2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following high-emetic-risk antineoplastic agents.

PURPOSE: This systematic review updates the MASCC/ESMO recommendations for high-emetic-risk chemotherapy (HEC) published in 2016-2017. HEC still includes cisplatin, carmustine, dacarbazine, mechlorethamine, streptozocin, and cyclophosphamide in doses of > 1500 mg/m2 and the combination of cyclophosphamide and an anthracycline (AC) in women with breast cancer. METHODS: A systematic review report following the PRISMA guidelines of the literature from January 1, 2015, until February 1, 2023, was performed. PubMed (Ovid), Scopus (Google), and the Cochrane Database of Systematic Reviews were searched. The literature search was limited to randomized controlled trials, systematic reviews, and meta-analyses. RESULTS: Forty-six new references were determined to be relevant. The main topics identified were (1) steroid-sparing regimens, (2) olanzapine-containing regimens, and (3) other issues such as comparisons of antiemetics of the same drug class, intravenous NK1 receptor antagonists, and potentially new antiemetics. Five updated recommendations are presented. CONCLUSION: There is no need to prescribe steroids (dexamethasone) beyond day 1 after AC HEC, whereas a 4-day regimen is recommended in non-AC HEC. Olanzapine is now recommended as a fixed part of a four-drug prophylactic antiemetic regimen in both non-AC and AC HEC. No major differences between 5-HT3 receptor antagonists or between NK1 receptor antagonists were identified. No new antiemetic agents qualified for inclusion in the updated recommendations.

Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study.

BACKGROUND: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. PATIENTS AND METHODS: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. RESULTS: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. CONCLUSIONS: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

Serotonin antagonists: a new class of antiemetic agents.

Despite a number of significant advances over the past decade, prevention and treatment of chemotherapy-induced emesis remain formidable problems, particularly with cisplatin-containing regimens. Nearly one third of patients receiving high-dose cisplatin still experience substantial emesis despite the best available conventional antiemetics, and the toxic effects of these agents remain quite troublesome. In recent years, a new class of agents, the serotonin antagonists, has been identified. These agents hold promise for clinical utility in a wide range of areas. Selective antagonists of the serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor have proven in early clinical trials to be potent antiemetic agents in patients receiving cytotoxic chemotherapy, with efficacy comparable to or superior to that of conventional antiemetics. Toxic effects to date with the 5-HT3 receptor antagonists have been modest. The current state of knowledge with respect to these agents as antiemetics for patients receiving cytotoxic chemotherapy is summarized.

Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence.

PURPOSE: To synthesize the available randomized evidence on the efficacy of dexamethasone when used for protection against acute and delayed nausea and vomiting in patients receiving highly or moderately emetogenic cancer chemotherapy. MATERIALS AND METHODS: A meta-analysis was performed using trials identified through MEDLINE (1966 to April 1999), Embase, Derwent Drug File, and the Cochrane Library's Database of Controlled Trials. Data on acute and delayed emesis and nausea were collected. All randomized studies comparing dexamethasone to placebo, no treatment, or other antiemetics qualified, including cross-over trials providing first-cycle data. RESULTS: Of 1,200 citations screened, 32 studies with 42 pertinent comparisons and 5,613 patients were included in the meta-analysis. Dexamethasone was superior to placebo or no treatment for complete protection from acute emesis (odds ratio, 2.22; 95% confidence interval [CI], 1.89 to 2.60) and for complete protection from delayed emesis (odds ratio, 2.04; 95% CI, 1.63 to 2.56). The results were similar for complete protection from nausea. The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively). The beneficial effect was similar in subgroups defined by various study design parameters. No trial addressed the efficacy of dexamethasone in the delayed phase without having administered dexamethasone for acute-phase protection as well. CONCLUSION: Dexamethasone is clearly effective in protecting from emesis both in the acute and delayed phases, with emesis avoided in one patient out of six treated. Future trials should determine whether the delayed-phase effect is independent of the acute-phase benefit.

Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group.

PURPOSE: To compare the efficacy and safety of granisetron and ondansetron, serotonin (5-HT3) receptor antagonists shown to be effective in the prevention of chemotherapy-induced emesis. PATIENTS AND METHODS: In a double-blind, randomized, stratified, parallel-group study, the efficacy and safety of granisetron and ondansetron were compared in 987 chemotherapy-naive patients who received cisplatin in doses > or = 60 mg/m2. Granisetron was administered as a single dose of 10 or 40 micrograms/kg before the start of chemotherapy. Ondansetron was administered in doses of 0.15 mg/kg before and 4 and 8 hours after the start of chemotherapy. The three treatment groups were well-matched with respect to demographic characteristics and the dose of cisplatin administered. RESULTS: For all evaluations, single doses of granisetron 10 or 40 micrograms/kg were as effective as three 0.15-mg/kg doses of ondansetron. Total control (no vomiting, no retching, no nausea, and no use of rescue) was attained by 38%, 41%, and 39% of all patients who received granisetron 10 microgram/kg, granisetron 40 micrograms/kg, and ondansetron, respectively. No vomiting or retching and no use of rescue antiemetics were reported in 47%, 48%, and 51% of patients who received granisetron 10 micrograms/kg, granisetron 40 micrograms/kg, and ondansetron, respectively; no nausea and no use of rescue antiemetics were reported in 39%, 42%, and 40% of patients, respectively. CONCLUSION: All three treatment regimens were well-tolerated. The results of this study indicate that a single dose of granisetron 10 or 40 micrograms/kg is as effective as three doses of ondansetron 0.15 mg/kg in the prevention of nausea and vomiting induced by cisplatin chemotherapy.

Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.

PURPOSE: A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. PATIENTS AND METHODS: Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. RESULTS: Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. CONCLUSION: The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.

GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis.

We evaluated, in a multi-center trial, the safety and efficacy of GR 38032F (GR-C507/75), a novel and selective serotonin antagonist, in preventing acute emesis in chemotherapy-naive patients receiving treatment with regimens containing high-dose cisplatin (greater than or equal to 100 mg/m2). Eighty-five patients were randomized to receive GR 38032F, 0.18 mg/kg, either every six or every eight hours for three doses, beginning 30 minutes before cisplatin. Patients were evaluated for emetic episodes (vomiting or retching) over a 24-hour period following cisplatin. All patients were evaluable for toxicity and 83 were evaluable for efficacy. The overall antiemetic response rate was 75% (55% complete response [CR], 20% major response). No difference in antiemetic control between the two administration schedules was noted. Patients with histories of heavy ethanol use had significantly better antiemetic control (74% CR) than modest or non-drinkers (33% CR). Toxicity of GR 38032F was modest and independent of administration schedule. The most common adverse events included mild hepatic transaminase elevations, self-limited diarrhea, dry mouth, headache, and mild sedation. Our data indicate that GR 38032F is a safe and effective agent in the control of acute cisplatin-induced nausea and vomiting. Additional trials exploring dosing, schedule, and comparison to standard antiemetic agents are indicated.

A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy.

Ondansetron (GR 38032F), a selective antagonist of serotonin subtype 3 receptors, is effective in the prevention of emesis associated with cisplatin as well as other chemotherapeutic agents. In this randomized, single-blind, multicenter, parallel group study, we compared the efficacy and safety of intravenous (IV) ondansetron with IV metoclopramide in the prevention of nausea and vomiting associated with high-dose (greater than or equal to 100 mg/m2) cisplatin chemotherapy. Three hundred seven patients receiving their first dose of cisplatin, either alone or in combination with other antineoplastic agents, were randomized to receive ondansetron 0.15 mg/kg IV every 4 hours for three doses or metoclopramide 2 mg/kg IV every 2 hours for three doses, then every 3 hours for three additional doses. The study prohibited the concurrent administration of other antiemetics or dexamethasone. Patients receiving ondansetron had a higher rate of complete protection from emesis (40% v 30%, P = .07), a higher complete plus major response rate (65% v 51%, P = .016), a lower rate of failure (21% v 36%, P = .007), and a lower median number of emetic episodes (one v two, P = .005) than did those receiving metoclopramide. The median time to the first emetic episode was longer on ondansetron (20.5 v 4.3 hours, P less than .001). Adverse events occurred in 48% of patients receiving ondansetron and 69% of those receiving metoclopramide (P less than .001). Akathisia and acute dystonic reactions occurred only on metoclopramide; headache (controlled with acetaminophen) was significantly more frequent with ondansetron. Ondansetron is more effective, produces fewer adverse events, and is easier to administer than metoclopramide for the prevention of emesis associated with high-dose cisplatin chemotherapy.

Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group.

PURPOSE: To assess the comparative antiemetic efficacy of single-dose intravenous (IV) dolasetron mesylate and ondansetron in preventing cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: Cancer patients (n = 609) receiving first-course cisplatin chemotherapy were randomized to one of three treatments: 1.8 or 2.4 mg/kg dolasetron mesylate salt (equivalent to 1.3 and 1.8 mg/kg dolasetron base, respectively) or 32 mg ondansetron. Each treatment was infused over 15 minutes, 30 minutes before cisplatin administration. Patients were stratified to cisplatin doses of > or = 70 and less than 91 mg/m2 (n = 368) or > or = 91 mg/m2 (n = 241), administered over < or = 3 hours. Protocol-defined efficacy criteria included complete response (zero emetic episodes and no rescue medication), major response (1 to 2 emetic episodes and no rescue medication), and patients' report of nausea severity and satisfaction recorded on a 100-mm visual analog scale (VAS). RESULTS: The three treatments met protocol-specified criteria for equivalence. Complete response rates for dolasetron mesylate 1.8 mg/kg, 2.4 mg/kg, and ondansetron, respectively, were 49.2%, 45.6%, and 50.4% for patients in the lower cisplatin stratum (mean, 74.7 mg/m2) and 36.8%, 31.3%, and 31.8% in the higher cisplatin stratum (mean, 100.6 mg/m2). No significant differences were observed in the extent of nausea with either dolasetron dose compared with ondansetron. Less nausea was noted with 1.8 mg/kg dolasetron compared with the 2.4 mg/kg dose (P = .044) All three antiemetic treatments were well tolerated. Asymptomatic electrocardiogram changes were recorded with both dolasetron and ondansetron. CONCLUSION: A single IV dose of dolasetron mesylate (1.8 or 2.4 mg/kg) has comparable safety and efficacy to a single 32-mg IV dose of ondansetron in patients receiving cisplatin chemotherapy.

Proposal for classifying the acute emetogenicity of cancer chemotherapy.

PURPOSE: To propose a classification of the acute emetogenicity of antineoplastic chemotherapy agents, and to develop an algorithm to define the emetogenicity of combination chemotherapy regimens. METHODS: A Medline search was conducted to identify (1) clinical trials that used chemotherapy as single-agent therapy, and (2) major reviews of antiemetic therapy. The search was limited to patients who received commonly used doses of chemotherapy agents, primarily by short (< 3 hours) intravenous infusions. Based on review of this information and our collective clinical experience, we assigned chemotherapy agents to one of five emetogenic levels by consensus. A preliminary algorithm to determine the emetogenicity of combination chemotherapy regimens was then designed by consensus. A final algorithm was developed after we analyzed a data base composed of patients treated on the placebo arms of four randomized antiemetic trials. RESULTS: Chemotherapy agents were divided into five levels: level 1 (< 10% of patients experience acute [< or = 24 hours after chemotherapy] emesis without antiemetic prophylaxis); level 2 (10% to 30%); level 3 (30% to 60%); level 4 (60% to 90%); and level 5 (> 90%). For combinations, the emetogenic level was determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. The following rules apply: (1) level 1 agents do not contribute to the emetogenic level of a combination; (2) adding > or = one level 2 agent increases the emetogenicity of the combination by one level greater than the most emetogenic agent in the combination; and (3) adding level 3 or 4 agents increases the emetogenicity of the combination by one level per agent. CONCLUSION: The proposed classification schema provides a practical means to determine the emetogenic potential of individual chemotherapy agents and combination regimens during the 24 hours after administration. This system can serve as a framework for the development of antiemetic guidelines.

Adjusting the dose of intravenous ondansetron plus dexamethasone to the emetogenic potential of the chemotherapy regimen.

PURPOSE: This pilot, open-label study evaluates the antiemetic efficacy and safety of a single 20-mg intravenous (IV) dose of dexamethasone combined with a single IV dose of ondansetron (32, 24, or 8 mg) in patients receiving highly emetogenic (HE), moderately high emetogenic (MHE), or moderately emetogenic (ME) chemotherapy, respectively. PATIENTS AND METHODS: One hundred forty-six patients received a single 20-mg IV dose of dexamethasone over 15 minutes beginning 45 minutes before chemotherapy and either a single 32-, 24-, or 8-mg IV dose of ondansetron over 15 minutes beginning 30 minutes before chemotherapy. Patients were evaluated for emetic episodes, extent of nausea, and adverse events for 24 hours after chemotherapy. RESULTS: Complete response (no emetic episodes) was noted in 72% (95% confidence interval [CI], 60% to 84%), 88% (95% CI, 79% to 97%), and 77% (95% CI, 63% to 92%) of patients in the HE, MHE, and ME categories, respectively. The proportion of patients who experienced no nausea on the posttreatment assessment was 51% (95% CI, 37% to 64%), 69% (95% CI, 56% to 81%), and 47% (95% CI, 29% to 65%), respectively. The antiemetic regimens were all well tolerated. The proportion of patients with any drug-related adverse events did not vary across the three study groups despite the range of ondansetron doses and variety of chemotherapy regimens. Mild headache was noted in 28% of patients. Other adverse events, all of which were noted in fewer than 10% of patients, included lightheadedness, fatigue, dizziness, and constipation. CONCLUSION: A single IV dose of either 8, 24, or 32 mg of ondansetron combined with a single 20-mg IV dose of dexamethasone resulted in good control of acute emesis across a wide spectrum of chemotherapy regimens. Nausea control proved somewhat more difficult, with approximately 50% of patients in the HE and ME emetogenic categories experiencing some degree of nausea. The results of our pilot study suggest that adjusting the dose of ondansetron to the intrinsic emetogenicity of the chemotherapy regimen permits a more efficient use of ondansetron while maintaining good antiemetic control. Such an approach appears worthy of further investigation.

Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis.

PURPOSE: To determine the efficacy and safety of the neurokinin type 1 receptor antagonist CJ-11,974 for the control of high-dose cisplatin-induced emesis. PATIENTS AND METHODS: A double-blind, randomized, phase II design with a group sequential stopping rule was used in this study. Sixty-one patients with cancer who were receiving cisplatin at a dose of at least 100 mg/m2 for the first time were enrolled. All patients received granisetron 10 microg/kg and dexamethasone 20 mg intravenously 30 minutes before they were given cisplatin. Patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg, and group 2 received placebo orally 30 minutes before and 12 hours after cisplatin and then twice daily on days 2 through 5 after cisplatin. The primary end point was the percentage of patients who developed delayed emesis (emesis on the second to fifth days after cisplatin). RESULTS: Thirty patients were enrolled in group 1, and 31 patients were enrolled in group 2. Fifty-eight patients were assessable for efficacy. Complete control of emesis (expressed as the percentage of patients who had no emesis) was as follows: day 1, 85.7% (group 1) and 66.7% (group 2) (P = .090); days 2 through 5, 67.8% (group 1) and 36.6% (group 2) (P = .0425, adjusted); days 1 through 5, 64.3% (group 1) and 30% (group 2) (P = .009). Patients in group 1 experienced significantly less nausea than patients in group 2 on day 1 (P = .024). Treatment was well tolerated in both groups. CONCLUSION: We conclude from this exploratory phase II trial that CJ-11,974 is superior to placebo in controlling cisplatin-induced delayed emesis and may provide additive benefit in acute emesis and nausea control when combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Additional larger trials are indicated to confirm the clinical value of CJ-11,974.

Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy.

PURPOSE: To compare the antiemetic efficacy of a single dose of an oral antiemetic (granisetron 2 mg) with a single dose of an intravenous (i.v.) antiemetic (ondansetron 32 mg) given before cisplatin-based chemotherapy. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, parallel-group study. Patients (N = 1,054) scheduled to receive cisplatin (> or = 60 mg/m2)-based chemotherapy were randomized to receive either 2 mg of oral granisetron tablets 1 hour before chemotherapy (n = 534) or i.v. ondansetron (32 mg) 30 minutes before chemotherapy (n = 520). The primary efficacy end point was total control (no emesis, no nausea, and no use of antiemetic rescue medication) over the initial 24 hours after the start of chemotherapy. Dexamethasone or methylprednisolone were permitted, but not required, as concomitant prophylactic antiemetics. RESULTS: Total control was equivalent 24 hours after cisplatin chemotherapy for single-dose oral granisetron (54.7%) and i.v. ondansetron (58.3%) (95% confidence interval [CI], -9.6 to 2.4). Similar proportions of patients remained nausea-free in the granisetron group (55.4%) and the ondansetron group (59%) (95% CI, -9.6 to 2.4). The rate of complete control of emesis was 61.2% in the granisetron group and 67.1% in the ondansetron group (95% CI, -11.7 to -0.1). Both treatment regimens were well tolerated, with similar patterns of adverse reactions, generally of a mild degree. The most common side effects included constipation (14%), headache (15%), and diarrhea (10%). CONCLUSION: Oral granisetron, administered as a single 2-mg dose, provided equivalent total antiemetic control when compared with i.v. ondansetron (32 mg) in patients who received highly emetogenic, cisplatin-based chemotherapy.

Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study.

PURPOSE: The antiemetic effectiveness and safety of single-dose oral granisetron were compared with intravenous (I.V.) ondansetron in chemotherapy-naive patients who received moderately emetogenic chemotherapy. PATIENTS AND METHODS: In this double-blind, parallel-group study, patients naive to emetogenic chemotherapy (N = 1,085) who were scheduled to receive cyclophosphamide- (500 to 1,200 mg/m2) or carboplatin (> or = 300 mg/m2) based chemotherapy, were randomized to receive either oral granisetron (n = 542) or I.V. ondansetron (n = 543). Efficacy assessments included the proportion of patients in each treatment group with total control over the 24 and 48 hours following chemotherapy initiation, as well as incidence and severity of nausea and emesis and use of antiemetic rescue medication. Prophylactic corticosteroids were allowed. Safety assessment was based on patients' reports of adverse experiences. RESULTS: Approximately 80% of patients received prophylactic corticosteroids. Single-dose oral granisetron (2 mg) and I.V. ondansetron (32 mg) resulted in equivalent levels of total emetic control during the first 48 hours after chemotherapy. The proportion of nausea- and emesis-free patients at 24 and 48 hours were also approximately equivalent. The most commonly reported adverse experiences were headache, asthenia, and constipation. More patients who received ondonsetron than granisetron reported dizziness (9.6% v 5.4%, respectively; P = .011) and abnormal vision (4.2% v 0.6%, respectively; P < .001). CONCLUSION: A single oral dose of granisetron (2 mg) resulted in equivalent levels of antiemetic protection as I.V. ondansetron (32 mg). Both agents were well tolerated, although more dizziness and abnormal vision were reported with ondansetron. Because the two antiemetic regimens exhibited equivalent efficacies, additional factors such as convenience and cost of therapy should be considered.

A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis.

PURPOSE: This study compares the efficacy and safety of ondansetron alone with that of ondansetron plus dexamethasone in the prevention of emesis induced by high-dose cisplatin (> or = 100 mg/m2). PATIENTS AND METHODS: This multicenter study used a randomized, double-blind, parallel-group design. Chemotherapy-naive patients were randomized to receive intravenous (IV) ondansetron (Zofran, Cerenex Pharmaceuticals, Research Triangle Park, NC) 0.15 mg/kg for three doses every 4 hours beginning 30 minutes before cisplatin administration either alone or in combination with dexamethasone 20 mg administered 45 minutes before cisplatin. Cisplatin (> or = 100 mg/m2) was administered as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes (EEs), adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 275 patients were enrolled. Of these, 245 were assessable for efficacy. Patients who received ondansetron plus dexamethasone had a higher complete antiemetic response rate (61% v 46%, P = .02) and less nausea (posttreatment visual analog scale mean 18.2 v 32.8, P < .001) than did those who received ondansetron alone. The time to the first EE was longer for patients in the group that received ondansetron plus dexamethasone (P = .005). Headache (12%), diarrhea (2%), and abdominal colic (1%) were the most common antiemetic-related adverse events reported. The incidence of adverse events was similar between the treatment groups. CONCLUSION: IV ondansetron in combination with dexamethasone is safe and more effective than ondansetron alone in the prevention of emesis induced by high-dose cisplatin.

Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.

PURPOSE: This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. PATIENTS AND METHODS: This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). CONCLUSION: A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.

Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS: Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%. CONCLUSION: Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.