102
Views
2
CrossRef citations to date
0
Altmetric
Review

Update on the management of chemotherapy-induced nausea and vomiting – focus on palonosetron

, , , , , & show all
Pages 713-729 | Published online: 05 May 2015

Abstract

Purpose

Nausea and vomiting are major adverse effects of chemotherapy and can greatly impact patients’ quality of life. Although chemotherapy-induced nausea and vomiting (CINV) prevalence is high, treatment remains difficult. Palonosetron is a 5-hydroxytryptamine receptor antagonist (5-HT3RA) approved for treatment of CINV. The purpose of this review is to discuss existing and emerging therapeutic options, and examine studies focusing on palonosetron with regards to efficacy, pharmacology, tolerability, safety, and patient-derived outcomes.

Methods

A literature search was conducted using Ovid MEDLINE and EMBASE to identify relevant studies using palonosetron alone or in combination with other antiemetics. Studies were extracted if they included complete response (CR), complete control (CC), no nausea, no vomiting, and no rescue medications as an endpoint. Studies were also included if safety endpoints were examined.

Results

Palonosetron alone has been shown to improve CR and CC rates for patients receiving low, moderate, or high emetogenic chemotherapy. Rates were further improved with the addition of dexamethasone, a corticosteroid. Furthermore, the addition of neurokinin-1 receptor antagonists, such as netupitant markedly improved efficacy profiles compared to palonosetron alone. Aprepitant is an antiemetic that has exhibited positive results in combination with palonosetron. Recently, a new drug consisting of netupitant and palonosetron (NEPA) has demonstrated significantly more efficacious prevention of CINV. Regardless of the combination, palonosetron has been well tolerated. The most common adverse events were constipation, headache, fatigue, and dizziness, with the majority of patients describing them as only mild or moderate.

Conclusion

Palonosetron, alone or with other antiemetics, has improved CINV treatment due to its ability to significantly reduce delayed phases of CINV, compared to similar 5-HT3RAs. Palonosetron is both more effective than first generation 5-HT3RAs and safer, as it results in a smaller prolongation of the QTc interval, compared to other 5-HT3RAs.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is considered a major adverse effect of cytotoxic chemotherapy and can greatly impact patients’ quality of life.Citation1Citation3 As a result, CINV is one of the major reasons for disruption or delay in treatment, which is often due to patient noncompliance.Citation3 The administration of a safe and efficacious prophylactic antiemetic regimen is thus important for current and future patients at risk for CINV.Citation4 In antiemetic clinical trials, there are five common endpoints that are employed for comparison: complete response (CR), defined as no emesis and no use of rescue medication; complete control (CC), defined as CR with the addition of no mild nausea; no emetic episodes; no episodes of nausea; and no use of rescue medication.Citation4

Trials that used first generation 5-hydroxytryptamine receptor antagonists (5-HT3RAs), including ondansetron, granisetron, tropisetron, and dolasetron, concluded that, although they were successful in controlling the rates of vomiting, nausea still remained a concern, especially in the delayed phase.Citation4 The addition of dexamethasone to 5-HT3RAs is highly effective for acute emetic control; however, the effect on delayed emesis is less evident.Citation5 Despite the introduction of more effective antiemetic agents, nausea and vomiting remain a significant complication of chemotherapy.Citation1

Mechanism of CINV

CINV is composed of an acute phase and delayed phase. The acute phase is defined as nausea and vomiting occurring 0–24 hours after administration of chemotherapy, whereas the delayed phase occurs between 24 hours and up to 5 days later.Citation6

Different but overlapping pathological pathways are involved in the pathogenesis of CINV.Citation3 The emetic center is believed to be a loosely organized network of neurons in the medulla oblongata.Citation3 Chemotherapy agents are thought to activate the release of neurotransmitters, in particular, serotonin, which activates vagal afferents leading to stimulation of the area postrema. Sensory inputs in vagal afferents and the area postrema are then consolidated at the emetic center, resulting in efferent signals that lead to contraction of abdominal muscles, the diaphragm, stomach, and esophagus, producing a reflexive emetic response.Citation3 Several neurotransmitters are thought to be involved in this process and include dopamine, serotonin (5-HT), and substance P (SP). As a result, drugs that antagonize the action of these neurotransmitters have been developed as prophylactic therapies for CINV.Citation3

Emerging and existing treatments

Early treatments of CINV involved the use of dopamine D2 receptor antagonists, the most common of which is metoclopramide.Citation1 Some believe that the antiemetic effects of metoclopramide are due to its weak inhibition of 5-HT3 receptors (which is achieved when it is administered at high doses).Citation1

Chemotherapy can also induce the release of SP, which acts on neurokinin-1 (NK-1) receptors located both peripherally and centrally.Citation6,Citation7 NK-1 receptor antagonists (NK-1 RAs) have been developed to prevent both acute and delayed CINV.Citation7 The broad spectrum of antiemetic activity allows these medications to control many forms of induced emesis.Citation8 Aprepitant was the first approved NK-1 RA whereas others, like netupitant, are still undergoing clinical trials.Citation5 Previous guidelines for CINV management have recommended NK-1 RAs for prophylaxis of delayed phases of CINV due to highly (HEC) or moderately emetogenic chemotherapy (MEC).Citation7

Enterochromaffin cells located in the small intestine release serotonin which binds to 5-HT3 receptors on vagal afferents.Citation4 Throughout the 1990s, several 5-HT3RAs including ondansetron, granisetron, tropisetron, and dolasetron were introduced as antiemetic agents.Citation1,Citation4 These agents bind to the same binding site as serotonin on the 5-HT3 receptor, and, as a result, the CINV effects normally produced by the vagal afferents are inhibited.Citation1

Typically, 5-HT3RAs alone are used for the treatment of acute-phase emesis, whereas both acute and delayed phases are treated with NK-1 RAs in conjunction with 5-HT3RAs and dexamethasone. A number of international groups have suggested that prior to chemotherapy, a combination of 5-HT3RA and dexamethasone be used for acute CINV prophylaxis.Citation1 However, postchemotherapy, dexamethasone should be used alone for delayed CINV prophylaxis.Citation1

A new 5-HT3RA known as palonosetron (Aloxi®, Helsinn Healthcare SA, Pazzallo, Switzerland) was developed to improve response rates, and was approved by the US Food and Drug Administration for delayed emesis treatment.Citation9 Palonosetron is a second-generation 5-HT3RA that has a uniquely strong binding affinity for the serotonin receptor.Citation10 Studies have shown that palonosetron can reduce the incidence of delayed CINV through inhibition of SP, which is not evident in certain first generation 5-HT3RAs.Citation11 The purpose of this review is to examine published data on palonosetron with regard to efficacy, pharmacology, tolerability, safety, and patient-derived outcomes.

Methods

A literature search was conducted using Ovid MEDLINE (1946 to August 2014 [Week 32]) and EMBASE (1947 to August 2014 [Week 32]). The following terms were combined in the search: “palonosetron” and “chemotherapy-induced nausea and vomiting”. Studies were screened for at least one of the following common endpoints: CR, CC, no nausea, no emesis, or no rescue medication. Studies were further stratified by inclusion of either acute or delayed phases. Another literature search was conducted using Ovid MEDLINE (2008 to August 2014 [Week 32]) and EMBASE (2008 to August 2014 [Week 32]) using the following search terms: “chemotherapy-induced nausea and vomiting” and “antineoplastic agents” for articles that were relevant to the mechanism of CINV or antiemetic agents.

Results

A total of 818 articles from the literature search were examined for potential inclusion. The literature search as well as additional references from relevant review articles yielded 32 full articles. Of these, six articles discussed the pharmacology of palonosetron ( and ). Articles that included safety and efficacy were as follows: ten discussed palonosetron alone ( and ); ten discussed safety and efficacy of palonosetron in combination with dexamethasone; six discussed safety and efficacy of palonosetron in combination with aprepitant and dexamethasone; and two discussed safety and efficacy of NEPA ( and ).

Table 1 Study characteristics and pharmacokinetics of palonosetron in healthy subjects with no history of disease

Table 2 Study characteristics and pharmacokinetics of palonosetron in cancer patients

Table 3 Study design and characteristics of patient population in palonosetron-only studies

Table 4 Response rates and adverse events in palonosetron-only studies

Table 5 Study design and characteristics of patient populations in studies administering PALO in combination with other antiemetics

Table 6 Efficacy outcomes and adverse events in studies administering PALO in combination with other antiemetics

Pharmacology

The summary of palonosetron pharmacokinetics can be found in and . Mean maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC0–∞) generally increased in a dose-dependent manner.Citation12,Citation13 In 32 healthy American subjects, doses ranged from 0.3 to 90 μg/kg giving rise to increases in both AUC0–∞ and Cmax: 5.8–750 ng·h/mL and 0.114–23.9 ng/mL, respectively.Citation12 Similarly, Eisenberg et alCitation13 reported the same trend in 35 cancer patients, with AUC0–∞ and Cmax ranging from 13.8 to 957 ng·h/mL and 0.89 to 336 ng/mL, respectively, when given doses of 1–90 μg/kg palonosetron.

Three studies involving healthy patients and one involving cancer patients found that total clearance (CLT) for palonosetron was low.Citation12Citation14 Additionally; volume of distribution (VD) levels for both populations in all studies was found to be elevated, indicating high partitioning into tissue. At comparable doses of intravenous (IV) palonosetron, cancer patients exhibited lower mean CLT and larger mean VD values than their healthy counterparts. At a dose of 1 μg/kg, cancer patients recorded mean CLT and VD levels of 1.51 mL/min/kg and 12.5 L/kg, respectively, whereas healthy patients recorded mean values of CLT =1.89 mL/min/kg and VD =5.31 L/kg.Citation12,Citation13

In both cancer and healthy populations, low CLT and high VD resulted in a longer half-life (t1/2).Citation12Citation16 The most extreme deviations in half-life from that noted by the manufacturer (ie, t1/2 of approximately 40 hours) were exhibited by cancer patients; the greatest of which was reported to be t1/2 = 128 hours, in a study with 161 cancer patients, while the shortest was t1/2 =12.71 hours.Citation15,Citation17

Efficacy

Dose-ranging study

In 2003, Eisenberg et alCitation13 conducted a dose-ranging study in patients receiving HEC to determine the efficacy and safety of palonosetron. A total of 161 patients were enrolled, with doses ranging from 0.3 to 90 μg/kg. Overall, those that received lower doses of palonosetron exhibited a lesser response to therapy than those that received higher doses. Within the first 24 hours, most patients receiving elevated doses (ie, 3, 30, and 90 μg/kg) experienced less nausea, and did not require rescue medication. CRs were exhibited in approximately 50% of the patients for each higher dose test group, whereas only 26% of patients in the low dose test group achieved CR. The authors also noted that the lower dose group exhibited decreased CC compared to the higher dose groups. They concluded that differences between the test groups reached significance at the 30 μg/kg point.Citation15

Phase II studies of palonosetron-only therapy

A number of Phase II studies have examined the use of palonosetron alone for CINV prevention ( and ). Within each study, the use of other antiemetics was prohibited. In an open label, single arm investigation of palonosetron with 34 patients receiving low emetogenic chemotherapy (LEC), 88.2% and 67.6% of patients experienced CR during the acute and delayed phases, respectively. CC was similar at 85.3% and 64.7% for acute and delayed phases. This group suggested that palonosetron was effective in preventing CINV for patients receiving LEC.Citation18

Another study evaluated the efficacy of palonosetron in 74 patients with aggressive non-Hodgkin’s lymphoma who were receiving MEC. Patients received a single dose of 0.25 mg of palonosetron IV. During the acute phase, 90.7% of patients reported a CR while 88.4% of patients reported a CR during the delayed phase. CC was observed in 89.5% of patients during the acute phase and 84.9% during the delayed phase. This study demonstrated the effectiveness and potential role of palonosetron in patients with non-Hodgkin’s lymphoma receiving MEC.Citation9

Phase III studies of palonosetron-only therapy

Several Phase III clinical trials have examined the safety and efficacy of palonosetron in preventing CINV ( and ). One study compared different doses of oral palonosetron with IV palonosetron in 635 patients receiving MEC ().Citation19 The proportion of CRs observed in the acute phase was higher for all doses administered orally (62.8%–70.1% orally versus 57.5% IV), with the highest resulting from the 0.25 mg dose (70.1%). In the delayed phase however, a greater proportion of CR was observed in patients who received IV palonosetron. Overall, it was found that the oral doses were similar in efficacy when compared to the IV formulation. However, this group also went on to recommend oral palonosetron 0.50 mg as a therapeutic option, citing its numeric superiority in efficacy.Citation19

In another study, the efficacy and safety of palonosetron was evaluated and compared to dolasetron in 569 subjects. The subjects were randomized to receive either IV palonosetron or dolasetron. The primary hypothesis was that at least one dose of palonosetron was noninferior to dolasetron. This hypothesis was supported during the acute phase as the CR rates were 63.0%, 57.1%, and 52.9% of patients for 0.25 mg palonosetron, 0.75 mg palonosetron, and 100 mg dolasetron, respectively. Furthermore, CR rates observed during the delayed phase were significantly higher for both doses of palonosetron compared to dolasetron. This group concluded that a single dose of palonosetron is more effective than a single dose of dolasetron in both acute and delayed CINV prophylaxis in patients receiving MEC.Citation20

Gralla et alCitation21 on the other hand, compared palonosetron with ondansetron. A total of 563 subjects were randomized to receive intravenously, either palonosetron or ondansetron. The CR rates observed in patients who received 0.25 mg of palonosetron were significantly different than those who received ondansetron during the acute (81.0% vs 68.6%) and delayed phases (74.1% vs 55.1%). However, 0.75 mg of palonosetron did not yield any significantly different CR rates in both acute and delayed phases. CC rates for 0.25 mg and 0.75 mg were both significantly higher than ondansetron during the delayed phase. The study group suggested that 0.25 mg of palonosetron was more effective than 32 mg ondansetron in preventing acute and delayed CINV.

Phase IV studies of palonosetron-only therapy

The efficacy of palonosetron in patients with non-Hodgkins’ lymphoma undergoing MEC was assessed in a Phase IV open-labeled, uncontrolled study. Patients received 0.25 mg of palonosetron on day 1 of cycle 1, and at each subsequent cycle. For all cycles, the initial CR rate observed during the acute phase increased as patients entered into the delayed phase. Within the delayed phase, the CR increased from 83.0% to 93.9% from cycle 1 to 2 and remained approximately the same in subsequent cycles. Overall, palonosetron showed control of CINV in both the acute and delayed phases in this patient group.Citation22

Other studies

Mattiuzzi et alCitation23 conducted a comparative randomized controlled trial in 143 patients with acute myelogenous leukemia receiving HEC. Subjects were allotted to receive either ondansetron 8 mg, 0.25 mg IV palonosetron from day 1 to day 5, or palonosetron 0.25 mg IV on days 1, 3, and 5. The CR during the delayed phase were reported to be 21% and 31% for the ondansetron and palonosetron study groups on days 1 to 5, respectively. Palonosetron study groups on days 1, 3, and 5 reported CR rates of 35% in the delayed phase. However, the CR rates were not significantly different across all study arms.

Dong et alCitation24 compared palonosetron to ondansetron in 89 subjects with non-small-cell lung carcinoma (NSCLC) receiving HEC. This group found that the proportion of CR and CC observed during the acute phase were not significantly different between palonosetron and ondansetron groups. Interestingly, the proportions observed during the delayed phases were significantly higher in the palonosetron group with a CR rate of 84.1% and CC rate of 79.5%, compared to 60.0% and 55.5%, respectively in the ondansetron group. This study suggested that palonosetron is more effective in preventing delayed nausea and vomiting than is ondansetron in patients with NSCLC.

Another study compared palonosetron with granisetron in 122 patients.Citation25 The subjects in this study received either HEC or MEC and were randomized to receive either palonosetron intravenously in the first cycle and granisetron intravenously in the second cycle or vice versa. The CR rates of palonosetron for acute and delayed phases were not statistically different than that of granisetron, but were higher than granisetron nonetheless. The CR for palonosetron was 71.09% in the acute phase as opposed to 60.16% in the delayed phase. Overall, palonosetron was effective and noninferior to granisetron in preventing CINV in both acute and delayed phases.

Safety and tolerability of palonosetron-only therapy

The most common adverse events reported by patients among the included studies can be found in . Palonosetron has been shown to be safe and tolerable as an antiemetic drug. The majority of patients who experienced adverse events reported them as mild or moderate, whereas severe symptoms were determined to be unrelated to the study medication. The most common symptoms across palonosetron-only therapy included studies were: constipation, headache, fatigue, and dizziness.Citation9,Citation15,Citation18Citation25

Combination studies – dexamethasone

Dexamethasone is a corticosteroid that when administered with 5-HT3RAs increases the antiemetic effect. One explanation of dexamethasone’s mechanism of action is that it increases the low cortisol level that is associated with nausea and vomiting.

Boccia et alCitation19 randomized patients to receive either oral or IV formulations of palonosetron, with or without dexamethasone. This group found that additional dexamethasone was associated with higher CR rates during the acute phase. In oral formulations, the 0.75 mg strength presented with the greatest difference in CR rates: 85.0% with concomitant dexamethasone, compared to 62.8% without. The difference was also substantial in the IV formulation (0.25 mg): 82.9% with concomitant dexamethasone; 57.5% without. There was also a greater CR rate in patients that were administered dexamethasone during the delayed phase, but the difference was much less pronounced. Interestingly, the oral 0.25 mg strength revealed CR rates that were lower with concomitant dexamethasone. This led the group to recommend 0.50 mg of palonosetron as the starting therapeutic option, should dexamethasone also be included in the drug regimen.

In a study by Maemondo et alCitation26 231 subjects were randomized to receive either 0.075, 0.25, or 0.75 mg of palonosetron along with a dose of dexamethasone (12–16 mg) on day 1, followed by dexamethasone doses over the subsequent 2 days. Groups were similar in baseline characteristics, and all individuals were receiving HEC. Across all groups, more than 75% of patients reported CR in the acute phase. Within the delayed phase, only the 0.25 mg and 0.75 mg groups noted that greater than 50% of patients had a CR. CC rates were similar to the CR rates in their respective phases.

A number of trials have demonstrated the utility of combining palonosetron and dexamethasone in specific patient cohorts, including breast and colorectal cancers, as well as glioblastoma; however, the results of these trials were not compared to single agent palonosetron ( and ).Citation16,Citation19,Citation26Citation34

Massa et alCitation27 examined palonosetron and dexamethasone in elderly and nonelderly individuals receiving either MEC or HEC. Across all groups, more than 75% of patients reported a CR in both the acute and delayed phases. Nonelderly patients reported higher percentages of CR in both phases. Additionally, this study found an increase in the percentage of CR from the acute to the delayed phases for both groups: a 4% increase in elderly individuals, and 5% in nonelderly individuals.

The efficacy of the dexamethasone–palonosetron combination, administered exclusively on day 1 as opposed to subsequent doses of dexamethasone, has also been examined.Citation28,Citation29 Both Aapro et alCitation28 and Celio et alCitation29 conducted their studies using 0.25 mg palonosetron with up to 8 mg of dexamethasone in patients receiving MEC. Patients received either 8 mg of dexamethasone or no dexamethasone, on days 2 and 3. In the acute phase, both studies reported a higher percentage of CR in patients, although the difference was not statistically significant. Both groups also found increased CR rates in the delayed phase. In terms of CC, Celio et alCitation29 uncovered a similar trend (ie, greater percentage of those achieving CC in those without subsequent doses of dexamethasone in the acute phase, followed by a greater percentage in those who received additional doses in the delayed phase), whereas the opposite trend was discovered in the study by Aapro et al.Citation28

Safety

Palonosetron, like other members of the 5-HT3RAs, has the potential to affect electrocardiographic parameters, in particular prolongation of the QT interval, which has been associated with life threatening arrhythmias and death.Citation4,Citation35,Citation36 One meta-analysis suggested that palonosetron was safer than first generation 5-HT3RAs with respect to the change in QT interval.Citation4 Additionally, Yavas et alCitation35 and Dogan et alCitation36 have also conducted prospective studies to determine the effect of antiemetic prophylaxis on QT interval. In both studies, patients were administered 8 mg of dexamethasone and 0.25 mg of palonosetron intravenously. Although changes in QT interval were found by both studies, neither groups found their results to be statistically significant. In both cases then, it was thus concluded that palonosetron has no acute arrhythmogenic potential.Citation35,Citation36

The most common side effects among these studies were headache and constipation, both of which were reported as mild to moderate in intensity. Treatments were well tolerated overall, as severe side effects experienced by test subjects were deemed unrelated to the dexamethasone and palonosetron regimen.Citation29,Citation31,Citation34

Combination studies – palonosetron, dexamethasone, and aprepitant

Studies have also been conducted to determine the efficacy of the combination of palonosetron, dexamethasone, and aprepitant in patients receiving HEC ( and ).Citation5,Citation37Citation41 Three studies examined the combination in patients receiving cisplatin-based chemotherapy, each lasting 3 days.Citation5,Citation37,Citation38 Each study utilized a single oral dose of aprepitant 125 mg on day 1, followed by single oral doses of aprepitant 80 mg on days 2 and 3. Longo et alCitation37 and Grote et alCitation38 both administered palonosetron as a single IV dose of 0.25 mg before chemotherapy to 222 patients and 58 patients, respectively. Palonosetron was not given to patients during the remaining 2 days in either study. Gao et alCitation5 on the other hand, administered palonosetron over the entire 3-day period as IV doses of 0.5 mg once daily to 41 patients. Dexamethasone was also administered differently between each study. Gao et alCitation5 revealed the lowest percentage of patients with CRs in both the acute and delayed stages (63.4% and 78.0% respectively), but noted that the efficacy of the study is maintained over multiple cycles. Longo et alCitation37 had the largest sample size of the three studies (n=222), and also reported the highest percentages in completed responses over the acute phase (97.7%). Despite slight differences in regimen, each study found the combination of medications to be effective and well tolerated. Constipation, headache, and fatigue were the most commonly reported side effects. However, Grote et alCitation38 reported that the majority of side effects experienced were mild in nature.

The triple therapy was also studied in patients receiving doxorubicin and cyclophosphamide (AC).Citation39,Citation40 Hesketh and Sanz-AltamiraCitation39 administered aprepitant 125 mg, dexamethasone 8–10 mg and palonosetron 0.25 mg on day 1, followed by dexamethasone 4 mg and aprepitant 80 mg once daily for days 2–3 to 36 patients. Grunberg et alCitation40 on the other hand, opted to administer aprepitant 286 mg, dexamethasone 20 mg, and palonosetron 0.25 mg on day 1 only to 41 patients. Both studies found the treatment to be well tolerated overall, with the majority of side effects to be minor in nature. Despite having a similar regimen to the studies involving cisplatin-based chemotherapy, Hesketh and Sanz-AltamiraCitation39 found that further improvement in efficacy is warranted, as a only half of the study patients were able to achieve CR overall.Citation39 On the other hand, single-day triple-therapy may be effective against MEC, and requires more study.Citation40

Despite the vast research that has been conducted using the triple therapy, one group concluded that this combination with palonosetron as the 5-HT3RA did not significantly improve CINV compared to those containing another 5-HT3RA in patients receiving multiday HEC.Citation41 The CR and CC rates in both study arms were similar with 89.0% and 87.7%, respectively in palonosetron-based triple therapy.

Combination studies – netupitant and palonosetron (NEPA)

A few studies have been conducted to evaluate the efficacy of a new NK-1 RA called netupitant that works in combination with palonosetron to improve control of CINV. The antiemetic effect is due to the ability of palonosetron to inhibit crosstalk between 5-HT3 and NK-1 receptors as well as both palonosetron and netupitant working to inhibit SP.Citation42 The characteristics of these studies have been summarized in and . A Phase II study was conducted to determine an appropriate clinical dose of NEPA to evaluate in subsequent Phase III trials.Citation43 Subjects were randomized to “PALO”, “NEPA100”, “NEPA200”, “NEPA300”, or “APR + OND” arms. The 136 patients in the PALO (palonosetron) arm received of 0.50 mg oral palonosetron, 20 mg oral dexamethasone, and placebo, followed by 8 mg of oral dexamethasone for days 2–4. There were 135, 136, 142, and 143 patients in each NEPA arm that received 100, 200, or 300 mg of netupitant rather than placebo, respectively. For the APR (aprepitant) + OND (ondansetron) arm, 125 mg oral aprepitant, 32 mg IV ondansetron, and 12 mg oral dexamethasone were given to subjects on day 1 followed by 80 mg oral aprepitant and 4 mg oral dexamethasone on days 2–4. Compared to the PALO arm, this group found that each NEPA dose increased the prevention of both acute and delayed CINV following HEC (). The CR of the PALO arm was 89.7% in the acute phase whereas the NEPA arms ranged from 92.7% to 98.5%. In the delayed phase, the CR of the PALO arm was 80.1% and the NEPA arms ranged from 90.4% to 91.2%. This group suggested NEPA300 was an appropriate dose due to the higher CR rate of 98.5% in the acute phase and 90.4% in the delayed phase, as observed in their patient group.Citation43

A subsequent Phase III study compared the safety and efficacy of the additional 300 mg netupitant to palonosetron.Citation42 Aapro et alCitation42 randomized patients being treated with MEC to receive either NEPA plus dexamethasone (n=724) or palonosetron plus dexamethasone (n=725). The researchers showed that NEPA plus a single dose of dexamethasone was significantly better than the combination of palonosetron and dexamethasone in preventing CINV in both the acute and delayed phases. Adding dexamethasone to NEPA increased the CR rate from 85.0% to 88.4% in the acute setting and from 69.5% to 76.9% in the delayed setting.Citation42

In both studies, the most common reported adverse event was headache (3.2%, and 0.7%–2.2%, respectively). Additionally, constipation and hiccups were also noted to be common adverse events (5.1% occurrence). The majority of these events were considered to be mild or moderate in nature.Citation42,Citation43

Patient satisfaction and quality of life

Only a few studies discussed patient satisfaction with antiemetic therapyCitation9,Citation30 and the impact of treatment on quality of life.Citation9,Citation28,Citation30,Citation37 Global satisfaction was rated based on a visual analog scale from 0 (completely unsatisfied) to 10 (completely satisfied).Citation9,Citation30 Di Renzo et alCitation9 found that patients receiving single dose palonosetron had a median global satisfaction score of 8.0 (based on a visual analog scale from 1 to 10) with the antiemetic therapy. With the administration of dexamethasone, the median patient reported global satisfaction score was 9.0.Citation30

Longo et alCitation37 found that fatigue and pain were the major factors that affected quality of life. In addition, 33% of patients felt a reduction in their social activity during antiemetic therapy.Citation37 However, a study conducted by Aapro et alCitation28 found that, overall, the quality of life was preserved. Evaluated with the functional living index-emesis (FLIE) questionnaire for nausea and vomiting, it was found that no statistically significant differences in quality of life were observed with respect to therapy.Citation28

Discussion

Nausea and vomiting is a common side effect of chemotherapy that can be difficult to prevent and subsequently control. The reason for this is likely multifactorial in nature, but may be due to the lack of complete understanding surrounding the mechanism of CINV, in addition to interpatient differences in toxicity to chemotherapy agents.Citation1

Many studies have been conducted in order to prevent the occurrence of CINV. Historically, dopamine receptors have been the targets of interest; however, since the discovery of 5-HT3 receptor involvement in the pathophysiology of CINV, a near paradigm shift has occurred in how this chemotherapy-induced toxicity is managed.

Palonosetron, a second generation 5-HT3RA, has a strong binding affinity to the 5-HT3 receptor and has been shown to be an effective treatment for both acute and delayed phase CINV.Citation9 In addition to its ability to bind tightly to serotonin receptors, palonosetron partitions into tissue to a high extent and as a result demonstrates a relatively long half-life of approximately 40 hours, which may contribute to its effect in the delayed phase of CINV.Citation10,Citation12Citation16

Many studies have found evidence supporting the potential role of palonosetron in CINV treatment. A Phase II study concerning palonosetron as a treatment with 34 patients given LEC found it to be an effective alternative, citing the fact that more than 50% of patients taking part achieved CC.Citation18 A number of studies have also examined its use in patients receiving MEC. Di Renzo et alCitation9 in particular found very promising results in terms of its effectiveness, as more than 75% of 86 patients were able to achieve CC in both acute and delayed phases. Treatment has also been conducted in 44 patients receiving HEC, where significantly higher rates of CR and CC have been found for palonosetron in the delayed phase.Citation24 Overall, palonosetron alone has been shown to be effective in emetogenic chemotherapy, particularly in the delayed phase. With respect to treatment following HEC, however, some studies have not been successfully reproduced, warranting further examination.Citation23

Formulations of palonosetron include oral and IV routes. Boccia et alCitation19 found that while oral administration provided greater results in the acute phase, an IV injection was more effective in the delayed phase, at comparable doses. In comparison to existing treatments; studies have suggested that palonosetron is superior or noninferior compared with first generation 5-HT3RAs, such as dolasetron and ondansetron, when administered at much lower doses.Citation20,Citation21

Several studies have also combined the palonosetron regimen with other. With the addition of dexamethasone, Boccia et alCitation20 found greater CR rates in the acute and delayed phases, with the increase in the acute phase being more pronounced. Evidence also favors the combination’s effect in response to many forms of chemotherapy.Citation26Citation34

Various studies have attempted to further increase the efficacy of the palonosetron–dexamethasone combination by adding yet another antiemetic known as aprepitant. Aprepitant is an NK-1 RA, and its addition was tested in patients receiving HEC. Although dosing regimens differed, the triple-therapy was found to be very well tolerated.Citation37Citation39 Some studies however, have found contrary evidence, citing disparities in efficacy.Citation40 In MEC cohorts, Grunberg et alCitation40 found that single-day triple-therapy may be effective in treating CINV. This represents yet another step toward realizing the full potential of this combination, and future studies should seek to establish its place in therapy as well. Overall, more research is required in order to establish the triple therapy’s place in CINV treatment. However, current results stand as a testament as to the steps that have been taken toward CINV treatment, particularly in individuals receiving HEC.

The combination of NEPA has also been examined. This combination has been reported to be very well tolerated, and it was found that CINV prevention increased with larger doses of netupitant. It is dosed at 300 mg once daily and has been shown to be very successful in the prevention of CINV following HEC and MEC.Citation35,Citation36

Overall, a major drawback of first generation 5-HT3RAs includes prolongation of the QT interval. Studies have shown alterations in the QT interval while on palonosetron are not statistically significant, making it less concerning for use in patients suffering from cardiac diseases.Citation42 While some severe adverse reactions have been reported, study coordinators have dubbed them as unrelated to the treatment regimen. Overall, side effects as a result of palonosetron administration, alone and in combination with other antiemetics, have all been mild to moderate in nature, with headache, constipation, and fatigue being the most common.

Overall, palonosetron stands as an effective option for CINV treatment. It is very well tolerated, and its use is advantageous over first generation serotonin receptor antagonists. Several studies have examined its relative efficacy and have deemed it superior to current antiemetic CINV treatments, as it is able to prevent both acute and delayed phase emesis. Future research should identify the most promising antiemetic combinations, especially for patients receiving HEC.

Acknowledgments

We thank the generous support of the Bratty Family Fund, Michael and Karyn Goldstein Cancer Research Fund, Pulenzas Cancer Research Fund, Joseph and Silvana Melara Cancer Research Fund, and Ofelia Cancer Research Fund.

Disclosure

The authors report no conflicts of interest in this work.

References

  • NavariRMManagement of chemotherapy-induced nausea and vomitingDrugs20137324926223404093
  • GrunbergSMSlusherBRugoHSEmerging treatments in chemotherapy-induced nausea and vomitingClin Adv Hematol Oncol2013112 Suppl 111823598819
  • RojasCSlusherBSPharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomitingEur J Pharmacol20126841–31722425650
  • PopovicMWarrDGDeangelisCEfficacy and safety of palonosetron for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis of randomized controlled trialsSupport Care Cancer20142261685169724590374
  • GaoHFLiangYZhouNNZhangDSWuHYAprepitant plus palonosetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapyIntern Med J2013431737622141732
  • RojasCRajeMTsukamotoTSlusherBSMolecular mechanisms of 5-HT3 and NK1 receptor antagonists in prevention of emesisEur J Pharmocol20147222637
  • AzizFNeurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomitingAnn Palliat Med20121213013625841473
  • NavariRMRole of neurokinin-1 receptor antagonists in chemotherapy-induced emesis: summary of clinical trialsCancer Invest200422456957615565815
  • Di RenzoNMontaniniAManninaDSingle-dose palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin’s lymphoma receiving moderately emetogenic chemotherapy containing steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL)Support Care Cancer2011191505151020694798
  • Product Monograph. Aloxi®Missisauga, ONEisai Limited2012
  • RojasCLiYZhangJThe antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivoJ Pharmacol Exp Ther2010335236236820724484
  • StoltzRCyongJCShahAParisiSPharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjectsJ Clin Pharmacol200444552053115102873
  • EisenbergPMackintoshFRRitchPCornettPAMacciocchiAEfficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical studyAnn Oncol200415233033714760130
  • IkariYOgataKNakashimaYSafety and pharmacokinetic evaluation of repeated intravenous administration of palonosetron 0.75 mg in patients receiving highly or moderately emetogenic chemotherapySupport Care Cancer20142271959196424590375
  • ShahADeGrootTApseloffGPharmacokinetic evaluation and safety profile of a 15-minute versus 30-second infusion of palonosetron in healthy subjectsJ Clin Pharmacol200646101139114516988202
  • HuntTLGallagherSCCullenMTJrShahAKEvaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjectsJ Clin Pharmacol200545558959615831783
  • SadabaBdel BarrioACampaneroMARandomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapyPLoS One201492e8974724587006
  • HeskethPJMorrowGKomorowskiAWAhmedRCoxDEfficacy and safety of palonosetron as salvage treatment in the prevention of chemotherapy-induced nausea and vomiting in patients receiving low emetogenic chemotherapy (LEC)Support Care Cancer20122012633267722733373
  • BocciaRGrunbergSFranco-GonzalesEEfficacy of oral palonosetron compared to intravenous palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trialSupport Care Cancer2013211453146023354552
  • EisenbergPFigueroa-VadilloJZamoraRImproved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetronCancer200398112473248214635083
  • GrallaRLichinitserMVan Der VegtSPalonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetronAnn Oncol200314101570157714504060
  • ChoiBSBorsaruGPBallinariGVoisinDDi RenzoNMulticenter phase IV study of palonosetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with non-Hodgkin lymphomas undergoing repeated cycles of moderately emetogenic chemotherapyLeuk Lymphoma201455354455023772665
  • MattiuzziGNCortesJEBlambleDADaily palonosetron is superior to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemiaCancer2010116245659566621218459
  • DongXHuangJCaoRLiuLPalonosetron for prevention of acute and delayed nausea and vomiting in non-small-cell lung carcinoma patientsMed Oncol2011281425142920602263
  • TianWWangZZhouJRandomized, double-blind, crossover study of palonosetron compared with granisetron for the prevention of chemotherapy-induced nausea and vomiting in a Chinese populationMed Oncol201128717820049561
  • MaemondoMMasudaNSekineIA phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapyAnn Oncol200920111860186619561037
  • MassaEAstaraGMadedduCPalonosetron plus dexamethasone effectively prevents acute and delayed chemotherapy-induced nausea and vomiting following highly or moderately emetogenic chemotherapy in pre-treated patients who have failed to respond to a previous antiemetic treatment: comparison between elderly and non-elderly patient responseCrit Rev Oncol Hematol2009701839118723369
  • AaproMFabiANolèFDouble-blind, randomized, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapyAnn Oncol20102151083108820080830
  • CelioLFrustaciSDenaroAPalonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trialSupport Care Cancer20111981217122520574663
  • BrugnatelliSGattoniEGrassoDRossettiFPerroneTDanovaMSingle-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patientsTumori201197336236621789017
  • RozziANardoniCCoronaMPalonosetron for the prevention of chemotherapy-induced nausea and vomiting in glioblastoma patients treated with temozolomide: a phase II studySupport Care Cancer201119569770120467757
  • LorussoVGiampagliaMPetrucelliLSaracinoVPerroneTGnoniAAntiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapySupport Care Cancer201220123241324622534864
  • AogiKSakaiHYoshizawaHA phase III open-label study to assess safety and efficacy of palonosetron for preventing chemotherapy-induced nausea and vomiting (CINV) in repeated cycles of emetogenic chemotherapySupport Care Cancer20122071507151421808994
  • LorussoVSpedicatoAPetrucelliLSaracinoVGiampagliaMPerroneTSingle dose of palonosetron plus dexamethasone to control nausea, vomiting and to warrant an adequate food intake in patients treated with highly emetogenic chemotherapy (HEC). Preliminary resultsSupport Care Cancer200917121469147319294429
  • YavasCDoganUYavasGArazMAtaOYAcute effect of palonosetron on electrocardiographic parameters in cancer patients: a prospective studySupport Care Cancer201220102343234722170340
  • DoganUYavasGTekinalpMYavasCAtaOYOzdemirKEvaluation of the acute effect of palonosetron on transmural dispersion of myocardial repolarizationEur Rev Med Pharmacol Sci201216446246822696873
  • LongoFMansuetoGLapadulaVPalonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapySupport Care Cancer20111981159116420552375
  • GroteTHajdenbergJCartmellAFergusonSGinkelACharuVCombination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: palonosetron, dexamethasone, and aprepitantJ Support Oncol20064840340817004515
  • HeskethPJSanz-AltamiraPAprepitant, dexamethasone, and palonosetron in the prevention of doxorubicin/cyclophosphamide-induced nausea and vomitingSupport Care Cancer201220365365622089429
  • GrunbergSMDuganMMussHEffectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapySupport Care Cancer200917558959419037667
  • KimKILeeDEChoIEffectiveness of palonosetron versus other serotonin 5-HT3 receptor antagonists in triple antiemetic regimens during multiday highly emetogenic chemotherapyAnn Pharmacother201246121637164423170032
  • AaproMRugoHRossiGA randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapyAnn Oncol20142571328133324603643
  • HeskethPJRossiGRizziGEfficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal studyAnn Oncol20142571340134624608196