A Narrative Review of Tropisetron and Palonosetron for the Control of Chemotherapy-Induced Nausea and Vomiting

Yunpeng Yang; Li Zhang

Disclosures

Chin Clin Oncol. 2020;9(2):17 

In This Article

Discussion

In our review of the clinical evidence supporting the use of 0.5 mg tropisetron IV and 0.25 mg palonosetron IV as antiemetic agents in the HEC and MEC settings, we have discussed data from 16 publications on tropisetron and data from 6 pivotal trials of palonosetron IV. Most papers that investigated the efficacy of tropisetron measured the rates of no emesis or no nausea (both reported as no episodes within a 24-hour period), with only a few reporting on rates of no nausea and/or no vomiting. Rescue medication use was varied, with four studies not specifying whether it was used. This contrasted with palonosetron IV, where the primary efficacy parameter in each study was complete response, defined as no emetic episodes and no rescue medication. Consequently, a direct comparison of the data was not possible, so overall trends were instead considered, where sample sizes permitted.

For tropisetron, the rates of no emesis were lower in patients receiving HEC vs. MEC. For palonosetron, the rates of complete response were comparable between both settings, thus demonstrating the effectiveness of this agent in patients receiving HEC. Tropisetron was less effective at controlling nausea than emesis regardless of the phase or emetogenic potential of the chemotherapy. Lower rates of no nausea, versus rates of no emesis, were also observed with palonosetron, although the effect was not as pronounced (rates of no nausea were 57.4–75.6% in the acute phase).

These data could indirectly suggest that palonosetron may be more effective than tropisetron in controlling CINV in patients with cancer. The results of two studies examining the effectiveness of palonosetron and tropisetron[48,49] within the same trial provided direct data to support this supposition. Palonosetron was seen to be more effective than tropisetron in controlling delayed vomiting in both the MEC and HEC settings. In both studies, significantly higher rates of no emesis were seen with palonosetron in the delayed phase, compared with tropisetron, and comparable efficacy was observed in the acute phase.[48,49] The results of a subgroup analysis within a recent meta-analysis of palonosetron versus the older 5-HT3 RA tropisetron also reported superiority of palonosetron in controlling CINV in the acute, delayed, and overall phases.[56]

Considering the efficacy of tropisetron versus other 5-HT3 RAs, tropisetron appears less effective in controlling CINV, regardless of the phase. One study reported that granisetron was significantly better in controlling emesis in the delayed phase, compared with tropisetron (P=0.01).[47] Another study reported significantly higher complete (no emesis or nausea) and major responses (single emetic episode or no emesis but moderate to severe nausea) in the acute phase across multiple cycles for ondansetron compared with tropisetron (P=0.021).[34]

Conversely, palonosetron had significantly higher rates of complete response compared with ondansetron in the acute, delayed, and overall phases, and was significantly superior to ondansetron in preventing acute emesis (lower bound of the 97.5% CI >0; P=0.009).[52] Palonosetron was non-inferior to dolasetron in the prevention of acute emesis,[51] with significantly higher response rates observed in the delayed (P=0.004) and overall (P=0.021) phases, significantly higher numbers of patients with no emesis, no rescue medication use, and no more than mild nausea in the delayed (P=0.0018) and overall phases (P=0.027), significantly fewer emetic episodes in the acute (P=0.0135), delayed (P=0.0183), and overall (P=0.0036) phases, as well as a greater proportion of patients with no emetic episodes in the delayed and overall phases for palonosetron, compared with dolasetron.[51] Finally, one pivotal Japanese study reported the non-inferiority of palonosetron to granisetron in controlling acute emesis, with significantly more patients reporting no emesis in the delayed phase.[55] While this study used 0.75 mg of palonosetron, data from a subgroup analysis of a larger meta-analysis of palonosetron in CINV have shown that the doses appear to be equivalent in terms of efficacy.[57] No statistical difference was seen between the 0.25- and 0.75-mg doses of palonosetron in controlling CINV) in the acute (P=0.50), delayed (P=0.68), and overall (P=0.38) phases.

Both tropisetron and palonosetron were generally well tolerated, with AE profiles consistent with drugs of this class.[19] In line with other 5-HT3 RA studies, the most common AEs were headache, constipation, and diarrhea, all of which were mild to moderate in severity.

It is worth noting that today multinational guidelines[12,13] recommend the use of 5-HT3 RAs in combination with an NK1 RA (such as aprepitant) and dexamethasone for preventing HEC- (and MEC-) mediated CINV. The inclusion of this class of drugs reflects their purported ability to inhibit emesis by blocking the binding of substance P to the NK1 receptor in the brain stem emetic center.[58]

Aprepitant was the first European Medicines Agency (EMA)- and US Food and Drug Administration (FDA)-approved NK1 RA for the prevention of CINV in the HEC setting [2003], and in the MEC setting [2005];[59–61] it was followed by fosaprepitant, its water-soluble prodrug. Various studies have demonstrated the safety and efficacy of both agents in the prevention of HEC- or MEC-mediated CINV.[62–65] Two other NK1 RAs have since become commercially available: rolapitant was approved for delayed CINV prevention,[66] and netupitant (administered as a convenient fixed combination with palonosetron, known as NEPA) was approved for the prevention of acute and delayed nausea and vomiting in the HEC and MEC settings.[67] In addition, in August 2019, oral NEPA was approved by the Chinese National Medical Products Administration (NMPA) for the prevention of acute and delayed CINV associated with HEC or MEC settings. This approval was granted on the basis of the outcomes of a phase III study in adult Asian patients, in which a single dose of NEPA demonstrated comparable efficacy to a standard 3-day regimen of aprepitant plus granisetron.[68] The IV formulation of NEPA was recently approved by FDA and is under evaluation by EMA. While the addition of rolapitant to a standard antiemetic regimen has proven effective [reviewed in Heo and Deeks, 2017[69]], evidence suggests there is no consistent improvement in nausea protection.[70,71] In contrast, the administration of oral NEPA and dexamethasone results in significant improvement in delayed and overall nausea control compared with oral palonosetron alone and dexamethasone in patients receiving cisplatin or anthracycline-cyclophosphamide.[72,73] Finally, the addition of an NK1 RA has proven to be more effective in controlling CINV in HEC and MEC settings, compared to the standard 5-HT3 RA plus dexamethasone combination.

In conclusion, this review has shown that the newer 5-HT3 RA, palonosetron, is an effective first-line agent in preventing CINV in patients receiving MEC or HEC, and its efficacy can be further increased in combination with an NK1 RA. The high levels of emetic control observed in the acute, delayed, and overall phases twinned with its safety profile suggest that palonosetron is a very feasible prophylactic agent with a potentially improved therapeutic profile compared with tropisetron for controlling CINV in acute and delayed phases.

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