1. Symptom Clusters in Patients with Advanced Cancer: Cachexia, Anorexia & Asthenia  Davis Wilkins, M.D. M.A.-Bioethics  Fellow, Palliative Medicine  May 2008

2. Goals  Discuss impact of symptom clusters on QOL  Review pathophysiology & current thinking  Current treatment strategies  Ongoing research & future directions

3. Definitions  Cachexia: involuntary profound loss of lean body mass and adipose tissue.  Anorexia: Loss of appetite  Asthenia/Fatigue: listlessness, decreased energy, decreased motivation; physical + cognitive components

4. Impact of Anorexia & Cachexia  Occurs in up to 20% at dx; up to 80% in advanced cancer  Attributed as main cause of death in ~20% patients  Loss of >10% of premorbid weight = poor prognostic indicator & associated w/ decreased survival Strasser & Bruera, Hematol Oncol Clin N Am 2002

5. Anorexia & Cachexia, continued  More common in solid tumors Exception: breast CA where fatigue more common Exception: breast CA where fatigue more common  Does not correlate well w/ tumor size or biology  Specific complications of tumor location & treatments may additionally exacerbate i.e. bowel obstruction & inflammation i.e. bowel obstruction & inflammation Strasser & Bruera, Hematol Oncol Clin N Am 2002

6. Impact of Asthenia/Fatigue  Asthenia/Fatigue has been ranked as the longest-lasting, most disruptive sx with the greatest impact on QOL 95% cancer patients endorse this as chief symptom: most common symptom 95% cancer patients endorse this as chief symptom: most common symptom Often lasts months or years after treatments Often lasts months or years after treatments Assessment difficult; multiple contributing factors Assessment difficult; multiple contributing factors Cancer, treatment, complications of tx or ca, meds, other physical & psychological conditionsCancer, treatment, complications of tx or ca, meds, other physical & psychological conditions Barnes & Bruera, Intl J Gynecol Cancer 2002

7. Additional impact of this sx cluster  Profound sense of loss associated with drastic changes in body image & ability to be active  Often a cause in people’s withdrawal from social life  Leads to increases stress around food/feeding by patient, family, friends  Loss of functional status  Decreased performance status = decreased treatment candidate  All 3 symptoms also very common in other life- limiting illnesses: AIDS, COPD, CHF, CKD, RA

8. Importance of better recognition & treatment  More ‘silent’ symptoms than pain or dyspnea; often go unrecognized, unaddressed  No good current single therapies  Probably a common pathway for many diseases  Targeted therapies may do much to improve QOL, possibly even survival.

9. Concept of symptom clusters  Definition: 3 or more symptoms that occur together, are stable, and relatively independent of other clusters  Anorexia, cachexia, fatigue: flu-like symptoms that manifest in cancer patients  Can also be accompanied by: Somatic complaints/aches Somatic complaints/aches Depression Depression Chronic nausea Chronic nausea Early satiety Early satiety Cognitve impairment Cognitve impairment Fan et al. Curr Oncol 2007; Gift, A. Seminar in Onc Nurs 2007

10. Current common treatments  Most single therapies often not very efficacious Megesterol Megesterol Marinol Marinol Mirtazepine Mirtazepine Olanzapine Olanzapine SSRI’s SSRI’s Exceptions: Exceptions: Corticosteroids, NSAIDs, ? methylphenidateCorticosteroids, NSAIDs, ? methylphenidate Del Fabbro. JAMA 2007.

11. It really IS all about cytokines….

12. Pathophysiology of cancer cachexia & anorexia  Complex metabolic syndrome/aberrant inflammatory response Pro-inflammatory/catabolic state; peripheral proteins & lipids mobilized to keep up; decreased sensitivity to orexigenic compounds Pro-inflammatory/catabolic state; peripheral proteins & lipids mobilized to keep up; decreased sensitivity to orexigenic compounds Tumor by-products formed from proteolysis inducing factor (PIF), lipid mobilizing factor (LMF) & activation of ubiquitin-proteosome degradative pathway Tumor by-products formed from proteolysis inducing factor (PIF), lipid mobilizing factor (LMF) & activation of ubiquitin-proteosome degradative pathway Host cytokines: IL-1, IL-6, TNF-a, interferon Host cytokines: IL-1, IL-6, TNF-a, interferon Host synthesis of acute phase proteins in liver at the expense of muscle protein, proteolysis, lipolysis, insulin resistance, decreased lipogenesis, elevated triglycerides, decreased HDlipoproteins Host synthesis of acute phase proteins in liver at the expense of muscle protein, proteolysis, lipolysis, insulin resistance, decreased lipogenesis, elevated triglycerides, decreased HDlipoproteins Neuroendocrine dysregulation & production of anorexigenic compounds Neuroendocrine dysregulation & production of anorexigenic compounds Del Fabbro et al J Pall Med 2006

13. Cancer cachexia signaling pathways Cancer cachexia signaling pathways Clinical Cancer Research 13, 1356-1361, March 2007

14. ? Role of cytokine genetic polymorphisms  Cytokine production & polymorphisms recently implicated in severity of cancer related pain Ongoing research into patient cytokine gene polymorphisms as explanation for pain variability in lung CA patients Ongoing research into patient cytokine gene polymorphisms as explanation for pain variability in lung CA patients Genes for TNF-alpha, IL-6, and IL-8Genes for TNF-alpha, IL-6, and IL-8 Reyes-Gibby et al. Cancer Epidemiol Biomarkers Prev. Dec 2007

15. Pathophysiology: cachexia & fatigue  CA patients have abnormal muscle, even when lean body mass = constant & caloric intake still normal: Excessive lactate in tumor free muscles Excessive lactate in tumor free muscles Animal studies show alterations in enzyme activity and isoenzyme distribution, as well as in synthesis & breakdown of myofibrils & sarcoplasmic proteins Animal studies show alterations in enzyme activity and isoenzyme distribution, as well as in synthesis & breakdown of myofibrils & sarcoplasmic proteins Patients w/ early impaired maximal strength Patients w/ early impaired maximal strength Boddaert, M. et al Curr Opin Oncol 2006

16. Pathophysiology, continued  Nutritional supplements and appetite stimulation alone cannot overcome progressive loss of muscle mass.  Treatments (chemo, XRT, surgery) often exacerbate tissue damage as well as lead to deconditioning. Boddaert, M. et al Curr OpinOncol 2006

17. Current Pharmacologic Management: cachexia, anorexia  Goal: delay cachexia, alleviate symptom burden w/o changing body composition Progestational agents Progestational agents MegesterolMegesterol CorticosteroidsCorticosteroids Cannabinoids Cannabinoids Marinol, dronabinolMarinol, dronabinol Hormonal/anti-catabolic Hormonal/anti-catabolic Testosterone,oxandrolone, GHTestosterone,oxandrolone, GH Psychotropics Psychotropics Antidepressants, anti-psychoticsAntidepressants, anti-psychotics Strasser & Bruera Hematol Oncol Clin N Am 2002

18. Current Pharmacologic Management: Asthenia  Corticosteroids  Progestins & androgens Megesterol, testosterone Megesterol, testosterone  Psychostimulants Methylphenidate, modafenil, perroline Methylphenidate, modafenil, perroline  Cholinesterase inhibitors donepezil donepezil

19. Current Research  Immune Modulator therapies Thalidomide Thalidomide Melatonin Melatonin Progestins- in combination with other drugs Progestins- in combination with other drugs Macronutrients Macronutrients (L-carnitine, Omega 3 fatty acids, fish oil)(L-carnitine, Omega 3 fatty acids, fish oil)  B-Agonists, Antagonists Norepinephrine, clenbuterolNorepinephrine, clenbuterol  Anti-inflammatories Corticosteroids, NSAIDS, EPA, macrolides Corticosteroids, NSAIDS, EPA, macrolides

20. Synergy?  May be synergistic if given with other therapies, due to targeting of multiple pathways simultaneously  Orexigens  Corticosteroids, progestins  Anti-catabolics  Oxandrolone, testosterone, GH  Anti-inflammatories  NSAIDs, EPA, melatonin, macrolides Yennu, Del Fabbro & Bruera, AAHPM, 2008

21. Corticosteroids Mechanism unknown. ? Related to central euphoria in combination with influence on prostaglandin metabolism & cytokine release. Mechanism unknown. ? Related to central euphoria in combination with influence on prostaglandin metabolism & cytokine release. Improve appetite, food intake, sense of well-being, performance status in advanced CA pts up to 4 weeks. NO significant weight gain. Pred 10-40 mg/day; dex 1-8 mg bid Pred 10-40 mg/day; dex 1-8 mg bid Longer use may induce myopathy, infxn,GIB, leading to worsening asthenia Longer use may induce myopathy, infxn,GIB, leading to worsening asthenia Lundstrom (sweden)2005, Bruera 1995

22. Melatonin  Most potent endogenous anti-oxidant Direct ROS scavenger & stimulates other anti-ox’s Direct ROS scavenger & stimulates other anti-ox’s  Has anti-tumor effects via multiple targets & may improve survival?  Recent studies: In many CA, melatonin production decreased In many CA, melatonin production decreased Adding melatonin enhances PPI protective effects & perhaps decreases chemo side effects Adding melatonin enhances PPI protective effects & perhaps decreases chemo side effects Improves multiple sx in solid tumor pts as well as decreases TNF- a serum levels, pain levels from 7-10/10  2-4/10. Improves multiple sx in solid tumor pts as well as decreases TNF- a serum levels, pain levels from 7-10/10  2-4/10. 20 mg/day x 4 weeks vs placebo, then crossover, then all (RCT)20 mg/day x 4 weeks vs placebo, then crossover, then all (RCT) (synthetic not cow) (IR not SR)(synthetic not cow) (IR not SR)  Downside: hard to assure quality of product/not FDA regulated. Need more trials/data. Plissoni (Italy) 2007; Del Fabbro AAHPM 2008

23. Thalidomide  In-vitro: Inhibits TNF-a, IL-6, IL-12 @ transcriptional level. Inhibits TNF-a, IL-6, IL-12 @ transcriptional level. Switches TH1->TH2 type cytokines; inhibits NFkB Switches TH1->TH2 type cytokines; inhibits NFkB  Modulate cytokines w/ CNS effects  Recent studies: 100-300 mg/day significantly improves mult. Sxs 100-300 mg/day significantly improves mult. Sxs Superior to Megace for improving appetite, modest decrease in wt. loss; side effect: + improved sleep Superior to Megace for improving appetite, modest decrease in wt. loss; side effect: + improved sleep  Downside: Narrow therapeutic window, Narrow therapeutic window, Combo w/ decadron = early data suggest highly thrombogenic Combo w/ decadron = early data suggest highly thrombogenic Unavailable in US except in CA Rx, research setting Unavailable in US except in CA Rx, research setting Dirt cheap in rest of world, ($200/tablet here)Dirt cheap in rest of world, ($200/tablet here) Bruera, AAHPM, 2008

24. Modafenil (Provigil)  Novel wake-promoting agent Increases release of monoamines, elevates histamine in certain brain regions. Increases release of monoamines, elevates histamine in certain brain regions. Unlikely to have addiction potential Unlikely to have addiction potential May have neuroprotective effects May have neuroprotective effects  Well tolerated; less side effects than than psychostimulants  Dosing: start at 50 mg qam; titrate to 100-200 mg/day. (400 mg/d for narcolepsy)  Downside: HA, nausea, insomnia, anxiety ; new/experimental. $$

25. Assessment & Management of Cancer Related Anorexia, Cachexia  Strasser & Bruera, Hematol Oncol Clin N Am 2002

26. Assessment & Management of Cancer Related Asthenia/Fatigue Algorithm for assessment and management of cancer-related fatigue From the NCCN 2002 cancer-related fatigue guideline, Supportive Care Practice Guidelines in Oncology

27. Non-pharmacologic measures  Nutritional support, counseling Meta-analysis of TPN in cancer patients showed decreased survival, increased susceptibility to infection; some patients may maintain weight w/ oral supplements for short time. Meta-analysis of TPN in cancer patients showed decreased survival, increased susceptibility to infection; some patients may maintain weight w/ oral supplements for short time.  Palliate other major contributing symptoms & reversible causes: Chronic nausea, dyspnea, deconditioning, depression, mucositis, GI obstruction, anemia, dehydration, pain, metabolic derangements Chronic nausea, dyspnea, deconditioning, depression, mucositis, GI obstruction, anemia, dehydration, pain, metabolic derangements

28. Nonpharmacologic measures, continued Increase activity as able Increase activity as able Benefit of resistance and endurance training on improved mood, quality of sleep, muscle mass maintenanceBenefit of resistance and endurance training on improved mood, quality of sleep, muscle mass maintenance Stress management, supportive counseling Stress management, supportive counseling Reframe family/pt. understanding Reframe family/pt. understanding Not: ‘starving to death’ but complex metabolic abnormalities caused by the cancerNot: ‘starving to death’ but complex metabolic abnormalities caused by the cancer Giving additional food will not result in additional fat or muscle restorationGiving additional food will not result in additional fat or muscle restoration Best chance may be to try and treat with multiple meds, but need to weigh risk-benefit, pt. ability/desire to take pillsBest chance may be to try and treat with multiple meds, but need to weigh risk-benefit, pt. ability/desire to take pills

29. Current novel research  Targeted therapies Proteasome inhibitors Proteasome inhibitors TNF inhibitors TNF inhibitors Monoclonal antibodies to IL-6 Monoclonal antibodies to IL-6  Anabolic cytokines (IL-15)  Specific cannabinoid-receptor antagonists  Role of Grehlin (‘gut-brain’ hormone), leptin  Alpha-melanocyte-stimulating hormone  Growth Hormone/IGF/IGF-I treatments  Immunonutrition (omega 3 EFA, L-arginine, L-carnitine glutamine, nucleotides) (omega 3 EFA, L-arginine, L-carnitine glutamine, nucleotides)  Anti-cytokine approaches Anti-sense NFkappa-B Anti-sense NFkappa-B Soluble TNF-alpha receptors Soluble TNF-alpha receptors Cytokine antagonists (pentoxifylline, bradykinin antagonists) Cytokine antagonists (pentoxifylline, bradykinin antagonists) Strasser & Bruera Hematol Oncol Clin N Am 2002

30. Further research needed  Need trials with patient-centered endpoints ?Does weight gain/increased lean body mass lead to better survival? ?Does weight gain/increased lean body mass lead to better survival? Function? Function? QOL? QOL? Improved chemo/XRT tolerance? Improved chemo/XRT tolerance?

31. Bibliography Barnes, EA & Bruera, E. “Fatigue in patients with advanced cancer: A review.” Intl Jour Gynecol Cancer Sept 2002; 12(5), 424-28. Boddaert et al.” On our way to targeted therapy for cachexia in cancer?” Curr Opin Oncolo 2006 18:335-340. Del Fabbro. “Cachexia & Wasting: A Modern Approach.” JAMA Feb 7,2007 297(5)536— 7. Del Fabbro et al. “ Symptom Control in Palliative Care—Part II: Cachexia, Anorexia, and Fatigue.” Journal of Palliative Medicine 2006 9 (2); 409-421. Fan, G, et al. “Symptom Clusters in Cancer Patients: A review of the literature.” Curr Oncol. October 2007; 14(5)173-179. Gift, A. Symptom Clusters Related to Specific Cancers.” Seminars in Onc Nursing, May 2007, 23(2): 136-141 Morrow et al. Management of Cancer-Related Fatigue. Cancer Investigation, 2005, 23:229-239 Reyes-Gibby et al. “Cytokine genes and pain severity in lung CA; exploring the influence..”Cancer Epidemiol Biomarkers Prev 2007 Dec; 16(12)2745-51. Strasser F, & Bruera, E. “ Update on Anorexia & Cachexia” Hematol Oncol Clin N AM 2002 (16) 589-617. Swarnali, A, & Guttridge, D. “Cancer Cachexia Signaling Pathways Continue to Emerge Yet Much Still Points to the Proteasome” Clinical Cancer Research 13, 1356-1361, March 2007 Yennurajalingam S, and Bruera E. “Palliative management of fatigue at the close of life: “It feels like my body is all worn out!” JAMA 2007; 297 (3): 295-304