Fasting and cancer treatment in humans: A case series report

Introduction

Chemotherapy can extend survival in patients diagnosed with a wide range of malignancies. However, side effects caused by toxicity to normal cells and tissues limit chemotherapy dose density and intensity, which may compromise efficacy. For instance, the cardiotoxicity and nephrotoxicity associated with the widely prescribed anti-cancer drugs, doxorubicin and cisplatin respectively limit their full therapeutic potential [1,4]. Thus, reduction of undesired toxicity by selective protection of normal cells without compromising the killing of malignant cells represents a promising strategy to enhance cancer treatment.

Calorie restriction (CR) is an effective and reproducible intervention for increasing life span, reducing oxidative damage, enhancing stress resistance and delaying/preventing aging and age-associated diseases such as cancer in various species, including mammals (mice, rats, and non- human primates) [5-8]. Recently, a fasting-based intervention capable of differentially protecting normal and cancer cells against high-dose chemotherapy in cell culture and in neuroblastoma-bearing mice was reported [9]. In the neuroblastoma xenograft model, mice were allowed to consume only water for 48 hours prior to etoposide treatment. Whereas high dose etoposide led to 50% lethality in ad libitum fed mice, fasting protected against the chemotoxicity without compromising the killing of neuroblastoma cells [9].

Previous human studies have shown that alternate day dietary restriction and short-term fasting (5 days) are well tolerated and safe [10-12]. In fact, children ranging from 6 months to 15 years of age were able to complete 14 to 40 hours of fasting in a clinical study carried out at the Children's hospital of Philadelphia [13]. Furthermore, alternate day calorie restriction caused clinical improvements and reduced markers of inflammation and oxidative stress in obese asthmatic patients [12,14].

Here, we report 10 cases of patients diagnosed with various types of cancer, who have voluntarily fasted prior to and following chemotherapy. The results presented here, which are based on self-assessed health outcomes (Table 1) and laboratory reports, suggest that fasting is safe and raise the possibility that it can reduce chemotherapy-associated side effects. However, only a randomized controlled clinical trial can establish its efficacy.

Results

Ten cancer patients receiving chemotherapy, 7 females and 3 males with a median age of 61 years (range 44-78 yrs), are presented in this case series report. Four suffered from breast cancer, two from prostate cancer, and one each from ovarian, uterine, non small cell carcinoma of the lung, and esophageal adenocarcinoma. All patientsvoluntarily fasted for a total of 48 to 140 hours prior to and/or 5 to 56 hours following chemotherapy administered by their treating oncologists (Table 2, Table 3).

Discussion

Dietary recommendations during cancer treatment are based on the prevention or reversal of nutrient deficiencies to preserve lean body mass and minimize nutrition-related side effects, such as decreased appetite, nausea, taste changes, or bowel changes [16]. Consequently, for cancer patients who have been weakened by prior chemotherapy cycles or are emaciated, many oncologists could consider a fasting-based strategy to be potentially harmful. Nevertheless studies in cell culture and animal models indicate that fasting may actually reduce chemotherapy side effects by selectively protecting normal cells [9]. Following the publication of this pre-clinical work,several patients, diagnosed with a wide variety of cancers, elected to undertake fasting prior to chemotherapy and shared their experiences with us. In this heterogeneous group of men and women fasting was safely repeated in multiple cycles for up to 180 hours prior and/or following chemotherapy. Minor complaints that arose during fasting included dizziness, hunger, and headaches at a level that did not interfere with daily activities. Weight lost during fasting was rapidly recovered in most of the patients and did not lead to any detectable harm.

We obtained self-reported assessments of toxicity from all 10 patients who incorporated fasting with their chemotherapy treatments. Since many of the chemotoxicities are cumulative, we evaluated serial data including all the combined fasting- and non-fasting (ad libitum diet) associated chemotherapy cycles (Supplementary Figure 1). Toxicity was graded utilizing a questionnaire based on the Common Terminology Criteria for Adverse Events of National Cancer Institute, version 3.0 (Table 1). Although the lack of prospective collection of toxicity data and grading are a significant limitation, this series provide an early insight into the feasibility and potential benefit of combining fasting with chemotherapy. Fewer and less severe chemotherapy-induced toxicity was reported by all the patients, even though fasting cycles were often carried out in the later portion of the therapy (Supplementary Figure 1). Nausea, vomiting, diarrhea, abdominal cramps, and mucositis were virtually absent from the reports of all 10 patients in the cycles in which fasting was undertaken prior to and/or following chemotherapy; whereas at least one of these symptoms was reported by 5 out of the 6 patients during cycles in which they ate ad libitum (Supplementary Figure 1). The four patients that fasted throughout their treatments reported low severity for the majority of the side effects, in contrast to the typical experience of cancer patients receiving the same chemotherapy regimens (Figures 8I, 9, 10, 11H). For the 6 patients who received chemotherapy with or without fasting, we compared the severity of the self-reported side effects in the 2 closest fasting/non-fasting (ad libitum diet) cycles in which the patient received the same chemotherapy drugs at the same dose. There was a general and substantial reduction in the self-reported side effects in combination with fasting (Figure 1). Symptoms such as fatigue and weakness were reported to be significantly reduced (p< 0.001 and p< 0.00193, respectively), whereas vomiting and diarrhea were virtually absent in combination with fasting (Figure 1). In addition, there was no side effect whose average severity was reported to be increased during fasting-chemotherapy cycles (Figure 1 and Supplementary Figure 1).

Challenging conditions such as fasting or severe CR stimulate organisms to suppress growth and reproduction, and divert the energy towards cellular maintenance and repair to maximize the chance of survival [17,19]. In simple organisms such as yeast, resistance to oxidants and chemotherapy drugs can be increased by up to 10-fold in response to fasting/starvetion and up to 1,000-fold in those cells lacking homologs of Ras, AKT and S6 kinase [9]. Nevertheless, such protection and oxidative stress resistance is completely reversed by the expression of oncogene-like genes [9,18]. In mammals, the mechanism(s) responsible for the protective effect of fasting against chemotherapy induced-toxic side effects is not completely understood. It may involve reduction in anabolic and mitogenic hormones and growth factors such as insulin and insuline-like growth factor 1 (IGF-1) as well as up-regulation of several stress resistance proteins[20-25]. In fact, mice with liver specific IGF-I gene-deletion (LID) which have ~80% reduction of circulating IGF-I and mice with genetic disruptions in the IGF-I receptor (heterozygous knockout IGF-IR +/-) or its downstream elements have been shown to be more resistant against multiple chemotherapy agents and oxidative stress, respectively [26,27]. Alternatively, fasting-dependent DSR may be, in part, mediated by cell cycle arrest in normal cells whereas transformed cells continue to proliferate, remaining vulnerable to anticancer drugs [25,28]. Although mutations driving cancer progression are heterogeneous across tumor types, the majority of the oncogenic mutations render cancer cells independent of growth signals [28,29], which we hypothesize prevents cancer cells from responding to the fasting-induced switch to a protected mode [9]. Therefore, DSR would have the potential to be applied independently of the cancer type. Although this has not been yet demonstrated, the remarkable effects of fasting on the down-regulation of a number of growth factors and signal transduction pathways targeted by anti-cancer drugs, including IGF-I and the TOR/S6 kinase pathways, raises the possibility that it could enhance the efficacy of cancer treatment drugs and may even be as effective as some of them.

In summary, in this small and heterogeneous group of cancer patients, fasting was well-tolerated and was associated with a self-reported reduction in multiple chemotherapy-induced side effects. Although bias could affect the estimation of the side effects by the patients, the case reports presented here are in agreement with the results obtained in animal studies and provide preliminary data indicating that fasting is feasible, safe and has the potential to differentially protect normal and cancer cells against chemotherapy in humans. Nevertheless, only a clinical trial, such as the randomized controlled clinical trial currently carried out at the USC Norris Cancer Cen-ter, can establish whether fasting protects normal cells and increases the therapeutic index of chemotherapies.

Methods

From April 2008 to August 2009, 10 unrelated patients diagnosed with a variety of cancer volunteered to incorporate fasting with their chemo-treatments. We invited these patients to complete a self-assessment survey based on the Common Terminology Criteria for Adverse Events of The National Cancer Institute version 3.0. For the purpose of this study only, we developed a questionnaire that contained 16 easy identifiable and commonly reported side effects; the seriousness of the symptoms was graded from 0 to 4 with each consecutive number corresponding to no side effect/mild/moderate/severe and life threatening. Adverse effects were further divided into 3 major categories including, general, gastrointestinal and central/peripheral nervous system side effects, (Table 1, original questionnaire). The survey was delivered to patients by mail, e mail or fax and every patient was instructed to complete it 7 days after each treatment cycle. Explanation and assistance to patient's concern were offered throughout the study. The eligibility criterion to participate was subjected to those patients that had voluntarily fasted prior and/or post chemotherapy. Medical records including basic demographical information, diagnosis, treatments, imaging studies and laboratory analysis were also retrospectively reviewed (Table 2, Table 3). All the aforementioned procedures were in compliance with the Internal review Board of the University of Southern California (USC).

Supplementary Materials

Supplementary Figure 1

Supplementary Table 1

Supplementary Table 2