Olanzapine at a 5-mg dose, when combined with aprepitant, palonosetron, and dexamethasone, significantly reduced the risk of delayed nausea and vomiting in patients receiving cisplatin-based chemotherapy, according to new research. The study investigators believe this approach may be considered a new standard antiemetic therapy.
When used prophylactically, olanzapine at 10 mg has been previously established as a highly effective antiemetic for patients undergoing highly emetogenic chemotherapy. However, the risk of sedation is high, which can have a significant impact on patients’ quality of life.
“There is no excuse for anyone to be vomiting after chemotherapy in the modern era. Those days, thankfully, can be behind us.”— Elizabeth Wulff-Burchfield, MD
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A randomized, double-blind, placebo-controlled phase III trial evaluated olanzapine at 5 mg combined with standard antiemetic therapy in patients receiving cisplatin-based chemotherapy. This study did not directly compare olanzapine at 5 mg to olanzapine at a 10-mg dose; however, the study results demonstrated equivalent activity and favorable toxicity when compared to the initial study employing the 10-mg standard dose.1 When used in the first 4 days of highly emetogenic chemotherapy, patients who received the reduced dose of olanzapine experienced statistically and clinically significant improvements in complete nausea control, with better sleep quality and a minimal impact on daytime sleepiness when compared with those who received a placebo.
These data were originally presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 11503) by Hironobu Hashimoto, BPharm, of the National Cancer Center in Tokyo, and colleagues.2 The study was later discussed at the Best of ASCO Austin by Elizabeth Wulff-Burchfield, MD, Assistant Professor in the Divisions of Medical Oncology and Palliative Medicine at the University of Kansas Medical Center, along with other top selected abstracts in symptoms and survivorship.3
Hironobu Hashimoto, BPharm
Elizabeth Wulff-Burchfield, MD
According to Dr. Wulff-Burchfield, these findings are practice-changing. “We all know that nausea is a terrible and burdensome symptom for our patients, and data actually suggest there are patients who are so fearful of nausea that they may choose less aggressive care or avoid cancer-directed therapy altogether,” she said. “This reduced dose appears to be safe. There is no excuse for anyone to be vomiting after chemotherapy in the modern era. Those days, thankfully, can be behind us.”
She added that this drug combination may not be appropriate in patients with prolonged QT or in those with altered mental status.
Improvement in Nausea With Better Sleep Quality
A total of 710 patients receiving cisplatin (≥ 50 mg/m2) were enrolled on the prospective trial. Participants were randomly assigned to receive either olanzapine 5 mg (n = 356) or placebo (n = 354) on days 1 to 4, combined with aprepitant, palonosetron, and dexamethasone. The primary endpoint of the study was complete response, defined as no vomiting and no rescue medications in the delayed phase (24 to 120 hours). The cohorts were well matched, and the largest patient populations represented were those with lung and esophageal cancers.
The complete response rate of nausea in the delayed phase was 79% in the olanzapine arm, compared with 66% in those who did not receive the drug (P < .001). “Clearly, this [lower dose] is still effective,” said Dr. Wulff-Burchfield.
The rate of somnolence was 43% in patients who received olanzapine, compared with 33% in the placebo arm. However, most somnolence was mild, with 4.3% of patients in the experimental arm experiencing it to a moderate or severe degree.
The investigators also compared clinically impactful daytime sleepiness to good quality sleep at night. “Although there was a small statistically significant difference in the rates of daytime sleepiness…, I don’t think it was terribly clinically significant vs the proportion of patients who reported good sleep quality, which was much higher in the patients who received olanzapine,” she observed. “So, that’s a win-win there.”
Reduced Dose of Olanzapine for Antiemesis
- A study reported that olanzapine at a dose of 5 mg, when combined with an NK1 receptor antagonist, a 5HT3 receptor antagonist, and dexamethasone, is effective in treating chemotherapy-induced nausea and vomiting in patients receiving cisplatin.
- Olanzapine at 10 mg is commonly prescribed for these patients, but the risk of somnolence is high, and daytime sleepiness can impact quality of life.
- According to the investigators, this combination can be considered a new standard antiemetic therapy.
According to Dr. Wulff-Burchfield, study limitations include the lack of data about anticholinergic side effects, particularly in older patients. Additionally, the study included just patients receiving cisplatin and no other highly emetogenic chemotherapies. And the study was conducted in Japan, with a relatively genetically homogeneous population.
Dr. Wulff-Burchfield interpreted the findings from this study in the context of existing data4 demonstrating favorable cost analyses for the addition of olanzapine (at a 10 mg dose) to the standard antiemetic regimen. She added that olanzapine at a lower dose could be expected to be of the same, if not greater, value in clinical practice and to payers. Patients might be effectively managed with fewer pills, thereby preventing symptom crises and associated costs while promoting a better quality of life for patients.
Future research opportunities will involve evaluating other, even more affordable antidopaminergic medications. Specifically, phase II data have suggested that haloperidol is noninferior to olanzapine, which comes with a lower price tag, she said. ■
DISCLOSURE: Mr. Hashimoto and Dr. Wulff-Burchfield reported no conflicts of interest.
REFERENCES
1. Navari, RM, et al: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 375:134-142, 2016.
2. Hashimoto H, Abe M, Nakao M, et al: A randomized, double-blind, placebo-controlled phase III trial evaluating olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy: J-FORCE study. 2019 ASCO Annual Meeting. Abstract 11503. Presented June 3, 2019.
3. Wulff-Burchfield EM: Symptoms and survivorship, including clinical applications for immune checkpoint inhibitors toxicities. 2019 Best of ASCO Austin. Presented July 27, 2019.
4. Chanthawong S, Lim YH, Subongkot S, et al: Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for managing highly emetogenic chemotherapy in Southeast Asia: A multinational study. Support Care Cancer 27:1109-1119, 2019.
