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Supportive Care of Cancer
- 1. Supportive Care of Cancer-- Part 2 Chirag Dave, Pharm. D. Candidate Class of 2012 Systems Pharmacology V
- 2. Learning Objectives 1. Explain the pathophysiology of chemotherapy induced nausea and vomiting (CINV). 2. Describe the classes of medications used to treat CINV; specifically where they act, when they should be used, and their major side effects. 3. Recognize Oral Cavity/GI tract complications associated with chemotherapy and how they can be prevented and treated. 4. Explore the concept of “Cancer-‐Related Fatigue” Side effects are what kill you!
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- 5. Overview • Estimated that 70-‐80% cancer patients experience chemotherapy induced nausea and vomiting, despite being treated for it. • Prophylaxis is the most effective method of managing CINV. • N/V can significantly affect quality of life (fatigue, treatment adherence, days off work, etc…) • What else? (Think physical implications) • Dehydration, electrolyte imbalances, malnutrition, aspiration pneumonia, and esophageal tears.
- 6. Definitions • Nausea: the subjective feeling of the need to vomit. • Vomiting: forceful expulsion of the stomach contents. • Retching: rhythmic contraction of the abdominal muscles without actual emesis.
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- 8. Pathophysiology of NV Areas involved in N/V Location Important Receptors Vomiting Center (VC) CNS H1 M1 NK1 5-‐HT3 Chemoreceptor Trigger Zone (CTZ) CNS 5-‐HT3 D2 NK1 Chemoreceptors GI System Periphery 5-‐HT3 Mechanoreceptors Chemoreceptors Vestibular System Periphery H1 M1 Cerebral cortex, Limbic system, Meninges, Thalamus & Hypothalamus CNS Complex
- 9. Vomiting Center • Located in the Medulla Oblongata. • Acts as the coordinator of the emetic response. • Receives afferent signals from CTZ, GI system, Vestibular system, and other areas of the brain. • Sends signals to effector organs (salivary glands, abdominal muscles, & cranial nerves)
- 10. CTZ • Chemoreceptors sense toxins and noxious substances (in blood & CSF). • This is where D2 receptors are located and where D2 antagonists act. • Also has mu-‐opioid receptors present.
- 11. GI System • GI mucosa contains enterochromaffin cells. • Contain large amount of body’s serotonin stores. • When chemically or physically stimulated/irritated, they release 5-‐HT. • This stimulates Cranial nerves IX, X (afferent nerves). • As well as VC & CTZ via 5-‐HT3 receptor activation.
- 12. Vestibular System • Implicated in motion sickness & vertigo. • Patients who are predisposed to motion sickness will have a harder time with chemotherapy. • Stimulate the VC through ACh and Histamine.
- 13. Cerebral Cortex & Limbic System • Implicated in anticipatory nausea/vomiting due to anxiety. • Which class of medications is often used to treat anxiety? • “Place & Taste” association is important to consider in treatment, especially with children • Can’t change the place. • Taste management.
- 14. CINV Classification • Acute Onset: • Occurs minutes-‐hours after drug administration. • Peaks after 5-‐6h • Commonly resolves within 24h. • Delayed-‐Onset: • Occurs >24h after CTX. • Commonly implicated agents: cisplatin, carboplatin, cyclophosphamide, doxorubicin. • Anticipatory: Incidence is 18-‐57%, and is more common in younger patients. • Breakthrough: vomiting that occurs despite Px that requires rescue antiemetic use. • Refractory: emesis that occurs despite Px and rescue antiemetic use.
- 15. Relevant Causes of NV • CNS disorders: brain metastases, anxiety. • Metabolic disorders: hyponatremia, uremia. • GI disorders: bowel obstructions, gastroparesis, distention • Medications: chemotherapy agents, antibiotics, antifungals, opiates, and irradiation. • Radiation can cause N/V, particularly when patients receive whole body or upper abdominal radiation.
- 16. Incidence & Severity of CINV 1. Agents used (refer to “Emetogenic Potential”). 2. Dosage of agents/duration of infusion 3. Schedule and Route of Administration 4. Concurrent radiation therapy 5. Patient factors: 1. Age: Younger (<50y/o) = More NV 2. Sex: Female 3. Prior CTX 4. Alcoholism: IMPROVES ability to tolerate NV 5. Previous history: motion sickness, other N/V
- 17. Emetogenic Potential Category Frequency in patients High emetic risk >90% frequency of emesis Moderate emetic risk 30-‐90% frequency of emesis Low emetic risk 10-‐30% frequency of emesis Minimal emetic risk <10% frequency of emesis • Antineoplastic agents’ emetogenic potential is established by the % of patients that experience emesis on the agent WITHOUT any anti-‐emetic therapy. • The risk of CINV is present for at least 3 days for “HIGH” risk CTX and 2 days for “MEDIUM” Risk CTX.
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- 21. Treatment of CINV • Various combinations of the following classes of medications are used, according to NCCN guidelines. 1. Serotonin Receptor Antagonists (5-‐HT3) 2. Dopamine Antagonists (D2) 3. NK-‐1 Receptor Antagonists 4. Systemic Corticosteroids (SCS) 5. Benzodiazepines (Bzd) 6. H2 blockers/PPIs
- 22. Recommended Prophylactic Combinations (IV Agents) Category Combination High (>90%) Day 1: 5-‐HT3 + SCS+ NK-‐1 Day 2-‐3: 5-‐HT3 (per institution) (+/-‐) H2/PPI (+/-‐) Bzd Moderate (30-‐90%) Day 1: 5-‐HT3 + SCS (+/-‐) NK-‐1 Day 2-‐3: 5-‐HT3 or SCS or NK-‐1 (+/-‐) H2/PPI (+/-‐) Bzd Low (10-‐30%) SCS or D2 (Metoclopramide or Prochlorperazine) (+/-‐) H2/PPI (+/-‐) Bzd Minimal (<10%) No routine prophylaxis All agents on Day 1 are started before chemotherapy (morning)
- 23. Breakthrough Emesis Management • The principle is to add an agent from a different drug class than the routine anti-‐ emetics. Recommended Classes: Used often Not used often Benzodiazepines Cannabinoids Dopamine Antagonists Scopolamine 5-‐HT3 SCS
- 24. 1. Serotonin Receptor Antagonists • Mechanism of Action: • Blocks 5-‐HT3 receptors, preventing Serotonin binding, thereby inhibiting afferent nerve transmission to VC. • PK/PD: • All agents are equally effective at equal doses. • Dose response curve is flat • Not more effective than other classes for delayed CINV (other than palonosetron). • Give 30 minutes prior to CTX. • Side effects: • *CONSTIPATION*…Treat with what? • QT Prolongation • Headache • Transient elevation of LFTs
- 25. 1. Serotonin Receptor Antagonists 4Half-‐life Metabolism Dose Cost Ondansetron 3-‐6h 3A4 substrate 16-‐24mg PO 8-‐24mg IV (MDD = 32mg) 30 tab x 4mg = $70.99 Granisetron (Patch too!) 6h PO 9h IV -‐ 2mg PO 0.01mg/kg IV (MDD = 1mg) 2 tab x 1mg = $45.99 1 patch = $359.98 Dolasetron (PO for CTX) 6-‐8h -‐ 100mg PO 5 tab x 100mg = $355.96 Palonosetron ~40h -‐ 0.25mg IV 1 vial = $406.98
- 26. 2. NK-‐1 Receptor Antagonists • Mechanism of Action: • Blocks NK-‐1 receptors, preventing Substance P from binding in the CNS. • PK/PD: • Watch for drug interactions: with CTX and other medications (e.g. Warfarin , OC) • 3A4 substrate, Inhibits 3A4, Induces 3A4 & 2C9 • Can be used for acute and delayed CINV, in combination with a 5-‐HT3 & SCS. • Give PO 1 hour prior to CTX, give IV 30 min prior TO CTX. • Side Effects: mild • Fatigue • Headache • Diarrhea
- 27. 2. NK-‐1 Receptor Antagonists Half-‐ life Metabolism Dose Cost Aprepitant (PO) 9-‐13h 3A4 substrate Inhibits 3A4 Induces 3A4 & 2C9 -‐125mg Day 1 -‐80mg on Day 2 & Day 3 3 day regimen = $383.99 Fosaprepitant (IV) 2min Rapidly converted to Aprepitant 115mg over 30 minutes, then 80mg on Day 2 & Day 3 1 vial (115mg) = $223.79 • +Warfarin (2c9): Monitor INR during the 7-‐10d period after administration. • +Oral Contraceptives: Decreases AUC for OCs, therefore use alternative method of contraceptive 1 month after administration.
- 28. 3. Dopamine Antagonists • Mechanism of Action: • Block D2 receptors, preventing Dopamine from binding in the CNS. • PK/PD: • Agent specific • Best used for breakthrough CINV, as PRN. • Side Effects: • *Somnolence* • Monitor for EPS symptoms (i.e. dystonia). • Pay attention to BBWs (i.e. with Olanzapine).
- 29. 3. Dopamine Antagonists Dose Cost Haloperidol 0.5-‐2mg PO/IV q4-‐6h PRN 90 tab x 1mg = $19.99 Metoclopramide 10-‐40mg PO/IV q4h or q6h PRN 30 tab x 5mg = $12.99 Olanzapine 2.5mg-‐5mg PO BID 30 tab x 10mg = ~$500 Prochlorperazine 25mg suppository q12h OR 10mg PO/IV q4h or q6h 12 Supp x 25mg = $33.99 30 tab x 5mg = $13.99 Promethazine 12.5-‐25mg PO or IV (via central line) q4h 30 tab x 12.5mg = $15.99
- 30. Misc. Agents 4. Systemic Corticosteroids: Main agent used is Dexamethasone • Exact MoA in CINV is unknown, but enhances efficacy of 5-‐HT3s (~20%) • Have anti-‐tumor properties (used in some regimens, i.e. CHOP) • Useful for acute and delayed CINV. 5. Benzodiazepines: Main agent used is Lorazepam • Used for anticipatory CINV due to anxiety. • Take night before/morning of. 6. H2s & PPIs: Used for dyspepsia.
- 31. Misc. Agents 7. Cannabinoids: Dronabinol, Nabilone • Used in refractory cases. • Exact mechanism is not known, but there are cannabinoid receptors in the CTZ and VC. 8. Scopolamine: • Antagonizes serotonin and histamine. • Used in motion sickness. • Patch is applied behind the ear.
- 32. Oral cavity &GI Complications
- 33. Overview • Approximately 40% of CTX patients have oral cavity complications, and almost 100% with head/neck radiation. • GI tract complications are also an issue as chemotherapy and radiation affects gut flora and may cause structural alterations. • Some of the issues that result are mucositis, xerostomia, infection, bowel movement changes, and intestinal malabsorption.
- 34. Mucositis • It is the inflammation and ulceration of affected mucosal membranes. • Most often, non-‐keratinized mucosa is affected @ basal layers. • VERY PAINFUL…It feels like you’re swallowing razors. • Occur about 5-‐7d after CTX (cell turnover is 7-‐14d), and resolves completely in 1-‐3 weeks. • Happens most often with antimetabolites (i.e. methotrexate, cytarabine) and antitumor antibiotics
- 35. Mucositis Presentation: • Severe pain, often requiring systemic opioids. • Decreased ability to eat, speak, swallow. • Infection (viral, bacterial, or fungal), most often local. Treatment: Palliative and Preventative • Prevention: • Time between CTX and Radiation. • Chlorhexidine rinses…AVOID ALCOHOL rinses (i.e. Listerine). • Cryotherapy: Ice chips in the mouth during treatment. • Palifermin: • A keratinocyte growth factor, resulting in proliferation of epithelial tissue. • Give IV 3 consecutive days before myelotoxic therapy. • Side effect: rash, edema.
- 36. Mucositis Palliation: • Magic mouthwash, BMX or its variants • Benadryl -‐ Inflammation • Maalox – Acid indigestion • Xylocaine – Topical anesthetic • Nystatin -‐-‐ ___________ • Swish, gargle, & spit 3-‐6x/day • Gelclair – Bioadherent gel barrier • Opioids
- 37. Xerostomia • Damage to salivary glands leads to “dry mouth” • Other effects: • Lower salivary pH • Decrease salivary IgA • *Altered sense of taste
- 38. Xerostomia Treatment: • Amifostine: • Preventative therapy • Not for everyone due to Cost & SEs (N/V, hypotension). • Pilocarpine: • Stimulates salivary flow. • Cholinergic side effects. • Any other agents that stimulate salivation (sugar free candy/ gum). • Why sugar free? • Salivary substitutes (MANY…but Biotene may be familiar).
- 39. Oral Complications • Because of all this, we see increased infection (aided by neutropenia), dental caries (tooth decay), and decalcification. • Prevention of caries is done through fluoride rinses and good dental hygiene. • What about…Osteonecrosis of the jaw?
- 40. Lower GI Complications • Microvilli on intestinal cells atrophy and function is affected. • Decreased medication absorption. Constipation: • Vinca alkaloids are known offenders (cause autonomic nerve dysfunction) • Also a troubling side effect of 5-‐HT3 antagonists.
- 41. Lower GI Complications Diarrhea: • Sometimes due to the cancer itself, often due to medications (i.e. 5-‐FU, cytarabine) • Irinotecan: SEVERE diarrhea & other cholinergic symptoms • Early (within 24h, linked to PSNS stimulation) and DELAYED diarrhea • Issues: dehydration, F&E imbalances, other cholinergic symptoms • Treatment: • F&E Management • Early: Atropine @ time of treatment. • Delayed: Loperamide @ promptly after first episode. • Octreotide: somatostatin analog which has many effects but reduction in GI motility + F&E retention is what we’re interested in.
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- 43. Overview • Cancer-‐ related fatigue (CRF) is rarely an isolated symptom and occurs with pain, distress, anemia, and sleep disturbances. • CRF can severely affect QoL, which is most of the battle, and activities of daily living (ADLs)
- 44. Causes • Anemia • Decreased RBC production & increased RBC destruction à net negative blood volume. • Managed acutely with blood transfusions and chronically with epoetin/darbopoetin alpha. • Pain • Nutritional deficits • Emotional distress
- 45. Management • Screening should be systematic and at the start of every visit (using a standardized assessment scale). • Nutritional consults • Exercise! • Limit naps to <1h to not interfere with night-‐time sleep. • Cognitive behavioral therapy.
- 46. Pharmacologic Treatment? • Psychostimulants can be considered, but use remains investigational. • Methylphenidate has more evidence of benefit than modafinil. • Caffeine?
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- 48. Additional Resources Lohr L. Nausea and Vomiting. In: Koda-‐Kimble MA, Young LY, Alldredge BK et al., eds. Applied Therapeutics: The Clinical Use of Drugs. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2009: 1-‐12. Falla, L. Implications of recent guideline updates on the management of chemotherapy induced nausea and vomiting. The Oncology Pharmacist. 2o1o; 3(6): 4-‐10. Ettinger DS, Armstrong DK, Barbour S et al. Antiemesis (Version 1.2012). NCCN Guidelines. 2011. Berger AM, Abernethy PA, Atkinson A et al. Cancer-‐Related Fatigue (Version 1.2011). NCCN Guidelines. 2010. Worthington HV, Clarkson JE, Bryan G et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane database of systematic reviews. 2011; 4: 1-‐275