Abstract
Background
No clinical standard currently exists for the optimal management of nausea induced by emetogenic chemotherapy, particularly delayed nausea.
Objective
To compare the efficacy and safety of palonosetron with older 5-HT3 receptor antagonists (RAs) in preventing chemotherapy-induced nausea.
Methods
Data were pooled from 4 similarly designed multicenter, randomized, double-blind, clinical trials that compared single intravenous doses of palonosetron 0.25 mg or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg, administered 30 minutes before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Pooled data within each chemotherapy category (MEC: n = 1,132; HEC: n = 1,781) were analyzed by a logistic regression model. Nausea endpoints were complete control rates (ie, no more than mild nausea, no vomiting, and no rescue medication), nausea-free rates, nausea severity, and requirement for rescue antiemetic/antinausea medication over 5 days following chemotherapy. Pooled safety data were summarized descriptively.
Results
Numerically more palonosetron-treated patients were nausea-free on each day, and fewer had moderate-severe nausea. Similarly, usage of rescue medication was less frequent among palonosetron-treated patients. Complete control rates for palonosetron and older 5-HT3 RAs in the acute phase were 66% vs 63%, 52% vs 42% in the delayed phase (24-120 hours), and 46% vs 37% in the overall phase. The incidence of adverse events was similar for palonosetron and older 5-HT3 RAs.
Limitations
This post hoc analysis summarized data for palonosetron and several other 5-HT3 RAs but was not powered for statistical comparisons between individual agents. Because nausea is inherently subjective, the reliability of assessments of some aspects (eg, severity) may be influenced by interindividual variability.
Conclusion
Palonosetron may be more effective than older 5-HT3 RAs in preventing nausea, with comparable tolerability.
Patients who receive cancer chemotherapy are at risk for nausea and vomiting. The incidence and severity of these effects depend on the inherent emetogenic potential of the chemotherapeutic agents and their dosage and administration schedules, and patient factors such as younger age, female gender, low use of alcohol, and perceived susceptibility to nausea.1-3 Chemotherapy-induced nausea and vomiting (CINV) may be responsible for numerous adverse outcomes, including nutritional deficiencies and anorexia, esophageal tears, deterioration of performance and mental status, functional ability, and discontinuation of potentially effective cancer treatment.1 Therefore, overall control of CINV is an important primary goal of preventive treatment.
CINV may occur acutely after the start of chemotherapy, or it can be delayed, not appearing until the second day after start of chemotherapy and continuing for 5 or more days.1 Although delayed CINV can occur independently of acute CINV, the risk of delayed CINV is greater if acute CINV is poorly controlled.4 Delayed CINV may be more common.5 In particular, delayed nausea seems to be more common and often more severe than acute nausea and it may be resistant to common preventive treatments.6 Indeed, although vomiting can often be controlled by prophylactic antiemetic therapy administered before emetogenic chemotherapy, patients may still experience acute or delayed nausea.5 Thus, nausea is generally more difficult to control than vomiting,1 and controlling delayed nausea in particular presents a challenge.
CINV seems to result from the release of 5-hydroxytryptamine (5-HT; serotonin) from chemotherapy-damaged enterochromaffin cells in the small intestine and the subsequent activation of 5-HT3 receptors on the vagal afferent nerves and stimulation of CNS centers involved in mediating emesis.7,8 Substance P and neurokinin-1 (NK-1) receptors also seem to play a role in CINV, particularly in the delayed phase.7
5-HT3 receptor antagonists (RA) have been widely studied and are standard therapies for cancer patients receiving emetogenic chemotherapy. Older 5-HT3 RA agents such as ondansetron, granisetron, dolasetron, and tropisetron have proven effective in preventing acute CINV in 50%-80% of patients on moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) regimens.9 However, many patients continue to have acute and/or delayed CINV despite such treatment.5,10
Palonosetron is a newer 5-HT3 RA with a distinct molecular and pharmacologic profile, including structural differences,11 stronger binding affinity for the 5-HT3 receptor,12 a different binding profile (ie, allosteric binding, positive cooperativity, and receptor internalization, leading to longer binding, as well as persistent functional effects11 and a longer elimination half-life (about 40 hours)12,13 relative to older agents. Palonosetron also inhibits substance P-mediated responses independent of serotonin14 and has been found to uniquely inhibit cross-talk between 5-HT3 and NK-1 receptor pathways.15 Palonosetron has not been associated with significant QT interval prolongation,16-18 an effect observed with other 5HT3 RAs.1,19 A recent analysis of data from 5 randomized, double-blind, comparative trials (n = 2,057) found that palonosetron was significantly more effective than were older 5-HT3 RAs (ondansetron, dolasetron, granisetron) in preventing acute and delayed CINV associated with MEC or HEC, whether or not corticosteroids were used concomitantly.20 Another recent study reported a lower incidence of nausea with palonosetron (n = 39) compared with granisetron (n = 49) in patients with advanced colorectal cancer who received mFOLFOX6 and FOLFIRI.21
The present analysis evaluates the safety and efficacy of palonosetron compared with older 5-HT3 RAs in preventing nausea in the acute phase (0-24 h) and the delayed phase (24-120 h) after emetogenic chemotherapy. Data were derived from 4 similarly designed comparative studies of palonosetron compared with ondansetron, dolasetron, or granisetron in patients treated with emetogenic chemotherapy.22-25 The primary published reports of the 4 studies focused on the occurrence of emetic episodes; here we report an analysis of pooled data for nausea endpoints.
Patients and methods
The studies in the present analysis were multicenter, randomized, double-blind, parallel-group investigations in patients with various types of cancer who were scheduled to receive emetogenic chemotherapy at sites in Europe or North America22-24 (in 2000-2001) or in Japan (in 2006-2007).25 In 2 studies,22,23 the patients’ chemotherapy regimens were associated with a moderate risk of emesis (MEC; frequency of emesis 30%-90%1,7). In the other 2 studies,24,25 the chemotherapy regimens were associated with a high risk of emesis (HEC; frequency of emesis > 90%1,7). All 4 trials were approved by institutional review boards or independent ethics committees at each study site and written informed consent was obtained from all of the patients before any study-related procedures were initiated.
Patients enrolled in the 4 clinical trials were required to be at least 18-20 years of age, have histologically or cytologically confirmed malignant disease, and a Karnofsky Performance Scale score of ≥ 50%. Exclusion criteria were similar for all 4 trials and included vomiting, retching, or nausea severity of grade ≥ 2 (National Cancer Institute Common Terminology Criteria for Adverse Events) in the 24 hours preceding chemotherapy; ongoing emesis from any organic etiology; use of any drug with potential anti-emetic activity from 24 hours before treatment until study day 5 (except dexamethasone in the HEC studies); active seizure disorder requiring anticonvulsant therapy (unless clinically stable); and known hypersensitivity to any 5-HT3 RA.22-25
Treatments
Eligible patients in the 4 studies were randomly assigned to receive treatment with palonosetron (0.25 mg or 0.75 mg) or another 5-HT3 RA (ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg). Investigators and patients were blinded to treatment assignment. Each drug was administered intravenously before the scheduled chemotherapy regimen on study day 1; dexamethasone was permitted or required in the HEC studies. Rescue antiemetic/antinausea medication (metoclopramide, prochlorperazine, antihistamines, or other agents) was permitted for patients who experienced nausea and emesis during follow-up.
Assessments and nausea prevention endpoints
After chemotherapy administration (on study day 1), clinical efficacy was assessed for 5 days and safety for 8-15 days by patient-reported outcomes, depending on the study. All of the assessments were completed at clinic visits or by follow-up telephone contact. Patients were given common diaries for documenting clinical and safety outcomes, including all episodes of emesis and nausea, the severity of nausea, and the use of rescue medication for each of the 5 days of follow-up (24-hour intervals).
The nausea outcomes evaluated in this analysis included: the complete control rate (defined as no more than mild nausea, no emetic episodes, and no use of rescue medication) during the acute (0-24 h), delayed (24-120 h), and overall (0-120 hours) postchemotherapy phases, and each of the 5 successive 24-hour phases; nausea-free rate (percentage of patients with no nausea on each day); nausea severity (rated on a 4-point categorical scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe); and use of rescue anti-emetic/antinausea medication.
Safety and tolerability
In all of the studies, safety was assessed by recording of adverse events (AEs) reported by patients at study visits and during follow-up phone contacts, vital signs, laboratory results (including hematology, blood chemistry, and urinalysis), and electrocardiogram (ECG) recordings.
Statistical analysis
Data for palonosetron compared with the other 5-HT3 RAs were pooled within each chemotherapy category (MEC, HEC) for this analysis. Because the study participants had similar demographic characteristics (apart from ethnicity) and were selected using similar inclusion and exclusion criteria, post hoc pooling of the derived data was considered valid. Pooling of data for the older 5-HT3 RAs was also considered valid based on similar clinical efficacy at therapeutically equivalent doses.9 Pooling of data for the 2 palonosetron doses (0.25 mg and 0.75 mg) was deemed valid, as few dose-dependent differences in overall efficacy for CINV have been noted in previous studies.22-24
Nausea outcomes were summarized for the intent-to-treat (ITT) cohorts of each study. The ITT population comprised all randomized patients who received study medication and the scheduled chemotherapy regimen (consistent with the definition used in the individual studies). Safety was summarized for all patients who received study medication and had at least 1 safety assessment (the safety cohort).
Results
The 4 clinical trials enrolled a total of 2,978 patients who received either MEC (n = 1,162) or HEC (n = 1,816) and who were randomly assigned to receive antiemetic treatment. Sixty-five patients were excluded from the ITT analysis for various reasons, including nonreceipt of study medications (n = 40), chemotherapy deemed to be of insufficient emetogenic potential (n = 6) , and enrollment at a disqualified investigative site (n = 19). Thus, the overall ITT population for the present analysis was 2,913 patients (MEC: n = 1,132 [palonosetron: n = 756; other 5-HT3 RA: n = 376]; HEC: n = 1,781 [palonosetron: n = 1,001; other 5-HT3 RA: n = 780]).
Demographic characteristics of the pooled ITT cohorts are shown in Table 1. The characteristics of the patients in the individual treatment arms within each study type were generally similar; however, there were some differences between patients in the MEC and HEC studies (eg, ethnicity, body weight) that reflect differences based on the geographical location of the studies. Most MEC recipients (≥ 97%) did not receive corticosteroids before or concomitantly with 5-HT3 RA treatment, whereas most of the HEC patients (> 85%) did receive them. In the HEC study by Aapro and colleagues,24 about 67% of patients in each treatment arm received concomitant dexamethasone; in the other HEC study (Saito and colleagues25), all of the patients received dexamethasone with the 5-HT3 RA. The most common tumors in the 4 clinical trials were breast and lung cancers.
TABLE 1.
Pooled demographic patient data (intent-to-treat cohorts)
| Variable | Moderately emetogenic chemotherapya,22,23 |
Highly emetogenic chemotherapyb,24,25 |
||
|---|---|---|---|---|
| PALO 0.25 mg and 0.75 mgc (n = 756) | OND 32 mg and DOL 100 mgc (n = 376) | PALO 0.25 mg and 0.75 mg (± Dex)d (n = 1,001) | OND 32 mg and GRAN 40 μg/kg (± Dex)d (n = 780) | |
| Mean age, y | 54.9 | 54.4 | 55.5 | 56.0 |
| Mean height, cm | 162.6 | 163.0 | 161.8 | 161.2 |
| Mean weight, kg | 70.9 | 71.8 | 62.5 | 60.8 |
| Gender, n (%) | ||||
| Male | 172 (22.8) | 87 (23.1) | 447 (44.7) | 343 (44.0) |
| Female | 584 (77.2) | 289 (76.9) | 554 (55.3) | 437 (56.0) |
| Ethnicity, n (%) | ||||
| White | 493 (65.2) | 242 (64.4) | 270 (27.0) | 127 (16.3) |
| Black | 20 (2.6) | 10 (2.7) | 14 (1.4) | 8 (1.0) |
| Hispanic | 230 (30.4) | 116 (30.9) | 156 (15.6) | 85 (10.9) |
| Japanese/Asian | 9 (1.2) | 6 (1.6) | 560 (55.9) | 559 (71.7) |
| Other | 4 (0.5) | 2 (0.5) | 1 (0.1) | 1 (0.1) |
| Alcohol use, n (%) | ||||
| None | 422 (55.8) | 212 (56.4) | 458 (45.8) | 355 (45.5) |
| Rarely | 201 (26.6) | 97 (25.8) | 199 (19.9) | 132 (16.9) |
| Occasionally/sometimes | 97 (12.8) | 43 (11.4) | 146 (14.6) | 108 (13.8) |
| Regularly/daily | 34 (4.5) | 24 (6.4) | 197 (19.7) | 185 (23.7) |
| Tobacco use, n (%) | ||||
| Nonsmoker | 498 (65.9) | 240 (63.8) | 462 (46.2) | 353 (45.3) |
| Ex-smoker | 135 (17.9) | 72 (19.1) | 239 (23.9) | 187 (24.0) |
| Smoker | 122 (16.1) | 64 (17.0) | 170 (17.0) | 120 (15.4) |
| Chemotherapy history, n (%) | ||||
| Naïve | 411 (54.4) | 203 (54.0) | 781 (78.0) | 647 (82.9) |
| Non-naïve | 345 (45.6) | 173 (46.0) | 220 (22.0) | 133 (17.1) |
| Corticosteroid use (pretreatment or concomitantly), n (%) | ||||
| Yes | 23 (3.0) | 8 (2.1) | 855 (85.4) | 706 (90.5) |
| No | 733 (97.0) | 368 (97.9) | 146 (14.6) | 74 (9.5) |
| Common tumor types, n (%) | ||||
| Breast | 464 (61.4) | 236 (62.8) | 256 (25.6) | 250 (32.1) |
| Lung | 75 (9.9) | 34 (9.0) | 349 (34.9) | 330 (42.3) |
| Colon/rectum | 36 (4.8) | 11 (2.9) | 0 | 0 |
| Ovarian | 19 (2.5) | 10 (2.7) | 76 (7.6) | 39 (5.0) |
| Hodgkin | 4 (0.5) | 2 (0.5) | 36 (3.6) | 17 (2.2) |
| Gastric | 12 (1.6) | 6 (1.6) | 19 (1.9) | 14 (1.8) |
Dex, dexamethasone; DOL, dolasetron; GRAN, granisetron; IV, intravenous; OND, ondansetron; PALO, palonosetron
Agents associated with a 30%-90% frequency of emesis.
Agents associated with > 90% frequency of emesis.
Combined data for the palonosetron 0.25 mg and 0.75 mg arms, and the ondansetron 32 mg and dolasetron 100 mg arms of the MEC studies.
Combined data for the palonosetron 0.25 mg and/or 0.75 mg ± dexamethasone arms, and the ondansetron 32 mg ± dexamethasone and granisetron 40 μg/kg + dexamethasone arms of the HEC studies.
Nausea outcomes
Nausea-free days and nausea severity
In the MEC studies, a numerically greater percentage of patients who received palonosetron were nausea-free on each of the 5 days after starting chemotherapy compared with the patients who received other 5HT3 RAs (Figure 1). The 6% difference (55% vs 49%, respectively) observed on day 1 expanded to a 12% difference on day 2 (52.4% vs 39.9%) and remained a 12% difference on day 3 (57.1% vs 45.5%). Fewer palonosetron recipients had moderate-to-severe nausea, particularly on days 2 and 3 (21.0% vs 30.1% and 14.7% vs 23.9%; Figure 2).
FIGURE 1.
Percentage of MEC and HEC recipients who had no nausea on days 1 to 5: pooled data for palonosetron versus older agents.22-25
HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy
FIGURE 2.
Severity of nausea in the MEC and HEC studies on days 1 to 5: pooled data for palonosetron versus older agents.22-25 The majority of patients in the HEC studies received dexamethasone concomitantly.
HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy
In the HEC studies, the percentage of patients who were nausea-free was similar for palonosetron and other 5-HT3 RAs on study day 1. Tereafter, the percentage of nausea-free patients was slightly higher for palonosetron than for other 5HT3 RAs (Figure 1). Nausea severity ratings were slightly more favorable with palonosetron (Figure 2), but the differences compared with the other 5-HT3 RAs were smaller than in the MEC studies. The greatest differences in the incidence of moderate-to-severe nausea were on days 4 and 5 (14.8% vs 20.4% and 10.8% vs 16.8%, respectively).
Requirement for rescue antiemetic/antinausea medication
The most commonly used rescue antiemetic/antinausea agents were metoclopramide and prochlorperazine. In the MEC studies, rates of rescue medication use in patients who received palonosetron vs older 5-HT3 RAs were: day 1: 17% vs 19%; day 2: 20% vs 25%; day 3: 16% vs 21%; day 4: 11% vs 13%; and day 5: 8% vs 7%. In the HEC studies, rates of rescue medication use for palonosetron and other 5-HT3 RAs were about 17% in each group on day 1; about 21% vs 23% on day 2; about 18% vs 21% on day 3; 18% vs 23% on day 4; and about 15% vs 18% on day 5.
Complete control rates
Overall, for MEC and HEC studies combined, the pooled complete control rates for palonosetron (0.25 mg and 0.75 mg) were higher than the rates for other 5HT3 RAs in the delayed phase (52% vs 42%; P < .0001, respectively) and overall phase (46% vs 37%; P < .0001), but not the acute phase (66% vs 63%; P = .137.26 Among patients who received MEC, complete control rates were numerically higher for palonosetron on each of the 5 study days after chemotherapy (Figure 3). The largest differences in complete control rates between palonosetron and the other 5-HT3 RAs were on day 2 (63.2% vs 50.3%, respectively) and day 3 (70.9% vs 54.3%). Among patients who received HEC, the pooled complete control rates for palonosetron were numerically higher than for other 5HT3 RAs on day 3 through day 5.
FIGURE 3.
Pooled complete control rates for palonosetron versus older agents, by chemotherapy category and time period.22-25 Complete control = no more than mild nausea, no emetic episodes, and no need for rescue medication.
Tolerability and safety
An analysis of pooled safety data from the 4 studies showed no clinically relevant difference in the incidence of AEs between palonosetron and the older 5-HT3 RAs (Table 2). Most AEs were likely attributable to the patients’ cancer and/or the chemotherapy regimens administered. This was presumed because the number of AEs considered to have a definite, probable, possible, or unknown relationship to the study medication was about one-third of the all-cause AE total (across all studies).
TABLE 2.
Pooled safety data (safety cohorts)
| Moderately emetogenic chemotherapya,22,23 |
Highly emetogenic chemotherapyb,24,25 |
|||
|---|---|---|---|---|
| Adverse event (AE) | PALO 0.25 and 0.75 mgc (n = 763) | OND 32 mg and DOL 100 mgc (n = 381) | PALO 0.25 and 0.75 mg (± Dex)d (n = 1,007) | OND 32 mg and GRAN 40 μg/kg (± Dex)d (n = 785) |
| At least 1 AE, n (%) | 543 (71.2) | 269 (70.6) | 885 (87.9) | 716 (91.2) |
| Treatment-relatede AE, n (%) | 163 (21.4) | 87 (22.8) | 275 (27.3) | 239 (30.4) |
| Serious AE, n (%) | 27 (3.5) | 14 (3.7) | 35 (3.5) | 28 (3.6) |
| Treatment-related serious AE, n (%) | 0 | 0 | 1 (0.1)f | 1 (0.1)f |
| Withdrew due to treatment-related AE, n (%) | 1 (0.1) | 0 | 1 (0.1) | 0 |
| Most common treatment-related AEs, n (%) | ||||
| Headache | 77 (10.1) | 42 (11.0) | 64 (6.4) | 45 (5.7) |
| Constipation | 41 (5.4) | 15 (3.9) | 124 (12.3) | 93 (11.8) |
| Dizziness | 6 (0.8) | 10 (2.6) | 8 (0.8) | 3 (0.4) |
| Diarrhea | 6 (0.8) | 4 (1.0) | 4 (0.4) | 5 (0.6) |
| Asthenia | 5 (0.7) | 1 (0.3) | 5 (0.5) | 2 (0.3) |
| Fatigue | 4 (0.5) | 4 (1.0) | 0 | 0 |
| Anxiety | 4 (0.5) | 0 | 0 | 0 |
| Increased ALT (> 1 toxicity grade) | 2 (0.3) | 1 (0.3) | 6 (0.6) | 19 (2.4) |
| Increased AST (> 1 toxicity grade) | 3 (0.4) | 0 | 3 (0.3) | 15 (1.9) |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events (National Cancer Institute); Dex, dexamethasone; DOL, dolasetron; GRAN, granisetron; IV, intravenous; OND, ondansetron; PALO, palonosetron
1Agents associated with a 30%-90% frequency of emesis.
1Agents associated with >90% frequency of emesis.
Combined data for the palonosetron 0.25 mg and 0.75 mg arms, and the ondansetron 32 mg and dolasetron 100 mg arms of the MEC studies.
Combined data for the palonosetron 0.25 mg and/or 0.75 mg ± dexamethasone arms, and the ondansetron 32 mg ± dexamethasone and granisetron 40 μg/kg + dexamethasone arms of the HEC studies.
Adverse events considered to have a definite, probable, possible, or unknown relationship to the study medications.
One case of hepatitis with palonosetron and one of QTc prolongation with granisetron was considered possibly related to the study medication.
In MEC studies, the proportion of patients with a treatment-related AE was 21.4% for palonosetron recipients and 22.8% for those who received older 5-HT3 RAs. For HEC studies, the percentages were 27.3% and 30.4%, respectively. More than 90% of the AEs reported for each treatment were mild or moderate in intensity (grade 1-2 Common Terminology Criteria for Adverse Events). Across all studies, the most common treatment-related AEs associated with palonosetron and other 5-HT3 RAs, were headache (8.0% and 7.5%, respectively), constipation (9.3% and 9.3%), dizziness (0.8% and 1.1%), and diarrhea (0.6% and 0.8%).
Although serious AEs (SAEs) were reported for about 3.5% of patients in both groups (palonosetron and older 5-HT3 RAs), only 2 patients were deemed to have treatment-related SAEs (both in the study by Saito and colleagues25). One patient had hepatitis, possibly related to palonosetron; the other had QTc prolongation, possibly related to granisetron. These events were confirmed as “in remission” or “recovering” 8 days after administration of the study drugs. All other SAEs were considered unrelated or unlikely to be related to the study medications.
Discussion
Chemotherapy-induced nausea is more difficult to control than vomiting.1 Nausea that occurs in the delayed (24-120 h) postchemotherapy phase, in particular, may be inadequately controlled by older antiemetic/antinausea medications.6 Tus, there is concern about the optimal management of nausea after the administration of emetogenic cancer chemotherapy.
Te present analysis includes the largest randomized, double-blind comparative clinical trials that have been conducted of palonosetron versus older 5-HT RAs.22-25 The pooled data indicate palonosetron (0.25 mg or 0.75 mg) is more effective in preventing nausea than ondansetron, dolasetron, or granisetron. The differences in nausea outcomes were most pronounced in the delayed phase (24-120 h) and on study days 2, 3, and 4. This finding was true in patients who received MEC and those receiving HEC. However, as expected, complete control rates and nausea-free rates were lower in the HEC studies (regardless of study medication).
It is likely the pharmacokinetic and pharmacodynamic properties of palonosetron contribute to the apparent improvement over older 5-HT3 RAs in preventing nausea in the delayed postchemotherapy phase. In addition to a longer elimination half-life (t½) that contributes to a longer duration of action,12,13 palonosetron has a distinctly different receptor binding profle: it acts as an allosteric antagonist with positive cooperativity to the 5-HT3 receptor, whereas ondansetron and granisetron exhibit simple bimolecular binding.11 Thus, palonosetron binds more strongly, is a more efficient receptor antagonist, and is less likely to be displaced by serotonin. Moreover, unlike ondansetron, granisetron, and dolasetron, palonosetron reportedly triggers 5-HT3 receptor internalization, thereby inducing prolonged inhibition of receptor function.27
NK-1–dependent mechanisms reputedly have an important role in the genesis of delayed CINV (through substance P acting centrally at NK-1 receptors), and NK-1 RAs such as aprepitant have inhibited delayed CINV more effectively than have older 5-HT3 RAs such as ondansetron and granisetron.28 Evidence suggests that the inhibitory effects of palonosetron on the substance P response can occur in the absence of serotonin, and a synergistic effect of palonosetron and the NK-1 RA netupitant on inhibition of the substance P response.29 Palonosetron also inhibited cisplatin-induced substance P enhancement (dose dependently) in experimental animals.15 Because substance P is an agonist at the NK-1 receptor, this suggests that palonosetron, even though it does not bind to the NK-1 receptor, may have the ability to inhibit cross-talk between 5-HT3 and NK-1 receptors.15 These effects, which have not been observed with other 5HT3 RAs, also help to explain the greater efficacy of palonosetron in preventing delayed nausea.
The findings of the present analysis complement those of an earlier meta-analysis of data from 5 randomized, double-blind trials of palonosetron compared with older 5-HT3 RAs in 2,057 patients receiving cancer chemotherapy.20 The studies in the meta-analysis included 3 of the studies analyzed here22-24 but not the large study by Saito and colleagues25 and evaluated only the 0.25-mg dose of palonosetron.20 In that analysis, palonosetron was associated with less nausea than were ondansetron, dolasetron, and granisetron in the acute phase (fixed effect: response rate, 0.86; 95% CI, 0.76-0.96; P = .007) and the delayed phase (fixed effect: RR, 0.82; 95% CI, 0.75-0.89; P < .0001).20 Our analysis differed in that the MEC and HEC data were considered separately. Our results therefore further support the previous findings and also demonstrate that the differences between palonosetron and older 5-HT3 RAs are less pronounced among patients who receive highly emetogenic regimens.
Safety data from the present analysis also are consistent with those of Botrel and colleagues.20 Both analyses found that the tolerability profiles of palonosetron and older 5-HT3 RAs are comparable. There were no clinically relevant differences between palonosetron and the other therapies in the incidence of AEs. Most AEs were attributable to the patients’ cancer and/or the chemotherapy regimens, because the percentages of patients with treatment-related AEs were similar. The most frequently reported AEs for all 4 studies were headache, constipation, and dizziness. With respect to laboratory values, vital signs, and ECG findings, there were no pronounced differences between palonosetron and older 5-HT3 RAs. The studies analyzed here did not thoroughly evaluate QTc measures; however, recent studies in patients with cancer17,18 and a thorough QTc study in healthy subjects that used a positive control (ie, moxifloxacin)16 demonstrated no significant QTc changes associated with palonosetron. This is in contrast to evidence of significant dose-related QTc prolongation with ondansetron, which led to the removal of the 32-mg single dose from its label,30 and an increased risk of cardiac arrhythmias with IV dolasetron, which is no longer recommended.1
This analysis of the efficacy and safety of palonosetron versus older 5-HT3 RAs (ondansetron, dolasetron, and granisetron) in patients receiving emetogenic cancer chemotherapy suggests that palonosetron may have an advantage in preventing nausea, particularly in the delayed post-chemotherapy phase (24-120 h) and throughout 5 days after chemotherapy administration. In addition, palonosetron was as well tolerated as the older agents. These findings are consistent with and further support various guidelines from the Multinational Association of Supportive Care in Cancer, the European Society of Medical Oncology,31 the American Society of Clinical Oncology,32 and the National Comprehensive Cancer Network,1 which recommend palonosetron as the preferred 5-HT3 RA for prevention of CINV with MEC,1,31,32 as the preferred 5-HT3 RA for AC (doxorubicin and cyclophosphamide) or regimens when an NK-1 RA is not available31 and as either preferred1 or among other 5-HT3 RAs31,32 for HEC.
Acknowledgments
The authors thank all of the patients, as well as the investigators and their teams, who participated in the studies that were used for this analysis. Tey also thank Sherri Jones, PharmD, of MedVal Scientifc Information Services, LLC, for providing medical writing and editorial assistance.
Disclosures and funding Dr Schwartzberg is a consultant to and Dr Cox an employee at Esai. Mr Ballinari is a member of staff at and Dr Thorn consults for Helsinn Healthcare SA. Funding to support this study and the preparation of this manuscript was provided by Eisai Inc.
References
- 1.NCCN clinical practice guidelines in oncology (NCCN Guidelines): Antiemesis. v1.2013. National Comprehensive Cancer Network; 2012. [Google Scholar]
- 2.Roscoe JA, Morrow GR, Colagiuri B, et al. Insight in the prediction of chemotherapy-induced nausea. Support Care Cancer. 2010;18:869–876. doi: 10.1007/s00520-009-0723-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new anti-emetic agents and definition of antineoplastic agent emetogenicity-state of the art. Support Care Cancer. 2011;19(suppl 1):43S–47S. doi: 10.1007/s00520-010-1003-x. [DOI] [PubMed] [Google Scholar]
- 4.Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol. 1999;17:2971–2994. doi: 10.1200/JCO.1999.17.9.2971. [DOI] [PubMed] [Google Scholar]
- 5.Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100:2261–2268. doi: 10.1002/cncr.20230. [DOI] [PubMed] [Google Scholar]
- 6.Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765–772. doi: 10.1016/S1470-2045(05)70325-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482–2494. doi: 10.1056/NEJMra0706547. [DOI] [PubMed] [Google Scholar]
- 8.Endo T, Minami M, Hirafuji M, et al. Neurochemistry and neu ropharmacology of emesis - the role of serotonin. Toxicology. 2000;153:189–201. doi: 10.1016/s0300-483x(00)00314-0. [DOI] [PubMed] [Google Scholar]
- 9.Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest. 2000;18:163–173. doi: 10.3109/07357900009038248. [DOI] [PubMed] [Google Scholar]
- 10.Hickok JT, Roscoe JA, Morrow GR, King DK, Atkins JN, Fitch TR. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: a University of Rochester James P. Wilmot Cancer Center Community Clinical Oncology Program Study of 360 cancer patients treated in the community. Cancer. 2003;97:2880–2886. doi: 10.1002/cncr.11408. [DOI] [PubMed] [Google Scholar]
- 11.Rojas C, Stathis M, Tomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107:469–478. doi: 10.1213/ane.0b013e318172fa74. [DOI] [PubMed] [Google Scholar]
- 12.Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT3-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother. 2003;4:2297–2303. doi: 10.1517/14656566.4.12.2297. [DOI] [PubMed] [Google Scholar]
- 13.Stoltz R, Cyong JC, Shah A, Parisi S. Pharmacokinetic and safety evaluation of palonosetron, a 5-hydroxytryptamine-3 receptor antagonist, in U.S. and Japanese healthy subjects. J Clin Pharmacol. 2004;44:520–531. doi: 10.1177/0091270004264641. [DOI] [PubMed] [Google Scholar]
- 14.Stathis M, Pietra C, Rojas C, Slusher BS. Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol. 2012;689:25–30. doi: 10.1016/j.ejphar.2012.05.037. [DOI] [PubMed] [Google Scholar]
- 15.Rojas C, Li Y, Zhang J, et al. Te antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivo. J Pharmacol Exp Ter. 2010;335:362–368. doi: 10.1124/jpet.110.166181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Morganroth J, Parisi S, Moresino C, Torn M, Cullen MT. High dose palonosetron does not alter ECG parameters including QTc interval in healthy subjects: results of a dose-response, double blind, randomized, parallel El4 study of palonosetron vs. moxifloxacin or placebo [abstract]. Eur J Cancer. 2007;5(suppl):158S–159S. [Google Scholar]
- 17.Yavas C, Dogan U, Yavas G, Araz M, Ata OY. Acute effect of palo-nosetron on electrocardiographic parameters in cancer patients: a prospective study. Supportive Care in Cancer. 2012;20:2343–2347. doi: 10.1007/s00520-011-1348-9. [DOI] [PubMed] [Google Scholar]
- 18.Gonullu G, Demircan S, Demirag MK, Erdem D, Yucel I. Electrocardiographic findings of palonosetron in cancer patients. Supportive Care in Cancer. 2012;20:1435–1439. doi: 10.1007/s00520-011-1226-5. [DOI] [PubMed] [Google Scholar]
- 19.Charbit B, Alvarez JC, Dasque E, Abe E, Demolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study. Anesthesiology. 2008;109:206–212. doi: 10.1097/ALN.0b013e31817fd8c8. [DOI] [PubMed] [Google Scholar]
- 20.Botrel TE, Clark OA, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of palonosetron (PAL) compared to other serotonin inhibitors (5-HT3R) in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately or highly emetogenic (MoHE) treatment: systematic review and meta-analysis. Support Care Cancer. 2011;19:823–832. doi: 10.1007/s00520-010-0908-8. [DOI] [PubMed] [Google Scholar]
- 21.Sato Y, Hayakawa Y, Tatematsu M, Muro K, Noma H, Okamoto H. Antiemetic effect of palonosetron in advanced colorectal cancer patients receiving mFOLFOX6 and FOLFIRI: a retrospective survey. Gan To Kagaku Ryoho. 2012;39:1215–1219. [PubMed] [Google Scholar]
- 22.Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron 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 ondansetron. Ann Oncol. 2003;14:1570–1577. doi: 10.1093/annonc/mdg417. [DOI] [PubMed] [Google Scholar]
- 23.Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved 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 dolasetron. Cancer. 2003;98:2473–2482. doi: 10.1002/cncr.11817. [DOI] [PubMed] [Google Scholar]
- 24.Aapro M, Grunberg S, Manikhas G, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441–1449. doi: 10.1093/annonc/mdl137. [DOI] [PubMed] [Google Scholar]
- 25.Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol. 2009;10:115–124. doi: 10.1016/S1470-2045(08)70313-9. [DOI] [PubMed] [Google Scholar]
- 26.Schwartzberg L, Barbour SY, Morrow GR, Ballinari G, Torn MD, Cox D. Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV). Support Care Cancer. 2014;22:469–477. doi: 10.1007/s00520-013-1999-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Rojas C, Tomas AG, Alt J, et al. Palonosetron triggers 5-HT(3) receptor internalization and causes prolonged inhibition of receptor function. Eur J Pharmacol. 2010;626:193–199. doi: 10.1016/j.ejphar.2009.10.002. [DOI] [PubMed] [Google Scholar]
- 28.Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:1074–1080. doi: 10.1016/s0959-8049(02)00674-3. [DOI] [PubMed] [Google Scholar]
- 29.Rojas C, Slusher BS. Pharmacological mechanisms of 5-HT3 and tachykinin NK1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol. 2012;684:1–7. doi: 10.1016/j.ejphar.2012.01.046. [DOI] [PubMed] [Google Scholar]
- 30.Zofran (ondansetron hydrochloride) tablets; Zofran ODT (ondansetron) orally disintegrating tablets; Zofran (ondansetron hydrochlo-ride) oral solution [prescribing information] GlaxoSmithKline; Research Triangle Park, NC: 2013. [Google Scholar]
- 31.Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):232V–243V. doi: 10.1093/annonc/mdq194. [DOI] [PubMed] [Google Scholar]
- 32.Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189–4198. doi: 10.1200/JCO.2010.34.4614. [DOI] [PMC free article] [PubMed] [Google Scholar]