Valdemarin F, Caffa I, Persia A, et al. Safety and feasibility of fasting-mimicking diet and effects on nutritional status and circulating metabolic and inflammatory factors in cancer patients undergoing active treatment. Cancers (Basel). 2021;13(16):4013.
To evaluate the feasibility, safety, and effects of a fasting-mimicking diet (FMD) during treatment for cancer with a variety of different anticancer drugs
The FMD is safe and relatively well-tolerated in patients undergoing active treatment for various cancers when monitored and adjusted for the specific needs of the individual patient.
Single-arm, unblinded, phase I/II clinical trial based in Italy
There were 90 original participants (86% female), with 81 completing at least 1 FMD cycle and 65 participants completing 2 to 21 FMD cycles.
The majority of participants had breast cancer (n=62), with 36 having hormone receptor–(HR) positive tumors and 26 HR-negative tumors. The remaining 14% of participants had 18 different tumor types in all.
At the time of enrollment, the average age was 50.4 years (range 19–72), and the average body mass index (BMI) was 25.9 (19–44) kg/m2. All participants were undergoing active treatment for cancer.
The intervention consisted of “5-day, low-calorie and low-protein diet that supplies approximately 4,600 kj (1,099 kcal) on Day 1 (11% protein, 46% fat and 43% carbohydrates), approximately 3,000 kj (717 kcal) (9% protein, 44% fat and 47% carbohydrates) on Days 2–5 and which consists of plant-based ingredients all generally recognized as safe (GRAS) according to the FDA.” (L-Nutra, proprietary product).
During the interim between FMD cycles, the participants were instructed to specifically eat adequate calories (20–30 kcal/kg weight/day) and protein (1.2–1.5 g protein/kg weight/day, mainly derived from fish, legumes, eggs, and dairy products). They were also given specific instructions on muscle training that included detailed exercises (each exercise demonstrated, with reps and rest periods given) to promote mild-moderate involvement of various muscle groups for 20 to 30 minutes, or 500 to 600 kJ/day.
For those receiving chemotherapy, the 5-day FMD was done for 4 days before chemo and on the day of the chemotherapy. For participants receiving other treatments (eg, hormone modulators, targeted agents), the FMD was done either every month or every 3 weeks.
NOTE: There was a change in the protocol if/when the phase angle indicated muscle mass loss without recovery. If the phase angle was low (5.0–5.2 degrees, then the FMD was shortened to 3 to 4 days. If it was below 5.0, then the corresponding FMD was not administered, amino acids (Aminotrofic®: 5.5 g 2 times a day) were given, and the patient was reassessed at 4 weeks.
Study Parameters Assessed
Body composition: Measures included fat-free mass, fat mass, phase angle, extracellular mass–to–body cell mass ratio (ECM/BCM), total body water, and intracellular water. Parameters were measured with a single frequency bioimpedance analyzer (BIA 101®, Akern, Florence, Italy) after at least 3 hours of fasting. These measurements were subsequently processed with the Bodygram Plus® software (Akern, Florence, Italy).
Handgrip strength was evaluated with the use of a dynamometer (T.K.K. 5001 GRIP A Hand Grip Analogue Dynamometer, Takei, Japan).
CT scans that were ordered as part of ongoing monitoring of select patients were used to estimate muscle mass at the level of the third lumbar vertebra (L3) transverse processes (bony landmark; n=6 participants).
Blood Parameters: Bloodwork including “leptin, adiponectin, resistin, c-peptide (as a proxy for insulin production), IGF1, insulin-like growth factor-binding protein 1 (IGFBP1), IGFBP3, matrix metalloproteinase 8 (MMP8), MMP9, myeloperoxidase (MPO), tissue inhibitor of metalloproteinase 1 (TIMP1), TIMP2, MMP9/TIMP1 complex (M/T c), osteopontin (OPN), intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), sclerostin, interleukin-6 (IL-6) and C-reactive protein (hs-CRP)” was done after overnight fast at enrollment and before each FMD cycle.
Patients who could return to the hospital immediately before re-feeding started also had their serum obtained then, allowing investigators to measure levels of the same factors at the end of the FMD period.
Primary Outcome Measures
Acute FMD changes (measured immediately after FMD): c-peptide (a proxy for insulin production), IGF1, leptin, and IGFBP3 levels were reduced. There was no effect of the diet on IGFBP1, resistin, adiponectin, or any of the cyto/chemokines and adhesion molecules tested.
Changes after 1 full cycle (just before FMD, then 2 to 3 weeks after a cycle and healthy diet plus exercise): The leptin, IGF1, and IGFBP3 levels remained lower as compared to the baseline levels, while the adiponectin and IGFBP1 levels were higher. The investigators again found no significant effect of the FMD on any of the cyto/chemokines tested was found.
While eventually muscle mass was preserved, weight loss during the FMD was commonly 2 to 2.5 kg. A total of 27 patients (30%) showed a significant decrease in phase angle and fat-free mass after 1 of their FMD cycles. (In these cases, the subsequent FMD cycles were reduced to 3 or 4 days.) Ten patients (11%) underwent a drop in their phase angle value below 5 degrees. These results suggest that careful oversight is necessary for the safe application of FMD.
Two of the authors are disclosed to be inventors on patents of medical uses of fasting and FMD in oncology and 1 author holds equity interest in L-Nutra Inc., the company whose product was used in the study.
As we approach fasting in integrative oncology, we need to keep an eye to safety first. One of the uphill battles that caloric restriction and fasting face, is that we, as a society, want to feed the sick. Add to this the fact that cancer tends to be a disease of nutritional wasting, with cachexia a real risk for those with advanced cancers. Not surprisingly, many physicians have balked at the idea of fasting their patients due to their concerns around nutritional status.
Preclinical data have shown many mechanisms and benefits of fasting/caloric restriction in animals, and we need to advance this safely for humans. FMD seeks to mimic a total fasting state through select deprivation of macronutrients, allowing a person to eat and somewhat alleviating the concerns of cotreating doctors and hesitation by patients. As a practitioner, using FMD and fasting myself, I know there is a good level of safety and benefit, and this study demonstrates that with close oversight it is both safe and feasible for those going through cancer treatment. The blood work confirms that FMDs are indeed achieving some of the end points presumed beneficial from fasting, such as lowering IGF-1.
Clinically, I’ve suspected that it makes sense to fast patients for some of the anticancer benefits it could have, even outside of a chemo scenario. A common scenario would be breast cancer patients undergoing endocrine therapy. This study states, "These results are especially relevant in the light of the fact that reduced blood levels of insulin, IGF1 and leptin were previously shown to enhance the activity of chemotherapy, endocrine therapies and inhibitors of the PI3K-mTOR pathway. Even more interestingly, we observed that the leptin, IGF1 and IGFBP3 levels remained lower than those found at the baseline two-to-three weeks after the end of the FMD period, while adiponectin and IGFBP1 stayed higher. This indicates that some metabolic effects of the FMD persist for extended periods, possibly contributing to create long-lasting unfavorable conditions for tumor growth."1
Naturopathically, we’ve long observed benefits of fasting in our patients, especially around inflammation and healthy cellular turnover. Now, the direct links are being made for anticancer mechanism.
Naturopathically, we’ve long observed benefits of fasting in our patients, especially around inflammation and healthy cellular turnover.”
To put this study in the context of the state of fasting science, we are still trying to get better human data to confirm the large amount of preclinical data we have. Early on, there were some very promising small-scale pilot studies performed by Longo, et al, published in 2009,2 showing protective effects alongside chemotherapy. In a more recent review of the data, we have more mechanisms, and our understanding has been clarified, but the authors conclude that more human data are still needed.3 It makes sense that the cost of conducting large-scale human trials on fasting is cost-prohibitive without an economic driver like a drug or product to sell.
This study was sponsored by a company, L-Nutra, that produces and sells the FMD product that was used. Having future studies done by independent third parties to verify the favorable changes, as well as the clinical challenges encountered, would be ideal.
This paper solidifies and builds upon the evolving rationale for using fasting as a tool in various oncology applications, at least for nutritionally stable patients. It’s hard to make too many direct claims from this type of study because it was designed to show basic safety and feasibility, not outcomes. In practice, I’ve seen the benefits of fasting in multiple scenarios and have felt good about the safety of fasting over many years of experience. The findings of this study should further encourage other doctors that FMDs can be used safely, even in patients who are undergoing various treatments for cancer.