To our knowledge, this study is the first to investigate the comparative effectiveness of palonosetron-only as the 5-HT3 RA treatment versus other 5-HT3 RA treatment regimens using claims from a large database compiled from real-world clinical practice. Results indicated that among patients with breast or lung cancer on HEC or MEC, those initiated and maintained with palonosetron throughout the chemotherapy treatment cycles experienced a significantly reduced risk of hospital/ED-associated CINV events, as compared to patients who received other 5-HT3 RA-based regimens.
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
], 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.
The calculations of the actual doses used in the various chemotherapy regimens depended on the level of details provided by HCPCS codes. There were 11 unique HCPCS codes to identify cyclophosphamide. In contrast, there were only one or two HCPCS codes for cisplatin or carboplatin, respectively. The lack of HCPCS codes did not allow the calculation of the actual doses for carboplatin/cisplatin consumed, or the further delineation of the relationship between chemotherapy dose and 5-HT3 RA utilization patterns in the two cohorts of patients with lung cancer. Moreover, this study had the inherent limitations associated with retrospective analyses using claims database, such as the potential for selection bias. While CCI and multiple regressions were employed to adjust for the differences between comparison groups, it is not possible to ascertain whether the adjustment was sufficient to account for all the selection bias. Additionally, other factors that would be relevant to CINV outcomes, such as staging of the cancer, race, alcohol consumption, and smoking history were not available. The study analysis was based on an intent-to-treat principle, thereby not allowing for the estimation of chemotherapy or antiemetic medication discontinuation rates, or for dose adjustment, or medication adherence. Finally, the database used in this study was employer-based, thus potentially limiting the generalizability of the study findings.