Medical Oncology

, 34:132 | Cite as

Beneficial effects of ketogenic diets for cancer patients: a realist review with focus on evidence and confirmation

Review Article

Abstract

Ketogenic diets (KDs) have gained popularity among patients and researchers alike due to their putative anti-tumor mechanisms. However, the question remains which conclusions can be drawn from the available human data thus far concerning the safety and efficacy of KDs for cancer patients. A realist review utilizing a matrix analytical approach was conducted according to the RAMESES publication standards. All available human studies were systematically analyzed and supplemented with results from animal studies. Evidence and confirmation were treated as separate concepts. In total, 29 animal and 24 human studies were included in the analysis. The majority of animal studies (72%) yielded evidence for an anti-tumor effect of KDs. Evidential support for such effects in humans was weak and limited to individual cases, but a probabilistic argument shows that the available data strengthen the belief in the anti-tumor effect hypothesis at least for some individuals. Evidence for pro-tumor effects was lacking completely. Feasibility of KDs for cancer patients has been shown in various contexts. The probability of achieving an anti-tumor effect seems greater than that of causing serious side effects when offering KDs to cancer patients. Future controlled trials would provide stronger evidence for or against the anti-tumor effect hypothesis.

Keywords

Cancer Evidence Ketogenic diet Realist synthesis Realist review 

Supplementary material

12032_2017_991_MOESM1_ESM.docx (39 kb)
Supplementary material 1 (DOCX 40 kb)
12032_2017_991_MOESM2_ESM.docx (38 kb)
Supplementary material 2 (DOCX 39 kb)

References

  1. 1.
    Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013;67:789–96.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35:515–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Vidali S, Aminzadeh S, Lambert B, Rutherford T, Sperl W, Kofler B, et al. Mitochondria: the ketogenic diet—a metabolism-based therapy. Int J Biochem Cell Biol. 2015;63:55–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Seyfried TN, Yu G, Maroon JC, D’Agostino DP. Press-pulse: a novel therapeutic strategy for the metabolic management of cancer. Nutr Metab (Lond). 2017;14:19.CrossRefGoogle Scholar
  5. 5.
    Klement RJ, Kämmerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab (Lond). 2011;8:75.CrossRefGoogle Scholar
  6. 6.
    Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, Sibenaller ZA, Mapuskar KA, et al. Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism. Redox Biol. 2014;2C:963–70.CrossRefGoogle Scholar
  7. 7.
    Klement RJ, Champ CE. Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation. Cancer Metasta Rev. 2014;33:217–29.CrossRefGoogle Scholar
  8. 8.
    Woolf EC, Syed N, Scheck AC. Tumor metabolism, the ketogenic diet and β-hydroxybutyrate: novel approaches to adjuvant brain tumor therapy. Front Mol Neurosci. 2016;9:122.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Winter SF, Loebel F, Dietrich J. Role of ketogenic metabolic therapy in malignant glioma: a systematic review. Crit Rev Oncol Hematol. 2017;112:41–58.PubMedCrossRefGoogle Scholar
  10. 10.
    Huebner J, Marienfeld S, Abbenhardt C, Ulrich C, Muenstedt K, Micke O, et al. Counseling patients on cancer diets: a review of the literature and recommendations for clinical practice. Anitcancer Res. 2014;34:39–48.Google Scholar
  11. 11.
    Howick J. The philosophy of evidence-based medicine. 1st ed. Oxford: Wiley; 2011.CrossRefGoogle Scholar
  12. 12.
    Walach H, Falkenberg T, Fønnebø V, Lewith G, Jonas WB. Circular instead of hierarchical: methodological principles for the evaluation of complex interventions. BMC Med Res Methodol. 2006;6:29.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Walach H, Loef M. Using a matrix-analytical approach to synthesizing evidence solved incompatibility problem in the hierarchy of evidence. J Clin Epidemiol. 2015;68:1251–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Tan-Shalaby JL, Carrick J, Edinger K, Genovese D, Liman AD, Passero VA, et al. Modified Atkins diet in advanced malignancies: final results of a safety and feasibility trial within the Veterans Affairs Pittsburgh Healthcare System. Nutr Metab (Lond). 2016;13:52.CrossRefGoogle Scholar
  15. 15.
    Bandyopadhyay PS, Brittan G Jr, Taper ML. Belief, evidence, and uncertainty: problems of Epistemic inference. 1st ed. Berlin: Springer Nature; 2016.CrossRefGoogle Scholar
  16. 16.
    Carnap R. On the application of inductive logic. Philos Phenomenol Res. 1947;8:133–48.CrossRefGoogle Scholar
  17. 17.
    Pawson R, Greenhalgh T, Harvey G, Walshe K. Realist review–a new method of systematic review designed for complex policy interventions. J Health Serv Res Policy. 2005;10:21–34.PubMedCrossRefGoogle Scholar
  18. 18.
    Greenhalgh T, Wong G, Westhorp G, Pawson R. Protocol–realist and meta-narrative evidence synthesis: evolving standards (RAMESES). BMC Med Res Methodol. 2011;11:115.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Wong G, Greenhalgh T, Westhorp G, Buckingham J, Pawson R, Pawson R, et al. RAMESES publication standards: realist syntheses. BMC Med. 2013;11:21.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Aronson JL. A realist philosophy of science. 1st ed. London: The Macmillan Press Ltd; 1984.CrossRefGoogle Scholar
  21. 21.
    Pérez-Guisado J, Muñoz-Serrano A, Alonso-Moraga Á. Spanish Ketogenic Mediterranean diet: a healthy cardiovascular diet for weight loss. Nutr J. 2008;7:30.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Clemens Z, Kelemen A, Fogarasi A, Tóth C. Childhood absence epilepsy successfully treated with the Paleolithic Ketogenic diet. Neurol Ther. 2013;2:71–6.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Nebeling LC, Lerner E. Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer. J Am Diet Assoc. 1995;95:693–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Jenkins DJA, Wong JMW, Kendall CWC, Esfahani A, Ng VWY, Leong TCK, et al. The effect of a plant-based low-carbohydrate (“Eco-Atkins”) diet on body weight and blood lipid concentrations in hyperlipidemic subjects. Arch Intern Med. 2009;169:1046–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Walach H. Mehr Daten? Mehr denken? Umdenken! Forschende Komplementärmedizin/Res Complement Med. 2016;23:3–5.CrossRefGoogle Scholar
  26. 26.
    Fearon KC, Borland W, Preston T, Tisdale MJ, Shenkin A, Calman KC. Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism. Am J Clin Nutr. 1988;47:42–8.PubMedGoogle Scholar
  27. 27.
    Nebeling L, Miraldi F, Shurin S, Lerner E. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr. 1995;14:202–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Chu-Shore CJ, Thiele EA. Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet. Brain Dev. 2010;32:318–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Schmidt M, Pfetzer N, Schwab M, Strauss I, Kämmerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr Metab (Lond). 2011;8:54.CrossRefGoogle Scholar
  30. 30.
    Schroeder U, Himpe B, Pries R, Vonthein R, Nitsch S, Wollenberg B. Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer. Nutr Cancer. 2013;65:843–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol. 2014;117:125–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Branca JJV, Pacini S, Ruggiero M. Effects of Pre-surgical vitamin D supplementation and Ketogenic Diet in a patient with recurrent breast cancer. Anticancer Res. 2015;35:5525–32.PubMedGoogle Scholar
  33. 33.
    Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Strowd RE, Cervenka MC, Henry BJ, Kossoff EH, Hartman AL, Blakeley JO. Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors. Neurooncol Pract. 2015;2:127–36.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Jansen N, Walach H. The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: a case series in general practice. Oncol Lett. 2016;11:584–92.PubMedGoogle Scholar
  36. 36.
    Klement RJ, Sweeney RA. Impact of a ketogenic diet intervention during radiotherapy on body composition: I. Initial clinical experience with six prospectively studied patients. BMC Res Notes. 2016;9:143.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Artzi M, Liberman G, Vaisman N, Bokstein F, Vitinshtein F, Aizenstein O, et al. Changes in cerebral metabolism during ketogenic diet in patients with primary brain tumors: 1H-MRS study. J Neurooncol. 2017;132:267–75.PubMedCrossRefGoogle Scholar
  38. 38.
    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;56:39–43.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Tisdale MJ, Brennan RA. A comparison of long-chain triglycerides and medium-chain triglycerides on weight loss and tumour size in a cachexia model. Br J Cancer. 1988;58:580–3.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer. 1989;59:677–81.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer. 2003;89:1375–82.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond). 2007;4:5.CrossRefGoogle Scholar
  43. 43.
    Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, et al. Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate. 2008;68:11–9.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Mavropoulos JC, Buschemeyer WC 3rd, Tewari AK, Rokhfeld D, Pollak M, Zhao Y, et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res. 2009;2:557–65.CrossRefGoogle Scholar
  46. 46.
    Masko EM, Thomas JA 2nd, Antonelli JA, Lloyd JC, Phillips TE, Poulton SH, et al. Low-carbohydrate diets and prostate cancer: how Low Is “Low Enough”? Cancer Prev Res. 2010;3:1124–31.CrossRefGoogle Scholar
  47. 47.
    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 (Lond). 2010;7:74.CrossRefGoogle Scholar
  48. 48.
    Maurer GD, Brucker DP, Bähr O, Harter PN, Hattingen E, Walenta S, et al. Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer. 2011;11:315.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, et al. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS ONE. 2012;7:e36197.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kim HS, Masko EM, Poulton SL, Kennedy KM, Pizzo SV, Dewhirst MW, et al. Carbohydrate restriction and lactate transporter inhibition in a mouse xenograft model of human prostate cancer. BJU Int. 2012;110:1062–9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Allen BG, Bhatia SK, Buatti JM, Cancer C, Published R, June O. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer Xenografts Ketogenic diets enhance oxidative stress and radio- chemo-therapy responses in lung cancer xenografts. Clin Cancer Res. 2013;19:3905–13.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Caso J, Masko EM, Thomas JA II, Poulton SH, Dewhirst M, Pizzo SV, et al. The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model. Prostate. 2013;73:449–54.PubMedCrossRefGoogle Scholar
  53. 53.
    Poff AM, Ari C, Seyfried TN, Agostino DPD. The Ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS ONE. 2013;8:e65522.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on Myeloid-Derived suppressor cells and NK cells. J Immunol. 2014;191:1486–95.CrossRefGoogle Scholar
  55. 55.
    Shukla SK, Gebregiworgis T, Purohit V, Chaika NV, Gunda V, Radhakrishnan P, et al. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer Metab. 2014;2:18.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zhuang Y, Chan DK, Haugrud AB, Miskimins WK. Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo. PLoS ONE. 2014;9:e108444.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gluschnaider U, Hertz R, Ohayon S, Smeir E, Smets M, Pikarsky E, et al. Long-chain fatty acid analogues suppress breast tumorigenesis and progression. Cancer Res. 2014;74:6991–7002.PubMedCrossRefGoogle Scholar
  58. 58.
    Healy ME, Chow JDY, Byrne FL, Breen DS, Leitinger N, Li C, et al. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine. J Hepatol. 2015;62:599–606.PubMedCrossRefGoogle Scholar
  59. 59.
    Hao G-W, Chen Y-S, He D-M, Wang H-Y, Wu G-H, Zhang B. Growth of human colon cancer cells in nude mice is delayed by Ketogenic diet with or without Omega-3 fatty acids and medium-chain triglycerides. Asian Pac J Cancer Prev. 2015;16:2061–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Morscher RJ, Aminzadeh-Gohari S, Feichtinger RG, Mayr JA, Lang R, Neureiter D, et al. Inhibition of neuroblastoma tumor growth by Ketogenic Diet and/or calorie restriction in a CD1-Nu mouse model. PLoS ONE. 2015;10:e0129802.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Poff AM, Ward N, Seyfried TN, Arnold P, D’Agostino DP. Non-toxic metabolic management of metastatic cancer in VM mice: novel combination of Ketogenic Diet, Ketone supplementation, and hyperbaric oxygen therapy. PLoS ONE. 2015;10:e0127407.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, et al. The Ketogenic Diet alters the hypoxic response and affects expression of proteins associated with angiogenesis, invasive potential and vascular permeability in a mouse glioma model. PLoS One. 2015;10:e0130357.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Stemmer K, Zani F, Habegger KM, Neff C, Kotzbeck P, Bauer M, et al. FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in Mice. Diabetologia. 2015;58:2414–23.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Dang MT, Wehrli S, Dang CV, Curran T. The Ketogenic Diet does not affect growth of Hedgehog pathway Medulloblastoma in Mice. PLoS ONE. 2015;10:e0133633.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Martuscello RT, Vedam-Mai V, McCarthy DJ, Schmoll ME, Jundi MA, Louviere CD, et al. A supplemented high-fat low-carbohydrate diet for the treatment of glioblastoma. Clin Cancer Res. 2016;22:2482–95.PubMedCrossRefGoogle Scholar
  66. 66.
    Liśkiewicz AD, Kasprowska D, Wojakowska A, Polański K, Lewin-Kowalik J, Kotulska K, et al. Long-term high fat Ketogenic Diet promotes renal tumor growth in a rat model of Tuberous Sclerosis. Sci Rep. 2016;6:21807.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic Ketogenic diet. BMC Cancer. 2016;16:10.CrossRefGoogle Scholar
  68. 68.
    Xia S, Lin R, Jin L, Zhao L, Kang H-B, Pan Y, et al. Prevention of dietary-fat-fueled Ketogenesis attenuates BRAF V600E tumor growth. Cell Metab. 2017;25:358–73.PubMedCrossRefGoogle Scholar
  69. 69.
    Allott EH, Macias E, Sanders S, Knudsen BS, Thomas G V, Hursting SD, et al. Impact of carbohydrate restriction in the context of obesity on prostate tumor growth in the Hi-Myc transgenic mouse model. Prostate Cancer Prostatic Dis. 2017;20:165–71.PubMedCrossRefGoogle Scholar
  70. 70.
    Rieger J, Bähr O, Maurer GD, Hattingen E, Franz K, Brucker D, et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol. 2014;44:1843–52.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Zahra A, Fath MA, Opat E, Mapuskar KA, Bhatia SK, Ma DC, et al. Consuming a Ketogenic Diet while receiving radiation and chemotherapy for locally advanced lung cancer and pancreatic cancer: The University of Iowa experience of two phase 1 clinical trials. Radiat Res. 2017;187:743–54.PubMedCrossRefGoogle Scholar
  72. 72.
    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:e115147.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Klement RJ, Champ CE, Otto C, Kämmerer U. Anti-tumor effects of Ketogenic diets in Mice: a meta-analysis. PLoS ONE. 2016;11:e0155050.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Fearon KC, Tisdale MJ, Preston T, Plumb JA, Calman KC. Failure of systemic ketosis to control cachexia and the growth rate of the Walker 256 carcinosarcoma in rats. Brit J Cancer. 1985;52:87–92.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Beck SA, Tisdale MJ. Nitrogen excretion in cancer cachexia and its modification by a high fat diet in Mice. Cancer Res. 1989;49:3800–4.PubMedGoogle Scholar
  76. 76.
    Otto C, Klingelhöffer C, Biggermann L, Melkus G, Mörchel P, Jürgens C, et al. Analysis of the metabolism of Ketone Bodies and lactate by gastrointestinal tumor cells in vitro. Aktuel Ernahrungsmed. 2014;39:51–9.CrossRefGoogle Scholar
  77. 77.
    Hao G, Wang H, He D, Chen Y, Wu G, Zhang B. Effect of ketogenic diet on growth of human colon cancer cells in nude mice. Chinese J Clin Oncol. 2014;41:1154–7.Google Scholar
  78. 78.
    Liu R-Q, Liu M-F, Jiang X-C, Guo Z-Z, Dong J-Y, Chen R, et al. Ketogenic diet affects tumor growth in the mouse model of EMT-6 breast cancer. Chinese J Cancer Prev Treat. 2015;22:827–31.Google Scholar
  79. 79.
    De Feyter HM, Behar KL, Rao JU, Madden-Hennessey K, Ip KL, Hyder F, et al. A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neuro Oncol. 2016;18:1079–87.PubMedCrossRefGoogle Scholar
  80. 80.
    Healy ME, Lahiri S, Hargett SR, Chow JDY, Byrne FL, Breen DS, et al. Dietary sugar intake increases liver tumor incidence in female mice. Sci Rep. 2016;6:22292.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Brünings W. Beiträge zum Krebsproblem. 1. Mitteilung: Ueber eine diätetisch-hormonale Beeinflussung des Krebses. Münch Med Wschr. 1941;88:117–23.Google Scholar
  82. 82.
    Brünings W. Beiträge zum Krebsproblem. 2. Mitteilung: Klinische Anwendungen der diätetisch-hormonalen Krebsbeeinflussung (“Entzuckerungsmethode”). Münch Med Wschr 1942; 89: 71–6.Google Scholar
  83. 83.
    Schulte G, Schütz H. Insulin in der Krebsbehandlung. Münch Med Wschr. 1942;89:648–50.Google Scholar
  84. 84.
    Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: case report. Nutr Metab. 2010;7:33.CrossRefGoogle Scholar
  85. 85.
    Moore K. Using the restricted ketogenic diet for brain cancer management: comments from neuro-oncologist. In: Seyfried TN, editor. Cancer as a metabolic disease: on the origin, management, and prevention of cancer. Hoboken: Wiley; 2012. p. 397–400.Google Scholar
  86. 86.
    Fine EJ, Segal-isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–35.PubMedCrossRefGoogle Scholar
  87. 87.
    Tóth C, Clemens Z. Halted progression of soft palate cancer in a patient treated with the paleolithic Ketogenic Diet alone. Am J Med Case Reports. 2016;4:288–92.Google Scholar
  88. 88.
    Schwalb M, Taubmann M, Hines S, Reinwald H, Ruggiero M. Clinical observation of a novel, complementary, immunotherapeutic approach based on Ketogenic diet, chondroitin sulfate, vitamin D 3, oleic acid and a fermented milk and colostrum product. Am J Immunol. 2016;12:91–8.CrossRefGoogle Scholar
  89. 89.
    Abdelbary M, Elsakka A, Salah H, Mokhtar W, Abdelzaher E. Does Metabolic management of gliomas using restricted Ketogenic diet combined with hyperbaric oxygen therapy (HBOT) improve clinical outcome and reduce epileptic risk? (poster presentation). Tampa: Metabolic Therapeutics Conference; 2017.Google Scholar
  90. 90.
    Klement RJ. Restricting carbohydrates to fight head and neck cancer—is this realistic? Cancer Biol Med. 2014;11:145–61.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Warburg O, Posener K, Negelein E. Über den Stoffwechsel der Carcinomzelle. Biochem Zeitschr. 1924;152:309–43.Google Scholar
  92. 92.
    Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int. 2009;9:14.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Seyfried TN, Shelton LM. Cancer as a metabolic disease. Nutr Metab (Lond). 2010;7:7.CrossRefGoogle Scholar
  94. 94.
    Seyfried TN. Cancer as a metabolic disease: on the origin, management, and prevention of cancer. Hoboken: Wiley; 2012.CrossRefGoogle Scholar
  95. 95.
    Marchut E, Gumińska M, Kedryna T. The inhibitory effect of various fatty acids on aerobic glycolysis in Ehrlich ascites tumour cells. Acta Biochim Pol. 1985;33:7–16.Google Scholar
  96. 96.
    Nakahara W. Studies on Lymphoid activity. VI. Immunity to transplanted cancer induced by injection of olive oil. J Exp Med. 1921;35:493–505.CrossRefGoogle Scholar
  97. 97.
    Nakahara W. Effect of fatty acids on the resistance of mice to transplanted cancer. J Exp Med. 1924;40:363–73.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Fine EJ, Feinman RD. Insulin, carbohydrate restriction, metabolic syndrome and cancer. Exp Rev Endocrin Metab. 2014;10:15–24.CrossRefGoogle Scholar
  99. 99.
    Klement RJ, Fink MK. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis. 2016;5:e193.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Sherwin RS, Hendler R, Felig P. Effect of ketone infusions on amino acid and nitrogen metabolism in man. J Clin Invest. 1975;55:1382–90.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Klement RJ, Sweeney RA. Impact of a ketogenic diet intervention during radiotherapy on body composition: II. Protocol of a randomised phase I study (KETOCOMP). Clin Nutr ESPEN. 2016;12:e1–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Ahmad IM, Aykin-Burns N, Sim JE, Walsh SA, Higashikubo R, Buettner GR, et al. Mitochondrial O2- and H2O2 Mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 2005;280:4254–63.PubMedCrossRefGoogle Scholar
  103. 103.
    Weiser MA, Cabanillas ME, Konopleva M, Thomas DA, Pierce SA, Escalante CP, et al. Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer. 2004;100:1179–85.PubMedCrossRefGoogle Scholar
  104. 104.
    McGirt MJ, Chaichana KL, Gathinji M, Attenello F, Than K, Ruiz AJ, et al. Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas. Neurosurgery. 2008;63:286–91.PubMedCrossRefGoogle Scholar
  105. 105.
    Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, Grossman SA. Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol. 2009;27:1082–6.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Lamkin DM, Spitz DR, Shahzad MMK, Zimmerman B, Lenihan DL, DeGeest K, et al. Glucose as a prognostic factor in Ovarian Carcinoma. Cancer. 2009;115:1021–7.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, et al. Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol. 2011;29:54–60.PubMedCrossRefGoogle Scholar
  108. 108.
    Villarreal-Garza C, Shaw-Dulin R, Lara-Medina F, Bacon L, Rivera D, Urzua L, et al. Impact of diabetes and Hyperglycemia on survival in advanced breast cancer patients. Exp Diabetes Res. 2012;2012:732027.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Minicozzi P, Berrino F, Sebastiani F, Falcini F, Vattiato R, Cioccoloni F, et al. High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease. Eur J Cancer. 2013;49:3881–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Mayer A, Vaupel P, Struss H-G, Giese A, Stockinger M, Schmidberger H. Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme. Strahlenther Onkol. 2014;190:933–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Tieu MT, Lovblom LE, McNamara MG, Mason W, Laperriere N, Millar B-A, et al. Impact of glycemia on survival of glioblastoma patients treated with radiation and temozolomide. J Neurooncol. 2015;124:119–26.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Monzavi-Karbassi B, Gentry R, Kaur V, Siegel ER, Jousheghany F, Medarametla S, et al. Pre-diagnosis blood glucose and prognosis in women with breast cancer. Cancer Metab. 2016;4:7.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Adeberg S, Bernhardt D, Foerster R, Bostel T, Koerber SA, Mohr A, et al. The influence of hyperglycemia during radiotherapy on survival in patients with primary glioblastoma. Acta Oncol (Madr). 2016;55:201–7.CrossRefGoogle Scholar
  114. 114.
    Klement RJ, Champ CE. Corticosteroids compromise survival in glioblastoma in part through their elevation of blood glucose levels. Brain. 2017;140:e16.PubMedGoogle Scholar
  115. 115.
    Fine EJ, Champ CE, Feinman RD, Márquez S, Klement RJ. An evolutionary and mechanistic perspective on dietary carbohydrate restriction in Cancer Prevention. J Evo Health. 2016;1:15.Google Scholar
  116. 116.
    Clemens Z, Tóth C. Vitamin C and disease: insights from the evolutionary perspective. J Evo Health. 2016;1:13.Google Scholar
  117. 117.
    Klement RJ, Feinman RD, Gross EC, Champ CE, D’Agostino DP, Fine EJ, et al. Need for new review of article on ketogenic dietary regimes for cancer patients. Med Oncol. 2017;34:108.PubMedCrossRefGoogle Scholar
  118. 118.
    Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017;36:11–48.PubMedCrossRefGoogle Scholar
  119. 119.
    Champ CE, Volek JS, Siglin J, Jin L, Simone NL. Weight Gain, metabolic syndrome, and breast cancer recurrence: are dietary recommendations supported by the data? Int J Breast Cancer. 2012;2012:506868.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Gonder U. Article on ketogenic dietary regimes for cancer highly misleading. Med Oncol. 2017;34:109.PubMedCrossRefGoogle Scholar
  121. 121.
    Cartwright N, Howick J. Evidence-based policy: where is our theory of evidence? J Child Serv. 2009;4:6–15.CrossRefGoogle Scholar
  122. 122.
    Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010;9:3506–14.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Rodrigues LM, Uribe-Lewis S, Madhu B, Honess DJ, Stubbs M, Griffiths JR. The action of β-hydroxybutyrate on the growth, metabolism and global histone H3 acetylation of spontaneous mouse mammary tumours: evidence of a β- hydroxybutyrate paradox. Cancer Metab. 2017;5:4.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Cahill GFJ, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149–61.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Ćirković MM. Who are the SETI sceptics? Acta Astronaut. 2013;89:38–45.CrossRefGoogle Scholar
  126. 126.
    Champ CE, Klement RJ. Commentary on “Strong adverse prognostic impact of hyperglycemic episodes during adjuvant chemoradiotherapy of glioblastoma multiforme”. Strahlenther Onkol. 2014;191:281–2.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Radiotherapy and Radiation OncologyLeopoldina Hospital SchweinfurtSchweinfurtGermany

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