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Supportive Care for Chemotherapy Induced Nausea & Vomiting

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Supportive Care for Chemotherapy Induced Nausea & Vomiting Supportive Care for Chemotherapy Induced Nausea & Vomiting (CINV): The next steps in improving outcomes Dr Richard Berman FRCP Supportive Care Physician Honorary Senior Lecturer in Cancer Sciences The Christie NHS Foundation Trust This session is sponsored by TESARO UK who selected the speaker and reviewed the slides, which may contain promotional content Funding Source and Conflicts of Interest • Consultations: Grunenthal, Astra Zeneca, Chugai • Honoraria for lectures: Tesaro, Kyowa Kirin, Chugai The content and interpretation of this presentation are the views and comment of the speaker and not of Tesaro. The Christie NHS Foundation Trust Supportive care [in cancer] is the prevention and management of the adverse effects of cancer and cancer treatment The landscape of cancer is changing More and more people are living longer with cancer Proactive supportive care can improve survival 1. Early Palliative Care for Patients with Metastatic Non–Small-Cell Lung Cancer, Temel JS et al, N Engl J Med 2010; 363:733- 742 August 19, 2010. 2. Palliative and Supportive Care: Early Versus Delayed Initiation of Concurrent Palliative Oncology Care: Patient Outcomes in the ENABLE III Randomized Controlled Trial - Marie A. Bakitas, Journal of Clinical Oncology May 1, 2015:1438-1445; published online on March 23, 2015; DOI:10.1200/JCO.2014.58.6362 3. Effect of Early Palliative Care on Chemotherapy Use and End-of-Life Care in Patients With Metastatic Non–Small-Cell Lung Cancer; Joseph A. Greer, JCO; Feb 1 2012, vol 30, no 4, 394-400) 4. Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment, Basch E, JAMA; Jul 11 2017;318(2):197-198 Chemotherapy-induced nausea and vomiting (CINV) Quality matters in CINV | Audit methods Disease sites Head & neck n=360 patients Breast Prospective study of case notes and Colorectal e-prescribing records Followed through 3 cycles of chemotherapy Ovarian Data was collected on Severity of nausea and vomiting Anti-emetic use Hospital admission Concordance with international guidelines Supportive Care Team, The Christie NHS Foundation Trust, CINV baseline audit, 2013-14 Quality matters in CINV | Headline results Disease Head & neck Breast Colorectal Ovarian sites N=59 N=101 N=100 N=100 • Males n =102, Females n=258 • Age range 27-86, mean 56, median 58 years • Concordance with MASCC guidelines ranged from 88% (Head and Neck) to 0% (colorectal and ovarian) • 57% of the total cohort reported nausea and 32% vomiting • 11% of patients were admitted to hospital with CINV a contributory factor • Aprepitant was added at a later cycle in 15% patients, which resulted in better symptom control (no further admissions in this group) Supportive Care Team, The Christie NHS Foundation Trust, CINV baseline audit, 2013-14 CLINICAL GUIDELINES FOR THE PREVENTION AND MANAGEMENT OF CHEMOTHERAPY AND RADIOTHERAPY INDUCED NAUSEA AND VOMITING IN ADULTS Supportive Care Team, The Christie NHS Foundation Trust, CINV clinical guidelines, 2015 What is the burden of CINV? CINV adversely impacts patients' quality of life Before chemotherapy (day 1) After chemotherapy (day 3) 130 (N = 122) 122 121 120 115 110 100 90 85 Mean FLIEscores Mean 80 70 Patients experiencing CINV Patients without CINV (n = 68) (n = 54) FLIE, Functional Living Index–Emesis . Adapted from CM Lindley et al. Qual Life Res. 1992;1:331-40. Who is more at risk? • Female gender • Young age • Anxious personality • Minimal alcohol use (caveat ≥ 5 drinks/week is protective) • History of emesis during pregnancy • History of motion sickness • History of previous CINV Morrow GR, et al. Support Care Cancer. 2002;10:96-105. Why optimal CINV treatment and prevention is important • Nausea and vomiting are common and feared symptoms among cancer patients • Up to 80% of patients will experience chemotherapy-induced nausea and vomiting (CINV) without prophylactic therapy • Nausea and vomiting can lead to deteriorated nutritional status • Inadequate emesis control may lead to anticipatory sickness Aziz F. Ann Palliat Med 2012;1(2):130-136; Laszlo J. N Engl J Med 1981;305:948-9; Morran C. Br Med J 1979;1:1323-4; Wilcox PM. Cancer Treat Rep 1982;66:1601-4 Why does CINV occur? Physiology and neuropharmacology of chemotherapy-induced emesis 5-HT3, 5-hydroxytryptamine receptor type 3; chemo, chemotherapy; CTZ, chemoreceptor trigger zone; GI, gastrointestinal; NK1, neurokinin 1; VC, vomiting centre. Artist rendering based on work of Paul Andrews and others. NEUROTRANSMITTERS AND ANTIEMETIC PATHWAYS: Targeting Key Pathways to Influence Emetic Control Dopamine / Histamine D2 RAs Serotonin / Endorphins 5-HT3 RAs Emetic reflex Substance P / Acetylcholine NK1 RAs GABA Cannabinoids DA =v dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin RAs = receptor antagonists Efficacy in controlling chemotherapy-induced emesis has progressed over the past 30 years 5-HT3 RA Added 5-day complete control: + steroids NK1 RA 100 85 Cisplatin (highly emetic) “AC” chemotherapy 75 75 60 50 50 50 50 % 25 10 0 1980 1990 2000 2010 Year AC, anthracycline + cyclophosphamide; RA, receptor antagonist. Gralla R, personal communication. Binding affinity of different 5-HT3 receptor antagonists 5HT3 antagonist pKi (nM) Palonosetron1 10.4 Granisetron2 8.4 Ondansetron2 8.1 Dolasetron3 7.6 1. Wong EH et al. Br J Pharmacol. 1995;114:851–859; 2. Van Wijngaarden I et al. Eur J Pharm Mol Pharmacol. 1990;188:301–312; 3. Miller RC et al. Drug Dev Res. 1993;28:87–93. NK-1 receptor antagonists: How do they work? • NK1 receptors antagonists exert their strongest antiemetic properties through central inhibition of the emesis pattern generator • This is one of the final common mechanisms involved in activation and coordination of the vomiting reflex • There is substantial evidence for involvement of substance P throughout the CINV response • NK1 – RAs prevent the sensitisation of NK1 receptors by substance P • This decreases the likelihood of vomiting • NK-1 RAs also increase the efficacy of steroids and 5-HT3 antagonists Saito R, Takano Y, Kamiya HO. Roles of substance P and NK(1) receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87- 94. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med 2001;111:106S-112S Antiemetics in 2018: practical issues 1. Good – if not perfect – antiemetic agents are available 2. Quality evidence exists that should guide all oncologists in preventing “CINV” 3. Still, many patients experience emesis 4. So do evidence-based guidelines actually work? CINV, chemotherapy-induced nausea and vomiting. Controlling emesis in chemotherapy: What’s new? Controlling Emesis during Chemotherapy: New findings which can affect Practice • New Agents • New Data • Updated Guidelines • Resource Utilisation Developing new antiemetic agents: what would be ‘the ideal’ / where are ‘the gaps’? • Better control during the ‘delayed phase’ • Single dose day 1 • Effective control over multiple chemotherapy cycles • Flexibility: Agents with different metabolic pathways to avoid drug-drug interactions Controlling Emesis during Chemotherapy: New agents • Rolapitant – NK1 receptor antagonist with different metabolic pathway – Highly selective agent • NEPA – Fixed-dose combination of netupitant (NK1 receptor antagonist) + palonosetron (5HT3 receptor antagonist) – Highly selective agents • Olanzapine – A non-specific, non-selective, neuroleptic agent – Antiemetic and anti-nausea properties – Questions persist regarding dose and role Controlling Emesis during Chemotherapy: New Agents • Rolapitant – NK1 receptor antagonist with different metabolic pathway – Highly selective agent • NEPA • Fixed-dose combination of netupitant (NK1 receptor antagonist) + palonosetron (5HT3 receptor antagonist) • Highly selective agents • Olanzapine • A non-specific, non-selective, neuroleptic agent • Antiemetic and anti-nausea properties • Questions persist regarding dose and role F C Rolapitant Background 3 O N H O CF3 N H . HCl H2O Selective, long-acting NK-1 receptor antagonist with reduced risk of drug interaction: not an inducer or inhibitor of CYP3A4 Single oral dose, give day 1 prior to chemo –Long t1/2 (~180 h) suggests a single dose may be sufficient to prevent CINV during the entire 5-day (0–120 h) at risk period –180mg dose achieved >90% NK-1 receptor occupancy in the brain and maintained level for up to 5 days post a single dose Wang X et al. Clin Pharmacol Ther 2017; 102(2):332-339 Rolapitant Phase III Trial Efficacy in Highly Emetic Chemotherapy (“HEC”) Rolapitant group achieved significantly higher CR rates in the primary endpoint of delayed phase (>24–120 h) compared to the control group in HEC studies HEC1 (mITT Population) HEC2 (mITT Population) p=0.005 p=0.233 p<0.001 p=0.001 p=0.043 p=0.084 Rapoport BL et al. Lancet Oncol. 2015 Rolapitant Phase III Trial: Efficacy in Moderately Emetic Chemotherapy mITT Population ) % p = 0.143 ( e t a 83.5% R p < 0.001 80.3% e s n p < 0.001 o p 71.3% s 68.6% e R e t 61.6% e l 57.8% p m o C Delayed Phase Acute Phase Overall Phase (>24–120 hr) (0–24 hr) (0–120 hr) Control (n=666) Rolapitant 200 mg (n=666) Chemotherapy: One or more of the following: cyclophosphamide, doxorubicin, epirubicin , carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine. More than 50% of patients received anthracycline + cyclophospamide (AC) chemotherapy. Primary endpoint = Complete Response in delayed emesis Schwarzberg et al Lancet Oncol 2015;16: 1071-8 Schwartzberg LS et al. Lancet Oncol. 2015 Controlling
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