Chemotherapy-Induced Nausea and Vomiting: Strategies for Achieving Optimal Control

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1 Chemotherapy-Induced Nausea and Vomiting Strategies for Achieving Learning Objectives Describe the challenges of assessing nausea in patients undergoing chemotherapy and the impact of nausea and also vomiting on patient health and QoL Review evidence-based data and guidelines on the management of delayed CINV Develop well-designed communication strategies to ensure that patients are armed with adequate knowledge regarding their prescribed therapy, including potential adverse events CINV = chemotherapy-induced nausea and vomiting; QoL = quality of life. Burden of CINV Debilitating AEs from cytotoxic chemotherapy; can lead to: Dehydration, electrolyte imbalance Anorexia Hospitalization Impaired QoL Patient concern over CINV can affect adherence to antineoplastic medicines Controlling CINV is an important component of maintaining patients QoL during cancer treatment AE = adverse event. Salsman JM, et al. J Natl Compr Canc Netw. 2012;10: ; Grunberg SM. J Support Oncol. 2004;2(1 Suppl 1):1-10. PCE Oncology

2 Clinical Impact of CINVINV Potential for treatment interruption or discontinuation Negative implications for QoL, ADLs 1 Physiologic manifestations 1-3 Malnutrition Anorexia Weight loss Dehydration Esophageal tears Patients With No Impa act on Daily Life (%) Multicenter Study Reporting No Impact on Daily Life for Nausea and Vomiting Domains on Day 6 Post Chemotherapy 2 (N = 298) All Patients (n = 144/271 nausea, n = 196/267 vomiting) Nausea Vomiting HEC Patients (n = 20/55 nausea, n = 32/53 vomiting) MEC Patients (n = 124/216 nausea, n = 164/214 vomiting) ADLs = activities of daily living; MEC = moderately emetogenic chemotherapy. 1. Wiser W, et al. Oncology. 2005;19: ; 2. Bloechl-Daum B, et al. J Clin Oncol. 2006;24: ; 3. Navari RM. Community Oncol. 2007;4(Suppl 1):3-11. Financial Impact of CINV Patient 1 : Increases direct costs Medication Office visits Hospitalizations ti Emergency room visits Increases indirect costs Missed work Caregiver 1 : Missed work to care for patient/family member Total Estimated Direct Medical Costs per Patient per Month 2 $12,000 $10,000 $8,000 $6,000 $4,000 $2,000 $0 $10,720 Uncontrolled CINV $8,923 Controlled CINV Uncontrolled CINV defined as having 1 office visit, emergency room visit, or hospitalization with ICD-9 diagnosis of nausea/vomiting or dehydration. 1. Broder MS, et al. Am Health Drug Benefits. 2014;7: ; 2. Shih YCT, et al. Cancer. 2007;110: CINV Remains a Significant Challenge % of Patients With CINV Despite Antiemetic Therapy CINV (%) 70% 60% 50% 51% 62% Therapy consistent with guidelines Therapy inconsistent with guidelines 46% 48% Patients Experiencing 40% 30% 20% 10% 0% HEC MEC Data from a prospective observational study enrolling chemotherapy-naïve patients who received single-day HEC or MEC at 4 oncology practice networks, all using electronic medical record systems, in Georgia, Tennessee, and Florida. CINV defined as emesis or clinically significant nausea on days 1-5. HEC = 5-HT 3 + NK 1 + CS on day 1; NK 1 on days 2-3; CS on days 2-4. MEC = 5-HT 3 + NK 1 + CS on day 1; 5-HT 3, NK 1, or CS on days 2-3. CS = corticosteroid; 5-HT 3 = 5-hydroxytryptamine-3 (serotonin); NK 1 = neurokinin-1. Gilmore JW, et al. J Oncol Pract. 2014;10: PCE Oncology

3 Case Study: Amanda 33-year-old woman with a new diagnosis of breast cancer Social history: Smoker, drinks socially, exercises regularly Medical history: Hypothyroidism, anxiety, gastroesophageal reflux disease, nausea during pregnancy First cycle of chemotherapy: Cyclophosphamide 600 mg/m 2 IV, doxorubicin 60 mg/m 2 IV on day 1 (pegfilgrastim support) Repeated every 14 days for 4 cycles IV = intravenous. CINV: Risk Factors Risk of CINV increases with the number of risk factors Patient-Related Treatment-Related Previous episodes of CINV Chemotherapy regimen Age <50 years Chemotherapy dose Female sex Route, rate of administration Pregnancy-induced Emetogenicity of treatment nausea/vomiting regimen History of motion sickness History of limited alcohol intake Grunberg SM. J Support Oncol. 2004;2(Suppl 1):1-10; Feinberg BA, et al. Community Oncol. 2010;7: CINV: Additional Risk Factors Physiologic Brain metastases Electrolyte disturbances Gastroparesis Gastritis Concurrent medications Bowel obstruction Vestibular dysfunction Behavioral Lack of guideline adherence Patient expectation of nausea Prechemotherapy anxiety PCE Oncology

4 Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy Rank Vomiting Nausea Nausea Nausea Fatigue 2 Nausea Chronic fatigue Hair loss Hair loss Nausea 3 Hair loss Hair loss Vomiting 4 5 Thought of coming for treatment Length of treatment time Effect on family Vomiting Chronic fatigue Injections Chronic fatigue Vomiting Changes in how things taste Sleep disturbances Weight loss Hair loss Coates A, et al. Eur J Cancer Clin Oncol. 1983;19:203-8; Griffin AM, et al. Ann Oncol. 1996;7: ; De Boer-Dennert M, et al. Br J Cancer. 1997;76: ;Lindley C, et al. Cancer Pract. 1999;7: Case Study: Sid 65-year-old man with lung cancer Social history: Former smoker; nondrinker Medical history: Myocardial infarction 2 years ago; being treated for hypertension and dyslipidemia Scheduled for second cycle of chemotherapy, but had nausea/vomiting several days after initiation of first cycle Chemotherapy regimen: carboplatin, pemetrexed, bevacizumab IV on day 1 Every 21 days for 4-6 cycles Definitions of CINV Acute: onset within minutes to hours of administration of chemotherapy Resolves in 24 hours Delayed: occurs 24 hours after administration of chemotherapy Typically resolves in 3 days Occurs in 50%-90% of patients receiving HEC and in 35%-70% of those treated with MEC in absence of prophylaxis Breakthrough/refractory: occurs despite appropriate prophylaxis; requires rescue medication, sometimes repeatedly Anticipatory: occurs before subsequent chemotherapy cycles Associated with poor control of CINV in a previous cycle PCE Oncology

5 Conceptual Model of Acute and Delayed CINV 5-HT 3 sensitive phase Prokinetic-sensitive phase Emesis 5-HT NK 1 -sensitive phase Intensity of Steroid-sensitive phase Disrupted gut motility Cell breakdown products Time (Days) Adapted from Andrews PL, Davis CJ. In: Andrews PL, Sanger GJ. Emesis in Anti-cancer Therapy: Mechanisms and Treatment. Chapman and Hall Medical; 1993: Neurotransmitters in Emesis Dopamine (D2) Histamine Cannabinoids Endorphins Emetic Reflex Serotonin (5-HT 3 ) Acetylcholine Substance P (NK 1 ) γ-aminobutyric acid Slide courtesy of Paul Hesketh, MD. Signaling Pathways Involved in CINV Brainstem Vomiting Center Area postrema Chemoreceptor trigger zone Nucleus tractus solitarius Dorsal motor nucleus of the vagus nerve Substance P/NK 1 receptors a Serotonin/5-HT 3 receptors GI Vagal Afferent Nerve Fibers Serotonin/5-HT 3 receptors Substance P/NK 1 receptors a Studies suggest NK 1 RAs in the brain are the primary site of anti-cinv activity for NK 1 RAs. RA = receptor antagonist. Aziz F. Ann Palliat Med. 2012;1: PCE Oncology

6 Key Principles of Antiemetic Therapy Goal No emesis or nausea Administration i ti Treatment choice Other considerations Administer prophylactically Combine agents with differing mechanisms Match antiemetic to emetogenic potential of chemotherapy Multidrug regimen: base on most emetogenic agent Schedule antiemetics for duration of risk of CINV Individualize regimens Prior experience with antiemetics Patient risk factors Lowest fully effective antiemetic dose(s) before chemotherapy PO vs IV antiemetics: convenience to patients, clinicians Choice based on cost, patient preference Drug-drug interactions of current NK 1 RAs Potential for serotonin syndrome Complications of repeated corticosteroid dosing PO = oral. Emetogenic Potential of Single Antineoplastic Agents High >90% of patients at risk Moderate 30%-90% of patients at risk Low 10%-30% of patients at risk Minimal <10% of patients at risk NCCN Clinical Practice Guidelines in Oncology. Antiemesis Version Emetogenic Potential of IV Antineoplastic Agents Level Agent HEC MEC AC combination, defined as doxorubicin or epirubicin with cyclophosphamide Carboplatin AUC 4 Carmustine >250 mg/m 2 Aldesleukin >12-15 million IU/m 2 Amifostine >300 mg/m 2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin AUC <4 a Carmustine a 250 mg/m 2 Cisplatin Cyclophosphamide >1500 mg/m 2 Dacarbazine Doxorubicin 60 mg/m 2 Clofarabine Cyclophosphamide 1500 mg/m 2 Cytarabine >200 mg/m 2 Dactinomycin a Daunorubicin a Dinutuximab Doxorubicin a <60 mg/m 2 Epirubicin a 90 mg/m 2 Idarubicin Epirubicin >90 mg/m 2 Ifosfamide 2 g/m 2 per dose Mechlorethamine Streptozocin Ifosfamide a <2 g/m 2 per dose Interferon alfa 10 million IU/m 2 Irinotecan a Melphalan Methotrexate a 250 mg/m 2 Oxaliplatin a Temozolomide Trabectedin a a May be highly emetogenic in some patients. AC = anthracycline + cyclophosphamide. NCCN Practice Guidelines in Oncology. Antiemesis Version PCE Oncology

7 Emetogenic Potential of Oral Antineoplastic Agents Level High or moderate Low or minimal Altretamine Busulfan ( 4 mg/d) Ceritinib Crizotinib Cyclophosphamide ( 100 mg/m 2 /d) Estramustine Etoposide Lenvatinib Agent Lomustine (single day) Mitotane Olaparib Panobinostat Procarbazine Rucaparib Temozolomide (>75 mg/m 2 /d) Trifluridine/tipiracil Afatinib Dabrafenib Melphalan Temozolomide Alectinib Erlotinib Mercaptopurine ( 75 mg/m 2 /d) Axitinib Everolimus Methotrexate Thalidomide Bexarotene Fludarabine Nilotinib Thioguanine Bosutinib Gefitinib Osimertinib Topotecan Busulfan (<4 mg/d) Hydroxyurea Pazopanib Trametinib Cabozantinib Ibrutinib Pomalidomide Tretinoin Capecitabine Idelalisib Ponatinib Vandetanib Chlorambucil Imatinib Regorafenib Vemurafenib Cobimetinib Ixazomib Ruxolitinib Venetoclax Cyclophosphamide Lapatinib Sonidegib Vismodegib (<100 mg/m 2 /d) Lenalidomide Sorafenib Vorinostat Dasatinib Sunitinib NCCN Clinical Practice Guidelines in Oncology. Antiemesis Version Pharmacologic Agents for CINV Serotonin receptor antagonists (5-HT 3 RAs) Neurokinin-1 receptor antagonists (NK 1 RAs) 5-HT 3 RA/NK 1 RA combination Olanzapine Corticosteroids Evolution of Antiemetics for CINV 1980s 1990s High-dose Approval of Approval of metoclopramide first-generation second-generation 5-HT 3 RAs 5-HT (ondansetron 3 RA (palonosetron) and granisetron) Approval of first oral NK 1 RA (aprepitant) Approval of IV NK 1 RA (fosaprepitant) Approval of oral lfixed-dose dd combination (palonosetron + netupitant) Approval of oral NK 1 RA (rolapitant) PCE Oncology

8 Considerations in Agent Selection: Comparison of 5-HT 3 RAs Agent Dolasetron Granisetron Ondansetron Palonosetron Recommended Dose 100 mg PO 1 mg (max) IV or 2 mg PO; 34.3 mg patch; 10 mg SC ER 8-16 mg IV or mg PO 0.25 mg IV (0.5 mg PO) Equivalent safety/efficacy at equivalent doses; can be used interchangeably Single dose preferred Palonosetron Longer half-life (40 hours) than other agents in class Greater 5-HT 3 receptor binding affinity ASCO = American Society of Clinical Oncology; ER = extended release; SC = subcutaneous. 1. NCCN Clinical Practice Guidelines in Oncology. Antiemesis Version ; 2. Basch E, et al. J Clin Oncol. 2011:29: ; 3. De Leon A. Proc (Bayl Univ Med Cent). 2006;19: Pharmacokinetic and Physiologic Differences Among 5-HT 3 RAs 5-HT 3 RA Half-life, Hours Binding Affinity, pki Dolasetron ~7.0 ~7.6 Granisetron ~9.0 (ER ~24) ~8.9 Ondansetron ~4.0 ~8.4 Palonosetron ~40.0 ~10.5 pki = concentration. Aapro M, et al. Springer Science & Business Media. Nov 12, 2013 ; Sustol [prescribing information]. Heron Therapeutics; HT 3 RAs: Treatment-Related Adverse Reactions Adverse Reaction Palonosetron mg IV (n = 187) Ondansetron 1 32 mg IV (n = 187) Granisetron 2 1 mg PO 2/day (n = 978) Headache, n (%) 9 (4.8) 10 (5.3) 205 (21) Constipation, n (%) 3(16) (1.6) 3(16) (1.6) 176 (18) Dizziness, n (%) 1 (0.5) 6 (3.2) NR Postdose change from baseline in QTc 1 ms 5 ms Adverse reactions judged by the investigator to have a definite, probable, possible, or unknown relationship to study medication; reported in 2% of patients in any treatment group NR = not reported as a major adverse event. 1. Gralla R, et al. Ann Oncol. 2003;14: ; 2. Kytril [prescribing information]. Roche; PCE Oncology

9 Are Short--acting 5-HT 3 Antiemetics Effective for Delayed CINV? 671 patients on doxorubicin-based chemotherapy All treated with first-generation 5-HT 3 RA + dexamethasone, day 1 Then randomized for days 2, 3: Arm 1: prochlorperazine 10 mg PO every 8 hours Arm 2: any oral 5-HT 3 RA, standard dosing regimens Arm 3: prochlorperazine 10 mg PO prn for nausea Rescue medications allowed Patients Wit th Delayed Nause ea, % Most Patients Had Nausea Prochlorperazine Every 8 Hours* 83 5-HT 3 87 Prochlorperazine prn *P =.002 (overall comparison); P =.06, prochlorperazine every 8 hours vs 5-HT 3 RA; P = NS, prochlorperazine as needed vs 5-HT 3 RA. NS = not significant. Hickock JT, et al. Lancet Oncol. 2005;6: Oral 5HT 3 RAs Not Effective and Not Indicated for Delayed CINV Vomiting More patients vomited 1 times during delayed period (34%) than on day of treatment (34% vs 9%, P <.01) Nausea Nausea severity greater during delayed period than on day of treatment (P <.01) More patients taking oral 5HT 3 RAs required rescue medication (45%) than did those taking prochlorperazine (27%-30%; P =.002) Hickock JT, et al. Lancet Oncol. 2005;6: MAGIC Trial: Granisetron SC Versus Ondansetron Complete Response, Delayed CINV CR (%) 100 Granisetron SC Ondansetron P = Delayed Delayed-phase CR rate: higher with granisetron SC vs ondansetron (64.7% vs 56.6%; P =.014) Overall population: CR rates: 8.0% higher with granisetron SC vs ondansetron (95% CI, ; 14 4; P =.014) (relative 14.2% improvement) Cisplatin stratum: CR rates: 10.6% higher with granisetron SC vs ondansetron (95% CI, -1.4 to 22.7; NS) (relative 19.4% improvement) Granisetron SC showed superiority vs another 5-HT 3 RA in HEC in a guidelineconsistent 3-drug vs 3-drug study design CR = complete response. Schnadig ID, et al. Future Oncol. 2016;12: PCE Oncology

10 Chemotherapy-Induced Nausea and Vomiting: Strategies for Achieving Current Status of NK 1 RAs in CINV FDA-approved agents Aprepitant: 125 mg PO day 1; 80 mg PO days 2 and 3 Fosaprepitant: 150 mg IV day 1 NEPA (netupitant 300 mg + palonosetron 0.5 mg) Rolapitant Good safety profile; significantly enhanced CINV control when combined with 5-HT 3 RA + dexamethasone More effective in emesis vs nausea control Consensus guideline-recommended use Single-day HEC (including AC) Other potential uses MEC Multiday HEC; high-dose chemotherapy with ASCT ASCT = autologous stem cell transplant; FDA = US Food and Drug Administration. NK 1 RAs Aprepitant 1 Netupitant 2-4 Rolapitant 5,6 Formulation PO, IV (fosaprepitant) Fixed-dose PO formulation with palonosetron (NEPA) Indication Dose CYP3A4 activity Prevention of acute and delayed Prevention of acute and nausea/vomiting associated with delayed nausea/vomiting initial/repeat courses of HEC associated with initial/repeat courses of chemotherapy 125 mg PO 1 hour before chemotherapy; 80 mg PO once daily in morning, days 2 and mg netupitant mg palonosetron ~1 hour before chemotherapy Can affect metabolism of Moderate inhibitor of CYP3A4, concomitantly administered although no clinically relevant medications (eg, corticosteroids, interaction with PO PO contraceptives, warfarin) contraceptives observed metabolized through this route PO and IV Prevention of acute and delayed nausea/vomiting associated with initial/repeat courses of chemotherapy 200 mg PO Does not affect metabolism of concomitantly administered medications metabolized by CYP3A4 1. Emend [prescribing information]. Merck; 2017; 2. Calcagnile S, et al. Support Care Cancer. 2013;21: ; 3. Stathis T, et al. Eur J Pharmacol. 2012;689:25-30; 4. Spinelli T, et al. J Clin Pharmacol. 2014;54:97-108; 5. Duffy RA, et al. Pharm Biochem Behav. 2012;102:95-100; 6. Poma A, et al. Support Care Cancer. 2013;21:S154. Abstract 441. NEPA Phase 3 Trial in AC Chemotherapy: CR Rates Patients (% %) P = P = P = Acute (0 24 h) Delayed ( h) Overall (0 120 h) NEPA + DEX PALO + DEX DEX = dexamethasone; PALO = palonosetron. CR: no emesis, no rescue medication. Based on full analysis set of 1449 patients. Aapro M, et al. Ann Oncol. 2014;25: PCE Oncology

11 CR With Rolapitant and NEPA in Phase 3 MEC Studies P =.143 CR Rate P <.001 P < % 68.6% 61.6% 57.8% 80.3% 83.5% Delayed Phase Overall Phase Acute Phase (> h) (0-120 h) (0-24 h) Active Control (N = 666) Rolapitant 200 mg (N = 666) CR Rate P =.001 P =.001 P = % 88.4% 76.9% 74.3% 69.5% 66.6% Delayed Phase Overall Phase Acute Phase (> h) (0-120 h) (0-24 h) PALO (N = 725) NEPA (N = 724) Schwartzberg L, et al. Lancet Oncol. 2015;16: ; Aapro M, et al. Ann Oncol. 2014;25: Olanzapine Olanzapine (atypical antipsychotic) Mechanism of action in CINV: unknown Possible neurotransmitter receptors blocked include dopaminergic, serotonergic, catecholamine α 1 adrenergic, acetylcholine muscarinic, histamine Use with caution in elderly Prophylaxis for acute/delayed CINV Alternative to aprepitant Also effective for breakthrough CINV Navari RM, et al. J Support Oncol. 2013;21: Olanzapine Versus Aprepitant for Prevention of CINV in Patients Receiving HEC Acute Delayed Overall CR (No Emesis, No Rescue), % OPD (n = 121) APD (n = 120) No Nausea, % OPD (n = 121) APD (n = 120) APD = aprepitant + palonosetron, dexamethasone; OPD = olanzapine + palonosetron + dexamethasone. Navari RM, et al. J Support Oncol. 2011;9: PCE Oncology

12 Addition of Olanzapine to CINV Regimen in Patients Receiving HEC All patients received dexamethasone, NK 1 RA, 5-HT 3 RA 74% * 45% No Nausea (%) 42% 25% 37% Olanzapine Placebo 22% 86% * 65% 67% CR (%) Olanzapine Placebo 52% 64% * 41% Time After Chemotherapy (Hours) *P <.001; P =.001; P =.002; P =.007. Navari RM, et al. N Engl J Med. 2016;375: Corticosteroids Uncertain mechanism of action May involve prostaglandin synthesis inhibition in hypothalamus Effective as single agent or in combination therapy Potentiate effects of other antiemetics Effective for acute and delayed CINV de Jong FA, et al. J Clin Oncol. 2005;23: ; Hesketh PJ. N Engl J Med. 2008;358: ; Jantunen IT, et al. Eur J Cancer. 1997;33:66-74; Perwitasari DA, et al. Int J Clin Pharm. 2011;33: Effect of Adding Dexamethasone to 5-HT 3 RAs for Acute Emesis Number of Patients Vomiting/Number of Patients Evaluable Author Hesketh Smith Roila Joss Smyth Heron Latreille Italian group Carmichael Sorbe Adams Total 0 5-HT 3 + Dexamethasone Better Treatment effect P < HT 3 2 Better Jantunen IT, et al. Eur J Cancer. 1997;33: PCE Oncology

13 Clinical Guidelines for Prevention of CINV Group Last Updated HEC NCCN HT 3 RA + DEX + NK 1 RA Olanzapine + PALO + DEX ASCO HT 3 RA + DEX + NK 1 RA MASCC/ HT 3 RA + DEX + ESMO 3 NK 1 RA Recommendation MEC 5-HT 3 RA (PALO, GRAN SQ preferred) + DEX ± NK 1 Olanzapine + PALO + DEX 5-HT 3 RA (PALO preferred) + DEX Palonosetron + DEX GRAN SQ = granisetron subcutaneous. 1. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version ASCO 2015 Antiemetics Focused Update; 3. MASCC/ESMO Antiemetic Guideline Update. Ann Oncol. 2016;27(Suppl 5):v119-v133. HEC: Guideline Recommendations NCCN 1 ASCO 2 Acute CINV 5-HT 3 RA + NK 1 RA + DEX PALO + olanzapine + DEX NK 1 RA + 5HT 3 RA + DEX + olanzapine 5-HT 3 RA + NK 1 RA + DEX NEPA + DEX Delayed CINV (Days 2-3) DEX + APR a Olanzapine DEX + APR a MASCC b3 5-HT 3 + DEX + APR DEX + APR a Delayed CINV (Day 4) DEX Olanzapine DEX a If fosaprepitant used, day 1 only; b AC. APR = aprepitant. 1. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version ASCO 2015 Antiemetics Focused Update; 3. MASCC/ESMO Antiemetic Guideline Update. Ann Oncol. 2016;27(Suppl 5):v119-v133. MEC: Guideline Recommendations Acute CINV Delayed CINV (Days 2-3) NCCN 1 5 HT 3 RA (PALO preferred) + DEX +/- NK 1 RA a,b Olanzapine + PALO + DEX 5-HT 3 (if PALO not used day 1) DEX APR +/- DEX a Olanzapine c ASCO 2 PALO + DEX b DEX MASCC d3 PALO + DEX d DEX a If fosaprepitant used, day 1 only; b If APR added, PALO not preferred; c If used on day 1; d Non-AC. 1. NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version ASCO 2015 Antiemetics Focused Update; 3. MASCC/ESMO Antiemetic Guideline Update. Ann Oncol. 2016;27(Suppl 5):v119-v133. PCE Oncology

14 Case Study: Amanda Amanda receives an antiemetic regimen consisting of palonosetron + dexamethasone + fosaprepitant on day 1, dexamethasone once daily on day 2, and dexamethasone twice daily on days 3 and 4 However, after 2 days, she experiences nausea and vomiting that severely weaken her Before the next cycle of therapy, she is given a 4-drug regimen as recommended in the 2017 NCCN guidelines Addition of Olanzapine to CINV Regimen in Patients Receiving HEC All patients received dexamethasone, NK 1 RA, 5-HT 3 RA No Nausea (%) CR (%) 74% * 86% * 45% 42% 25% 37% Olanzapine Placebo 22% 65% 67% 52% Olanzapine Placebo 64% * 41% Time After Chemotherapy (Hours) *P <.001; P =.001; P =.002; P =.007. Navari RM, et al. N Engl J Med. 2016;375: Principles for Managing Breakthrough CINV Add agent from a different class Consider around-the-clock rather than as-needed administration If patient is vomiting, IV or rectal administration may be required Before next cycle of chemotherapy, reassess response in both acute and delayed setting Consider an alternative regimen if needed Add an NK 1 RA if not previously included NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version PCE Oncology

15 Radiation-Induced Nausea and Vomiting: Prophylaxis and Treatment For patients treated with highly or moderately emetogenic radiation therapy, a 5-HT 3 RA before each fraction; a 5-day course of dexamethasone 4 mg is recommended/optional Breakthrough treatment: same as for CINV NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Version ; ASCO 2015 Antiemetics Focused Update. Much Progress Has Been Made But Challenges Remain Prevention of nausea remains a challenge Many patients consider CINV a necessary evil Adherence to guidelines is poor, due to: Lack of knowledge by healthcare providers Differing recommendations Cost/financial/insurance issues Lack of institutional enforcement Inadequate measurement of quality of care and outcomes Grunberg SM. J Natl Compr Cancer Netw. 2009;7: Improving Adherence Through Education Communicating with and educating patients about CINV is a critical component of oncology patient care Patients need to be aware of the differences between prophylaxis and treatment of symptoms Important to educate patient about how and why to take medication as instructed even if they do not have symptoms Symptom monitoring Use of patient diaries, proactive follow-up calls Give clear communication/contact information Patients should understand that if they have symptoms, they should contact someone regardless of the time Young A, et al. Ecancermedicalscience. 2013;7:296. PCE Oncology

16 PCE Action Plan Consider the burden of CINV, including clinical and financial impact, on patients and caregivers Evaluate risk factors for CINV in patients with cancer Recognize that the goal of antiemetic therapy is prevention, not treatment, of CINV Evaluate the antiemetic potential of anticancer regimens Consider multiple strategies to manage breakthrough CINV Develop strategies to prevent radiation-induced nausea and vomiting Educate patients about the potential for CINV and the importance of prevention with an antiemetic regimen PCE Promotes Practice Change PCE Oncology