The effect of metoclopramide, dexamethasone and antihistamine in the prevention of PAC chemotherapy-induced emesis

The effect of antiemetic agents on the nausea and emesis of ovarian cancer patients treated with CDDP (45 mg/m2), ADM (45 mg/m2) and CPM (450 mg/m2) combination chemotherapy was examined in a randomized parallel study. Metoclopramide (1 mg/kg, 4 times every 2.5 hours), dexamethasone (3.8 mg, 4 times every 2.5 hours) and antihistamine (10 mg, 2 times every 5 hours) were used as antiemetic agents and these agents were gradually decreased for 5 days. The above regimen significantly suppressed the frequency and volume of vomiting on the day of the first PAC chemotherapy but showed no effect on the delayed persistent nausea during chemotherapy. The frequency and volume of vomiting on the day of chemotherapy were 1.6 times and 102 ml respectively in the antiemetic group, but 8.9 times and 352 ml, respectively, in the control group. Although this antiemetic regimen sufficiently suppressed acute drug-induced emesis during chemotherapy, delayed persistent nausea was not eliminated. We next investigated whether these combined antiemetic agents protected the quality of life of patients during maintenance chemotherapy. Our data indicated that about 2 weeks was necessary to recover health after maintenance PAC chemotherapy. These results indicated that this regimen was effective in suppressing the acute drug-induced emesis and in maintaining the quality of life following maintenance PAC chemotherapy.     

Prochlorperazine and transdermal scopolamine added to a metoclopramide antiemetic regimen. A controlled comparison

Cisplatin-induced nausea and vomiting occurs both acutely and over a prolonged period of time. These symptoms may be incapacitating and are frequently given as a reason to discontinue therapy. We compared prochlorperazine and transdermal scopolamine when added to a standardized metoclopramide antiemetic regimen. Twenty-seven patients receiving cisplatin at 100 mg/m2 were randomly assigned to one of the two treatment arms. Patients were observed during chemotherapy and answered a standard questionnaire 24-26 hours later. Among similar treatment groups no differences were seen regarding the number of emetic events, level of nausea, degree of sedation or overall acceptability of one treatment arm or another. While not superior to prochlorperazine, transdermal scopolamine is a useful antiemetic agent and can be combined with metoclopramide in an attempt to reduce cisplatin-induced nausea and vomiting. Further evaluation of this approach is needed.     

High-dose metoclopramide as an antiemetic in patients receiving cis-platinum-based combination chemotherapy

Thirty-seven patients with advanced malignancies, who received cis-platinum-based combination chemotherapy, were evaluated for the antiemetic efficacy of high-dose metoclopramide. Most of the patients suffered from ovarian carcinoma. The dose of metoclopramide was 7.5 or 10 mg/kg per course. A total of 69 courses were given to 37 patients and in 22% of the courses, nausea and vomiting were eliminated altogether. In an additional 48% of the courses, a partial protection from chemotherapy-induced emesis was evident. No serious side effects were observed. The administration of high-dose metoclopramide is recommended for prevention of cis-platinum chemotherapy-induced emesis.     

Effectiveness of serotonin-receptor antagonist antiemetic therapy over successive courses of carboplatin-based chemotherapy

PURPOSE: There are extremely limited data available in the general oncology or gynecologic cancer literature to document the effectiveness of antiemetic therapy over multiple courses of cytotoxic chemotherapy. METHODS: To examine this highly clinically relevant issue, we analyzed the complete treatment course of patients with gynecologic cancers receiving carboplatin-based chemotherapy regimens who had participated in one of four institutional serotonin-receptor antagonist antiemetic trials, which had specifically evaluated the benefits of such therapy during only the first treatment course. Medical records were reviewed to examine the development of emesis during subsequent chemotherapy treatment cycles. RESULTS: The 91 patients included in this analysis received a median of 6 courses (range 1-18) of carboplatin (initial AUC dose 4, 5, and 6 in 29, 29, and 32 patients, respectively). All received ondansetron or granisetron plus dexamethasone with every treatment course. Complete control of emesis (no acute or delayed nausea or vomiting) was experienced by 56 (62%) patients during every cycle. Conversely, 20% of women noted one or more episodes of nausea without vomiting and 19% developed at least one incidence of vomiting. In no case was emesis considered to be severe (grade 3), and no patient required either discontinuation of carboplatin or a dose reduction due to the development of emesis. CONCLUSION: In the large majority of patients, serotonin-receptor antagonist antiemetic therapy, administered in combination with dexamethasone, is highly effective over multiple courses in preventing significant carboplatin-induced nausea and vomiting.     

Antiemetic efficacy of high-dose corticosteroids and droperidol in cisplatin-induced emesis: A controlled trial with droperidol and metoclopramide

The nausea and vomiting associated with cisplatin chemotherapy make care of the patient more difficult for nurses and physicians, can cause severe metabolic and pathologic sequelae, and preclude further courses of chemotherapy. Current reports suggest that the two most efficacious agents for antiemetic prophylaxis are metoclopramide and corticosteroids. These two agents in combination with droperidol have been compared in a randomized controlled prospective fashion. Patients had less nausea and vomiting on the steroidal regimen than the nonsteroidal regimen (P less than 0.05), and the duration of nausea and vomiting was significantly less on the steroidal regimen (P less than 0.05). Patients expressed a preference for the steroidal regimen over the nonsteroidal one and the steroidal regimen retained its antiemetic effectiveness through repeated courses of chemotherapy. The results of the study suggest that corticosteroids and droperidol are superior antiemetic agents for cisplatin-induced nausea and vomiting.     

The prevention of CDDP-induced emesis with a combination regimen including metoclopramide, dexamethasone, droperidol and diphenhydramine

The dose limiting factors of cisplatinum are nephrotoxicity and emesis. Nephrotoxicity has been reduced by hydration but nausea and vomiting caused by cisplatinum have led to refusal of potentially curative therapy by a number of patients. The prevention of nausea and vomiting by a combination of antiemetic drugs administered to ovarian patients receiving chemotherapy inducing (cisplatinum 50mg/m2, adriamycin 300 mg/m2, cyclophosphamide 300 mg/m2 and 5FU 350 mg/m2) was studied. the combination antiemetic drugs were metoclopramide (1mg/kg), dexamethasone (10mg/m2), droperidol (1mg/m2) and diphenhydramine (20mg/body). These drugs without diphenhydramine were administered intravenously 30 minutes before and 2.5 hours, 5 hours and 7.5 hours after chemotherapy. Diphenhydramine was administered intramuscularly 30 minutes before and 5 hours after chemotherapy. No vomiting was noted in 82.6% (19/23) of cases, and no patient vomited more than four times. This combination regimen provided very good protection against cisplatinum induced emesis.     

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.     

Effect of medical vagotomy on the CDDP induced nausea and vomiting evaluated by the chemotherapy-vomiting time (CV time)

Twenty-eight patients with gynecologic malignancies receiving combination chemotherapy containing cisplatin (80 mg/m2) entered into a randomized controlled trial to evaluate the effect of medical vagotomy for acute cisplatin-induced emesis. Medical vagotomy consisted of 0.5 mg of atropine and 50 mg of hexamethonium bromide, and was injected three times at two hour intervals intramuscularly. A good antiemetic effect (no emesis during the 24 hours after cisplatin administration) was obtained in 40% (6/15) of patients with medical vagotomy but in 0% (0/13) in controlled cases. The time free of vomiting after cisplatin injection (CV time) was statistically prolonged in patients with medical vagotomy (805 +/- 563 min.) when compared with controlled cases (148 +/- 70 min.) (p less than 0.01). Toxicities with medical vagotomy were slight; mild hypotension and dimness of vision only. Individual differences in responding to medical vagotomy were investigated by the acetaminophen method, which showed that high and low responded cases were among these tested patients who had undergone medical vagotomy. In conclusion, medical vagotomy has an excellent antiemetic effect on acute cisplatin-induced emesis without notable side effects. If combined with other antiemetics, a much better antiemetic effect can be expected.     

Control of Carboplatin-Induced Emesis with a Fixed Low Dose of Granisetron (0.5 mg) plus Dexamethasone

In an effort to develop a cost-effective antiemetic regimen for carboplatin-based chemotherapy, we examined a fixed (0.5 mg) low dose of granisetron (a new 5-HT₃(serotonin) antagonist) plus dexamethasone (20 mg) in 23 patients with gynecologic malignancies receiving this antineoplastic drug. Nineteen (83%) patients experienced complete control of acute emesis (nausea and vomiting) while 22 (96%) individuals demonstrated complete or major control (≤2 episodes of vomiting, ≤5 episodes of retching, minimal interference with eating) of emetic events. We conclude that this fixed low-dose granisetron plus dexamethasone regimen is a safe, convenient, and cost-effective antiemetic program for individuals receiving carboplatin-based chemotherapy.     

Antiemetic treatment of chemotherapy-induced nausea in ovarian carcinoma patients

In a prospective, randomized, double-blind trial the combination betamethasone-dixyrazine was compared with high-dose metoclopramide as antiemetic treatment during combination chemotherapy (melphalan-doxorubicin and cisplatin) of ovarian carcinoma. Of 40 evaluable patients, 15 (38%) had previous experience with chemotherapy. Efficacy and side effects were recorded on patient and nurse questionnaires using the visual analog scale. Nausea and vomiting were prevented in 55% of the patients treated with melphalan-doxorubicin (Day 1) and in 36% of the patients treated with cisplatin (Day 2). Betamethasone-dixyrazine was superior to high-dose metoclopramide and prevented nausea in 76% compared to 32% during melphalan-doxorubicin therapy. Akathisia was noted in 21% and acute dystonic reactions in 2.6% during metoclopramide treatment but not in any case during betamethasone-dixyrazine therapy.     

Antiemetic efficacy of high-dose metoclopramide, diphenhydramine, methylprednisolone and diazepam on chemotherapy-induced emesis in gynecological malignancy

The antiemetic efficacy of high-dose metoclopramide (MCP), diphenhydramine (DPH), methylprednisolone (MPL), and diazepam (DZP) was investigated in 40 gynecologic cancer patients for a total of 98 chemotherapy courses, treated with cisplatin (50 mg/m2). With MPL (500 mg i.v. x 2) plus DZP (5 mg i.m. x 2), no vomiting occurred in 0% and mild emesis (vomiting 1-2 times) occurred in 20% of 25 courses. With MCP (2 mg/kg i.v. x 5) plus DPH (40 mg i.v. x 3), no vomiting occurred in 35% and mild emesis occurred in 10% of 20 courses. With a combination of MCP plus DPH and MPL plus DZP, no vomiting occurred in 51% and mild emesis occurred in 25% of 53 courses. These results indicate that high-dose MCP plus DPH are effective in preventing cisplatin-induced vomiting. Furthermore, the antiemetic efficacy of MCP plus DPH (0-2 vomiting episodes: 45%) was significantly enhanced (p less than 0.05) by the combined use of MPL plus DZP (0-2 vomiting episodes: 76%).     

Betamethasone-dixyrazine versus betamethasone-metoclopramide as antiemetic treatment of cisplatin-doxorubicin-induced nausea in ovarian carcinoma patients

In a prospective and randomized pilot study two antiemetic regimens comprising dixyrazine (240 mg) and metoclopramide (10 mg/kg) in high doses and given by continuous i.v. infusion were compared as means of preventing cisplatin-doxorubicin-induced nausead and vomiting. Twenty chemotherapy-naive women with the diagnosis of ovarian carcinoma stages III-IV (FIGO) were included in the study. Medium doses (50 mg/m2) of cisplatin and doxorubicin were used. The antiemetic drugs (the above-mentioned ones plus betamethasone 20 mg, and biperiden 5 mg) were administered by small portable infusion pumps during 24 hours. The effects and adverse reactions were evaluated during the course of chemotherapy and the first week thereafter. Complete protection from nausea during the first 24 hours was achieved in 80% by the metoclopramide cocktail and in 50% by the dixyrazine combination. During days 2-7 there were no significant differences between the two regimens. Vomiting was not satisfactorily prevented by either treatment. Sedation was significantly more common after dixyrazine than after metoclopramide but other recorded side effects were similar for the two antiemetic regimens. Serum concentrations of dixyrazine and metoclopramide were determined.     

Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy.

OBJECTIVE: This study compares pyridoxine-metoclopramide combination therapy to prochlorperazine and promethazine monotherapies in the outpatient treatment of nausea and vomiting in pregnancy. STUDY DESIGN: In total, 174 first trimester, singleton pregnancies were evaluated for nausea and vomiting. Patients were prospectively randomized into three treatment groups: pyridoxine-metoclopramide, prochlorperazine, or promethazine. Prior to, and on the third day, patients recorded their subjective responses to the given treatment and their number of emesis episodes. The three treatment groups were compared for therapy response. RESULTS: There were no differences in the number of emesis episodes prior to treatment. Both subjective and objective responses to treatment differed among the three groups when comparing the combination therapy to the monotherapies (p<0.05). CONCLUSION: Combination therapy with pyridoxine and metoclopramide appears to be superior to either monotherapy in the treatment of nausea and vomiting in pregnancy.     

A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy

OBJECTIVE: Hyperemesis gravidarum, a severe form of nausea and vomiting due to pregnancy for which there is no proven pharmacological treatment, is the third leading cause for hospitalization during pregnancy. Corticosteroids are commonly used for the treatment of nausea and vomiting due to cancer chemotherapy-induced emesis and might prove useful in hyperemesis gravidarum. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 126 women who previously had not responded to outpatient therapy for hyperemesis gravidarum during the first half of pregnancy. Intravenous methylprednisolone (125 mg) was followed by an oral prednisone taper (40 mg for 1 day, 20 mg for 3 days, 10 mg for 3 days, 5 mg for 7 days) versus an identical-appearing placebo regimen. All women also received promethazine 25 mg and metoclopramide 10 mg intravenously every 6 hours for 24 hours, followed by the same regimen administered orally as needed until discharge. The primary study outcome was the number of women requiring rehospitalization for hyperemesis gravidarum. RESULTS: A total of 110 women delivered at our hospital and had pregnancy outcomes available for analysis; 56 were randomized to corticosteroids and 54 were administered placebo. Nineteen women in each study group required rehospitalization (34% versus 35%, P =.89, for corticosteroids versus placebo, respectively). CONCLUSION: The addition of parenteral and oral corticosteroids to the treatment of women with hyperemesis gravidarum did not reduce the need for rehospitalization later in pregnancy.     

Evaluation of the relation between patient characteristics and the state of chemotherapy-induced nausea and vomiting in patients with gynecologic cancer receiving paclitaxel and carboplatin

Purpose

An antiemetic regimen for patients taking paclitaxel and carboplatin (TC) includes dexamethasone (20 mg) to protect against hypersensitivity. Chemotherapy-induced nausea and vomiting (CINV), however, is difficult to adequately control in patients receiving TC. In the present study, we retrospectively investigated risk factors for CINV in patients receiving TC with this antiemetic regimen based on a questionnaire.

Methods

Eligible patients were diagnosed with gynecologic cancer and receiving paclitaxel (175 mg/m²) intravenously for 3 h and carboplatin (area under the curve 5 mg/mL per min) on day 1 every 3 weeks in our institution, and treated with granisetron (3 mg) and dexamethasone (20 mg) for antiemesis. Data of nausea and vomiting assessed by Common Terminology Criteria for Adverse Events version4.0 were collected from the medical records. Patients were asked to complete a questionnaire including items such as age and hyperemesis. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with items on nausea of grade 2 or greater and vomiting of grade 1 or greater.

Results

On univariate logistic analysis, no item was significantly associated with nausea of grade 2 or greater. Hypertension and hyperemesis gravidarum and adjuvant chemotherapy were significantly associated with delayed vomiting of grade 1 or greater. Multivariate analysis was performed with delayed vomiting of grade 1 or greater as an endpoint, and the resulting independent items were hypertension and hyperemesis gravidarum.

Conclusions

The present study showed that the risk factor for delayed vomiting of grade 1 or higher was a history of hyperemesis gravidarum in patients receiving conventional TC with dexamethasone (20 mg) and granisetron. Therefore, in patients with this risk factor, criteria of major organizations should be followed first.     

Does increasing the steroid dose enhance the efficacy of the antiemetic combination of granisetron and methylprednisolone in gynecologic cancer patients--a randomized study

OBJECTIVE: The authors administered two doses of oral methylprednisolone in combination with 3mg granisetron intravenously for the prophylaxis of cisplatin-induced emesis in gynecologic cancer patients. MATERIALS AND METHODS: Thirty-nine patients received 100mg (group A) and 25 received 200mg (group B) methylprednisolone in the antiemetic combination in a randomized prospective trial. RESULTS: No vomiting in 90.2 and 96.7%, one emetic episode in 3 and 1.1% and two episodes in 3 and 2.2% were detected in groups A and B, respectively. More than two emetic episodes were considered to be a failure and were observed only in group A (3.8%). There was no significant difference between the two treatment groups (P=0.3160). CONCLUSIONS: There was no evidence for enhanced antiemetic effect of elevated steroidal dose in combination with granisetron.     

Methylprednisolone as an antiemetic during cancer chemotherapy—a pilot study

The possibility that prostaglandin release is involved in the nausea and emesis of chemotherapy prompted this investigation to determine if prostaglandin inhibition by corticosteroid administration would be beneficial. Methylprednisolone (Solu-Medrol, Upjohn) was given to 19 patients receiving cancer chemotherapy. Of 11 patients with prior chemotherapy and emesis, 8 obtained noticeable relief. Six patients had no prior chemotherapy and only 1 experienced emesis. Two patients with prior chemotherapy had no emesis associated with their chemotherapy, although 1 had marked nausea which did not recur when treated with the steroid.     

A phase II double-blind randomized study of the simultaneous administration of recombinant human interleukin-6 and recombinant human granulocyte colony-stimulating factor following paclitaxel and carboplatin chemotherapy in patients with advanced epithelial ovarian cancer

PURPOSE: Recombinant human interleukin-6 (rhuIL-6) is a glycosylated cytokine with hematopoietic stimulatory effects. In particular, preclinical studies suggest the agent can stimulate thrombopoiesis, even in conjunction with chemotherapy. We attempted to determine whether higher dose chemotherapy for ovarian cancer was possible given the pharmacologic use of this important growth factor. METHODS: We conducted a randomized, double-blind phase II study of IL-6 plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in combination with a standard chemotherapy regimen. Patients with epithelial ovarian cancer, stages Ic to IV, were eligible. All patients were previously untreated with chemotherapy and had Karnofsky performance status >/=60. rhuIL-6 (Escherichia coli, SDZ ILS 969) 1.0 micrograms/kg or placebo was given subcutaneously on days 2-8 every cycle together with G-CSF 5.0 micrograms/kg subcutaneously days 2-15, following administration of paclitaxel 175 mg/m2 as a 3-h infusion and carboplatin given to a desired AUC of 7.5 on day 1 every 21 days. RESULTS: Fifty patients were entered in this study, although the study was temporarily suspended by the FDA in midstudy over manufacturing concerns. Therefore, 37 patients were evaluable for efficacy of growth factor; 19 patients received placebo plus G-CSF and 18 rhIL-6 plus G-CSF. There was no difference in prognostic variables between these two groups. Platelet nadirs were lower in the first cycle for the placebo group (P = 0.004, Wilcoxon sum-rank test) but not in other cycles. There was no statistically significant difference in cycle treatment delays, carboplatin dose delivered, number of patients with grade 4 thrombocytopenia, or platelet transfusion. Nonetheless, the trend of the data favored IL-6 in all cases. CONCLUSIONS: This study demonstrated a minimal effect (statistically significant in the first cycle only) on thrombopoiesis in women undergoing paclitaxel and carboplatin therapy of ovarian cancer. No clinically significant effect on actual chemotherapy delivery was demonstrated, however. Future studies, if warranted, to ameliorate thrombocytopenia should be carried out with regimens producing even greater thrombocytopenia than the current regimen in the control arm.     

Antiemetic combination for PAC (cisplatin-adriamycin-cyclophosphamide) chemotherapy-induced emesis in ovarian cancer

Twenty-six patients suffering from disseminated epithelial ovarian cancer (FIGO stages III and IV) under treatment with Cisplatin (80-100 mg/m2 in 8 hours) in combination on the same day with Cyclophosphamide (500 mg/m2 IV) and Adriamycin (50 mg/m2), a severely emetogenic regimen, entered a randomized, double-blind, cross-over trial comparing the antiemetic activity of high-dose IV Metoclopramide (1 mg/kg/dose X 5 doses) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (50 mg PO X 2 doses) plus Thiethylperazine (10 mg IV X 3 doses). The antiemetic combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at the central emetic pathways (dopamine D-2, histamine H-1 and muscarinic cholinergic). This combination significantly reduced the emesis due to chemotherapy when compared with Metoclopramide alone and was also preferred by a significant number of patients after passing through both the antiemetic arms being compared.     

Methylprednisolone in cis-platinum induced nausea and emesis: a placebo-controlled trial

In a double-blind, placebo-controlled trial, the antiemetic efficacy of a total of 1-2 g methylprednisolone sodium succinate (MPSS) alone versus placebo was evaluated over the first three courses of chemotherapy in a group of 27 women receiving moderate to high-dose cis-platinum (50-118 mg/m2) for ovarian or cervical carcinomas. Antiemetic protection was classified as total (no emesis), major (one or two bouts), minor (three to five bouts), or minimal (six or more bouts). Total or major protection occurred in 10/26 (38.5%) of the MPSS cycles and in 6/24 (25%) of the placebo cycles (NS). A significant number of placebo patients (7/14 placebo versus 1/13 MPSS, P = 0.02) dropped out of the study due to lack of efficacy. Patient evaluations completed 24 hr before and after each course of chemotherapy indicated no treatment effect on pain, appetite, nausea, drowsiness, anxiety, sense of well-being, or sleep. Physician and patient global evaluations of antiemetic efficacy favored treatment with MPSS. Evidence of the efficacy of single-drug MPSS antiemetic therapy during non-cis-platinum or low-dose cis-platinum (less than 50 mg/m2) chemotherapy can be found in the literature. The results of this study, however, do not support the use of MPSS alone with high-dose cis-platinum chemotherapy.