Efficacy of triple antiemetic therapy (palonosetron, dexamethasone, aprepitant) for chemotherapy-induced nausea and vomiting in patients receiving carboplatin-based, moderately emetogenic chemotherapy
In Japan, some patients are hesitant to receive cancer chemotherapy because they are afraid of adverse effects such as CINV. Much progress has been made in supportive care, but clinical experts frequently underestimate the severity of nausea and vomiting, and many patients suffer from CINV without optimal management of symptoms (Di Maio et al. 2015). The aim of antiemetic therapy should be to minimize or eliminate CINV in all cancer patients. However, recommended treatments for CINV vary among guidelines, and half of patients receiving MEC are afflicted by CINV (Ihbe-Heffinger et al. 2004). An investigational study to establish optimal antiemetic treatment for MEC is thus warranted.
Several studies have reported that combination treatment using a 5-HT3 receptor antagonist, an NK-1 receptor inhibitor, and dexamethasone are useful for prevention of the CINV caused by HEC (Miura et al. 2013; Longo et al. 2011). Triple therapy comprising palonosetron, aprepitant and dexamethasone seems to be the strongest antiemetic treatment. Miura et al. (2013) reported on the efficacy of triple treatment for CINV in lung-cancer patients receiving HEC. Prevalence of a CR and CC overall was 81.1 and 66.7%, respectively, and treatment carried a good safety profile. None of the severe adverse events exceeded grade 3 of the CTCAE. Mild constipation that was readily manageable was reported to be the most common adverse effect. Considering the excellent profile of that treatment, triple therapy should be investigated as prophylaxis against the CINV observed with MEC.
Warr et al. (2005) demonstrated that addition of aprepitant to ondansetron and dexamethasone enhances the antiemetic effect of MEC using cyclophosphamide plus doxorubicin or epirubicin (AC). However, the prevalence of a CR was only 51% in the aprepitant group and only 42% in the control group over 5 days. Grunberg et al. (2009) reported on the efficacy of a triple regimen comprising palonosetron, dexamethasone and aprepitant for prevention of acute and delayed CINV caused by MEC. Prevalence of a CR was relatively good in the acute phase (76%), but was not satisfactory overall (51%). Those results are confusing because most patients were treated with an AC regimen, which is now classified as HEC in the MASCC/ESMO guidelines. The value of antiemetic treatment should be evaluated more strictly according to the respective characteristics of each chemotherapy drug.
The MASCC/ESMO guidelines updated in 2016 state that addition of an NK-1 inhibitor to a 5-HT3 receptor antagonist and dexamethasone is recommended to prevent carboplatin-induced acute nausea and vomiting (Roila et al. 2016). Ito et al. (2014) reported a randomized phase-2 trial that compared standard antiemetic therapy with a 5-HT3 receptor antagonist and dexamethasone with aprepitant add-on triple antiemetic therapy in patients with NSCLC who received carboplatin-based first-line chemotherapy. The aprepitant group showed a better overall CR of 80.3% compared with that of 67.2% for the control group. Tanioka et al. (2013) reported on a randomized study of aprepitant in women receiving MEC comprising mainly a carboplatin- or irinotecan-containing regimen. Prevalence of a CR overall was superior, but not significantly higher, in the aprepitant, granisetron and dexamethasone group than in the placebo, granisetron and dexamethasone group (aprepitant group, 62.2%; placebo group, 52.1%). The authors concluded that the addition of aprepitant seemed to be effective and that an antiemetic regimen equivalent to that used for HEC was well tolerated and seemed to be more effective for CINV prevention in women receiving MEC. Use of palonosetron instead of granisetron might improve delayed CINV because American Society of Clinical Oncology guidelines recommend palonosetron as the preferred 5-HT3 receptor antagonist for a non-AC MEC regimen (Basch et al. 2011). However, no clinically relevant differences between palonosetron and other 5-HT3 receptor antagonists have been demonstrated by randomized trials for a non-AC MEC regimen. There is a lack of evidence of comparative studies in MEC agents demonstrating an advantage of the use of palonosetron with respect to other 5-HT3 receptor antagonists. According to the general rule of MASCC/ESMO guidelines, a benefit of ?10% is sufficiently clinically meaningful to warrant a change in guidelines. In our study, triple antiemetic therapy comprising palonosetron, dexamethasone, and aprepitant achieved a CR of 100 and 91.9% in acute and delayed phases, respectively. These data suggest that triple antiemetic therapy could increase the prevalence of a CR by ?10%. Hence, the efficacy of triple therapy should be investigated.
Results of antiemetic studies in patients treated with MEC are summarized in Table 3. Celio et al. (2011) reported that the prevalence of a CR in the acute phase and delayed phase was 88.6 and 68.7%, respectively, in patients treated with palonosetron and dexamethasone as antiemetic treatment. Prevalence of a CR in other reports treated MEC not specified regimen tended to be equal or less than in that report. In the present study, the chemotherapy regimens administered to enrolled patients were based on carboplatin. Prevalence of a CR in the acute phase and delayed phase was excellent (100 and 91.9%, respectively). Prevalence of a CR was remarkably better than that in other studies stating that palonosetron, dexamethasone and aprepitant is the strongest antiemetic treatment that produces excellent antiemetic effects against MEC using a carboplatin-based regimen.
Summary of studies focusing on the efficacy of antiemetic therapy in patients receiving MEC
Doses of Ap were the standard doses recommended by various guidelines such as 125 mg on day 1 and 80 mg on days 2 and 3. “MEC” in the chemotherapy column indicates that the MEC was not specified
CR complete response, Palo palonosetron, Gra granisetron, Dex dexamethasone, Ap aprepitant, Rol rolapitant, MEC moderately emetogenic chemotherapy, CBDCA carboplatin, PAC paclitaxel
Hesketh et al. (2016) reported that addition of rolapitant to a 5-HT3 receptor antagonist and dexamethasone provided patients who received carboplatin-based chemotherapy with superior protection against CINV. Prevalence of a CR was significantly higher with rolapitant treatment than that achieved with the control overall and in the delayed phase. Prevalence of a CR in the acute phase was 91.7%, which is close to that obtained in the present study.
The mechanism of action of delayed CINV is not entirely understood, but it is considered to be different to that of acute CINV. Delayed CINV is thought to arise through the effects of substance P in the central chemotrigger zone (Curran and Robinson 2009). Even though the introduction of a first-generation 5-HT3 receptor antagonist has elicited significant improvements in prophylactic care against CINV, control of delayed emesis remains an unaddressed need. Schmoll et al. (2006) reported that a 5-HT3 receptor antagonist administered on multiple occasions may be more effective than a 5-HT3 receptor antagonist administered once for control of delayed CINV. Palonosetron is a second-generation selective antagonist against the 5-HT3 receptor that has an ?100-fold stronger binding affinity for the 5-HT3 receptor compared with first-generation agents, and an extended plasma elimination half-life of ?40 h (Aporo et al. 2006). If the long half-life of palonosetron compensates for the effect of the delayed phase, a single dose of palonosetron could be more convenient than multiple doses of a first-generation 5-HT3 receptor antagonist. Roscoe et al. (2012) presented data from a double-blind randomized clinical trial for control of delayed nausea. They reported that addition of dexamethasone on days 2 and 3 reduced CINV in the delayed phase. Conversely, Celio et al. (2013) demonstrated that a dexamethasone-sparing regimen is not associated with a significant loss in overall antiemetic protection in women undergoing AC if palonosetron is used as an antiemetic.
The beneficial effect of an NK-1 inhibitor for control of delayed CINV is also controversial. Efficacy of addition of aprepitant for control of delayed CINV has been reported to be identical to that elicited by addition of prochlorperazine (an antipsychotic drug that acts on dopaminergic receptors at the chemoreceptor trigger zone) (Roscoe et al. 2012). Olanzapine is another antipsychotic drug whose effect is manifested through blockade of multiple neurotransmitter receptors. Navari et al. (2016) reported on a randomized, double-blind, phase-3 trial comparing olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and 5-HT3 receptor antagonist in patients receiving cisplatin or AC. Olanzapine significantly improved nausea prevention, as well as the prevalence of a CR, among patients receiving HEC. They concluded that olanzapine was a very promising candidate for control of acute and delayed CINV in patients receiving HEC.
In the present study, the prevalence of a CR and CC in the delayed phase was excellent (91.9 and 84.9%, respectively), but dietary intake decreased significantly on days 3 to 6. Admittedly, there is room for improvement in treatment of delayed nausea, but the triple regimen has a tremendous effect on patients receiving MEC based on carboplatin.
This clinical trial assessed the efficacy of triple treatment only in the first cycle of chemotherapy. However, sustained efficacy of the same antiemetic regimen has been reported throughout repeat chemotherapy cycles in a population receiving HEC (Sakai et al. 2008). Control of CINV in the first cycle is important because the CINV of subsequent cycles and anticipatory emesis are related to the degree of CINV of the first cycle (Chan et al. 2015). Maximally effective antiemetics as first-line therapy should be used rather than withholding more effective drugs for subsequent use at the time of antiemetic failure.
Being female and young is considered to contribute to the variance in acute nausea and severity of delayed nausea when chemotherapy is administered (Molassiotis et al. 2014). In our study, the prevalence of a CR and CC was consistently better for male patients, but the number of patients was not sufficient to power statistical analyses. Future clinical trials should consider differences in CINV prevalence according to sex. The cost of medication is another important issue: the antiemetic drugs evaluated in our study are indicated and covered by insurance from the Japanese government.