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Ketogenic Diet in Advanced Cancer Final Results of a Safety and Feasibility Study

Ketogenic Diet in Advanced Cancer Final Results of a Safety and Feasibility Study. Jocelyn Tan MD FACP, Jennifer Carrick RN, MS, Krystal Edinger RD, Dana Genovese RN, Andrew Liman MD, Vida Passero MD, Rashmikant Shah MD Pittsburgh VA Healthcare System.

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Ketogenic Diet in Advanced Cancer Final Results of a Safety and Feasibility Study

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  1. Ketogenic Diet in Advanced CancerFinal Results of a Safety and Feasibility Study Jocelyn Tan MD FACP, Jennifer Carrick RN, MS, Krystal Edinger RD, Dana Genovese RN, Andrew Liman MD, Vida Passero MD, Rashmikant Shah MD Pittsburgh VA Healthcare System

  2. Disclosure InformationAVAHO 11th Annual Meeting/Oct. 2-4, 2015Jocelyn Tan MD, FACP Disclosure of Relevant Financial Relationships I have no financial relationships to disclose. Disclosure of Off-Label and/or investigative Uses I will not discuss off label use and/or investigational use in my presentation.

  3. What is the ketogenic diet?

  4. Introduction • Ketogenic diets KD = standard treatment for refractory epilepsy 1920s • Long term KD >10 yrs-safe • Carbohydrate restriction slows tumor growth - animal /in vitro models • Human case reports suggest benefit in cancer

  5. Background • 1921 A. Braunstein -observed disappearance of glucosuria in diabetics who developed cancer • 1922 R.Bierich–noted higher lactate accumulation around tumor tissue • 1924 Ketogenic diet – Dr. Russell Wilder - Mayo Clinic

  6. HK2 Tan-Shalaby J, Seyfried TN; J Clin Trials 2013

  7. Warburg Effect • Cancer cells' glycolytic activity • abnormally high • Energy production via Citric Acid Cycle • and oxidative phosphorylation -Lacking • Lactate levels are increased.

  8. Effects of Lactate on Autoimmunity • Low pH activates MMPs Dendritic cell maturation • normal cell apoptosis->selective survival of cancer cells T cell cytolytic activity HDAC , transcription and NK cell activity

  9. LIPOLYSIS GLUCONEOGENESIS Effects of Hyperglycemia CACHEXIA Insulin and IGF1 VITAMINC Monocytes Macrophages IR and IGF1 R Adipose PI3K/Akt/HIF-1α Phagocytosis NORMAL MITOSIS Anti apoptosis Pro growth cytokines IL6 LACTATE INFLAMMATION

  10. VDACs Voltage dependent anion channels, ANT adenine nucleotide transferase + MPTP form a complex with Hexokinase 2 Deactivates BaD/ BaX/BaK caspase-mediated apoptosis Cell immortality Cytochrome C APOPTOSIS HK2 ATP HK2 Energy for glycolysis

  11. HDAC

  12. KETONES- direct anti tumor effect • Xenograft prostate cancer model • Ketones directly cytotoxic • Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, et al: Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 2008, 68:11-19.

  13. GKI

  14. GKI Low Glucose Ketone Index values prognoses in humans and mice with brain tumors ✔Therapeutic action of calorie restriction distal invasion, proliferation, and angiogenesis in the VM-M3 model of glioblastoma

  15. Hypoglycemia was stratified as follows. Negative for blood glucose levels of ≥ 100 mg/dl, +1 for FBS ≥95 or<100 mg/dl, +2 for FBS ≥70 but <95 mg/dl, and +3 hypoglycemia for FBS <70 mg/dl.

  16. Hunger studies Jonsson T, Granfeldt Y, Erlanson-Albertsson C, Ahren B, Lindeberg S: A paleolithic diet is more satiating per calorie than a mediterranean-like diet in individuals with ischemic heart disease. NutrMetab (Lond) 2010, 7:85. Nickols-Richardson SM, Coleman MD, Volpe JJ, Hosig KW: Perceived hunger is lower and weight loss is greater in overweight premenopausal women consuming a low-carbohydrate/high-protein vs high-carbohydrate/low-fat diet. J Am Diet Assoc 2005, 105:1433-1437. hunger with low carbohydrate versus high carbohydrate diet

  17. Is weight loss unhealthy? Malignant cells-lack key mitochondrial enzymes ---–-- unable to convert ketone bodies and fatty acids to ATP van Ness van Alstyne E, Beebe SP: Diet studies in transplantable tumors. I. The effect of non-carbohydrate diet upon the growth of transplantable sarcoma in rats. J Med Res 1913, 217-232. 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.

  18. ANIMAL TRIALS • Ketogenic diet • Less cachexia • Tumors grew more slowly • Provided energy to brain /muscles • Unable to convert fatty acids and ketones to ATP • Slow down proteolysis/lipolysis/stabilized wt 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.

  19. ANIMAL TRIALS Rats w/ Buffalo Sarcoma CHO-free diet versus Controls > gained more weight > slower tumor growth > fewer deaths van Ness van Alstyne E, Beebe SP: Diet studies in transplantable tumors. I. The effect of non-carbohydrate diet upon the growth of transplantable sarcoma in rats. J Med Res 1913, 217-232.

  20. Human Case studies KoroljowS: Two cases of malignant tumors with metastases apparently treated successfully with hypoglycemic coma. Psychiatr Q 1962, 36:261-270. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN: Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. NutrMetab (Lond) 2010, 7:33. NebelingLC, Miraldi F, Shurin SB, Lerner E: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am CollNutr 1995, 14:202-208. GLIOMA STUDIES

  21. Human Feasibility trials Fine EJ, Segal-Isaacson CJ, Feinman RD, etal A pilot safety and feasibility trial of a reduced carbohydrate diet in patients with advanced cancer. J ClinOncol 2011, 29(suppl; abstr e13573). Schmidt M, Pfetzer N, Schwab M, Strauss I, KammererU:Effectsof a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. NutrMetab (Lond) 2011, 8:54. New York- single institution RECHARGE Germany-multi institutional - Wurzburg trial

  22. >18 Y/O US VETERAN NO ACTIVE WEIGHT LOSS EXPECTED LIFESPAN >3 MO Advanced solid cancer Adequate hematologic, hepatic or renal function ECOG PS 0-2 No brain metastases OVER 300 INQUIRIES 11ELIGIBLE 17 CONSENTED

  23. Study Endpoints PrimaryEndpoint Secondary Endpoint Quality of life Tumor response measured by PET CT • Safety • Bloodwork every week x 4 then monthly • Physical exam and imaging tests

  24. Enrollment-FDG + SOLID TUMORS • 2 days trial diet • EORTC QLQ-c30 questionnaire version 3 • Dietary counseling, Weekly bloodwork, Clinic visits, weight, • Vitals, Physical exam Dietary diary review • PET CT after 4, 8 , 16 weeks if stable or + response • END OF STUDY disease progression, early drop out /16 weeks) NCT 0171664686 PROTOCOL

  25. Diet Plan • Subject will consume <20g carbohydrate a day • Unlimited calories, protein, and fat • Subject will keep detailed food diaries • Sample menus, grocery list, and recipes provided

  26. Modified Atkins Diet (MAD) • Less restrictive then the KD • No protein or calorie restriction • Limits carbohydrates to <20g/day • Similar long term side effects as the KD

  27. MAD Food List Cont.

  28. Menu- M.A.D. • Fats • real mayonnaise, butter, sour cream, olive oil, cream cheese, canola oil, oil based salad dressings (limit to <4g of carbohydrate/2T), heavy cream , coconut oil, olives (limit 5 /day), pork rinds • cream based salad dressings(unless otherwise noted on the shopping list), light or fat free mayonnaise or sour cream, fat free salad dressings

  29. M.A.D. Food List

  30. Menu M.A.D. • Vegetables Allowed • asparagus, Bok choy, cabbage, celery, spinach, lettuce, watercress, brussel sprouts, kale, broccoli, cauliflower, cucumbers, radishes, zucchini, mushrooms, onions/peppers (limit to 2 tablespoons/day) • Not Allowed • carrots, corn, peas, tomatoes, lima beans, avocado, sauerkraut, squash

  31. MAD Food List Cont.

  32. Baseline Characteristics

  33. PatientDemographics • All except one patient - heavily pre-treated • Two indolent advanced disease • 12 had rapidly progressive disease • Average # previous treatments = 2.18

  34. RESULTSPatient Demographics • Primary sites • cholangiocarcinoma(n=1), colon (n=1),pancreatic (n=1), liver (n=1) • glioma (n=2), parotid (n=1), • prostate (n=1) and thyroid (n=2), renal (n=1) • melanoma (n=3)

  35. Ketosis

  36. Weight loss, Body Mass Index

  37. Weight loss

  38. Ketosis

  39. Effect on Lipid Profile

  40. Effect on Glucose & Ketones Numbers remained stable

  41. Quality of Life measures

  42. Calculated SUVStandard Uptake Value No change from baseline to last visit values P= 0.878 2 tailed paired t test 95% CI

  43. QOL Functional scores

  44. QOL Digestive Scores

  45. QOL Symptom scores

  46. Global Health and Financial Scores

  47. Glucose/Ketone Index

  48. Effect on SUV, Weight, Ketones, Glucose

  49. Correlations • No correlation of Glucose to Lipids • Not all patients fasted • Fasting times varied (6-12 hours) • No correlation of Glucose to Ketones

  50. Summary of Results Responders lost significantly more weight. None achieved therapeutic GKI levels (<1.0) Benefit seen despite normal Glucose levels. Responders vs. non responders had no difference in glucose or ketone levels. Prolongation of life beyond expected lifespans were observed in a few patients.

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