Chemotherapy Induced Nausea and Vomiting

Transcription

1 Chemotherapy Induced Nausea and Vomiting Aminah Jatoi, M.D. Professor of Oncology Mayo Clinic Rochester, Minnesota April 27, 2017 clinical and biologic fundamentals of chemotherapy induced nausea and vomiting management derived from randomized, controlled trials Brief comment on the ceiling effect newer agents 1

2 Emetogenic Risk of Chemotherapy Agents/Regimens High >90%: cisplatin Moderate 30 90%: oxaliplatin, ifosfamide Low 10 30%: paclitaxel, 5 fluorouracil < 10%: vincristine, bleomycin Time Related Definitions of Chemotherapy Induced Nausea and Vomiting: Acute: within 24 hours of chemotherapy Delayed: at 24 hours or later Anticipatory: 12 hours prior to chemotherapy 2

3 Basis: the Effects of Cisplatin Rappaport, 2017 Modified from Meda Pharmaceuticals 3

4 Taken from Medscape. MAIN CATEGORIES OF AGENTS: 5 HT3 antagonists (ondansetron, granisetron, palonosetron) NK1 antagonists (aprepitant, fosfoaprepitant) Corticosteroids (dexamethasone) 4

5 Matching Agents to Mechanism: Modified from Medscape. APPROACH: Rank chemotherapy drugs/regimens and apply the most appropriate antiemetic regimen based on clinical trials. 5

6 A history of nausea and vomiting should prompt a challenge of guidelines: Hayashi, et al clinical and biologic fundamentals of chemotherapy induced nausea and vomiting management derived from randomized, controlled trials brief comment on the ceiling effect newer agents 6

7 Management based on clinical trial data: For highly emetogenic chemotherapy, a 5 HT3 receptor antagonist, an NK1R antagonist, and dexamethasone is best. For moderately emetogenic chemotherapy, a 5 HT3 receptor antagonist and dexamethasone provides control. For patients receiving low risk chemotherapy, dexamethasone as a single 8 mg dose provides control. An alternative might be prochlorperazine. Management based on clinical trial data (continued): For high risk patients who do not receive adequate control, consider the addition of olanzapine (to be reviewed further). Anticipatory nausea and vomiting is best prevented by effectively preventing chemotherapy induced nausea; benzodiazepines can be used if it occurs. 7

8 Management based on clinical trial data (continued): Palonosetron is better than other 5 HT3 receptor antagonists for delayed nausea and vomiting. Rojas and Slusher,

9 Rojas and Slusher, 2015 Palonosetron Does Not Result in Prolonged QT Interval Morganroth, et al,

10 clinical and biologic fundamentals of chemotherapy induced nausea and vomiting management derived from randomized, controlled trials brief comment on the ceiling effect newer agents 80% ceiling effect 10

11 Comments on 80%: Better control of nausea and vomiting hinges on better drugs: FURTHER DRUG DEVELOPMENT IS KEY. Off study, a greater percentage of patients likely suffer nausea/vomiting: GUIDELINES AND RESEARCH ON THEIR IMPLENTATION ARE ALSO KEY. Anti Emetic Guidelines Adherence Leads to Better Symptom Control Gilmore,

12 clinical and biologic fundamentals of chemotherapy induced nausea and vomiting management derived from randomized, controlled trials brief comment on the ceiling effect newer agents NEPA netupitant (NK1 receptor antagonist) + palonosetron (5 HT3 receptor antagonist) 12

13 Modified from the ASCO Post, 2014 Aapro M, et al,

14 NEPA for Chemotherapy Induced Nausea and Vomiting Key findings from 3 pivotal trials of fixed dose NEPA showed the novel combination to be more effective than oral palonosetron alone in patients receiving moderately and highly emetogenic chemotherapy. NEPA is consistently effective across multiple cycles of chemotherapy. NEPA is effective in preventing chemotherapy induced nausea and vomiting in patients receiving carboplatin and regardless of which agent is partnered with cisplatin. Modified from the ASCO Post, 2014 OLANZAPINE 14

15 Rationale: Olanzapine is an antipsychotic that blocks multiple neurotransmitters (dopaminergic, serotonergic, muscarinic, and other receptors) 15

16 $$$ Olanzapine for the prevention of chemotherapy induced nausea and vomiting: patients receiving highly emetogenic chemotherapy End Points: Primary: No nausea Secondary: Complete response (no emesis, no rescue) Olanzapine + 5-HT 3 RA + Aprepitant + Dexamethasone N=192 Placebo + 5-HT 3 RA + Aprepitant + Dexamethasone N=188 16

17 Olanzapine/Placebo Administration Olanzapine 10 mg, or matching placebo Given orally prior to chemotherapy on day 1 Repeated on days

18 Navari, et al Main Outcome Measures No Nausea 0 on scale 0 10 Acute (0 24 hours post chemotherapy) Delayed ( hours post chemotherapy) Overall (120 hours post chemotherapy) Complete Response (No emesis, No rescue) Acute (0 24 hours post chemotherapy) Delayed ( hours post chemotherapy) Overall (120 hours post chemotherapy) 18

19 Toxicities Sedation Appetite Adverse Events, via CTCAE Version 4.0 Navari, et al

20 Sedation Scores on Day 2 Sedation Olanzapine (n=192) Placebo (N=188) Scores 0 58% 65% 1 6% 10% 2 2% 7% 3 8% 4% 16% 4 2% 4% 19% 5 4% 4% 6 4% 2% 7 3% 1% 8 8% 20% 2% 7% 9 2% 1% 10 3% 1% Missing

21 Conclusion: Efficacy results are consistent with current NCCN guidelines for olanzapine and suggest this agent could be added to standard antiemetic regimens to augment palliation. EXTENDED RELEASE GRANISETRON 21

22 The efficacy of Sustol : a randomized, non inferiority study of 733 patients: Sustol to palonsetron injection primary endpoints: proportion of patients with complete response (CR) no vomiting and no use of rescue medication during the acute phase (0 to 24 hours) and the delayed phase (> 24 to 120 hours) following the administration of chemotherapy in cycle 1 of moderate and highly emetogenic chemotherapy non inferiority demonstrated Overall Conclusions Antiemetic combinations are effective in 80% of patients if used appropriately. The 80% ceiling effect can be improved upon by better drugs but also, importantly, by better guideline adherence. NEPA, olanzapine, and sustained release granisetron are newer agents. Improving adherence appears to improve outcomes. 22

23 Thank you! 23