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.     

Double-blind, randomized trial for the control of delayed emesis in patients receiving cisplatin: comparison of placebo vs. adrenocorticotropic hormone (ACTH).

Delayed nausea and vomiting is a significant problem for the majority of patients receiving cisplatin. We designed a double-blind randomized study comparing the effects of ACTH and placebo on delayed emesis. Sixty-four adult cancer patients entered this trial; all received a chemotherapy regimen containing cisplatin (greater than or equal to 60 mg/m2) and a combination of metoclopramide and dexamethasone for the control of acute emesis during the period from 0 to 24 h after cisplatin (day 1). Twenty-four hours after cisplatin (day 2) they were randomized to receive 1 mg of ACTH i.m. in its long-acting form, or placebo in an identical vial. All patients were asked to keep a daily record of the incidence and severity of delayed vomiting and nausea for each of the five consecutive 24-h periods after cisplatin administration. Sixty patients were evaluable. The percentages of patients experiencing vomiting in the ACTH and placebo arms were, respectively, 17% vs. 43% on day 2 (24-48 h after cisplatin) (P = 0.04), 13% vs. 40% on day 3 (48-72 h) (P = 0.04), 20% vs. 34% on day 4 (72-96 h), and 20% vs. 30% on day 5 (96-120 h). During the entire 5-day study period, 33% of the patients in the ACTH group experienced delayed vomiting as opposed to 57% in the placebo arm (P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dexamethasone vs. placebo for cisplatin-induced emesis. A randomized cross-over trial

A randomized cross-over trial of dexamethasone (10 mg I.V. before therapy, and 4 mg I.V. q 4 h X 6 doses) vs. placebo as antiemetic therapy was conducted in 19 patients receiving high-dose cisplatin. Sixteen patients and 32 treatment courses were fully evaluable. There was no significant difference between regimens in the number of emesis-free patients or the number of emetic episodes, though the duration of nausea symptoms may have been reduced. We conclude that dexamethasone as used in our trial is not an effective antiemetic in patients receiving cisplatin.     

Improved control of cisplatin-induced emesis with a combination of high doses of methylprednisolone and metoclopramide: a single-blind randomized trial

Forty-seven patients undergoing their first course of chemotherapy containing cisplatin in combination with other drugs were randomized to compare the antiemetic efficacy of high dose metoclopramide vs. high dose methylprednisolone added to metoclopramide. The number of patients who experienced no emetic episodes was significantly higher with the combination regimen (P < 0.01). In addition, both the mean number of emetic episodes (P = 0.01) and the duration of nauseas (P = 0.025) were decreased with the combination regimen. Both antiemetic regimens were well tolerated. Sex affected the response, with women having more nausea and vomiting than did men (P < 0.05).     

恩丹西酮加甲基强的松龙预防化疗所致胃肠反应的临床观察

目的观察甲基强的松龙与恩丹西酮联用预防所致的胃肠反应及毒副作用,并与单用恩丹西酮比较.方法43例恶性肿瘤患者接受联合化疗,采用随机、交叉、自身对照方法.结果顺铂组21例,非顺铂组22例.联合组对顺铂所致食欲不振第1～3天的完全控制率(80%、60%和50%)、恶心第1天的完全控制率(90%)、呕吐第2天的完全控制率(100%)均明显高于单药组(P<0.05);对非顺铂组中食欲不振、急性恶心呕吐的完全控制率高于单药组,但无统计学差异,两组对迟发性恶心呕吐控制率相仿.联合组明显减少了头晕、便秘的发生率.结论甲基强的松龙能增强恩丹西酮预防化疗所致的食欲不振、急性恶心呕吐,明显减少不良反应的发生率.但对迟发性恶心呕吐的控制率两组相似,仍需探索新的止吐方案以改善对迟发性恶心呕吐的控制.     

Double-blind randomized cross-over trial of dexamethasone and prochlorperazine as anti-emetics for cancer chemotherapy

A double-blind randomized cross-over trial of dexamethasone and prochlorperazine as adjunctive anti-emetics with cancer chemotherapy was undertaken. The drugs were compared for cisplatin, doxorubicin and several other chemotherapy regimens. A total of 44 eligible patients were analysed. Assessment was made by questionnaire answered by the patient 24 h after the chemotherapy. The parameters compared were period of time for nausea and vomiting, number of vomiting episodes, degree of somnolence and insomnia and overall preference. In all cases there was no significant difference for either drug in its ability to suppress emetic effects. Neither drug gave adequate protection against cisplatin-containing regimens. We conclude that dexamethasone alone is equivalent to the more standard dopamine antagonists.     

Metoclopramide versus metoclopramide and lorazepam. Superiority of combined therapy in the control of cisplatin-induced emesis

Sixty-four patients treated with cisplatin-containing regimens were entered into a randomized, double-blinded study examining the antiemetic efficacy of metoclopramide with and without lorazepam for control of cisplatin-induced emesis. Metoclopramide was administered to all patients at 2 mg/kg, intravenously, 30 minutes before chemotherapy and 1.5, 3.5, and 5.5 hours posttreatment. Patients randomized to receive combined antiemetic therapy were administered lorazepam at 2 mg/m2 (maximum, 4 mg dose) intravenously, 30 minutes before chemotherapy. Those patients not receiving lorazepam were given normal saline placebo. Degree of nausea and number of vomiting episodes were recorded on a data flow sheet with a visual analogue scale. Drug toxicities were evaluated before each administered dose. Patients receiving both metoclopramide and lorazepam experienced significantly less vomiting episodes (P less than 0.05) and nausea (P less than 0.01) when compared to patients given metoclopramide alone. Forty-four percent of those receiving the combined therapy reported no nausea or vomiting episodes compared to only 22% receiving metoclopramide alone. Sedation was significantly more common in patients receiving lorazepam (88%) as opposed to patients receiving only metoclopramide (43%), P less than 0.01. Amnesia was seen in 25% receiving lorazepam. No significant difference in diarrhea, dystonia, or disinhibition was observed between the two arms. The authors conclude that the combination of lorazepam and metoclopramide was superior to metoclopramide alone in the prevention of cisplatin-induced nausea and vomiting, with sedation and amnesia more commonly observed in the combined regimen.     

Improvement in the control of chemotherapy induced emesis with ondansetron, methylprednisolone and lorazepam combination in patients treated by a moderate emetic treatment and uncontrolled by a previous antiemetic combination

The objective of this double blind parallel-group multicentre study was to compare the efficacy and safety of the combination ondansetron + methylprednisolone + lorazepam (O + M + L) in the prevention of emesis induced by chemotherapy with cyclophosphamide or adriamycin . This tritherapy was compared to a bitherapy O + M. Patients included were suffering from severe haemopathy or breast cancer. They had to have an incomplete response to a previous antiemetic association of 5HT3 serotoninergic receptor antagonist and corticoid. One hundred and thirty-five adult patients were included and were randomised to receive : O + M + L or O + M for 3 days. The emesis control during the 3 days of treatment (no emetic episode during the complete course) was significantly superior in the group O + M + L than in the group O + M (69% versus 46%, p = 0. 042); nausea control on the worst day of the cure was significantly superior in the group O + M + L than in the group O + M (p = 0.04) with 76% of patients in the group O + M + L having complete or major nausea control compared to 51% in the group O + M. The stability of quality of life during the days following chemotherapy measured by one questionnaire, including two scales, one cancer specific (FLIC) and one emesis specific (FLIE), appeared significantly better in group O + M + L (p = 0.04 and p = 0.019). Safety of both antiemetic regimens was good and similar between the two treatment groups. This trial shows that the adjunction of lorazepam to ondansetron and corticoid in combination increases the antiemetic control for patients with an incomplete response to a previous regimen containing a 5HT3 serotoninergic receptor antagonist and a corticosteroid in the prevention of chemotherapy-induced emesis.     

Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis

Summary A prospective randomized double-blind trial comparing the butyrophenone analogue domperidone (D) and the synthetic cannabinoid nabilone (N) in the treatment of cytotoxic-induced emesis was conducted in 38 patients receiving highly emetogenic chemotherapy regimens (70% containing cisplatin). Patients received 20 mg D or 1 mg N the night before chemotherapy and 8-hourly on each chemotherapy day for two consecutive cycles of treatment.Three of 19 patients randomized to N completed only one cycle because of disease progression (2) or subjectively adverse effects (1). Four of 19 patients completed only one cycle of D because of lack of efficacy (3) or chemotherapy toxicity (1). In all, 32 cycles of N and 33 cycles of D were evaluable for efficacy. The mean number of vomiting episodes in cycle 1 was 4.76 for N and 12.95 for D (P<0.02). The corresponding values for cycle 2 were 4.27 and 7.69 (P>0.10), and for cycles 1 and 2 combined, 4.53 for N and 10.81 for D (P<0.01). Nausea and food intake scores did not differ significantly, although there was a trend towards less nausea and an increased food intake with N. Subjectively adverse effects were more frequent with N and included drowsiness, dizziness, dry mouth, and postural hypotension. N is superior to D for the control of cytotoxic-induced emesis.     

Double-blind,randomized crossover study of metoclopramide and batanopride for prevention of cisplatin-induced emesis

Summary We conducted a double-blind, randomized crossover study to compare the toxicity and antiemetic efficacy of the 5-hydroxytryptamine₃ receptor antagonist batanopride with that of metoclopramide in 21 chemotherapy-naive patients receiving at least 70 mg/m² cisplatin. The study was terminated when hypotension was observed following the infusion of batanopride at other institutions testing similar drug schedules. Although we observed no hypotension following treatment with batanopride in this trial, we did note asymptomatic prolongation of the corrected QT interval (QTc), PR interval, and QRS complex on the EKG in the batanopride arm. Of 15 evaluable patients, 8 experienced 2 episodes of emesis within 24 h of the first batanopride infusion, whereas 9/15 subjects experienced 2 emetic episodes following the administration of metoclopramide. Overall, the evidence suggests that this dosing schedule for batanopride may be too toxic for clinical used.     

Effective control of CMF-related emesis with high-dose dexamethasone: results of a double-blind crossover trial with metoclopramide and placebo

To establish the antiemetic activity of both dexamethasone (DXM) and metoclopramide (MCP) in patients receiving i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), 25 women with stage II breast cancer were entered into this study. A randomized, double-blind, crossover design was employed to evaluate DXM (24 mg in 5 doses) versus MCP (1 mg/kg as a single dose) versus a combination of both drugs (as above) or placebo (PLC). The patients were requested to complete a questionnaire evaluating the antiemetic effect. All but one patient completed the planned antiemetic program during the first four CMF courses. As compared to PLC, both the DXM-MCP combination and DXM alone provided a higher complete antiemetic protection rate (p = 0.01 and p = 0.006, respectively). The DXM regimens were more effective than both PLC (p = 0.004 and p = 0.01) and MCP (p = 0.002 and p = 0.006) in reducing the prevalence of severe vomiting. As compared to MCP, the DXM regimens provided a better control of the nausea (p less than 0.04 and p less than 0.01) and reduced both the episodes and the duration of vomiting (p less than 0.02 and p less than 0.05). The DXM regimens were also associated with a better patient opinion than the PLC (p less than 0.002 and p less than 0.0002). No significant differences were found between MCP and PLC, nor between the DXM regimens. Except for two dystonic reactions, MCP-related toxicity was mild, whereas that induced by DXM was negligible in patients with no contraindications to corticosteroids. As employed in this study, DXM provided safe and effective antiemetic protection for patients receiving adjuvant i.v. CMF. Data available do not support the use of a short-course MCP, either alone or in combination with DXM. The search for better antiemetic treatments is mandatory, especially for patients receiving adjuvant chemotherapy. To date, we recommend the use of DXM as a standard regimen and as a control for further studies.     

Randomized trial for the control of acute vomiting in cisplatin-treated patients: high-dose metoclopramide with dexamethasone and lorazepam as adjuncts versus high-dose alizapride plus dexamethasone and lorazepam. Study of the incidence of delayed emesis.

This study investigated the antiemetic activity of two different acute antiemesis regimens in patients receiving cisplatin-based chemotherapy. Seventy-four patients were treated with high-dose metoclopramide, dexamethasone and lorazepam (MDL) and 71 patients received high-dose alizapride, dexamethasone and lorazepam (ADL). Complete protection from vomiting was 50% in MDL-treated patients as compared with 30% in the ADL arm (p = 0.04). Incidence of delayed emesis was assessed in the first 82 patients accrued for the 120 h postcisplatin, being 69 and 60% in MDL and ADL, respectively.     

A randomized control study of the antiemetic efficacy of betamethasone versus methylprednisolone

A randomized control study of the antiemetic activity of betamethasone (B) vs. methylprednisolone (MP) was carried out. Fifty-six patients receiving CDDP (60 mg/m2-80 mg/m2) were entered. B (8 mg/body on day 1, 4 mg/body on days 2 and 3) was administered intravenously in 18 patients, and MP (1,000 mg/body on day 1, 500 mg/body on days 2 and 3) was administered intravenously in 19 patients. Severe vomiting occurred in 5 of the 19 (26.3%) with MP, 10 of the 18 (55.6%) with B, and 11 of 19 (57.9%) controls. Severe nausea occurred in 3 of the 19 (15.8%) with MP, 6 of the 18 (33.3%) with B, and 5 of the 19 (26.3%) controls. Methylprednisolone was thus considered effective (P less than 0.05) for CDDP-induced emesis.     

The antiemetic efficacy of thiethylperazine and methylprednisolone versus thiethylperazine and placebo in breast cancer patients treated with adjuvant chemotherapy (fluorouracil, doxorubicin and cyclophosphamide). A randomized, double-blind, cross-over trial

Forty-six women with breast cancer treated with adjuvant FAC (fluorouracil, doxorubicin and cyclophosphamide) entered a multicenter, randomized, double-blind, cross-over trial in which thiethylperazine (T) (6.5 mg p.o every 8 h x 3 days) plus methylprednisolone (MP) (250 mg i.v. x 2 doses) was compared with thiethylperazine plus placebo. Forty-four patients were evaluable for efficacy. T + MP was significantly better in reducing vomiting (p less than 0.01) and nausea (p less than 0.02). The complete protection rate against vomiting was 36% for T + MP compared to 18% for T + placebo, and the percentage of nausea grades 0 + 1 (none or slight) was 59% and 27% respectively. The patient preference after cross-over was strikingly in favor of T + MP (70% versus 13%) (p less than 0.001). The most important side-effects of T + MP were facial flushing (22%) and euphoria (27%). Other side-effects, such as dryness of the mouth and sedation, were common after both treatments. In conclusion, the study suggested that T + MP is superior to T alone in protecting from nausea and vomiting induced by FAC.     

A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma

We conducted a long-term follow-up (median, 10.5 years) of patients included in a randomized trial of levamisole versus placebo as surgical adjuvant therapy in 203 patients with malignant melanoma. Of the patients randomized, 104 received levamisole, and 99 received placebo. The results show that there is no difference between the treatment and control groups with regard to any of the three end points analyzed. These included disease-free interval, time to appearance of visceral metastasis, and survival. Moreover, there was no significant difference between the treatment and control groups after adjusting for age, sex, or stage of disease.     

Antiemetic superiority of lorazepam over oxazepam and methylprednisolone as premedicants for patients receiving cisplatin-containing chemotherapy

Lorazepam, oxazepam, and methylprednisolone were compared for antiemetic efficacy in patients receiving cisplatin chemotherapy. Three consecutive courses of cisplatin-containing chemotherapy were administered at equal doses so that each patient acted as his own control. Of 100 patients randomized, 85 received at least two of the three agents and were evaluable for analysis. Lorazepam significantly reduced the number of patients with more than ten vomits compared to either oxazepam (P less than 0.05) or methylprednisolone (P less than 0.001). Lorazepam also significantly reduced the number of patients with the most severe degrees of vomiting compared to either oxazepam or methylprednisolone (both P less than 0.005). The duration of vomiting was reduced significantly after the first 48 hours postchemotherapy for those patients receiving lorazepam over those receiving methylprednisolone (P less than 0.05). Lorazepam significantly reduced the number of patients with severe nausea compared to both oxazepam and methylprednisolone (both P less than 0.05), but there were no significant differences in duration of nausea among the groups. The results of linear analogue self-assessment scores indicated a strong patient preference for lorazepam over both oxazepam and methylprednisolone. Drowsiness was significantly more common with both lorazepam and oxazepam compared to methylprednisolone (both P less than 0.001). Patients who received lorazepam or oxazepam also experienced significantly more severe drowsiness than those patients receiving methylprednisolone (both P less than 0.001). Lack of recall was significantly more common with lorazepam than with oxazepam and methylprednisolone (both P less than 0.001) and was more profound when lorazepam was compared with oxazepam (P less than 0.05) and with methylprednisolone (P less than 0.001). Methylprednisolone was administered with minimal side effects. The results of this randomized cross-over study indicate that, in the dosage/schedule used, lorazepam is a significantly superior premedicant than is either oxazepam or methylprednisolone in alleviating the distress of cytotoxic-induced emesis in patients receiving cisplatin-containing chemotherapy.     

格拉司琼加甲泼尼龙预防含顺铂化疗所致恶心呕吐的临床研究

目的　观察格拉司琼 (凯特瑞、Kytril)与甲泼尼龙 (甲基强的松龙 )联用预防含顺铂的联合化疗所致的恶心、呕吐及其它不良反应 ,并与单用格拉司琼比较。方法　采用随机、交叉、自身对照法 ,将 4 0例接受含顺铂 30mg/( m2 · d)× 3的联合化疗的恶性肿瘤患者 ,随机分为 A、B两组。 A组第 1周期用格拉司琼 ,第 2周期用格拉司琼加甲基强的松龙 ;B组第 1周期用格拉司琼加甲基强的松龙 ,第 2周期用格拉司琼。止吐方案 :格拉司琼 3mg,静注 ,第 1～ 3天 ,甲基强的松龙 12 0 mg,静注 ,第 1～ 3天。结果　格拉司琼加甲基强的松龙 (联合组 )第 1～ 6天无恶心和轻度恶心 ,发生率均高于单用格拉司琼 (单用组 ) ,其中第 1～ 4和第 6天差异有显著性 ( P<0 .0 5 )。格拉司琼加甲基强的松龙 (联合组 )第 1～ 6天呕吐完全控制率 ( CR率 )和有效控制率 ( CR+ PR)均高于单用格拉司琼 (单用组 ) ,其中第 2、3天差异有显著性 ( P<0 .0 5 )。结论　甲基强的松龙能增强格拉司琼对含顺铂化疗所致的恶心、呕吐的控制 ,可作为预防和控制含顺铂联合化疗所致恶心、呕吐的一线治疗。