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.

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response.

GOALS OF WORK: Prevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response. PATIENTS AND METHODS: 1,044 patients receiving cisplatin (> or = 70 mg/m2) were randomly assigned to control regimen [ondansetron (O) 32 mg i.v. and dexamethasone (D) 20 mg p.o. on day 1; D 8 mg twice daily on days 2-4] or aprepitant (A) regimen (A 125 mg p.o. plus O 32 mg and D 12 mg on day 1; A 80 mg and D 8 mg once daily on days 2-3; and D 8 mg on day 4). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1-5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression. MAIN RESULTS: Women comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men. CONCLUSION: The addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference.

BACKGROUND: In the late 1990s, several professional organizations convened antiemetic guideline groups and published the findings of these expert panels. Each of these documents was based on analyses of the available published trials and provided nearly similar recommendations. Nonetheless, small differences in emetic risk categories and treatment recommendations led to confusion in antiemetics selection. With the emergence of new findings and agents since the guidelines were initially published, many of the oncology professional societies have updated the antiemetic guidelines. MATERIALS AND METHODS: A literature review up to March 2004 was carried out using MEDLINE with evaluation of the evidence by an expert panel composed of 23 oncology professionals in clinical medicine, medical oncology, radiation oncology, oncology nursing, statistics, pharmacy, medical policy and decision making, and pharmacology. The experts represented nine oncology professional societies and came from 11 different countries on four continents. RESULTS: Recommendations on antiemetic regimens to prevent emesis induced by high, moderate, low and minimal risk chemotherapy were suggested as well as management of anticipatory emesis. Furthermore, recommendations for refractory emesis, emesis induced by high-dose chemotherapy and radiotherapy and for antiemetics in children receiving chemotherapy were elaborated. CONCLUSIONS: Recommendations about antiemetic prophylaxis in patients receiving treatment with chemo- and radiotherapy have been updated by representatives of nine oncological organizations.

Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

An ultrathin platinum film sensor to measure biomolecular binding.

A sensitive conductimetric immunosensor has been demonstrated based on an ultrathin platinum film on an oxidized silicon base. The film is about 25 A thick and is seen to consist of a discontinuous layer with channels 20-30 A wide. Monoclonal antibodies were bound to the sensor surface using conventional biosensor chemistry. Impedance at fixed frequencies across the film was used to track modification and binding at the surface. Impedance increased 55% at 20 Hz during the activation of the surface with anti-alkaline phosphatase (anti-AP). Binding of alkaline phosphatase (AP) to the prepared surface results in a further increase of 12%. p-Nitrophenyl phosphate hydrolysis confirmed binding and activity of the AP. About 40 amol AP were bound on the 0.5 cm(2) electrode. Non-specific binding of horseradish peroxidase caused an impedance change <6%. Control experiments showed small impedance changes and trace enzyme activity. Since the mechanism of electrical conduction of the thin film was not established, modeling of thin-film response was used to distinguish between redox processes, capacitance and tunneling mechanisms. The data fit well with the diffusion distributed elements (DE) model as well as a transmission line distribution element (DX) model. The first model, DE, is distributed elements for diffusion. The second DX model represents a transmission line. The sensors behave in a distributed network or like a transmission line.

Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting.

Better tolerated and more effective means of controlling chemotherapy-induced nausea and vomiting have been introduced over the past decade. Despite the progress made, incompletely controlled emesis is a persistent problem for significant numbers of patients receiving chemotherapy. Efforts to improve antiemetic control further are ongoing. The most interesting new class of antiemetics under development focuses on antagonism of the neurotransmitter substance P. Substance P exerts its effects by binding to the tachykinin neurokinin NK1 receptor. A number of selective antagonists of the NK1 receptor have been synthesized and, when used in preclinical models, have demonstrated an ability to antagonize the emetic effects of a number of stimuli, including chemotherapy agents such as cisplatin. Over the past 3 years, results of the initial studies evaluating this class of agents for cisplatin-induced emesis in cancer patients have begun to appear. These agents have been well tolerated. As single agents, they appear to be no more effective than 5-HT3 receptor antagonists in preventing acute cisplatin-induced emesis. Their real value may be found in combination with existing agents and in the treatment of delayed emesis. The results of ongoing clinical trials will hopefully define the utility and appropriate place for this new class of agents in the management of chemotherapy-induced nausea and vomiting.

Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer.

Paclitaxel is an active agent for adenocarcinomas and squamous cell carcinomas of the esophagus and is a radiation sensitizer. We sought to investigate the toxicity and complete response rate of paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Forty-one patients with esophageal cancer were studied, 29 with adenocarcinomas and 12 with squamous cell cancers. Twelve patients had tumor extension into the proximal stomach and/or abdominal adenopathy. Patients received paclitaxel 60 mg/m2 by 3-hour intravenous (i.v.) infusion, and cisplatin 25 mg/m2 weekly on days 1, 8, 15, and 22. Radiation was administered concurrently to a total dose of 39.60 Gy, in 1.80 Gy fractions, for 22 treatments. Patients with medical or surgical contraindications to esophagectomy received 2 additional weeks of paclitaxel with a radiation boost to 50.4 Gy. Neutropenia was the most common grade 3/4 toxicity occurring in 10 patients (24%). Only 2 patients (5%) had grade 4 esophagitis requiring parenteral nutrition. Twelve patients (29%) obtained a complete response. The 2-year progression-free and overall survival rates were 40% and 42%, respectively. Esophagitis was less severe than expected and prophylactic enteral feeding tubes were not necessary. Additional effective systemic treatments are needed to reduce the development of distant metastases.

Prospective evaluation of antiemetic outcome following high-dose chemotherapy with hematopoietic stem cell support.

Considerable progress has been made in improving the control of chemotherapy-induced emesis. The impact of available antiemetic options for patients receiving stem cell transplants is unclear, as few prospective data have been collected. We prospectively evaluated antiemetic outcome in patients receiving stem cell transplantation over a 7-day period following the initiation of chemotherapy. The primary endpoints were the number of emetic episodes and the extent of nausea measured on a four-point scale. Eighty-two patients were evaluated. Ninety-five percent of patients had nausea during the first week of treatment; 80% had at least one emetic episode. The percentage of patients with emesis was as follows: day 1: 13%, day 2: 21%, day 3: 30%, day 4: 38%, day 5: 44%, day 6: 39%, day 7: 18%. In multivariate analysis, gender, emesis with prior chemotherapy, history of morning or motion sickness, type of transplant (auto vs allo), use of total body irradiation, or use of dexamethasone did not effect emesis control. Most patients receiving high-dose chemotherapy experience incompletely controlled emesis. Control of nausea and emesis progressively worsened with each subsequent day following initiation of chemotherapy, reaching a nadir on day 5. New treatment approaches are needed to improve emesis control in this patient population.

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.

Antiemetic efficacy of single-dose oral granisetron (1 mg vs 2 mg) with moderately emetogenic chemotherapy.

PURPOSE: To compare the efficacy of oral granisetron, 1 mg and 2 mg, administered as one dose in patients who receive moderately emetogenic chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients, scheduled to receive intravenous cyclophosphamide (500 to 1200 mg/m2) or carboplatin (> or = 300 mg/m2), were stratified by dexamethasone/methylprednisolone use (+ DEX, n = 92) or nonuse (- DEX, n = 5). Patients were randomized to one dose of either 1 mg (n = 48) or 2 mg (n = 49) of granisetron administered 60 minutes before chemotherapy. Known important prognostic variables (gender, age, alcohol) were well balanced between groups. RESULTS: Using the most rigorous criterion of total control (no emetic episodes, no nausea, no rescue therapy during the first 24 hours), response rates were 54.2% (26/48) and 57.1% (28/49) in patients receiving 1 mg and 2 mg of granisetron, respectively (95% confidence interval, -0.17, 0.23). Total control rates in patients who received 1 mg and 2 mg of granisetron + DEX were also comparable: 57.8% (26/45) and 55.3% (26/47), respectively. Response rates were similar for the parameters of nausea, emesis, and complete response (no emetic episodes, no more than mild nausea, no antiemetic rescue). Among all patients, one (2.1%) who received 1 mg of granisetron and three (6.1%) who received 2 mg experienced severe nausea. The proportions of 1- and 2-mg-treated patients who received rescue therapy within the first 24 hours were 31.3% (15/48) and 34.7% (17/49), respectively. Reported adverse experiences were generally mild in severity. DISCUSSION: The results of this trial demonstrate good control of emesis with a single 1-mg dose of oral granisetron, with efficacy that compares favorably with that of a 2-mg dose.

Vaccination against coccidiosis: host strain-dependent evocation of protective and suppressive subsets of murine lymphocytes.

BALB/c mice are normally more resistant than C57BL/6 (B6) mice to infection with Eimeria vermiformis, but these phenotypes can be reversed by oral or parenteral vaccination with a crude antigen prepared from the parasite. Treatment of mice with antibodies specific for CD4+ or CD8+ T cells showed that the increased susceptibility of vaccinated BALB/c mice was associated with the presence of CD4+ T cells. This finding was confirmed when the recipients of CD4+ T cells selected from the mesenteric lymph nodes (MLN) of vaccinated BALB/c mice produced more oocysts after challenge than the recipients of a similar population of cells from sham-vaccinated mice. The residual population of cells (presumably enriched for CD8+ T cells, 'CD8+'), on the other hand, conferred some protection and, in B6 mice, the findings were reversed. Thus, vaccination induced suppressive or protective CD4+ cells and protective or suppressive 'CD8+' cells, depending upon the normal resistance/susceptibility phenotype of the host. Examinations of the isotypes (IgG1, IgG2a) of specific serum antibodies, and of the levels of IFN-gamma and IL-5 cytokines released by MLN cells stimulated ex vivo, did not allow any further characterization of the mechanisms involved.

Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting.

Since their introduction, 5-HT3 receptor antagonists have become the agents of choice in the prevention of acute chemotherapy-induced nausea and vomiting and are generally superior to high-dose metoclopramide regimens. The availability of four different agents (ondansetron, granisetron, dolasetron, and tropisetron) within this class has prompted investigations into potential differences between the drugs, which appear to be few. More importantly, the results of recently conducted randomized comparative trials in patients receiving moderately or highly emetogenic chemotherapy have demonstrated similar efficacy. Although study designs and patient populations differed, seven large comparative trials in patients receiving highly emetogenic chemotherapy reported no significant differences in complete or complete plus major response rates among the agents. Similar results were generally reported in trials evaluating patients receiving moderately emetogenic chemotherapy. The safety and tolerability of these agents also appear to be similar. The most common adverse events include headache, gastrointestinal effects, lightheadedness, and sedation. All agents are available in both intravenous and oral dosage forms and may be administered as a single dose.

Paclitaxel and concurrent radiation for gastric cancer.

PURPOSE: To determine the activity and toxicity of paclitaxel and concurrent radiation for gastric cancer. METHODS AND MATERIALS: Twenty-seven patients were studied. Twenty-five had proximal gastric cancers, two had distal cancers. Eight had esophageal extension, 6 had celiac adenopathy, and 7 had retroperitoneal adenopathy. Patients received paclitaxel, 50 mg/m(2) by 3-hour intravenous (IV) infusion, weekly, on days 1, 8, 15, 22, and 29. Radiation was administered concurrently to a total dose of 45.0 Gy, in 1.80 Gy fractions, for 25 treatments. Patients who were medically or surgically inoperable received a sixth week of paclitaxel with a radiation boost to 50.4 Gy. RESULTS: Esophagitis and gastritis were the most important toxicities, Grade 3 in four patients (15%), and Grade 4 in three patients (11%). Five patients (19%) had Grade 3 nausea. The overall response rate was 56%, including three patients (11%) with a complete response. The 2-year progression-free and overall survival rates were 29% and 31%, respectively. CONCLUSION: Concurrent paclitaxel and radiation demonstrates substantial local-regional activity in gastric cancer. Future investigations combining paclitaxel and radiation with other local-regional and systemic treatments are warranted.

Control of high-dose-cisplatin-induced emesis with an all-oral three-drug antiemetic regimen.

In this pilot trial, the antiemetic efficacy and tolerability of an all-oral antiemetic combination in the prevention of both acute and delayed nausea and vomiting following high-dose cisplatin was evaluated. Fifty-two patients receiving cisplatin (median dose 100 mg/m2) were entered. Patients received (1) 60 min prior to cisplatin: prochlorperazine spansule 15 mg, dexamethasone 20 mg, granisetron 2 mg; (2) 12 h after cisplatin: prochlorperazine spansule 15 mg, dexamethasone 10 mg; (3) on days 2 and 3: prochlorperazine spansule 15 mg b.i.d., dexamethasone 8 mg b.i.d.; (4) on days 4 and 5: dexamethasone 4 mg b.i.d. All antiemetics were administered orally. The study period was the 120 h after cisplatin administration. The primary efficacy end-point was complete control (no vomiting, retching or antiemetic rescue) of delayed emesis (24-120 h after cisplatin). Complete control of delayed emesis was achieved in 26 patients (53%). Nineteen patients (39%) noted no delayed nausea. Complete control of acute emesis (24 h after cisplatin) was attained in 44 patients (86%). The no nausea rate during the first 24 h was 74%. Overall, 39 patients (80%) were satisfied or very satisfied with their outcome. Treatment was well tolerated with infrequent and minor adverse events. In conclusion, an all-oral combination of granisetron, dexamethasone and prochlorperazine is a highly effective and well-tolerated regimen for preventing acute cisplatin-induced emesis. Control of delayed emesis was not better than with current standard treatment, and more effective approaches are needed.