Intermittent Fasting in Breast Cancer: A Systematic Review And Critical Update Of Available Studies Part 2

3.1.4. Endocrine-Related Outcomes      

We identified four studies that reported data on insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1), and IGF-binding protein (IGFBP) concentrations.     

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Zorn et al. [25] studied the effects of IF on serum metabolic parameters before each chemotherapy cycle. Metabolic parameters included insulin, IGF-1, thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) serum concentrations. The authors reported a significant decrease in mean fT3 concentrations in the STF group (−0.47 ± 0.09; 95% CI, 0.64–(−0.30); p < 0.001), while mean fT4 increased significantly during the STF cycles compared to the norm caloric cycles (0.82 ± 0.37; 95% CI, 0.09–1.55;  p = 0.028). Finally, both mean insulin (−169.4 ± 44.1; 95% CI, 257.1–(−81.8); p < 0.001) and IGF-1 concentrations (−33.3 ± 5.4; 95% CI, 44.1–(−22.5); p < 0.001) significantly decreased during the STF cycles [25].

De Groot et al. (2015) [27] studied serum glucose, insulin, IGF-1, thyroid-stimulating hormone (TSH), and insulin growth factor binding protein 3 (IGF-BP3) concentrations, in both IF and non-IF (controls). Venous blood samples were drawn before randomization,  at a maximum of 2 weeks before treatment (baseline), and directly before chemotherapy administration. Median blood glucose values increased in both groups, between the two time points (p = 0.042 and p = 0.043, respectively).

In the STF group, no significant difference in median insulin concentrations between the two-time points was reported, but in the non-STF group, fasting insulin was increased (p = 0.043). Mean IGF-1 concentrations increased (p = 0.012) in the STF group (who fasted 24 h before and after commencing chemotherapy), but no change was reported in the non-STF group, whereas no change was observed in any group for IGF-BP3 concentrations. Finally, TSH significantly decreased (p = 0.034) in the non-STF group, but not in the STF  group [27].

Dorff et al. [28] studied three cohorts who fasted before chemotherapy for 24, 48,  and 72 h (divided into 48 pre-chemo and 24 post-chemo) in BC patients who had been previously treated with TCH (docetaxel, carboplatin, trastuzumab). Of major interest, IGF-1  concentrations decreased by a mean of −30% (−44%, −12%) in the 24 h cohort, −33% in the 48 h cohort, and −8% in the 72 h cohort 1-day post-chemotherapy (p = 0.32 comparing all 3 cohort groups), whereas serum β-hydroxybutyrate concentrations increased in the 48 and 72 h cohorts, post-chemotherapy [28]. Marinac et al. also reported that each 2 h increase in nightly fasting duration was associated with a 0.37 mmol/mol lower hemoglobin A1C (HbA1c) level (β = −0.37; 95% CI, −0.72 to −0.01) [23].

3.1.5. Adverse Effects of IF

Adverse fasting-related effects were reported in four studies. In the vast majority,  adverse effects occurred upon initiation of chemotherapy [19], including headaches, fever,  insomnia, fatigue, dizziness, lightheadedness, weight loss, hypoglycemia, hyponatremia and hypotension, hunger, slight nausea after intake of broth or juices, and orthostatic reactions, while in some cases, malnutrition and undernutrition were reported [19,20,28]. No severe fasting-related adverse effects were reported, and fasting-induced weight loss was quickly regained by most patients.

4. Discussion

To our knowledge, this is the first systematic review of the effects of IF subtypes on BC patients.

We divided the available data into patient-reported symptoms through the QoL scores, as well as clinical and objective serum markers of chemotherapy-induced toxicity and endocrine-related outcomes, to identify any potential clinical benefit of IF in the daily clinical setting. The available results were characterized by a high degree of heterogeneity regarding IF regimens, duration, and pre-specified health outcomes in conjunction with the timing of IF implementation, as well as the lack of the inclusion of control groups in most of the studies (n = 7). However, we postulate that the improvement in laboratory markers of chemotherapy-induced toxicity identified in three studies could comprise a useful tool for future well-designed controlled trials in the field.

Most studies (n = 4) that focused on the potential effects of IF on the QoL of BC  patients undergoing chemotherapy reported an improvement in the FACT-G and FACIT-F  scales, as well as the score-based Common Terminology Criteria for Adverse Events of The National Cancer Institute [16–19]. However, no additional validated measures of the QoL were incorporated, as well as any adjustments for additional factors that could interfere with patient-reported symptoms. Although BC patients displayed higher tolerance to chemotherapy and manifested an improvement in chemotherapy-induced side effects (such as fatigue, nausea, vomiting, appetite loss, and anxiety), we consider the available data scarce and of low quality for improving the QoL of BC patients.

In our analysis, we identified an improvement in the markers of DNA damage after chemotherapy, outlining a practical approach for identifying clear benefits through future well-designed trials.

Improvement in leukocytic oxidative stress and γ-H2AX (formed by the phosphorylation of the Ser-139 residue of the histone variant H2AX) [24], as well as Olive tail moment as markers of chemotherapy-induced double-stranded DNA breaks. These markers are extensively used to measure DNA damage post-irradiation, where the expression has been proven to be related to healthy tissue damage [27]. γ-H2AX phosphorylation denotes double-strand DNA breaks’ presence and could be, therefore, used as a marker for chemotherapy-induced toxicity in healthy cells, as observed in phase I/II trial with patients treated with a combination of chemotherapy and belinostat [27]. Nevertheless, the use of γ-H2AX as a marker for chemotherapy-induced toxicity to normal cells is relatively uninvestigated [27].

We failed to identify significant effects of IF on chemotherapeutic or radiological response and tumor recurrence. The available results were limited and have not incorporated validated measures of disease recurrence, as well in one case based on self-reported data and semi-annual telephone calls.

These results could not confirm previous results in mouse models, where two fasting cycles in combination with cyclophosphamide were found to be sufficient to slow down tumor growth in the short-term period [29].

It could be hypothesized that, in humans, a higher number of FMD cycles might be even more important to observe some clinical benefit. In that context, improving patient adherence, for longer periods, could be useful to observe any potential FMD-related antitumor activity [29]. Another interesting finding was a reported decrease of insulin and IGF-1 concentrations in the fasting groups in two studies, as well as a rise in serum β-hydroxybutyrate concentrations after 48 and 72 h, post-chemotherapy; however, these findings were not adjusted to body weight, age, and muscle mass. Previous animal models indicate that serum β-hydroxybutyrate is a potent endogenous histone deacetylase inhibitor, protecting cells from oxidative stress. On the other hand, increased IGF-1 concentrations inhibit apoptosis, boost cell proliferation, and cause genetic instability, augmenting tumorigenesis [30]. Future studies are required to establish a cause-and-effect association between IF-induced ketogenesis and the effects on the IGF-1 axis and specific BC-related outcomes in humans.

In general, IF was well tolerated in the populations included in this analysis, highlighting that it could be a feasible and safe approach for improving health outcomes in conjunction with validated chemotherapeutic regimens or other treatment modalities. One of the included studies [23] reported that patients who fasted ≥13-h had a decreased risk for BC recurrence, but these findings were not confirmed in other available studies. It should be emphasized that fasting-induced weight loss was abolished after the cessation of IF periods, a finding that could be considered important for patients with cachexia, but also poses the challenge of weight regain in obese women with the disease. Currently,  there are four undergoing clinical trials (one was withdrawn) (Table 2) studying the effects of IF in BC patients, which highlights the changing spectrum in the field and the need for well-designed interventional controlled trials.

This systematic review has several limitations. First, we included only studies published in English. Second, due to the heterogeneity of the cancer types, interventions, and endpoints of the included studies, we could not conduct a meta-analysis. Finally, although we contacted the authors requesting additional data for additional outcomes,  responses were only limited to those presented in the current analysis, thus additional health outcomes were not included.

As far as the strengths of our systematic review are concerned, the included studies contain several types of fasting, providing a thorough insight into the wide spectrum of IF  subtypes. Additionally, the subject of this review falls under a quite unexplored field of high interest, therefore making our study, from our point of view, innovative.

In conclusion, we failed to identify any IF-related beneficial effects on the QoL, response after chemotherapy, or related symptoms, as well as measures of tumor recurrence in BC patients. We identified a potential beneficial effect of IF on chemotherapy-induced toxicity, based on markers of DNA and leukocyte damage; however, these results were derived from three studies and require further validation.

Author Contributions: Literature search, title/abstract screening, full-paper assessment, quality assessment of the papers, and data extraction were performed independently by M.A., A.V., and V.K. Any differences in these outcomes were discussed, and the consensus was reached and referred to S.N.K. for resolution and/or confirmation. M.A., A.V., and S.N.K. drafted the manuscript. S.N.K. wrote the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. 

Institutional Review Board Statement: Not applicable. 

Informed Consent Statement: Not applicable.

Data Availability Statement: The data presented in the study are available upon request from the corresponding author. 

Conflicts of Interest: The authors declare no conflict of interest. 

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