Treatments for the Anorexia-Cachexia Syndrome: Pharmacological and Non-Pharmacological

Dr Martin Chasen MBChB FCP(SA) MPhil (Pall Med)

Medical Director, Palliative Care William Osler Health System Disclosure slide

Nothing to Disclose Nothing to Disclose Dr Martin Chasen MBChB FCP(SA) MPhil (Pall Med) Associate Professor, Palliative Care, University of Ottawa Medical Director, Palliative Care, Ottawa Cancer Centre Anorexia and Cancer Cachexia

• Anorexia is the loss of appetite or the desire to eat.

• Cancer Cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutrition support and leads to progressive functional impairment. Weight loss is evident.

• Losses associated with cancer cachexia are in excess of that explained by anorexia alone; however anorexia can hasten the course of cachexia.

Fearon K, Strasser F, Anker SD, et al. Lancet Oncol 2011; 12:489–495

Stages of Cancer Cachexia

Assessment of Cachexia according to :

• Anorexia or reduced food intake • Catabolic drivers • Functional and psychosocial effects • Muscle mass and strength

Fearon K, Strasser F, Anker SD, et al. Lancet Oncol 2011; 12:489–495 Impact of anorexia - cachexia

Anorexia-cachexia contributes directly to morbidity, mortality and impaired quality of life

-Reduced functional capacity -Increased side effects of treatment -Decreased treatment options -Dependency on family members and healthcare institutions -Increased healthcare costs -Cachexia kills Pharmacological Treatments Pharmacological agents

• Synthetic progestogens – Contraindicated in thromboembolic disease – Expensive – Megesterol acetate (Megace) • Increases appetite and weight • Increases fat/water, but not muscle mass • Start at 160 mg daily, may need to increase to tid – Medroxyprogesterone acetate (MPA) • Increase in appetite but effect on weight not yet confirmed • 200mg daily

Cancer Care Ontario – Symptom Management Guide to Practice, March 2012 Pharmacological agents

• Corticosteroids – Temporary improvement of appetite (2 – 4 weeks) – Initial dose: dexamethasone 4mg daily OR prednisolone 30mg daily in the morning. – Prescribe for 1 week, if no benefit, stop. – If helpful, increase or decrease to most effective dose; review regularly and withdraw if no longer improving symptoms – Side effects: fluid retention, hyperglycemia, trush, insomnia, catabolic effect on muscles, gastric irritation – Assess need for a proton pump inhibitor Cancer Care Ontario – Symptom Management Guide to Practice, March 2012 Selective androgen receptor modulators (SARM)

• Enobosarm (GTx-024; GTx, Memphis, TN, USA) is a selective androgen receptor modulator that induces conformational changes in the androgen receptor upon binding, and changes the receptor’s ability to regulate gene expression.

• Improvements in lean body mass and physical function were shown in a phase 2, double-blind, placebo controlled study of Enobosarm in healthy postmenopausal women and elderly men.

GTx Presents Results from Enobosarm POWER Trials 15th World Conference on Lung Cancer. 2 June 2014. Indication: Prevention and treatment of muscle loss in patients with NSCLC

• • Stage III/IV NSCLC patients initiating 1st line chemotherapy • • Co-primary endpoints (responders analysis): • (1) no loss of lean body mass (LBM) by DEXA; • (2) at least 10% improvement in Stair Climb Power (SCP) • • Each endpoint α=0.05, power >93% • • Assumes 30% drop out rate by 3 months

Co-primary endpoints Secondary endpoints •Lean body mass • Durability of effect •Physical function SCP @ 5 months @ 3 months • Overall survival Enobosarm 3 mg 150 patients Other endpoints platinum + taxane •QoL – FAACT, FACIT Placebo 150 patients fatigue scales •Healthcare resource utilization Enobosarm 150 patients •Adherence to chemo 3 mg plans •Tolerance to chemo platinum + non taxane Placebo 150 patients

GTx Presents Results from Enobosarm POWER Trials 15th World Conference on Lung Cancer. 2 June 2014. • Phase 3 G300504-Platinum+taxane is a positive study using continuous variable analysis – Declines in both lean body mass and stair climb power were observed in placebo group – Statistical and clinically meaningful differences between GTx-024 and placebo were observed for both lean body mass (muscle) and stair climb test (physical function)

• Phase 3 G300505-Platinum+nontaxane is a supportive study using continuous variable analysis – Declines in lean body mass and stair climb power were observed in placebo group – Statistically and clinically meaningful differences between GTx-024 and placebo were observed for lean body mass (muscle) – Different populations and chemotherapy side effects (anemia & vomiting) appear to explain physical function responses

• GTx-024 was very well tolerated in both trials – Minor differences in AEs between enobosarm and placebo add on groups were observed MT-102: ACT-ONE trial

Multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design

• MT-102, a novel anabolic/catabolic transforming agent, has a multi-functional effect upon three potential pharmacological targets in cancer cachexia: – reduced catabolism through non-selective β-blockade, – reduced fatigue, and thermogenesis through central 5-HT1a antagonism and – increased anabolism through partial β-2 receptor agonism.

Andrew J. Stewart Coats et al. – The ACT-ONE trial J Cachexia Sarcopenia Muscle (2011) 2:201–207 MT-102: ACT-ONE trial

Primary Study objective: • To investigate, compared to placebo, the effect of a 10 mg/BD dose of MT-102 in comparison to placebo on the rate of change of body weight over a 16-week period in patients with cachexia related to underlying stages III and IV colorectal or non-small cell lung cancer.

Secondary objectives: • The slope of weight change; the short physical performance battery test(SPPB); the six-minute walk test (SMWT); hand grip strength (HGS); measures of quality of life (QOL); change of body composition (DEXA)

Randomisation • 132 patients were randomised in a 3:1:2 ratio as follows: – 66 patients randomised received high-dose MT-102 (i.e. 10 mg/BD), – 22 patients randomised received low-dose MT-102 (i.e. 2.5 mg/BD), and – 44 patients randomised received placebo.

Results: – Only high dose of 10 mg twice daily improves lean and fat mass after 16 weeks – Only handgrip strength significantly increased after 16 weeks in the low-dose and high-dose treatment groups, but stair climbing power and 6-min walking distance were left unaffected.

Coats AJS. Novel beta blockers. Abstracts, 7th Cachexia Conference. Kobe 2013, p.51.

Anamorelin

Therapeutic potential of Anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study.

Methods: • Randomly assigned anamorelin 50 mg/day or placebo for 3 days. • 3- to 7-day washout period then treatments were switched. • Assessments included bodyweight, appetite, food intake, growth hormone (GH) levels, patient reported symptom assessments (ex. Anderson Symptom Assessment Scale).

Results • Increased body weight compared with placebo (0.77 kg vs. −0.33 kg). • Food intake increased compared with placebo. • GH significantly increased at all time points (0.5–4 h post dose). • Insulin-like growth factor-1 (IGF-1) significantly increased • Significant changes in insulin-like growth factor-binding protein 3 (IGFBP-3) • Patient reported symptoms, including appetite as measured by ASAS, significantly improved

Conclusions: Anamorelin showed significant metabolic, clinical, and patient-rated effects in cancer cachexia.

Garcia JM et al. Support Care Cancer (2013) 21:129-137 Phase II study of Anamorelin in patients with non-small cell lung cancer Temel J et al. Bondarde S, Jain M, Yun Y, Duus E, Allen S, et al. Phase II study of anamorelin HC21, in NSCLC patients. J Cachexia Sarcopenia Muscle. 2013;4:334

• Randomised, double-blind, placebo-controlled international study • 226 patients enrolled • 3 groups of 50 mg anamorelin, 100 mg anamorelin and placebo.

• As early as 1 week after treatment initiation, beneficial effects on weight were observed in anamorelin-treated groups. Over 12 weeks of treatment with anamorelin, in both treatment groups (50 and 100 mg anamorelin), significant increases in body weight were observed compared to placebo. • Then • Phase III study with anamorelin at a dose of 100 mg once daily compared to placebo • 477 patients with NSCLC over 12 weeks of treatment • Abernethy A, Temel J, Currow D, Gleich L, Friend J. • Phase III clinical trial ROMANA 2 (HT-ANAM-302) J Cachexia Sarcopenia Muscle. 2013 • Patients assigned to anamorelin had a significant increase in lean body mass in both ROMANA 1 (1.10 vs. -0.44 kg; p < 0.001) and ROMANA 2 (0.75 vs. -0.96 kg; p < 0.001), but no difference in handgrip strength was found in either of the study arms.

• Treatment with anamorelin compared with placebo also resulted in: – Significant improvements in body weight for patients in ROMANA 1 (2.20 vs. 0.14 kg; p < 0.001) and ROMANA 2 (0.95 vs. -0.57 kg; p < 0.001), and – Improvements were seen in anorexia/cachexia symptoms, for which higher scores represent a lower symptom burden (ROMANA 1 fatigue scale, 0.26 vs. -1.91; p = 0.05; ROMANA 2 anorexia/cachexia scale, 3.48 vs. 1.34; p = 0.002).

Overall, treatment with anamorelin was well tolerated, and the rate of grade 3/4 adverse events was low, with no significant difference between the study arms.

ASCO 2015 http://bcove.me/r8m3k7dk ESMO 2016

• Dr Junji Uchino from Fukuoka University School of Medicine, Japan, l reported the findings of a phase II double-blind study of, ONO- 7643/anamorelin, for the treatment of cachexia in Japanese patients with non-small-cell lung cancer (NSCLC; Abstract 1434O

• In this confirmatory study of 173 patients with advanced NSCLC (63% stage IV) randomised to 100 mg anamorelin or placebo orally once daily for 12 weeks, anamorelin significantly increased LBM versus placebo (p<0.0001). Significant improvements in body weight (p<0.0001) and anorexia symptoms (p<0.05) were also noted with anamorelin versus placebo, and the treatment was well tolerated over the 12-week study period. Delta-9-Tetrahydrocannabinol

Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial

• THC increases appetite via endocannabinoid receptors (CB1r); • Appetite stimulation is documented in healthy human and acquired immunodeficiency syndrome (AIDS) populations. • THC may increase food intake by stimulating the orosensory reward pathway, increasing motivation to eat energy dense foods and enhancing food enjoyment. • CB1r are located in reward-related areas of the brain and in the olfactory epithelium and bulb and are involved in peripheral odor processing and potentially taste function .

Brisbois TD, Chasen M, MacDonald N, et al. Ann Oncol (2011) 22(9):2086-93 Delta-9-Tetrahydrocannabinol

Results:

• THC and placebo groups were comparable at baseline. • Compared with placebo, THC-treated patients reported : – Improved (P = 0.026) and enhanced (P < 0.001) chemosensory perception – Food ‘tasted better’ (P = 0.04) • Premeal appetite (P = 0.05) and proportion of calories consumed as protein increased compared with placebo (P = 0.008). • THC-treated patients reported increased quality of sleep (P = 0.025) and relaxation (P = 0.045). • QOL scores and total caloric intake were improved in both THC and placebo groups.

Conclusions:

THC may be useful in the palliation of chemosensory alterations and to improve food enjoyment for cancer patients.

Brisbois TD, Chasen M, MacDonald N, et al. Ann Oncol (2011) 22(9):2086-93 Novel Peptide- Nucleic Acid OHR118 [Data presented at the 7th International Cachexia Conference –Dec.2013 in Kobe, Japan]

Phase II Study of the Novel Peptide- Nucleic Acid OHR118 in the Management of Cancer-Related Anorexia/Cachexia

• OHR Pharmaceutical Inc (New York, NY, USA) have developed the broad-spectrum peptide nucleic acid immune modulator drug • OHR/AVR118 (NCT01206335), targets both TNF-α and IL-6 and maintains immune homeostasis.

In a Phase II study, in advanced cancer patients with cachexia eighteen patients completed the treatment protocol. – At completion of treatment, patients achieved stabilization of body weight, body fat and muscle mass with a significant increase in appetite. – Patients experienced enhanced quality of life as indicated by the Patient Generated Subjective Global Assessment

Chasen M, Hirschman SZ, Bhargava R J Am Med Dir Assoc. 2011;12:62–7. AND J Cachexia Sarcopenia Muscle. 2013;4:335 NSAID

• Aspirin and ibuprofen are non-selective blockers of the cyclooxygenase pathway, they inhibit production of prostaglandins that cause inflammation and pain.

• Aspirin may be an important chemopreventive drug, with two trials suggesting that low dose aspirin reduces incidence of cancer, death from cancer and cancer metastasis.

Lundholm in 2004 reported retrospective case control study results in patients treated with indomethacin matched with controls without NSAID treatment.

• Indomethacin treated patients had higher body weight, higher food intake, lower CRP and resting energy expenditure (REE). • The lean body mass being the same in both groups, with no differences in survival.

In a review by Solheim, Fearon et al. (2013) it was suggested that the evidence is ‘too frail’ to recommend NSAID for cachexia outside clinical trials, despite there being some evidence on physical performance, self-reported quality of life and inflammatory parameters .

Lundholm K et al. - Int J Oncol 2004 ; 24 : 505 – 12 Solheim TS et al.- Acta Oncologica, 2013; 52: 6–17 Non Pharmacological Exercise in Cachexia

• Exercise has an anti-inflammatory effect with levels of CRP being inversely proportional to the level of physical activity, it decreases protein catabolism and increases protein synthesis .

• The PROTAGE study group has highlighted the role of protein supplementation to restore muscle mass, they suggest 1 to 1.5 g/kg of high quality protein (leucine-enriched, balanced essential amino acids) to patients with sarcopenia . Bauer J, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE, et al. Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. J Am Med Dir Assoc. 2013;14:542–59.

• Another randomized, double-blind, placebo-controlled trial that supports the use of protein supplementation to increase muscle synthesis concludes that this can best be achieved in conjunction with exercise . Tieland M, van de Rest O, et al. Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc. 2012;13:720–6

• 16 randomized controlled trials showed that in early stage cancer, exercise can reduce CRP and improve outcomes. Psychosocial Interventions

Effective psychosocial interventions to alleviate the negative impact of cancer cachexia, include:

• Providing information about cachexia will alleviate anxiety and break the cycle of conflict • Aiding conscious control can facilitate adaptation • Enhancing personal coping resources will aid self-management and alleviate cachexia- related suffering • The weight loss taboo is an obstacle to the communication necessary to address cachexia- related problems, such as nutritional impact symptoms .

These interventions have all been theorised to reduce the negative emotional consequences of cancer cachexia.

• If multimodal interventions are to be offered in early stages of cachexia before disease is refractory to treatment, then they should perhaps become part of treatment regimes and psychosocial support integrated with supportive care in oncology clinics.

Hopkins JB. J Cachexia Sarcopenia Muscle. 2014 The Effect of Ginger (Zingiber Officinal Roscoe) in patients with the Cancer Anorexia Cachexia Syndrome

Martin Chasen, Ravi Bhargava Palliative Care, Bruyere Research Institute, Ottawa, Canada ElectroGastrography (EGG) EGG measures the gastric myoelectrical activity (GMA) using electrodes placed on abdominal wall.

Objective:

(i) To determine the EGG patterns of patients with advanced cancer.

(ii) To determine the most frequent gastrointestinal symptoms reported on the Dyspepsia Symptom Severity Index (DSSI).

(iii) To determine and analyze the EGG diagnosis and correlations with gastrointestinal symptoms, ghrelin, and inflammatory markers. Gastric Pacesetter and EGG Waves

3 EGG Procedure Visipace Electrogastrogram Analyzer

1. Baseline (10 min) 2. Water load 3. Test (30 min)

3 EGG Waves

EGG Normal (2.5 – 3.75 cpm) Respiration

• Baseline

Baseline Bradygastria (1 – 2.5 cpm) • After water load After water load

Baseline Tachygastria (3.75 – 10 cpm)

After water load

3 EGG Summary Report

3 EGG (Electrogastrography)

Male Female (n=48) (n=14) Distribution of Histological Diagnosis (n=62)

Others (Hemat. and Hepatobiliary HNC Genitourin.) 25% 3%

CNS 6%

Colorectal 10%

Lung (NSCLC) 19% Breast 11%

Gastro Esophageal EGG Diagnosis (n=62)

30

25 27

20 19 15

10 9 5 6 1 0 Normal Bradygastria Tachygastria Mixed Gastric outlet dysrythmia obstruction Dyspepsia symptom severity index (DSSI) (N=62) Group of Symptoms Symptom Mean SD Range Frequency Group I: Dysmotility - like Frequent burping or belching 45 (63.4%) 1.19 0.99 0-4 Bloating 36 (50.7%) 1.05 1.09 0-4 Full feeling after meals 46 (64.8%) 1.32 1.14 0-4 Inability to finish normal sized meals 41 (57.7%) 1.32 1.29 0-4 Stomach discomfort without pain after meals 28 (39.4%) 0.73 0.96 0-4 Stomach distension 31 (43.7%) 0.77 0.95 0-4 Nausea before meals 24 (33.8%) 0.61 0.91 0-4 Nausea after meals 29 (40.8%) 0.69 0.90 0-4 Nausea in the morning 18 (25.4%) 0.35 0.68 0-4 Retching 7 (9.9%) 0.19 0.65 0-4 Vomiting 4 (5.6%) 0.10 0.39 0-2 Group II: Reflux - like Burping with bitter fluid in throat 23 (32.4%) 0.48 0.72 0-3 Reflux during the day 25 (35.2%) 0.53 0.72 0-2 Reflux at night 20 (28.2%) 0.47 0.78 0-3 heartburn 24 (33.8%) 0.50 0.72 0-3 burning feeling in your stomach 23 (32.4%) 0.48 0.72 0-3 Group III: Ulcer-like Stomach ache or pain right after meals 18 (25.4%) 0.44 0.80 0-3 Stomach pain before meals or when hungry 25 (35.2%) 0.50 0.70 0-2 Stomach pain at night 20 (28.2%) 0.50 0.88 0-4 DSSI and EGG diagnosis

Lower CI Mean UpperCI EGG diagnosis Tukey Adjustment p-value

Total Bradygastria 1.71 2.56 3.40 Bradygastria-Normal 0.01 Mixed 1.18 1.67 2.15 Normal -0.70 0.33 1.37 Tachygastria 1.16 1.74 2.32

DSSI1 Bradygastria 8.70 12.33 15.96 Bradygastria-Normal 0.01 Mixed 6.01 8.11 10.21 Normal -2.11 2.33 6.78 Tachygastria 5.92 8.42 10.92

DSSI-1Frequent burping or belching Bradygastria 1.38 2.00 2.62 Bradygastria-Normal 0.01 Mixed 0.79 1.15 1.51 Normal -0.43 0.33 1.09 Tachygastria 0.73 1.16 1.58 EGG diagnosis and Inflammatory markers – Median (Range)

EGG CRP mg/L Albumin g/L Diagnosis [Range <10mg/L] [Range 38-50g/L]

Normal (n=6) 6 38.5 (5-8) (34 - 42)

Bradygastria (n=9) 13.4 35 (10-31.7) (30-40)

Tachygastria (n=19) 17 36 (9-30) (26-40)

Mixed Dysrythmia (n=27) 8 39 (6-22) (28-42)

Gastric outlet obstruction (n=1) 1 49 (1) (49)

PGSGA (subsections) comparison with Normal and Abnormal EGG rhythm

EGG Normal EGG Abnormal EGG (n=6) (n=56) P-Value Diagnosis Median [Range] Median [Range] Box 1 0 [ 0-1 ] 0 [0-1 ] 0.98 Weight Box 2 1 [ 0-3 ] 1 [ 0-5 ] 0.09 Food Intake Box 3 4.5 [ 0-7 ] 4 [ 0-18 ] 0.57 Symptoms Box 4 Activities and 1 [ 0-2 ] 2 [ 0-3 ] 0.02 Function

Total PGSGA 9.5 [ 1-13 ] 9 [ 0-29 ] 0.79 Electrogastrography (EGG) Conclusion

❖ Abnormal EGG diagnosis, Albumin and CRP levels are found in the majority of patients with advanced cancer.

❖ Total sum of all the DSSI variables and dysmotility like symptoms specifically the frequent burping and belching allows us to distinguish between normal EGG and Bradygastria.

❖ Further studies are needed to better understand the correlation of these abnormal serum levels and their interaction with the pathogenesis of abnormal electrogastrographic rhythms. Ginger (Zingiber officinale Roscoe)

• Ginger is a plant and phytomedicine native to Southeast Asia.

• Clinical trials have reported that ginger and its active constituents can :

-Enhance gastrointestinal motility and accelerate gastric emptying in healthy volunteers and in patients with functional dyspepsia 6-8

-Can reduce nausea and affect gastrointestinal motility in patients with cancer receiving chemotherapy 9-11

However, clinical trial with Ginger in patients with advanced cancer having ACS and not on chemotherapy has not been reported. Mechanism of Action

• The aromatic, spasmolytic and carminative properties of ginger suggest it has direct effects on the gastrointestinal tract

• The antiemetic action of ginger is attributed to the Shogaol and Gingerol

Constituents in ginger :

• Serotonin (5-HT) antagonist, • Reduce tachygastric activity • Weakly cholinergic.

They are believed to :

• Stimulate the flow of saliva, bile, and gastric secretions • Improve the intestinal muscle tone and peristalsis Nutrition Rikkunshito – Traditional Japanese Medicine

• Increases plasma ghrelin levels • Improves muscle weight • Enhance ghrelin secretion via 5-HT2BR antagonism

Rikkunshinto consists of: 1. Glycyrrhizae radix 2. Zingiberis 3. Rhizoma 4. Atractylodis 5. Lanceae rhizoma 6. Zizyphi fructus 7. Aurantii nobilis pericarpium 8. Ginseng radix To determine the effectObjective of oral Ginger administration on gastric myoelectical activity (GMA) in patients with the anorexia-cachexia syndrome (ACS).

Therapeutic Program

• Thirty patients diagnosed with cancer will be enrolled. • EGG on day 1 and day 14. • Subjects will take the oral daily dose of Ginger capsule (1650 mg), once daily, for fourteen days. • Blood samples and three questionnaires will be collected at day 1 and day 14, pre and post oral ingestion of Ginger (Zingiber officinale).

Outcome Measures

Patients asked to complete two (3) questionnaires:

• The Dyspepsia Symptom Severity Index– clinical tool for screening and evaluating the severity of upper gastro-intestinal symptoms 2 • The Patient generated subjective Global assessment form – nutrition assessment tool for quick identification of malnutrition and GI symptoms 3 • Edmonton Symptom Assessment Scale – is a patient-rated symptom visual analogue scale to assess the symptoms of patients 4. • Blood Tests- CRP, Albumin and Ghrelin DSSI Demographics (n=9)

Male (n=3) Female (n=6) Patient EGG Diagnosis Clinical Symptoms EGG Diagnosis Clinical Symptoms

Number Visit # 1 Visit # 1 Visit # 2 Visit # 2

P1 Tachygastria Bloating, Early satiety, Post-prandial Mixed Dysrythmia Early satiety fullness, Delayed Gastric Emptying

P2 Mixed Dysrythmia Bloating, GERD, Early satiety, Post-prandial Mixed Dysrythmia Bloating, Early satiety fullness

P3 Bradygastria Nausea, Bloating, GERD, Early satiety, Post- Mixed Dysrythmia Early staiety prandial fullness, Delayed Gastric Emptying

P4 Bradygastria Bloating, GERD, Early satiety, Post-prandial Mixed Dysrythmia Early satiety, Post-prandial fullness fullness

P5 Bradygastria Nausea, Bloating, GERD, Early satiety, Post- Mixed Dysrythmia Bloating prandial fullness, Delayed Gastric Emptying

P6 Tachygastria Nausea, Vomiting, GERD, Early satiety, Post- Mixed Dysrythmia Nausea, GERD prandial fullness

P7 Tachygastria Bloating, GERD, Early satiety, Post-prandial Mixed Dysrythmia Bloating, Post-prandial fullness, Delayed Gastric Emptying fullness

P8 Tachygastria Nausea, Bloating, Early satiety Normal Bloating P9 Mixed Dysrythmia Bloating, Early satiety, Post-prandial Mixed Dysrythmia Bloating fullness, Delayed Gastric Emptying 20 18 16 p= 0.001 14 12 10 T1 8 6 p= 0.002 T2 4 p= 0.038 2 0 Dysmotility Refluxlike Ulcerlike Symptoms Symptoms Symptoms PGSGA 12.4 12.2 12 p= 0.697 11.8 11.6 11.4 11.2 11 10.8 10.6 T1 T2 6 5 4 3 T… 2 T… 1 0 CRP 6 5 4 3 2 1 0 T1 T2 Albumin 43 42 41 p= 0.003 40 39 38 37 T1 T2 Conclusion

• Ginger may normalize gastric motility as measured by EGG.

• Ginger may improve a range of GI symptoms that can affect oral intake and quality of life. 1. Martin Chasen, Ravi Bhargava. GastrointestinalReferences symptoms, Electro-Gastrography, Inflammatory markers and PG-SGA in patients with Advanced Cancer. Supportive Care in Cancer, 2011, DOI: 10.1007/s00520-011-1215-8 2. Leidy NK, Farup C, Rentz AM, Ganoczy D, Koch KL (2000) Patient-based assessment in dyspepsia: development and validation of Dyspepsia Symptom Severity Index (DSSI). Dig Dis Sci 45:1172– 1179 3. Ottery FD (2000) Patient-generated subjective global assessment. In: McCallum PD, Polisena CG (eds) The clinical guide to oncology nutrition. The American Dietetic Association, Chicago, pp 11–23 4. Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton symptom assessment system (ESAS): a simple method for the assessment of palliative care patients. J. Palliat Care 1991; 7(2):6- 9. 5. Koch KL: Electrogastrography. In: Schuster M, Crowel M. Koch KL, eds. Atlas of Gastrointestinal Motility. Hamilton, Ontario, Canada: BC Decker:2002: 185-201 6. Yamahara J, et al. Gastrointestinal motility enhancing effect of ginger and its active constituents. Chem Pharm Bull (Tokyo) 1990; 38: 430-431 7. Micklefield GH et al. Effects of ginger on gastroduodenal motility. Int J Clin Pharmacol Ther 1999; 37: 341-346 8. Lumb AB. Mechanism of antiemetic effect of ginger. Anaesthesia 1993;48:1118. 9. Levine ME, Gillis MG, Koch SY, Voss AC, Stern RM, Koch KL. Protein and ginger for treatmentof chemotherapy-induced delayed nausea.J Altern Complement Med. 2008;14(5):545-51. 10. Panahi Y et al. Effect of ginger on acute and delayed chemotherapy-induced nausea and vomiting: a pilot, randomized, open-label clinical trial. Integr Cancer Ther. 2012 Sep;11(3):204-11. 11. J. L. Ryan et al.. Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients. Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 27, No 15S, 2009: 9511 12. Fearon, Kenneth, et al. "Definition and classification of cancer cachexia: an international consensus." The lancet oncology 12.5 (2011): 489-495

GTx Presents Results from Enobosarm POWER Trials for the Prevention and Treatment of Muscle Wasting in Patients with Non-Small Cell Lung Cancer • POWER1 (platinum plus taxane) and • POWER2 (platinum plus non-taxane) trials, which were chemotherapy add-on placebo controlled studies

-Results from the POWER trials: Enobosarm 3 mg once daily had a significant effect on LBM through Day 84 and 147 in both trials, compared to placebo

-large proportion of patients receiving enobosarm maintained or increased LBM at Day 84 and 147 in both trials, as compared to placebo.

-Additionally, enobosarm treated patients in POWER1 achieved the primary endpoint in SCP through Day 84 (p= 0.0185) and the secondary endpoint of SCP through Day 147 (p=0.0486).

Source Citation: (MLA 7th Edition) "GTx Presents Results from Enobosarm POWER Trials for the Prevention and Treatment of Muscle Wasting in Patients with Non-Small Cell Lung Cancer at 15th World Conference on Lung Cancer." Clinical Trials Week 4 Nov. 2013: 85. Academic OneFile. Web. 2 June 2014. ASCO 2015 http://bcove.me/r8m3k7dk Thalidomide

• Has complex immunomodulatory and anti-inflammatory properties.

• Downregulates the production of TNF-α and other proinflammatory cytokines, inhibits transcription factor nuclear factor (NF-kB), downregulates COX-2, and inhibits angiogenesis.

• Meta-analysis was performed to assess whether thalidomide is an effective treatment for CACS and the authors concluded that there is inadequate evidence to recommend the use of this drug in clinical practice.

• Clinical trials are presently underway assessing the efficacy of lenalidomide (derivative of thalidomide).

Reid J et al. Cochrane Database Syst Rev. 2012;4:CD008664