Themes. Evaluer (defini:on, diagnos:c criteria) Recherche clinique en cancérologie : quid du statut nutri:onnel? Agir Adapter 03/04/15

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1 Recherche clinique en cancérologie : quid du statut nutri:onnel? Pierre Senesse, Laboratoire Epsylon, Ins:tut Régional du Cancer de Montpellier SIRIC Vickie Baracos, Department of Oncology, University of Alberta, Edmonton Canada Montpellier March 2015 Themes Evaluer (defini:on, diagnos:c criteria) Agir Adapter 1

2 Cachexia/Malnutri:on: Research and Clinical prac:ce Normal At risk Malnourished Severely Malnourished Normal Precachexia Cachexia Refractory Cachexia Death Physical func:oning Infec:on Toxicity of chemotherapy Cachexia/Malnutri:on in guidelines ESPEN guidelines No clear defini:on ASPEN guidelines Recommenda:ons to use PGSGA or SGA or NRI French guidelines 201 Weight loss 10% in surgery Weight loss 5% in medical oncology 1 Arends et al. Clinical Nutri,on (2006) 25, August et al. JPEN J Parenter Enteral Nutr 2009; ; Senesse et al. Dig Liver Disease 201;Apr 29 2

3 Cachexia/Malnutri:on in prac:ce Weight loss Ingesta analog scale Cachexia: consequences Direct consequences Indirect consequences Morbi- mortality Side- effects Well- being Cost No screening, no plan Therefore Subop:mal nutri:onal treatment

4 Prevalence of cachexia Severity of cancer associated malnutri:on (cachexia). is classified according to the rate of ongoing loss of weight in combina:on with the concurrent degree of deple:on Defini:on and classifica:on of cancer cachexia, an interna:onal consensus Fearon K et al. Lancet Oncology 2011: 12(5): 89-95

5 Diagnos:c criteria for the classifica:on of cancer associated weight loss Mar:n L et al 2015 January J Clin Oncol Interna:onal data set: Canada / Europe advanced cancer cohort (n=8160) and valida:on cohort (n=296). Mul:variate survival analysis controlling for age, sex, cancer site, stage, and performance status. Rela:onships for BMI and %WL to overall survival were examined Hypothesis: Risk of Mortality is a Simultaneous Func:on of Body Mass Index and Weight Loss in Pa:ents with Advanced Solid Tumors Risk of Mortality is a Simultaneous Func:on of Body Mass Index and Weight Loss in Pa:ents with Advanced Solid Tumors Mar:n et al J Clin Oncol 2015 BMI kg/m 2 Median survival, months Different colors denote p<0.001 adjusted for age, sex, site, stage and Performance Status N=8160 N= in each of 25 cells Weight loss %

6 Risk of Mortality is a Simultaneous Func:on of Body Mass Index and Weight Loss in Pa:ents with Advanced Solid Tumors A single cut off for weight loss combines groups with disparate prognosis Weight loss % BMI kg/m Weight loss % BMI kg/m (BMI- Adjusted) Weight Loss Grade Median overall survival (months) Mul:variate p adjusted for age, sex, site, stage and PS * Mean survival, did not reach median survival. Grade P Colon Esophagus Pallia:ve care Lung

7 Macronutrient intake considera:ons BMI kg/m 2 Underweight, severe general deple:on Obese, insulin resistant, hypertensive NUTRITION Limited energy?; Protein dense Weight loss % NUTRITION Energy dense Protein dense Ar:ficial nutri:on? Evaluer Agir (nutri:on team, nutri:on therapy) Adapter 7

8 Cachexia: treatment plan A Physician led Cancer Nutri:on Program Die:cians Nurses Physicians 8

9 Evaluer Agir Adapter (malnourished pa:ents with deple:on of lean :ssue show excessive chemotoxicity) 9

10 Hazard ra:o, for death,5,5 2,5 1,5 * * Sarcopenia: a low level of muscle, characterized by sta:s:cally significant* increase in health risk (mortality, toxicity, physical disability). *sta:s:cal test for a threshold value - i.e. Op:mal stra:fica:on 0, c 1 c 2 c Prado CM et al Prevalence and clinical implica:ons of sarcopenic obesity in pa:ents with solid tumours of the respiratory and gastrointes:nal tracts: a popula:on- based study. Lancet Oncology 2008; 9(7): N=250 pa:ents BMI > 0 kg/m 2 Sarcopenia, independent of age, disease stage and performance status 11 months vs 21 months median survival Sarcopenic 10

11 Not sarcoepnic <20 mg/kg LBM Dose /m Sarcopenic >20 mg/kg LBM Dose / kg LBM 16.1 ± ± 0.9 <0.001 Dose limi:ng toxicity, % 52% 9% BSA m ± ± Weight, kg 68. ± ± LBM, kg 1. ± ± P Chemotherapy is reduced >20% or terminated in sarcopenic pa:ents, due to excess toxicity Colon, FOLFIRI Normal Sarcopenic Colon, FOLFOX Lung, carbopla:n Phase I Thyroid, vandetanib Liver, sorafenib Renal, suni:nib Renal, sorafenib Colon, 5 fluorouracil Breast, capecitabine Dose- limi:ng toxicity, % Clin Cancer Res :2920-6; Clin Cancer Res 2007;1:26-8; Ann Oncol. 2010; 21:159-8; Br J Cancer. 201; 108:10-1; PLoS One. 2012;7(5):e756; Clin Endocrinol Metab. 201;98:201-8, Inv New Drugs, 201; PLoS One. 2012;7(1):e290; Baracos & Senesse unpublished. 11

12 Pharmaco- cine:que Maximum tolerated concentra:on Minimum effec:ve concentra:on A Pharmacokine:c Basis? Sarcopenia relates to higher drug exposure measured as Area Under the :me- concentra:on Curve Median adjusted dose for AUC (mg/l.h) on day 28. Range Sarcopenic Non sarcopenic P value =0.01 Patients with DLT Patients without DLT Median adjusted dose for AUC (mg/l.h) on day 28. Range =0.09 Mir, PLoS ONE,

13 Bad dance Oncologist not aware of nutri:onal deficits such as lean :ssue deple:on Chemotherapy too aggressive, severe toxicity, treatment interrup:on, worse nutri:onal status.. Treatment Decision Making Adapted for Nutri:onal Status Cispla:n Carbopla:n Pemetrexed Efficacy & Toxicity greatest Least Performance status Comorbidity Renal func:on Hepa:c func:on + Presence of lean :ssue deple:on 1

14 Good dance Early nutri:on assessment Oncologist integrates presence of sarcopenia in treatment planning Enhance efficacy and reduce toxicity Conclusions Evolu:on of defini:ve diagnos:c criteria is a high current priority, weight loss scoring, body composi:on Malnutri:on is related to cancer specific mortality and morbidity Nutri:on therapy integra:on in cancer therapy 1

15 Master plan of nutri:onal care in medical oncology 15