In this retrospective cohort study of patients with aggressive B-cell lymphoma receiving their first cycle of multiday, inpatient DA-EPOCH, we found that those receiving an NK1RA-containing CINV prophylactic regimen experienced an improved CR. When adjusting for known risk factors of age and female sex, CINV CR significantly improved between groups [11–13]. We did not observe any significant differences between as-needed antiemetic use in acute and delayed phases, CR without escalating prophylactic antiemetics in cycle 2, or complete control between groups. A subgroup analysis revealed that men in the NK1RA group had improved CR, while women had similar CR in both the NK1RA and without NK1RA groups. Overall, these data add to the growing body of evidence describing the unmet clinical need for adults with hematologic malignancies receiving multiday chemotherapy and experiencing CINV [3, 4, 14–16].
It is critical to report our rates of CINV from those reporting emetogenicity of highly emetogenic multiday chemotherapy for hematologic malignancies. In one study with a similar population of 111 patients with lymphoma receiving DA-EPOCH or DA-R-EPOCH, 48.6% of patients receiving prophylactic antiemetics without NK1RA experienced a CINV event during their treatment[4] compared to 58.3% of our non-NK1RA patients who did not achieve CR. Another study examining patients with acute leukemia receiving induction with moderately emetogenic multiday chemotherapy, reported that the patients who received 5HT3RA-only prophylaxis experienced a 32.6% CR[15], similar to our without NK1RA group’s CR of 41.7%.
Despite the established role of NK1RAs in preventing delayed CINV [6], optimal CINV control was not achieved in our patients receiving the multiday regimen DA-R-EPOCH with an NK1RA. Even when utilizing the 2016 MASCC and ESMO consensus recommended multiday highly emetogenic chemotherapy prophylactic regimen of NK1RA, 5HT3RA, and corticosteroid[5] (with all patients receiving higher than CINV dexamethasone dose equivalents due to the lymphoma treatment protocol), most patients who had documented nausea and/or vomiting experienced this in the delayed phase (25 to 120 hours after chemotherapy initiation). Although the CINV CR improved in those receiving the NK1RA, it remained suboptimal in the delayed phase (60.7% and 47.2% in NK1RA and without NK1RA groups, respectively) compared to the acute phase (80.4% vs. 77.8%) in both groups. This finding was supported by the incidence of as-needed antiemetics use in the delayed phase compared to the acute phase, where over half of patients in both the NK1RA and non-NK1RA groups required as-needed antiemetics compared to less than one-fifth in the acute phase. Furthermore, we observed that both groups experienced similar complete control rates, where approximately one-third of patients experienced complete control.
The routine administration of a short-acting 5HT3RA (ondansetron) primarily benefits the acute phase [17]. Data suggest that palonosetron may be superior to ondansetron during the delayed phase, given its longer half-life [18]. In both arms, most patients received ondansetron daily on days 1–5, with only 9 patients in the NK1RA group and 5 in the non-NK1RA group receiving palonosetron. With the small number of patients in both arms receiving palonosetron, limited conclusions may be drawn comparing CINV outcomes between our patients who received ondansetron versus palonosetron.
Another pharmacologic approach that may improve CINV outcomes in our patients receiving multiday chemotherapy is the routine use of olanzapine. For example, a study published in 2022 evaluated using olanzapine in addition to triple prophylaxis (i.e., fosaprepitant, ondansetron, and dexamethasone) in patients receiving multiday, highly emetogenic chemotherapy. This study found the proportion of patients who achieved CR was significantly higher with the addition of olanzapine [19]. Notably, the most recent guidelines include olanzapine as a standard of care in AC-containing regimens [1, 5]. Lastly, data suggest extending the duration of NK1RA, such as administering oral aprepitant 125 mg followed by 80 mg orally on days 2 through 7, may improve CR in patients receiving multiday highly emetogenic chemotherapy regimens [20, 21]. To date, daily aprepitant use through day 7 is not a standard practice at our institution, given formulary restrictions.
Study Limitations
This study provides additional information on comparing prophylactic antiemetic regimens in patients receiving DA-R-EPOCH, which is underreported in the literature despite its clinical impact. Yet, given the study's retrospective nature, we recognize multiple limitations. First, we lack data on individual CINV risk factors beyond age and sex not routinely documented in the EMR (e.g., motion sickness, previous history of nausea during pregnancy, and low alcohol use). Previous studies suggest the effects of these unmeasured potential confounders are likely minor [11–13], and we suspect this documentation challenge affected both groups. Second, CINV-related admissions occurred at other healthcare facilities, leading to underreporting affecting both groups. Third, CINV CR rates may be worse than reported because nausea is a subjective measure that may introduce patient-reporting bias and/or underreporting. Furthermore, clinician-reported CINV may be lower than patient-reported CINV[22], leading to lower documentation rates, but it likely impacted both groups and had a minimal effect on our reported risk estimates. Fourth, this study had barriers to measuring and quantifying nausea because our institution did not utilize a standardized nausea scale or patient-reported outcome tool (e.g., MASCC Antiemesis Tool[23]) to assess daily CINV severity. We offset this limitation by incorporating objective measures of nausea control, such as breakthrough antiemetic use and prophylactic escalation with cycle 2. Also, there was use of both a shorter-acting 5HT3RA (ondansetron) and a longer-acting 5HT3RA (palonosetron); however, the small sample size of this study did not allow for adequate comparisons across different types of 5HT3RA prophylaxis.