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FACULTY Egidio Del Fabbro, MD – CHAIR Jeffrey Crawford, MD Dorothy MK Keefe, PSM, MD David Warr, MD, FRCPC FACULTY Egidio Del Fabbro, MD – CHAIR Associate Professor Director, Palliative Care Program Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, Virginia Jeffrey Crawford, MD George Barth Geller Professor for Research in Cancer Co-Director, Solid Tumor Therapeutics Program Duke Cancer Institute Durham, North Carolina Dorothy MK Keefe, PSM, MD Service Director, SA Cancer Service Professor of Cancer Medicine, University of Adelaide Adelaide, Australia David Warr, MD, FRCPC Associate Professor, Department of Medicine University of Toronto Head, Breast Medical Oncology Princess Margaret Cancer Centre Toronto, Canada
Managing the Conundrum of Anorexia-Cachexia in Advanced NSCLC Jeffrey Crawford, MD Duke Cancer Institute
1. conundrum –kə ˈ nəndrəm/ –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
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.
Frequency 6 month weight loss history (%) Distribution of Pre-Diagnosis Weight Loss in Patients Presenting with NSCLC IIIB / IV Among a Population Cohort in Northern Alberta 15% weight stable Baracos VE, et al. Am J Clin Nutr. 2010;91(4):1133S-1137S. Mean weight loss at presentation 6%
Body mass index (kg/m 2 ) Frequency BMI Distribution of Patients Presenting with NSCLC IIIB / IV Population Cohort Northern Alberta, n=950 Gallagher D and DeLegge M. JPEN J Parenter Enteral Nutr. 2011 Sep;35(5 Suppl):21S-8S. BMI < 18.5 kg/m 2
BMI and Overall Survival in Advanced NSCLC Patients Dahlberg SE, et al. J Thorac Oncol. 2013 Sep;8(9):1121-7.
Computerized Tomography: An Opportunistic Method Subcutaneous adipose tissue Visceral adipose tissue Intermuscular adipose tissue Skeletal muscle Baracos V, et al. Int J Biochem Cell Bio. 2013;45(10):2302-2308.
Muscle Wasting in Cancer: A Hidden Condition Prado CM, et al. Curr Opin Support Palliat Care. 2009 Dec;3(4):269-75. SARCOPENICNORMAL Same BSA = 2.07 and BMI = 30.3
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.
Sarcopenic Obesity: Prevalence of Physical Impairment P = 0.005 47% 26% Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.
Survival and Sarcopenic Obesity Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35. p <0.0001 Sarcopenic patients: 11.3 months Non-sarcopenic obese: 21.6 months Non-sarcopenic obese Sarcopenic obese HR 2.3, P = 0.022 Functional status Cancer type Stage of disease Age Gender History of weight loss
And physical disability, infections, complications during hospitalization, length of hospital stay, etc. Sarcopenia (Severe Muscle Wasting) Predicts Key Health Outcomes
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 Muscle Wasting in Lung Cancer Patients Baracos VE, et al. Am J Clin Nutr. 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.
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
Loss of Muscle Mass Impairs Physical Function and Metabolic & Immunologic Health Protein Stores Changes in enzymes, peptide hormones, antibodies and cytokines, etc Immunity Impaired immunity and ineffective antitumor response Metabolism Insulin resistance Mobility Disability Physical performance Anorexia Fatigue QOL Weakness Muscle strength Disease Muscle mass Independence Hospitalization Response to chemo Tolerability to chemo Mortality
Fearon KC, et al. Cell Metab. 2012 Aug 8;16(2):153-66. 1.Interfere with atrophy signaling Myostatin /activin inhibitors Anti-TNFα Anti- IL-6 Therapeutic Approaches to Muscle Wasting 2.Stimulate hypertrophy signaling Ghrelin mimetics/GH secretagogues Androgenic anabolic steroids / SARMs
Targeting Muscle Wasting vs Cancer Cachexia Product Description/ MOA Stage (Indication) Last Reported Activity Comments Enobosarm (GTx-024) Selective Androgen Receptor Modulator (SARM) Phase III (prevention and treatment of muscle wasting in NSCLC) Aug 2013 Two phase III pivotal, international studies Topline results reported Aug 2013 Anamorelin (RC-1291) Ghrelin receptor agonist Phase III (anorexia/ cachexia in NSCLC) Sept 2013 Two phase III studies completed enrollment Fall 2013 MT-102 Anabolic catabolic transforming agent (ACTA) Phase II (cachexia) April 2012 Initiated Phase II multinational study in Mar 2011, est. completion June 2013 Macimorelin (AEZS-130) Growth hormone secretagogue (GHS) Phase IIa (cancer cachexia) Sept 2012 Phase IIa study initiated under a cooperative agreement with the DeBakey VA Med Ctr in Mar 2012 APD209 Fixed combination of progestin and selective β2-agonist Phase II (cancer cachexia) Dec 2011 Results of a Phase IIa pilot study in 7 patients were presented at the Cachexia Conference in Milan, Dec 2012 BYM338 Human HuCAL-based antibody targeting ActRIIB Phase II (cancer cachexia) Sept 2012 Initiated Phase II trial in patients with Stage IV NSCLC and Stage III/IV pancreatic cancer in Aug 2011. Currently enrolling LY2495655 Anti-myostatin monoclonal antibody Phase I/II (cancer cachexia and disuse muscle atrophy) July 2013 Phase II study in pancreatic cancer dose- escalation study est. compl. July 2014
The Role of Ghrelin in Anorexia- Cachexia Syndromes Guillory B. Vitam Horm. 2013;92:61-106. Currow DC and Abernethy AP. Future Oncol. 2014 Apr;10(5):789-802. Ghrelin – The “hunger hormone” Stimulates food intake Stimulates release of GH/IGF-1 increase Decreases inflammatory cytokines
Anamorelin for the Treatment of Anorexia-Cachexia in NSCLC Phase 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
SARM – Selective Androgen Receptor Modulator The AR is a ligand-dependent transcription factor 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) Benefits and risks of androgens AR-DNA interaction AR-Protein interaction HSP AR a b c.... genes Androgen a b c.... genes SARM Androgen or SARM 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.
International Pivotal Phase III Clinical Trials: POWER 1 and POWER 2 Indication: Prevention and treatment of muscle wasting in patients with NSCLC Stage III/IV NSCLC patients at initiation of 1 st line chemotherapy 150 patients Primary endpoints @ Day 84 Lean body mass DEXA Physical function SCP Placebo Enobosarm 3 mg Secondary endpoints Durability of effect @ Day 147 Overall survival (safety analysis) POWER 1 Platinum + taxane POWER 2 platinum + non-taxane Day 84Day 147 Observation for vital status SCP screening, baseline (Day 0), Day 42, Day 84 and Day 147 DEXA baseline (Day 0), Day 42, Day 84 and Day 147 150 patients Efficacy Assessments Placebo Enobosarm 3 mg Crawford J et al. Presented at the European Cancer Congress. September 28, 2013. Amsterdam, Netherlands. Late Breaking Abstract 21.
Clinical Practice Guidelines on Cancer Cachexia Consensus Recommendations Enteral nutritional therapyYes Parenteral nutritional therapy No SupplementsInsufficient data Non-pharmacologic therapyYes Nutritional counselingYes Psychotherapeutic interventions Yes (QOL) Physical trainingYes 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
Pharmacologic Therapy Consensus Recommendations ThalidomideInsufficient data CannabinoidsMay increase appetite Omega-3-fatty acidsInsufficient data Megestrol/progestinsStimulate appetite + increase weight, but not muscle SteroidsYes (short term) Anti-inflammatory agentsLittle benefit ProkineticsYes, for GI symptoms 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
Consensus Recommendations Anticancer therapyCan be beneficial or detrimental Multimodal therapy (nutrition, physical training, medications) Yes (but more research needed) Prophylaxis for patients at risk Nutritional counseling Physical training Yes (but little data) 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
Nutrition in Cancer Care (PDQ ® ) Health Professional Version National Cancer Institute Last Updated 2/26/2014 Useful Resource for Health Professionals
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
Mitigating Chemotherapy-Induced Constipation / Diarrhea in Newly Diagnosed CRC Dorothy MK Keefe, PSM, MBBS, MD, FRACP, FRCP University of Adelaide
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
NCI Common Toxicity Criteria Diarrhea 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 Ileus, (functional obstruction of bowel, ie neuroconstipation) 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 Constipation Adverse Event 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 2 1 345 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
Opposite Ends of a Continuum Diarrhea Increased frequency Decreased consistency ± blood ± mucus Constipation Decreased frequency Increased consistency ± blood
OUT Fluid Into and Out of the Adult Alimentary Tract in 24 Hours (ml) IN Small bowel 1500 TOTAL IN ~ 9000ml TOTAL Absorbed ~ 8300ml Stools estimated 150ml By mouth 2000 Salivary glands 1500 Stomach 2500 Liver 500 Pancreas 1500 Colon 1300 Ileum 2000 DuodenumJejunum5000
Which Anti-Cancer Agents Do What? 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
Constipation Diarrhea (Unlikely to have increased intake) Decreased oral intake (dehydration)Decreased oral intake (dehydration) Decreased motility (increases time for re-absorption to occur)Decreased motility (increases time for re-absorption to occur) Autonomic neuropathyAutonomic neuropathy Increased re- absorptionIncreased re- absorption BlockageBlockage Overtreated diarrheaOvertreated diarrhea Anti-nauseantsAnti-nauseants AnalgesicsAnalgesics Decreased exerciseDecreased exercise Decreased surface area of small bowel and colon (secretory)Decreased surface area of small bowel and colon (secretory) Increased motility (osmotic + secretory)Increased motility (osmotic + secretory) Decreased enzyme activity (osmotic)Decreased enzyme activity (osmotic) Increased infective agents (infectious)Increased infective agents (infectious) Increased mucous secretions (exudative)Increased mucous secretions (exudative) Overtreated constipationOvertreated constipation How Can Chemotherapy Alter the Balance?
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.
Infectious Diarrhea 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
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
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
Pathway for Treatment Requires understanding of underlying mechanism Remembering that the body has a limited response repertoire to insult
Pathway for Diarrhea & Constipation HISTORY AXR Obstruction Bowel wall thickening ACTION Maintain hydration Optimize motility of gut Do you need to – secretion – osmolality – treat infection Current bowel function Duration of change Frequency (nocturnal?) Consistency Blood Mucus Color Other symptoms Nausea/vomiting Oral intake– fluid – solid Exacerbating features Fever/chills Abdominal pain – location – nature Weight loss Bloating EXAMINATION Stool frequency Consistency Color Blood results Culture PATIENT STATUS Hydration Abdominal examination Bowel sounds (Rectal examination) Temperature Blood Pressure “Normal” bowel function Frequency Consistency Color Drug treatment Chemotherapy Targeted agents Analgesics Antibiotics Anti-emetics Complementary & alternative Other
Treatment Octreotide at least 100µg bd s/c Consider antibiotics Diarrhea Reduce dairy intake Re-hydrate (oral or IV fluids) If no response Ioperamide 2 stat + 1 with each loose stool Maximum 11/day
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.
Immune Colitis Aggressive use of steroids Some evidence for infliximab May need surgical resection Life-threatening toxicity
Microlax G & O enema Movicol Treatment Constipation Mild exercise if appropriate Stool Softener Bulking Agent If no response Enema Maintain Adequate Hydration
Palliation of Constipation Bulking Agents Lubricants Anthracenes Osmotic laxatives
Agents Under Investigation Diarrhea Glp-2 analogues Immune globulins Nutritional supplements Early work looking at TLR- 4 pathway Constipation Methylnaltrexone
MASCC/ISOO Guidelines 2014 Panel recommendations in favor of an intervention: Intravenous amifostine be used, at a dose of at least 340mg/m 2, to prevent radiation proctitis in patients receiving radiation therapy (Level II evidence) Octreotide, at a dose of at least 100 mcg subcutaneously twice daily, be used to treat diarrhea induced by standard- or high-dose chemotherapy associated with hematopoietic stem cell transplant, if loperamide is ineffective (Level II evidence) MASCC/ISOO Evidence-Based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy V2.2014. Available at: http://www.mascc.org/assets/Guidelines-Tools/mascc%20isoo%20mucositis%20guidelines%20summary%201feb2014.pdf. Accessed June 2014.
Recommendations in Favor of an Intervention Intravenous amifostine be used to prevent esophagitis induced by concomitant chemotherapy and radiation therapy in patients with non-small cell lung carcinoma (III) Sucralfate enemas be used to treat chronic radiation-induced proctitis in patients with rectal bleeding (III) Systemic sulfasalazine, at a dose of 500 mg administered orally twice a day, be used to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis (II) Probiotics containing Lactobacillus species be used to prevent diarrhea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy (III) Hyperbaric oxygen be used to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumor (IV) MASCC/ISOO Evidence-Based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy V2.2014. Available at: http://www.mascc.org/assets/Guidelines-Tools/mascc%20isoo%20mucositis%20guidelines%20summary%201feb2014.pdf. Accessed June 2014.
Recommendations Against an Intervention Systemic sucralfate, administered orally, not be used to treat gastrointestinal mucositis in patients receiving radiation therapy for a solid tumor (I). 5-acetyl salicylic acid (ASA), and the related compounds mesalazine and olsalazine, administered orally, not be used to prevent acute radiation-induced diarrhea in patients receiving radiation therapy for a pelvic malignancy (I). Misoprostol suppositories not be used to prevent acute radiation-induced proctitis in patients receiving radiation therapy for prostate cancer (I). MASCC/ISOO Evidence-Based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy V2.2014. Available at: http://www.mascc.org/assets/Guidelines-Tools/mascc%20isoo%20mucositis%20guidelines%20summary%201feb2014.pdf. Accessed June 2014.
Summary Diarrhea and constipation are common problems in cancer patients Etiology is often multi-factorial Treatments are largely palliative Targeted agents are complicating the situation More work is required on mechanisms and mechanism-driven treatments
Bring it all Together: Symposium Pearls from the Chair Egidio Del Fabbro, MD - CHAIR Virginia Commonwealth University
Bringing It All Together Individualized patient assessment 1,2 A multidisciplinary approach 3,4 Evidence based management 5,6 Improved outcomes 7,8 1.Gioulbasanis Ann Oncol 2011. 2.Vigano J Acad Nutr Diet 2014. 3.Ravasco JCO 2005. 4.Del Fabbro J Pall Med 2011 5.Roila FAnn Oncol 2010. 6. Davis JPSM 2010. 7.Mantovani Oncologist 2010. 8.Quinten Lancet Oncol 2009
Bringing It All Together Limitations of current therapies 1 Unmet needs 2 Opportunities for improvement 3,4 Earlier is better 5,6 1.Ruiz-Garcia Cochrane 2013. 2.Donithireddy J Supp Oncol 2007. 3.Garcia Supp Care Cancer 2013. 4.Lundholm Cancer 2010. 5.Prado Am J Clin Nutr 2013. 6 Aapro Ann Oncol 2014