Olanzapine Effective for Higher-Risk Chemo-Induced Nausea

The addition of olanzapine (Zyprexa) to standard antiemetic therapy among patients receiving highly emetogenic chemotherapy provides better nausea and vomiting relief across subgroups at high risk for the chemotherapy-induced symptoms, new research shows.

The researchers found significantly more patients receiving olanzapine demonstrated a complete response — no vomiting or use of rescue medication — between 24 hours and 5 days following cisplatin-based chemotherapy.

"For better control of nausea and vomiting during the entire treatment cycle, findings of this study suggest that adding olanzapine to triplet antiemetic therapy at the initiation of chemotherapy is beneficial regardless of risk factors, unless olanzapine is difficult to administer," the authors, led by Masakazu Abe, MD, of Hamamatsu University School of Medicine, Japan, conclude.

The research was published online May 2 in JAMA Network Open.

Although side effects can vary according to chemotherapy type, nausea and vomiting are reported in most patients receiving highly emetogenic chemotherapy. These side effects can have profound impacts on a patient's quality of life and impact treatment compliance.

The standard antiemetic therapy for highly emetogenic regimens — which include cisplatin-based chemotherapy and anthracycline plus cyclophosphamide therapies — is a triplet combination of 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, neurokinin-1 (NK-1) receptor antagonist, and dexamethasone.

However, standard antiemetic treatment is not effective for all patients, and in the important delayed phase, which occurs 24 hours after the start of chemotherapy, only about 60%–70% of patients respond.

The off-label use of the atypical antipsychotic olanzapine, along with its mood stabilizing effects in schizophrenia and bipolar disorder, has demonstrated remarkable improvement of chemotherapy-induced nausea and vomiting. Two recent placebo-controlled phase 3 trials found that the combination of olanzapine and the triplet antiemetic therapy significantly improved nausea and vomiting compared with triplet therapy alone.

The updated antiemetic guidelines from the American Society of Clinical Oncology recommend a combination of 5-10 mg of olanzapine with triplet therapy as a standard antiemetic therapy for patients receiving highly emetogenic chemotherapy. The 2021 recommendation from the National Comprehensive Cancer Network suggests an antiemetic regimen based on an individual patient's risk.

To further investigate the effects among subgroups of patients known to be at high risk for chemotherapy-induced nausea and vomiting, the authors of one trial conducted a secondary analysis of their study.

The original study of 710 patients found that the combination of olanzapine 5 mg with the triplet regimen had a 79.1% rate of complete response in the delayed phase after chemotherapy, compared with a 65.8% among those with the triplet regimen alone (P < .001). The trial, which was conducted in Japan from February 2017 to July 2018, included patients enrolled from 26 centers, who were cisplatin-naive and had a mean age of 63 years.

For the secondary analysis, Abe and colleagues evaluated 705 patients from the study, most of whom (82.4%) were 55 or older and were receiving a cisplatin dose of 70 mg/m² or more (74.6%).

The patients were randomly assigned 1:1 to receive either 5 mg of olanzapine or placebo alongside the triplet antiemetic therapy. The major risk factors for chemotherapy-induced nausea and vomiting included the type and dose of treatment, younger age, female sex, motion and morning sickness experiences, and drinking habits. Complete response, the primary endpoint, was defined as no vomiting or need for rescue medication in the delayed phase, which began 24 hours after chemotherapy initiation.

The researchers found improvements in complete responses among patients receiving olanzapine in all subgroups. Specifically, the addition of olanzapine led to a greater likelihood that both male and female patients would experience a complete response in the delayed phase (risk difference [RD] for males, 12.6%; RD for females, 14.5%) as well as both older and younger patients (RD for age 55 and above, 11.1%; RD for younger patients, 23.6%).

A significantly greater olanzapine effect was observed among patients receiving a cisplatin dose of 70 mg/m² or more (RD, 13.5%), those without a history of motion sickness (RD, 13.9%), those with a drinking habit (RD, 14.9%) or without a drinking habit (RD, 12%). And the effect was particularly strong among those with a history of morning sickness during pregnancy (RD, 27.2%).

The rate of complete responses in the delayed phase was also higher with olanzapine in other subgroups, but those differences were not statistically significant.

The most common side effect associated with of olanzapine was drowsiness, but the authors noted that drowsiness appeared to be well-tolerated and not as severe as the weakness caused by chemotherapy-induced nausea and vomiting.

The new results provide reassurance about the benefits of olanzapine across a range of subgroups and risk factors, the authors concluded.

Although the study did not identify any groups that did not respond, Mellar Davis, MD, noted that in clinical practice, olanzapine isn't always successful.

"We have not detected a resistant phenotype to olanzapine, though clinically we have all had patients not respond," said Davis, section head of the Palliative Care Department at the Geisinger Health System, Danville, Pennsylvania.

Still, he recommended, "olanzapine should be used routinely in highly emetogenic as well as moderately emetogenic chemotherapy. It particularly adds to the control of delayed nausea where aprepitant [Emend] is relatively ineffective." At Geisinger, "olanzapine has become a routine addition to emetogenic chemotherapy. I believe it should be standard protocol," he added.

Plus, Davis noted, among cancer patients who do respond, the benefits may extend beyond chemotherapy-induced nausea and vomiting.

"Olanzapine is an agent that also improves sleep architecture and may block opioid craving, though the latter has weak evidence," Davis said. "So, treatment of associated symptoms of insomnia and anorexia during chemotherapy with one drug is smart prescribing."

The study was funded in part by a grant from the Japan Agency for Medical Research and Development and by the Japan Supportive, Palliative, and Psychosocial Oncology Group. Abe reports no relevant financial relationships. The other authors' disclosures are detailed in the published study. Davis reports no relevant financial relationships.

JAMA Network Open. Published May 2, 2023. Full text

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