When less may be more: calorie restriction and response to cancer therapy

Ciara H O'Flanagan, Laura A Smith, Shannon B McDonell, Stephen D Hursting, Ciara H O'Flanagan, Laura A Smith, Shannon B McDonell, Stephen D Hursting

Abstract

Calorie restriction (CR) extends lifespan and has been shown to reduce age-related diseases including cancer, diabetes, and cardiovascular and neurodegenerative diseases in experimental models. Recent translational studies have tested the potential of CR or CR mimetics as adjuvant therapies to enhance the efficacy of chemotherapy, radiation therapy, and novel immunotherapies. Chronic CR is challenging to employ in cancer patients, and therefore intermittent fasting, CR mimetic drugs, or alternative diets (such as a ketogenic diet), may be more suitable. Intermittent fasting has been shown to enhance treatment with both chemotherapy and radiation therapy. CR and fasting elicit different responses in normal and cancer cells, and reduce certain side effects of cytotoxic therapy. Findings from preclinical studies of CR mimetic drugs and other dietary interventions, such as the ketogenic diet, are promising for improving the efficacy of anticancer therapies and reducing the side effects of cytotoxic treatments. Current and future clinical studies will inform on which cancers, and at which stage of the cancer process, CR, fasting, or CR mimetic regimens will prove most effective.

Keywords: Autophagy; Cachexia; Calorie restriction; Chemotherapy; Drug resistance; Fasting; Insulin-like growth factor 1; Ketogenic diet; Metabolism; Radiation therapy.

Figures

Fig. 1
Fig. 1
Mechanisms through which calorie restriction (CR) affects response to anticancer therapy. CR, fasting, or fasting-mimicking diets (FMDs) cause reduced Akt/mTOR and Ras signaling in normal cells, resulting in senescence, reduced growth, and protection from cytotoxic treatment, while in tumor cells, oncogenic signals remain and cells are sensitive to anti-mitotic therapies. CR, fasting, and FMD also reduce pro-inflammatory cytokines in the circulation and in the tumor microenvironment niche, as well as reduced leptin, insulin, IGF-1, and glucose. CR can reduce desmoplasia surrounding the tumor tissue, which may facilitate better therapeutic drug delivery to the tumor cells. CR can also aid in immunosurveillance of tumors by reducing Treg populations that inhibit cytotoxic CD8+ T cells. This figure has not been published elsewhere

References

    1. Berrigan D, Lavigne JA, Perkins SN, Nagy TR, Barrett JC, Hursting SD. Phenotypic effects of calorie restriction and insulin-like growth factor-1 treatment on body composition and bone mineral density of C57BL/6 mice: implications for cancer prevention. In Vivo. 2005;19(4):667–74.
    1. Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, Cuzick J, Jebb SA, Martin B, Cutler RG, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes. 2011;35(5):714–27. doi: 10.1038/ijo.2010.171.
    1. Harvie MN, Sims AH, Pegington M, Spence K, Mitchell A, Vaughan AA, Allwood JW, Xu Y, Rattray NJ, Goodacre R, et al. Intermittent energy restriction induces changes in breast gene expression and systemic metabolism. Breast Cancer Res. 2016;18(1):57. doi: 10.1186/s13058-016-0714-4.
    1. Hursting SD, Dunlap SM, Ford NA, Hursting MJ, Lashinger LM. Calorie restriction and cancer prevention: a mechanistic perspective. Cancer Metab. 2013;1(1):10. doi: 10.1186/2049-3002-1-10.
    1. Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: an update. Ageing Res Rev. 2016. doi:10.1016/j.arr2016.08.005.
    1. Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS One. 2014;9(12) doi: 10.1371/journal.pone.0115147.
    1. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063. doi: 10.1038/ncomms14063.
    1. Harvey AE, Lashinger LM, Otto G, Nunez NP, Hursting SD. Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression. Mol Carcinog. 2013;52(12):997–1006. doi: 10.1002/mc.21940.
    1. Lashinger LM, Malone LM, McArthur MJ, Goldberg JA, Daniels EA, Pavone A, Colby JK, Smith NC, Perkins SN, Fischer SM, et al. Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. Cancer Prev Res (Phila) 2011;4(7):1030–40. doi: 10.1158/1940-6207.CAPR-11-0027.
    1. Nogueira LM, Lavigne JA, Chandramouli GV, Lui H, Barrett JC, Hursting SD. Dose-dependent effects of calorie restriction on gene expression, metabolism, and tumor progression are partially mediated by insulin-like growth factor-1. Cancer Med. 2012;1(2):275–88. doi: 10.1002/cam4.23.
    1. Harvey AE, Lashinger LM, Hays D, Harrison LM, Lewis K, Fischer SM, Hursting SD. Calorie restriction decreases murine and human pancreatic tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression in an insulin-like growth factor-1-dependent manner. PLoS One. 2014;9(5) doi: 10.1371/journal.pone.0094151.
    1. Bowers LW, Rossi EL, O'Flanagan CH, de Graffenried LA, Hursting SD. The role of the insulin/IGF system in cancer: lessons learned from clinical trials and the energy balance-cancer link. Front Endocrinol. 2015;6:77. doi: 10.3389/fendo.2015.00077.
    1. Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res. 2008;14(20):6364–70. doi: 10.1158/1078-0432.CCR-07-4879.
    1. Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, et al. Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis. 2015;2(1):13–25. doi: 10.1016/j.gendis.2014.10.004.
    1. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis. 2010;31(1):83–9. doi: 10.1093/carcin/bgp280.
    1. Mukherjee P, Abate LE, Seyfried TN. Antiangiogenic and proapoptotic effects of dietary restriction on experimental mouse and human brain tumors. Clin Cancer Res. 2004;10(16):5622–9. doi: 10.1158/1078-0432.CCR-04-0308.
    1. Mukherjee P, Mulrooney TJ, Marsh J, Blair D, Chiles TC, Seyfried TN. Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer. 2008;7:37. doi: 10.1186/1476-4598-7-37.
    1. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016–23. doi: 10.1038/ncb2329.
    1. Selman C, Kerrison ND, Cooray A, Piper MD, Lingard SJ, Barton RH, Schuster EF, Blanc E, Gems D, Nicholson JK, et al. Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiol Genomics. 2006;27(3):187–200. doi: 10.1152/physiolgenomics.00084.2006.
    1. Lashinger LM, O'Flanagan CH, Dunlap SM, Rasmussen AJ, Sweeney S, Guo JY, Lodi A, Tiziani S, White E, Hursting SD. Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors. Cancer Metab. 2016;4:18. doi: 10.1186/s40170-016-0158-4.
    1. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619–34. doi: 10.1038/nrc.2016.71.
    1. Currie E, Schulze A, Zechner R, Walther TC, Farese RV., Jr Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18(2):153–61. doi: 10.1016/j.cmet.2013.05.017.
    1. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21(3):297–308. doi: 10.1016/j.ccr.2012.02.014.
    1. Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, Schoenfeld JD, Buatti JM, Spitz DR, Fath MA. Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol. 2014;2:963–70. doi: 10.1016/j.redox.2014.08.002.
    1. White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res. 2015;21(22):5037–46. doi: 10.1158/1078-0432.CCR-15-0490.
    1. Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015;34(7):856–80. doi: 10.15252/embj.201490784.
    1. Cheong H, Lu C, Lindsten T, Thompson CB. Therapeutic targets in cancer cell metabolism and autophagy. Nat Biotechnol. 2012;30(7):671–8. doi: 10.1038/nbt.2285.
    1. Harvie M, Howell A. Energy restriction and the prevention of breast cancer. Proc Nutr Soc. 2012;71(2):263–75. doi: 10.1017/S0029665112000195.
    1. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, et al. Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res. 2012;72(9):2314–26. doi: 10.1158/0008-5472.CAN-11-3092.
    1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. doi: 10.1038/nature01322.
    1. O'Flanagan CH, Bowers LW, Hursting SD. A weighty problem: metabolic perturbations and the obesity-cancer link. Horm Mol Biol Clin Investig. 2015;23(2):47–57.
    1. Weiss EP, Racette SB, Villareal DT, Fontana L, Steger-May K, Schechtman KB, Klein S, Holloszy JO, Washington University School of Medicine CALERIE Group Improvements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial. Am J Clin Nutr. 2006;84(5):1033–42.
    1. Powolny AA, Wang S, Carlton PS, Hoot DR, Clinton SK. Interrelationships between dietary restriction, the IGF-I axis, and expression of vascular endothelial growth factor by prostate adenocarcinoma in rats. Mol Carcinog. 2008;47(6):458–65. doi: 10.1002/mc.20403.
    1. Mulrooney TJ, Marsh J, Urits I, Seyfried TN, Mukherjee P. Influence of caloric restriction on constitutive expression of NF-kappaB in an experimental mouse astrocytoma. PLoS One. 2011;6(3) doi: 10.1371/journal.pone.0018085.
    1. Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp Gerontol. 2009;44(1-2):41–5. doi: 10.1016/j.exger.2008.04.005.
    1. Peters JM, Shah YM, Gonzalez FJ. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer. 2012;12(3):181–95.
    1. Staudt LM. Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol. 2010;2(6):a000109. doi: 10.1101/cshperspect.a000109.
    1. Saleh AD, Simone BA, Palazzo J, Savage JE, Sano Y, Dan T, Jin L, Champ CE, Zhao S, Lim M, et al. Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle. 2013;12(12):1955–63. doi: 10.4161/cc.25016.
    1. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011;30(30):3305–16. doi: 10.1038/onc.2011.91.
    1. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008;105(24):8215–20. doi: 10.1073/pnas.0708100105.
    1. Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP, Baracco EE, Levesque S, Castoldi F, Jacquelot N, Yamazaki T, et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell. 2016;30(1):147–60. doi: 10.1016/j.ccell.2016.05.016.
    1. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012;4(124):124ra127. doi: 10.1126/scitranslmed.3003293.
    1. Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation. Cancer Metastasis Rev. 2014;33(1):217–29. doi: 10.1007/s10555-014-9495-3.
    1. Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 2016;23(6):1048–59. doi: 10.1016/j.cmet.2016.06.001.
    1. Sancar A, Lindsey-Boltz LA, Gaddameedhi S, Selby CP, Ye R, Chiou YY, Kemp MG, Hu J, Lee JH, Ozturk N. Circadian clock, cancer, and chemotherapy. Biochemistry. 2015;54(2):110–23. doi: 10.1021/bi5007354.
    1. Lee C, Raffaghello L, Longo VD. Starvation, detoxification, and multidrug resistance in cancer therapy. Drug Resist Updat. 2012;15(1-2):114–22. doi: 10.1016/j.drup.2012.01.004.
    1. Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, Cacciottolo M, Martin-Montalvo A, de Cabo R, Wei M, et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell. 2016;30(1):136–46. doi: 10.1016/j.ccell.2016.06.005.
    1. Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai870. doi:10.1126/scitranslmed.aai8700.
    1. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S, Mirisola M, Quinn DI, Dorff TB, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810–23. doi: 10.1016/j.stem.2014.04.014.
    1. Farazi M, Nguyen J, Goldufsky J, Linnane S, Lukaesko L, Weinberg AD, Ruby CE. Caloric restriction maintains OX40 agonist-mediated tumor immunity and CD4 T cell priming during aging. Cancer Immunol Immunother. 2014;63(6):615–26. doi: 10.1007/s00262-014-1542-y.
    1. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle. 2010;9(22):4474–6. doi: 10.4161/cc.9.22.13954.
    1. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: a case series report. Aging. 2009;1(12):988–1007. doi: 10.18632/aging.100114.
    1. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–5.
    1. Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, Pollak MN, Hursting SD. Metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct microRNA-regulated mechanisms. Diabetes. 2015;64(5):1632–42. doi: 10.2337/db14-1132.
    1. Nogueira LM, Dunlap SM, Ford NA, Hursting SD. Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer. 2012;19(1):57–68. doi: 10.1530/ERC-11-0213.
    1. Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat. 2008;11(3):63–76. doi: 10.1016/j.drup.2008.03.001.
    1. Zhou Y, Zhao RH, Tseng KF, Li KP, Lu ZG, Liu Y, Han K, Gan ZH, Lin SC, Hu HY, et al. Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression. Acta Pharmacol Sin. 2016;37(4):519–29. doi: 10.1038/aps.2015.153.
    1. Linden MA, Lopez KT, Fletcher JA, Morris EM, Meers GM, Siddique S, Laughlin MH, Sowers JR, Thyfault JP, Ibdah JA, et al. Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats. Appl Physiol Nutr Metab. 2015;40(10):1038–47. doi: 10.1139/apnm-2015-0236.
    1. Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012;2(9):778–90. doi: 10.1158/-12-0263.
    1. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69(19):7507–11. doi: 10.1158/0008-5472.CAN-09-2994.
    1. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71(9):3196–201. doi: 10.1158/0008-5472.CAN-10-3471.
    1. Catalgol B, Batirel S, Taga Y, Ozer NK. Resveratrol: French paradox revisited. Front Pharmacol. 2012;3:141. doi: 10.3389/fphar.2012.00141.
    1. Carter LG, D'Orazio JA, Pearson KJ. Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer. 2014;21(3):R209–25. doi: 10.1530/ERC-13-0171.
    1. Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB. Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci. 2011;1215:150–60. doi: 10.1111/j.1749-6632.2010.05852.x.
    1. Fukui M, Yamabe N, Zhu BT. Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur J Cancer. 2010;46(10):1882–91. doi: 10.1016/j.ejca.2010.02.004.
    1. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8(4):311–21. doi: 10.1016/j.ccr.2005.09.008.
    1. Thazhath SS, Wu T, Bound MJ, Checklin HL, Standfield S, Jones KL, Horowitz M, Rayner CK. Effects of intraduodenal hydroxycitrate on glucose absorption, incretin release, and glycemia in response to intraduodenal glucose infusion in health and type 2 diabetes: a randomised controlled trial. Nutrition. 2016;32(5):553–9. doi: 10.1016/j.nut.2015.11.004.
    1. Schwartz L, Buhler L, Icard P, Lincet H, Steyaert JM. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res. 2014;34(2):973–80.
    1. Dupuis N, Curatolo N, Benoist JF, Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia. 2015;56(7):e95–8. doi: 10.1111/epi.13038.
    1. Martin K, Jackson CF, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2016;2
    1. Yancy WS, Jr, Foy M, Chalecki AM, Vernon MC, Westman EC. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab. 2005;2:34. doi: 10.1186/1743-7075-2-34.
    1. Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab. 2015;3:3. doi: 10.1186/s40170-015-0129-1.
    1. Tóth C, Clemens Z. Halted progression of soft palate cancer in a patient treated with the paleolithic ketogenic diet alone: a 20-months follow-up. Am J Med Case Rep. 2016;4(8):288–92.
    1. Ho VW, Leung K, Hsu A, Luk B, Lai J, Shen SY, Minchinton AI, Waterhouse D, Bally MB, Lin W, et al. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res. 2011;71(13):4484–93. doi: 10.1158/0008-5472.CAN-10-3973.
    1. Caso J, Masko EM, Ii JA, Poulton SH, Dewhirst M, Pizzo SV, Freedland SJ. The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model. Prostate. 2013;73(5):449–54. doi: 10.1002/pros.22586.
    1. Stafford P, Abdelwahab MG, Kim DY, Preul MC, Rho JM, Scheck AC. The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab. 2010;7:74. doi: 10.1186/1743-7075-7-74.
    1. Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker HU, Thiede A, Coy JF. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer. 2008;8:122. doi: 10.1186/1471-2407-8-122.
    1. Tisdale MJ, Brennan RA, Fearon KC. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer. 1987;56(1):39–43. doi: 10.1038/bjc.1987.149.
    1. de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems A, Houtsma D, Putter H, van der Hoeven JJ, Nortier JW, et al. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer. 2015;15:652. doi: 10.1186/s12885-015-1663-5.

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