Efficacy of the granisetron transdermal system for the control of nausea and vomiting induced by highly emetogenic chemotherapy: a multicenter, randomized, controlled trial.

BACKGROUND/AIMS: We compared the efficacy of the granisetron transdermal system (GTS) with that of ondansetron for controlling chemotherapy-induced nausea and vomiting (CINV) in patients treated with highly emetogenic chemotherapy (HEC). METHODS: We randomized a total of 389 patients to groups treated by GTS and ondansetron before HEC. The primary endpoint was the percentage of patients achieving complete response (CR; no retching/vomiting/rescue medication) of CINV from the time of chemotherapy initiation to 24 hours after the last administration of chemotherapy (prespecified non-inferiority margin of 15%). Quality of life (QoL) was also assessed using the Functional Living Index-Emesis (FLIE). RESULTS: The per protocol analysis included 152 (47.80%) and 166 patients (52.20%) in the GTS and ondansetron groups, respectively. In the full analysis set, the most common diagnosis, regimen, and period of chemotherapy were lung cancer (149 patients, 40.27%), cisplatin-based regimen (297 patients, 80.27%), and 1 day chemotherapy (221 patients, 59.73%). The CR rates were 86.84% and 90.36% in the GTS and ondansetron groups, respectively; the treatment difference was -3.52% (95% confidence interval, -10.52 to 3.48) and met the primary endpoint, indicating that GTS was not inferior to ondansetron. Patient satisfaction, assessed on the FLIE, showed significantly higher scores in the GTS group compared to the ondansetron group (mean ± standard deviation, 1,547.38 ± 306.00 and 1,494.07 ± 312.05 mm, respectively; p = 0.0449). CONCLUSION: GTS provided effective, safe, and well-tolerated control of CINV and improved the QoL in HEC.

Economic Value of Fosaprepitant-Containing Regimen in the Prevention of Chemotherapy-Induced Nausea and Vomiting in China: Cost-Effectiveness and Budget Impact Analysis.

Objective: The purpose of this study was to evaluate the cost-effectiveness and budget impact of fosaprepitant (FosAPR)-containing regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) among patients receiving high emetogenic chemotherapy (HEC) from the Chinese payer's perspective. Methods: A decision tree model was established to measure the 5-day costs and health outcomes between the APR-containing regimen (aprepitant, granisetron, and dexamethasone) and FosAPR-containing regimen (fosaprepitant, granisetron, and dexamethasone). Clinical data were derived from a randomized, double-blind controlled trial on Chinese inpatients who received HEC. Quality-adjusted life-years (QALYs) were used to estimate the utility outcomes and the incremental cost-effectiveness ratio (ICER) was calculated to assess the economics of FosAPR. A static budget impact model was developed to assess the impact of FosAPR as a new addition to the National Reimbursement Drug List (NRDL) on the medical insurance fund within 3 years in Nanjing, China. Results: Compared with APR, FosAPR had a mean health-care savings of ¥121.56 but got a reduction of 0.0001815 QALY, resulting in an ICER of ¥669926.19 per QALY. Deterministic sensitivity analysis revealed that the cost of APR was the most influential factor to the ICER. The cost of FosAPR and the complete control rate of the delayed period also had a high impact on the results. According to the probabilistic analysis, the acceptability of FosAPR was more than 80% when the Chinese willingness-to-pay (WTP) was ¥215,999. FosAPR would lead to a 3-year medical insurance payment increase of ¥1.84 million compared with ¥1.49 million before FosAPR entered NRDL in Nanjing. The total budget increased with a cumulative cost of ¥694,829 and covered an additional 341 patients who benefited from FosAPR in Nanjing. Deterministic sensitivity analysis showed that the model of budget impact analysis was stable. Conclusion: FosAPR had a similar treatment effect to APR but was cost-effective in China at the current WTP threshold. The total budget of medical insurance payments of Nanjing slightly increased year by year after the inclusion of FosAPR. Its inclusion in the NRDL would be acceptable and also expand the coverage of patients who benefited from FosAPR.

Postoperative Serotonin Syndrome Following Administration of Preoperative Intrapulmonary Methylene Blue and Intraoperative Granisetron: A Case Report.

BACKGROUND Methylene blue (MB), which is often used perioperatively, is a potent monoamine oxidase inhibitor that can strongly block the clearance of extracellular serotonin. Granisetron, a serotonin receptor subtype 3 (5-HT3) antagonist, is an antiemetic used to prevent or treat postoperative nausea and vomiting (PONV). Through its antagonism, granisetron can increase the extracellular serotonin concentration. Serotonin syndrome is a potentially life-threatening condition resulting from a drug reaction that affects serotonin levels. This report is of a 50-year-old woman with postoperative serotonin syndrome following co-administration of preoperative intrapulmonary methylene blue and intraoperative granisetron. CASE REPORT A 50-year-old woman with well-controlled gastroesophageal regurgitation disease presented under impression of lung cancer. She received a computed tomography (CT)-guided localization followed by video-assisted thoracic surgery under endotracheal general anesthesia. The surgery was completed uneventfully. Her postoperative course was significant for serotonin syndrome, likely triggered by co-administration of preoperative intrapulmonary MB for tumor localization and intraoperative granisetron. Other differential diagnoses were ruled out. Her management was primarily supportive, using benzodiazepine administration, and resulted in full neurologic recovery. CONCLUSIONS Intrapulmonary MB can lead to serotonin syndrome in combination with 5HT-3 antagonists when used for preoperative tumor localization. Because both MB and 5-HT3 antagonists are being widely used clinically at present, this report has highlighted that physicians, surgeons, and anesthesiologists should be aware of serotonin syndrome, its presenting features, and management, and its association with the use of methylene blue and 5-HT3 receptor antagonists, including granisetron.

Granisetron or ondansentron to prevent hypotension after spinal anesthesia for elective cesarean delivery: A randomized placebo-controlled trial.

STUDY OBJECTIVE: This study aimed to compare the effects of high doses of ondansetron and granisetron before spinal anesthesia on hemodynamic parameters in patients undergoing elective cesarean section. DESIGN: A double-blinded randomized placebo-controlled trial. SETTING: Operating room. PATIENTS: A total of 120 parturients with term pregnancy undergoing elective cesarean section with combined spinal-epidural anesthesia were included. INTERVENTIONS: Three groups (n = 40 for each group) were formed by randomization. Five minutes before the anesthesia procedure, Group I received 8 mg intravenous (IV) ondansetron diluted in 10 ml normal saline, Group II received IV 3 mg granisetron diluted in 10 ml normal saline, and Group III received IV 10 ml normal saline. MEASUREMENTS: Following intrathecal drug administration, intraoperative hemodynamic changes were recorded every 2 min for 20 min and then every 5 min until the end of the operation. MAIN RESULTS: Twenty patients (50%) in Group I, 12 patients (30%) in Group II, and 29 patients (72.5%) in Group III had hypotension requiring treatment with IV ephedrine (P = 0.001). The ephedrine requirement in Group III was significantly higher than in Groups I (P = 0.033) and II (P < 0.001). Also, the ephedrine requirement in Group II was lower than in Group I, but the difference was not statistically significant (P = 0.055). The mean arterial pressure for the three groups differed in the 10th, 18th, and 60th minutes. The number of patients with nausea or vomiting was lower in Groups I and II than in Group III (P < 0.001). At 5 min, the Apgar scores were higher than 8 for all neonates. Postoperative scores for the visual analogue scale were similar for all groups. CONCLUSIONS: It was concluded that prophylactic IV administration of 3 mg of granisetron or 8 mg of ondansetron before spinal anesthesia results in a significantly lower ephedrine requirement compared to placebo.

Effectiveness of palonosetron versus granisetron in preventing chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) commonly occurs after chemotherapy, adversely affecting patients' quality of life. Recently, studies have shown inconsistent antiemetic effects of two common 5-hydroxytryptamine 3 receptor antagonists, namely, palonosetron and granisetron. Therefore, we conducted a meta-analysis to evaluate the effectiveness of palonosetron versus granisetron in preventing CINV. METHODS: Relevant studies were obtained from PubMed, Embase, and Cochrane databases. The primary outcome was the complete response (CR) rate. Secondary outcomes were headache and constipation events. RESULTS: In total, 12 randomized controlled trials and five retrospective studies were reviewed. Palonosetron was consistently statistically superior to granisetron in all phases in terms of the CR rate (acute phases: odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.06-1.54; delayed phases: OR = 1.38, 95% CI = 1.13-1.69; and overall phases: OR = 1.37, 95% CI = 1.17-1.60). Moreover, a non-significant difference was found between the two groups in terms of the headache event, but the occurrence of the constipation event was lower in the granisetron group than in the palonosetron group. CONCLUSION: Palonosetron showed a higher protective efficacy in all phases of CINV prevention, especially in delayed phases, and no relatively severe adverse effects were observed.

Effects of 5-HT3 receptor antagonists on cisplatin-induced kidney injury.

Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

Potential drug-drug Interactions in hospitalized cancer patients: A report from the Middle-East.

INTRODUCTION: Patients suffering from solid tumors use a wide range of cytotoxic drugs. In this study, we aimed to detect, document, and descriptively analyze the potential drug-drug interactions in hospitalized solid tumor's patients in a Middle Eastern referral oncology-hematology University-affiliated hospital. MATERIALS AND METHODS: In this cross-sectional study, the medical record of solid tumor's patients who were admitted to the referral oncological center in Isfahan, Iran, during the six months period (2018) were considered. We included all patients who had received at least two chemotherapy or nonchemotherapy drugs simultaneously. The potential drug-drug interactions between chemotherapy and nonchemotherapy drugs were evaluated with Lexi-Interact ver.1.1 online software. RESULTS: During the study period, a total of 141 cancer patients were recruited, and their drug therapy regiment was thoroughly analyzed. We detected 227 drug-drug interactions with moderate or major severity out of included patients in which 96, 71, 32, and 28 interactions were in the category of C, D, B, and X, respectively. One hundred and fourteen patients (80.8%) encountered at least one potential drug-drug interactions during their hospitalization. Mechanistically, most of drug-drug interactions (56.4%) were pharmacodynamics. Interaction between granisetron and metoclopramide were the top 10 detected interaction (11.4%). The interaction between docetaxel and carboplatin was the most frequent drug-drug interactions between oncology drugs (2.6% of total drug-drug interactions). CONCLUSION: Potentially moderate or major drug-drug interactions frequently occur among solid tumor's cancer patients necessitate the establishment of a clinical pharmacy service for providing relevant pharmacotherapy consultations to prevent this potentially serious concern.

The safety of early pregnancy exposure to granisetron.

OBJECTIVE: Current guidelines suggest that granisetron is an optional treatment for nausea and vomiting in pregnancy (NVP) despite lack of evidence to support fetal safety. We aimed to determine the association between early pregnancy exposure to granisetron and fetal/neonatal outcomes. DESIGN: Medical records of patients treated for NVP during the first and second trimester between June 2013 to September 2015 were reviewed. Patients were asked to participate in the study by answering a detailed questionnaire regarding newborn's health and complementary data. Pregnancy outcomes of patients exposed to granisetron were compared with those of patients who were not exposed to granisetron. RESULTS: 100 Granisetron exposed pregnancies were compared with 108 granisetron unexposed pregnancies. Exposure to granisetron occurred in the first trimester in 88 patients (94 fetuses). Maternal characteristics, history of anomalies in first degree relatives, co-exposure to other substances and extent of prenatal sonographic surveillance were comparable between both groups. Miscarriage rate was significantly lower among granisetron exposed patients compared to controls (0 vs 5.5 %, respectively, p = 0.03). Three major malformations were identified prenatally or postnatally in each of the groups (2.77 % Vs 2.83 %, p = 1). The rate of major malformations was similar between exposed and unexposed fetuses even after excluding second trimester exposure (3.2 % vs. 2.83 %, respectively p = 1). Mean gestational age at delivery, mean newborn weight and incidence of small for gestation age, were not significantly different between the groups. CONCLUSION: Granisetron exposure was not associated with increased risk for minor or major fetal anomalies. This study provides preliminary reassurance regarding the safety of in-utero exposure to granisetron.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy.

PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Comparison between Antiemetic Effects of Palonosetron and Granisetron on Chemotherapy-Induced Nausea and Vomiting in Japanese Patients Treated with R-CHOP.

In the present study, the antiemetic effect of palonosetron, not combined with dexamethasone and aprepitant, on chemotherapy-induced nausea and vomiting was evaluated in patients with malignant lymphoma receiving first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy, and was compared to that of granisetron. A total of 74 patients with non-Hodgkin lymphoma were included in this study (April 2007 to December 2015). Palonosetron (0.75 mg) or granisetron (3 mg) was intravenously administered before R-CHOP therapy. The proportions of patients with complete response (CR) during the overall (0-120 h after the start of R-CHOP therapy), acute (0-24 h) and delayed (24-120 h) phases were evaluated. CR was defined as no vomiting and no use of antiemetic rescue medication. A total of 32 and 42 patients were treated with palonosetron and granisetron, respectively. The CR rate in the palonosetron group was significantly higher than that in the granisetron group during the delayed phase (90.6 and 61.9%, respectively; p=0.007). Logistic regression analysis showed that use of palonosetron improved the CR rate during the delayed phase, compared to use of granisetron. Female sex, age less than 60 years, no habitual alcohol intake, and Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 1 were significant risk factors associated with non-CR. The findings of this study suggested the superiority of palonosetron to granisetron, without accompanying dexamethasone and aprepitant, for chemotherapy-induced nausea and vomiting in patients with malignant lymphoma.

Clinical Impact of Aprepitant in Patients Receiving High-Dose Chemotherapy prior to Autologous Peripheral Blood Stem Cell Transplantation: A Cost-Effectiveness Analysis.

OBJECTIVE: To evaluate the clinical and cost benefits of the administration of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) during high-dose chemotherapy (HDCT). METHODS: We retrospectively reviewed the charts of patients who received HDCT at our institution between January 2009 and December 2013. Cost-effectiveness was analyzed using direct medical costs. RESULTS: We identified a total of 38 patients (27 with non-Hodgkin lymphoma and 11 with multiple myeloma). Thirteen patients received aprepitant and granisetron (aprepitant group) for CINV prophylaxis, whereas 25 patients received granisetron only (non-aprepitant group). The incidence of severe nausea (≥grade 3) was significantly lower in the aprepitant group than in the non-aprepitant group (p = 0.039). The total mean cost per patient during hospitalization, excluding the cost of HDCT and transplantation, was USD 10,941.8 in the aprepitant group and USD 14,577.2 in the non-aprepitant group (p = 0.041). This cost benefit reflected reductions in the costs of hospitalization, transfusion, and infection treatment. CONCLUSIONS: Our data indicated that the addition of aprepitant for CINV prophylaxis during HDCT reduced the incidence of severe nausea and might also provide economic benefit in the overall management of HDCT prior to autologous peripheral blood stem cell transplantation.

Efficacy of palonosetron in postoperative nausea and vomiting (PONV)-a meta-analysis.

INTRODUCTION: Palonosetron is a second-generation 5-HT3 receptor antagonist with proposed higher efficacy and sustained action for prophylaxis of postoperative nausea and vomiting (PONV). METHODS: Randomized controlled trials involving adult population undergoing elective surgery under general anesthesia comparing palonosetron to placebo, ramosetron, granisetron, and ondansetron were included. Data were extracted for vomiting incidence (VI), complete response (no nausea/vomiting; Complete Response [CR]), and rescue antiemetic need. This was categorized as early phase (24 hours postoperative for ramosetron and 6 hours for rest) and delayed phase (48 hours for ramosetron and 24 hours for rest). VI and CR were used as markers of drug efficacy. Any adverse effects were evaluated. RESULTS: Twenty-two trials (4 with 3 groups) were included (comparing palonosetron to placebo in 5, ramosetron in 5, granisetron in 4, and ondansetron in 12 subgroups). Palonosetron demonstrated statistical superiority over placebo for VI and CR, both early/delayed PONV prevention. For delayed phase, palonosetron surpassed ramosetron in all 3 variables; however, none of the variables attained statistical significance during early phase. In early phase, palonosetron had better VI and CR than did granisetron; however, variables other than CR (better for palonosetron) failed to achieve statistical significance for delayed phase. All 3 outcomes were significantly better for palonosetron compared with ondansetron in delayed phase, but statistical superiority could only be demonstrated for VI in early phase. Being inconsistently documented across trials, nausea scores could not be evaluated. CONCLUSION: Palonosetron is as safe as and more effective than placebo, ramosetron, granisetron, and ondansetron in preventing delayed PONV. For early PONV, it has higher efficacy over placebo, granisetron, and ondansetron.

A CASE OF GRANISETRON ASSOCIATED INTRAOPERATIVE CARDIAC ARREST.

We report a case of intraoperative severe bradycardia that resulted in asystole and cardiac arrest shortly after (<2 min) intravenous granisetron 1mg for postoperative nausea and vomiting prophylaxis, that occurred in a female patient who underwent an elective total thyroidectomy. After two cycles of cardiopulmonary resuscitation and defibrillation, spontaneous circulation and sinus rhythm returned successfully. Postoperatively, the patient was diagnosed with a drug-induced long QT syndrome. At the time of the event, granisetron was the only medication administered. Furthermore, there was no reason to suspect electrolyte abnormalities. We explore the association of the onset of severe sinus bradycardia with the intravenous administration of granisetron.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy.

OBJECTIVE: Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC. PATIENTS AND METHODS: Patients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6-8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2-6. RESULTS: Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021). Over cycles 1-6, time-to-first emesis was significantly longer with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2-6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. CONCLUSIONS: Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated.

Slow-release granisetron (APF530) versus palonosetron for chemotherapy-induced nausea/vomiting: analysis by American Society of Clinical Oncology emetogenicity criteria.

BACKGROUND: APF530 is a novel sustained-release formulation of granisetron. In a Phase III trial, APF530 500 mg was noninferior to palonosetron 0.25 mg in preventing acute chemotherapy-induced nausea and vomiting (CINV) after moderately (MEC) or highly emetogenic chemotherapy (HEC) and delayed CINV after MEC, but not superior in preventing delayed CINV after HEC. Emetogenicity was classified by Hesketh criteria; this reanalysis uses newer American Society of Clinical Oncology criteria. METHODS: Complete responses (no emesis or rescue medication) after cycle one were reanalyzed after reclassification of MEC and HEC by American Society of Clinical Oncology criteria. RESULTS: APF530 maintained noninferiority to palonosetron. CONCLUSION: Single-dose APF530 is a promising alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC. The Clinicaltrials.gov identifier for this study is NCT00343460.

A randomized study of the efficacy and safety of transdermal granisetron in the control of nausea and vomiting induced by moderately emetogenic chemotherapy in Korean patients.

BACKGROUND: The granisetron transdermal system (GTS) showed non-inferior efficacy to oral granisetron to control chemotherapy-induced nausea and vomiting (CINV) during multiday chemotherapy. We compared the efficacy and safety of GTS with that of intravenous and oral granisetron in Korean patients receiving moderately emetogenic chemotherapy (MEC). PATIENTS AND METHODS: A total of 276 patients were randomized into GTS (n = 139, one patch on days 1-4) or control group (n = 137, intravenous on day 1 and oral on days 2-4). The primary endpoint was the percentage of patients achieving complete response (CR) from chemotherapy initiation until 24 h after the final administration. RESULTS: Out of 234 patients (112 in GTS and 122 in control group) included in the per protocol analysis, 97.9 % had gastrointestinal cancer and 76.9 % received 3-day chemotherapy. The GTS showed non-inferior efficacy achieving CR in 75.0 % of the patients; 74.6 % of the patients in the control group achieved CR (95 % confidence interval -10.73 to 11.55 %). The CR rate did not change after subgroup analyses by sex, age, and chemotherapy naivety and analysis per day and overall days of treatment. The GTS group showed sustained CR from day 1 to day 4. Patients' satisfaction, assessed using Functional Living Index-Emesis (FLI-E), showed no difference. Both treatments were well tolerated and safe. CONCLUSION: The GTS showed non-inferior efficacy to intravenous and oral granisetron. The safety, tolerability, and FLI-E scores of the GTS were comparable to those of control group. The GTS offers a convenient alternative option for relieving CINV in patients receiving MEC.

5-Hydroxytryptamine3 receptor antagonists and cardiac side effects.

INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events (AEs) from 5-HT3-RAs, with focus on the three most commonly used, ondansetron, granisetron and palonosetron. EXPERT OPINION: Most of the studies analyze electrocardiogram (ECG) changes after 5-HT3-RA administrations in healthy, young adults, or in noncancer patients to treat postoperative nausea and vomiting (PONV). Only a few studies have addressed ECG changes in cancer patients treated for chemotherapy-induced nausea and vomiting (CINV). Investigations in cancer patients are essential, because these patients are older and have a higher incidence of comorbidity, than those usually included in clinical trials. Furthermore, polypharmacy is frequent and drug-drug interactions between chemotherapy and other QTc-prolonging drugs may influence the pharmacokinetics and pharmacodynamics of the 5-HT3-RAs. During the next 10 - 15 years a huge increase in the number of cancer patients is expected, primarily in the group of 65-plus-year old. Therefore it will be crucial to address the incidence of cardiac AEs in cancer patients with known heart disease receiving chemotherapy and a 5-HT3 RA for the prophylaxis of CINV.

Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial.

PURPOSE: The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. PATIENTS AND METHODS: Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m(2) was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index-Emesis (FLIE) questionnaire on days -1 and 6. RESULTS: Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001). CONCLUSION: The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.