A new phase 3 randomized controlled trial has found that a lower dose of olanzapine is non-inferior to the standard dose for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy, while causing significantly less daytime somnolence. The study, published on January 12, 2024 in The Lancet Oncology, suggests that the lower 2.5 mg dose of olanzapine could become a new standard of care for CINV prevention.
The single-center, open-label, non-inferiority trial was conducted at the Tata Memorial Centre in Mumbai, India. It was funded by the Progressive Ladies Welfare Association. The study aimed to compare the efficacy of low-dose (2.5 mg) versus standard-dose (10 mg) olanzapine, when combined with a triple antiemetic regimen, for preventing CINV in patients with solid tumors receiving highly emetogenic chemotherapy.
CINV is a common and distressing side effect of cancer treatment that can significantly impact patients' quality of life and potentially lead to treatment interruptions. While olanzapine has shown efficacy in preventing CINV when added to standard antiemetic regimens, the currently recommended 10 mg dose is associated with substantial daytime somnolence. This side effect has limited its widespread adoption in clinical practice.
The study enrolled 275 patients between February 9, 2021, and May 30, 2023. Eligible patients were aged 13-75 years, had a diagnosis of a solid tumor, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and were scheduled to receive either doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² or cisplatin ≥70 mg/m² as their first chemotherapy regimen. Key exclusion criteria included pregnancy, breastfeeding, symptomatic brain metastases, concurrent radiotherapy, known psychiatric illnesses requiring antipsychotic treatment, uncontrolled diabetes, and recent use of antiemetic or psychoactive medications.
Patients were randomized 1:1 to receive either 2.5 mg or 10 mg of oral olanzapine daily for 4 days, starting on the day of chemotherapy. Both groups also received a standard triple antiemetic regimen consisting of a 5-HT3 receptor antagonist, single-dose dexamethasone (8 mg IV on day 1), and an NK1 receptor antagonist. The primary endpoint was complete control of CINV, defined as no emetic episodes, no use of rescue medications, and no or only mild nausea in the overall phase (0-120 hours after chemotherapy initiation).
Of the 275 randomized patients, 267 were included in the modified intention-to-treat (mITT) analysis (132 in the 2.5 mg group and 135 in the 10 mg group). The study population was predominantly female (94%) and the majority (91%) had breast cancer. The median age was 45 years.
The results showed that the 2.5 mg olanzapine dose was non-inferior to the 10 mg dose for the primary endpoint. In the overall phase, 59 patients (45%) in the 2.5 mg group achieved complete control compared to 59 patients (44%) in the 10 mg group (difference -1.0%, one-sided 95% CI -100.0 to 9.0; p=0.87). The upper bound of the confidence interval did not exceed the pre-specified non-inferiority margin of 10%.
Importantly, the lower dose was associated with significantly less daytime somnolence. In the overall phase, 86 patients (65%) in the 2.5 mg group experienced any grade of daytime somnolence compared to 121 patients (90%) in the 10 mg group (p<0.0001). The difference was particularly striking for severe daytime somnolence on day 1, which affected only 6 patients (5%) in the 2.5 mg group versus 54 patients (40%) in the 10 mg group (p<0.0001).
There were no significant differences between the groups in secondary efficacy endpoints, including complete control in the acute (0-24 hours) and delayed (25-120 hours) phases, complete response (no emesis and no rescue medication use), and total control (no emesis, no rescue medication use, and no nausea) in any phase.
An exploratory analysis found that fewer patients in the 2.5 mg group reported decreased appetite on days 2-5 compared to the 10 mg group. The authors speculate that this could be related to the higher incidence of daytime somnolence in the 10 mg group interfering with daily activities, including food intake.
The study has several strengths, including its randomized design, adequate power, and use of both categorical and visual analog scales to assess outcomes. The focus on a practical, lower dose of olanzapine that significantly reduces daytime somnolence while maintaining antiemetic efficacy is clinically relevant and addresses an important barrier to olanzapine's use in CINV prevention.
However, there are some limitations to consider. The trial was conducted at a single center and the study population was predominantly women with breast cancer receiving anthracycline-based chemotherapy. This may limit the generalizability of the results to other patient populations and chemotherapy regimens. The open-label design, while pragmatic, could potentially introduce some bias in symptom reporting, although outcome assessors were blinded to treatment allocation.
Another notable aspect of the study was the use of a single dose of dexamethasone, which is lower than typically recommended in standard antiemetic guidelines. While this approach may help reduce steroid-related side effects, it's possible that using standard dexamethasone dosing could have further improved CINV control in both groups. The authors suggest that future studies could explore the optimal balance between steroid dosing and olanzapine dosing for CINV prevention.
The authors conclude that low-dose olanzapine (2.5 mg daily for 4 days) is non-inferior to the standard 10 mg dose for controlling CINV when given as part of a triple antiemetic regimen for patients receiving highly emetogenic chemotherapy. They argue that the significantly lower incidence of daytime somnolence with the 2.5 mg dose, combined with its maintained efficacy, supports its use as a new standard of care for CINV prevention in this setting.
The potential clinical impact of these findings is substantial. CINV remains a significant problem for many cancer patients, and current antiemetic regimens, while effective, often come with bothersome side effects. The ability to use a lower dose of olanzapine that maintains antiemetic efficacy while causing less daytime somnolence could improve patients' quality of life and potentially increase adherence to antiemetic regimens.
For oncologists and other clinicians managing patients receiving highly emetogenic chemotherapy, this study provides evidence to support using a lower dose of olanzapine as part of CINV prevention strategies. The 2.5 mg dose appears to offer a better balance between efficacy and tolerability compared to the standard 10 mg dose.
However, it's important to note that these results may not necessarily apply to all patient populations or chemotherapy regimens. Clinicians should consider individual patient factors and may need to adjust antiemetic regimens based on response and tolerability.
The study also raises interesting questions for future research. For example, studies comparing different steroid dosing strategies in combination with low-dose olanzapine could help further optimize CINV prevention regimens. Additionally, investigations in more diverse patient populations and with other highly emetogenic chemotherapy regimens would be valuable to confirm the broader applicability of these findings.
In conclusion, this well-designed phase 3 trial provides strong evidence supporting the use of low-dose olanzapine for CINV prevention. The ability to maintain antiemetic efficacy while significantly reducing daytime somnolence represents an important step forward in supportive care for cancer patients. As with any change in clinical practice, careful monitoring and ongoing research will be important to confirm these benefits in real-world settings and diverse patient populations.
References
Bajpai J, Kapu V, Rath S, et al. Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial. Lancet Oncol. 2024;25(2):246-254. doi:10.1016/S1470-2045(23)00628-9
