The meta-analysis conducted by Yang T et al indicates that OLZ have a equal or better efficacy comparing with aprepitant (APR) in preventing CINV. Phase 2 study demostrated that lower 5mg dose and 10mg dose are equally effective, but the former has a lower occurrence rate of somnolence. In 2019, Hirotoshi Iihara launched the first single arm multicentre phase 2 clinical trial about the efficacy of 5mg dose OLZ in the prevention of CINV induced by carboplatin. We conducted this prospective randomized clinical trial of the efficacy of the low-dose 5mg olanzapine triplet regimen and standard doublet regimen in preventing CINV induced by carboplatin.
This study indicated that the primary end-point TC rate of the OLZ triplet regimen is notably improved when comparing with the corresponding rates in the standard doublet regimen during the overall phase (OP), acute phase (AP) and delayed phase (DP)(P = 0.001; P = 0.003; P = 0.001). The 15% absolute improvment in the TC rate of overall phase is expected to have a practical clinical meaningful, and there is a 30% absolute increasing in the overall phase TC rate in the OLZ triplet regimen against the control in this study. However the TC rate in the OP, AP and DP from this study are evidently lower than the results 62.50% vs 86.00%、87.50% vs 100%、64.28% vs 86% when compared with Sakai et al’s phase 2 clinical trial in 2021. Such discrepancies is possibly caused by different possible reasons. Firstly, the enrolled patients in t Sakai et al’s study all had thoracic malignancies, and 30% of the enrolled patients are female and 50% had no history of alcohol consumption. Nevertheless, 30% of the patients enrolled in this study had gynecologic cancer such as ovaria cancer and etc,. 51.78% are females, and 71.42% have no history of alcohol consumption. Various studies had shown that female and nondrinker has a high risk of CINV, and carboplatin combination chemotherapy has a low control rate in prevention CINV in gynecologic cancer[13, 17, 18]. In addition, the median age of the patients in this study is 62 years old, researches about prevention of CINV suggested that control rate increases along with the age of the patients, age of 65 and younger is one of the risk factors may explain the lower TC rate in this study[13, 19]. Again, another reason that could explain the comparatively lower TC rate in this study is due to the prevalence of the immune checkpoint inhibitors in recent years, Arbour et al reported that corticosteroid lowers the therapeutic effect of such medications. We employed the 1 day DEX treatment in this study on the previous related clinical trials which confirmed that the 1day and 3 days DEX treatment have a similar effect in preventing anthracyclines-induced nausea and vomiting. But it could also mean a decrease in the delayed phase control rate when compared with the 3 days DEX regimen in Sakai et al’s study. Moreover, patients of this study underwent chemotherapy with different cycles which scenario is more realistic, the control rate of CINV may decrease with the chemotherapy cycles progressed.
The secondary end-point CR rate during OP, AP and DP of this study were similar to the results from Saiki et al’s study (91.00% vs 94.00%, 98% vs 100% and 91% vs 94% ) respectively and the differences between the OLZ triplet regimen and the standard doublet regimen does not get statistical significant. In Yasuhiro Ito et al’s study which compared the efficacy and safety of of aprepitant on the basis of 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and dexamethasone in patients with advanced non-small-cell lung cancer (NSCLC) who received carboplatin-based first-line chemotherapy induced CINV, the CR rate of aprepitant triplet regimen is 80.30% during OP, which also does not get significantly different than the control. Yoko watanabe further demonstrated that the CR rate between aprepitant and control groups was 74.1% vs 73.1% during OP and showed no significant difference in their 2021 study, which compared the efficacy of the same aprepitant triplet regimen in patients with gynecologic cancer patients who receiving paclitaxel and carboplatin combination chemotherapy induced CINV . The CR rates of these two clinical studies are lower than it reported by the 5mg OLZ triplet regimen in this study, which are also consistent with the results of a single centre randomised phase 2 study with 94 patients receiving HECs (cisplatin, carboplatin, doxorubicin and etc. ) conducted by Rumyantsev et al in 2019, OLZ group got higher CR rate than aprepitant group 74.4% vs. 54.0% during OP (P = 0.04). In 2020, Suthinee et al conducted a randomized, double-blind, controlled study compared the efficacy of aprepitant or 5mg olanzapine in combination with ondansetron and dexamethasonepatients in prevention CINV in patients receiving cyclophosphamide plus doxorubicin or cisplatin[14, 25]. The results showed CR rates of the 5mg olanzapine group were comparable the aprepitant group 68% vs 66% during the overall phase(P = 0.83), similar results observed in this study and in previous meta-analysis further proven that 5mg olanzapine are not inferior than aprepitant in prevention carboplatin induced CINV .
FILE index were adopted in this study to evaluate the impact of CINV on patients’ daily life, scores greater than 108 indicates that no impact is observed, the results of patients scoring greater that 108 between olanzapine triplet groud and control is 62.50% vs.43.85% (P = 0.047), with significant difference. Quality of life for patients in the OLZ triplet regimen groups were notably improved, 62.50% of the patients did not experience any episodes of vomiting or nausea, such result also corresponds with results from previous studies that supports the superiority of olanzapine in controlling nausea during delayed phase. Instead of adopted CR as the primary end-point in previous carboplatin induced CINV clinical trials, this study adopted TC rate as the primary end-point and observed its positive clinical effect in prevention carboplatin induced CINV, this result is in accordance with the advantageous characteristics of olanzipine. Kaplan–Meier curves had shown that time to first emesis was delayed for the OLZ triplet reginmen group comparing with control, this result indicated that 5mg OLZ may not only reduced bu also delayed the occurrence of vomiting. The olazapine related adverse effects in enrolled patients are observed and studied in this study, 75.00% patients reported somnolence, similar to the 78.00% occurrence rate observed in Sakai et al’s phase 2 study in japan, also, 78.30% of these patients’ symptoms were mild, hence OLZ is tolerable and safe. This study discovered a clear decrease of the incidence rate of anorexia, 50.00% for patients in the OLZ triplet regimen, and 70.17% for control, which is consistent with results from other clinical reports that confirmed OLZ improves the appetite of patients with gastric cancer when receiving chemotherapy treatments.
In conclusion, 5mg olanzipine triplet regiment is a more effective than the standard regimen in preventing carboplatin induced CINV(AUC ≥ 5) in Chinese population, particularly effective in nausea control, which is also tolerable, safe and economical. In future studies, more detailed clinical trials of the efficacy of lower dose olanzipine regimen in preventing CINV should be conducted with a larger and diversified sample.