1. Steroids in Palliative Care A Short Review Edward (Ted) St. Godard MA CCFP Consultant Physician WRHA Palliative Care

2. Steroids in Palliative Care PharmacologyPharmacology Common palliative symptomsCommon palliative symptoms Role of SteroidsRole of Steroids Common side-effectsCommon side-effects

4. Steroids in Palliative Care

5. Adrenal medulla: EpinephrineAdrenal medulla: Epinephrine Adrenal Cortex: Cortisol, aldosterone, dehydroepiandrosterone (DHEA)Adrenal Cortex: Cortisol, aldosterone, dehydroepiandrosterone (DHEA)

6. Steroids in Palliative Care Cortisol:Cortisol: Glucocorticoid secreted by Zona FasciculataGlucocorticoid secreted by Zona Fasciculata Numerous physiological effectsNumerous physiological effects

7. Steroids in Palliative Care TissueEffects Liver Increased gluconeogenesis Increased glycogen synthesis Skeletal Muscle Decrease glucose uptake Decrease protein synthesis Increased protein degradation Adipose Decrease glucose uptake Increase lipid mobilization General Anti-inflammatory: inhibit phospholipase A2 and production of leukotrienes and prostaglandins

8. Steroids in Palliative Care

9. Often not significantly better than other therapies for single symptom control (opioids for pain, for instance)Often not significantly better than other therapies for single symptom control (opioids for pain, for instance) Useful adjuncts in context of multiple symptomsUseful adjuncts in context of multiple symptoms

10. Steroids in Palliative Care ~ 60 % PC patients Rx’d steroids~ 60 % PC patients Rx’d steroids Dexamethasone, 4 – 16 mg/day drug of choiceDexamethasone, 4 – 16 mg/day drug of choice Mercadante et al. “The Use of Steroids in Home Palliative Care.” Support Care Cancer (2001) 9 :386–389

11. Steroids in Palliative Care SBGH Jan. – June 2005SBGH Jan. – June 2005 ~ 65 % patients Rx’d steroids during admission~ 65 % patients Rx’d steroids during admission 38 % on steroids at admission38 % on steroids at admission DexamethasoneDexamethasone Pain, dyspnea, bowel obstruction, brain tumor, SCCPain, dyspnea, bowel obstruction, brain tumor, SCC Pilkey and Daenicnk. Publication pending

12. Steroids in Palliative Care Brain tumorBrain tumor Dexamethasone and WBRT improves performance status, improves neurological function (short-term benefit)Dexamethasone and WBRT improves performance status, improves neurological function (short-term benefit) No current standard dosing based on evidenceNo current standard dosing based on evidence Dexamethasone 8 mg bid (4 Qid)Dexamethasone 8 mg bid (4 Qid) Shih et al. “Role of Steroids in Palliative Care.” Journal Pain and Palliative Pharmacotherapy. 21 (4); 2007

13. Steroids in Palliative Care Brain tumorBrain tumor Pain, delirium/dementia, N/V, SZ, motor deficits (all mainly due to increased ICP)Pain, delirium/dementia, N/V, SZ, motor deficits (all mainly due to increased ICP) Dexamethasone decreases capillary bed permeability, thus decrease peritumor edemaDexamethasone decreases capillary bed permeability, thus decrease peritumor edema The use and toxicity of Steroids in Mgmt Brain Metastasis.” Support Care Cancer (2008) 16:1041–1048

14. Steroids in Palliative Care Malignant bowel obstructionMalignant bowel obstruction N/V, pain, global distressN/V, pain, global distress Decrease peri-tumor edemaDecrease peri-tumor edema NNT 6: “Trend toward improvement…”NNT 6: “Trend toward improvement…” No evidence of impact on mortalityNo evidence of impact on mortality No dosing recommendations, SE increase with doseNo dosing recommendations, SE increase with dose Feuer et al. “Systematic review and meta-analysis of corticosteroids for malignant bowel obstruction in advanced gynaecological and gastrointestinal cancers.” Annals of Oncology 10: 1035 - 1041, 1999.

15. Steroids in Palliative Care Malignant bowel obstructionMalignant bowel obstruction Steroid (Dex: 4 – 16 mg/d)Steroid (Dex: 4 – 16 mg/d) MetoclopramideMetoclopramide OctreotideOctreotide Mercadante et al. “Aggressive Pharmacological Treatment for Reversing Malignant Bowel Obstruction.” Journal Pain and Symptom Mgmt. 28:4; 2004

16. Steroids in Palliative Care Nausea, emesisNausea, emesis ?reduced permeability BBB to chemicals that induce emesis?reduced permeability BBB to chemicals that induce emesis Good evidence as adjuncts (with D2 antagonists, 5-HT3 antagonists)Good evidence as adjuncts (with D2 antagonists, 5-HT3 antagonists) Dexamethasone 4 – 16 mg/dDexamethasone 4 – 16 mg/d

17. AnorexigenicNeuropeptide Neurotensin Melanocortin CRF OrexigenicNeuropeptide Glucogon CCKLeptin Blood Brain Barrier NPY AGRP MCHNeurotensin Melanocortin CRF Glucogon CCKLeptin NPY AGRP MCH CNS Cytokinase Cytokinase CNTF IL-1 CNTF IL-1 Food Intake Energy Expenditure Food Intake Energy Expenditure Seratonin Blood Brain Barrier IL-6 Tryptophan Glucocorticoids ACTH AnorexigenicNeuropeptide OrexigenicNeuropeptide IL-1IL-6 TNF-  INF-  _ + + + + + + + ++ + + + + _ _ _ _ _ _ _ _ A B

18. AnorexigenicNeuropeptide Neurotensin Melanocortin CRF OrexigenicNeuropeptide Glucogon CCKLeptin Blood Brain Barrier NPY AGRP MCHNeurotensin Melanocortin CRF Glucogon CCKLeptin NPY AGRP MCH CNS Cytokinase Cytokinase CNTF IL-1 CNTF IL-1 Food Intake Energy Expenditure Food Intake Energy Expenditure Seratonin Blood Brain Barrier IL-6 Tryptophan Glucocorticoids ACTH AnorexigenicNeuropeptide OrexigenicNeuropeptide IL-1IL-6 TNF-  INF-  _ + + + + + + + ++ + + + + _ _ _ _ _ _ _ _ A B

19. Steroids in Palliative Care AnorexiaAnorexia Terribly distressing symptom (worse for families than patients)Terribly distressing symptom (worse for families than patients) Predictive of early demise?Predictive of early demise? Matin and Jatoi. “Megesterol Acetate for the Palliatiation of Anorexia in Advance Incurable Cancer.” Clinical Nutrition. 2006. 25:5

20. Steroids in Palliative Care Anorexia and cachexiaAnorexia and cachexia Short-term appetite stimulationShort-term appetite stimulation Comparable to MegesterolComparable to Megesterol Lowest dose, pulse, titrate downLowest dose, pulse, titrate down Matin and Jatoi. “Megesterol Acetate for the Palliatiation of Anorexia in Advance Incurable Cancer.” Clinical Nutrition. 2006. 25:5

21. Steroids in Palliative Care Fatigue and depressionFatigue and depression Fatigue and “weakness” huge problemFatigue and “weakness” huge problem Pulse steroids significantly improve fatigue in number of patientsPulse steroids significantly improve fatigue in number of patients Short-livedShort-lived Side-effects (increased appetite)Side-effects (increased appetite) Lundstrom et al. “The Existential Impact of Starting Steroids in Advanced Metastatic Cancer.” Palliative Medicine. 2009: 23

22. Steroids in Palliative Care Fatigue and depressionFatigue and depression Depression 15 – 30 % cancer patientsDepression 15 – 30 % cancer patients Optimal anti-depressants take too longOptimal anti-depressants take too long Steroids promote sense of “well-being”Steroids promote sense of “well-being” Short-livedShort-lived Side effectsSide effects Lundstrom et al. “The Existential Impact of Starting Steroids in Advanced Metastatic Cancer.” Palliative Medicine. 2009: 23

23. Steroids in Palliative Care Spinal cord compressionSpinal cord compression Reduce edema, alleviate pain, improve neurologic outcomesReduce edema, alleviate pain, improve neurologic outcomes Some benefit from “high dose,” but significantly increased SESome benefit from “high dose,” but significantly increased SE Dexamethasone 10 mg IV, then 8 mg bidDexamethasone 10 mg IV, then 8 mg bid Loblaw et al. J. Clin Oncol. 2005. 23 (30)

24. Steroids in Palliative Care SVC syndromeSVC syndrome Often useful in dyspnea 2 airway edemaOften useful in dyspnea 2 airway edema Steroids as temporizing measureSteroids as temporizing measure Chronic use of course leads to SEChronic use of course leads to SE Lack of robust evidence baseLack of robust evidence base Dex: dose?Dex: dose? Wan et al. “Superior Vena Cave Syndrome.” Emergency clinics North America. 27:2. 2009

25. Steroids in Palliative Care Bone painBone pain Weak evidence baseWeak evidence base Strong anecdotal supportStrong anecdotal support Dex 4 – 16 mg/dDex 4 – 16 mg/d

26. Steroids in Palliative Care Equivocal evidence; STRONG DRUGSEquivocal evidence; STRONG DRUGS Potential for multiple adverse effectsPotential for multiple adverse effects Clearly dose-relatedClearly dose-related Many preventableMany preventable Most reversibleMost reversible

27. Steroids in Palliative Care TissueEffects Liver Increased gluconeogenesis Increased glycogen synthesis Skeletal Muscle Decrease glucose uptake Decrease protein synthesis Increased protein degradation Adipose Decrease glucose uptake Increase lipid mobilization General Anti-inflammatory: inhibit phospholipase A2 and production of leukotrienes and prostaglandins

28. Steroids in Palliative Care Hyperglycemia commonHyperglycemia common Symptoms (polyuria, etc.)Symptoms (polyuria, etc.) Susceptible to infx, neuropathySusceptible to infx, neuropathy Monitor, treatMonitor, treat Late afternoon capillary glucoseLate afternoon capillary glucose

29. Steroids in Palliative Care TissueEffects Liver Increased gluconeogenesis Increased glycogen synthesis Skeletal Muscle Decrease glucose uptake Decrease protein synthesis Increased protein degradation Adipose Decrease glucose uptake Increase lipid mobilization General Anti-inflammatory: inhibit phospholipase A2 and production of leukotrienes and prostaglandins

30. Steroids in Palliative Care Immune modulationImmune modulation Compromised patientsCompromised patients Oral candidiasis “Thrush”Oral candidiasis “Thrush” Painful and frustratingPainful and frustrating Nystatin, fluconazoleNystatin, fluconazole

31. Steroids in Palliative Care GI bleed, gastritisGI bleed, gastritis Potentially catastrophicPotentially catastrophic PreventablePreventable H2 blocker, PPIH2 blocker, PPI

32. Steroids in Palliative Care TissueEffects Liver Increased gluconeogenesis Increased glycogen synthesis Skeletal Muscle Decrease glucose uptake Decrease protein synthesis Increased protein degradation Adipose Decrease glucose uptake Increase lipid mobilization General Anti-inflammatory: inhibit phospholipase A2 and production of leukotrienes and prostaglandins

33. Steroids in Palliative Care MyopathyMyopathy Aches and painsAches and pains WeaknessWeakness AmbiguousAmbiguous Decrease dose or discontinueDecrease dose or discontinue

34. Steroids in Palliative Care MiscellaneousMiscellaneous “moon facies,” Cushing“moon facies,” Cushing AddissonianismAddissonianism “Jitters,” poor sleep“Jitters,” poor sleep Weight gain, voracious appetiteWeight gain, voracious appetite OsteoporosisOsteoporosis

35. Steroids in Palliative Care Re-capRe-cap Multiple indicationsMultiple indications Variable evidenceVariable evidence Good anecdotal supportGood anecdotal support Dexamethasone PO/IV/SQDexamethasone PO/IV/SQ 4 – 16 mg/day4 – 16 mg/day Short term trialsShort term trials GUT PROTECTIONGUT PROTECTION