The primary endpoint was no nausea; this is different [from past studies] because most of the antiemetic trials in the literature use complete response as the primary endpoint and look at nausea as a secondary endpoint.
—Rudolph M. Navari, MD, PhD
The addition of olanzapine to standard antiemetics significantly reduced chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, according to Rudolph M. Navari, MD, PhD, and colleagues.
“As far as I know, this is the first trial that looked at no nausea as the primary endpoint,” said Dr. Navari, who presented the results of the phase III trial at the 2015 Palliative Care in Oncology Symposium in Boston.1 He is currently based in Geneva, Switzerland, serving as Director of the World Health Organization Cancer Care Program in Eastern Europe.
Olanzapine is approved by the U.S. Food and Drug Administration (FDA) as an antipsychotic but does not have an FDA indication as an antiemetic.
Investigators sought to determine the additional efficacy of olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving their first course of highly emetogenic chemotherapy, with a primary endpoint of no nausea and a secondary endpoint of complete response (no emesis, no rescue).
“The primary endpoint was no nausea; this is different [from past studies] because most of the antiemetic trials in the literature use complete response as the primary endpoint and look at nausea as a secondary endpoint,” said Dr. Navari.
A randomized, double-blind, phase III trial was performed in chemotherapy-naive patients receiving cisplatin (≥ 70 mg/m2), or cyclophosphamide (600 mg/m2) plus an anthracycline (60 mg/m2), comparing olanzapine to placebo in combination with aprepitant, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist (ie, palonosetron, ondansetron, or granisetron), and dexamethasone.
The study included 192 patients in the olanzapine arm and 188 in the placebo arm. The two arms were well balanced in terms of age, gender, performance status, and diagnosis.
Patients received 10 mg of oral olanzapine or matching placebo, plus 125 mg of aprepitant, a 5-HT3 agent, and 12 mg of oral dexamethasone prior to chemotherapy on day 1, followed by 10 mg/d of oral olanzapine or matching placebo and 8 mg of dexamethasone on days 2 to 4 post chemotherapy, plus 80 mg of aprepitant on days 2 and 3 post chemotherapy.
The pre- and postchemotherapy regimens of aprepitant, 5-HT3 agent, and dexamethasone were identical in the olanzapine and placebo arms. On day 1, fosaprepitant (Emend, 150 mg intravenously) was allowed as a substitute for the oral aprepitant.
Nausea was measured on a 0-to-10 visual analog scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be.” Measurements were taken in the acute (0–24 hours post chemotherapy), delayed (24–120 hours post chemotherapy), and overall (120 hours post chemotherapy) phases. Measurements of complete response were taken during the same time periods.
“A very significant P value in favor of no nausea in the olanzapine arm was observed in all three phases,” said Dr. Navari. The proportion of patients who had no nausea was significantly greater for the olanzapine arm compared with the placebo arm for the acute period (74% vs 45%, P < .0001), delayed period (42% vs 25%, P = .0008), and overall period (37% vs 22%, P = .0015).
Complete response was also significantly improved for olanzapine recipients compared to placebo recipients for all three phases: acute (86% vs 65%, P < .0001), delayed (67% vs 52%, P = .0073), and overall (64% vs 41%, P < .0001).
“In previous studies where olanzapine was used, there was concern about toxicities, mainly short-term sedation and increased appetite,” Dr. Navari stated. Transient sedation was observed in the olanzapine arm on day 2, but this sedation resolved despite continued use of olanzapine on days 3 and 4. “The important issue is that no patient in the study on olanzapine discontinued the study or discontinued olanzapine, despite sedation,” he added. No difference in appetite was observed in either arm on days 2 to 6.
Other than transient sedation, no significant adverse effects were observed with the use of olanzapine.
‘A Milestone in Antiemetics’
“As someone who’s been in the field of oncology for 40-plus years, I’ve come to realize that the elimination of cancer as a disease in our society is never going to happen,” said Lawrence H. Einhorn, MD, a medical oncologist and Distinguished Professor of Medicine at Indiana University School of Medicine in Indianapolis. “But what we can do is eliminate the fear from cancer. What are the two biggest fears that cancer patients have when they have metastatic disease? First is [chemotherapy-induced nausea and vomiting], and the second is pain.”
“In this study, the primary endpoint of no nausea is a unique and appropriate endpoint,” said Dr. Einhorn. “I agree 100% with Dr. Navari that it’s far more important to have no nausea [as a primary endpoint] than to have a complete remission with no episodes of emesis.”
The investigators concluded that olanzapine in combination with a 5-HT3 receptor antagonist, aprepitant, and dexamethasone significantly improves the control of nausea and emesis in the acute, delayed, and overall phases for patients receiving highly emetogenic chemotherapy.
“There were many skeptics about the utility of this drug,” added Dr. Einhorn. “But olanzapine does represent a true milestone in antiemetic therapy.”
The investigators noted that the study results were consistent with current guidelines from the National Comprehensive Cancer Network, which recommends the use of olanzapine with standard antiemetics as an option for preventing chemotherapy-induced nausea and vomiting in patients receiving emetogenic chemotherapy.2 ■
Disclosure: Drs. Navari and Einhorn reported no potential conflicts of interest.
1. Navari R, Qin R, Ruddy J, et al: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): Alliance A221301, a randomized, double-blind, placebo-controlled trial. 2015 Palliative Care in Oncology Symposium. Abstract 176. Presented October 9, 2015.
2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis, Version 2.2015. Available at nccn.org. Accessed November 20, 2015.