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19.11.2015
1
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, ...)
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
19.11.2015
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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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?
19.11.2015
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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
Slid
e c
ourt
esy
ofV
ickie
Bara
cos
9.2
014
Co-Occurrence in cancer patients
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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
19.11.2015
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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
19.11.2015
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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
“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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
19.11.2015
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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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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%)
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
„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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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 !
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
● 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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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
SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
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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SIOG 13. Nov 2015 Anorexia Cachexia / F. Strasser
Thank you
MANY SESSIONS ON CANCER CACHEXIA
www.cachexia.org