This study demonstrated the remarkable efficacy of olanzapine as a rescue medication for patients who experience nausea and vomiting despite receiving the standard primary prevention against CINV. The overall and complete remission rates of CINV of 83% and 33%, respectively, consolidate the excellent efficacy of olanzapine as a secondary prevention drug for CINV, which had not been extensively evaluated until recently. Navari et al. performed one of the few published randomized, double-blind studies in this setting. They demonstrated the superiority of olanzapine (10 mg once daily for 3 days orally) over metoclopramide (10 mg three times daily for 3 days orally), either added to the conventional three-drug regimen, for patients with breakthrough CINV after they received HEC (≥ 70 mg/m2 cisplatin or doxorubicin-cyclophosphamide-containing regimens). In this study, the proportion of patients without nausea during the 72-h observation period was significantly higher in the olanzapine group compared with the metoclopramide group (65% [38 of 56] and 23% [12 of 52], p < 0.01) [8]. Chanthawong et al. performed a phase 2 study that evaluated olanzapine (5 mg every 12 h for two doses orally) in patients who received HEC and experienced breakthrough emesis despite antiemetic prophylaxis with ondansetron, corticosteroids, and metoclopramide. The complete responses for breakthrough emesis and nausea among 46 evaluated patients during a 24-h observation period were 61% and 50%, respectively [9]. Vig et al. performed a retrospective analysis of 33 patients with breakthrough CINV refractory to dopamine antagonists and benzodiazepines, who received at least one dose of 5–10 mg oral olanzapine. They concluded that the overall success rate, defined as lower than five emesis events in 24 h or < 10 cumulative doses of rescue antiemetics, was 70%. Post hoc analysis showed that efficacy of olanzapine was observed regardless of sex, degree of chemotherapy emetogenicity, number of prophylactic antiemetics, or age [10]. Since these previous studies were limited by the chemotherapy regimens or olanzapine doses, our results provide new insights into the secondary prevention of breakthrough CINV using olanzapine.

Notably, we found that olanzapine was not as effective in patients receiving non-HEC as in those receiving HEC, although statistical differences were marginal. This finding was contrary to the favorable response observed in the HEC group, which was expected based on the results of a previous study [8]. In a randomized, double-blind, placebo-controlled study evaluating the use of olanzapine with palonosetron and dexamethasone in 56 patients receiving MEC, the reduction in CINV incidence was limited despite better QOL in the olanzapine group [12]. In this context, a recent systematic review of olanzapine for CINV described the paucity of data on the utility of olanzapine in MEC regimens [13]. However, these previous studies evaluated olanzapine for MEC regimens mostly in a primary prophylaxis setting. Although the prophylactic efficacies of olanzapine for breakthrough CINV in our patients in the non-HEC group were not as satisfactory as those in the HEC group, substantial improvements in CINV symptoms were found in the non-HEC group. This result prompts the further exploration of effective treatments for breakthrough CINV in these populations.

Another remarkable finding of the study was the acceptable efficacy of a low dose (2.5 mg/day) of olanzapine compared with that of the standard doses (5 or 10 mg/day). The complete response rate in the low-dose group was unexpectedly higher than that in the standard-dose group. In treating schizophrenia, the standard dose of olanzapine is 5–20 mg/day, since an adequate plasma olanzapine concentration is required to improve the psychiatric symptoms [14] [15]. Therefore, the earliest studies used 10 mg/day as the experimental dose of olanzapine to prevent CINV [16] [17]. However, the sedative side effects of olanzapine are particularly problematic for patients who do not have psychotic symptoms. After exploration of less toxic treatment regimens that can retain sufficient antiemetic effect in several randomized studies, 5 mg/day olanzapine is now considered the new standard for the prevention of CINV [18] [19]. However, in our daily oncology practice, we observed that even 5 mg/day of olanzapine treatment could produce sedative effects in patients. Whereas the approved dose of olanzapine for CINV is 5–10 mg daily in Japan, we prescribe 2.5 mg/day olanzapine in cases where the side effects of olanzapine are anticipated, such as in patients with low body weight or elderly individuals. We also hypothesized that olanzapine at lower doses could effectively occupy the D2 receptor to prevent CINV [20]. Thus, 2.5 mg/day of olanzapine can be a reasonable alternative dose for carefully selected patients with breakthrough CINV.

Given the retrospective nature of our study that was conducted at a single institution, several concerns should be addressed before interpreting the results. First, the sample size was not powered to identify intergroup differences. In addition, our study population was relatively heterogeneous in terms of cancer type, age, disease advancement, treatment risks for CINV, and baseline antiemetic therapies. Therefore, well-designed prospective studies should be performed to verify our results. Next, based on case-by-case decisions, the treatment regimen of olanzapine for breakthrough CINV was not appropriately organized according to dosage or duration. As a result, the treatment schedule for olanzapine was not uniform in our study, possibly affecting the efficacy or toxicity of the medication. Finally, the effectiveness of 2.5 mg/day of olanzapine treatment in secondary or primary prevention of CINV requires prospective studies.