recognizing anorexia cachexia early how to intervene · 19.11.2015 5 siog 13. nov 2015 anorexia...

19.11.2015

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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser

Disclosure Slide (last 5 years)

Unrestricted industry-grants for clinical research- Celgene (Lenalidomide Cachexia trial)

- Fresenius (Survey parenteral nutrition malignant bowel obstruction)

- Helsinn (for Palliative Research Center, MENAC trial & other)

Participation in company-lead clinical cachexia trials- Novartis (BYM338 cachexia trial)

Punctual Advisorship (Boards, Expert meetings)Acacia, ACRAF, Amgen, Baxter, Celgene, Danone, Fresenius, GSK, Grünenthal, Helsinn, ISIS Global, Millennium/Takeda, Mundipharma,

Novartis, Novelpharm, Nycomed, Obexia, Otsuka, Ono, Pharm-Olam, Pfizer, Psioxus, PrIME, Santhera, Sunstone, Teva, Vifor

No: Mono-sponsored industry-controlled Sattelite meetings No: Personal financial interest (stocks, private use of honoraria, ...)


Florian Strasser, MD ABHPM

Oncological Palliative Medicine,

Clinic Oncology/Hematology, Dept Internal Medicine & Palliative Centre

Cantonal Hospital St.Gallen, Switzerland

Special SIOG & MASCC partnership session 13. Nov 2015

Multinational Association of Supportive Care in Cancer

Nutrition issues and challenges in older patients with cancer

Recognizing anorexia cachexia early how to intervene

ESMO Palliative Supportive Care Working Group, Chair

MASCC Working Group Nutrition and Cachexia, Co-Chair

Society Cachexia Wasting Sarcopenia, Board

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Mr K, 72-j, Pancreas-adenocarcinoma liver-metsGemcitabine weekly second-line, since 3 weeks

„How are you“: swollen legs, people do nothing about it.

Am tired and weak, poor appetite, I want living at my home.

„It is difficult

seeing him

getting thinner

he does not

eat enough


clinical «nutritional» challenges in care of theolder patient with cancer

● how to screen for and assess nutritional issues?

● how to set goals to motivate patients forpalliative rehabilitation?

● who is the patient who profits from nutritional interventions or drugs for anorexia/cachexia?

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Age-related Sarcopenia- Aging of the neuromuscular junctions, loss of motoneurons,

of the myogenic capacity and muscle mass

- Loss of muscle strenght and physical function

Secondary Sarcopenia- Hypogonadism, Corticosteroids, Thyroid, physical inactivity

Malnutrition („Starvation“)- Many causes for decreased oral intake in elderly patients

Cancer cachexia- hypercatabolic, hypoanabolic, inflammatory changes,

decreased intake, loss of muscle & function

Cachexia caused by Comorbidities- chronic heart failure, COPD, etc.

Nutritional issues in the older patient with cancer


Slid

e c

ourt

esy

ofV

ickie

Bara

cos

9.2

014

Co-Occurrence in cancer patients

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Sarcopenia caused by:

Hypogonadism

Physical inactivity

Corticosteroids

Thyroid dysfunction

Age-related*

- Less muscle stem cell response to acute

resistance exercise

- Same Type I, less Type II fibres

- myogenic program reduced

- impaired induction of MyoD in Pax7 cells

* McKay B etz al. FASEB J 2012;(26):2509–2521

Joseph AM et al. Aging Cell 2012; 11: 801–809


Malnutrition

van der Pols-Vijlbrief R et al. Ageing Res Rev 2014;18:112-31

Systematic Literature review for cofactors: 28 studies,

122 unique potential & 37 sufficiently used determinants

Association of determinant with protein-energy

malnutrition

Strong evidence poor appetite

Moderate evidence for edentulousness, having no diabetes,

hospitalization and poor self-reported health.

Strong evidence for no association: anxiety, chewing difficulty,

few friends, living alone, feeling lonely, death of spouse, high

number of diseases, heart failure and coronary failure, stroke,

anti-inflammatory medications.

Frequency in older people 5-35%,

depending on population

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Malnutrition causes in cancer patients

●●●● Diet mistakes / misconceptions: too healthy, ..

●●●● neglect for maintenance of nutritional intake- Periods of “no eating” due to procedures

- helping patients to eat (dentures)

●●●● Secondary Nutrition-Impact symptoms1

(pain, breathlessness, constipation, dysgeusia, …)

- Periods of nausea/vomiting, stomatitis, dysphagia, gastric acid

- (partial) bowel obstruction, diarrhea, malabsorption, prolonged constipation, ..

1: Omlin A et al. J Cach Sarcop Muscle 2013;55-61


Hyper-catabolism(Inflammation, cancer dynamics)

Hypo-anabolismAnorexiaNutritional Intake ▼Autonomic Dysfunction

European Association Palliative Care - Research Network 2012 // 1: Tan BH et al.

EMBO Mol Med 2012;4(6):462-71; 2: Solheim TS et al. Br J Cancer. 2011;105(8):1244-51.

Cancer anorexia cachexia

Pa

tien

t X

Pa

tien

t Y

Loss of mass and quality

of skeletal muscle

Decline of “neuro”- &

muscular function

Pa

tien

t Z

Fearon K & Strasser F, et al. Lancet Oncol 2011 ;12:489-95Argilés JM et al. J Am Med Dir Assoc 2010;11:229-30

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How to screen for nutritional issues in our patients?

When should we start in the course ofcancer disease?

Measure what mattersto patients QoL and anticancer Tx


Anorexia & cachexia related symptoms are frequent ….

Seow H, et al. J Clin Oncol 2011:1151-8

Tired & Appetite: top 2 / 10 (ESAS)

� Many patients have cachexia

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Chochinov H et al. JPSM 2009;38:641-9

N=253 adult pts (545 eligible)

Life expectancy < 6 mts

In palliative care program

Age mean 69, SD 13.5

Patient Dignity Inventory

(Scale 1-5; Problem ≥ 3)

� Several distressing

factors (directly)

related to Sarcopenia -

Starvation

Distress in advancedincurable patients


“nutritional issues” (malnutrition & cachexia) �� survival

● Performance Status (abundant data from various tumors)

●BMI●Weight loss abundant data1 (mixed with starvation)

●Weight loss & BMI2 (BMI: available reserves)

● Muscle mass (Sarcopenia)3

● Muscle attenuation3 (pro-catabolism, hypo-anabolism)

● Inflammation (CRP) & Albumin4 / Lymphocytes5

1: Bozzetti F Crit Rev HemOnc 2013;173; 2: Martin L JCO 2015;90; 3: Martin L JCO

2013;1539; 4 Laird BJ Clin Cancer Res 2013;5456; 5:Jafri BMC Cancer 2013;158

modified Glasgow Prognostic Score4

mGP

S

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Renfro

L e

t al. J

Clin

Oncol2015;3

3Associationof BMI and

Survival

Renfro L et al.

J Clin Oncol

2015;33

SIOG 13. Nov 2015 Anorexia Cachexia / F. StrasserMartin L JCO 2015;90

Grade

0

Grade

1

Grade

2

Grade

3

Grade

4

22.1 13.6 14.1 9.8 5.3

Survival in months

Weight loss and BMI

CRP ≥ 10 mg/L

Grade

0

Grade

1

Grade

2

Grade

3

Grade

4

38.3 30.6 27.8 18.1 8.1

Grade

0

Grade

1

Grade

2

Grade

3

Grade

4

10.7 7.7 7.0 6.0 4.8

CRP < 10 mg/L

Survival in months

Weight loss and BMI

CRP

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SIOG 13. Nov 2015 Anorexia Cachexia / F. StrasserSlide courtesy of Vickie Baracos 9.2014

Surgical complicationspost-operative

infections, reha-

bilitation effect

Lieffers JR Br J Cancer 2012

But other (not

North America)

data seem less

dramatic ..?

Gu W et al. JCSM 2015:222


How to screen for nutritional issues in ourpatients?

Fatigue, Anorexia: just ask, VAS (ESAS)BMI, weight loss

Anticancer treatment toxicities

When should we start in the course ofcancer disease?

Early ! Means together with anticancer tx

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Reserves Weight loss history (%; 1, 2, 6 mts), BMI(muscles) if fluid retention: CT L3/4 or DEXA

Secondary sarcopenia (C-steroids, bed rest,.)

Intake 2 day diet diary, % kcal/protein / needs

(gut-brain) Appetite, hunger, satiety, taste/smellSecond. nutrition impact (S-NIS, PG-SGA)

Catabolism Cancer dynamics & responsivenessCRP >10mg/l (no clinical infection)

Albumin

Function Physical function (KPS), muscle strenght

Motivation/Participation

Impact on TxPrior anticancer treatment toxicities

�� Decide on cachexia phase and goals of intervention

Assess sarcopenia, malnutrition, cancer cachexia


Timon CM et al. British Journal of Nutrition 2015;113, 654–664

Novel Assessment of Nutrition and Ageing

Self assessed on a computer screen

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Timon CM et al. British Journal of Nutrition 2015;113, 654–664

Novel Assessment of Nutrition and Ageing

not bad compared to four day assessment


Conceptual Framework: Fearon K & Strasser F, et al. Definition and classification of cancer cachexia, an international consensus. Lancet Oncol 2011;12(5):489-95

Performance Status low ([2],3,4)

Close to End of life

What can I (meaningful, worthwhile) do? Setting fair goals «managing» Sarcopenia-Starvation

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Normal Precachexia Cachexia Refractory

CachexiaDeath

cachexia therapy goals, influencing interventions

Reserves prevent loss stablilize - improve unavoidable loss

Nutritional Intake prevent decrease stablilize - improve alleviate distress

Inflam / Cancer Act. control cancer control cancer not controllable

Function maintain maintain - improve unavoidable loss

Cancer Supportive

& Palliative Care

Cancer Therapy

ToxicitiesImportant effects Short-term alle-

viation, EOL

Anticancer therapy early lines ≥ 2nd lines no standards

Goals Pre-emptive Stabilize Alleviate

Influencing factors & interventions


If not refractory: Multidimensional Cachexiainterventions delivered by multiprofessional teams

● Depletion of reserves:

muscle mass and fat mass

● Nutritional intake and „gut-brain

axis“ symptoms

● Inflammation and tumor dynamics

● Neuro-muscular and emotional-

cognitive function

►needs-adjusted adequate nutritional intake

►adequate physical function(resistance training & activity)

►multidimensional symptom control, patient education

►anticachexia drugs (coming soon)

► tolerable anticancer therapy to

control tumor activity

► Illness & prognosis under-standing, disease coping

►continuity of care for patient &

family members

►needs-adjusted adequate nutritional intake

►adequate physical function(resistance training & activity)

►multidimensional symptom control, patient education

►anticachexia drugs (coming soon)

► tolerable anticancer therapy to

control tumor activity

► Illness & prognosis under-standing, disease coping

►continuity of care for patient &

family members

These interventions areoverlapping with

interventions of cancerpalliative care, and

cancer rehabilitation

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To define goals of intervention, assess before (the need

for) each Key Intervention Palliative Care

llness & prognosis understanding

Multidimensonal Symptom Control: Appetite, Fatigue

Decision processes structured, guided, value-based process

End of life preparation legacy, premortal grief/role, finish business

Continuity of care Network multiprofessional workforce, family

Care of family members burden of caregiving, distress

Spirituality meaning of life, transcendence, religion, connectedness

Adapted (Magaya N, Strasser F et al 2015) from Temel J et al,

NEJM 2010; Jacobsen J, et al. J Pall Med 2011

Possible form: Interactive checklist-based needs-assessment


Nutritional counselling and patient education

1: Shragge JE, et al. Palliat Med 2007;21: 227-33.

2: Halfdanarson T et al. J Support Oncol 2008;6:234–237;

3: Ravasco P et al. J Clin Oncol 2005.

Prado CM et al. Can J Diet Pract Res. 2012 ;73(4):e298-303.

Concious control of eating1

Eat, even if you are not feeling hungry, moderate pressure

Nutritional counselling2,3

● Assess and improve intake of calories and protein

(Harris-Benedict, disease factor, mobility factor)

● Assess patients‘ individual eating habits

● Check and increase frequencies of daily meals1

● Empower patients to change their daily habits

● Help patients and family members to understand (early satiety, no hunger, taste changes, etc.)

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Baldwin C et al. J Natl Cancer Inst 104, 371–385

Effectiveness of oral nutritional interventions in the management of weight loss in patients with cancer

Metaanalysis: Dietary advice or ONS or both, 13 RCTs, 1414 pts

Evans WK JCO 1987; Macia E Nutrition 1990; Nayel H Nutrition 1991; Ravasco P JCO 2005; Ravasco P Head Neck 2005

Significant benefit on nutritional status, but heterogenity high (I2=76%)


Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial

65 frail elderly subjects: either daily protein or placebo supple-

mentation (15 g protein at breakfast and lunch) x 24 wks

Skeletal muscle mass: no change protein- (45.8 ± 1.7 to 45.8 ±

1.7 kg) vs placebo (46.7 ± 1.7 to 46.6 ± 1.7 kg)

Muscle strength (leg extension) increased in both groups

(P < .01): protein (57±5 to 68±5 kg), placebo (57±5 to 63±5 kg)

Physical performance improved (8.9±0.6 to 10.0±0.6) protein

group, not change placebo (from 7.8±0.6 to 7.9 ±0.6)

Tieland M et al. J Am Med Dir Assoc 2012;13(8):720-6

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„physical activity: any bodily movement produced by

the skeletal muscles resulting in a substantial increase

in energy expenditure over resting levels“.

� individualized, maybe a program

Therapeutic Physical Activity in cancer cachexia

„Prescribe“: 3-4 x week both muscles & walk- Muscle: 2 x 10 Repetitions of arms & legs- Walk 10-15 Minutes Borg 4 (0-10): mild sweating

Evidence in advanced cancer patients*: some to many

patients do profit, mixed populations contaminate effects

* Stene GB et al. Crit Rev Oncol Hematol. 2013 Aug 8

Effect on muscle strength in cancer

Both aerobic & resistance training are importantThe less inflammation, cachexia – the better it works

combined aerobic

and resistance

aerobic exercise resistance exercise

Effect of physical activity on muscle strenght in incurable cancer patients

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Misconceptions of physical activity in patients having cancer cachexia

● „Resting and sleeping will help muscles to recover“

● „Physical activity will absorbe too much energy“

● Standard Rehabilitation programs are for all patients

● Walking is sufficient for muscle training

● ...

�� Educate !


Cortico-steroids: effect only on appetite, only 1-2 weeks

placebo-ctrl RCTs: 4 mg Dexamethasone 2 wks or 16mg

methylprednisolone bid 7 days improve fatigue, anorexia1,2

SE: proximal myopathy, candidiasis, depression, anxiety

�C-Steroids are only drugs to relieve short term distress

1: Yennu S et al. J Clin Oncol 2013;31:3076; 2: Paulsen O et al., J Clin Oncol 2014;32:3221

3: Ruiz Garcia V et al. Cochrane Database Syst Rev 2013;3:CD004310

4: Dev R et al. Cancer 2007;110:1173; 5:

Current drugs used for cachectic patients

Progestins: effect appetite (NNT 4), weight (NNT 12)

but only fluid or fat mass, no better QoL, anti-anabolic effect 3,4

SE: Dyspnea, edema, impotence, thromboembolism, mortality

Procinetics: effect only on satiety, clinically important5

(Metoclopramide 4 x 10mg, Domperidon 4 x 10mg)

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CannabinoidsFull plant contains many cannabinoids & 9-d-THC (dronabinol)

Two negative big RCTs (vs placebo, vs megestat)

Recent RCT: Dronabinol improves taste & protein consumption

in dysgesuia pts1

Drugs with in-sufficient evidence to improve cachexia

1: Brisbois TD Ann Oncol 2011; 2: Ries A Palliat Med 2012; 3: Murphy RA Cancer 2011; 4: van der

Meij BS Eur J Clin Nutr 2012; 5: Maccio A Gynecol Oncol 2012; 6: Solheim TS Acta Oncol 2012

Fish oil or eicosapentanoic acidFish oil contains EPA (omega-3-fatty acids)

Insufficient evidence (3 systematic literature reviews)2

Recent (small) RCTs: may improve muscle mass NSCLC3,4

NSARInsufficient evidence from small trials or only in combinations5


● Melanocortin Receptor 4-antagonists

● Ghrelin & its analogues (natural Ghrelin, Anamorelin, etc.)

� Anamorelin two finished global phase III trials (Romana)

● Androgen (SARMs, ...), β2-mimetics,...� Enobosarm two finished phase III trials (Power) 1

Increase muscle mass, associated with stair climb power, fat ↓

● Muscle pathways (anti-myostatin, Act-RIIB,.)

● Anti-inflammatory (anti-IL-12, anti-IL-6,

anti-TNF, Lenalidomide, Thalidomide, EPA)

● many other promises

Anti-cachexia emerging drugs

1: Dobs AS et al. Lancet Oncol 2013;14:335;

Phase III: Crawford J et al oral presentation MASCC 2014;0546;

2: Hong DS Phase I Lancet Oncol 2014

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Stores:Muscle increase

Fat increase

Muscle strenght:Handgrip no change

Legs & physical activity not measured

Symptoms:Cachexia-related

Symptoms improved

(FAACT)

Fatigue (FACIT)

improved

Anamorelin

Anticancer treatment toxicity not measured


Multimodal Intervention: pre-MENAC randomized Phase II 12 weeks

Exercise Physiotherapist – initial instruction and assessmentAerobic – >= 2 x 30 minute sessions per week (Borg scale 12-14)Resistance – tailored 0.5-5kg weights. 3x20 minute sessions / week

NutritionNutritionist – instruction & assessment, dietary advice & ONS

Anti-inflammatory MedicationNSAID (celecoxib 200mg BID), EPA 2g/day (ONS)

Patientsadvanced lung or pancreatic cancer start palliative chemotherapy

Primary outcome: feasibility (compliance, enrolment).Secondary outcomes: weight, physical activity (using ActivPAL)

CT based muscle mass.

PreMENAC - Kaasa S et al. ASCO 2015 Poster

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Compliance with the multimodal intervention: adequate

Week 0-6 <50% compliance 50-80% compliance >80% compliance

n % n % n %

Celecoxib 6 24 2 8 17 68

ONS 13 52 2 8 10 40

Exercise

-Strength 10 40 3 12 12 48

-Aerobic 10 40 3 12 12 48

PreMENAC - Kaasa S et al. ASCO 2015 Poster

Multimodal Intervention: pre-MENAC

Encouraging weight increase

in the treatment arm

� Phase III started 6.2015


Conclusion

Nutritional issues in older patients having cancer include often

co-occuring malnutrition, age-related sarcopenia and th

ecancer anorexia-cachexia syndrome

Screening shall focus on physical fatigue, BMI, weight loss,

decreased appetite and intake: not the tool, the do matters

A rational therapeutic strategy for the older patient with

nutritional issues is based on the and the defined phase of

cancer cachexia andcause its target domains

Care for these multidimensional problems are mechanism-based interventions focused on patients‘ quality of life,

including both rehabilitation and alleviating suffering.

A close interplay of oncology and all providers of key interventions palliative care is required to achieve goals.

New drugs are needed, promising in pipeline

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[email protected]

Thank you

MANY SESSIONS ON CANCER CACHEXIA

www.cachexia.org

recognizing anorexia cachexia early how to intervene · 19.11.2015 5 siog 13. nov 2015 anorexia...

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