Methylprednisolone versus metoclopramide as antiemetic treatment in patients receiving adjuvant cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy: a randomized crossover blind study

Nineteen women receiving their first cycle of adjuvant chemotherapy for early breast cancer were randomized between two antiemetic drugs: methylprednisolone (MPN) 125mg and metoclopramide (MCP) 20mg, both given by intravenous push as a single dose. The chemotherapy included: cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The total response rates for MPN and MCP were: complete protection 11% versus 0% and partial protection 63% versus 11% of the patients, respectively (P = 0.007). Eighteen patients (95%) preferred MPN over MCP. Common side effects with both drugs were: drowsiness, headache and diarrhea. MPN is recommended as an antiemetic in patients receiving CMF adjuvant chemotherapy.     

Methylprednisolone versus Metoclopramide as Antiemetic Treatment in Patients Receiving Adjuvant Cyclophosphamide,Methotrexate, 5-Fluorouracil (CMF) Chemotherapy: A randomized crossover blind study.

Summary

Nineteen women receiving their first cycle of adjuvant chemotherapy for early breast cancer were randomized between two antiemetic drugs: methylprednisolone (MPN) 125mg and metoclopramide (MCP) 20mg, both given by intravenous push as a single dose. The chemotherapy included: cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The total response rates for MPN and MCP were: complete protection 11% versus 0% and partial protection 63% versus 11% of the patients, respectively (P = 0.007). Eighteen patients (95%) preferred MPN over MCP. Common side effects with both drugs were: drowsiness, headache and diarrhea. MPN is recommended as an antiemetic in patients receiving CMF adjuvant chemotherapy.     

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

Summary 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.     

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.     

Methylprednisolone for the control of CMF-induced emesis

Sixty-eight breast cancer patients for outpatient adjuvant chemotherapy (CT) with cyclophosphamide, methotrexate, and fluorouracil (CMF) on a 1-day schedule entered a randomized trial comparing the antiemetic-efficacy of different doses of methylprednisolone (MPN). Treatment was administered concomitantly with the first course of CT and consisted of MPN in either 375 or 120-mg doses divided into 3 equal parts, the first administered i.v. just prior to CMF and then i.m. 6 and 12 h after CT. Overall, antiemetic protection was appreciable: complete emetic protection (no emetic episodes) was observed in 71 and 66% of patients receiving MPN 375 and 120 mg, respectively. In 43 and 54% of patients receiving MPN 375 and 120 mg, respectively, nausea did not occur. Efficacy of the two treatment arms was not statistically different for either emesis or nausea. Antiemetic protection with MPN was reproducible over time at subsequent courses: 60% of patients in either treatment arm experienced less than 5 emetic episodes at their 12th CMF course. Facial flush was the most frequently observed side effect (36% with MPN 120 mg vs. 68% with MPN 375 mg). Other acute untoward effects consisted of headache, pyrosis, and edema. However, the latter was observed only with the higher dose. In patients receiving CMF, MPN alone provides effective and reproducible emetic protection. No dose-response relationship was observed.     

Low dose, oral lorazepam: a safe and effective adjuvant to antiemetic therapy

Twenty-five patients with acute nonlymphoblastic leukemia undergoing 41 cycles of chemotherapy with daunorubicin/cytosine arabinoside (ara-C) or with etoposide/ara-C received metoclopramide (MCP; 0.5 mg/kg 6 hourly i.v.) or MCP (same dose) plus oral lorazepam (1 mg/d) during and 24 hours following the chemotherapy as antiemetic medication. Control of vomiting was achieved is 55% (complete 5%, partial 50%) of the patients receiving MCP alone and in 100 percent (complete 76.1%; partial 23.8%) of those receiving MCP plus lorazepam (p less than 0.001). Eighteen of the 21 patients (85.7%) receiving MCP plus lorazepam opted for the same antiemetic regimen as compared to six of the 20 (30%) receiving MCP alone (p less than 0.01). One patient in each group developed mild sedation during the treatment. It is concluded that oral lorazepam is an effective and safe adjuvant to MCP for the control of vomiting during cancer chemotherapy.     

Antiemetic efficacy of cimetidine randomized, double-blind, crossover study with dexamethasone in cancer patients receiving emetogenic chemotherapy

In a randomized, double-blind, crossover study the antiemetic effect of cimetidine was compared with that of dexamethasone in cancer patients receiving emetogenic chemotherapy. Thirty-two patients were evaluable and all were chemotherapy-naive. Eight patients (25%) received high doses of cisplatin, 17 (53%) had cyclophosphamide in combination treatment, 2 (6%) received adriamycin, and 1 another chemotherapy of less emetogenic potential. Complete protection (CR) rates of 59.4% and 62.5% were achieved with cimetidine and dexamethasone, respectively. In addition, three (9.4%) and 1 (3%) patients attained partial protection with cimetidine and dexamethasone, respectively. No significant difference was noted between the two antiemetic therapies (p = 0.07). Although CR has not been achieved in any of those patients who received cisplatin, a comparable antiemetic effect was attained. Both antiemetic regimens were well tolerated with minimal side effects. We conclude that the antiemetic potential of cimetidine and its safety deserve further investigation in a larger study, perhaps in combination with other antiemetic agents.     

Methylprednisolone and chlorpromazine in patients receiving cancer chemotherapy: a prospective non-randomized study

Seventy-six consecutive patients receiving chemotherapy were evaluated for the antiemetic efficacy and side-effects of the combination of chlorpromazine (CPM) and methylprednisolone (MPN). All patients had previously received the same chemotherapy with metoclopramide in conventional dosage and experienced severe emesis. A significant antiemetic response was achieved in 70% of the patients, and in 28% of them the antiemetic protection was complete. The most common side effects were drowsiness, dry mouth and headache. The combination of CPM and MPN is effective, well tolerated and is recommended for outpatients receiving chemotherapy for cancer.     

Double-blind randomized trial of lorazepam versus placebo with methylprednisolone for control of emesis due to non-cisplatin containing chemotherapy

Fifty-three breast cancer patients receiving adjuvant chemotherapy entered a double-blind randomized trial of lorazepam 2.5 mg orally prior to chemotherapy and repeated after 12 hours (Arm A) versus placebo (Arm B) with methylprednisolone (MPN) 375 mg in 3 equal doses: 125 mg i.v. prior to chemotherapy and repeated i.m. 6 and 12 hours later. Adjuvant therapy with 5-fluorouracil 600 mg/m2, 4'-epi-doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 (FEC) day 1 was alternated every 21 days with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2 (CMF) day 1 for a total of 12 courses. The majority of patients experienced greater than or equal to 5 emetic episodes with FEC therapy (Arm A = 52%; Arm B = 55%). Mild and moderate nausea were reported by 60% and 68% of patients in Arms A and B, respectively. With CMF therapy complete control of emesis was observed in 33% (Arm A) and 35% (Arm B) of patients. The addition of lorazepam did not improve results either with FEC or CMF. Sedation was experienced by 86 to 92% of patients treated with lorazepam and amnesia was observed in 48-50% of cases. FEC therapy must be considered a highly emetic regimen and antiemetic therapy planned accordingly.     

Methylprednisolone and Chlorpromazine in Patients Receiving Cancer Chemotherapy: A prospective non-randomized study

Summary

Seventy-six consecutive patients receiving chemotherapy were evaluated for the antiemetic efficacy and side-effects of the combination of chlorpromazine (CPM) and methylprednisolone (MPN). All patients had previously received the same chemotherapy with metoclopramide in conventional dosage and experienced severe emesis. A significant antiemetic response was achieved in 70% of the patients, and in 28% of them the antiemetic protection was complete. The most common side effects were drowsiness, dry mouth and headache. The combination of CPM and MPN is effective, well tolerated and is recommended for outpatients receiving chemotherapy for cancer.     

High-dose metoclopramide and dexamethasone as an antiemetic in outpatients receiving chemotherapy for breast cancer. Second study

Forty-six outpatients with breast cancer who had experienced severe emesis as a result of chemotherapy were evaluated for the antiemetic efficacy of high-dose metoclopramide (HD-MCP) and dexamethasone (DXM). Chemotherapy consisted of: cyclophosphamide 600, methotrexate 40 and 5-fluorouracil 600 mg/m2 (CMF) given intravenously every 3 weeks. The dosage of antiemetic drugs was MCP 2 mg/kg and DXM 0.2 mg/kg given by slow intravenous drip 0.5 h before the administration of chemotherapy. 138 courses of combined chemotherapy--HD-MCP and DXM--were administered, with a mean of 3 courses and a range of 1-10 courses per patient. Complete protection--no nausea and no vomiting--was achieved in 17.7% of the courses. Partial protection--no vomiting with mild nausea or 1-3 episodes of vomiting--in 45.3% of the courses. The total antiemetic efficacy was 63%. The most common side effects were: drowsiness, dry mouth, restlessness and diarrhea. Sixteen patients (35%) refused to continue the antiemetic regimen because of the side effects. HD-MCP and DXM have antiemetic efficacy, but because of these side effects, further studies are required to determine the optimal dose of each of these drugs.     

Evaluation of the antiemetic activity of bromopride in cancer patients treated with i.v. CMF

In more than 70% of patients undergoing surgery for breast cancer with histologically positive lymph nodes, precautional therapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) causes nausea and vomiting. At the present time, the optimal antiemetic therapy has not been found. From May 1983 to March 1984, 35 patients, of whom 34 were evaluable, were entered in a randomized double blind antiemetic treatment with either bromopride (16 patients), a procainamide derivative structurally similar to metoclopramide, or placebo (18 patients). Bromopride (20 mg) and the placebo were administered in a 3-min i.v. injection half an hour before chemotherapy and at 3 1/2 and 7 1/2 following chemotherapy. A complete antiemetic protection was obtained in 9 patients (56.3%) treated with bromopride compared to 5 patients (27.8%) treated with the placebo. A major antiemetic (less than or equal to 2 vomiting episodes) was obtained in 3 patients (18.7%) treated with bromopride compared to 5 patients (27.8%) treated with the placebo. Statistical analysis showed a trend in favor of bromopride (P = 0.058). The most frequent side effect was sedation reported in 6 patients (37.5%) treated with bromopride and 2 patients (11.1%) treated with the placebo (P = 0.06). The study was interrupted when several patients presented vomiting episodes more than 12 h after CMF administration, and thus beyond the foreseeable protective effect of the antiemetic treatment. It is our opinion that the search for an optimal antiemetic regimen in the course of i.v. CMF therapy should consider the administration of antiemetic drugs at least until 12 h after chemotherapy.     

High-dose metoclopramide and dexamethasone as an antiemetic in chemotherapy of breast cancer

Twenty-six patients with breast carcinoma who experienced severe emesis due to chemotherapy were evaluated for the antiemetic efficacy of high-dose metoclopramide (HD-MCP) and dexamethasone (DXM). Most of the patients received the CMF (cyclophosphamide, methotrexate and 5-fluorouracil) combination chemotherapy. The MCP and DXM dosage were: 2 X 2 mg/kg and 2 X 0.2 mg/kg, respectively. In 41% of eighty evaluable courses, nausea and vomiting were eliminated altogether. The common side effects were: drowsiness, restlessness and diarrhea. HD-MCP and DXM are recommended in modified dose for preventing CMF chemotherapy induced emesis.     

Double-Blind Randomized Trial of Lorazepam versus Placebo with Methylprednisolone for Control of Emesis Due to Non-Cisplatin Containing Chemotherapy

Summary

Fifty-three breast cancer patients receiving adjuvant chemotherapy entered a double-blind randomized trial of lorazepam 2.5 mg orally prior to chemotherapy and repeated after 12 hours (Arm A) versus placebo (Arm B) with methylprednisolone (MPN) 375 mg in 3 equal doses: 125 mg i.v. prior to chemotherapy and repeated i.m. 6 and 12 hours later. Adjuvant therapy with 5-fluorouracil 600 mg/m², 4’-epi-doxorubicin 60 mg/m², cyclophosphamide 600 mg/m² (FEC) day 1 was alternated every 21 days with cyclophosphamide 600 mg/m², methotrexate 40 mg/m², 5-fluorouracil 600 mg/m² (CMF) day 1 for a total of 12 courses. The majority of patients experienced ≥ 5 emetic episodes with FEC therapy (Arm A = 52%; Arm B = 55%). Mild and moderate nausea were reported by 60% and 68% of patients in Arms A and B, respectively. With CMF therapy complete control of emesis was observed in 33% (Arm A) and 35% (Arm B) of patients. The addition of lorazepam did not improve results either with FEC or CMF. Sedation was experienced by 86 to 92% of patients treated with lorazepam and amnesia was observed in 48–50% of cases. FEC therapy must be considered a highly emetic regimen and antiemetic therapy planned accordingly.     

Antiemetics in children receiving cancer chemotherapy: a double-blind prospective randomized study comparing metoclopramide with chlorpromazine

This is the first prospective randomized study comparing commonly used antiemetics in children receiving cancer chemotherapy. We compared metoclopramide (MCP) with chlorpromazine (CLP), both administered in conventional doses, in 50 cancer patients aged 6 to 18 years who were receiving emetic chemotherapy. CLP proved significantly better than MCP in reducing both the frequency of vomiting (P less than .05) and the duration of nausea and vomiting (P less than .025). Extrapyramidal reactions (EPRs) were more common in MCP-treated patients. We conclude that, in the standard doses used, CLP is a better overall antiemetic than MCP for children receiving intensive chemotherapy. However, further prospective pediatric studies of antiemetic combinations are needed.     

Adjuvant chemotherapy for early breast cancer: Is cyclophosphamide,methotrexate and 5‐fluorouracil still the standard?

Background: Oral cyclophosphamide, methotrexate and 5‐fluorouracil (CMF) was one of the first combination chemotherapy regimens used as adjuvant chemotherapy for early breast cancer. The value of CMF in reducing both recurrence and mortality from early breast cancer has been firmly established by the overviews of randomized trials of polychemotherapy, which have used CMF as their standard. The purpose of this review is to review the usage of oral CMF and the variants of CMF and to compare both the activity and side‐effects of CMF with more modern adjuvant chemotherapy regimens. Results: There are many variants of CMF but oral (or classical) CMF is probably more effective than intravenous (i.v.) CMF, at least in metastatic disease. When oral CMF is used in early breast cancer it reduces the annual hazard of recurrence by 24% and the annual hazard of mortality by 14% overall, although it appears more effective in younger patients. Anthracycline‐based regimens are more effective for reduction of recurrence and mortality than CMF but are associated with more severe acute toxicities and potentially greater risks of long‐term toxicities. Taxane‐based regimens have not been compared with CMF directly; however, in comparison with anthracycline‐based regimens, the early information suggests that taxane‐based regimens may be even more effective. The acute toxicities of taxane‐based regimens are probably less severe than anthracycline‐based regimens, but their long‐term toxicities are less well defined. Conclusion: Oral CMF as adjuvant chemotherapy for early breast cancer is the standard by which newer regimens are compared. Although newer regimens appear more effective than CMF, they may be associated with greater acute and potentially greater long‐term toxicities than CMF. Thus, CMF remains the standard by which future regimens should be judged, either directly or indirectly.     

Oral ondansetron in the prophylaxis of nausea and vomiting induced by cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in women with breast cancer. Results of a prospective, randomized, double-blind, placebo-controlled study

BACKGROUND:: The combination of cyclophosphamide, methotrexate and 5-fluorouracil(CMF) is a widely used chemotherapy regimen in breast cancerpatients. However, the control of nausea and vomiting inducedby oral CMF is a rarely examined problem. Therefore we felta randomized, placebo controlled study justified in order toimprove currently available antiemetic therapy. SUBJECTS AND METHODS:: In a randomised double-blind trial ondansetron given orally,8 mg three times a day for 15 days, was compared with placeboin 82 breast cancer patients receiving chemotherapy with CMF(cyclophosphamide 100 mg/m² orally days 1–14, methotrexate40 mg/m² i.v. days 1 and 8 and 5-fluorourcil 600 mg/m² i.v.days 1 and 8). The patients recorded nausea and the number ofvomits and retches daily on diary cards. Forty-two patientsreceived ondansetron and 40 received placebo. RESULTS:: Significantly more patients who received ondansetron experiencedneither vomiting nor retching (emesis) compared to those receivingplacebo over a 15 day treatment period (60% vs. 35%, p = 0.027).The difference, with 95% confidence limits, was estimated as25 (4.45%). Furthermore, there was a trend in favour of ondansetronin the control of nausea. Ondansetron was well tolerated, with25 patients (59%) reporting at least 1 adverse event comparedto 18 patients (45%) receiving placebo (p = 0.191). CONCLUSION:: The results indicate that ondansetron given orally for 15 daysis safe and effective in the control of emesis induced by CMF.It is however too early to recommend ondansetron as standardantiemetic therapy for oral CMF, as the treatment of nauseaand vomiting in this setting has not been studied thoroughlyenough. prospective, randomized, double-blind trial, ondansetron and placebo, oral CMF-regimen, breast cancer     

CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus cnf (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study

A multicenter phase III randomized study compared the efficacies of two adjuvant polychemotherapeutic regimens in 145 patients with stage II node-positive breast cancer. The standard chemotherapy combination, CMF (cyclophosphamide, methotrexate, 5-fluorouracil), was administered to 77 women. The experimental protocol, CNF (cyclophosphamide, mitoxantrone, 5-FU), in which mitoxantrone (Novantrone) replaced methotrexate, was given to 68 patients. Follow-up of the 145 patients by six participating hospitals showed no statistically significant difference (p = 0.6) between the two treatment regimens during a median follow-up of 4.5 years in terms of overall survival. There was, however, a significant advantage (p = 0.04) in the disease-free survival for those receiving mitoxantrone (mean survival 4.4 years for CNF versus 2.7 years for CMF). Toxic side effects associated with CNF (particularly alopecia and myelotoxicity) were relatively more frequent but acceptable and did not lead to dose reduction. In light of its association with improved disease-free survival in this study, larger studies should be undertaken on the role of mitoxantrone as adjuvant treatment in stage II breast cancer.     

A prospective, randomized double-blind trial comparing metoclopramide alone with metoclopramide plus dexamethasone in preventing emesis induced by high-dose cisplatin

We observed 50 patients receiving high-dose cisplatin-based chemotherapy in a prospective, randomized double-blind trial. One group received metoclopramide (MCP) alone (total dose, 6 mg/kg), whereas the other group was given dexamethasone (DMS) (total dose, 60 mg) in addition to MCP. The patient characteristics of the two groups were comparable, confirming satisfactory randomization. Multivariate regression analysis failed to show any statistical significance in the antiemetic response between the two treatment groups. However, female patients receiving Adriamycin (Adria Laboratories, Columbus, OH) concurrently and obese persons exhibited more vomiting. The overall antiemetic response rate was 66%. Because the side effects were minimal, a higher dose of MCP is expected to improve emetic control without increasing toxicity. The use of a 36-hour assessment period in our study gave more meaningful data. An exponential increase in the dose of MCP is probably required, with respect to weight, to obtain the same antiemetic efficacy.     

p53 immunohistochemical staining and survival after adjuvant chemotherapy for breast cancer

We have investigated the relationship between immunohistochemically determined p53 status and outcome in 277 women with node-positive primary breast cancer who, following tumour excision and axillary clearance, were randomised to receive either 6 cycles of cyclophosphamide/methotrexate/5-fluorouracil (CMF) (n = 130) or no such post-operative treatment (n = 147). Follow-up data (median = 9 years) were available on all patients. A significant association was found between p53 status and survival. Patients with p53-positive tumours had a less favourable outcome than those with p53-negative disease. Women receiving adjuvant CMF chemotherapy had a significantly more favourable outcome compared to those who did not. The effect was seen both in women with p53-positive and p53-negative tumours; multivariate analysis showed relative risks for overall survival attributable to chemotherapy of 2.3 (95% CI 1.2–4.3) for women with p53-positive tumours and of 2.1 (95% CI 1.4–3.0) for those with p53-negative tumours. Thus, adjuvant chemotherapy with CMF is associated with a survival benefit in women with node-positive breast cancer irrespective of immunohistochemically determined p53 status. Int. J. Cancer 74:605–608, 1997.© 1997 Wiley-Liss, Inc.