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

Results

Overall, 193 publications on tropisetron were retrieved (Figure 1), comprising 131 records and two congress abstracts from EMBASE and 60 records from PubMed. After removal of 22 duplicates, 171 records were screened. Of these, 19 records fulfilled the inclusion criteria and were extracted for full analysis: a further four were discounted, and a previously identified study of interest was added,[34] making a total of 16 included studies.

Figure 1.

PRISMA flow diagram for tropisetron literature. a, records were excluded according to the exclusion criteria in Table 2.

For palonosetron, a total of six papers describing pivotal studies on the use of Aloxi® IV in controlling CINV were identified and included; see Table 3 for study designs.

Tropisetron

Efficacy—Tropisetron-only Data. Definitions of the extent of nausea/vomiting control differed across publications; therefore, only complete control rates for nausea and/or vomiting were considered in this review. For the majority of papers, complete control of vomiting was described as no vomiting or retching within a 24-hour period, and complete control of nausea was defined as no episodes of nausea within 24 hours, where one episode was any period of 1 hour in which nausea occurred.

Most studies were conducted in Europe, with Navoban® or generic tropisetron used equally across studies. Nine studies were undertaken in the highly emetogenic chemotherapy (HEC) setting[34,36–38,42,43] [where 93% of the patients received HEC[39,41,45]], two in the moderately emetogenic chemotherapy (MEC) setting,[46,47] and three in a mixed HEC/MEC setting.[35,40,44] Dexamethasone, at varying doses, was included in six studies,[36,38,40,42,45,46] although in the Hulstaert et al. study,[40] it was only administered in the second cycle of treatment (data not reported). The comparator arms of each study are detailed in Table 3.

Complete Control of Vomiting/Emesis (No Emesis): Overall, ten studies report data on the rates of no emesis[35–39,42,43,45–47] (Table 4). In the HEC setting, between 52.0–90.0% of patients in the acute phase,[36–39,43] 53.0–75.0% in the delayed setting,[36–38] and 22.5–45.0% in the overall phase[36,39,43] reported no emesis. When tropisetron was administered with dexamethasone, the rates of no emesis were 75.0–97.0% in the acute phase,[36,38,42,45] 50.0–90.0% in the delayed setting,[36,38,42,45] and 42.5–76.0% in the overall phase.[36,42]

In the MEC setting, no emesis occurred in 28.3% of patients in the acute phase.[46] Adding dexamethasone to tropisetron increased the rate to 41.7–58.8% in the acute phase,[46,47] while 52.9% of patients reported no emesis in the delayed phase.[47] Neither study reported data for the overall phase.

In the HEC/MEC setting, 45% of patients in the acute phase and 50.0–80.0% of patients in the delayed phase reported no emesis.[35]

Complete Control of Nausea (No Nausea): In the HEC setting, six studies investigated the effect of tropisetron on controlling nausea, three of which investigated the addition of dexamethasone to tropisetron (Table 4). Tropisetron alone resulted in no-nausea rates of 32–75.0% in the acute phase,[36–39,43] 29.0–83.0% in the delayed phase,[36–38] and 12.5–34.0% in the overall phase.[36,39,43] The addition of dexamethasone to tropisetron increased these rates to 35.0–90.0% in the acute phase,[36,38,42,45] 42.0–88.0% in the delayed phase,[36,38,42,45] and 59% in the overall phase.[36]

Only one study in the MEC setting evaluated nausea. In total, 30% of patients reported no nausea, which increased to 38.3% when dexamethasone was added to tropisetron in the second cycle of treatment.[46]

In the HEC/MEC setting, only one study reported data on nausea prevention. Approximately 23% of patients in the acute phase reported no nausea, and while absolute values were reported, a graphical representation of the data indicated that more people in the delayed phase experienced no nausea.[35]

Complete Control of Vomiting and Nausea (No Emesis and No Nausea): Several studies defined complete control as no emesis and/or nausea in 24 hours. In the HEC setting, 62.5–72.5% of tropisetron-treated patients reported no acute emesis and/or nausea,[34,38,41] with 100% control of emesis or nausea observed in 52.5% of patients in the delayed phase;[41] 26% of patients reported no nausea and vomiting in the overall phase, increasing to 49.0% when dexamethasone was added.[38] In the HEC/MEC setting, 64% of tropisetron-treated patients in the acute phase and 45.0–58.0% in the delayed phase had no emesis or nausea, respectively.[44] Another study reported no-emesis or no-nausea rates of 72.0% in the acute phase and 48% over the entire 6-day study period.[40]

Efficacy—Tropisetron Versus Other 5-HT3 RAs. Several studies assessed the effectiveness of tropisetron versus other 5-HT3 RAs. Tropisetron was compared with ondansetron and granisetron in the MEC setting.[47] The rates of no emesis in the acute phase were 38.8% with ondansetron, 58.8% with tropisetron, and 73.7% with granisetron; in the delayed phase, the rates were 38.8%, 52.9%, and 73.7%, respectively, demonstrating that tropisetron was not significantly better in controlling emesis compared with ondansetron or granisetron. Indeed, granisetron promoted a significantly greater major response rate [defined as the sum of complete and partial (1–4 vomiting episodes/retches in 24 hours)] in the control of delayed emesis (P=0.01), compared with tropisetron.[47]

Another study compared the effects of tropisetron, ondansetron, and granisetron on complete response (defined as no nausea or vomiting, or only mild nausea in 24 hours) across multiple cycles in cisplatin-treated patients.[34] In the first cycle, observed response rates in the acute phase were 72.5% with tropisetron, 82.1% with ondansetron, and 84.2% with granisetron; across multiple cycles, these values were 67.6%, 73.3%, and 72.1%, respectively. Ondansetron resulted in significantly higher numbers of patients with major efficacy [complete response plus major response (single vomiting or no vomiting but moderate to severe nausea in 24 hours)] versus tropisetron (P=0.021).[34]

Safety. The two most commonly reported adverse events (AEs) were headache (incidence range, 5–41.7%),[34,35,37–47] and constipation (incidence range, 2.5–58%).[35–47] Other AEs that were reported were: abdominal distention;[42] effects on appetite and activity;[46] sedation;[45,46] asthenia;[43,46] dizziness;[39,40,43–45] tiredness;[35,36,38–40,44] mild "mouth dryness";[41] diarrhea;[36,38,40,43,47] other gastrointestinal symptoms[38] and sleep disturbances;[38,47] paresis, anxiety, and somnolence;[43] abdominal pain;[40,43,45] epigastric pain;[40,44] allergy and heart symptoms;[44] pyrosis, hiccups, and fever;[40] depression, migraine, and confusion;[35] anorexia and fatigue;[36] and edema.[45]

Palonosetron

Efficacy—Palonosetron Only. Six pivotal trials evaluated the efficacy of palonosetron (Aloxi®) IV in CINV prevention[50–55] (Table 5). Three studies evaluated the 0.25- and 0.75-mg doses of palonosetron IV, and included a third arm that featured an older-generation 5-HT3 RA,[50–52] while two trials compared the efficacy of the oral and IV formulations of palonosetron in the MEC[53] and HEC[54] settings. The final study evaluated the efficacy of 0.75 mg palonosetron versus granisetron in patients from Japan (where the standard dose is 0.75 mg IV).[55] Studies used the same definitions for complete response (no emesis and no rescue medication use) and complete control (no emesis, no rescue medication use, and no more than mild nausea).

In the MEC setting, 63.0–81.0% of patients had a complete response during the acute phase.[51–53] For the delayed and overall phases, the complete response rates were 54.0–74.1%[51–53] and 46.0–69.3%,[51–53] respectively. Moreover, the Gralla study[52] reported that >70% of patients had no emetic episodes in any phase. In the Boccia study,[53] the rates of no emesis and no nausea were also reported. In the acute, delayed, and overall phases, the proportion of patients with no emesis was 77.2%, 74.7%, and 67.3%, respectively, and the rates of no nausea were 57.4%, 47.5%, and 42.6%, respectively.[53] This study also reported complete response rates in patients who received dexamethasone versus those who did not; these were 82.9% vs. 57.5%, 68.3% vs. 62.5%, and 65.9% vs. 52.5% in the acute, delayed, and overall phases, respectively.[53]

In the HEC setting, the rates of complete response during acute, delayed, and overall phases were 59.2%, 45.3%, and 40.8%, respectively.[50] The proportion of patients with no emesis was 68.5%, 56.5%, and 46.6% in the acute, delayed, and overall phases, respectively. In another study where dexamethasone was administered to all patients, 86.2% achieved a complete response in the acute phase, 74.8% in the delayed phase, and 70.2% in the overall phase. In the delayed and overall phases, 77.5% and 73.2% of patients reported no vomiting, and rates of no nausea were 75.6%, 53.4%, and 47.4%, in the acute, delayed, and overall phases, respectively.[54]

Finally, a Japanese study[55] evaluated the effect of 0.75 mg palonosetron plus dexamethasone. The rates of complete response during the acute, delayed, and overall phases were 75.3%, 56.8%, and 51.5%, respectively. Complete control was observed in 73.7% of patients in the acute phase, 53.0% in the delayed phase, and 47.9% in the overall phase. Rates of no nausea were 58.7%, 37.8%, and 31.9% in the acute, delayed, and overall phases, respectively, and for no emesis these values were 77.5%, 63.2%, and 57.5%, respectively.

Efficacy—Palonosetron Versus Older-generation 5-HT3 RAs. Four studies featured a comparator arm containing an older-generation 5-HT3 RA. Two compared the antiemetic activity of 0.25 mg palonosetron, 0.75 mg palonosetron, and 32 mg ondansetron, with one study in the MEC setting,[52] and the other in the HEC setting.[50] The other studies compared palonosetron with dolasetron in patients receiving MEC,[51] and with granisetron in patients receiving HEC.[55]

In the MEC setting, 0.25 mg palonosetron was significantly superior to ondansetron in preventing acute vomiting (lower bound of the 97.5% CI >0; P=0.009), and non-inferiority was demonstrated for both the 0.25- and 0.75-mg doses of palonosetron.[52] The 0.25-mg palonosetron dose was also significantly better than ondansetron at controlling complete response in the delayed (74.1% vs. 55.1%; P<0.001) and overall (69.3% vs. 50.3%; P<0.001) phases. Significantly higher rates of patients with no emesis, no rescue medication use, and no more than mild nausea were observed with palonosetron 0.25 and 0.75 mg, compared with ondansetron during the delayed (66.7% vs. 50.3%; P=0.001) and overall (63.0% vs. 44.9%; P=0.001) phases. Palonosetron 0.25 mg was also superior to ondansetron in terms of the number of patients who experienced no emesis, used no rescue medication, and experienced no more than mild nausea on days 2, 3, and 4 (P=0.001, P=0.001, and P=0.003, respectively). At no point was palonosetron inferior to ondansetron.[52]

The efficacy of 0.25 mg palonosetron, 0.75 mg palonosetron, and 100 mg dolasetron was compared in patients receiving MEC.[51] Both the 0.25- and 0.75-mgdoses of palonosetron were non-inferior to dolasetron in terms of complete response in the acute phase, with numerically higher rates of complete response achieved with 0.25 mg (63.0% vs. 52.9%; P=0.049) and 0.75 mg palonosetron (57.1% vs. 52.9%; P=0.412), compared with dolasetron. In the delayed and overall phases, significantly higher complete response rates were observed for 0.25 mg palonosetron compared with dolasetron (54.0% vs. 38.7%; P=0.004, and 46.0% vs. 34.0%; P=0.21, respectively) and for 0.75 mg palonosetron (56.6% vs. 38.7%; P<0.001, and 47.1% vs. 34.0%; P=0.012, respectively). There were a significantly higher proportion of patients who experienced no emesis, used no rescue medication, and experienced no more than mild nausea for 0.25 mg palonosetron and 0.75 mg palonosetron, compared with dolasetron, during the delayed phase (48.1% and 51.9% vs. 36.1%, respectively; P=0.018 and P=0.002 for palonosetron 0.25 and 0.75 mg vs. dolasetron, respectively) and overall phases (41.8% and 42.9% versus 30.9%; P=0.027 and P=0.016, respectively). The lower dose of 0.25 mg palonosetron led to significantly fewer emetic episodes during the acute, delayed, and overall phases compared with dolasetron (P=0.0135, P=0.0183, and P=0.0036, respectively), with more patients reporting no emetic episodes during the delayed and overall phases (P=0.028 and P=0.014, respectively).[51]

Non-inferiority of palonosetron compared with ondansetron in terms of acute complete response was also demonstrated in the HEC setting.[50] Numerically higher increases in the complete response rates for palonosetron 0.25 mg during the delayed (45.3% vs. 38.9%) and overall (40.8% vs. 33.0%) phases were reported. The percentage of patients who experienced no emesis, used no rescue medication, and experienced no more than mild nausea was slightly higher for palonosetron 0.25 mg compared with ondansetron in the acute phase (56.5% vs. 51.6%, respectively), although the rates were comparable in the delayed and overall phases.[50]

Finally, in Japanese patients receiving HEC, 0.75 mg palonosetron was non-inferior to granisetron in terms of acute-phase complete response [75.3% vs. 73.3%, respectively; mean difference 2.9% (95% CI, −2.70% to 7.27%)]. In the delayed phase, palonosetron resulted in significantly higher complete response rates compared with granisetron (56.8% vs. 44.5%; P<0.0001).[55]

Safety. Palonosetron was well tolerated. Most AEs were mild in intensity, and the majority were assessed as not related, or unlikely to be related to the study medication.[50–53] The most frequently reported were: headache (incidence range, 1.6–26.4%);[50–54] constipation (incidence range, 1.6–17.4%);[50–55] fatigue (10.9%);[51] dizziness (0.5%);[52] diarrhea (1.3%);[50] gastrointestinal disorders (3.0%); and nervous system disorders (1.6%).[54] No significant changes related to study drug were observed with respect to laboratory parameters, vital sign measurements, and electrocardiogram recordings.[50–54]

Palonosetron vs. Tropisetron

Two Chinese studies evaluated the efficacy of tropisetron and palonosetron.[48,49] One study determined the effectiveness of these drugs in preventing emesis and nausea in the MEC (an anthracycline-based regimen) and HEC (a cisplatin-based regimen) settings.[48] In patients receiving MEC, the rates of no emesis in the acute phase were 61.8% for palonosetron and 55.3% for tropisetron; in patients receiving HEC, the rates were 44.6% and 46.4%, respectively. In the delayed phase, the rates of no emesis were 63.2% for palonosetron and 47.4% for tropisetron in the MEC setting, and 39.3% and 26.8%, respectively, in the HEC setting. Considering data from the MEC and HEC settings together, no significant difference (P>0.05) was observed between the two drugs in preventing acute vomiting. This contrasted with the data observed in the delayed setting, where significantly higher rates of no emesis were observed for palonosetron versus tropisetron (53.0% vs. 38.6%; P=0.01). The overall incidence of AEs between the two drugs was similar [4.9% (palonosetron) vs. 7.4% (tropisetron); P>0.05]; the majority were mild, and there was no incidence of severe AEs. The most common were headache (2.7% vs. 2.1% for palonosetron versus tropisetron, respectively) and dizziness (2.7% vs. 2.1%, respectively).

The second study evaluated the effectiveness of palonosetron and tropisetron in the HEC setting.[49] There was no significant difference in the rates of no emesis in the acute phase between palonosetron and tropisetron (79.7% vs. 75.8%, respectively; P=0.45). However, palonosetron appeared significantly more effective in controlling delayed emesis (no emesis rates: 70.3% vs. 50.8%, respectively; P<0.01). AEs were generally mild to moderate in severity and the incidence was similar for both drugs. The most commonly observed AEs were constipation (palonosetron versus tropisetron: 14.8% vs. 17.2%), distention (3.9% vs. 7.8%), headache (1.6% vs. 2.3%), fatigue (7.8% vs. 10.9%), and increased aminotransferase (2.3% each).

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