Classification of (cancer) cachexia: Any improvements to expect?

6 th Research Congress of EAPC Glasgow, June 11th 2010 Session Cachexia of EPCRC and EAPC RN Classification of (cancer) cachexia: Any improvements to expect? The joint work of many persons involved, thank you! Ken Fearon, Stefan Anker, Ingvar Bosaeus, Eduardo Bruera, Robin Fainsinger, Aminah Jatoi, Charles Loprinzi, Neil MacDonald, Giovanni Mantovani, Mellar Davis, Maurizio Muscaritoli, Faith Ottery, Lukas Radbruch, Paula Ravasco, Declan Walsh, Andrew Wilcock, Stein Kaasa, Vickie Baracos, Paddy Stone, David Blum, Tora Skeidsvoll, Ben Tan, Marianne Hjermstad, Susanne Linder, Rolf Oberholzer, and many others PD Florian Strasser, MD ABHPM Head, Oncological Palliative Medicine Oncology; Dept. Internal Medicine & Palliative Care Center, Cantonal Hospital St.Gallen, Switzerland

My patients Who has cachexia? All: detect cachexia Prioritize and diagnose cachexia Goal-directed inteventions Drugs. cachexia. cancer Nutrition Physical Psychosocial Effectiveness

Ed1 Definitions ACS Old Definition of Cancer Cachexia Weight # * (involuntay, 2% 2 Mts or 5% 6 Mts) Appetite # (VAS >=3/10 or a Problem ) Oral Intake # * (<20 kcal/kg or <75% normal) # Anorexia/Cachexia Loprinzi C et al., early 90-ies * Malnutrition Kondrup J et al. Clin Nutr 2003;22:415-21

Ed1 Definitions ACS Why is an improvement needed? 1/3 Ask Eduardo Late referrals: too late to improve cachexia Uncertainty about fatigue patients: cachexia?. Physical, cognitive, emotional fatigue 1. Multidimensional causes of fatigue 2 1: Strasser F, Müller-Käser I, Dietrich D. J Pain Symptom Manage 2009;38(4):505-14. 2: Strasser F. Curr Opin Clin Nutr Metab Care 2008;11(4):417-21

Ed1 Definitions ACS Why is an improvement needed? 2/3 Anti-cachexia drugs: Progestins, C-steroids high price for short-term better appetite 1 Anti-cancer treatment variable cachexia improvement & deterioration 2 Nutrition: supplement, enteral, parenteral very variable results from nutrition studies 3 ESPEN guidelines leave many questions open 4 Physical function interventions responses seem to vary, not explained: age, sex 5 Psychosocial interventions uncertainty when and how to counsel 6 1: Oxford Textbook of Palliative Medicine, 4 th Edition; 2: Oberholzer R et. al., EAPC 2010, Poster #281; 3: Ravasco P et al., Clin Nutr 2007;26:7-15; 4: Bozzetti F et al. Clinical Nutrition 28 (2009) 445 454; 5: Oldervoll L et al. EAPC 2010, oral comm. #30; 6: Hopkinson J et al., EAPC 2010, oral comm. #106

Ed1 Definitions ACS Why is an improvement needed? 3/3 Patient Population in Clinical trials high attrition rate 1,2,et.al. promising drugs (phase I/II) were not effective 1 mechanism-based treatment (α-tnf) in unselected patients (trial negative) 3 substantial improvement in placebo controls: variability of basic cachexia management 1,2,et.al Endpoints in clinical trials endpoint not reflecting key mechanism of action (anabolic agent, endpoint appetite) 4 too many co-factors (weight: obese, fluids) 1: Fearon KC et al. J Clin Oncol 2006;24:3401-7; 2: Strasser F et al. J Clin Oncol 2006;24:3394-400. 3: Jatoi A, et al. Cancer 2007;110:1396-403; 4: Loprinzi C et al. J Clin Oncol. 1999;17:3299-306

The solution now?

Process with Systematic Literature Reviews, formal delphi consensus processes, pilot validation SLR Secondary SLR Impact of tumor control SLR Psychosocial consequences NEW Consensual Cancer Cachexia Classification. Definition and Diagnosis. Phases (early, cachexia, refractory). Phenotypes (inflamm, anorexia, muscle)

New Cancer Cachexia definition 2010 1,2 international accepted 3 Cancer cachexia is a multifactorial syndrome defined by a ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by negative protein and negative energy balance driven by a variable combination of reduced food intake and abnormal metabolism. 1: Blum D et al. (EPCRC) Support Care Cancer 2010;18(3):273-9 2: Fearon K & Strasser F, et al., (EPCRC) submitted 2010 3: Argilés JM et al. J Am Med Dir Assoc 2010;11:229-30

New Cancer Cachexia definition 2010 Cancer cachexia is a multifactorial syndrome defined by a ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by negative protein and negative energy balance driven by a variable combination of reduced food intake and abnormal metabolism. IMPROVEMENT: Diagnose both patients who have cachexia with poor appetite or good appetite but substantial catabolism Example: Literature Review: 1 Of patients with >10% WL, 39% had no anorexia and 16% had normal food intake, while 12% of patients having anorexia had no WL 2 1: Blum D et. al., submitted 2:Sarhill N et al. Support Care Cancer 2003;11:652-9.

New Cancer Cachexia definition 2010 Cancer cachexia is a multifactorial syndrome defined by a ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by negative protein and negative energy balance driven by a variable combination of reduced food intake and abnormal metabolism. IMPROVEMENT: To assess, treat, and evaluate patients with cachexia, no longer is fatigue (alone) used, but now (objective) physical function. 1 1: Helbostad JL et al. Supp care Cancer 2010

New Cancer Cachexia definition 2010 Cancer cachexia is a multifactorial syndrome defined by a ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by negative protein and negative energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Diagnosis of cancer cachexia: In the absence of simple starvation, cancer cachexia syndrome is diagnosed by [ ] IMPROVEMENT: clear requirement to diagnose and treat secondary nutrition-impact symptoms 1,2 1: Kubrak C et al. Head Neck. 2009 Jul 22. 2: Omlin AG & Strasser F. J Clin Oncol, 2007; 25 (Proceedings):9058

Comprehensive Nutritional Counselling improves survival WHY? Updated data from ESMO Symposium Nutrition and Cancer 1.2009 Zürich

Intervention for patients with treatment-related Secondary Nutrition-Impact Symptoms 1 ( simple Starvation )

New Diagnosis of Cancer Cachexia 2010 In the absence of simple starvation, cancer cachexia syndrome is diagnosed by involuntary weight loss >5% over the last 6 months. Weight loss should be ongoing during the last 1 2 months. In patients with significant fluid retention, large tumor mass or obesity (BMI >30kg/m2) significant muscle wasting may occur without weight loss. A direct measure of muscularity is recommended. Any cancer patient with involuntary weight loss who develops a BMI < 20 kg/m 2.

Old Cancer Cachexia diagnosis Definitions of weight loss in papers included in the systematic literature review on cancer cachexia: 1 5% [n=12 papers], 10% [n=20], specific percentages [n=29], or absolute quantity lost in kilograms (n=10) compared with either pre-illness weight [n=33] or during a recent time period (6 months [n=18], 3 months [n=4], or not specified [n=16]). IMPROVEMENT: Common international Diagnostic Criteria to describe (comparable) patient populations 1: Blum D et. al., submitted

New Classification of Cancer Cachexia 2010: Pre-cachexia Cachexia Phases Late (irreversible) cachexia al Normal - Pre-cachexia Weight loss 5% Metabolic/endocrine change Weight loss > 5% Often reduced food Intake/Systemic Inflammation Cachexia cachexia Severe muscle wasting Low performance score Immunocompromised <3 months expected survival Refractory Death Weight loss 5% Anorexia Metabolic change Often r Weight loss >5% or BMI<20 & WL >2% reduced food Intake/Systemic Inflammation Cancer disease: pro- catabolic and not responsive to anticancer treatment. Low performance score. <3 months expected survival

Classification of Cancer Cachexia: Phases Pre-clinical cachexia (or early cachexia) In patients with cancer, early clinical (e.g., loss of appetite, decreased nutritional intake) and metabolic (e.g. insulin resistance, inflammation), signs of cachexia can be present, without the presence of significant involuntary weight loss (i.e. 5%) IMPROVEMENT: Defined (?) clinical entity for innovative clinical trial design (early intervention) The Multidimensional Cancer Cachexia Intervention Trial (MENACE) of EAPC-RN/PRC

Classification of Cancer Cachexia: Phases Refractory (late) cancer cachexia Advanced muscle wasting (with or without loss of fat) due to progressive cancer, not anymore responding to anticancer treatment. Patients have a low performance status and short life expectancy (<3months). It is evident that the burden of artificial nutritional support would outweigh any potential benefit. Therapeutic interventions focus typically on alleviating the consequences/complications of cachexia, e.g. symptom control (appetite stimulation, nausea), eating-related distress of patients and families.

Classification of Cancer Cachexia: Phases Refractory (late) cancer cachexia Advanced muscle wasting (with or without loss of fat) due to progressive cancer, not anymore responding to anticancer treatment. Patients have a low performance status and short life expectancy (<3months). It is evident that the burden of artificial nutritional support would outweigh any potential benefit. Therapeutic interventions focus typically on allevi-ating the consequences/complications of cachexia, e.g. symptom control (appetite stimulation, nausea), eating-related distress of patients and families. IMPROVEMENT: Defined (?) clinical entity for intervention studies: patients symptoms, and psychosocial distress, as well as family member A new EORTC-refractory cachexia module reflecting patients experiences is planned Psychosocial intervention studies

Classification of Cancer Cachexia: Domains Anorexia/ food intake (central, chemosensory, gut) Catabolic drive (Tumor, Inflammation) Decreased muscle mass and strength IMPROVEMENT: Definition Phenotype for genetic studies Option for mechanism-based clinical trials Lenalidomid cachexia study: for inflammatory cachexia Anti-IL-6 antibody trial, u.a.

Lenalidomide for in inflammatory cancer cachexia: randomized, 3-arm (CRP-guided vs fixed dose) placebo-controlled proof-of-concept study Aim: To investigate the safety and efficacy of lenalidomide in patients with advanced solid tumors having inflammatory cancer cachexia on the background of basic cachexia management (treatment of secondary anorexia, nutritional support, physical activity, symptom control) Protocol coordinator: Susanne Linder, RN; Rolf Oberholzer, MD PI: Florian Strasser, St.Gallen, Switzerland Protocol supported by Clinical Trials Unit, St.Gallen Swiss Group for Clinical Cancer Research labeled study Sponsor Cantonal Hospital St.Gallen. Free Drug & Support by Celgene

IMPROVEMENT: New generation of clinical trials in cancer cachexia awaited - Common, international Definition - Common, international Diagnosis - Key domains, mechanism-based - Phases: pre-cachexia, cachexia, refractory - Assessments: (more) relevant for endpoints Population: define Phase define basic management (combinations) presence of target mechanism

IMPROVEMENT: new endpoints in Cancer Cachexia Clinical trials awaited old Endpoints Appetite stimulation subjective Symptom Nutritional intake estimation by patient invalid Body weight invalid if obesity, fluid retention Quality of life to broad concept new Endpoints Nutritional intake requires measurement Muscle mass by DEXA or CT/MRI Muscle strenght intrapatient change Physical functionactivity checklists (ADL + ) 6-min-walk, body-worn-sensors

Improvements for daily clinical care?

Cancer Cachexia Classification for Clinical Use SIPP Cancer Cachexia Assessment Tool Storage Intake Potential Weight loss: compared to usual weight, duration, fluid retention/obesity Anorexia, early satiety, chemosensory % normal intake, 1-2 day dietary record, Secondary nutrition-impact symptoms Tumor [catabolic] activity, Prognosis C-reactive protein Performance Physical functioning, muscle strenght Psychosocial consequences From SIPP: classify cachexia (phase, phenotype) multidimensional interventions

Are IMPROVEMENTS awaited for clinical care? Validation of the SIPP tool needed Cancer Cachexia-SIPP-Validation Study Prospective, multicenter study, applying SIPP together with basic cachexia management recommendations, assess definition of phases by investigators and characterisation of responders (goal-achievement) to multimodal interventions. Modular approach with EPCS. Writing Committee Proposal: Blum D, Strasser F, Fearon K, Baracos V, Fainsinger R Kaasa S, et al.

Conclusions The new (cancer) cachexia classification has the potential to improve Clinical care by allowing. definition of cachexia phases, namely refractory cachexia. define phenotype-, and phase-directed multidimensional interventions Clinical research by. Better and common definition of patients. Improved classification-based endpoints Further validation work is needed (model ECS-CP)

Thank you! Contact Florian.strasser@kssg.ch Fstrasser@bluewin.ch

Simple Starvation: Secondary Nutrition-Impact Symptoms Nausea Vomiting Constipation Diarrhea Defecation after meal Pain Dyspnoea Fatigue Anxiety/depression Sense of hopelessness Stomatitis Dysgeusia Dental problems Difficulty chewing Dysosmia Xerostomia Thick saliva Dysphagia Epigastric pain Abdominal pain Practical Implications: SCREEN SEARCH for S-NIS & Treat

Secondary nutrition impact symptoms Chemosensory Dysfunction Hutton J et al. J Pain Symptom Manage 2007; 33:156-65

Secondary nutrition impact symptoms Xerostomia N=75 head and neck cancer patients >6 mts after radiotherapy, cured Dirix P et al. Supp Care Cancer 2008;16:171-9

Simple starvation - secondary nutrition impact symptoms: few evidence for impact on oral intake Master search "cancer-cachexia" 14344 citations 1893 abstracts Systematic Literature Review snow-balling (ongoing) 264 papers hand-search (ongoing) 43 papers in systematic review publication 3 Papers: O-NI & Secondary - Ravasco P et al. Head & Neck 2005 - Macqueen CE et al. J Hum Nutr Dietet 1998 - Hutton JL et al. J Pain Symptom Manage 2007 3 papers: oral nutritional intake correlated with secondary causes 11 papers: weight loss correlated with secondary causes 4 papers: qualitative papers 25 papers: descriptive papers, supporting the hypothesis Omlin A et al. EAPC 2008, Poster #11

Multidisciplinary Cancer Cachexia Clinic 1 (nurse, nutritionist, psycho-oncologist, palliative cancer care MD) 58 pts (age 65 years [38, 85]; 28 female / 30 male) Cancer types: 24 GI, 13 GU, 12 lung/ent, 9 other Survival 151 days [7, 776]) 6.9% weight loss (-6, 22; 21%<2%), 21 kg/m2 BMI (15, 26), 52 mg/dl CRP (1, 272; 32% normal), 5.6 anorexia VAS (10: bad) First visit: 68% of Nutritional Intake needs 1466 kcal [400, 2700], 47g protein [15, 108] Follow-up visit (21 days; 13, 64): 15/19 pts increased kcal (400kcal), 15/16 protein (32g) Palliative Cancer Care can improve nutritional intake and often stabilises body weight 1: Blum D, Omlin A et al. Comprehensive cancer cachexia staging and its impact in the outpatient oncology setting: A phase II study. J Clin Oncol Ann Meeting ASCO 2009.