ESPEN Congress Geneva 2014LLL LIVE COURSE: NUTRITIONAL SUPPORT IN CANCER

Drug therapy for cancer cachexiaJ. Arends (DE)

ESPEN LLL CourseNutritional Support in Cancer Patients

Jann Arends

PHARMACOLOGIC THERAPY

Dept. Medical OncologyTumor Biology Center at Freiburg University

arends@tumorbio.uni-freiburg.de

Module 26.4

Targets forpharmacologic therapy

anorexiaGI dysfunctioncatabolismsystemic inflammation

Pharmacologic Topics

Appetite stimulationGI modulation

Anticatabolic/anabolic agents

Anti-inflammatory agents

CorticosteroidsProgestinsCannabinoidsGhrelinCyproheptadineBranched-chain amino acidsHerbal medicine, bitters

Appetite stimulation

effectivity typical dose

Hydrocortisone 1Prednisolone, methylprednisolone 5 20 mgDexamethasone 20 4 mg

Systematic review: 6 RCT (n=647; duration 4d to 8w):Stimulation of appetite, anti-emetic, increase well-beingEffects disappear after 4 weeks !

Side-effects: myopathyosteoporosis

immune suppressionedema

insulin resistanceGI ulcers

Corticosteroids

Yavuszen T et al. J Clin Oncol 2005LoE=I

typical dose

Megestrolacetate (MA) 160-1600 mgMedroxyprogesterone acetate (MPA) 300-1200 mg

Stimulation of appetite Increase in body weight, but no increase in LBMImprove QoL

Side-effects: thromboembolism (5%)impotence in malesvaginal spotting or bleedinghypertension, hyperglycemiaedemaadrenal insufficiency

Progestins

progestins worse progestins better

Progestins: Effect on weight in patientswith cancer cachexia (11 RCT)

Maltoni et al. Ann Oncol 2001

compared to placebo

Cochrane metaanalysis 2005

31 RCT (n=4123) MA vs PLAC: app +, WT +

Metaanalysis 200830 RCT (n=4430) MA vs PLAC app +, WT +

survival ∅, QoL ∅

Berenstein EG et al. Cochrane Database Syst Rev 2005Lesniak W et al. Pol Arch Med Wewn 2008LoE=I

Not approved for cancer anorexia

Progestins

Marijuana stimulates appetite

- Marijuana extracts- Delta-9-tetrahydrocannabinol = THC / Dronabinol

Stimulation of appetite with 5-20 mg Effects on mood, nausea, pain

Use regulated by narcotics law

Side-effects: dizzinessslurred speech

Cannabinoids

Appetite improved

Weight increased

Quality of life improved

C

M

D

Dronabinol (D) vs megestrolacetate (M) vs combination (C)in patients with cancer cachexia (4 wk)

Jatoi A et al. J Clin Oncol 2002

RCT (n=164 cancer cachexia) 6 weeks:

cannabis extract (5 mg THC)vs THC (5 mg)vs placebo: app ∅, QoL ∅

Strasser F et al. J Clin Oncol 2009

Cannabinoids

Unfortunately: no dose escalation allowed

Anamorelin, oral GH secretagogue receptor agonist2012: RCT 12 w: WT +, grip strength +2013: RCT 3 d: WT +

Ghrelin and Analogues

Lundholm K et al Cancer 2010Garcia J et al. Supp Care Cancer 2012 + 2013LoE=I experimental agent

Ghrelin, peptide hormone of gastric mucosa2004: RCT (n=7) 3 h: food intake +2008: RCT (n=21) 1 h: app ∅2010: RCT (n=15) 10 d: app +, food +, WT-loss -2010: RCT (n=31) 8 w: fat loss -

Neary NM et al. J Clin Endocrinol Metab 2004Holst B et al. Br J Cancer 2008

Adachi S et al. Gastroenterol 2010

Anamorelin

Garcia JM et al. Supp Care Cancer 2013

App +Food intake ØGH +IGF-1 +IGFBP3 +

hyperglycemia (2)nausea (1)dizziness (1)

Cyproheptadine5-HT2-antagonist: RCT adults: ∅

RCT children: WT +

Branched-chain amino acids (BCAA)RCT (n=28 pre-surgery) 7d: app +RCT (n=84 HCC) 1 year: QoL +

Herbal medicine, bittersno controlled studies

Other appetite stimulants

Kardinal CG et al. Cancer 1990Couluris M et al. J Pediatr Hematol Oncol 2008

Cangiano C et al. J Natl Cancer Inst 1996Poon RT et al. Aliment Pharmacol Ther 2004

AntiemeticsPsychotropic drugsAnalgesics

Prokinetic agentsInhibitors of GI motilityProton pump inhibitorsParasympathomimetics

GI modulationand supportive agents

CorticosteroidsProgestagensCannabinoidsNon-steroidal anti-inflammatory drugs (NSAID)N-3 fatty acidsAnti-cytokinesMelatoninAntioxidants

Anti-inflammatory agents

CorticosteroidsProgestagensCannabinoidsNon-steroidal anti-inflammatory drugs (NSAID)N-3 fatty acidsAnti-cytokinesMelatoninAntioxidants

Anti-inflammatory agents

Indomethacin, ibuprofen, celecoxib, etc.

Side-effects: GI ulcerskidney failureetc.

NSAID

PUFA ProstanoidsCOX‐1COX‐2

Lundholm K et al. Cancer Res 1994

NSAID

Systematic review: 13 studies (6 controlled studies)

studies are smallsuboptimal designmany studies without comparator

in 11/13: stabilization or improvement of WT or LBM

„NSAIDs may improve weight in cancer patients..“„Evidence is too frail to recommend..“

NSAID in cancer cachexia

Solheim T et al. Acta Oncol 2012Not approved for cancer anorexia

N-6PUFA

Prostanoids2 and 4 series

N-3PUFA

Prostanoids3 and 5 series

COX

pro-inflammatory

anti- / less inflammatory

Arachidonic acid

Eicosapentaenoic acid

Side effects: dyspepsia, nauseaprolonged bleeding time

Long chain fatty acids

Cochrane systematic reviewon 5 RCT: insufficient data

but: poor complianceonly short trials

Systematic review Colomer et al.on 17 clinical trials: >1.5 g/d app +, WT +, QoL +

but: not based on RCTs

LoE=II Dewey A et al. Cochrane Database Syst Rev 2007Colomer R et al. Br J Nutr 2007

N-3 Fatty acids

2010 RCT, double-blind; n=40 NSCLC stage III2 pack ONS ± (2 g EPA + 0.9 g DHA) for 5 w

WT+, FFM+, REE -, intake +

LoE=I van der Meij et al., J Nutr 2010Murphy et al., Cancer 2011

N-3 Fatty acids in NSCLC

2011 “free-choice-study”, n=40 NSCLC stage IIIstd (n=24) vs fish oil (n=16) = 2.2 g EPA

during ..1st-line CHT WT -2.3 vs +0.5, +muscle 29 vs 69%

1st year CHT RR 26 vs 60%, survival 39 vs 60%

Open label study / free choicen=46 NSCLC: N=31 „Standard-of-care“

N=15 fish oil: 2.5 g (EPA+DHA) per day as capsule or oilChemother: different regimensDuration: 1 year

Results Control Fish oil

Response rate = CR + PR 26% 60%

CR + PR + stable disease 42% 80%

Dose limiting toxicity no difference

1-Year survival 39% 60%

ONS with fish oil in NSCLC

Murphy et al., Cancer 2011

Anti-cytokinesInfliximab RCT (n=89) 8 w: ∅Etanercept RCT (n=63) 3 m: ∅Pentoxifylline RCT (n=70) 8 w: ∅Thalidomide RCT (n=37) 10 d: app +

CT (n=10) 2 w: WT +RCT (n=33) 4 w: WT +

Clarithromycin CT (n=66) 3 m: WT +

Melatonin RCT (n=86) 3 m: WT-loss -systematic review: survival +

Antioxidants no high-quality controlled studies

Other anti-inflamm. agents

Insulin and insulin sensitivity modulatorsGrowth hormone, secretagogues, IGF-1Anabolic androgenic steroids and SARMsProteasome inhibitorsß-receptor modulatorsß-hydroxy ß-methylbutyrate and amino acidsHydrazine sufateAdenosine triphosphate (ATP)

Anticatabolic agents

Central anabolic hormoneinhibits proteolysis, stimulates protein synthesis

RCT (n=338) 0.1 U/kg/d s.c. Fat +, survival +

Metformin: stimulates AMPK, improves insulin sensitivity

RCT (n=8 burn pats.) 7 d protein synthesis +hyperglycemia -

Insulin and sensitizers

Lundholm K et al. Clin Cancer Res 2007Gore DC et al. Ann Surg 2005LoE=I

Not approved for cancer anorexia

Growth hormone (GH)decrease fat, increase muscle mass, increase bone density, improve immune and sexual functions

Does GH stimulate tumor growth?GH in ICU patients increased mortality !

Insulin-like growth factor (IGF-1)Does IGF-1 stimulate tumor growth?

Growth Hormone, IGF-1

Ghrelin GH IGF‐1

Burney BO et al. JCEM 2012

Testosterone in cachexia

Nandrolone RCT (n=37) 4 w WT (+)Fluoxymesterone RCT (n=475) 4 w app +, WT (+)Oxandrolone RCT (n=155) 12 w WT ∅, LBM +

less effective than corticosteroids/progestinsdepression, thromboembolism, virilizing effects, hypertension etc.

Anabolic androgenicsteroids / SARMs

Chlebowski RT et al. Cancer 1986Loprinzi CL et al. J Clin Oncol 1999Dobs et al., Lancet Oncology 2013

Nandrolone RCT (n=37) 4 w WT (+)Fluoxymesterone RCT (n=475) 4 w app +, WT (+)Oxandrolone RCT (n=155) 12 w WT ∅, LBM +

less effective than corticosteroids/progestinsdepression, thromboembolism, virilizing effects, hypertension etc.

Anabolic androgenicsteroids / SARMs

Chlebowski RT et al. Cancer 1986Loprinzi CL et al. J Clin Oncol 1999Dobs et al., Lancet Oncology 2013

Selective androgen response modifiersEnobosarm Phase 2b trial (n=100; 3m) LBM+, muscle str.+

Ph3 trial in NSCLC NCT 01355484

Enobosarm: Change in LBM

Dobs et al., Lancet Oncology 2013

Enobosarm: Stair climb time and power

Dobs et al., Lancet Oncology 2013

Interleukin-6 antibody

BMS945429 in NSCLC symptoms-, fatigue-, LBM+

Selumetinib in CCC 84% gain muscle

Myostatin antibody

LY2495655 in Pa-Ca + GEM (Ph2)

BYM338 in Pa-Ca (Ph2)

MC4R - Melanocortin-4 receptor antagonists

Interleukin 15 agonists

New agents

Bayliss et al. Exp Opin Biol Ther 2011Prado et al., Br J Cancer 2012Dallmann R et al., JSCM 2011

Stofkova A 2012

● To improve appetite, relieve psychological distress and chronic pain

● Optimize gastrointestinal function and relieve nausea

● To stimulate appetite, corticosteroids and progestins are best established; both have unwanted side-effects that need to be considered

● Anti-cancer treatment may improve metabolism and decrease inflammation

● Anti-inflammatory agents, like NSAIDs and N-3 fatty acids may be used to counteract chronic inflammatory states in cancer patients

● Hunger-inducing peptides like ghrelin and MC4R antagonists, anabolic-androgenic agents and antibodies against myostatin and IL6 are being investigated as potential anticachectic agent

● All anticachectic agents should be accompanied by exercise training

Key Messages