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Methylprednisolone as antiemetic treatment in breast-cancer patients receiving cyclophosphamide, methotrexate, and 5-fluorouracil: a prospective, crossover, randomized blind study comparing two different dose schedules.

The antiemetic response and side effects resulting from treatment with methylprednisolone (MPA) given on two different dose schedules were evaluated in 20 women with breast cancer who were undergoing chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). This randomized, crossover, double-blind study compared the antiemetic efficacy of a single dose of 125 mg MPN with that of two such doses. The study demonstrated the superiority of the latter protocol in preventing CMF-induced nausea and vomiting. The rate of antiemetic response to single vs double doses was as to follows: complete protection, 17% vs 30%; partial and minimal protection, 39% vs 55%; and no protection, 44% vs 15% of the courses, respectively (P = 0.0087). No difference in the antiemetic response rate was found between the first and the second course. Treatment with MPN was well tolerated, and no difference in the incidence of side effects was found between the single-dose and the double-dose schedule. We recommend the use of two doses of 125 mg MPN as prophylactic antiemetic treatment in breast-cancer patients receiving CMF chemotherapy.

Adult↗

Antiemetic efficacy of a droperidol-morphine combination in patient-controlled analgesia.

STUDY OBJECTIVES: To evaluate the antiemetic effectiveness and side effects of adding low-dose droperidol to morphine delivered via a patient-controlled analgesia (PCA) device. DESIGN: Randomized, double-blind, clinical study. SETTING: University-affiliated women's hospital. PATIENTS: 60 healthy women, 18 to 60 years of age, who underwent total abdominal hysterectomy with a standardized anesthetic regime. INTERVENTIONS: After surgery, the control group (n = 20) had access via PCA to two cartridges, each containing morphine 1 mg/ml and saline 1 ml. The two treated groups (n = 20 each) had access via PCA to either droperidol 0.5 mg or droperidol 1 mg added to two cartridges containing morphine 1 mg/ml. MEASUREMENTS AND MAIN RESULTS: Preoperative data, including each patient's history of nausea and vomiting with and without previous anesthesia, motion sickness, smoking, and alcohol intake, and date of her last menstrual period, were obtained. All patients received a standardized anesthetic with droperidol 0.5 mg given at closure of the peritoneum. Among those patients who received droperidol added to morphine for their postoperative analgesic regimen, fewer required rescue antiemetic medication (p < 0.05, test of trend in proportions), and they had a lower incidence of vomiting (p < 0.05, test of trend in proportions), as well as a decrease in the number of times a rescue antiemetic was needed during the 24-hour postoperative period (linear trend, p = 0.013). CONCLUSIONS: An intermittent intake of low-dose droperidol with morphine given via a PCA delivery system in two treatment groups gave evidence for a dose-response relation between the amount of droperidol added and the proportion of patients needing a rescue antiemetic. The same result applied to the proportion of patients having an emetic episode and the number of times a rescue antiemetic had to be administered. There was no evidence that the low dose of droperidol added to morphine delivered via a PCA device increased unwanted side effects.

Adolescent↗

Randomized crossover comparison of high-dose intravenous metoclopramide versus a five-drug antiemetic regimen.

In a randomized open crossover study, the antiemetic efficacy of a five-drug antiemetic regimen consisting of metoclopramide, dexamethasone, diazepam, diphenhydramine, and thiethylperazine was compared to that of high-dose metoclopramide. Thirteen patients treated with cisplatin combination chemotherapy regimens were evaluated. The study was terminated prior to accrual of the planned number of patients because of the statistically significant difference in efficacy between treatments found at interim analysis. The duration of nausea and number of vomiting episodes on the day of chemotherapy were significantly less (p less than 0.01) after receiving the five-drug combination. After receiving the five-drug regimen, 77% of the patients did not experience any episodes of vomiting on day 1, and 8% of patients had only one episode. In contrast, only 31% of patients treated with high-dose metoclopramide did not have any episodes of vomiting on day 1, and 61% of the patients had five or more episodes. None of the patients treated with the five-drug regimen required additional antiemetic administration. Although both regimens were, in general, well tolerated, when given the choice of continuing antiemetic therapies, 92% of the patients preferred the five-drug antiemetic combination.

Adult↗

Antiemetic therapy in patients treated with high-dose cytosine arabinoside.

The antiemetic efficacy of metoclopramide (MCP) was evaluated in 33 consecutive patients treated with high-dose cytosine arabinoside (HiDAC), greater than or equal to 3 g/m2, a highly emetogenic agent increasingly used in patients with hematologic malignancies for which no previous formal antiemetic trials have been reported. Administration of MCP in conjunction with prophylactic diphenhydramine resulted in major antiemetic responses (0-2 episodes of emesis in the 24 h after therapy) in 23 of 33 (70%) patients. The addition of lorazepam (LZP) to MCP resulted in major antiemetic response in 7 or 8 (88%) patients who failed to respond to MCP alone. Major side effects were extrapyramidal reactions (5%) and moderate diarrhea (18%). MCP alone or in conjunction with LZP is effective antiemetic therapy in patients treated with HiDAC.

Adolescent↗

Antiemetic efficacy of alprazolam in carboplatin-induced emesis.

In order to potentiate the efficacy of antiemetic drugs such as metoclopramide (MCP) and the new drug GR 38032F, adjuvant antiemetic drugs such as benzodiazepines are used in cancer patients receiving chemotherapy. The purpose of our prospective study was to investigate the efficacy of alprazolam (APZ), a newer diazepam, as an adjuvant antiemetic drug, when combined with MCP, in carboplatin (JM8)-based chemotherapy. Thus, 42 patients entered this study. First they received only MCP 1 mg/kg in 15 min infusion (arm A). In the next cycle they received the combination of MCP in the same dose and a tablet of APZ 0.25 mg, 30 min before JM8 infusion and then 3.5, 5.5 and 11.5 h after (arm B). JM8 was administered alone (400 mg/m2) or in combination (300 mg/m2) with vinblastine (6 mg/m2), etoposide (100 mg/m2) or 5-fluorouracil (1,000 mg/m2). In arm A, according to the WHO classification, nausea was intense (p less than 0.003) and the duration of nausea longer (p less than 0.002). In arm B more patients did not present vomiting (p less than 0.018). Secondary effects such as appetite (p less than 0.04), diarrhea (p less than 0.064), diaphoresis (p less than 0.085) and headache (p less than 0.024) were worst in arm A. We conclude that APZ increases the antiemetic effect of MCP on JM8. APZ is a useful adjuvant antiemetic drug, especially against the development of anticipatory anxiety, nausea and vomiting that many cancer patients presented during chemotherapy.

Administration, Oral↗

Metoclopramide: dose-related toxicity and preliminary antiemetic studies in children receiving cancer chemotherapy.

Prior studies in adults have shown that metoclopramide (MCP), when given in high intravenous (IV) doses (2 mg/kg), is a highly effective antiemetic for chemotherapy-induced vomiting. It is well-tolerated in older adults, but younger adults have an increased disposition to acute extrapyramidal reactions (EPRs). Before studying the efficacy of MCP as an antiemetic in children, we first had to establish the safe dose range. We performed a dose-increase MCP toxicity study in children receiving highly emetic chemotherapy such as cisplatin (120 mg/m2) or cyclophosphamide (greater than 900 mg/m2), beginning with a dose of 0.2 mg/kg and increasing the dose in nine steps to 3 mg/kg. MCP was given every two hours for four doses beginning one-half hour before chemotherapy. To reduce the incidence of EPRs, we added concomitant diphenhydramine. In MCP doses less than 2 mg, toxicity was minimal. In doses greater than or equal to 2 mg, 4/27 (15%) had EPRs and 9/27 (33%) had akathisia. Children who received two consecutive days of MCP had a higher frequency of EPRs. Metoclopramide (2 mg/kg) had promising antiemetic efficacy in a preliminary nonrandomized trial. Chemotherapy-experienced children vomited fewer than five times in 9/21 (43%) trials, and new patients vomited fewer than five times in 7/10 (70%) trials. MCP will become more useful as an antiemetic in children if better measures to prevent EPRs can be developed. Chemotherapy-induced emesis has the same negative implications in children as it does in adults and optimum antiemetic regimens can only be discovered by conducting randomized clinical trials in children.

Adolescent↗

[Prophylactic antiemetic treatment for cancer chemotherapy--comparison of domperidone and chlorpromazine].

The antiemetic effect of domperidone against nausea, vomiting, and anorexia induced by antineoplastic agents was compared with that of chlorpromazine. Twenty patients with malignant neoplasms given 2 cycles of a combination chemotherapy including cisplatinum and adriamycin received domperidone in one cycle and chlorpromazine in another cycle. Antiemetics 10-20 mg were given 30 minutes before chemotherapy and every 4-6 hours afterwards by div, iv, or po. No significant differences in severity of nausea and vomiting and duration of anorexia were noted between domperidone and chlorpromazine. Side effects were observed in 11 patients who received chlorpromazine, while none was observed in domperidone. It was concluded that domperidone was as effective as chlorpromazine as antiemetics and more useful because of its lower incidence of side effects. The antiemetic effect of domperidone, however, was not great enough for some patients, especially when they received cisplatinum. A higher dose of domperidone or domperidone with concomitant use of glucocorticoids should be considered as promising antiemetics for these patients.

Adult↗

Comparison of intermittent ondansetron versus continuous infusion metoclopramide used with standard combination antiemetics in control of acute nausea induced by cisplatin chemotherapy.

BACKGROUND: Ondansetron is a serotonin antagonist that recently has been introduced as a preventive agent for chemotherapy-induced nausea and vomiting. The current study was performed to determine the degree of antiemetic control of ondansetron in combination with dexamethasone and lorazepam, and to compare this combination to the previously very effective regimen of lorazepam, dexamethasone, diphenhydramine, and continuous-infusion metoclopramide. METHODS: Eighty chemotherapy-naive patients with newly diagnosed neoplasms undergoing cisplatin combination chemotherapy were randomized to receive one of two combination antiemetic regimens: lorazepam, dexamethasone, intermittent intravenous ondansetron; or lorazepam, dexamethasone, continuous-infusion metoclopramide, and diphenhydramine. RESULTS: There was major control (0-1 episodes) of acute nausea-vomiting in all of the patients receiving the ondansetron combination antiemetic regimen, which was significantly better (P < 0.05) than the major control of the acute nausea-vomiting of the patients receiving the metoclopramide combination antiemetic regimen. The ondansetron-treated patients experienced only a mild headache as their only toxicity and had significantly (P 0.0026) less diarrhea, akathisia, and acute dystonic reactions than the patients receiving the metoclopramide regimen. Delayed nausea was controlled with prophylactic prochlorperazine. CONCLUSIONS: The ondansetron regimen was more effective and less toxic, but its cost was 20 times more than the metoclopramide regimen.

Adult↗

Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.

BACKGROUND: Vomiting caused by acute gastroenteritis is very common in children and adolescents. Treatment of vomiting in children can be problematic and the use of antiemetics remains a controversial issue. There have been concerns expressed about apparently unacceptable levels of side effects such as sedation and extrapyramidal reactions, which are associated with some of the earlier generation of antiemetics. OBJECTIVES: To assess the effectiveness of antiemetics on gastroenteritis induced vomiting in children and adolescents. SEARCH STRATEGY: We searched the Cochrane Central register of Controlled Trials (CENTRAL), which includes the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register (searched 28 July 2005), MEDLINE (1966 to July 2005) and EMBASE (1980 to July 2005). Published abstracts from conference proceedings from the United European Gastroenterology Week and Digestive Disease Week were handsearched. Members of the Cochrane UGPD Group were contacted for details of any ongoing or relevant unpublished clinical trials. SELECTION CRITERIA: Randomised controlled trials comparing antiemetics and/or placebo in children and adolescents, under the age of 18, with vomiting due to gastroenteritis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects data was collected from the studies. MAIN RESULTS: Two trials involving 181 participants were included. Although no data were available for the precise time to cessation of vomiting (the primary outcome specified in the protocol for this review), one trial reported that the proportion of patients without vomiting over a 24 hour period was higher in the ondansetron and metoclopramide groups than placebo. In the second trial, ondansetron ensured complete anti-emesis for 8/12 (67%) patients within the first 4 hours and in 7/12 (58%) patients in the first 24 hr period. A few secondary outcomes were reported in the included trials. AUTHORS' CONCLUSIONS: The small number of included trials provided some, albeit weak and unreliable, evidence which appeared to favor the use of ondansetron and metoclopramide over placebo to reduce the number of episodes of vomiting due to gastroenteritis in children. The increased incidence of diarrhea noted with both ondansetron and metoclopramide was considered to be as a result of retention of fluids and toxins that would otherwise have been eliminated through the process of vomiting.

Acute Disease↗

Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.

BACKGROUND: Vomiting caused by acute gastroenteritis is very common in children and adolescents. Treatment of vomiting in children can be problematic and the use of antiemetics remains a controversial issue. There have been concerns expressed about apparently unacceptable levels of side effects such as sedation and extrapyramidal reactions, which are associated with some of the earlier generation of antiemetics. OBJECTIVES: To assess the effectiveness of antiemetics on gastroenteritis induced vomiting in children and adolescents. SEARCH STRATEGY: We searched the Cochrane Central register of Controlled Trials (CENTRAL), which includes the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register (searched 28 July 2005), MEDLINE (1966 to July 2005) and EMBASE (1980 to July 2005). Published abstracts from conference proceedings from the United European Gastroenterology Week and Digestive Disease Week were handsearched. Members of the Cochrane UGPD Group were contacted for details of any ongoing or relevant unpublished clinical trials. The search was re-run on 12th July 2006 and one new trial was found. SELECTION CRITERIA: Randomised controlled trials comparing antiemetics and/or placebo in children and adolescents, under the age of 18, with vomiting due to gastroenteritis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects data was collected from the studies. MAIN RESULTS: Three trials involving 396 participants were included. Although no data were available for the precise time to cessation of vomiting (the primary outcome specified in the protocol for this review), one trial reported that the proportion of patients without vomiting over a 24 hour period was higher in the ondansetron and metoclopramide groups than placebo. In the second trial, ondansetron ensured complete anti-emesis for 8/12 (67%) patients within the first 4 hours and in 7/12 (58%) patients in the first 24 hr period. A few secondary outcomes were reported in the included trials. The third trial reported that 14% of patients who received ondansetron vomited during oral rehydration (which was given over one hour period after randomization) compared to 35% of the placebo group. AUTHORS' CONCLUSIONS: The small number of included trials provided some, albeit weak and unreliable, evidence which appeared to favor the use of ondansetron and metoclopramide over placebo to reduce the number of episodes of vomiting due to gastroenteritis in children. The increased incidence of diarrhea noted with both ondansetron and metoclopramide was considered to be as a result of retention of fluids and toxins that would otherwise have been eliminated through the process of vomiting.

Acute Disease↗

The antiemetic efficacy of oral ondansetron plus intravenous dexamethasone in patients with gynecologic malignancies receiving carboplatin-based chemotherapy.

PURPOSE: The purpose of this study was to develop a cost-effective prophylactic antiemetic regimen for the prevention of carboplatin-induced emesis. METHODS: Patients being treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center with a carboplatin-based chemotherapy regimen received a prophylactic antiemetic program consisting of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) approximately 30 min prior to chemotherapy. Evaluation of the effectiveness of this antiemetic regimen was performed during a single treatment course. RESULTS: A total of 27 patients (median age, 62; range, 41-83) participated in this phase 2 trial. Three patients received single-agent carboplatin, and 24 were treated with either a carboplatin/paclitaxel or carboplatin/docetaxel regimen. The carboplatin AUC dosing level was 4, 5, or 6 in 6, 5, and 16 individuals, respectively. No patient developed vomiting; 2 (7%) individuals experienced nausea during the 24-h period following chemotherapy administration. CONCLUSION: The combination of a single dose of oral ondansetron (16 mg) plus intravenous dexamethasone (20 mg) is an effective prophylactic antiemetic regimen for patients receiving carboplatin-based chemotherapy.

Administration, Oral↗

Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy.

Oral delta-9-tetrahydrocannabinol (THC), 15 mg/m2, was compared to prochlorperazine (PCZ), 10 mg. for the control of cancer chemotherapy-related emesis. Thirty-six patients whose vomiting was refractory to standard antiemetic therapy were entered in this randomized comparative cross-over study. THC decreased nausea and vomiting in 23 of 36 (64%) patients compared to 1 of 36 receiving PCZ. THC efficacy was not dependent on the class of antineoplastic-agent inducing the emetic symptoms, age of patients or type of sensorial change experienced. Using the 15 mg/m2 dose, all patients experienced transient sensorial changes, characterized as a pleasant "high" in 19 or a variable state of dysphoria in 17 cases. This study confirms the usefulness of THC in patients whose chemotherapy-induced nausea and vomiting is refractory to other standard antiemetics. While excellent antiemetic control was achieved at the dosage 15 mg/m2, dysphoria was encountered at this dose level and we recommend that an initial dose of 5 mg/m2 which, if necessary, can be carefully increased to achieve maximum antiemetic benefit.

Adult↗

Two antiemetic regimens do not impair chemical xenogenization induced in vivo by 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide.

The possible interference with 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC)-mediated chemical xenogenization (CX) by antiemetic drugs was studied. DTIC was given alone or in combination with either dexamethasone or metoclopramide plus orphenadrine hydrochloride plus diazepam to CD2F1 mice bearing the histocompatible L1210 leukemia. Tumor cells were collected from treated animals and inoculated into histocompatible untreated and drug-treated recipients, for eight transplant generations. More than 50% of intact hosts rejected tumor cells between the fourth and sixth transplant generation, independently of antiemetic treatments. Positive controls treated with DTIC plus quinacrine (QC) confirmed that this antimutagenic compound entirely abrogates CX. The present results point out that the antiemetic regimens investigated in this study do not prevent CX. Since DTIC treatment requires intensive antiemetic support in man, these data are of clinical relevance for CX-oriented immunochemotherapy protocols.

Animals↗

Antiemetic activity of the new 5-HT3 antagonist DAU 6215 in animal models of cancer chemotherapy and radiation.

The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1-1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.

Animals↗

New perspectives in antiemetic treatment.

Though antiemetic therapy has improved markedly in the past 15 years, patients still regard nausea and vomiting as two of the most distressing adverse events during chemotherapy. A major progress was the development of the serotonin3 (5-HT3) receptor antagonists. A possible antiemetic effect, achieved by interference with the "serotonergic system", is not restricted to antagonism at 5-HT3 receptors, however, but also includes agonism at 5-HT1A and 5-HT2 receptors, and serotonin synthesis inhibitors. The number of receptors thought to be involved in the emetic reflex has been augmented by neurokinin1 receptors with substance P as the preferred ligand. Animal studies have demonstrated a broad antiemetic profile of substance P antagonists. The somatostatin analogue octreotide has an antiemetic effect in patients with gastrointestinal obstruction, but has not been investigated against chemotherapy-induced emesis. The next few years will disclose, whether the efficacy and safety profiles of one or more of these drugs will make it clinically useful in the treatment of chemotherapy-induced nausea and vomiting.

Antiemetics↗

Epirubicin cytotoxicity but not oxygen radical formation is enhanced by four different antiemetics.

The anthracycline epirubicin (0.1-1.0 mg l.-1) caused a dose-dependent inhibition of the clonogenic survival of Chinese hamster fibroblasts. Four antiemetics (dixyrazin, metoclopramide, chlorpromazine and droperidol) augmented the inhibition by epirubicin. Furthermore, by using oxygen consumption as an index, epirubicin-induced free oxygen radical formation was not potentiated by the tested antiemetics. The results justify further studies on the antineoplastic and adverse effects pertaining to interaction between anthracyclines and antiemetics. Finally, the results suggest that interference of antiemetics on fibroblast toxicity does not directly involve the generation of free oxygen radicals.

Animals↗

Continuous infusion prochlorperazine: pharmacokinetics, antiemetic efficacy, and feasibility of high-dose therapy.

PURPOSE: The purpose of these sequential phase I studies was to evaluate the antiemetic efficacy and pharmacokinetics of high-dose continuous infusion prochlorperazine. METHODS: A total of 52 patients with advanced cancer were treated in two sequential phase I studies utilizing high-dose prochlorperazine. In study 1, designed to investigate the antiemetic effects of dose-intensive prochlorperazine, various cisplatin-based multiagent chemotherapeutic regimens were administered in combination with escalating doses of prochlorperazine. In study 2, a fixed dose of cisplatin (60 mg/m2) was administered over 24 h as a continuous intravenous infusion in combination with infusional high-dose prochlorperazine. Antiemetic efficacy in the first trial was assessed in terms of the number of episodes of nausea, retching, and/or emesis during the 24 h following cisplatin administration. The pharmacokinetics of high-dose prochlorperazine were evaluated in eight patients treated in study 2 at the two dose levels below those at which dose-limiting toxicity was noted. RESULTS: The maximally tolerated dose of prochlorperazine in combination with cisplatin (60 mg/m2 administered as a continuous infusion over 24 h) was 24 mg/h. The dose-limiting toxicity was grade 4 agitation and confusion noted in one patient treated at 26 mg/h. This patient died 3 days following cessation of chemotherapy due to the toxicity of the regimen in combination with the debilitating pulmonary effects of the disease. The mean end of infusion prochlorperazine level at the 24 mg/h dose level was 1.1 microM, a concentration previously reported to be consistent with the reversal of the multidrug resistance phenotype. Two partial responses were observed in study 2. CONCLUSIONS: We conclude that the antiemetic efficacy of high-dose infusional prochlorperazine does not appear to be improved over more convenient bolus administration. However, prochlorperazine levels consistent with those required in vitro for drug resistance reversal are attainable within the dose range having a tolerable toxicity profile.

Adult↗

Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update.

Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.

Antiemetics↗