Efficacy of low-dose olanzapine in preventing chemotherapy-induced nausea and vomiting in patients with steroid intolerance

INTRODUCTION

Chemotherapy-induced nausea and vomiting (CINV) is a common and distressing side effect of cancer treatment, significantly affecting patients’ quality of life.^[1] Despite the use of standard antiemetic regimens, including 5-HT3 receptor antagonists, NK1 receptor antagonists, and corticosteroids like dexamethasone, CINV remains inadequately controlled in some patients.^[2] Dexamethasone, while effective, has adverse effects such as hyperglycemia and hypertension, making it unsuitable for patients with comorbidities.^[3]Olanzapine, an antipsychotic with antiemetic properties, offers a potential alternative.^[4-7] This study evaluates the efficacy of low-dose olanzapine in preventing CINV in patients unable to tolerate corticosteroids.

MATERIAL AND METHODS

This was a prospective single-institution observational study conducted in patients receiving moderately or highly emetogenic chemotherapy (MEC/HEC). Eligible patients were > 18 years old, had an Eastern Cooperative Oncology Group (ECOG) performance status < 2, and were scheduled to receive chemotherapy or chemo-immunotherapy. Patients with uncontrolled vomiting prior to chemotherapy, known CNS disease, or concurrent use of other antipsychotics were excluded.

Patient details were collected, including all pertinent demographic characteristics and medical data. Participants were stratified based on sex, ECOG PS, Comorbidities, diagnosis, chemotherapy/immunotherapy regimen and frequency, intent, and emetogenic potential risk of the chemotherapy/immunotherapy regimen used. The patients were assessed at each cycle for two cycles. Depending on clinical circumstances, rescue therapy for nausea, emesis, or retching was permitted as per the treating investigator’s choice.

Informed consent was taken from every patient, and the study was approved by the Institutional Review Board.

All participants received a 5–HT3–receptor antagonist (ondansetron, intravenously at a dose of 8mg), dexamethasone 8mg (4mg for weekly chemotherapy), and an NK1-receptor antagonist (for highly emetogenic or combination chemotherapy) on day 1 of chemotherapy. The NK1-receptor antagonist was intravenous fosaprepitant (150 mg on day 1) or oral aprepitant (125 mg on day 1, and 80 mg on days 2 and 3). In addition, patients received low-dose olanzapine (2.5 mg per day orally) on days 2 through 4 for MEC and days 2 through 6 for HEC.

Participants were asked to complete daily records of episodes of vomiting or retching (number and time), use of rescue therapy from the first day of chemotherapy through day 5, and daily levels of nausea. Patients were contacted daily on days 2 through 5 to ask about any toxic effects. Adverse events were graded according to the terminology and grading categories defined in the National Cancer Institute’s Common Terminology Criteria (NCICTC) for Adverse Events, version 4.0. Patients were also asked about undesired sedation and increased appetite.

RESULTS

A total of 50 patients receiving moderate or highly emetogenic chemotherapy were enrolled in the study. Baseline demographics are summarized in Table 1. Of these, 26 (52%) were women, and 24 (48%) were men. All the patients had underlying comorbidities, with diabetes mellitus being the most common (80%), followed by hypertension (38%). Other comorbidities included coronary artery disease (6%), Hepatitis B (4%), and hypothyroidism (4%).

In terms of chemotherapy regimen frequency, 54% of patients received weekly chemotherapy, while 32% received treatment every two weeks, and 12% every three weeks. Additionally, 66% of patients underwent chemotherapy alone, while 22% received a combination of chemotherapy and targeted therapy. The majority (62%) were receiving treatment with palliative intent.

The incidence of chemotherapy-induced nausea was observed in 3 patients (6%), while vomiting occurred in only 1 patient (2%) , as demonstrated in Table 2. The remaining 47 patients (94%) did not experience nausea, and 49 patients (98%) were free from vomiting throughout the observation period. This indicates a high overall efficacy of the low-dose olanzapine regimen in preventing CINV.

Olanzapine-related adverse effects were minimal, as shown in Table 3. Sedation was reported in 6 patients (12%), weight gain in 2 patients (4%), and increased appetite in 16 patients (32%). Other reported side effects included fatigue (4%), impaired vision (2%), and abdominal pain (2%). All adverse events were mild; no Grade > 3 toxicities were reported. Importantly, no instances of hyperglycemia were observed, highlighting olanzapine’s safety in patients with diabetes.

Treatment adherence was excellent, with no patients discontinuing therapy due to intolerable side effects. The low dose of olanzapine (2.5 mg daily for three to five days) appeared to provide an optimal balance between efficacy and tolerability.

These findings suggest that low-dose olanzapine is a well-tolerated and effective option for CINV prevention, particularly in patients with corticosteroid intolerance.

DISCUSSION

Managing nausea remains a critical challenge in preventing CINV. International guidelines recommend the use of NK1 Receptor antagonists, such as fosaprepitant or aprepitant, in combination with 5-HT3 receptor antagonists and corticosteroids, particularly for patients receiving HEC. However, the adverse effects associated with standard corticosteroid doses necessitate alternative approaches. Patients recruited in our study could not tolerate steroids for 4 days (as included in standard antiemetic regimens) because of comorbidities. Hence, low-dose olanzapine was given alongside standard antiemetic therapy, and high-dose steroids were skipped for patients with comorbidities, which demonstrated a significant reduction in CINV occurrence.

The prolonged use of corticosteroids, such as dexamethasone, in antiemetic regimens is often associated with a range of side effects, including hyperglycemia, insomnia, mood disturbances, gastrointestinal discomfort, and an increased risk of infections. These adverse effects can negatively impact patients’ quality of life and may lead to poor adherence to antiemetic therapy. As a result, there is growing interest in minimizing steroid exposure without compromising the efficacy of CINV prevention. Olanzapine, with its broad antiemetic properties targeting multiple neurotransmitter pathways, presents a promising alternative or adjunct to corticosteroids, offering effective symptom control with a potentially more favorable side effect profile when used at lower doses.

Our findings align with those of Liu et al., who reported that olanzapine effectively managed nausea in patients undergoing HEC.^[8] Similarly, Wu et al. found that olanzapine provided superior protection against CINV in patients receiving MEC.^[9] These results reinforce the potential of olanzapine as a valuable addition to antiemetic regimens.

While olanzapine is known to cause side effects such as sedation, fatigue, and visual disturbances, our study utilized a lower dose (2.5 mg daily for three days) to minimize these risks. Prior studies have shown that lower doses, such as 5mg, provide similar antiemetic efficacy to the standard 10mg dose while causing fewer adverse events.^[6,10] Research by Bun et al. further supports the effectiveness of 2.5 mg olanzapine for CINV prevention, forming the basis for our dosing strategy.^[11]However, there is a paucity of data on the usage of low-dose olanzapine (2.5mg dose) in the prevention of CINV.

Importantly, our study observed a favorable safety profile with low-dose olanzapine, with minimal adverse effects such as sedation and weight gain, which were manageable and did not significantly impact treatment adherence. These findings are encouraging, as concerns about olanzapine-related adverse effects have previously limited its widespread use.

Despite these promising results, our study has several limitations. The sample size was relatively small, and the follow-up period was limited to the immediate post-chemotherapy phase. Larger, multicenter randomized trials with extended follow-up are warranted to confirm our findings and further assess the long-term tolerability and impact on quality of life. Additionally, future studies could explore optimal dosing strategies to balance efficacy and side effect profiles in diverse patient populations.

CONCLUSION

The results of this study demonstrated the clinical efficacy of 2.5 mg olanzapine in preventing CINV induced by MEC or HEC and affirmed the result across all groups. Olanzapine also led to improvement in appetite in a section of patients. Low-dose olanzapine resulted in a low incidence of daytime somnolence and other side effects associated with the drug and can be considered as a new standard of care. However, more studies with a larger sample size and the incorporation of all potential risk factors are needed.