First-generation 5-HT3 Receptor Antagonists Research Articles

Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials.

PurposeDelayed chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of moderately emetogenic chemotherapy not containing anthracyclines and cyclophosphamide (non-AC MEC). In this review, we summarize current literature to update recommendations for delayed CINV prophylaxis after non-AC MEC.MethodsWe conducted a systematic search in PubMed and conference proceedings from ASCO, ESMO, and MASCC. Included randomized controlled trials (RCTs) aimed to prospectively evaluate the efficacy of two or more antiemetic strategies in the prevention of delayed CINV after the administration of non-AC MEC. At least one of the following endpoints was used: complete response, complete control, no nausea, no vomiting, and/or no use of rescue medication.ResultsOur search provided 247 publications. Nine met the predefined criteria. Included RCTs reported outcomes on palonosetron, aprepitant, casopitant, netupitant/palonosetron (NEPA), olanzapine, and megestrol acetate.ConclusionsSuperiority of palonosetron over first-generation 5-HT3 receptor antagonists for the prevention of acute and delayed CINV after non-AC MEC has not been proven. The addition of an NK1 receptor antagonist to first-generation 5-HT3 receptor antagonists does not significantly improve the incidence of delayed CINV after non-AC MEC. The efficacy of a single-day regimen of dexamethasone with palonosetron is non-inferior to multiday dexamethasone. NEPA, olanzapine, and megestrol acetate show highly effective complete response (CR) rates.Electronic supplementary materialThe online version of this article (doi:10.1007/s00520-015-2778-6) contains supplementary material, which is available to authorized users.

Palonosetron versus first-generation 5-hydroxytryptamine type 3 receptor antagonists for emesis prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation

First-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (RAs) are currently the standard of care for prophylaxis against allo-HSCT-induced emesis. However, the efficacy of this combination in allo-HSCT recipients is not entirely satisfying. We sought to compare the efficacy of first-generation 5-HT3 RAs with that of second-generation 5-HT3 RAs in emesis prevention in allo-HSCT recipients. A total of 51 consecutive patients undergoing allo-HSCT for various hematological diseases in our institution were retrospectively reviewed. Patients who received daily first-generation 5-HT3 RAs, and 60-h palonosetron for emesis prophylaxis were stratified into the standard (n = 23) and palonosetron (n = 28) groups, respectively. Emesis severity and rescue therapy requirements in patients between these two groups were compared. Our results showed patients in standard and palonosetron groups had comparable severity of both acute and delayed emesis. However, 52.2% of the patients in the standard group required rescue therapy, compared to only 21.4% of the patients in the palonosetron group (p = 0.046). Subgroup analysis showed rescue therapy for acute emesis was required by 26.1% of the patients in the standard group and by only 3.6% of the patients in the palonosetron group (p = 0.037). In conclusion, palonosetron and first-generation 5-HT3 RAs were at least equally effective in emesis prophylaxis for allo-HSCT recipients. Patients receiving palonosetron, especially for acute emesis, required rescue therapy less frequently than those receiving first-generation 5-HT3 RAs.

Palonostron with aprepitant plus dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) during gemcitabine/cisplatin (GC) in urothelial cancer (UC) patients: A multi-institutional retrospective study in Japan.

362 Background: GC combination chemotherapy of is a standard regimen for advanced UC. Although this is a highly emetogenic chemotherapy, there has been no study concerning antiemetic prophylaxis for CINV during GC. The aims of this study were to evaluate CINV during GC and to compare the antiemetic efficacy of the triple combination of palonosetron, aprepitant and dexamethasone with that of our old regimen using first-generation 5-HT3 receptor antagonists and dexamethasone. Methods: We conducted a retrospective multi-institutional review of the medical records of 122 patients who received GC for advanced urothelial cancer between February 2005 and January 2012. Uncontrolled CINV events were identified through records of nausea and vomiting, additional infusion, rescue medications, and/or records of food intake. Nausea, vomiting, and anorexia were classified using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Results: A total of 75 and 47 patients were treated with first-generation 5-HT3 receptor antagonists (ondansetron or granisetron) plus dexamethasone (group 1) and palonosetron with dexamethasone plus aprepitant (group 2), respectively. There was no significant difference in age, sex, or the dose of cisplatin between the 2 groups. Patients in group 2 had significantly higher CR (defined as no emetic episodes and no rescue medication use) rates than those in group 1 during the overall phase in the first cycle (85.7% versus 65.3%, p=0.012) and all cycles (78.7% versus 50.7%, p=0.0019) of GC. Patients in group 2 were more likely to achieve more favorable CINV control, e.g., a lower grade of nausea, vomiting, or anorexia, lower incidence of rescue therapy required, and shorter time to become CINV-free, than patients in group 1. Conclusions: This study shows that palonosetron in combination with aprepitant and dexamethasone is more effective to prevent chemotherapy-induced nausea and vomiting in UC patients treated with GC than first-generation 5-HT3 receptor antagonists plus dexamethasone.

Multicenter nonrandomized trial of ramosetron versus palonosetron in controlling chemotherapy-induced nausea and vomiting for colorectal cancer.

PurposeChemotherapy-induced nausea and vomiting (CINV) have a negative impact on patients' quality of life and frequently pointed to as a major factor for treatment abandonment. Serotonin (5-HT3) receptor antagonist is considered as key treatment for CINV. Ramosetron and palonosetron are recently developed 5-HT3 receptor antagonists and known as more superior than other first-generation 5-HT3 receptor antagonists. The purpose of this study was to compare the efficacy of ramosetron and palonosetron and determine which drug is more effective for prevention of CINV.MethodsColorectal cancer patients treated with chemotherapy were enrolled consecutively. Patients were assigned to receive intravenous injection of ramosetron 0.3 mg or palonosetron 0.25 mg at 30 minutes before initiation of moderately emetogenic chemotherapy. Ramosetron group added oral administration of 0.1 mg ramosetron on the second and third days of chemotherapy. Efficacy parameter consisted of nausea and vomiting.ResultsNinety-one patients received ramosetron and 89 patients received palonosetron. Presentation of vomiting and nausea symptoms was not significantly different between the two groups during acute (0-24 hours) and delayed period (after 24 hours).ConclusionThe incidence of CINV between the ramosetron and the palonosetron group has not shown any difference during acute, delayed, and overall period.

Management of Chemotherapy-Induced Nausea and Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a serotonin 5-HT3 receptor antagonist, dexamethasone and a neurokinin 1 (NK1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first and only agent clinically available in the NK1 receptor antagonist drug class has been used effectively as an additive agent to the 5-HT3 receptor antagonists and dexamethasone to control CINV. Rolapitant and netupitant are other NK1 receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a US-FDA approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as a very effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Effectiveness of Palonosetron Versus Other Serotonin 5-HT3 Receptor Antagonists in Triple Antiemetic Regimens During Multiday Highly Emetogenic Chemotherapy

The second-generation serotonin 5-HT(3) receptor antagonist palonosetron has shown improved efficacy in the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, there have been no randomized controlled trials supporting the preferential use of palonosetron in triple antiemetic regimens for patients receiving multiday highly emetogenic chemotherapy (HEC). To compare the effectiveness of palonosetron-based and first-generation 5-HT(3) receptor antagonist-based triple antiemetic regimens in cancer patients receiving multiday HEC. This was a review and analysis of medical record data. A total of 115 patients who had received multiday HEC were included and grouped into a palonosetron-based antiemetic group (n = 73) or a first-generation 5-HT(3) receptor antagonist-based antiemetic group (n = 42). Data on CINV were collected in 24-hour intervals for 120 hours after the start of chemotherapy. Complete response rates did not differ significantly between the 2 groups during any of the 3 phases: acute (0-24 hours), p = 0.877; overlap (24-120 hours), p = 0.997; and overall (0-120 hours), p = 0.723. The proportion of patients with complete control was similar between the groups during each phase: acute, p = 0.862; overlap, p = 0.838; and overall, p = 0.828. There was also no significant difference in other end points between the 2 groups. Among all patients, females experienced significantly more acute nausea (p = 0.040) and vomiting (p = 0.046) than males. Compared with nondrinkers, patients who consumed alcohol had a lower overall incidence of vomiting (p = 0.020). Within a triple antiemetic regimen, a palonosetron-based antiemetic regimen was not significantly different from regimens based on first-generation 5-HT(3) receptor antagonists in preventing CINV during multiday HEC.

Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis

A number of studies have reported the difference between the 5-HT3 receptor antagonists and palonosetron in preventing the chemotherapy-induced nausea and vomiting (CINV). Through analysing the efficacy and safety in palonosetron-treated patients, it can provide evidence for palonosetron administration. We identified randomised controlled clinical trials comparing palonosetron with the first-generation 5-HT3 receptor antagonists in the prevention of CINV in cancer patients. Nine studies investigated the outcomes in a total of 3463 cases. Compared with the first-generation 5-HT3 receptor antagonists, the cumulative incidences of emesis were significantly reduced in the patients treated with palonosetron (0.25 mg i.v.) on the first day [relative risk (RR) = 1.11, 95% confidence interval (CI): 1.05-1.17], from 2 to 5 days (RR = 1.26, 95% CI: 1.16-1.36) and the overall five days (RR = 1.23, 95% CI: 1.13-1.34). Regarding the drug safety, there was no significant difference between palonosetron-treated group and the first-generation 5-HT3 receptor antagonists-treated group. Results from the analysis suggest that palonosetron is highly effective in preventing nausea and vomiting in the days after administration of moderately or highly emetogenic chemotherapy agents.

Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in glioblastoma patients treated with temozolomide: a phase II study

Chemotherapy-induced nausea and vomiting (CINV) is a side effect related to administration of the adjuvant temozolomide (TMZ) in patients affected by glioblastoma. After chemoradiotherapy, adjuvant TMZ is administered as an oral multiple-day regimen, and TMZ-associated CINV may interfere with the continuation of chemotherapy, with potentially negative consequences on clinical efficacy. The aim of the present study was to investigate the efficacy of palonosetron for prevention of CINV-induced by adjuvant TMZ. From March 2007 to August 2008, 33 patients with confirmed glioblastoma and eligible for adjuvant treatment with TMZ were enrolled in the study. All patients with responding or stable disease after concomitant radiotherapy plus daily TMZ (75 mg/m(2)) received a single i.v. bolus 0.25 mg of palonosetron 30 min before the beginning of adjuvant TMZ (150-200 mg/m(2)/day for five consecutive days every 4 weeks). The primary endpoint was the percentage of patients with complete response (CR), defined as no emetic episodes and no rescue medication during the overall phase (0-168 h). Secondary endpoints included CR during the 0-120 h and 0-168 h phases and complete control (CC; CR and no more than mild nausea) during the 0-120 h, 120-168 h, and 0-168 h phases. Thirty-three patients were enrolled in the study (median age 57.6 years, 23 male and 10 female, median Karnofsky Performance Status = 80). Each patient was receiving fixed doses of dexamethasone (range 2-8 mg/day). CR in the 0-120 h, 120-168 h, and 0-168 h phases was seen in 91% of patients. CC was observed in 88%, 91%, and 88% of cases during the 0-120 h, 120-168 h, and 0-168 h phases, respectively. Anti-emetic prophylaxis with palonosetron was well tolerated and the most frequent adverse event was grade 1-2 headache reported by seven patients (21%). A single dose of palonosetron before the initiation of multiple oral doses of TMZ, in patients on treatment with steady doses of dexamethasone, provides a high protection against CINV throughout the overall phase (0-168 h). The pharmacological profile of palonosetron, compared to first-generation 5-HT3 receptor antagonists, may have an impact on its clinical efficacy.

Palonosetron induced anaphylaxis in an adult female

We report a case of anaphylactic shock following intravenous (i.v.) administration of palonosetron. A 40 year old woman with relapsed breast cancer was scheduled for first cycle of chemotherapy with cyclophosphamide, epirubicin, 5-flurouracil and docetaxel. Prior to the start of chemotherapy, i.v. palonosetron 0.25 mg (5 ml) was administered to prevent nausea and vomiting. Within a few seconds the patient experienced difficulty in breathing, generalized itching and dizziness. Bronchial wheeze was present, blood pressure was unrecordable and oxygen saturation by pulse oximetry was 75%. She was immediately moved to the intensive care unit and was resuscitated with oxygen, i.v. crystalloid and i.v. adrenaline (1 : 10 000), hydrocortisone and pheniramine. Within 1 h the patient was haemodynamically stabilized. Laboratory tests revealed no abnormality in liver or renal function. Palonosetron was discontinued and the next day she was premedicated with i.v. metoclopramide, dexamethasone, pheniramine and ranitidine and chemotherapy was initiated. Thereafter, the patient did not develop any other problem and was asymptomatic after 72 h of follow-up. The patient had no history of concomitant medications (including herbal medicines), allergy to food or other drugs (including other 5-HT3-receptor antagonists) or addiction to tobacco or alcohol. Medical history of any chronic systemic disease was also absent. However, she revealed a history of allergic dermatitis to household detergents and caustic soda. Re-challenge with palonosetron was not carried out due to the life threatening nature of the adverse drug reaction (ADR). Causality assessment was carried out using the World Health Organization-Uppsala Monitoring Centre criteria and the adverse reaction had ‘certain’ relationship with palonosetron administration. The strong temporal relationship between administration of palonosetron and onset of symptoms of anaphylaxis and their amelioration with discontinuation of the drug suggested this relationship. The casual association was also evaluated using the Naranjo algorithm and a score of 7 indicated a ‘probable’ relationship [1]. The ADR was reported to the national pharmacovigilance centre under the National Pharmacovigliance Programme, India. Palonosetron is a relatively new 5-HT3 receptor antagonist that was approved in 2003 by the US FDA for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderate to highly emetogenic cancer chemotherapy. It has at least 30-fold higher affinity for the 5-HT3 receptor compared with the first-generation 5-HT3 receptor antagonists like ondansetron, granisetron and dolasetron. In addition, palonosetron also has higher potency and is three-fold more potent than granisetron and up to 55-times more potent than ondansetron [2]. It is generally well tolerated, and in clinical trials, headache (9%) and constipation (5%) were the most commonly reported adverse drug reactions. Less frequently reported adverse reactions include diarrhoea, dizziness, fatigue, abdominal pain and insomnia. The severity and frequency of the adverse reactions are similar to those observed with ondansetron and dolasetron [3]. A recent case report described the occurrence of generalized tonic clonic seizures after i.v. palonosetron in a patient with breast carcinoma scheduled for chemotherapy [4]. To the best of our knowledge, this is probably the first case of i.v. palonosetron-induced anaphylaxis to be reported. However, anaphylactoid reaction has been reported with the use of i.v. ondansetron. The very rare (less than 1/10 000) incidence of hypersensitivity encountered during post marketing surveillance of palonosetron has been mentioned in its package insert and the use of palonosetron has been contraindicated in patients who are hypersensitive to it or other 5-HT3 receptor antagonists [5]. Although this patient did not have a history of drug allergy, it is possible that she may have been pre-sensitized to 5-HT3 receptor antagonists during her earlier hospital visits for surgery of the tumour. The widespread and easy availability of 5HT3-receptor antagonists in the Indian market has promoted the off label use of these drugs, such as in the treatment of antimalarial-induced vomiting, gastritis, migraine and other emetogenic conditions [6]. In view of the life threatening yet avoidable nature of the anaphylactic reaction developing after i.v. palonosetron, those prescribing it or other 5-HT3 receptor antagonists should exercise extreme caution, especially in patients with history of any sort of hypersensitivity. Whenever possible, alternatives like metoclopramide or domperidone should be prescribed for such patients.

Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. This review provides a detailed description of palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonist. The chemistry and pharmacology of palonosetron are described, as well as the initial and recent clinical trials. Palonosetron has a longer half-life and a higher binding affinity than the first-generation 5-HT(3) receptor antagonists. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. In recent studies, compared to the first-generation 5-HT(3) receptor antagonists, palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the palonosetron clinical trials which were different from the common reactions reported for the 5-HT(3) receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.

Palonosetron

Palonosetron is a second-generation serotonin 5-HT3 receptor antagonist, with a distinct pharmacological profile that differs from first-generation 5-HT3 receptor antagonists. Intravenous palonosetron is widely indicated for the prevention of chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases following moderately emetogenic chemotherapy (MEC) and the prevention of CINV in the acute phase following highly emetogenic chemotherapy (HEC). In the US, oral palonosetron is approved for the prevention of CINV in the acute phase following MEC (although this formulation is not currently available), and intravenous palonosetron is indicated for the prevention of postoperative nausea and vomiting (PONV) in the first 24 hours following surgery. All indications are currently limited to adult patients. Intravenous palonosetron was noninferior to intravenous ondansetron (with statistically greater efficacy than ondansetron) or dolasetron in preventing CINV following MEC, or to intravenous ondansetron or granisetron in preventing CINV following HEC, in the acute phase. Statistically greater efficacy was seen with intravenous palonosetron than ondansetron or dolasetron in preventing CINV following MEC in the delayed phase. Oral palonosetron was noninferior to intravenous palonosetron in preventing CINV in the acute phase in patients receiving MEC. Intravenous palonosetron was superior to placebo in preventing PONV in the first 24 hours following surgery. Palonosetron was generally well tolerated in clinical trials. Intravenous palonosetron is a valuable option in the prevention of acute- and delayed-phase CINV in adult patients receiving MEC, and of acute-phase CINV in patients receiving HEC. Oral palonosetron is likely to be a useful addition to oral formulations of other 5-HT3 receptor antagonists in preventing CINV in patients receiving MEC. Intravenous palonosetron is a useful alternative to currently recommended agents in PONV prevention.

Antiemetic control: toward a new standard of care for emetogenic chemotherapy

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone have significantly improved the control of acute CINV, but delayed CINV remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have been approved for the prevention of both acute and delayed CINV. Palonosetron is a second-generation 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 (NK-1) receptor antagonists. Casopitant is another NK-1 receptor antagonist that is under review by the FDA after recent completion of Phase III clinical trials. The introduction of these new agents has generated revised antiemetic guidelines for the prevention of CINV. Future studies may consider the use of palonosetron, aprepitant and casopitant with other antiemetic agents (olanzapine, gabapentin, cannabinoids) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Palonosetron: A Second-Generation 5-Hydroxytryptamine Receptor Antagonist

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine (5-HT)3 receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a clinical problem. A new agent, palonosetron, has recently been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. In a single dosing study, palonosetron was highly effective in controlling CINV compared with a single dose of dolasetron or ondansetron in patients receiving moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone demonstrated control of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron appeared to be as effective in subsequent courses of chemotherapy compared with the initial course of chemotherapy. There were no clinically relevant differences seen among palonosetron, ondansetron or dolasetron in laboratory, electrocardiographic or vital-sign changes, and adverse reactions reported in the clinical trials were the most common reactions reported for the 5-HT3 receptor antagonist class. Recent studies using palonosetron-based anti-emetic combinations in moderately and highly emetogenic chemotherapy, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Future studies may consider the use of palonosetron with current and other new agents and in other clinical settings, such as bone marrow transplantation and radiation therapy.

Emerging drugs for chemotherapy-induced emesis

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, no alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have recently been approved for the prevention of both acute and delayed CINV. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 receptor (NK-1) antagonists. There are a number of 5-HT3 receptor antagonists and NK-1 receptor antagonists currently in Phase II and III clinical trials. Revised antiemetic guidelines for the prevention of CINV are reviewed. Future studies may consider the use of palonosetron and aprepitant with current and other new agents (olanzapine, gabapentin) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Prevention of delayed nausea and vomiting (D-CINV): Carryover effect analysis of pooled data from 2 phase III studies of palonosetron (PALO)

8051 Background: Control of acute chemotherapy-induced nausea and vomiting (A-CINV) is a positive predictor of control of D-CINV. First-generation 5-HT3 receptor antagonists (RA) are highly effective in preventing A-CINV but less so in preventing D-CINV. PALO is a pharmacologically distinct 5-HT3 RA with a 30+ fold higher binding affinity, a 40 hr plasma half-life, and has greater efficacy than ondansetron (OND) and dolasetron (DOL) in preventing both A-CINV and D-CINV in patients receiving moderately emetogenic chemotherapy (Aapro, ASCO '03, Rubenstein ASCO '03). Methods: Establishing whether this efficacy benefit in control of D-CINV is strictly a carryover effect from better control of A-CINV was analyzed using pooled data from 2 identically designed phase III trials where 754 patients received either a single IV dose of 0.25 mg PALO or 32 mg OND (study 1) or 100 mg DOL (study 2). Two methods for evaluating the carryover effect were conducted: evaluating control of D-CINV in all patients with or withou...

Prevention of delayed nausea and vomiting (D-CINV): Carryover effect analysis of pooled data from 2 phase III studies of palonosetron (PALO)

8051 Background: Control of acute chemotherapy-induced nausea and vomiting (A-CINV) is a positive predictor of control of D-CINV. First-generation 5-HT3 receptor antagonists (RA) are highly effective in preventing A-CINV but less so in preventing D-CINV. PALO is a pharmacologically distinct 5-HT3 RA with a 30+ fold higher binding affinity, a 40 hr plasma half-life, and has greater efficacy than ondansetron (OND) and dolasetron (DOL) in preventing both A-CINV and D-CINV in patients receiving moderately emetogenic chemotherapy (Aapro, ASCO '03, Rubenstein ASCO '03). Methods: Establishing whether this efficacy benefit in control of D-CINV is strictly a carryover effect from better control of A-CINV was analyzed using pooled data from 2 identically designed phase III trials where 754 patients received either a single IV dose of 0.25 mg PALO or 32 mg OND (study 1) or 100 mg DOL (study 2). Two methods for evaluating the carryover effect were conducted: evaluating control of D-CINV in all patients with or without A-CINV (Grunberg, ASCO '03) and hierarchical models evaluating treatment effects adjusting for risk factors over time. Results: Of the 500 pts across all groups with no A-CINV, 376 (75%) had no D-CINV. Of these pts controlled for A-CINV, more pts (218/272; 80%) receiving PALO had no D-CINV compared with those receiving OND or DOL (158/228; 69%) [P = 0.005]. A similar benefit was also seen among the 254 pts who did have A-CINV. 24/106 (23%) receiving PALO had no D-CINV while 18/148 (12%) receiving OND or DOL had no D-CINV [P = 0.027]. Conclusions: The same magnitude of improved prevention of D-CINV with PALO in patients with or without A-CINV provides evidence that this greater efficacy in preventing D-CINV is a true pharmacologic effect rather than carryover from better prevention of A-CINV. Complete results utilizing a hierarchical (random-effects) model accounting for risk factors and trial heterogeneity will also be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MGI Pharma Helsinn; MGI Pharma MGI Pharma Merck; MGI Pharma MGI Pharma Helsinn

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

BackgroundAlthough all first-generation 5-HT3 receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT3 receptor antagonist, with ondansetron. Patients and methodsIn this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg or ondansetron 32 mg, each administered 30 min before initiation of moderately emetogenic chemotherapy. The primary end point was the proportion of patients with no emetic episodes and no rescue medication [complete response (CR)] during the 24 h after chemotherapy administration (acute period). Secondary end points included efficacy in treatment of delayed CINV (≤5 days post-chemotherapy) and overall tolerability. Results563 patients were evaluable for efficacy. CR rates were significantly higher (P <0.01) for palonosetron 0.25 mg than ondansetron during the acute (0–24 h) (81.0% versus 68.6%, respectively), delayed (24–120 h) (74.1% versus 55.1%) and overall (0–120 h) (69.3% versus 50.3%) periods. CR rates achieved with palonosetron 0.75 mg were numerically higher but not statistically different from ondansetron during all three time intervals. Both treatments were well tolerated. ConclusionsA single i.v. dose of palonosetron 0.25 mg was significantly superior to i.v. ondansetron 32 mg in the prevention of acute and delayed CINV.