of the United States, National Cancer Institute Frequency and circadian timing of eating may influence biomarkers of
of Canada. J Natl Cancer Inst 2000;92(3):205–16. inflammation and insulin resistance associated with breast cancer risk.
32. Faubion SS, MacLaughlin KL, Long ME, Pruthi S, Casey PM. PLoS One 2015;10(8):e0136240.
Surveillance and care of the gynecologic cancer survivor. J Womens 46. Gabel K, Hoddy KK, Haggerty N, Song J, Kroeger CM, Trepanowski JF,

Downloaded from https://academic.oup.com/advances/article/13/2/667/6425731 by guest on 05 April 2023

Health (Larchmt) 2015;24(11):899–906. Panda S, Varady KA. Effects of 8-hour time restricted feeding on body
33. Pearce A, Haas M, Viney R, Pearson SA, Haywood P, Brown weight and metabolic disease risk factors in obese adults: a pilot study.
C, Ward R. Incidence and severity of self-reported chemotherapy Nutr Healthy Aging 2018;4(4):345–53.
side effects in routine care: a prospective cohort study. PLoS One 47. Gill S, Panda S. A smartphone app reveals erratic diurnal eating patterns
2017;12(10):e0184360. in humans that can be modulated for health benefits. Cell Metab
34. Huisman SA, Bijman-Lagcher W, Uzermans JNM, Smits R, de 2015;22(5):789–98.
Bruin RW. Fasting protects against the side effects of irinotecan but 48. Chow LSea. Time-restricted eating effects on body composition and
preserves its anti-tumor effect in apc15lox mutant mice. Cell Cycle metabolic measures in humans with overweight: a feasibility study.
2015;14(14):2333–9. Obesity (Silver Spring) 2020;28(5):860–69.
35. Huisman SA, de Bruijn P, Ghobadi Moghaddam-Helmantel IM, 49. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S,
Uzermans JNM, Wiemer EA, Mathijssen RH, de Bruin RW. Fasting Shoghi A, Wang X, Fleischer JG, Navlakha S, Panda S, et al. Ten-hour
protects against the side effects of irinotecan treatment but does time-restricted eating reduces weight, blood pressure, and atherogenic
not affect anti-tumour activity in mice. Br J Pharmacol 2016;173(5): lipids in patients with metabolic syndrome. Cell Metab 2020;31(1):92–
804–14. 104.e5.
36. Zorn S, Ehret J, Schauble R, Rautenberg B, Ihorst G, Bertz H, Urbain P, 50. Gabel K, Hoddy KK, Varady KA. Safety of 8-h time restricted feeding
Raynor A. Impact of modified short-term fasting and its combination in adults with obesity. Applied Physiology, Nutrition, and Metabolism
with a fasting supportive diet during chemotherapy on the incidence 2018;44(1):107–109.
and severity of chemotherapy-induced toxicities in cancer patients - a 51. Cienfuegos S, Gabel K, Kalam F, Ezpeleta M, Wiseman E, Pavlou V, Lin
controlled cross-over pilot study. BMC Cancer 2020;20(1):578. S, Oliveira ML, Varady KA. Effects of 4- and 6-h time-restricted feeding
37. Lugtenberg RT, de Groot S, Kaptein AA, Fischer MJ, Kranenbarg on weight and cardiometabolic health: a randomized controlled trial in
EM, Carpentier MD, Cohen D, de Graaf H, Heijns JB, Portielje JEA, adults with obesity. Cell Metab 2020;32(3):366–378.e3.
et al. Quality of life and illness perceptions in patients with breast 52. Martens CR, Rossman MJ, Mazzo MR, Jankowski LR, Nagy EE,
cancer using a fasting mimicking diet as an adjunct to neoadjuvant Denman BA, Richey JJ, Johnson SA, Ziemba BP, Wang Y, et al. Short-
chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial. Breast term time-restricted feeding is safe and feasible in non-obese healthy
Cancer Res Treat 2021;185(3):741–58. midlife and older adults. Geroscience 2020;42(2):667–86.
38. Groenvold M, Klee MC, Sprangers MA, Aaronson NK. Validation of 53. de Oliveira Maranhão Pureza IR, da Silva Junior AE, Silva Praxedes
the EORTC QLQ-C30 quality of life questionnaire through combined DR, Lessa Vasconcelos LG, de Lima Macena M, Vieira de Melo IS, de
qualitative and quantitative assessment of patient-observer agreement. Menezes Toledo Florêncio TM, Bueno NB. Effects of time-restricted
J Clin Epidemiol 1997;50(4):441–50. feeding on body weight, body composition and vital signs in low-
39. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman income women with obesity: a 12-month randomized clinical trial. Clin
M, Yellen SB, Winicour P, Brannon J, et al. The functional assessment Nutr 2021;40(3):759–66.
of cancer therapy scale: development and validation of the general 54. Jamshed H, Beyl RA, Della Manna DL, Yang ES, Ravussin E, Peterson
measure. J Clin Oncol 1993;11(3):570–9. CM. Early time-restricted feeding improves 24-hour glucose levels and
40. Bauersfeld SP, Kessler CS, Wischnewsky M, Jaensch A, Steckhan N, affects markers of the circadian clock, aging, and autophagy in humans.
Stange R, Kunz B, Bruckner B, Sehouli J, Michalsen A. The effects of Nutrients 2019;11(6):234.
short-term fasting on quality of life and tolerance to chemotherapy in 55. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on
patients with breast and ovarian cancer: a randomized cross-over pilot health and disease processes. Ageing Res Rev 2017;39:46–58.
study. BMC Cancer 2018;18(1):476. 56. Chaix A, Manoogian ENC, Melkani GC, Panda S. Time-restricted
41. de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems eating to prevent and manage chronic metabolic diseases. Annu Rev
A, Houtsma D, Putter H, van der Hoeven JJ, Nortier JW, et al. The effects Nutr 2019;39:291–315.
of short-term fasting on tolerance to (neo) adjuvant chemotherapy in 57. Levesque S, Pol JG, Ferrere G, Galluzzi L, Zitvogel L, Kroemer G.
HER2-negative breast cancer patients: a randomized pilot study. BMC Trial watch: dietary interventions for cancer therapy. Oncoimmunology
Cancer 2015;15:652. 2019;8(7):1591878.

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