The present study demonstrated a higher incidence of CINV in patients who received CBDCA+PEM than in those who received CBDCA+PTX therapy. Further, the CBDCA+PEM regimen was an independent risk factor for nausea in the delayed phase. While acute CINV was well controlled in both groups, the incidence of delayed nausea was significantly higher in the CBDCA+PEM group than that in the CBDCA+PTX group (51.1% vs. 36.2%, P = 0.040). Although the incidence of delayed vomiting was not significantly different between the two groups, the incidence of vomiting in the CBDCA+PEM group tended to be high (23.4% vs. 14.9%, P = 0.138).
Knowing the CINV incidence pattern is important for determining the optimal antiemetic treatment. In patients who received anthracycline + cyclophosphamide regimens with antiemetic prophylaxis, nausea peaked on day 2 . Meanwhile, in this study, nausea and vomiting peaked on day 5 in patients who received CBDCA regimens with antiemetic prophylaxis. This incidence pattern was similar to that observed for cisplatin . Although there were no significant differences in the time to nausea event (p = 0.076), the incidence rate of CINV, patterns of CINV incidence, and TTF suggest that the control of delayed nausea in patients receiving CBDCA+PEM needs to be improved.
Moreover, it is important to identify patients with a high risk of CINV so that appropriate measures to preserve the quality of life and ensure continuity of chemotherapy can be implemented. In this study, logistic regression analysis identified younger age, female sex, and CBDCA+PEM as independent risk factors associated with delayed nausea, and female sex as associated with delayed vomiting. Female sex and young age are well-known risk factors for CINV [16,17,18,19]. It is worth noting that the CBDCA+PEM regimen has been identified in this study as an independent risk factor for delayed nausea, along with these well-known patient-related risk factors.
We previously reported that the incidence of CINV was significantly higher in patients receiving pemetrexed or gemcitabine (GEM) than that in patients receiving taxane , and consistent results were obtained in this study. The CBDCA+PTX regimen requires premedication of 20 mg DEX, H1-blocker, and H2-blocker for allergy prevention on day 1. Although these agents may enhance the antiemetic effect, they have limited efficacy, as indicated by the incidence and pattern of CINV observed in this study. Therefore, the optimal antiemetic therapy still needs to be determined carefully for each CBDCA-based regimen, even for those in the same emetic risk category.
CINV in patients receiving CBDCA+PTX can be controlled relatively well by two antiemetics [8, 15]. Ito et al.  reported that the CBDCA+PEM regimen had relatively high emetic potential, and triple antiemetic therapy with a 5-HT3 receptor antagonist, DEX, and aprepitant may be an effective prophylactic treatment in patients receiving the CBDCA+PEM regimen. However, they evaluated CINV according to complete response (no vomiting and no rescue medication), and the incidence of nausea was unclear. In our study, the incidence of nausea was higher in the CBDCA+PEM group than that in the CBDCA+PTX group at the delayed phase, highlighting the need for improving the control of nausea in the delayed phase. Meanwhile, GEM may also have a higher risk of emesis among low emetic risk chemotherapies . Data from previous clinical trials suggest that CBDCA+GEM may have a higher risk of CINV than CBDCA+PTX [20, 21]. However, we were unable to analyze this case because of the small number of patients who received CBDCA+GEM. In addition, there are no reports directly comparing the incidence of nausea and vomiting between CBDCA+GEM and CBDCA+PTX. It is also unclear whether there is a clinically meaningful difference in terms of emetic risk between CBDCA+PEM and CBDCA+GEM.
The efficacy and safety of 10 mg olanzapine and standard triplet antiemetic therapy were shown in a randomized, double-blind phase III study in patients who received highly emetogenic chemotherapy including anthracycline/cyclophosphamide and cisplatin . Hashimoto et al.  reported that 5 mg of olanzapine combined with aprepitant, palonosetron, and dexamethasone provided a significant improvement in delayed CINV. Further, there were no significant differences in the incidence of daytime sleepiness between the olanzapine group and the placebo group among the patients receiving cisplatin-based chemotherapy. Tanaka et al.  reported that adding olanzapine to aprepitant, 5-HT3RA, and DEX improved CINV control in patients receiving CBDCA-based chemotherapy. Adding olanzapine to standard triplet antiemetic therapy is considered a promising option to improve control of delayed nausea in patients receiving CBDCA+PEM.
This study has some limitations. First, it was not a blinded, randomized control trial. Second, some risk factors of CINV such as smoking habits and morning sickness could not be analyzed. Finally, the results of this study were obtained from a Japanese population, and while the results may be applicable to other Asian populations, further research is needed to verify the generalizability of these results to other races. Despite these limitations, the findings described the emetogenicity of and risk factors for CBDCA-based regimens in routine clinical practice, rather than in a controlled trial, and therefore might reflect the real-world conditions. Further, the use of data with a sufficient number of events from two prospective observational studies and PSM enabled high accuracy and robustness of the results.