Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Journal Club Breakdown for the Alternative Use of Olanzapine (Zyprexa®) to Prevent Nausea/Vomiting from Chemotherapy

Study Background

  • Chemotherapy Induced Nausea and Vomiting (CINV) is a major side effect of chemotherapy and strongly affects the quality of life for cancer patients
  • Standard therapy includes combination 5-HT3 antagonists, NK1 antagonists, and dexamethasone
  • Despite several therapeutic options available, CINV is still a significant issue with many cancer patients
  • Olanzapine is FDA approved as an antipsychotic and blocks several neurotransmitters potentially associated with emesis including: D2, 5-HT2c, and 5-HT3

Study Relevance

Olanzapine was previously investigated as a potential anti-emetic alternative.

Olanzapine vs. aprepitant for the prevention of CINV (Phase III)

  • Effectively controlled early and long term nausea and vomiting

Clinical research of olanzapine for prevention of CINV (Phase III)

  • Improves control of nausea and vomiting

A review of prior studies:

  • Possible issues with methodology from “single institution” studies

Well planned, randomized, double-blind, “multicenter” studies are needed to further investigate clinical effectiveness of olanzapine for CINV

Study Objectives

Primary

  • Evaluate olanzapine against placebo:
  • Control nausea in patients receiving highly emetogenic chemotherapy
  • Prevention of nausea during three time periods: 0–24 hours | 25–120 hours | 0–120 hours after chemotherapy

Secondary

  • Compare complete response in both study arms
  • Evaluate potential side effects of olanzapine

Study Methods

Essential Eligibility Criteria

  • ≥18 years of age with malignant disease, no prior chemotherapy, and new chemotherapy regimen indicated as ”highly emetogenic”
  • ECOG performance score: 0, 1, or 2 (Maximum of 5)
  • ANC 1500 mm3 or greater
  • No nausea or vomiting 24 hours prior to enrollment
  • No prior treatment with antipsychotic 30 days before enrollments (and cannot take during study)
  • Highly emetogenic: cisplatin ≥70 mg/m2

Patient Randomization

No significant differences between the olanzapine and placebo groups in terms of age, race, sex, 5HT3 received, chemo regimen, and the distribution of institutions was balanced between the study groups

Study Design

  • Double Blind | Placebo Controlled
  • Total 401 patients randomly assigned at 46 academic/community practice institutions in the USA
  • Pocock & Simon dynamic randomization procedure to balance stratification factors

Stratification Factors

  • a)Sex
  • b)Chemotherapy Regimen
  • c)Specific 5-HT3 used
  • Assessed for only one chemotherapy cycle
  • Rescue anti-emetic therapy was permitted if needed

Study Treatment Regimens

  • All patients received the following:
  • 5HT3 Agents: Palonosetron, Granisetron, or Ondansetron
  • Steroid: Dexamethasone
  • NK1 Agent: Fosaprepitant
  • Treatment Arms: Olanzapine or Placebo
  • Standard doses for 5HT3 agents, steroid, and NK1 agent
  • Anti-emetic dose of olanzapine 10mg daily x 4 days was chosen based on Passik et at.’s Phase I trial using olanzapine as prophylactic anti-emetic
  • Yielded no major toxic side effects (except sedation)

Post Chemotherapy Protocols

  • Patients were instructed to record episodes of vomiting or retching (total frequency)
  • Indicated whether or not they used rescue therapy from days 1 to 5 of chemotherapy
  • Patients recorded frequency of daily nausea based on visual-analog scale (from 0–10)
  • Nurse contacted patients to report toxic side effects
  • Patients rated undesirable sedation and increased appetite (from 0–10)

Primary Endpoints

0–24 hours after chemotherapy

  • Olanzapine: 26% of patients experienced nausea
  • Placebo: 55% of patients experienced no nausea

25–120 hours after chemotherapy

  • Olanzapine: 58% of patients experienced nausea
  • Placebo: 75% of patients experienced nausea

0–120 hours after chemotherapy

  • Olanzapine: 63% of patients experienced nausea
  • Placebo: 78% of patients experienced nausea

Secondary Endpoints

0–24 hours after chemotherapy

  • Olanzapine: 86% of patients achieved complete response
  • Placebo: 65% of patients achieved complete response

25–120 hours after chemotherapy

  • Olanzapine: 67% of patients achieved complete response
  • Placebo: 53% of patients achieved complete response

0–120 hours after chemotherapy

  • Olanzapine: 36% of patients achieved complete response
  • Placebo: 41% of patients achieved complete response

Statistical Analysis

  • Primary endpoint utilized chi-squared test to compare proportion of patients with no nausea
  • Results indicated a statistically significant difference between olanzapine and placebo, olanzapine achieved higher percentage of patients that did not have nausea
  • Modified Intent to Treat Principle
  • Needed to enroll at least 332 patients (166 patients per group) to achieve a 90% power in order to achieve a clinical significance
  • Secondary endpoints were exploratory only (added for clinical benefit)

Study Results

  • Proportion of patients who had no nausea was significantly greater in the olanzapine group vs. the placebo group

Comparing patients that had no clinically significant nausea (ECOG greater than 3)

  • Early Period: 87% olanzapine vs. 70% placebo (P=0.001)
  • Later Period: 72% olanzapine vs. 5% placebo (P=0.001)
  • Overall Period: 67% olanzapine vs. 52% placebo (P=0.001)

Proportion of patients with a complete response was significantly greater in olanzapine group vs. placebo

Study Results — Olanzapine Adverse Event

  • Significant increase in sedation compared to placebo group on day 2 post chemotherapy cycle
  • Sedation eventually resolved by days 3, 4, and 5
  • Did not result in discontinuation
No Significant difference between olanzapine vs. placebo with respect to undesired increase in appetite

Clinical Discussion

Strength of the study

  • Addition of olanzapine to standard anti-emetic therapy showed significant benefit in reducing nausea/vomiting compared to placebo
  • The first multicenter trial to strictly evaluate the clinical effectiveness of olanzapine for CINV

Weakness of the study

  • Additional studies need to evaluate sedative side effects — may be an unwanted for some patients
  • Only evaluated one dose of olanzapine
  • Perhaps, a lower dose would decrease sedation and maintain antiemetic effect?

Impact of Study

  • CINV is as major side effect of of highly emetogenic chemotherapy and often can discourage many patients from undergoing chemotherapy
  • If we can better manage CINV and virtually eliminate this side effect, we can improve patient adherence and clinical efficacy of chemotherapy
  • The addition of olanzapine has shown to make a significant impact in reducing CINV when added to traditional anti-emetic therapy
  • If a patient can tolerate the known sedative effects, olanzapine could potentially improve the management of CINV

Reference

  1. Rudolph M. Navari, M.D., Rui Qin, Ph.D., Kathryn J. Ruddy, M.D., Heshan Liu, Ph.D., Steven F. Powell, M.D., Madhuri Bajaj, M.D., Leah Dietrich, M.D., David Biggs, M.D., Jacqueline M. Lafky, M.S., and Charles L. Loprinzi, M.D. N Engl J Med 2016; 375:134–142July 14, 2016DOI: 10.1056/NEJMoa1515725 (http://www.nejm.org/doi/full/10.1056/NEJMoa1515725#t=article)