Antiemetic activity of high-dose metoclopramide combined with methylprednisolone versus metoclopramide alone in dacarbazine-treated cancer patients. A randomized double-blind study of the Italian Oncology Group for Clinical Research

In a double-blind randomized trial, we compared the efficacy and tolerability of high-dose (2 mg/kg X 4) intravenous metoclopramide (MTC) versus metoclopramide plus high-dose (250 mg X 2) intravenous methylprednisolone (MP) administered for the first 2 days in untreated patients submitted to dacarbazine chemotherapy for 5 days. Thirty-four patients entered the study. Complete protection from nausea and vomiting was achieved in the majority of patients all through the study period with both antiemetic treatments, with slightly greater efficacy at day 2 for the combination. However, after suspension of the antiemetic therapy, there was a relapse of vomiting in patients. Side effects were not different between the two treatments, but extrapyramidal reactions were significantly increased on the second day of antiemetic therapy. In conclusion, high-dose MTC with or without MP can give good antiemetic protection and the combination seems to be slightly more efficacious. However, the relapse of vomiting after discontinuing antiemetic treatment and the high incidence of extrapyramidal reactions justify further studies to find a better antiemetic treatment.     

Effect of acupuncture compared with placebo-acupuncture at P6 as additional antiemetic prophylaxis in high-dose chemotherapy and autologous peripheral blood stem cell transplantation: a randomized controlled single-blind trial.

PURPOSE: The purpose is to investigate an additional antiemetic effect to ondansetron with needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture in patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation. EXPERIMENTAL DESIGN: Eighty patients who were admitted to hospital for high-dose chemotherapy and autologous peripheral blood stem cell transplantation were included into a randomized placebo-controlled single-blind trial. The patients were randomized to receive acupuncture (n = 41) or noninvasive placebo acupuncture (n = 39) at the acupuncture point P6 30 min before first application of high-dose chemotherapy and the day after. All patients received 8 mg ondansetron/day i.v. as basic antiemetic prophylaxis. The main outcome measure was the rate of patients who either had at least one episode of vomiting or required any additional antiemetic drugs on the first 2 days of chemotherapy. RESULTS: The main outcome measure showed no significant difference (P = 0.82): 61% failure in the acupuncture group and 64% in the placebo acupuncture group (95% confidence interval of 3% difference: -18.1 and 24.3%). Comparing nausea, episodes of vomiting or retching and number of additionally required antiemetic drugs did not provide any discrepancy with the main result. CONCLUSIONS: This study suggests that in combination with ondansetron i.v., invasive needle acupuncture at P6 compared with nonskin-penetrating placebo acupuncture has no additional effect for the prevention of acute nausea and vomiting in high-dose chemotherapy.     

Five-drug antiemetic combination for cisplatin chemotherapy.

A combination of metoclopramide, dexamethasone, droperidol, lorazepam, and diphenhydramine was used in prophylaxis of high-dose (greater than or equal to 100 mg/m2) or moderate dose (greater than or equal to 50 mg/m2) cisplatin. Sixty minutes prior to starting cisplatin, 16 mg dexamethasone, 50 mg diphenhydramine, and 0.5 mg lorazepam were given orally (PO). Droperidol 1 mg was given intramuscularly (IM) 15 minutes prior to beginning cisplatin. Repetitive doses of intravenous (IV) metoclopramide, 2 mg/kg in 75 ml 5% dextrose in water over 15 minutes was given 30 minutes prior to, and at 1 1/2, 4 1/2, and 7 1/2 hours after beginning cisplatin chemotherapy. Only patients with nausea and/or vomiting received subsequent doses of 2 mg/kg metoclopramide IV every 3 hours as needed. Patients refractory to metoclopramide were given 1 mg droperidol IM and 50 mg of diphenhydramine PO every 6 hours. There were 19 men and 9 women with a median age of 58 (range 31-75) years. Complete protection from nausea and vomiting in all courses of treatment occurred in 17 (61%) patients. In 63% and 70% of the 57 evaluable courses, there was neither nausea nor vomiting, during the first 24 hours after cisplatin. When present, nausea was mild and the median number of vomiting episodes was 2 (range 1-3). This antiemetic regimen was well tolerated. Toxicities were mild and occurred in 3 patients (angioneurotic edema, transient episode of facial twitching, and heaviness of tongue, respectively). The 5-drug antiemetic combination can prevent cisplatin-induced nausea and vomiting in a majority of patients.     

Amelioration of cytotoxic-induced emesis with high-dose metoclopramide,dexamethasone and lorazepam

Summary A double-blind randomised controlled trial comparing the antiemetic effects of sublingual lorazepam combined with high-dose, short course metoclopramide (3 mg/kg) infused twice 3 h apart with or without i.v. dexamethasone is reported. Sixty patients receiving a total of 209 cycles of potentially severely emetic cytotoxic chemotherapy were randomised to receive one or other antiemetic regimen. In those receiving platinum-based chemotherapy the addition of dexamethasone was associated with an improvement in freedom from nausea (P<0.01) and freedom from vomiting (P<0.05). In the non-platinum-based chemotherapy group the addition of dexamethasone led to a reduction in the duration and severity of nausea, and duration of vomiting (P<0.05 in each case). Both antiemetic regimens were well tolerated with a low incidence of adverse effects and could be administered easily in an outpatient setting.     

Prevention of delayed emesis induced by moderately emetogenic chemotherapy in patients with acute emesis

The rates of delayed nausea and vomiting by moderately emetogenic chemotherapy in patients with previous experience of acute emesis are usually quite high. This is a pilot study aiming to evaluate the safety of a new antiemetic schedule to prevent delayed emesis in this subset of patients. During 5 consecutive cycles of moderately emetogenic chemotherapy, we evaluated 50 patients (15 males) who experienced acute emesis in the first cycle of treatment. The regimen for prevention of delayed emesis consisted of daily tropisetron (5 mg orally from d 2 to d 6 of each chemotherapeutic cycle) associated to ACTH-Depot (1 mg intramuscularly 24 and 68 h after the initiation of chemotherapy). In 77% of chemotherapy cycles, there was a total elimination of nausea and vomiting, whereas in the remaining 23% of cycles, there was a major response defined as ≤ 2 vomiting episodes per cycle or nausea grade 1 according to the WHO. The efficacy of the antiemetic regimen persisted during the entire treatment program without the appearance of toxic effects. The proposed antiemetic regimen is highly active in preventing delayed nausea and vomiting episodes in patients receiving moderately emetogenic chemotherapy. Moreover, no toxic effects were observed. These promising results require confirmation by a randomized trial.     

Randomized cross-over study on the effects of methylprednisolone, metoclopramide and droperidol on the control of nausea and vomiting associated with cis-platinum chemotherapy

A randomized cross-over study on the effects of methylprednisolone (MP), metoclopramide (MT) and droperidol (DP) on the control of nausea and vomiting associated with cis-platinum chemotherapy was performed. Sixty-three patients were entered into the study; 60 patients (21 treated with MP, 18 with MT and 21 with DP) were eligible for evaluation of antiemetic efficacy, whereas the side effects of these drugs were evaluated in all of the 63 patients. Out of the above 60 patients, 36 were entered into the cross-over treatment. Antiemetic efficacy was evaluated in terms of duration of nausea, duration of vomiting, frequency of vomiting, duration of inability to take food and the amount of food first taken after cis-platinum treatment. Generally, the MP-treated group of patients showed favorable effects in these points, MP being especially more effective than other drugs with a statistically significant difference for the control of nausea and disturbed intake of food during the first 24 hours after the treatment with CDDP. Anticipatory nausea and vomiting were not observed in this study. Side-effects were minimal and all of the patients except one, who showed severe diarrhea following administration of MT and could not tolerate the treatment thereafter, were safely treated.     

High-dose intravenous metoclopramide versus combination high-dose metoclopramide and intravenous dexamethasone in preventing cisplatin-induced nausea and emesis: a single-blind crossover comparison of antiemetic efficacy

We tested the safety and antiemetic effectiveness of intravenous (IV) dexamethasone (DXM) as an adjunct to high-dose IV metoclopramide (MCP) to prevent nausea and vomiting induced by high-dose cisplatin chemotherapy. Response was determined by using objective and subjective criteria. Thirty patients were randomly assigned to receive MCP alone at a dose of 2 mg/kg IV for three doses or the same dose of MCP plus 20 mg of DXM IV for three doses. Twenty evaluable patients received a second course of cisplatin and were crossed over to the opposite arm. Study results did not show a statistically significant advantage of combination MCP plus DXM over MCP alone using strict objective criteria for antiemetic response. However, patients subjectively preferred MCP plus DXM over MCP alone by nearly a 6:1 ratio, regardless of the randomization sequence. Although the addition of DXM does not appear to objectively improve emetic protection with high-dose MCP, we recommend MCP plus DXM to prevent nausea and vomiting induced by high-dose cisplatin chemotherapy when the use of steroids is not contraindicated, in view of patient preference for the combination.     

Antiemetic regimens in outpatients receiving cisplatin and non-cisplatin chemotherapy. A randomized trial comparing high-dose metoclopramide plus methylprednisolone with and without lorazepam

Results of a randomized trial on antiemesis for cisplatin (CDDP) and non-CDDP chemotherapy-induced vomiting are reported. One hundred and sixty-three outpatients received 282 chemotherapy courses (141 with CDDP and 141 without CDDP). Patients were randomly assigned to receive either high-dose metoclopramide plus methylprednisolone (arm A) or the same drugs plus lorazepam (arm B). In both arms a high protection rate for vomiting was obtained, on the whole without statistically significant differences. Patients who received lorazepam had, however, significantly fewer nausea episodes during first day post-chemotherapy (p less than 0.05). Arm B was also superior in anxiety control during the first day of chemotherapy (p less than 0.01). Both regimens were significantly more effective in patients who had not been given chemotherapy previously (p less than 0.01). No differences in antiemetic protection were found between CDDP and non-CDDP courses. No significant differences were found in premonitory vomiting control between the two arms of the trial. Toxicity was very mild with both regimens, although sedation was significantly higher in arm B (p less than 0.001). We conclude that high-dose metoclopramide plus methylprednisolone is a highly effective combination for chemotherapy-induced nausea and vomiting, and that it is quite suitable for outpatient use. Lorazepam did not significantly increase the antiemetic potency of the combination, nor did it improve premonitory vomiting control, although it gave a better control of acute nausea and anxiety.     

Sustained-Release Metoclopramide Plus Methylprednisolone Versus Placebo Plus Methylprednisolone as Antiemetic Prophylaxis During Non-Cisplatin Chemotherapy: A randomized double-blind cross-over trial

In a randomized double-blind cross-over trial, sustained-release metoclopramide (S) plus methylpred-nisolone (M) was compared with placebo (P) plus methylprednisolone as antiemetic prophylaxis during two cycles of non-cisplatin chemotherapy. S was administered as 60 mg every 12 h commmencing on the evening before chemotherapy up to total of 300 mg metoclopramide in 2.5 days. Evaluation of nausea and vomiting was done by self-assessment schemes and visual analog scales. Fifty patients were included and 36 fulfilled both cycles. Mild nausea and vomiting were experienced by 81% and 83% in the S + M and P + M groups, respectively, while 42% and 39% showed complete control of nausea and vomiting during the first day of treatment. Moderate-dose S did not add to the antiemetic efficacy of M in non-cisplatin chemotherapeutic regimens.     

Single, high-dose intravenous dexamethasone as an antiemetic in cancer chemotherapy

The antiemetic effect of graded, single high-dose intravenous dexamethasone was studied in 27 patients receiving combination chemotherapy with either doxorubicin (50 mg/m2) or cis-platinum (100 mg/m2). A total of 57 cycles were individually evaluated, utilizing a detailed rating system. Nausea and vomiting did not occur in 20 of 57 cycles; in 17, the chemotherapy was doxorubicin-based, and in 3 it was cis-platinum-based. Of the 37 cycles associated with nausea and vomiting, 32 contained cis-platinum and 5 doxorubicin. The average dexamethasone dosages for doxorubicin and platinum-containing combinations were 40 and 95 mg/m2, respectively. Side effects included a dose-dependent sensation of perineal pruritis (11 patients, 17 cycles) lasting for several minutes, and subjective feelings of increased appetite and well-being. Dexamethasone administered intravenously 15 min prior to chemotherapy in a dose of 40 mg/m2 apparently provides highly effective antiemetic protection for patients receiving treatment cycles containing doxorubicin; however, for patients receiving regimens containing cis-platinum, the antiemetic effect of dexamethasone as a single agent is limited.     

Maintenance of antiemetic effect of a metoclopramide-dexamethasone combination during subsequent cisplatin courses

In two previous consecutive studies on antiemetic combination of metoclopramide and dexamethasone was found to be very active against nausea and vomiting induced by cisplatin (DDP; 50 mg/m2) alone or in combination with other cytotoxic emetogenic drugs. In the present study the activity of the same antiemetic combination has been followed in 18 patients during subsequent DDP courses. Twelve out of 18 patients (67%) had a complete control of the side effect after the first course of chemotherapy. No statistically significant differences were found as regards the intensity of nausea and vomiting, the patients' overall opinions and preference and the emesis duration. In conclusion this antiemetic combination can guarantee a high degree and long-term control of DDP-induced emesis at a dose of 50 mg/m2 given alone or in combination.     

Efficacy and tolerability of tropisetron in the prevention of cisplatin-induced nausea and vomiting in advanced non-small cell lung cancer

The efficacy and tolerability of tropisetron were studied in an open trial comprising a total of 30 patients with advanced non-small cell lung cancer undergoing high-dose, cisplatin-based chemotherapy (cisplatin dosage 100 mg/m2). Patients received tropisetron 5 mg intravenous infusions for 15 min on day 1. followed by 5 mg tropisetron taken orally in the morning on days 2 6. All treated patients were assessed during the entire treatment period (6 days). Acute nausea and vomiting were evaluated during the 24 h after chemotherapy. Delayed nausea and vomiting were evaluated during days 2-6 after chemotherapy. Response to tropisetron was graded as: complete control, major control, minor control and failure for nausea or vomiting. Rates for complete plus major control of acute nausea and vomiting in cycles 1-5 were 77%, 81%, 86%, 67% and 75%, respectively. Rates for complete plus major control of delayed nausea and vomiting in cycles 1-5 were 87%, 76%, 86%, 78% and 75%, respectively. Adverse reactions were mainly headache and diarrhea, but both reactions were mild and are common in most patients treated with this type of antiemetic agent. It is concluded that tropisetron is an effective drug for the prevention of side effects of highly emetogenic drugs such as cisplatin. The dosage and schedule of tropisetron reported here can prevent both acute and delayed nausea and vomiting.     

Combination antiemetics for cisplatin chemotherapy

Nausea and vomiting occur in a majority of patients receiving cisplatin chemotherapy despite prophylactic single agent antiemetic therapy. Three potent antiemetics, metoclopramide, droperidol and dexamethasone, and diphenhydramine to prevent potential extrapyramidal reactions, were combined in prophylaxis of 67 patients receiving cisplatin chemotherapy. Of the patients studied, 76.1% experienced complete protection from both nausea and vomiting in their first course and 62.7% in all their courses of treatment. In 73.3% of 161 evaluable courses, there was neither nausea nor vomiting. Vomiting did not occur in 79.5% of courses. There was no evidence to suggest tachyphylaxis. The efficacy in preventing nausea and vomiting was independent of primary disease site, age, sex, performance status, prior chemotherapy, and prior vomiting. Toxicities were mild and infrequent. Reversible transient extrapyramidal reactions, sweating or twitches occurred in 5.6% of courses. The combination of metoclopramide, diphenhydramine, droperidol and dexamethasone was highly efficacious in preventing nausea and vomiting in moderate or high-dose cisplatin chemotherapy with little toxicity.     

An antiemetic effect of methylprednisolone plus droperidol against nausea and vomiting caused by administration of high-dose adriamycin to breast carcinoma patients

An antiemetic combination of methylprednisolone and droperidol was administered to 10 patients with breast cancer showing postoperative recurrence, receiving high-dose adriamycin. Methylprednisolone was given twice intravenously at a dose of 500 mg, before and after administration of adriamycin, and droperidol was given just before administration of adriamycin. The 10 patients received a total of 20 chemotherapy courses. Complete relief of vomiting was achieved in 95% of these 20 courses, and mild nausea occurred in 40%. Side effects were drowsiness, acne and akathisia, which were minimal. It was concluded that an antiemetic combination of methylprednisolone and droperidol was very effective for prevention of high-dose adriamycin-induced nausea and vomiting.     

Tropisetron plus haloperidol to ameliorate nausea and vomiting associated with high-dose alkylating agent cancer chemotherapy

Tropisetron is a novel antiserotoninergic drug with potent and specific activity against cancer chemotherapy-induced emesis. High-dose cyclophosphamide or high-dose melphalan are chemotherapeutic regimens associated with severe nausea and vomiting refractory to current antiemetic medications. We compared in a randomised open label study the antiemetic efficacy of tropisetron and alizapride in a first group of 32 consecutive patients treated with high-dose alkylating agent chemotherapy with or without autologous bone marrow transplantation. Tropisetron was more effective than alizapride in reducing vomiting episodes. In the first 24 h of treatment the median number of episodes in patients treated with tropisetron was 5 compared with 9 episodes in the alizapride group (P = 0.005). In the 72 h study period the median number of emetic episodes was 6 in the tropisetron group and 12 in the alizapride group (P = 0.004). In a second group of 26 consecutive patients, a combination of tropisetron plus haloperidol, a dopamine antagonist, was employed for prevention of emesis. This combination was more effective than tropisetron as single agent in preventing emetic episodes, as the median number of emetic episodes in the 72 h of observation was only 3, while they were 6 in the tropisetron group. The side-effects of tropisetron were mild and reversible upon discontinuation of the drug. We conclude that tropisetron is an effective antiemetic drug when employed in high-dose alkylating agent chemotherapy, and that its activity is potentiated by the association with haloperidol.     

盐酸帕洛诺司琼预防含顺铂化疗所致恶心、呕吐的临床观察

目的通过与格拉司琼比较,观察和评价帕洛诺司琼预防含高度催吐危险化疗药物顺铂所致恶心、呕吐的疗效和安全性。方法采用随机、交叉、自身对照法,将84例含顺铂化疗方案治疗的恶性肿瘤患者分成两组：A组第1周期用帕洛诺司琼及地塞米松;B组第1周期用格拉司琼及地塞米松;第2周期A、B组交叉使用。止吐方案：帕洛诺司琼0．25mg,静脉推注d1,d3;格拉司琼3mg,静脉滴注dl-3;地塞米松10nag,静脉推注d1—3。观察化疗后7天内恶心、呕吐的情况以及与止吐药相关不良反应。结果帕洛诺司琼与格拉司琼对化疗后急性呕吐完全控制率分别为77．4％和71．4％,总有效率分别为90．5％和86．9％,差异均无统计学意义（均P〉0．05）;帕洛诺司琼与格拉司琼对化疗后延迟性呕吐完全控制率分别为66．7％和47．6％,总有效率82．1％和59．5％,差异均具有统计学意义（均P〈0．05）;与止吐药相关不良反应主要为便秘和头痛,两药发生率分别为22．6％和25．0％,差异无统计学意义（P〉0．05）。结论帕洛诺司琼对预防含顺铂化疗所致的急性呕吐的疗效与格拉司琼相当,但对预防延迟性呕吐的疗效优于格拉司琼,且不良反应发生率低、程度较轻、安全性好。     

Efficacy of Intravenous Granisetron to Control Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy

The safety and efficacy of granisetron (10 µg/kg and 40 µg/kg) were evaluated during a second (n = 393) and third (n = 200) cycle of chemotherapy in this multicenter, double-blind, randomized, parallel-group study. Granisetron was administered as a single intravenous dose before the start of cisplatin chemotherapy (≥60 mg/m²). Total control (no vomiting, no retching, no nausea, and no use of antiemetic rescue medication) after the first 24 hr following chemotherapy was achieved in 40% and 49% of patients in Cycles 2 and 3, respectively, for the 10 µg/kg group, and in 42% and 38% of patients in Cycles 2 and 3, respectively, for the 40 µg/kg group. Both dose levels of granisetron were well tolerated. The results demonstrate comparable efficacy between the 10 µg/kg and 40 µg/kg doses of granisetron in preventing nausea and vomiting during repeat cycles of high-dose cisplatin-based chemotherapy. The results of this study show that granisetron 10 µg/kg is safe and well tolerated, and remains effective with repeat cycle use.     

High-dose dexamethasone and high-dose metoclopramide versus high-dose dexamethasone and sulpiride in the management of cisplatin-induced emesis

Twenty-eight courses of combination chemotherapy including cisplatin at the dose of 50 mg/m2 were analyzed in this antiemetic randomized double-blind study. The combination of high-dose dexamethasone and high-dose metoclopramide (regimen A) was compared with the combination of high-dose dexamethasone and sulpiride (regimen B). Regimen A was found to be more effective than regimen B when the mean score for intensity of vomiting was presented in only two categories. Four patients (14.3%) treated with regimen A suffered neither from nausea nor from vomiting. No serious side effects were observed.     

A phase III trial comparing the antiemetic activity of tetracosactide with dexamethasone in combination with metoclopramide, diphenhydramine and clorazepate during chemotherapy including cisplatin

In order to compare the safety and the antiemetic effectiveness of tetracosactide (TCS) or beta 1,24 ACTH with those of dexamethasone (DXM) as an adjunct to high-dose metoclopramide, diphenhydramine and clorazepate, 33 patients receiving cisplatin based cancer chemotherapy were enrolled in a double-blind cross-over clinical trial. TCS and DXM were given intravenously, respectively at a dose of 2 mg and 20 mg, and concurrently to the cisplatin infusion. No statistically significant difference was noted between the two drugs with regard to efficacy or side effects. We conclude that TCS can serve as a substitute for DXM in combination antiemetic regimens for management of cisplatin-induced nausea and vomiting.     

Betamethasone-dixyrazine combination versus high-dose metoclopramide as antiemetic treatment in doxorubicin and cisplatin chemotherapy

In a prospective randomized and double-blind cross-over study, a new antiemetic regimen consisting of betamethasone (1 x 8 mg) and dixyrazine (a phenothiazine derivative) (4 x 10 mg) was compared with a standard high-dose metoclopramide (4 x 1 mg/kg) schedule for antiemetic treatment in doxorubicin and cisplatin chemotherapy. 100 consecutive patients (62 without prior experience of chemotherapy and 38 with prior experience) entered the study and were followed during 1-4 courses of chemotherapy. Effect and side effect parameters were recorded on questionnaires for patients and nurses using the visual analog scale for quantification. The correlation between the two ways of recording (self-scoring versus recording by nursing staff) was very high, both for effect variables (nausea and vomiting) and the adverse reactions (sedation and extrapyramidal reactions). The median number of courses per patient was 3.0 (range 1-4) and altogether 299 courses were studied. Full emetic protection was achieved in 58% with betamethasone-dixyrazine and in 34% with high-dose metoclopramide regardless of prior patient experience or the cytostatic agents administered. With doxorubicin regimens, betamethasone-dixyrazine gave full protection in 80% compared to 40% for metoclopramide. Cisplatin regimens were a greater challenge and protection against nausea and vomiting was achieved only in 27% with betamethasone-dixyrazine and in 18% with metoclopramide. Adverse reactions were a significant problem with metoclopramide: restlessness 33%, akathisia 19%, parkinsonism 16%, and acute dystonia 3%. Sedation was the same with the two regimens (80%).