In four phase III trials, palonosetron was reported to have improved efficacy relative to the older 5-HT₃ RAs in the prevention of nausea and vomiting associated with initial and repeat courses of MEC or HEC [2, 8–10]. Gralla and colleagues evaluated patients randomized to receive single intravenous (i.v.) palonosetron doses of 0.25 or 0.75 mg, or ondansetron (32 mg), before initiating MEC. Palonosetron at 0.25 mg was significantly superior to ondansetron in the prevention of acute and delayed CINV events. Complete response rates were significantly higher for palonosetron-treated patients during the acute phase (81.0% vs. 68.6%), the delayed phase (74.1% vs. 55.1%), and the overall phase (69.3% vs. 50.3%) [8]. In the second MEC trial, Eisenberg et al. reported on a multicenter, double-blind, phase III study in patients who were randomized to receive i.v. palonosetron doses of 0.25 or 0.75 mg, or dolasetron (100 mg) before initiating MEC [9]. Complete response rates were significantly higher for palonosetron during the acute phase (63.0% and 52.9% for 0.25 mg palonosetron and dolasetron, respectively), the delayed phase (54.0% and 38.7%, respectively), and the overall phase (46.0% and 34.0%, respectively).

The Aapro et al. study [2] was one of the two phase III trials that studied the efficacy and safety of palonosetron in preventing CINV following HEC. Single-dose palonosetron was found as efficacious as ondansetron in preventing acute CINV. Moreover, palonosetron was significantly more efficacious than ondansetron during the delayed (42.0% vs. 28.6%) and the overall phases (40.7% vs. 25.2%) when patients were pre-treated with dexamethasone [2]. In a second phase III HEC trial carried out in Japan, patients with cancer and treated with HEC were randomly assigned to either single-dose palonosetron (0.75 mg) or granisetron (40 mcg/kg) given 30 min before HEC on day 1. Reported results indicated that when palonosetron was administered with dexamethasone before HEC, it exerted efficacy against CINV which was non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments [10].

While the efficacy of palonosetron in preventing CINV events has been well documented in clinical trials, its effectiveness in the real-world clinical practice has not been systematically reported. Hence, the present study was performed with a large claims database to investigate the comparative effectiveness of palonosetron versus other 5-HT₃ RAs as prophylaxis for resource-intensive CINV events associated with hospital and/or emergency department (ED) admissions in patients with breast or lung cancer receiving MEC or HEC. The secondary objective was to compare the effectiveness results reported in this study with the efficacy data previously reported in phase III clinical trials.

Results of this retrospective cohort study corroborate data obtained from earlier published clinical trials. The clinical trials and real-world community setting practice data indicate that prophylaxis and treatment with palonosetron was associated with a significant risk reduction for more severe CINV events. Although this study focused only on CINV events associated with admission to emergency departments or hospitals as opposed to all CINV events reported in clinical trials, the relative risk reductions reported here are comparable to those reported in these trials. More specifically, the relative risk reductions computed from the four trials ranged between 11.6% and 38.2% for the palonosetron group as compared to the older 5-HT3 RAs. This study focused on the more severe CINV events, while the clinical trials conducted with palonosetron reported on all CINV events. In spite of the difference in severity of CINV between this study and the earlier conducted clinical trials, our calculated relative risk reductions ranging between 25.9% and 43.4% were in line with the trials’ data. Additionally, a recently published study using medical record review reported that patients with gynecological cancer treated with cisplatin when prophylaxed with palonosetron experienced a lower risk of CINV-related hospital readmission versus patients prophylaxed with ondansetron [14].

Depending on the chemotherapy regimens, cyclophosphamide is given in a dose of 300–600 mg/m² as adjuvant therapy to patient with breast cancer [15]. The average dose of cyclophosphamide used in the breast cancer cohort was at the lower end of the dosing range, which might imply that our study cohort might have a less severe clinical status than patients with breast cancer receiving higher doses of cyclophosphamide. As such, one might anticipate that the impact of palonosetron on CINV may be more pronounced if a patient cohort with more intense chemotherapy regimens was studied. There were additional noteworthy clinical differences between the two comparison groups. In the breast cancer cohort, patients on palonosetron-only received, on average, 27 mg/m² (or 7%) higher cyclophosphamide dose per treatment cycle than the dose received by patients treated with the other 5-HT₃ RA regimens. One of the plausible explanations of this finding maybe that patients who received palonosetron-only were better able to tolerate higher cyclophosphamide doses. This finding is relevant to the extent that high and moderate-dose intensity regimens were reported to result in significantly better disease-free survival and overall survival than the low-dose intensity regimens [16]. Similarly, the palonosetron-only group of the lung cancer cohorts needed fewer total CT days (cisplatin-treated lung cancer, 4.9 days vs. 5.7 days, p<0.0001; carboplatin-treated lung cancer, 6.1 days vs. 6.2 days, p>0.05) to complete their chemotherapy regimens. One of the plausible explanations, based on the study findings, is that patients who received the palonosetron-only regimen may have been better able to complete their chemotherapy treatment regimen within fewer days, in light of their CINV experience. The results of the logistic regressions support our contention. Patients with more CT days showed a lower risk of CINV, indicating that spreading CT over more days, and thus potentially lowering the dose given per day, might have been a strategy used to reduce the burden of CINV. Further comparative studies are required to investigate whether the differences seen between the two study groups in chemotherapy doses/days may in fact impact patients’ clinical status or result in some economic efficiency.

The proportion of patients who used a 5-HT₃ RA alone without adding dexamethasone and/or aprepitant was higher in the palonosetron-only group. It is important to note that the pattern of antiemetic utilization observed in this analysis did not conform to the recommendations of the major CINV guidelines. The ASCO, MASCC-ESMO, and NCCN guidelines all recommend utilizing doublet therapy (dexamethasone and a 5-HT₃ RA) for MEC and a triplet regimen (dexamethasone, a 5-HT₃ receptor antagonist and an NK1 RA) for HEC as well as anthracycline–cyclophosphamide chemotherapy. In this analysis, single-agent 5-HT₃ RA therapy was received by 43% of breast cancer patients, 67% of carboplatin-treated patients and 47% of cisplatin-treated patients. Furthermore, only 19% of cisplatin-treated lung cancer patients received triple therapy. These findings suggest that undertreatment with antiemetics was widespread during this period and the number of visits to the ED could be improved with a higher percentage of patients adhering to the current CINV prevention guidelines.

Although a triplet regimen of dexamethasone, palonosetron, and aprepitant has been shown to be an effective regimen for emesis prevention [17–19], whether palonosetron would similarly improve upon the results relative to other 5-HT₃ RA regimens when evaluated in a population of patients who all received the recommended standard triplet antiemetic therapy remains an important question. The patient numbers from the current study were insufficient to carry out this type of analyses. However, a recent retrospective claims data analysis in over 4,000 patients all receiving a triplet regimen suggests that a difference persists even when guideline recommended regimens are given [20]. The triplet regimen that included palonosetron was associated with a lower risk for an uncontrolled CINV event than the triplet regimen that included an older 5-HT₃ RA. Further prospective studies are warranted to further clarify an answer to this question [20].

In this study, we did not differentiate the individual first generation 5-HT₃ RAs used, in part, to simplify the study design, and also based on an earlier report of no significant difference between the antiemetic efficacy of dolasetron, granisetron, or ondansetron in controlling CINV in patients on platinum-based chemotherapy regimens [21].

Finally, our ability to identify CINV depended on the availability of unique identifiers such as ICD-9-CM or CPT codes. As such, this study focused on CINV events resulting in ED or hospitalization episodes needed to manage these events without being able to address the significant negative impact of CINV events on patients’ health-related quality of life.