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Valdemarin F, Caffa I, Persia A, et al. Safety and feasibility of a fasting-like diet and effects on nutritional status and circulating metabolic and inflammatory factors in cancer patients undergoing active treatment.Cancer (Basel). 2021;13(16):4013.
Study objective
To evaluate the feasibility, safety and effect of a fasting-like diet (FMD) during the treatment of cancer with a variety of different anticancer drugs
Key to take away
FMD is safe and relatively well tolerated in patients undergoing active treatment for various types of cancer when monitored and adjusted to the specific needs of the individual patient.
Draft
Single-arm, open-label phase I/II clinical trial in Italy
Participant
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 having HR-negative tumors. The remaining 14% of participants had a total of 18 different tumor types.
At the time of enrollment, the mean age was 50.4 years (range 19–72) and the mean body mass index (BMI) was 25.9 (19–44) kg/m2. All participants were actively being treated for cancer.
intervention
The intervention consisted of a “five-day, low-calorie, low-protein diet providing approximately 4,600 kJ (1,099 kcal) on day 1 (11% protein, 46% fat, and 43% carbohydrate), approximately 3,000 kJ (717 kcal) (9% protein, 44% fat, and 47% carbohydrate) on days 2-5, and that from plants ingredients that are all generally recognized as safe (GRAS) by the FDA.” (L-Nutra, proprietary product).
In the interim between FMD cycles, participants were instructed to specifically consume adequate calories (20–30 kcal/kg weight/day) and protein (1.2–1.5 g protein/kg weight/day, primarily from fish, legumes, eggs, and dairy products). They also received specific muscle training instructions that included detailed exercises (each exercise demonstrated, with specified repetitions and rest times) to promote mild to moderate engagement of various muscle groups for 20 to 30 minutes or 500 to 600 kJ/day.
For patients receiving chemotherapy, the 5-day FMD was performed 4 days before chemotherapy and on the day of chemotherapy. For participants receiving other treatments (e.g., hormone modulators, targeted agents), FMD was performed either monthly or every 3 weeks.
NOTE: There was a change in the protocol if/when the phase angle indicated muscle mass loss without recovery. At low phase angle (5.0–5.2 degrees), the FMD shortened to 3 to 4 days. If below 5.0, the corresponding FMD was not administered, amino acids (Aminotrofic®: 5.5 g twice daily) and the patient was re-examined after 4 weeks.
Study parameters assessed
Body composition: Measurements included fat-free mass, fat mass, phase angle, extracellular mass to body cell mass ratio (ECM/BCM), total body water, and intracellular water. The parameters were measured using a single frequency bioimpedance analyzer (BIA 101®, Akern, Florence, Italy) after fasting for at least 3 hours. These measurements were then processed using Bodygram Plus®Software (Akern, Florence, Italy).
Handgrip strength was assessed using a dynamometer (TKK 5001 GRIP A Hand Grip Analogue Dynamometer, Takei, Japan).
CT scans ordered as part of ongoing surveillance of selected patients were used to estimate muscle mass at the level of the transverse processes of the third lumbar vertebra (L3) (bony landmark; n = 6 participants).
Blood parameters: Blood values 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 performed after overnight fasting at enrollment and before each FMD cycle.
Patients who were able to return to the hospital immediately before refeeding began also had their serum collected at that time so that researchers could 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 diet on IGFBP1, resistin, adiponectin, or any of the cyto/chemokines and adhesion molecules tested.
Changes after a full cycle (just before FMD, then 2 to 3 weeks after a cycle and healthy diet plus exercise): Leptin, IGF1 and IGFBP3 levels remained lower compared to baseline, while adiponectin and IGFBP1 levels were higher. The researchers again noted that no significant effect of FMD was found on any of the cyto-/chemokines tested.
Key insights
Finally, while muscle mass was retained, weight loss during FMD was typically 2 to 2.5 kg. A total of 27 patients (30%) demonstrated a significant decrease in phase angle and fat-free mass after 1 of their FMD cycles. (In these cases, subsequent FMD cycles were shortened to 3 or 4 days.) Ten patients (11%) experienced a decrease in their phase angle value below 5 degrees. These results suggest that careful monitoring is required for the safe use of FMD.
transparency
Two of the authors are identified as inventors on patents for medical applications of fasting and FMD in oncology, and 1 author holds an equity interest in L-Nutra Inc., the company whose product was used in the study.
Practice implications
As we approach fasting in integrative oncology, we must first keep safety in mind. One of the tough battles that calorie restriction and fasting face is that we as a society want to feed the sick. Add to this the fact that cancer is typically a disease of food waste, with cachexia posing a real risk to patients with advanced cancer. Not surprisingly, many doctors are resistant to the idea of fasting their patients due to concerns about nutritional status.
Preclinical data have demonstrated many mechanisms and benefits of fasting/caloric restriction in animals, and we need to advance this safely for humans. FMD attempts to mimic a total fasting state through targeted macronutrient deficiencies, allowing a person to eat and somewhat alleviating the concerns of co-treating physicians and hesitations of patients. As a practitioner who uses FMD and fasts myself, I know there is a good level of safety and benefit, and this study shows that with careful monitoring it is both safe and feasible for those undergoing cancer treatment. The blood test confirms that FMDs do indeed meet some of the endpoints thought to benefit from fasting, such as: B. the reduction of IGF-1.
Clinically, I have suspected that there is value in fasting patients because of some of the anti-cancer benefits it might have, even outside of a chemo scenario. A common scenario would be breast cancer patients undergoing endocrine therapy. This study states: "These results are particularly relevant given that reduced blood levels of insulin, IGF1 and leptin have previously been shown to enhance the activity of chemotherapy, endocrine therapies and inhibitors of the PI3K-mTOR pathway. Even more interestingly, we observed that leptin, IGF1 and IGFBP3 levels increased two to three weeks after remained lower at the end of the FMD period than at the beginning, while adiponectin and IGFBP1 remained higher. This suggests that some metabolic effects of FMD persist for longer periods of time, potentially contributing to creating long-lasting adverse conditions for tumor growth.”1
From a naturopathic perspective, we have long observed benefits of fasting in our patients, particularly in relation to inflammation and healthy cell turnover. Now the direct links to the anticancer mechanism are being made.
From a naturopathic perspective, we have long observed benefits of fasting in our patients, particularly in relation to inflammation and healthy cell turnover.”
To put this study in the context of the state of fasting science, we are still trying to obtain better human data to confirm the large amount of preclinical data we have. Early on there were some very promising small pilot studies conducted by Longo et al. were carried out and published in 2009.2have a protective effect 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 is still needed.3It makes sense that the cost of conducting large-scale human studies on fasting is prohibitive without an economic driver such as a drug or product to sell.
This study was sponsored by a company, L-Nutra, that manufactures and sells the FMD product used. It would be ideal to have future studies conducted by independent third parties to confirm the beneficial changes as well as the clinical challenges encountered.
This paper consolidates and builds on the evolving rationale for the use of 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, as it was designed to show basic safety and feasibility, not results. In practice, I have seen the benefits of fasting in several scenarios and have felt good about the safety of fasting over many years of experience. The results of this study should further encourage other physicians that FMD can be used safely, even in patients undergoing various cancer treatments.