Why Patients Experience Nausea and Vomiting and What to Do About It

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1 Why Patients Experience Nausea and Vomiting and What to Do About It Rebecca Clark-Snow, RN, BSN, OCN The University of Kansas Cancer Center Westwood, Kansas

2 Multiple Roles for Supportive Care in Cancer Reduce or eliminate associated symptoms and side effects Preserve or improve quality of life Enhance the use of the most effective antineoplastic agents Positively affect survival and the quality of that survival Cancer patients are living longer and better lives, thanks to better symptom control, more effective therapies, and a deeper understanding of cancer Dr Harold Varmus, Director NCI, PBS Newshour, September 24, 2012

3 CONTROLLING EMESIS - Making Progress - Understanding the clinical problem Understanding the physiology and neuropharmacology

4 CONTROLLING EMESIS - Making Progress - Understanding the clinical problem Understanding the physiology and neuropharmacology

5 NEUROTRANSMITTERS AND ANTIEMETIC PATHWAYS: Targeting Key Pathways to Influencing Emetic Control Dolasetron Granisetron Ondansetron Palonosetron Aprepitant Netupitant Rolapitant Serotonin/ 5-HT 3 RAs Substance P/ NK 1 RAs Dopamine/ D 2 RAs GABA Emetic reflex Histamine Cannabinoids Endorphins Acetylcholine GABA, gamma-aminobutyric acid; NK, neurokinin; RAs, receptor antagonists DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin 1.Gralla RJ, et al. J Clin Oncol. 1999;17: Grunberg SM, Hesketh PJ. N Engl J Med. 1993;329: Hesketh PJ. Support Care Cancer. 2001;9: RAs = receptor antagonists

6 Neuropharmacology of Chemotherapy-Induced Emesis

7 Risk level High Risk Factors for Radiation-Induced Nausea and Vomiting Irradiated area TBI Antiemetic guidelines 1. Prophylaxis with 5-HT3 antagonist 2. + Dexamethasone MASCC evidence (level of scientific confidence/level of consensus) 1-High/High 2-Moderate/High ASCO evidence (type of evidence/grade of recommendation) Moderate Upper abdomen Prophylaxis with 5-HT3 antagonist High/High II/A Low Minimal 1-Lower thorax region, pelvis 2-Cranium (radiosurgery), craniospinal Head and neck, extremities, cranium, breast Prophylaxis or rescue with 5-HT3 antagonist Rescue with dopamine receptor antagonist or 5-HT3 antagonist 1-Moderate/High 2-Low/High Low/High 1- II/B 2-III/C 1-III/B 2-IV/D IV/D

8 Major Antiemetic Classes Therapy: Based on Physiology and Clinical Studies Corticosteroids Dexamethasone in acute emesis: Appropriate doses in high-risk and moderate-risk settings have been defined Single dosing is as good as multiple in most settings Dexamethasone in acute and delayed emesis: Documentation of safety Serotonin antagonists Remain the agents of choice in broad antiemetic applications NK 1 antagonists Benefits in both acute and delayed emesis

9 Antiemetic Drugs Mode of action Class Antiemetic efficacy of treatments Acute emesis Delayed emesis 5-HT3 receptor 5-HT3 antagonists ++ +/- NK-1 receptor NK-1 antagonists + ++ Multiple Dopamine D2 receptor Steroids Benzamides GABA-chloride channel complex Benzodiazepines (+) (+) Dopamine D2 receptors Multiple receptors Cannabinoid receptor type 1 receptor Classical neuroleptics Olanzapine +(+) (+) (+) + +(+) (+) (+) + Cannabinoids (+) (+) Muscarinic/cholinergic recs Antihistamines - - Jordan K, et al. Crit Rev Oncol Hematol. 2007;61(2):

10 Rolapitant A potent, selective, long-acting NK-1 receptor antagonist Long t 1/2 (~180 h) suggests a single dose may be sufficient to prevent chemotherapy-induced nausea and vomiting during the entire 5 day (0-120 h) at risk period 180 mg dose achieved >90% NK-1 receptor occupancy in the brain and maintained level for up to 5 days post a single dose Reduced risk of drug interaction; not an inducer or inhibitor of CYP3A4

11 NEPA: A Combination of Netupitant (NETU) and Palonosetron (PALO) An oral fixed-dose combination of netupitant, a new highly selective NK-1 receptor antagonist and palonosetron, a pharmacologically distinct and clinically superior agent compared to the older 5-HT3 receptor antagonist Developed to provide a convenient treatment, consistent with treatment guidelines for antiemetic prophylaxis NEPA targets two critical pathways associated with acute and delayed CINV, the serotonin- and substance P-mediated pathways 1. Gralla R, et al. Eur J Cancer. 2013;49 (suppl 2): Abstract Aapro M, et al. Eur J Cancer. 2013; 49(suppl 2): Abstract Gralla RJ, et al. Eur J Cancer. 2013;49(suppl 2): Abstract Feyer P, et al. Ann Oncol. 2011;22(1): Rojas C, et al. Eur J Pharmacol. 2012;684(1-3):1-7.

12 CONTROLLING EMESIS - Making Progress - Understanding the clinical problem Understanding the physiology and neuropharmacology

13 ANTIEMETIC TREATMENT Goals With Chemotherapy: All major guideline groups: The strategy is to prevent nausea and vomiting, rather than treat Complete control in all settings No side effects Convenient and easy to use

14 Identify emetic problem Acute emesis Delayed emesis ANTIEMETIC TREATMENT Assessing Effectiveness Conditioned or anticipatory emesis Vomiting Number of episodes: Complete control Nausea Intensity (patient-generated visual analog scale [VAS]) Presence or absence: Complete control Personalizing care and risk Identifying key patient risk factors

15 RISK FACTORS FOR EMESIS AND CONTROL - Clinical Risk Factors and Personalization - Chemotherapy regimen Gender Age Chronic alcohol intake history

16 Making Progress in Controlling Emesis Can we achieve complete elimination of chemotherapy-induced nausea and vomiting? Nausea and vomiting are well correlated but the control of vomiting exceeds the control of nausea and more progress has been made in the control of vomiting Our strategy is to maximize vomiting control and then expand on nausea control How should we approach the issue of complete elimination of CINV?

17 Areas of Greatest Need for Improvement Marked improvement in controlling emesis has been made since 1980 However, help needed in Control of delayed emesis Control of acute emesis, especially for women (particularly with AC chemotherapy) Control of nausea Enhanced communication with patients about the effectiveness of their individual treatments AC, cyclophosphamide, doxorubicin

18 Nausea and Vomiting: Observations and Conclusions Progress in antiemetic control reflects the use of evidence from both clinical and basic studies Current treatment is based on a sound understanding of the physiology involved and the neuropharmacology of available agents Future research needs to build on increasing the understanding of the physiology of nausea and vomiting and the completion of high quality clinical trials