Fasting-mimicking diet safe, may benefit patients on anticancer therapy
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A cyclic, 5-day fasting-mimicking diet appeared safe and showed potential to improve outcomes among patients on anticancer therapy for different tumor types, according to study results published in Cancer Discovery.
Based on these findings, the diet — which involves short-term, severe caloric restriction — merits further investigation among selected populations of patients, with the aim of improving tumor responses and prolonging survival, Claudio Vernieri, MD, PhD, oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori and director of the metabolic reprogramming in solid tumors program at FIRC Institute of Molecular Oncology in Milan, Italy, told Healio.
“Our research was prompted by results of preclinical studies conducted in several laboratories that showed nutrient starvation, in the form of a cyclic fasting or fasting-mimicking diet, sensitizes several types of tumor models to the antitumor effects of chemotherapy, targeted therapies and immunotherapy,” Vernieri said. “Based on those results, we reasoned that a cyclic fasting-mimicking diet could be a new weapon against cancer, and we decided to conduct a clinical trial to evaluate if a specific calorie-restricted, low-carbohydrate, low-protein diet is safe and feasible in patients with cancer, and if it can recapitulate the metabolic and immunologic effects that were shown to mediate its antitumor activity in laboratory experiments.”
Investigators examined the safety and biological efficacy of the fasting-mimicking diet combined with standard antitumor therapies among 101 patients with cancer, including breast (n = 56), colorectal (n = 10), lung (n = 7) and other types.
The regimen, which was repeated every 3 to 4 weeks for up to eight cycles, consisted of a low-carbohydrate, low-protein, plant-derived diet that provided up to 600 kilocalories on day 1 followed by up to 300 kilocalories on days 2, 3, 4 and 5, for a total of no more than 1,800 kilocalories within the 5-day period. This was followed by 16 to 23 days of patients not subjected to specific dietary restrictions but being advised to adhere to international guidelines for a healthy diet and lifestyle.
Results showed the trial met its primary safety endpoint, with an incidence of severe (grade 3 or grade 4) fasting-mimicking diet-associated adverse events of 12.9% (90% CI, 7.8-19.7) — significantly below the 20% prespecified threshold. The most common adverse event was fatigue, most cases of which were mild.
Among 99 evaluable patients, the diet regimen reduced median plasma glucose concentration by 18.6%, serum insulin by 50.7% and serum insulin-like growth factor 1 by 30.3% — these modifications remained stable for eight consecutive cycles.
Results of a subset analysis including 38 patients at the completion of a 5-day cycle showed a significant decrease in circulating immunosuppressive myeloid subpopulations and an increase of activated CD8+ T cells. Of note, both effects were independent of concomitant antitumor therapies and also occurred in healthy volunteers.
“A fasting-mimicking diet reduces the blood levels of glucose and growth factors associated with tumor growth, and it also activates several populations of potentially antitumor immune cells,” Vernieri said. “In addition, some patients with metastatic cancers who were included in our study achieved long-term and complete tumor responses, suggesting that fasting-mimicking diet could potentiate the antitumor effects of standard anticancer therapies in some patients.”
Based on the results of this trial, Vernieri and colleagues initiated three additional clinical trials to assess the biological and antitumor activity of a fasting-mimicking diet among a select group of patient populations.
“The first of these studies, DigesT, is exploring the immunomodulatory effects of one 5-day fasting-mimicking diet cycle at the tumor level in patients with early-stage breast cancer or melanoma during the 7 to 10 days before surgery,” he said.
Results of an interim analysis of the DigesT trial showed a significant increase in tumor infiltrating CD8+ T cells among 22 patients with breast cancer whose tumor tissue was collected before and after the diet cycle. This suggests a functional switch toward an antitumor immune microenvironment after the diet cycle.
“Another ongoing study, the randomized phase 2 BREAKFAST trial, is investigating whether combining a cyclic fasting-mimicking diet, with or without metformin in combination with standard preoperative chemotherapy, is capable of increasing the rate of pathologic complete tumor responses in patients with stage I to stage III triple-negative breast cancer,” Vernieri said. “The FAME trial is a phase 2 randomized trial aimed at investigating the antitumor efficacy of combining metformin or metformin plus a fasting-mimicking diet with standard chemoimmunotherapy among patients with advanced non-small cell lung cancer bearing inactivating alterations in the LKB1 oncogene.”
Other trials set to begin within the next few months will investigate the efficacy of combining a fasting-mimicking diet with standard therapies in specific clinical contexts, he added.
For more information:
Claudio Vernieri, MD, PhD, can be reached at claudio.vernieri@istitutotumori.mi.it.
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