The present study provides incidences of, and risk factors for, delayed CINV in CRC patients receiving L-OHP-based chemotherapy, based on three prospective studies [25,26,27]. Delayed nausea occurred frequently but was less common in patients who received three antiemetics adding an NK1RA than those who received two antiemetics. Delayed vomiting incidence was relatively low, and significant lower in the 3 antiemetics group. Multivariate analysis identified female sex and 2 antiemetics regimens as independent risk factors for delayed CINV.
Although adding a NK1RA to a 5HT3RAs and a steroid is well established and clearly recommended by all international guidelines for patients undergoing HEC, [8,9,10, 12] its benefit is still controversial for MEC other than carboplatin (CBDCA) -based regimens, and recommendations for using NK1RAs with MEC vary considerably among guidelines. As few clinical trials have attempted to clarify optimal antiemetic prophylaxis for CRC patients who receive L-OHP-based chemotherapy, evidence-based guidance in this setting is lacking.
Risk/benefit profiles and medication costs are important factors in treatment decisions, including antiemetic treatment. Choosing Wisely, an initiative of the American Board of Internal Medicine (ABIM) Foundation that seeks to advance a national dialogue on avoiding unnecessary medical tests, treatments and procedures, suggests that patients receiving MEC not use NK1RAs, for tolerability and economic reasons [28].
Iihara et al. [29] reported that use of two antiemetics—5HT3RA and dexamethasone—was sufficient for prevention of CINV in most MEC regimens, and found no significant differences in control of CINV among L-OHP, carboplatin and irinotecan. A recent meta-analysis [24] indicates that adding NK1RAs for patients undergoing L-OHP-based chemotherapy did not have a very pronounced effect. However, the two major studies that included patients with CRC with similar L-OHP doses showed conflicting results. In addition, one of them used casopitant, which was never approved due to safety concerns. Therefore, the results have to be interpreted with caution. Hesketh et al. [13] advocated the need for routine antiemetic prophylaxis for delayed CINV following L-OHP-based chemotherapy. Tsuji et al. [25] reported that delayed nausea incidence was still high for MEC, and patients on L-OHP-based regimens seemed to benefit from doublet therapy with palonosetron or triplet therapy with aprepitant. Nishimura et al. [27] reported that three antiemetics that included aprepitant was more effective than two antiemetics in preventing CINV in CRC patients on L-OHP-based regimens. In addition, the antiemetic effects of aprepitant did not significantly differ whether combined with palonosetron or not. In the present study, although the 2 antiemetics group included patients who received palonosetron, it was less effective than the 3 antiemetics regimens.
Within the MEC classification, L-OHP has relatively high risks of CINV, as well as CBDCA, which suggests a different antiemetic prophylaxis strategy is appropriate. In the last update of the MASCC/ESMO guidelines, [9] experts discussed different recommendations for CBDCA-based and L-OHP-based chemotherapies, as L-OHP-based chemotherapy is estimated to carry a high emetic risk within MEC. The MASCC/ESMO guideline indicates that a 10% difference in CINV rates would be noticeable to the patient, [30] and appears to be a reasonable threshold to warrant a change in clinical practice. In the present study, 3 antiemetics regimens reduced delayed vomiting incidence by 11.93% and delayed nausea incidence by 9.07%, compared with 2 antiemetics.
Younger age, female sex, a history of CINV, and low alcohol consumption have been reported as well-known risk factors [15,16,17,18,19,20,21,22,23]. Roscoe et al. [17] reported that a chemotherapy history was a stronger predictor than other predictors, including morning sickness, age, and motion sickness. Study cohorts for these reports included large percentages of breast cancer patients, whereas few studies of risk factors for CINV in CRC patients have been performed. Takemoto et al. [31] reported that female sex and aprepitant use were risk factors for CINV in CRC patients who received L-OHP-based chemotherapy, and that 3 antiemetics regimens that included aprepitant were more effective for women than for men in preventing CINV in this setting. Our integrated analysis showed that female sex and 2 antiemetics regimens were independent risk factors for both delayed nausea and delayed vomiting in CRC patients on L-OHP-based chemotherapy.
In the analysis focused on the efficacy of 3 antiemetics compared with 2 antiemetics containing palonosetron, a second-generation 5-HT3RA which is more effective than first-generation 5-HT3RAs against delayed CINV, 3 antiemetics was superior than 2 antiemetics for preventing delayed CINV, and female sex was identified as an independent risk factor for delayed vomiting [32].
In addition, the randomized trial in Chinese female patients with gastrointestinal cancer at high risk for CINV (younger than 50 years, no or low alcohol consumption) demonstrated significantly better antiemetic effect of 3 antiemetics, palonosetron plus dexamethasone plus aprepitant, compared with palonosetron plus dexamethasone for CINV caused by L-OHP or irinotecan-based chemotherapy [33].
On the other hand, the incremental benefits by adding aprepitant in men (3% delayed nausea, 6% delayed vomiting) was very small compared to women where the absolute benefits in delayed CINV are large in this study. These data suggest that 2 antiemetics for prevention of delayed CINV may be sufficient for men receiving L-OHP-based regimen. Although there may be some operational issues such as the complexity electronic order sets at medical institutions, it is worth considering individualizing antiemetic prophylaxis by gender.
Our study also found no significant difference between XELOX and FOLFOX regimens with respect to delayed CINV, as we hypothesized. Many physicians prefer XELOX as it does not need continuous 5-FU infusion, and our results support XELOX administration.
Study limitation
The present study had some limitations. First, as its design was neither randomized nor blind, present findings should be interpreted within the limitations of the observational study design. Second, the two integrated studies had a bias in the number of patients, which we attempted to mitigate by using the IPTW method to balance the observable characteristics of the two antiemetic treatments. Despite these limitations, the findings describe CINV incidence and its risk factors in routine clinical practice, rather than in a controlled trial.