Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More

The laboratory and clinical evidence that exists for calorie restriction is reviewed, showing compelling evidence through the molecular pathways calorie restriction induces about how it may be used as a treatment in tandem with radiation therapy to improve rates of disease control.

CME Learning Objectives

1. Identify molecular pathways that are potential targets of calorie restriction combined with radiation therapy.

2. Identify cancer patients for whom calorie restriction would be contraindicated.

Abstract

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%–40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.

Implications for Practice:

Dietary manipulation via caloric restriction (CR) has been shown to decrease the incidence of cancer and enhance cancer treatment. CR affects several molecular pathways, such as the insulin and AMP-kinase pathway, which are also known to enhance the effectiveness of radiation therapy in preclinical studies. These pathways are a source of interest, as they are targeted by several current anticancer agents currently being used in clinical trials. Therefore, CR may provide a cost-effective addition to current treatment modalities that enhances cancer therapy while minimizing side effects, and may improve metabolic profiles during survivorship. CR may be unsuitable for some cancer patients, but it has been shown to decrease treatment side effects, and may be efficacious in cancer subtypes whose outcomes appear to correlate with metabolic status, such as breast cancer. Since CR may provide a therapeutic intervention that enhances current standard cancer therapy such as radiation, and decreases treatment toxicity, clinical trials are now warranted.

Introduction

Calorie restriction (CR) is, to date, the only modality proven to increase longevity across multiple species. Recently, there has been growing interest in investigating the role of nutrient deprivation as a treatment intervention for age-related diseases, including cardiovascular disease, diabetes, ocular disease, and cancer [1]. Evidence suggests a metabolic component to cancer that would make CR an attractive therapy to be combined with conventional treatment, such as radiation therapy (RT).

CR is a diet modification that aims to reduce total caloric intake to a level 20%–40% lower than that of a typical diet, without limiting essential vitamins and nutrients [2]. CR can be achieved through overall dietary reduction (DR) or by intermittent fasting (IF) [3]. CR has been further shown to induce changes in molecular pathways, many of which are also altered in cancer, making CR an attractive modality to explore. Altering these pathways can leave cells more susceptible to treatment with RT. The primary objective of this article is to review the laboratory and clinical evidence supporting the role of CR as a novel cancer treatment intervention that may be used as an adjunct to traditional treatment approaches such as RT to improve disease control.

Laboratory and Clinical Evidence

Over a century of in vivo laboratory research has demonstrated the utility of CR in the oncologic setting [1]. In 1909, Moreschi demonstrated that transplanted sarcoma tumors in mice fed a CR diet prior to the transplantation had significantly slower growth than those fed an ad libitum (AL) diet [3]. A year later, Rous initiated CR after tumor induction and confirmed Moreschi's results showing lower rates of spontaneous tumor development, metastasis, and tumor recurrence [4, 5]. Tannenbaum furthered the field by applying strict food measurement techniques to evaluate the extent of CR and showed that carbohydrates may be the important macronutrient to restrict [6]. These findings have been confirmed in the last three decades, demonstrating 1.7- to 44-fold lower spontaneous tumor growth in CR-fed mice [6, 7] than in AL-fed animals [2]. These studies demonstrate the ability of CR to slow tumor growth by 50%–80% [3, 8–10]. Perhaps most importantly, CR has also been shown to lead to longer survival times after cancer induction [11, 12]. Recent studies have revealed slower breast cancer growth, angiogenesis, and metastasis [9].

Human data have paralleled animal studies, suggesting a benefit of CR for cancer treatment [12–14]. Multiple population-based studies of underweight patients have revealed a significantly lower cancer incidence than in the general population. Data from Swedish patient registries have shown a lower risk for breast cancer in patients with anorexia nervosa [15] and a similar Danish registry revealed a lower overall cancer risk [16]. A lower cancer-related death rate was also seen in populations who have overall lower calorie consumption. This has been shown in gastric bypass surgery patients, who often reduce their caloric intake >50% (with patients consuming as low as 820 kcal/day 18 months after surgery) and experience a significantly lower incidence of cancer and lower cancer mortality rate [17–20]. A study comparing cancer rates in people from mainland Japan with those of residents of Okinawa, where significantly fewer calories are consumed, found the Okinawa population to have lower cancer rates and cancer mortality rates [21]. It is unknown, however, if these effects were related to CR or the adoption of a more westernized diet in mainland Japan.

Conversely, it is known that obesity can lead to a higher risk for developing cancer [22, 23], and prospective studies have demonstrated an association between obesity and cancer-specific mortality in multiple sites [23]. Biologically, obesity is associated with high levels of circulating insulin, lower insulin sensitivity, and insulin resistance [24]. Additionally, breast cancer patients often undergo a period of less physical activity and greater weight gain during treatment and subsequently present with an unfavorable metabolic profile following chemotherapy [25]. Weight gain after a breast cancer diagnosis is associated with poor outcomes [26], and CR has been shown to lower body weight and increase fat loss. Consequentially, the antitumorigenic effects of CR seem to be particularly relevant to our breast cancer population during treatment and survivorship.

The relationship among insulin metabolism, obesity, exercise, and cancer has led to a recent surge of interest in dietary intervention during cancer treatment. This is exemplified with newer trials, such as the National Cancer Institute of Canada MA.32 trial, which is treating early-stage breast cancer patients with standard therapy and randomizes them to placebo or metformin, which affects several metabolic pathways.

Molecular Evidence Connecting CR and RT

The ability of CR to slow tumor growth is likely attributable to the induction of several molecular changes (Table 1). CR increases apoptosis while augmenting antiproliferative effects and decreasing DNA synthesis [27, 28]. It is hypothesized that this reduction in cell proliferation is a major effect by which CR decreases tumor growth [29, 30]. In fact, many novel therapeutic agents for cancer treatment are targeted against molecules known to also be targets of CR, such as insulin grown factor-1 receptor (IGF1-R), the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). Therefore, CR may be a novel anticancer intervention given that many molecular targets can be altered simultaneously. Furthermore, evidence in humans suggests that CR via IF may potentiate the antitumor effects of chemotherapy while protecting normal cells, resulting in lower rates of treatment-related side effects [31].

Table 1.

Biologic factors affected by CR

Abbreviations: AMPK, AMP-activated protein kinase; CR, calorie restriction; IGF-1, insulin like growth factor 1; IGF1-R, IGF-1 receptor; LKB1, liver kinase B1; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

IGF Pathway

The IGF-1R pathway plays a role in the pathogenesis of breast cancer, and higher expression levels are associated with poor outcomes [32–35]. IGF-1, a circulating growth factor that modulates cell proliferation by binding to IGF-1R, protects cells from apoptosis, increasing cancer risk through activation of insulin receptor substrate (IRS) and PI3K [32, 36]. The activation of these pathways and inhibition of apoptosis have led to the proposition that IGF-1R and the glucose pathway should be considered targets for cancer treatment. Further, it has been noted that IGF-1 is decreased in response to CR [33].

Breast tumors often express higher IGF-1 and IGF-1R levels than normal breast tissue [37–40]. Overexpression of IGF-1 is associated with aggressive breast cancer phenotypes, such as triple-negative breast cancer [41, 42]. IGF-1 and IGF-1R have also been correlated with earlier recurrence and resistance of breast cancer to chemotherapy and RT as well as a shorter relapse-free survival interval in human studies [43, 44]. Data from other cancer sites has shown IGF-1 to decrease effectiveness of RT, which is reversed when IGF-1R is blocked [45].

DR can reduce serum IGF-1 concentration by up to 40% [1]. In a breast cancer mouse model, a CR diet decreased both IGF-1R expression and serum insulin levels [46]. Human data are lacking, but studies of female adolescents suffering from anorexia reveal lower levels of IGF-1 [47].

Cytotoxic cancer treatments such as RT and chemotherapy decrease IGF and IGF-1R levels (Fig. 1). Conversely, IGF-1 has been shown to inhibit apoptosis induced by tamoxifen and 5-fluorouracil, decreasing their efficacy in human breast cancer cells in a mouse model [48]. RT causes upregulation of IGF-1R within as little as 10 minutes of treatment [49], likely as a survival mechanism for cancer cells after radiation-induced damage. Inhibiting IGF-1R can increase the radiosensitivity of breast cancer cells and the potential therapeutic efficacy of RT against these cells [43]. The same study revealed higher early breast cancer relapse rates within 4 years of treatment in patients whose tumor specimens showed overexpression of IGF-1R. Inhibition of IGF-1R in human breast cancer cells leads to induced apoptosis, inhibited proliferation, and enhanced radiosensitivity [50]. Fasting results in a 75% decrease in IGF-1 after 2–5 days [51, 52], while chronic DR results in only a 23% reduction [53].

Figure 1.

Molecular pathways affected by CR and irradiation. CR icon indicates pathway affected by calorie restriction. Lightening symbol indicates pathways that affect radiation sensitivity. IGF-1R, AKT, IRS, mTOR, and PI3K pathways are decreased with CR, and decrease radiation sensitivity. LKB1 and AMPK are upregulated by CR, and AMPK activation increases radiosensitivity.

Abbreviations: AMPK, AMP-activated protein kinase; CR, calorie restriction; IGF-1, insulin grown factor-1; IRS, insulin receptor substrate; LKB1, liver kinas B1; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Taken together, these data suggest that reduction of IGF-1 and IGF-1R may increase tumor cell kill with RT, and this can potentially be achieved through CR diet modification using an approach that is targeted to tumor cells.

IRS, PI3K, AKT

Both IRS-1 and PI3K have also been shown to be overexpressed in breast cancer [54, 55]. IRS-1 and IRS-2 activate PI3K following IGF-1 binding to its receptor [56]. AKT is then directly affected by PI3K further downstream.

CR decreases IRS-1 and PI3K [57], resulting in greater radiosensitivity and significant tumor regrowth delay, both in vivo and in vitro [58–62]. AKT potently increases radioresistance by providing irradiated cells the ability to overcome radiation-induced apoptosis and bypass the p53-independent G₂-M cell-cycle checkpoint [58]. Like PI3K, AKT is also reduced by CR in mammary tumors [63]. Interestingly, disruption of IGF-1R and the downstream PI3K and AKT pathways by nutrient deprivation and stress also increased longevity in experiments with C. elegans by inducing dauer [64]. Thus, CR-induced reduction in both PI3K and AKT may be another mechanism through which CR potentiates the antitumor effects of RT.

mTOR: The Pathway Connecting IGF and AMPK

mTOR is one of the most commonly altered cellular pathways in tumors [65]. mTOR, which is activated by PI3K, regulates cell growth via nutrient import, cell survival, protein translation, and decreased autophagy [66]. Studies suggest that the mTOR inhibitor rapamycin partially mimics the effects of CR by inhibiting activation of AKT and mTOR and simultaneously decreasing circulating IGF-I [67, 68]. Inhibition of mTOR pathways by upstream inhibition through CR and downregulation of mTOR protein production may also lead to radiosensitization of cancer cells, but this has not yet been studied in detail.

AMPK

mTOR is also inhibited by the AMPK pathway. This recently received much attention in the oncology community because of pilot trials using metformin, which activates this pathway [56]. AMPK, a tumor suppressor gene [69], serves as a functional sensor of cellular energy status and regulates metabolism by impeding cell growth, proliferation, and metabolic signaling. It inactivates synthesis of fatty acids and cholesterol [70] and directly and indirectly inhibits mTOR [71], resulting in greater mitochondrial activity [72, 73]. During times of stress, mTOR engages AMPK to promote catabolic cell behavior while decreasing the anabolic pathways of protein and fatty acid synthesis [70].

In this manner, AMPK is activated by CR and other low energy conditions, leading to cell autophagy and mitophagy [69, 70]. CR may therefore reduce the ability of cancer cells to repair damage and continue metabolism for cell survival. Metformin mimics CR by lowering circulating insulin, increasing insulin sensitivity, decreasing circulating IGF-1, and decreasing the IGF-1R pathway [74].

AMPK is activated by RT in breast cancer cells and potentially radiosensitizes cancer cells [75]. Although the mechanism of radiosensitization is unclear [71, 75, 76], loss of AMPK results in inactivated radiation-induced G₁/S checkpoints [72] and G₂/M arrest [75]. Metformin allows for AMPK to regain its activity, leading to shorter survival times of breast cancer cells [77]. The loss of metabolic control after RT likely results in a lower rate of cell proliferation, defective checkpoints, and ultimately greater cell kill.

Metformin has been shown to decrease the incidence of breast cancer and mortality rate of breast cancer patients and is currently being assessed in several phase II and phase III trials [56, 78]. This combined metabolic advantage and direct manipulation of cancer pathways, such as mTOR, PI3K, and AKT, further exemplify the potential benefits of CR (Table 2). CR can theoretically inhibit several critical pathways in the development and progression of cancer, while simultaneously rendering malignancies more sensitive to treatments such as chemotherapy and RT.

Table 2.

Studies on the effects of CR

^aAssessed spontaneous tumor occurrence.

^bAssociated dose response.

^cBased on time point when CR initiated.

^dIGF-1 given.

Abbreviations: AL, ad libitum; CR, calorie restriction; DCIS, ductal carcinoma in situ; IGF-1, insulin-like growth factor 1; VEGF, vascular endothelial growth factor.

Clinical Trials

CR, especially via fasting, is an attractive adjunctive treatment for cancer because it is a lifestyle intervention that may provide patients with a better metabolic profile. While long-term DR may result in chronic weight loss, IF prior to and after each RT treatment may be a potential method to induce CR and inactivate molecular pathways of radioresistance while avoiding significant weight loss.

To date, CR has been successfully implemented alone in several human trials dealing with metabolic disorders. CR studies from the 1950s by Ancel Keys are often referenced; however, these studies employed extreme dietary modifications whereas current CR studies have evolved to become more tolerable for patients [79]. More recently, several CR studies have been undertaken to evaluate the feasibility and efficacy of CR and the metabolic changes induced in patients. CR regimens vary widely across these trials, and although some are extreme, for example, allowing patients only 400 calories per day for 2 months [80], most employ regimens that would be more easily tolerated during a course of RT and in normal life. Also, IF may be a method to further increase adherence while mitigating weight loss and potential side effects.

Methods of measuring adherence to a diet modification such as CR remain difficult in an outpatient setting. To date, di-etary trials for diseases such as diabetes have relied on food journals and questionnaires. Methods of increasing adherence include weekly meetings, frequent phone calls, cognitive–behavioral techniques [81], and newer online resources that track dietary patterns for patients who are able to be monitored directly by the physician. Cognitive–behavioral techniques have shown utility by assisting patients in identifying eating triggers and reinforcing and rewarding positive behaviors to help limit caloric consumption [82]. The Health Resource Calorie System is another method to train study participants to estimate the caloric content of food, which may also be employed in future studies.

Potential Contraindications

Although CR, especially as IF, may provide multiple benefits for patients undergoing treatment, it is not an option for all patients. Patients who are cachectic at presentation or at risk for severe weight loss may not be suitable because of the risk for further weight loss. Chronic DR may impair wound healing [83] and immune function [84], a potential issue for postoperative cancer patients as well. This issue may be mitigated by using IF based around RT, because it has been shown to result in less weight loss, especially when used for only 2–3 months [85]. Also, although many radiation and medical oncologists may approach the potential of fasting or DR in cancer patients with trepidation because of studies that linked weight loss with poor outcomes, further studies revealed this to more likely be a component of aggressive tumor biology and metabolism rather than malnutrition [86]. Regardless, cachexia occurs much less often in cancer patients than previously thought [87], and data show that breast cancer patients more often gain weight during treatment [88].

Whereas targeted therapy for several of the molecular pathways discussed above may cause serious side effects, CR through fasting in appropriate patients may actually decrease the side effects of cancer therapy. A study in which patients fasted before and after chemotherapy revealed less toxicity from treatment [89]. Patients undergoing IF have also noted less fatigue, less weakness, and fewer gastrointestinal issues [90]. Although data regarding the side effects of CR are limited, chemotherapy data have revealed that CR via IF may result in less toxicity when combined with RT as well.

Conclusions

During the last decade, the link among weight modification, dietary changes, and their influence on cancer incidence, treatment, and survival has strengthened. Based on the evidence outlined above, the benefits to overall health, weight, and metabolic risks, coupled with the potential therapeutic benefit of nutrient restriction by fasting, provide a compelling case for conducting clinical trials to tests the efficacy of CR and potential implementation in the care of cancer patients. Molecularly, both CR and RT have been shown to downregulate several signaling pathways that are also upregulated in cancer progression. Although CR is not currently implemented in cancer treatment strategies, studies of CR for indications other than cancer have effectively implemented CR-based diets for a period of 6 months [81].

CR by fasting is likely an effective method to potentiate the cytotoxicity of chemotherapy and RT because of the overlapping induction of molecular profiles, and it may also provide a beneficial means of improving the overall health and metabolic profiles of patients. At this time, clinical trials evaluating CR as a complementary therapy in the treatment of cancer are warranted.

Author Contributions

Conception/Design: Nicole L. Simone, Colin E. Champ, Mark V. Mishra, Lianjin Jin, Federica Sotgia, Adam P. Dicker

Provision of study material or patients: Adam P. Dicker

Collection and/or assembly of data: Nicole L. Simone, Colin E. Champ, Renato Baserga, Adam P. Dicker

Data analysis and interpretation: Nicole L. Simone, Colin E. Champ, Renato Baserga, Mark V. Mishra, Michael P. Lisanti, Richard G. Pestell, Adam P. Dicker

Manuscript writing: Nicole L. Simone, Colin E. Champ, Mark V. Mishra, Lianjin Jin, Federica Sotgia, Michael P. Lisanti, Richard G. Pestell, Adam P. Dicker

Final approval of manuscript: Nicole L. Simone, Colin E. Champ, Renato Baserga, Mark V. Mishra, Lianjin Jin, Federica Sotgia, Michael P. Lisanti, Richard G. Pestell, Adam P. Dicker

Disclosures

The authors indicated no financial relationships.

Section Editors: Suresh Senan: Lilly, Varian Medical Systems (C/A); Varian Medical Systems (H); Varian Medical Systems (H); Andrew Turrisi: None.

Reviewer “A”: None

Reviewer “B”: None

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board