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Responding to the Challenge of Chemotherapy-Induced Nausea and Vomiting

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Responding to the Challenge of Chemotherapy-Induced Nausea and Vomiting Responding to the Challenge of Chemotherapy-Induced Nausea and Vomiting Rudolph M. Navari, MD, PhD, FACP Professor of Medicine Associate Dean and Director Clinical Director, Harper Cancer Research Institute Indiana University School of Medicine – South Bend South Bend, Indiana A nervous-appearing 68-year-old female presents to the infusion center to receive her 1st cycle of AC → T for newly diagnosed breast cancer. Her past medical history includes hypertension, hypothyroidism, and generalized anxiety. Her risk factors for chemotherapy-induced nausea and vomiting include all of the following EXCEPT … 25% 1. Female Gender 25% 2. Anxiety 25% 3. Highly emetogenic chemotherapy 25% 4. Advanced Age 1 Highly Emetogenic Chemotherapy • Pre-chemotherapy (Prevent Acute N/V): Dexamethasone 5-HT3 Receptor Antagonist NK-1 Receptor Antagonist • Post-chemotherapy (Prevent Delayed N/V): Dexamethasone NK-1 Receptor Antagonist A 70-year-old male with a PMH of a-fib, MI, CAD, chronic alcoholism, and GERD presents for cycle #1 of carboplatin + paclitaxel → bevacizumab for advanced lung cancer. His risk factors for CINV include … 25% 1. History of chronic alcoholism 25% 2. Age 25% 3. Male gender 25% 4. History of GERD 2 Moderately Emetogenic Chemotherapy • Pre-chemotherapy (Prevent Acute N/V): Dexamethasone 5-HT3 Receptor Antagonist • Post-chemotherapy (Prevent Delayed N/V): Dexamethasone 3 Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy Rank 19831 19932 19953 19994 1 Vomiting Nausea Nausea Nausea 2 Nausea Constantly Loss of hair Loss of hair tired 3 Loss of hair Loss of hair Vomiting Constantly tired 4 Thought of Effect on Constantly Vomiting coming for family tired treatment 5 Length of Vomiting Having to Changes in time have the way treatment an injection things taste takes 1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-208; 2. Griffin AM, et al. Ann Oncol. 1996;7:189-195; 3. De Boer-Dennert M, et al. Br J Cancer. 1997;76:1055-1061; 4. Lindley C, et al. Cancer Pract. 1999;7:59-65. Syndromes Associated With CINV (1 of 2) • Acute emesis – Usually starts within 1-2 hours after administration – Peak intensity within 5-6 hours, resolution 12-24 hours • Delayed Emesis – Peak onset 48-72 hours after chemotherapy, diminishing after 1-3 day – Occurs in 50-90% of patients treated with highly emetogenic regimens – 35-70% with moderately emetogenic therapy – More common with platinum containing regimens • Breakthrough CINV – Nausea and vomiting occurring despite preventive therapy 4 Syndromes Associated With CINV (2 of 2) • Anticipatory emesis – Associated with uncontrolled emesis during prior chemotherapy • Refractory CINV – N/V occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in previous cycles • Potential to cause: – Dehydration and electrolyte imbalance – Impaired health-related quality of life • Negative impact on activities of daily living – Rehospitalization Chemotherapy-Induced Emesis Risk Factors • Patient-related risk factors1 – Younger age – Female gender – No/minimal prior history of alcohol use – Prior CINV –Anxiety • Treatment-related risk factors1,2 – Moderate to high emetogenicity of chemotherapy agents or regimens – Moderate to high drug dose 1. Gregory RE, et al. Drugs. 1998;55:173-189; 2. Hesketh PJ, et al. J Clin Oncol. 1997;15:103-109. 5 Risk Factors for CINV Chemotherapy-Specific Factors • Use of moderately or highly emetogenic regimens such as – AC (Anthracycline + cyclophosphamide) - High – Carboplatin-based regimens - Moderate – Cisplatin-based regimens - High – Cyclophosphamide-based regimens - Moderate – FOLFOX/FOLFIRI - Moderate – ABVD - Moderate • Short IV infusion time • Repeated cycles of chemotherapy Navari RM. J Support Oncol. 2003;1(2):89-103; Hesketh PJ, Oncologist. 1999;4(6):191-196; NCCN Clinical Practice Guidelines In Oncology. Antiemesis. Version 2.2010. Available at: http:://www.nccn.org. 6 Neurotransmitters in CINV Dopamine/ Cannabinoids DA RAs Serotonin Endorphins Emetic reflex Substance P Acetylcholine GABA Histamine GABA = gamma-aminobutyric acid Classes of Antiemetics Drug Pathway Target Side Effects Ondansetron Serotonin Acute Headache, constipation, Palonosetron asthenia, diarrhea, sedation. Aprepitant, Substance P Delayed Prolonged INR, Netupitant, slows dex, benzo metabolism Rolapitant Dexamethasone Prostaglandins? Delayed HTN, glucose, psych. Breakthrough Prochlorperazine Dopamine Breakthrough Akathisias, sedation, dizziness Metoclopramide Gut motility, Delayed dopamine Haloperidol Dopamine Delayed Akathisias, dystonia, prolong QT, Olanzapine Breakthrough urinary retention, dizziness. Olanzapine Dopamine Acute, Sedation Serotonin Delayed Dronabinol Cannabinoid Breakthrough Sedation, dizziness, dysphoria, Refractory euphoria, hallucinations Diphenhydramine Histamine Breakthrough Sedation 7 Dexamethasone • Mechanism of action unknown • More effective than placebo and prochlorperazine in some controlled trials • Effective against vomiting caused by variety of anticancer agents, including cisplatin • efficacy in combination antiemetic regimens • No significant side effects when used at recommended doses and schedules • Possible insomnia and hyperglycemia • No incidence of infections or change in frequency and site of metastases • Inexpensive The Best Dose of Dexamethasone? • Rx: Dexamethasone • Indication: Acute emesis • Patients: Cisplatin • Results: All received ondansetron 8 mg IV randomized to single IV dexamethasone doses Dexamethasone N No Emesis No Nausea 4 mg 133 69% 61% 8 mg 136 69% 61% 12 mg 130 79% 67% 20 mg 131 83% 71% • Conclusions: No difference in adverse effects. Dexamethasone 20 mg should be the standard (20 vs 12 mg: 4% observed – 95% CI 5-14%) The Italian Group. J Clin Oncol. 2000;18(19):3409-3422. 8 Mechanism of Action of Pharmacologic Therapies • Older agents of low therapeutic index – Dopamine RA’s • Dopamine receptor blockage in area postrema – Cannabinoids • Agonist antiemetic effect on enterochromaffin cells •5HT3 RAs – Binding to 5HT3 receptors in periphery & CNS • Primary mechanism for acute emesis control • NK-1 RA’s – Predominantly central action • agents must cross blood-brain barrier Hesketh PJ, et al. N Engl J Med. 2008;358:2482-2494 5-HT3 Receptor Antagonists • First Generation: Ondansetron Granisetron Dolasetron • Second Generation: Palonosetron 9 1st Generation 5-HT3 Antagonists Are Therapeutically Equivalent • Highest Level Evidence & Pts receiving MEC* (N = 1085) Not Debated Oral granisetron 2 mg – MASCC 2004 IV ondansetron 32 mg – NCCN 2004 71.0 72.0 60.0 • 1st Generation Agents are 59.0 58.0 58.0 Therapeutically Equivalent – Dolasetron – Ondansetron – Granisetron Complete Control (%) • 1st Generation oral and IV Total Nausea Emesis doses equally effective 80% of pts received prophylactic steroids *Cyclophosphamide 500-1200 mg/m2, carboplatin ≥ 300 mg/m2 MEC = moderately emetogenic chemotherapy. Perez EA, et al. J Clin Oncol. 1998;16:754-760. Mechanisms for Differences in Efficacy of 5-HT3 antagonists • Palonosetron has greater efficacy in prevention of acute & delayed CINV •Why? – Higher binding affinity & longer t1/2 cannot fully account for this – Palonosetron has a unique binding site on the 5-HT3 receptor • Increases its affinity at other sites Jin Y et al. Eur J Cancer Care (Engl). 2012 Apr 22. Epub ahead of print. 10 Palonosetron Indication • Palonosetron 0.25 mg is indicated for: – The prevention of acute N/V associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy – The prevention of delayed N/V associated with initial and repeat courses of moderately emetogenic cancer chemotherapy • The first and only 5-HT3 receptor antagonist specifically indicated for delayed CINV Pooled Efficacy: Moderately Emetogenic Chemotherapy (N = 1132) 100.0 80.0 72.0 65.3 64.0 60.6 60.6 Palonosetron 0.25 mg 60.0 * * 46.8 **** Palonosetron 0.75 mg 40.0 Comparators (OND/DOL) 20.0 Complete response (%) 0.0 0-24 h 24-120 h *P ≤ 0.025 . Rubenstein EB, et al. Proc Am Soc Clin Oncol. 2003;22:729. Abstract 2932 11 Complete Response: Acute and Delayed Emesis With Highly Emetogenic Chemotherapy Palonosetron 0.25 mg (n = 223) Palonosetron 0.75 mg (n = 223) 100 Ondansetron 32 mg (n = 221) 80 65.5 59.2 57.0 60 45.3 48.0 42.2 38.9 40.8 33.0 40 (% of patients) of (% 20 Complete Response 0 Acute: 0-24 Delayed: 24-120 Overall: 0-120 (Day 1) (Days 2-5) (Days 1-5) Complete Response (CR) = no emesis, no rescue medication. Time (h) Aapro M, et al. Support Care Cancer. 2003; Abstract A-17. Complete Response in Patients Taking Concomitant Dexamethasone (N = 447) 100 Palonosetron 0.25 mg (n = 150) Palonosetron 0.75 mg (n = 150) 80 Ondansetron 32 mg (n = 147) 64.7 62.7 60 55.8 * * 42.0 41.3 40.7 35.3 40 28.6 25.2 (% of patients) of (% Complete Response 20 0 Acute: 0-24 Delayed: 24-120 Overall: 0-120 (Day 1) (Days 2-5) (Days 1-5) Time (h) *97.5% CIs and 2-sided Fisher’s exact test (significance level = 0.025) indicate a difference between palonosetron and ondansetron. Of note, prophylactic dexamethasone was given at the investigator’s discretion (not randomized). Therefore, it is not appropriate to compare this subgroup to the overall population. Aapro M, et al. Support Care Cancer. 2003; Abstract A-17. 12 Palonosetron plus dexamethasone versus granisetron plus dexamethasone in patients receiving AC/EC and CDDP regimens Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomized, comparative phase III trial. Lancet Oncol. 2009;10(2):115-124. Palonosetron + Dexamethasone vs Granisetron + Dexamethasone in Japanese Patients Complete Response 90 80 † Palonosetron 0.75 mg IV (n = 555) 75.3 73.3 Granisetron 40 mcg/kg IV (n = 559) 70 60 56.8* 51.5* 50 44.5 40.4 40 30 (% of patients) 20 Complete Response 10 0 Acute (0-24 h) Delayed (24-120 h) Overall (0-120 h) * P = 0.0001 * P = 0.0001 †Statistical non-inferiority (lower limit of 95% CI > -10%; 95% CI [-2.7; 7.27]). *Statistically significant difference, significance level = 0.05). Saito M, et al. Lancet Oncol. 2009;10:115-124.
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