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Disclaimer. This slide deck in its original and unaltered format is for educational purposes and is current as of July 2014. All materials contained herein reflect the views of the faculty, and not those of Educational Concepts Group, LLC or the commercial supporter(s).

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  1. Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of July 2014. All materials contained herein reflect the views of the faculty, and not those of Educational Concepts Group, LLC or the commercial supporter(s). Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

  2. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Educational Concepts Group, LLC. Additional terms and conditions may apply.

  3. FACULTYEgidioDel Fabbro, MD – CHAIRAssociate Professor Director, Palliative Care Program Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, VirginiaJeffrey Crawford, MDGeorge Barth Geller Professor for Research in CancerCo-Director, Solid Tumor Therapeutics ProgramDuke Cancer InstituteDurham, North CarolinaDorothy MK Keefe, PSM, MDService Director, SA Cancer Service Professor of Cancer Medicine, University of Adelaide Adelaide, AustraliaDavid Warr, MD, FRCPCAssociate Professor, Department of MedicineUniversity of TorontoHead, Breast Medical OncologyPrincess Margaret Cancer Centre Toronto, Canada

  4. Managing the Conundrum of Anorexia-Cachexia in Advanced NSCLC Jeffrey Crawford, MD Duke Cancer Institute

  5. 1. co•nun•drum • kəˈnəndrəm/ • noun • noun: conundrum; plural noun: conundrums • 1. a confusing and difficult problem or question. • "one of the most difficult conundrums for the experts" • synonyms: problem, difficult question, difficulty, quandary, dilemma Google.com

  6. International Consensus Definition of “Cancer Cachexia” “Multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without fat mass)that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.” Fearon K, et al. Lancet Oncol. 2011 May;12(5):489-95.

  7. Distribution of Pre-Diagnosis Weight Loss in Patients Presenting with NSCLC IIIB / IV Among a Population Cohort in Northern Alberta 15% weight stable Frequency Mean weight loss at presentation 6% 6 month weight loss history (%) BaracosVE, et al. Am J Clin Nutr. 2010;91(4):1133S-1137S.

  8. BMI Distribution of Patients Presenting with NSCLC IIIB / IV Population Cohort Northern Alberta, n=950 Frequency Body mass index (kg/m2) BMI < 18.5 kg/m2 Gallagher D and DeLegge M. JPEN J ParenterEnteralNutr. 2011 Sep;35(5 Suppl):21S-8S.

  9. BMI and Overall Survival in Advanced NSCLC Patients Dahlberg SE, et al. J ThoracOncol. 2013 Sep;8(9):1121-7.

  10. Computerized Tomography: An Opportunistic Method Subcutaneous adipose tissue Visceral adipose tissue Intermuscular adipose tissue Skeletal muscle BaracosV, et al. Int J Biochem Cell Bio. 2013;45(10):2302-2308.

  11. Muscle Wasting in Cancer: A Hidden Condition NORMAL SARCOPENIC Same BSA = 2.07 and BMI = 30.3 Prado CM, et al. Curr Opin Support Palliat Care. 2009 Dec;3(4):269-75.

  12. Prevalence of Low Muscle Mass in Patients with Solid Tumors of the Lung or Gastrointestinal Tract, N = 1476 Consecutive patients referred to a medical oncology service in a regional cancer center in Alberta, Canada. Unpublished data from VE Baracos.

  13. Sarcopenic Obesity: Prevalence of Physical Impairment 26% 47% P= 0.005 Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

  14. Survival and SarcopenicObesity • Functional status • Cancer type • Stage of disease • Age • Gender • History of weight loss Non-sarcopenic obese HR 2.3, P = 0.022 Sarcopenic obese p <0.0001 Sarcopenic patients: 11.3 months Non-sarcopenic obese: 21.6 months Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

  15. Sarcopenia(Severe Muscle Wasting) Predicts Key Health Outcomes And physical disability, infections, complications during hospitalization, length of hospital stay, etc.

  16. Muscle Wasting in Lung Cancer Patients • Muscle wasting is common in lung cancer patients regardless of body weight • Cancer induced wasting begins early in the course of malignancy • Up to 50% of lung cancer patients have severe muscle wasting at diagnosis Baracos VE, et al. Am J ClinNutr. 2010 Apr;91(4):1133S-1137S. Bruera E. BMJ. 1997 ;8;315(7117):1219- 22. Schootman M, et al. Cancer. 2009 Nov 15;115(22):5329-38. Braithwaite D, et al. J Natl Cancer Inst. 2010 Oct 6;102(19):1468-77. Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

  17. Prevalence of Cachexia Among Patients with Solid and Hematologic Malignancies at a National Cancer Institute (NCI) Designated Cancer Center During the 12 Months Preceding Death - E. Del Fabbro, N. Skoro, B. Cassel MASCC 2014 PARALLEL SESSION: CACHEXIA & FATIGUE 2 Saturday, June 28, 2014

  18. Loss of Muscle Mass Impairs Physical Function and Metabolic & Immunologic Health Weakness Mobility Disability Anorexia Fatigue Muscle strength Physical performance QOL Disease Metabolism Independence Hospitalization Response to chemo Tolerability to chemo Mortality Muscle mass Protein Stores Insulin resistance Changes in enzymes, peptide hormones, antibodies and cytokines, etc Immunity Impaired immunity and ineffective antitumor response

  19. Therapeutic Approaches to Muscle Wasting • Interfere with atrophy signaling • Myostatin /activin inhibitors • Anti-TNFα • Anti- IL-6 • Stimulate hypertrophy signaling • Ghrelinmimetics/GH secretagogues • Androgenic anabolic steroids / SARMs FearonKC, et al. Cell Metab. 2012 Aug 8;16(2):153-66.

  20. Targeting Muscle Wasting vs Cancer Cachexia

  21. The Role of Ghrelin in Anorexia-Cachexia Syndromes • Ghrelin – The “hunger hormone” • Stimulates food intake • Stimulates release of GH/IGF-1 increase • Decreases inflammatory cytokines Guillory B. VitamHorm. 2013;92:61-106. Currow DC and Abernethy AP. Future Oncol. 2014 Apr;10(5):789-802.

  22. Anamorelin for the Treatment of Anorexia-Cachexia in NSCLCPhase III Randomized, Double Blind, Placebo Controlled Trials • Eligibility • Stage III/IV NSCLC • Weight loss > 5% body weight or • BMI < 20 kg/m2 • Co-Primary Endpoints at 12 weeks • Lean Body Mass by DXA scan • Muscle Strength by Hand Grip Strength D. Currow MASCC 2014 PARALLEL SESSION: CACHEXIA & FATIGUE 2 Saturday, June 28, 2014

  23. The AR is a ligand-dependent transcription factor Benefits and risks of androgens • Benefits • Increase muscle mass and strength • Increase bone mass • Positive effects on mood, energy level, sense of well being and libido • Risks • Hirsutism and virilization (women) • Prostate hyperplasia (men) • Polycythemia • Decrease in serum HDL cholesterol • Elevations in transaminases (oral androgens) AR-DNA interaction Androgen a b c . . . . genes Androgen or SARM AR AR-Protein interaction SARM HSP a b c . . . . genes SARM – Selective Androgen Receptor Modulator Crawford J. Results from two Phase 3 randomized trials of enobosarm, selective androgen receptor modulator (SARM), for the prevention and treatment of muscle wasting in NSCLC. Presented at the European Cancer Congress, September 28, 2013, Amsterdam, Netherlands. Late Breaking Abstract 21. Mohler ML, et al. J Med Chem. 2009;52(12):3597-3617.

  24. International Pivotal Phase III Clinical Trials: POWER 1 and POWER 2 150 patients 150 patients 150 patients Indication: Prevention and treatment of muscle wasting in patients with NSCLC Stage III/IV NSCLC patients at initiation of 1st line chemotherapy Efficacy Assessments SCPscreening, baseline (Day 0), Day 42, Day 84 and Day 147 DEXA baseline (Day 0), Day 42, Day 84 and Day 147 • Primary endpoints @ Day 84 • Lean body mass DEXA • Physical function SCP • Secondary endpoints • Durability of effect @ Day 147 • Overall survival (safety analysis) Enobosarm 3 mg 150 patients POWER 1 Platinum + taxane Placebo Enobosarm 3 mg 150 patients POWER 2 platinum + non-taxane Placebo Observation for vital status Day84 Day 147 Crawford J et al.Presented at the European Cancer Congress. September 28, 2013. Amsterdam, Netherlands. Late Breaking Abstract 21.

  25. Clinical Practice Guidelines on Cancer Cachexia European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced Cancer Patients with a Focus on Refractory Cachexia – European Clinical Guidelines. Available at: www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

  26. Clinical Practice Guidelines on Cancer Cachexia European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced Cancer Patients with a Focus on Refractory Cachexia – European Clinical Guidelines. Available at: www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

  27. Clinical Practice Guidelines on Cancer Cachexia European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced Cancer Patients with a Focus on Refractory Cachexia – European Clinical Guidelines. Available at: www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

  28. Useful Resource for Health Professionals • Nutrition in Cancer Care (PDQ®) • Health Professional Version • National Cancer Institute • Last Updated 2/26/2014

  29. Conclusions • Cancer cachexia is prevalent at diagnosis and increases in frequency and severity during the disease and treatment course of our patients • Muscle wasting/sarcopenia is central to cancer cachexia, both at the molecular and clinical level and impacts function/QOL, treatment response/toxicity and survival • Non-pharmacologic approaches with nutritional counseling and physical training, as well as selective pharmacologic interventions can be helpful in current management • Promising approaches for earlier detection and monitoring, as well as new agents for treating cachexia/sarcopenia are under study

  30. Mitigating Chemotherapy-Induced Constipation / Diarrhea in Newly Diagnosed CRC Dorothy MK Keefe, PSM, MBBS, MD, FRACP, FRCP University of Adelaide

  31. Balance between oral intake secretions into gastrointestinal tract fluid re-absorption in the gastrointestinal tract (metabolism) Varies between 3 times daily and once every 3 days Consistency also important Normal volume depends on diet Normal Bowel Function

  32. NCI Common Toxicity Criteria Adverse Event 2 3 4 5 1 Constipation Occasional or intermittent symptom, occasional use of stool softeners, laxatives, dietary modification, or enema Persistent symptoms with regular use of laxatives or enema indicated Symptoms interfering with ADL: constipation with manual evacuation indicated Life-threatening consequences (eg obstruction, toxic megacolon) Death Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline; not interfering with ADL Increase of 4–6 stools per day over baseline; IV fluids indicated < 24 hrs; moderate increase in ostomy output compared to baseline, not interfering with ADL Increase of ≥ 7 stools per day over base-line; incontinence; IV fluids ≥ 24 hrs; hospitalization; severe increase in ostomy output compared to baseline, interfering with ADL Life-threatening consequences (eg hemodynamic collapse) Death Diarrhea Ileus, (functional obstruction of bowel, ieneuroconstipation) Asymptomatic, radiographic findings only Symptomatic altered GI function (eg altered dietary habits); IV fluids, tube feeding, or TPN indicated < 24 hrs Symptomatic and severe altered GI function; IV fluids, tube feeding, or TPN indicated ≥ 24 hrs Life-threatening consequences Death Common Terminology Criteria for Adverse Events v 4.0. Available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

  33. Opposite Ends of a Continuum Diarrhea Increased frequency Decreased consistency ± blood ± mucus Constipation Decreased frequency Increased consistency ± blood

  34. By mouth 2000 • Salivary glands 1500 • Stomach 2500 • Liver 500 • Duodenum • Jejunum • Pancreas 1500 • 5000 • Small bowel 1500 • Ileum 2000 • Colon 1300 Fluid Into and Out of the Adult Alimentary Tract in 24 Hours (ml) • IN • OUT • TOTAL IN~ 9000ml • Stools estimated150ml • TOTAL Absorbed~ 8300ml

  35. Diarrhea 5-Fluorouracil Methotrexate Irinotecan Taxanes Monoclonal antibodies Small molecule TKIs Hormonal agents And most agents that have been tested Constipation Vinca Alkaloids Thalidomide Hormonal agents Probably others Which Anti-Cancer Agents Do What?

  36. Constipation • Diarrhea How Can Chemotherapy Alter the Balance? • (Unlikely to have increased intake) • Decreased oral intake (dehydration) • Decreased motility (increases time for re-absorption to occur) • Autonomic neuropathy • Increased re-absorption • Blockage • Overtreated diarrhea • Anti-nauseants • Analgesics • Decreased exercise • Decreased surface area of small bowel and colon (secretory) • Increased motility (osmotic + secretory) • Decreased enzyme activity (osmotic) • Increased infective agents (infectious) • Increased mucous secretions (exudative) • Overtreated constipation

  37. Mechanism of Diarrhea • Villous atrophy • Rebound hyperplasia • Excess mucus secretion • Infection • Transient lactose intolerance • Immune colitis

  38. Gastrointestinal Syndrome • Constellation of symptoms (not limited to Irinotecan) • Severe diarrhea • Nausea/vomiting • Anorexia • Abdominal cramping • Accompanied by • Severe dehydration • Neutropenia • Fever • Electrolyte imbalance Benson AB, et al. J Clin Oncol. 2004 Jul 15;22(14):2918-26.

  39. InfectiousDiarrhea • Chemotherapy patients are at increased risk of infection • Leaky tight junctions between cells allow bacterial translocation • Bacteria can invade directly, and can kill enterocytes • Complex micro-organisms can cause intestinal anaphylaxis (proteases, ROS, mast cells and phagocytes) • Immunological mechanisms cause damage via PMNs, macrophage activation and T-lymphocytes • However, very little evidence that chemotherapy actually causes infectious diarrhea

  40. Diarrhea from Targeted Agents • Very little mechanistic study even now • Poor understanding of natural history and prevention or treatment • High risk of new drugs having major toxicity • Anastamotic leaking / breakdown complicates situation • Immune colitis not fully understood • Animal models few and far between

  41. Mechanisms of Constipation • Very poorly defined • Often secondary to opioids / anti-emetics rather than anti-cancer drugs • Vinca alkaloids via autonomic neuropathy leading to gastrointestinal dysmotility • Thalidomide via neuropathy

  42. Pathway for Treatment • Requires understanding of underlying mechanism • Remembering that the body has a limited response repertoire to insult

  43. “Normal” bowel function • Frequency • Consistency • Color • Other symptoms • Nausea/vomiting •  Oral intake – fluid – solid • Exacerbating features • Fever/chills • Abdominal pain • – location – nature • Weight loss • Bloating • Current bowel function •  Duration of change • Frequency (nocturnal?) • Consistency • Blood • Mucus • Color PATIENT STATUS AXR • Hydration • Abdominal examination • Bowel sounds • (Rectal examination) • Temperature • Blood Pressure • Stool frequency • Consistency • Color • Blood results • Obstruction • Bowel wall thickening  Culture ACTION • Maintain hydration • Optimize motility of gut • Do you need to • – secretion – osmolality – treat infection Pathway for Diarrhea & Constipation HISTORY • Drug treatment • Chemotherapy • Targeted agents • Analgesics • Antibiotics • Anti-emetics • Complementary & alternative • Other EXAMINATION

  44. Treatment Diarrhea Ioperamide2 stat + 1 with each loose stoolMaximum 11/day Re-hydrate(oral or IV fluids) Reduce dairy intake If no response Octreotide at least 100µg bd s/c Consider antibiotics

  45. Gastrointestinal Syndrome • Aggressive treatment of diarrhea • Addition of oral fluoroquinolone if • Diarrhea persists >24 hours • ANC < 500 cells / microlitre (+ / - fever / diarrhea) • Fever + Diarrhea (+ / - neutropenia) • Evidence for antibiotics is limited Rothenberg ML, et al. J Clin Oncol. 2005 Dec 20;23(36):9265-74.

  46. ImmuneColitis • Aggressive use of steroids • Some evidence for infliximab • May need surgical resection • Life-threatening toxicity

  47. If no response Enema Treatment Constipation Maintain Adequate Hydration Mild exercise if appropriate Stool Softener Bulking Agent MicrolaxG & O enemaMovicol

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