COMMENTARIES
Palonosetron
COMMENTARIES
Evidence to support use of palonosetron over generic serotonin type 3–receptor antagonists for chemotherapy-induced nausea and vomiting Yu-Chen Yeh, Gayle C. Blouin, and Prabashni Reddy Am J Health-Syst Pharm. 2014; 71:500-6
P
alonosetron, a serotonin type 3–receptor (5-HT 3 ) antagonist, was approved by the Food and Drug Administration (FDA) in 2003 for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC).1 It is also approved for the prevention of delayed CINV in patients receiving MEC. Other 5-HT 3 antagonists—ondansetron, granisetron, and dolasetron—are available in the United States. Guidelines recommend using a 5-HT3 antagonist in combination with other agents for the prevention of CINV in patients receiving HEC or MEC.2-4 Despite the limitations of the evidence currently
available, palonosetron was recently designated as the preferred 5-HT3 antagonist for CINV prevention after single-day MEC in practice guidelines independently developed by the American Society of Clinical Oncology (ASCO),2 the National Comprehensive Cancer Network (NCCN), 3 and the Multinational Association of Supportive Care in Cancer (MASCC). 4 In addition, the NCCN guideline recommends palonosetron as the preferred 5-HT3 antagonist for patients receiving single-day HEC.3 Given that other 5-HT3 antagonists are available generically at a lower price, using palonosetron as the first-line agent in all patients requiring CINV prevention after HEC or MEC would cause a substantial economic burden on the U.S. health
Y u -C h e n Y e h , M.S., B.S.P h a r m ., is Senior Pharmacist, Center for Drug Policy, Partners Healthcare, Needham, MA. Gayle C. Blouin, Pharm.D., BCOP, is Senior Attending Pharmacist and Clinical Lead—Ambulatory Oncology, Yawkey Center for Outpatient Care, Massachusetts General Hospital, Boston. Prabashni Reddy, Pharm.D., M.Med.Sc., is Director, Center for Drug Policy, Partners Healthcare. Address correspondence to Ms. Yeh (yyeh@ partners.org).
Portions of the data in this article were presented in poster format at the International Society of Pharmacoeconomics and Outcomes Research Annual Meeting, Toronto, Ontario, Canada, May 3–7, 2008. The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0302-0500$06.00. DOI 10.2146/ajhp130394
500
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
care system.5 The objectives of this article are (1) to compare the recommendations in the pertinent practice guidelines, (2) to summarize the evidence of palonosetron in comparison with other 5-HT3 antagonists for CINV associated with HEC or MEC, and (3) to critique the evidence that supports the preferred status of palonosetron. A search for relevant systematic reviews, meta-analyses, practice guidelines, and randomized controlled trials (RCTs) published up to March 2013 was conducted in MEDLINE and the Cochrane Database. Practice guidelines were reviewed with a focus on the recommendations with regard to 5-HT3 antagonists for the management of CINV associated with HEC and MEC. Systematic reviews, meta-analyses, RCTs, and economic evaluations comparing palonosetron with other 5-HT3 antagonists for CINV related to HEC or MEC were identified. Comparison of 5-HT 3 antagonists. Palonosetron is indicated for the prevention of acute and delayed CINV associated with MEC and for acute CINV after HEC.1 Dolasetron, granisetron, and ondansetron also carry an indication for the prevention of CINV.6-11 All four agents are approved for the prevention of postoperative nausea and vomiting.1,6-8,11,12 In addition, ondansetron and granisetron are approved for the prevention of nausea and vomiting associated with radiotherapy (Table 1).7,9 The main advantage of palonosetron over dolasetron, granisetron, and ondansetron is its long half-life (40 hours versus 4–9 hours for the other agents), which allows one-time
a
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
b
$190 (0.25 mg) Cost per dose5
$67 (100 mg)
0.25 mg i.v. Recommended dose for CINV
CINV = chemotherapy-induced nausea and vomiting, PONV = postoperative nausea and vomiting, NV = nausea and vomiting. None reported to date.
I.V. form: $5 (32 mg) Oral form: $1 (24 mg)
I.V. form: 0.15 mg/kg × 3 doses Oral form: 8 mg × 2–3 doses
. . .b Drug interactions
I.V. form: 10 mg/kg Oral form: 2 mg Transdermal system: 1 patch (delivers 3.1 mg/24 hr) for up to 7 days I.V. form: $4 (0.7 mg) Oral form: $3 (2 mg)
Hypersensitivity
Other drugs that cause Q-T interval prolongation
~4–6 hr Q-T interval prolongation and torsades de pointes Hypersensitivity; concomitant use of apomorphine Other drugs that cause Q-T interval prolongation; tramadol
~7–8 hr Q-T interval prolongation and torsades de pointes Hypersensitivity; use in CINV (i.v. form) Other drugs that cause Q-T interval prolongation; atenolol, cimetidine, rifampin 100 mg orally ~40 hr No significant effects
Elimination half-life Reported cardiac effects Contraindications
Prevention of CINV (oral and i.v. forms); prevention of PONV (oral and i.v. forms); prevention of NV associated with radiotherapy (oral form) Prevention of CINV (oral form); prevention and treatment of PONV (oral and i.v. forms) Prevention of CINV; prevention of PONV for up to 24 hr after surgery
Prevention of CINV (oral, i.v., transdermal forms); prevention of NV associated with radiotherapy (oral form); prevention and treatment of PONV in adults (i.v. form) ~9 hr Q-T interval prolongation and torsades de pointes Hypersensitivity
Palonosetron
Indications
Ondansetron6,7 Granisetron8-10 Dolasetron11,12 Palonosetron1 Variable
Comparative Data on Serotonin Type 3–Receptor Antagonistsa
dosing even when prolonged inhibition of 5-HT3 receptors over multiple days is desired (e.g., in the setting of multiday chemotherapy or to prevent delayed CINV).1 Other benefits include (1) the lack of a warning on Q-T interval prolongation and torsades de pointes in patients with preexisting cardiac conduction disorders, (2) no known clinically significant drug–drug interactions, and (3) the lack of a contraindication to concomitant use of apomorphine. Palonosetron is available only in the injectable form; an oral formulation was approved by FDA but is not available on the U.S. market.13 Dolasetron is approved for CINV in an oral form only (an i.v. form is contraindicated in CINV due to dose-dependent Q-T interval prolongation). 11,12 Ondansetron and granisetron are approved for CINV in both injectable and oral forms.6-9 Granisetron can also be delivered through a transdermal patch that can be worn for up to seven days.10 Based on the 2013 Medicare payment rate, the cost of palonosetron is substantially higher than that of other i.v. and oral 5-HT3 antagonists (except for dolasetron).5 Practice guidelines. ASCO, 2 NCCN,3 and MASCC4 recently updated their guidelines for the management of CINV. For single-day chemotherapy, palonosetron is designated as the preferred 5-HT3 antagonist for CINV caused by either HEC or MEC in the NCCN guideline,3 while the other two guidelines list palonosetron as the preferred agent only for the management of CINV associated with MEC.2,4 For patients receiving multiday chemotherapy, none of the guidelines designates a preferred 5-HT3 antagonist.2-4 Single-day HEC. For the management of CINV associated with singleday HEC, a three-drug regimen, including a neurokinin-1 (NK1) antagonist (aprepitant on days 1–3 or fosaprepitant on day 1 only), a 5-HT3 antagonist (on day 1), and
Table 1.
COMMENTARIES
501
COMMENTARIES
Palonosetron
dexamethasone (on days 1–3 or 1–4), is recommended in all guidelines.2-4 A new regimen, containing olanzapine, palonosetron, and dexamethasone, was recently added to one of the guidelines based on lower-level evidence.3 Preferential use of palonosetron is noted in the NCCN guideline3 but not in the ASCO and MASCC guidelines. In fact, the MASCC panel members indicated that there was insufficient evidence to support the preferred status of palonosetron.4 Single-day MEC. For patients receiving single-day MEC, a 5-HT3 antagonist plus dexamethasone is recommended on day 1, with palonosetron being the preferred 5-HT3 antagonist in all three guidelines.2-4 The practice recommendations vary, however, in terms of whether an NK1-receptor antagonist should be added and which regimens should be used on days 2 and 3. One of the options that NCCN recommends is to continue the 5-HT3 antagonist on days 2 and 3 when palonosetron is not used on day 1.3 Alternatively, the NCCN guideline includes an option to use olanzapine in combination with palonosetron and dexamethasone.3 Multiday regimens. For CINV prevention during multiday chemotherapy regimens, ASCO proposes the use of the same antiemetic on each day of chemotherapy (with antiemetic agent selection based on the regimen’s emetogenic risk class) and for two days after chemotherapy if appropriate.2 NCCN notes that multiday aprepitant therapy may be used for HEC, while dexamethasone should be given daily to patients receiving HEC or MEC and for two to three days after chemotherapy if the regimen is expected to cause significant delayed CINV.3 In addition, a 5-HT3 antagonist should be given before each dose of HEC or MEC; palonosetron may be given on day 1 at the start of a three-day regimen (the need for repeat dosing is not yet known).3 For patients receiving 502
multiday cisplatin therapy, MASCC recommends a 5-HT3 antagonist plus dexamethasone for acute CINV and dexamethasone for delayed CINV.4 An NK1 receptor antagonist may be considered.4 None of the guidelines designates a preferred 5-HT3 antagonist in this specific setting.2-4 Meta-analyses. Three metaanalyses that compared palonosetron with other 5-HT3 antagonists were identified.14-16 Despite differences in the inclusion and exclusion criteria of the evaluated studies, the three analyses consistently showed that palonosetron significantly increased the rate of complete response (CR)—defined as no emetic episodes and no rescue medication use in the acute (0–24 hours), delayed (24–120 hours), and overall (0–120 hours) p h a s e s a f te r ch e m o t h e r a py — compared with other 5-HT3 antagonists. A significant difference in favor of palonosetron was demonstrated in two subgroup analyses of patients treated with HEC and MEC, respectively.15,16 However, when used in combination with dexamethasone in the setting of HEC, palonosetron significantly reduced the risk of CINV in the delayed and overall phases but not in the acute phase.15 No difference in the risk of constipation was found between palonosetron and other 5-HT3 antagonists in any of the studies.14-16 Results of RCTs. Single-day HEC. The four RCTs in patients receiving single-day HEC compared a single dose of i.v. palonosetron with a single dose of i.v. ondansetron17,18 or granisetron.19,20 One study was conducted in North America and Europe 17; the other three studies enrolled patients in China18,20 and Japan.19 Dexamethasone was part of the study regimens in two of the four studies17,19; these two studies were cited in the NCCN guideline to support the preferred status of palonosetron.3 In the study by Aapro et al.,17 patients receiving HEC were randomly assigned to receive palonosetron 0.25
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
mg i.v. (n = 223), palonosetron 0.75 mg i.v. (n = 223), or ondansetron 32 mg i.v. (n = 221). About 67% of the patients received dexamethasone on day 1 of antiemetic therapy. CR rates in the acute phase were comparable in patients treated with palonosetron and those receiving ondansetron (59% with palonosetron 0.25 mg, 66% with palonosetron 0.75 mg, 57% with ondansetron); those two palonosetron doses were associated with numerically higher CR rates relative to the CR rate with ondansetron in the delayed phase (45%, 48%, and 39%, respectively) and in the overall phase (41%, 42%, and 33%, respectively), but the differences were not statistically significant. In addition, the time to the first emetic episode was significantly longer for patients treated with palonosetron versus ondansetron; there was no difference between the two evaluated palonosetron doses in this regard, suggesting the lack of a dose–response relationship. The subgroup analysis in patients who received concomitant dexamethasone showed that the CR rate in the acute phase was similar in the palonosetron 0.25mg group (n = 150) and the ondansetron group (n = 147) (65% versus 56%). However, significantly higher CR rates with palonosetron 0.25 mg versus ondansetron were observed in the delayed phase (42% versus 29%, p = 0.021) and the overall phase (41% versus 25%, p = 0.005). Similarly, the study by Saito et al.,19 which compared palonosetron 0.75 mg i.v. (n = 555) with granisetron 40 mg/kg i.v. (n = 559) in patients receiving HEC found that palonosetron was comparable to granisetron in preventing acute emesis (CR rate, 75% versus 73%) but significantly more effective in preventing delayed emesis (57% versus 45%, p < 0.001). The superiority of palonosetron in the delayed phase was evident in all subgroups by age (≥55 years versus
Palonosetron
COMMENTARIES
Evidence to support use of palonosetron over generic serotonin type 3–receptor antagonists for chemotherapy-induced nausea and vomiting Yu-Chen Yeh, Gayle C. Blouin, and Prabashni Reddy Am J Health-Syst Pharm. 2014; 71:500-6
P
alonosetron, a serotonin type 3–receptor (5-HT 3 ) antagonist, was approved by the Food and Drug Administration (FDA) in 2003 for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC).1 It is also approved for the prevention of delayed CINV in patients receiving MEC. Other 5-HT 3 antagonists—ondansetron, granisetron, and dolasetron—are available in the United States. Guidelines recommend using a 5-HT3 antagonist in combination with other agents for the prevention of CINV in patients receiving HEC or MEC.2-4 Despite the limitations of the evidence currently
available, palonosetron was recently designated as the preferred 5-HT3 antagonist for CINV prevention after single-day MEC in practice guidelines independently developed by the American Society of Clinical Oncology (ASCO),2 the National Comprehensive Cancer Network (NCCN), 3 and the Multinational Association of Supportive Care in Cancer (MASCC). 4 In addition, the NCCN guideline recommends palonosetron as the preferred 5-HT3 antagonist for patients receiving single-day HEC.3 Given that other 5-HT3 antagonists are available generically at a lower price, using palonosetron as the first-line agent in all patients requiring CINV prevention after HEC or MEC would cause a substantial economic burden on the U.S. health
Y u -C h e n Y e h , M.S., B.S.P h a r m ., is Senior Pharmacist, Center for Drug Policy, Partners Healthcare, Needham, MA. Gayle C. Blouin, Pharm.D., BCOP, is Senior Attending Pharmacist and Clinical Lead—Ambulatory Oncology, Yawkey Center for Outpatient Care, Massachusetts General Hospital, Boston. Prabashni Reddy, Pharm.D., M.Med.Sc., is Director, Center for Drug Policy, Partners Healthcare. Address correspondence to Ms. Yeh (yyeh@ partners.org).
Portions of the data in this article were presented in poster format at the International Society of Pharmacoeconomics and Outcomes Research Annual Meeting, Toronto, Ontario, Canada, May 3–7, 2008. The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/0302-0500$06.00. DOI 10.2146/ajhp130394
500
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
care system.5 The objectives of this article are (1) to compare the recommendations in the pertinent practice guidelines, (2) to summarize the evidence of palonosetron in comparison with other 5-HT3 antagonists for CINV associated with HEC or MEC, and (3) to critique the evidence that supports the preferred status of palonosetron. A search for relevant systematic reviews, meta-analyses, practice guidelines, and randomized controlled trials (RCTs) published up to March 2013 was conducted in MEDLINE and the Cochrane Database. Practice guidelines were reviewed with a focus on the recommendations with regard to 5-HT3 antagonists for the management of CINV associated with HEC and MEC. Systematic reviews, meta-analyses, RCTs, and economic evaluations comparing palonosetron with other 5-HT3 antagonists for CINV related to HEC or MEC were identified. Comparison of 5-HT 3 antagonists. Palonosetron is indicated for the prevention of acute and delayed CINV associated with MEC and for acute CINV after HEC.1 Dolasetron, granisetron, and ondansetron also carry an indication for the prevention of CINV.6-11 All four agents are approved for the prevention of postoperative nausea and vomiting.1,6-8,11,12 In addition, ondansetron and granisetron are approved for the prevention of nausea and vomiting associated with radiotherapy (Table 1).7,9 The main advantage of palonosetron over dolasetron, granisetron, and ondansetron is its long half-life (40 hours versus 4–9 hours for the other agents), which allows one-time
a
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
b
$190 (0.25 mg) Cost per dose5
$67 (100 mg)
0.25 mg i.v. Recommended dose for CINV
CINV = chemotherapy-induced nausea and vomiting, PONV = postoperative nausea and vomiting, NV = nausea and vomiting. None reported to date.
I.V. form: $5 (32 mg) Oral form: $1 (24 mg)
I.V. form: 0.15 mg/kg × 3 doses Oral form: 8 mg × 2–3 doses
. . .b Drug interactions
I.V. form: 10 mg/kg Oral form: 2 mg Transdermal system: 1 patch (delivers 3.1 mg/24 hr) for up to 7 days I.V. form: $4 (0.7 mg) Oral form: $3 (2 mg)
Hypersensitivity
Other drugs that cause Q-T interval prolongation
~4–6 hr Q-T interval prolongation and torsades de pointes Hypersensitivity; concomitant use of apomorphine Other drugs that cause Q-T interval prolongation; tramadol
~7–8 hr Q-T interval prolongation and torsades de pointes Hypersensitivity; use in CINV (i.v. form) Other drugs that cause Q-T interval prolongation; atenolol, cimetidine, rifampin 100 mg orally ~40 hr No significant effects
Elimination half-life Reported cardiac effects Contraindications
Prevention of CINV (oral and i.v. forms); prevention of PONV (oral and i.v. forms); prevention of NV associated with radiotherapy (oral form) Prevention of CINV (oral form); prevention and treatment of PONV (oral and i.v. forms) Prevention of CINV; prevention of PONV for up to 24 hr after surgery
Prevention of CINV (oral, i.v., transdermal forms); prevention of NV associated with radiotherapy (oral form); prevention and treatment of PONV in adults (i.v. form) ~9 hr Q-T interval prolongation and torsades de pointes Hypersensitivity
Palonosetron
Indications
Ondansetron6,7 Granisetron8-10 Dolasetron11,12 Palonosetron1 Variable
Comparative Data on Serotonin Type 3–Receptor Antagonistsa
dosing even when prolonged inhibition of 5-HT3 receptors over multiple days is desired (e.g., in the setting of multiday chemotherapy or to prevent delayed CINV).1 Other benefits include (1) the lack of a warning on Q-T interval prolongation and torsades de pointes in patients with preexisting cardiac conduction disorders, (2) no known clinically significant drug–drug interactions, and (3) the lack of a contraindication to concomitant use of apomorphine. Palonosetron is available only in the injectable form; an oral formulation was approved by FDA but is not available on the U.S. market.13 Dolasetron is approved for CINV in an oral form only (an i.v. form is contraindicated in CINV due to dose-dependent Q-T interval prolongation). 11,12 Ondansetron and granisetron are approved for CINV in both injectable and oral forms.6-9 Granisetron can also be delivered through a transdermal patch that can be worn for up to seven days.10 Based on the 2013 Medicare payment rate, the cost of palonosetron is substantially higher than that of other i.v. and oral 5-HT3 antagonists (except for dolasetron).5 Practice guidelines. ASCO, 2 NCCN,3 and MASCC4 recently updated their guidelines for the management of CINV. For single-day chemotherapy, palonosetron is designated as the preferred 5-HT3 antagonist for CINV caused by either HEC or MEC in the NCCN guideline,3 while the other two guidelines list palonosetron as the preferred agent only for the management of CINV associated with MEC.2,4 For patients receiving multiday chemotherapy, none of the guidelines designates a preferred 5-HT3 antagonist.2-4 Single-day HEC. For the management of CINV associated with singleday HEC, a three-drug regimen, including a neurokinin-1 (NK1) antagonist (aprepitant on days 1–3 or fosaprepitant on day 1 only), a 5-HT3 antagonist (on day 1), and
Table 1.
COMMENTARIES
501
COMMENTARIES
Palonosetron
dexamethasone (on days 1–3 or 1–4), is recommended in all guidelines.2-4 A new regimen, containing olanzapine, palonosetron, and dexamethasone, was recently added to one of the guidelines based on lower-level evidence.3 Preferential use of palonosetron is noted in the NCCN guideline3 but not in the ASCO and MASCC guidelines. In fact, the MASCC panel members indicated that there was insufficient evidence to support the preferred status of palonosetron.4 Single-day MEC. For patients receiving single-day MEC, a 5-HT3 antagonist plus dexamethasone is recommended on day 1, with palonosetron being the preferred 5-HT3 antagonist in all three guidelines.2-4 The practice recommendations vary, however, in terms of whether an NK1-receptor antagonist should be added and which regimens should be used on days 2 and 3. One of the options that NCCN recommends is to continue the 5-HT3 antagonist on days 2 and 3 when palonosetron is not used on day 1.3 Alternatively, the NCCN guideline includes an option to use olanzapine in combination with palonosetron and dexamethasone.3 Multiday regimens. For CINV prevention during multiday chemotherapy regimens, ASCO proposes the use of the same antiemetic on each day of chemotherapy (with antiemetic agent selection based on the regimen’s emetogenic risk class) and for two days after chemotherapy if appropriate.2 NCCN notes that multiday aprepitant therapy may be used for HEC, while dexamethasone should be given daily to patients receiving HEC or MEC and for two to three days after chemotherapy if the regimen is expected to cause significant delayed CINV.3 In addition, a 5-HT3 antagonist should be given before each dose of HEC or MEC; palonosetron may be given on day 1 at the start of a three-day regimen (the need for repeat dosing is not yet known).3 For patients receiving 502
multiday cisplatin therapy, MASCC recommends a 5-HT3 antagonist plus dexamethasone for acute CINV and dexamethasone for delayed CINV.4 An NK1 receptor antagonist may be considered.4 None of the guidelines designates a preferred 5-HT3 antagonist in this specific setting.2-4 Meta-analyses. Three metaanalyses that compared palonosetron with other 5-HT3 antagonists were identified.14-16 Despite differences in the inclusion and exclusion criteria of the evaluated studies, the three analyses consistently showed that palonosetron significantly increased the rate of complete response (CR)—defined as no emetic episodes and no rescue medication use in the acute (0–24 hours), delayed (24–120 hours), and overall (0–120 hours) p h a s e s a f te r ch e m o t h e r a py — compared with other 5-HT3 antagonists. A significant difference in favor of palonosetron was demonstrated in two subgroup analyses of patients treated with HEC and MEC, respectively.15,16 However, when used in combination with dexamethasone in the setting of HEC, palonosetron significantly reduced the risk of CINV in the delayed and overall phases but not in the acute phase.15 No difference in the risk of constipation was found between palonosetron and other 5-HT3 antagonists in any of the studies.14-16 Results of RCTs. Single-day HEC. The four RCTs in patients receiving single-day HEC compared a single dose of i.v. palonosetron with a single dose of i.v. ondansetron17,18 or granisetron.19,20 One study was conducted in North America and Europe 17; the other three studies enrolled patients in China18,20 and Japan.19 Dexamethasone was part of the study regimens in two of the four studies17,19; these two studies were cited in the NCCN guideline to support the preferred status of palonosetron.3 In the study by Aapro et al.,17 patients receiving HEC were randomly assigned to receive palonosetron 0.25
Am J Health-Syst Pharm—Vol 71 Mar 15, 2014
mg i.v. (n = 223), palonosetron 0.75 mg i.v. (n = 223), or ondansetron 32 mg i.v. (n = 221). About 67% of the patients received dexamethasone on day 1 of antiemetic therapy. CR rates in the acute phase were comparable in patients treated with palonosetron and those receiving ondansetron (59% with palonosetron 0.25 mg, 66% with palonosetron 0.75 mg, 57% with ondansetron); those two palonosetron doses were associated with numerically higher CR rates relative to the CR rate with ondansetron in the delayed phase (45%, 48%, and 39%, respectively) and in the overall phase (41%, 42%, and 33%, respectively), but the differences were not statistically significant. In addition, the time to the first emetic episode was significantly longer for patients treated with palonosetron versus ondansetron; there was no difference between the two evaluated palonosetron doses in this regard, suggesting the lack of a dose–response relationship. The subgroup analysis in patients who received concomitant dexamethasone showed that the CR rate in the acute phase was similar in the palonosetron 0.25mg group (n = 150) and the ondansetron group (n = 147) (65% versus 56%). However, significantly higher CR rates with palonosetron 0.25 mg versus ondansetron were observed in the delayed phase (42% versus 29%, p = 0.021) and the overall phase (41% versus 25%, p = 0.005). Similarly, the study by Saito et al.,19 which compared palonosetron 0.75 mg i.v. (n = 555) with granisetron 40 mg/kg i.v. (n = 559) in patients receiving HEC found that palonosetron was comparable to granisetron in preventing acute emesis (CR rate, 75% versus 73%) but significantly more effective in preventing delayed emesis (57% versus 45%, p < 0.001). The superiority of palonosetron in the delayed phase was evident in all subgroups by age (≥55 years versus
