ESPEN Congress Geneva 2014 NUTRITION AT EXTREMES: THE UNLIKELY BENEFITS OF STARVATION

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1 ESPEN Congress Geneva 2014 NUTRITION AT EXTREMES: THE UNLIKELY BENEFITS OF STARVATION A calorie is not a calorie: caloric restriction vs modulation of diet composition? F. Bozzetti (IT)

2 ESPEN 2014 A calorie is not a calorie: calorie restriction vs modulation of diet composition Federico Bozzetti Faculty of Medicine, University of Milan, Italy

3 A calorie is not a calorie TOPICS Calorie restriction in cancer patients Normocaloric ketogenic regimen in cancer patients

4 A calorie is not a calorie TOPICS Calorie restriction in cancer patients - To better control the tumour growth - To decrease toxicity from chemotherapy Normocaloric ketogenic regimen in cancer patients

5 Calorie restriction to control the tumour growth In 1914, P Rous (J Exp Med 1914;20:433-51) was the first to suggest that restricted food intake decreased tumour growth and 10 years later O Warburg discovered the anaerobic glycolysis of cancer cells (J Gen Physiol 1927;8: )

6 From P Rous, J Exp Med 1914;20:433-51

7 Calorie restriction to control the tumour growth Some discrepancies between experimental and human tumours Flexner-Jobling tumour grows about 0.6 mm/day and after 1 month it can account for 10-20% of the weight of the host Nutritional modulation lasted for 2/3 of the life of the animal Most of the cancer patients die with cachexia when tumour burden is only 0.1% of BW

8 Glucose utilization by human cancer Glucose net uptake by the tumor exceeds peripheral glucose uptake by a factor of 30 (Holm 1995) Lactate output from the tumor was 43 times greater than peripheral release (Holm 1995)

9 Calorie restriction to control the tumour growth: is it due to a CHO metabolic competition between tumour and the host? Competition for CHO between tumour and the host does not exist in humans! A 70-kg patient usually ingests g CHO/d and has an endogenous glucose production of 200 g/d (from hepatic glycogen, lactate, glycerol, glycogenic AA). His 500-g sarcoma would consumes 9.8 g CHO/d (Norton&Brennan 1980) that is 2% of total daily glucose disposal.

10 Metabolic effects of CHO restriction Low glucose insulin IGFBP-1 IGF-1 PPARα glycolysis FA synthesis FA oxidation (mithocondrial/peroxisomal)

11 Calorie restriction and tumour growth in experimental settings Effects of calorie restriction are mediated by elevation of KB KB are toxic for cancer cells (Maggee 1979, Skinnner 2009, Scheck 2012) A ketogenic diet the growth of human gastric cancer cells in nude mice (Otto 2008) and in xenograft models of prostate cancer (Freedland 2008) High glucose level brain tumour growth, angiogenesis and prevent apoptosis (Seyfried 2003,2010,2011, Yang 2009, Marie 2011, Marsh 2011, PuzioKuter 2011)

12 Calorie restriction and tumour growth in humans Anedoctal data are conflicting

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17 Calorie restriction and tumour growth in humans High glucose tumour uptake poor outcome in headneck, ovary cancer patients (Kubicek 2010, Chang 2013) According to a review of 12 papers (Bozzetti&Mori, 2009) involving 140 pts receiving PN or EN and 84 controls, it appears that - No change of TG was observed in control pts - An increase of TG was found in 7 out 12 studies

18 Calorie restriction and tumour growth in humans Author # pts Primary Regimen (weeks) Comments Zuccoli CNS 9.3 Kcal/kg/d, (8) Radiochemotherapy: complete response Fine mixed 17 Kcal/kg/d, KD (4) Champ CNS <21 Kcal/kg/d, CHO 36 g, KD, (28) Level of ketosis (not weight loss) correlated with PET response CR safe and well tolerated during RT&CT

19 A calorie is not a calorie TOPICS Calorie restriction in cancer patients - To better control the tumour growth - To decrease toxicity from chemotherapy Normocaloric ketogenic regimen in cancer patients

20 Calorie restriction and tolerance to chemotherapy Good results in cell cultures, in mice and in neuroblastoma xenograft models (Blagosklonny 2001,2002, Holzenberger 2003, Seyfried 2003,2010, Raffaghello 2008, Safdie 2012, Shi 2012, Lee 2010,2012, Brandhorst 2013)

21 Calorie restriction and toxicity from chemotherapy (Longo 2014)

22 Calorie restriction and tolerance to chemotherapy in humans Author Safdie 2009 # pts 10 Primary mixed Schmidt mixed Regimen (time) Comments CR: hrs pretherapy Low 8-56 hrs posttherapy chemotherapy side-effects <528 kcal/d (7 wks) 1/3 completed CR, 3/4 tolerated well, few side-effects from CR

23 A calorie is not a calorie TOPICS Calorie restriction in cancer patients Normocaloric ketogenic regimen in cancer patients

24 A normocaloric ketogenic regimen in cancer patients What about tolerance? tumour effects? metabolic and nutritional effects?

25 About tolerance (personal communication of B Zupec-Kania 2014)* The average time that children with epilepsy are on the ketogenic diet is 3 years. Those with metabolic defects such as Glucose-1 Transporter Defect or Pyruvate Dehydrogenase Deficiency will be on the diet for life. The longest period that I've managed a patient on the ketogenic diet is 18 years via feeding tube. 40% of our patients have a feeding tube. The ketogenic diet may be liberalized to make it more tolerable and still be effective. *Ketogenic Therapies LLC, Elm Grove, Wisconsin, USA

26 About tumour effects Tumour uptake of glucose during a ketogenic PN (Bozzetti 2004) pts&met 12 CR liver M+ pts given subsequently 23 npkcal/d as glucose (GPN) vs fat (LPN) and 0.7gAA/kg FDG uptake measured through PET and compared with pre-pn period results GPN increased tumour glucose uptake by 6% LPN decreased tumour glucose uptake by 8%

27 About metabolic&nutritional effects Fat metabolism in cancer patients in postabsorptive state Efficient mobilization and oxidation (53%) of fat (6078% of the REE) in both weight-stable and weightlosing patients (Arbeit 1984, Hansell 1986, Legaspi 1987, Selberg 1991) Fat oxidation rate (kgbw/d): 1.3 to 1.9 g (12 to Kcal)

28 Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism (Fearon 1988) Control pts: Glucose : 55% and fat 31% of total energy Study pts: Fat (MCT): 70% of total energy Results: no significant alteration in host N balance or wholebody protein synthesis, degradation, or turnover rates.

29 Effects of a high-fat diet on body composition in cancer patients receiving chemotherapy: a randomized controlled study (Breitkreutz 2005) 23 pts randomised to 8 wks of standard EN (35npKcal + 1.1g AA/kg/d) vs EN with 66% of energy from fat Results Fat-enriched EN increased BW and allowed a better maintenance of LBM and BCM as well as of some variables of QoL

30 Clinical experience with a normocaloric ketogenic regimen in cancer patients Author # pts Nibeling Bozzetti Primary Regimen (time) Comments KD >85Kcal/kg/d(12mos) PET, >88Kcal/kg/d (8 wks) 1pt alive at 4yrs and 1 at 10 yrs abdominal iv, 28Kcal/kg/d (5 mos) Stable disease, treatment well tolerated CNS

31 Conclusion CR per se has no direct role to decrease TG in cancer pts but this effect is mediated by elevation of KB Tumour and host do not compete for glucose in humans A KD «may» decrease TG in humans but the evidence is weak There is no demonstration that KD may allow a better tolerance to chemotherapy A ketogenic normocaloric regimen is metabolically adequate for cancer pts, may be well-tolerated (especially via TF or IV line) and is potentially beneficial on the nutritional status

32 Conclusion Diets whose non-protein energy content is accounted mainly from fat or CHO can maintain long-term healthy subjects, even if they are not «ideal»

33 Cancer as a model of disease-oriented diet Energy metabolism of the tumor-bearing patient Energy metabolism of the cancer cells

34 we will probably never know whether dietary restriction can extend the human life span because of low compliance to such a demanding nutrition regime (L Partridge, N Engl J Med 2012; 367: )

35 AA utilization by the human cancer High tumoral uptake of EAA and BCAA compared to a low peripheral release (Norton 1980, Hagmuller 1995) Glutamine retention is highly variable (Holm 1993) Colon cancer does not extract more glutamine than tumor-free colon (Van der Hulst 1997)

36 Glucose consumption (g/d/100g tumor) Colon cancer Lung cancer Limb sarcoma 8.2 (X 4.3 cancer-free colon) 4.1 (X 6.7 cancer-free lung) 1.8 From Hagmuller 1992, Nolop 1987, Norton 1980