Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Comparison of Antiemetic Activity of Chloropromazine and High Doses of Metoclopramide in Cisplatin-Based Chemotherapy N. B. Tsavaris, D. Papaioannou, D. Beldecos, S. Kakoliris, N. Mylonakis, N. Karvounis, P. Komitsopoulou, P. Karagiaouris, J. Sarmas, I. Tzannou, C. Bacoyannis & P. Kosmidis To cite this article: N. B. Tsavaris, D. Papaioannou, D. Beldecos, S. Kakoliris, N. Mylonakis, N. Karvounis, P. Komitsopoulou, P. Karagiaouris, J. Sarmas, I. Tzannou, C. Bacoyannis & P. Kosmidis (1990) Comparison of Antiemetic Activity of Chloropromazine and High Doses of Metoclopramide in Cisplatin-Based Chemotherapy, Acta Oncologica, 29:8, 1005-1009, DOI: 10.3109/02841869009091791 To link to this article: http://dx.doi.org/10.3109/02841869009091791
Published online: 08 Jul 2009.
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Citing articles: 1 View citing articles
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Date: 07 May 2017, At: 12:50
Acta Oncologica 29 (1990) Fasc. 8
FROM THE SECOND DEPARTMENT O F MEDICAL ONCOLOGY, 'METAXA' CANCER HOSPITAL, PIRAEUS, GREECE.
COMPARISON OF ANTIEMETIC ACTIVITY OF CHLOROPROMAZINE AND HIGH DOSES OF METOCLOPRAMIDE IN CISPLATIN-BASED CHEMOTHERAPY N. B. TSAVARIS, D. PAPAIOANNOU, D. BELDECOS,S. KAKOLIRIS, N. MYLONAKIS, N. KARVOUNIS, P. KOMITSOPOULOU, P. KARAGIAOURIS, J. SARMAS,I. TZANNOU,C. BACOYANNIS and P. KOSMIDIS
Abstract High dose metoclopramide and different phenothiazines are widely used antiemetics in cancer patients receiving Chemotherapy. In a prospective randomized study we compared the antiemetic efficacy of high dose metoclopramide (M) and chloropromazine (C). We also tested the role of dexamethazone (D) when combined with either of these drugs. A total of 165 patients were randomly allocated to 5 groups with 33 patients in each group. Group A received only M, group B: M + D , group C: C + D , group D: M + D + C and group E M + C. All patients received combination chemotherapy with cisplatin for the first time and were evaluated only once in order to exclude anticipatory nausea and vomiting. Patients in group C had less antiemetic protection than the other groups (p < 0.001). Groups A, B, D, E, had more or less equal antiemetic efficacy, although the efficacy in group B was somewhat better; this difference was not statistically significant. Side-effects were minimal. Chloropromazine seemed to protect patients who received metoclopramide from extrapyramidal manifestations. In conclusion the results suggest that high dose metoclopramide has a better antiemetic effect than chloropromazine, dexamethazone is a helpful adjuvant drug when used in combination with an effective antiemetic agent, and chloropromazine and dexamethazone may prevent the extrapyramidal sideeffects that can occur when metoclopramide is used as single antiemetic drug. Key words: Cancer, chemotherapy, cisplatin, metoclopramide, chloropromazine, antiemetic effect.
Nausea and vomiting are frequent and serious sideeffects in patients receiving cancer chemotherapy and may sometimes be the limiting factor of chemotherapy (1 -4). Fear of these side-effects can result in rejection of potentially curative or effective palliative chemotherapy (1, 5).
In addition, some patients may be unable to tolerate the number of cycles necessary to complete their course of chemotherapy (1). Prevention of chemotherapy-induced nausea and vomiting is therefore important. Standard antiemetic treatment is of limited value. The most commonly used antiemetic drugs are metoclopramide and phenothiazines. Metoclopramide like phenothiazines acts on the brain in the chemoreceptor trigger zone by blocking dopamine receptors (2). In contrast to the phenothiazines, which have anticholinergic effects, metoclopramide is a cholinergic stimulant acting peripherally on the musculature of the proximal gut (2). The antiemetic efficacy of metoclopramide has been shown in several well controlled studies, and many investigators consider the drug to a very useful agent against nausea and vomiting associated with chemotherapy (6-9). Corticosteriods have been used in combination with these two drugs and seem to improve the antiemetic effect (10- 13). In order to investigate the effectiveness of these drugs in different combinations, we compared the efficacy of metoclopramide alone with the following four combinations: metoclopramide + dexamethazone, chloropromazine +corticosteriods, metoclopramide + cloropromazine dexamethazone, and metoclopramide + chloropromazine in cancer patients receiving cisplatin-containing chemotherapy. The study was prospective and randomized.
+
Submitted 18 October 1989. Accepted for publication 24 March 1990.
1005
1006
N. B. TSAVARIS ET AL.
Material and Methods From January 1986 to June 1988, 165 patients with histologically confirmed cancer were entered into this study (Table 1). Only Patients < 70 years old who had not previously received chemotherapy and with a Karnofsky index of >60% were included in the trial. All patients received combination chemotherapy with cisplatin. As required for the concurrent chemotherapy protocols, each patient had a leukocyte count above 4 OOO/mm3, a platelet count above 100 OOO/mm3,serum creatinine below 14 mg/l, and serum bilirubin below 10 mg/l. Pretreatment evaluation included complete history and physical examination, blood counts, 12-channel biochemical profile, serum electrolytes and creatinine (creatinine clearance), electrocardiogram and chest roentgenogram. Follow-up biochemical and hematologic tests were performed twice a week during the first week of treatment and weekly thereafter; chest roentgenogram and creatinine clearance were obtained monthly. Age, sex, Karnofsky index and site of primary cancer did not differ significantly between the five groups. All patients were hospitalized to receive cisplatin at a dose of 100 mg/m2 of body surface area in 30 min intravenous infusion. Cisplatin treatment followed intravenous hydration with mannitol diuresis. Patients with non-small cell lung cancer received also vinblastine (6mg/m2) or vinblastine (6 mg/m2) plus mitomycin, agents that generally do not induce emesis. Patients with ovarian cancer also received doxorubicin, cyclophosphamide, and etoposide.
We tested three antiemetic drugs in five combinations. The drugs were administered as follows: Metoclopramide was given at a dose of 1.5 mg/kg every 2 h for five intravenous doses. The first dose was given 30 min prior to cisplatin and then at 1 1/2, 3 1/2, 5 1/2 and 7 1/2 h after cisplatin. Intravenous doses of metoclopramide were diluted in 50ml of 0.9% sodium chloride and infused in 15 min. Dexamethazone was given at a dose of 8 mg, every 6 h, for four intravenous doses. The first dose was given 30 min prior to cisplatin, and then at 5 1/2, 11 1/2, and 17 1/2 h after cisplatin. Chloropromazine was given at a dose of 12.5 mg, every 6 h, for four intravenous doses. The first dose was given 30 min prior to cisplatin, and then 5 1/2, 11 1/2 and 17 1/2 h after cisplatin. The three drugs were combined in 5 different ways: Group A: Metoclopramide alone. Group B: Metoclopramide plus dexamethazone. Group C: Chloropromazine plus dexamethazone. Group D: Metoclopramide plus chloropromazine plus dexamethazone. Group E: Metoclopramide plus chloropromazine. Food or liquids by mouth were restricted during the 24 h of the trial; only 400 ml of water and 3 pieces of fried bread were allowed. The patients were randomly allocated to one of these 5 groups and each group included 33 patients. The patients received the paticular antiemetic treatment only once.
Table 1 Patieni characteristics
Group Antiemetic drugs
A M
B M+D
C C+D
D M+C+D
E M+C
Total
Number of patiens Median age (years) Range Sex Males Females Performance status Karnofsky 90-100 80 70 Type of cancer Lung cancer Ovarian cancer Soft tissue sarcoma Head and neck tumors Melanoma Others (germ cell testicular, uterus cancer and mesothelioma)
33 56 (39-79)
33 58.2 (37-70)
33 54.3 (24-68)
33 53.2 (23-70)
33 56.9 (40-69)
165 55.7 ( 24-70)
21 12
22 11
19 14
22 11
23 10
107 58
4 17 12
3 16 14
9 11 13
4 18 11
4 19 10
24 81 60
21 5
23 4 0 2 1 3
15 6 1 3 7
1
23 5 0 2 0 3
100 25 3 11
1
18 5 1 4 4
I 0 4 2
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
10 16
1007
ANTIEMETIC EFFECT OF METOCLOPRAMIDE AND CHLOROPROMAZINE
Nausea and vomiting were evaluated by the medical personnel for 24 h following cisplatin infusion by interviewing the patients. Vomiting was graded as 0 (none, absent), 1 ( < 5 vomiting episodes), 2 (6-10 episodes), 3 ( > 10 episodes). Nausea was graded as follows: 0 (none), 1 (mild, no interference with activity), 2 (moderate, interference with activity), 3 (severe, bedridden for over 2 h). Side-effects of treatment were also directly observed and recorded. Activity during the trial was graded as follows: 0 (normal activity), 1 (mild impairment of activity), 2 (moderately severe impairment of activity). The influence on the patients appetite was graded as follows: 0 (normal appetite), 1 (mild impairment due to symptoms). Any sedative effect was evaluated as follows: 0 (none), 1 (mild, patient lethargic but wakened by verbal stimuli and completely oriented as to time, place, and persons when awake), 2 (moderate, patient wakened only by physical stimuli but completely oriented when awake), and 3 (marked, patient wakened only by physical stimuli and disoriented when awake). Diarrhea during the tiral was
graded as follows: 0 (none), 1 ( < 3 episodes), 2 (3-6 episodes), 3 ( >6 episodes, intolerable requiring therapy). Patients were assessed for the side-effect of antiemetics such as: chills diaphoresis, diarrhea, headache, dizziness, hypotensive symptoms, ataxia, hallucination, euphoria, extrapyramidal manifestation or any other symptoms. Patients were awakened if necessary and side-effects assessed before each dose of antiemetic medications, at the end of the 24-h observation period, and at least every 3 h during the trial. For statistical analysis Pearson’s X2-test was used to compare frequencies.
Results As is seen in Table 2 the least antinausea and antivomiting effect was noticed in group C (p c 0.001). Group B had the highest antinausea and antivomiting protection but it was not statistically significant from groups A, D, and E. Regarding toxicity, sedation was slightly more prominent in groups C , D, and E, i.e. patients who received
Table 2 Evaluation of side-effects. The grading systems used are described in ihe test. The WHO recommendations were used for grading of vomiiing and nausea
Side-effects
Grading
Group
D (M+C+D)
E (M+C)
5 22
3 3
8 18 6 1
12 11 8 2
19 6 4 4
15
19
11 I
13 1 0
17 14 2 0
9 24
16 17
18 15
3
21 10 2
20 10
27 5
25 8 0 0
A (M)
B (M+D)
C (D+C)
0 1 2
5 15 10
3
3
6 24 2 1
12 6 12
0 1 2
12 7 8 6
17 9 5 2
6 4 7 16
24 9 0 0
26 7 0 0
0
14 19
18 15
17 9
26 7 0
16 14
Vomiting 3
Nausea
3
Sedative effects 0 1 2
3
Appetite 0
1
Activity 0
I 2
7
3
Diarrhea 0 1 2
3
22 9 2 0
26 6
I 0
33 0 0 0
1 0
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
1008
N. B. TSAVARIS ET AL
Table 3 Other side-effects among the 33 patients in each group
Side-effects
Chills Diaphoresis Headache Dizziness Hypotensive symptoms Ataxia Hallucinations Euphoria Extrapyramidal manifestation Insomnia Mouth dryness
Group A (M)
B (M+D)
C (D+C)
D (M+D+C)
E (M+C)
0 6 8 7 2 0 0 0 6 2 10
4 8 12 3 1 0 0 6 2 3 12
0 6 26 29 0 0 0 0 0 0 6
3 4 19 23 1 0 0 1 0 0 18
0 0 21 26 4 0 0 0 0 0 12
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
chloropromazine, whereas diarrhea was completely absent only in group C. Headache and dizziness were significantly more common in groups C, D, and E. Extrapyramidal manifestation appeared in a few patients of groups A and B but was absent in group E. All results are presented in detail in Tables 2 and 3.
Discussion Nausea and vomiting have been the most common devastating acute side-effects of cisplatin-based chemotherapy. Many trials undertaken during the last 8 years have shown different groups of drugs to ameliorate chemotherapy-induced emesis. Among these drugs high dose metoclopramide and phenothiazines are the most widely used. Corticosteroids have been added in different combinations to the principle drugs and seem to contribute to the antiemetic effect (10-13). In our trial, patients who had no metoclopramide in their combination presented the least antiemetic effect, which was statistically significant when compared with the other groups. In all the other groups the antiemetic protection was more or less equal and all patients in these groups had received high doses of metoclopramide. It is interesting to note that the addition of chloropromazine to the combination metoclopramide and dexamethazone did not potentiate the antiemetic effect in our trial. However, we have to recognize that the number of patients in each group was small, which means that the statistical power of the study was low. Metoclopramide in large doses sometimes causes extrapyramidal symptoms, and some such cases were also observed in the present trial. However, no case of extrapyramidal side-effects was observed in the groups which also received chloropromazine suggesting a preventive effect of this drug.
Toxicities in the groups which received metoclopramide alone and metoclopramide plus dexamethazone were mild and well tolerated. They consisted mainly of diarrhea and, in a few patients, extrapyramidal manifestations attributable to metoclopramide. Sedation, dizziness and headache were the most prominent side-effects in the groups which received chloropromazine-containing combinations. Our study suggests that metoclopramide in high doses is a better antiemetic agent for patients who receive cisplatinbased chemotherapy than chloropromazine and that the addition of dexamethazone improves the antiemetic efficacy. Chloropromazine does not seem to potentiate the effectiveness of high dose metoclopramide. Higher doses of metoclopramide are used today with perhaps better efficacy and reduced frequency of administrations. The new drug G R 38032F (GR), a selective serotonine type 3 (5HT,) receptor antagonist, and similar drugs have demonstrated complete efficacy in preventing cisplatin-induced emesis without side-effects in clinical trials (14, 15). These new drugs will probably replace both metoclopramide and all phenothiazine substances within the next few years. Request for reprints: Dr N. B. Tsavaris, Second Department of Medical Oncology, ‘METAXA Cancer Hospital, 56 Botassi Street, Piraeus 18537, Greece.
REFERENCES 1. Whitehead VM. Cancer treatment needs better antiemetics
(Letter). N Engl J Med 1975; 293: 199-200. 2. Seigel LJ, Longo DL. The control of chemotherapy-induced emesis. Ann Intern Med 1981; 95: 352-9. 3. Morrow GR. The assessment of nausea and vomiting: past problems current issues, and suggestions for future research. Cancer 1984; 53: 2267-78.
ANTIEMETIC EFFECT OF METOCLOPRAMIDE AND CHLOROPROMAZINE
4. Frytac S, Moertel CG. Management of nausea and vomiting in cancer patients. JAMA 1981; 245: 393-6. 5. Enck RE. Mallory-Weiss lesion following cancer chemotherapy (Letter). Lancet 1977; 2: 927-8. 6. Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high dose metoclopramide: randomized trials with placebo and prochlororperazine in patients with chemotherapyinduced nausea and vomiting. N Engl J Med 1981; 305: 905-9. 7. Hamesley HD, Gainey JM, Jobson VW,Welander CE, Muss HB, Wells HB. Double-blind placebo-controlled study of metoclopramide. N Engl J Med 1982; 247: 2683-6. 8. Schultz-Delrien K. Metoclopramide. N Engl J Med 1981; 305: 28-33. 9. Strum SB, McDermed JE, Opfell RW, Riech LP. Intravenous metoclopramide: An effective antiemetic in cancer chemotherapy. JAMA 1982; 247: 2683-6. 10. Cassleth PA, Lusk EJ, Torri S, DiNebile N, Gerson SL. Antiemetic efficacy of dexamethasone therapy in patients receiving cancer chemotherpy. Arch Intern Med 1983; 143: 1347-9.
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11. Allan SG, Cornbleet MA, Warrington PS, Golland IM, Leonard RCF, Smith JF. Dexamethasone and high dose metoclopramide. Efficacy in controlling cisplatin induced nausea and vomiting. Br Med J 1984; 289: 878. 12. Kris MG, Gralla RJ, Tyson LB. Improved control of cisplatin induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethazone and diphenhydramine. Cancer 1985; 55: 527-34. 13. Markman M, Sheidler V, Ettinger DS, Quaskey SA, Mellits ED. Antiemetic efficacy of dexamethazone: Randomized, double-blind, crossover study with prochlorperazine in patients receiving cancer chemotherapy. N Engl J Med 1984; 311: 549-52. 14. Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR-38032Fa selective SHT, receptor antagonist. Lancet 1987; 1: 1461-2. 15. Hesketh PJ, Murphy WK, Knojasyeh A, Carr B, Gandara D, Chubb JM. GR-38032F: A novel compound effective in the treatment of cisplatin-induced nausea and vomiting (Abstract). ASCO 1988; 280: 1087.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Comparison of Antiemetic Activity of Chloropromazine and High Doses of Metoclopramide in Cisplatin-Based Chemotherapy N. B. Tsavaris, D. Papaioannou, D. Beldecos, S. Kakoliris, N. Mylonakis, N. Karvounis, P. Komitsopoulou, P. Karagiaouris, J. Sarmas, I. Tzannou, C. Bacoyannis & P. Kosmidis To cite this article: N. B. Tsavaris, D. Papaioannou, D. Beldecos, S. Kakoliris, N. Mylonakis, N. Karvounis, P. Komitsopoulou, P. Karagiaouris, J. Sarmas, I. Tzannou, C. Bacoyannis & P. Kosmidis (1990) Comparison of Antiemetic Activity of Chloropromazine and High Doses of Metoclopramide in Cisplatin-Based Chemotherapy, Acta Oncologica, 29:8, 1005-1009, DOI: 10.3109/02841869009091791 To link to this article: http://dx.doi.org/10.3109/02841869009091791
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 28
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Download by: [80.82.77.83]
Date: 07 May 2017, At: 12:50
Acta Oncologica 29 (1990) Fasc. 8
FROM THE SECOND DEPARTMENT O F MEDICAL ONCOLOGY, 'METAXA' CANCER HOSPITAL, PIRAEUS, GREECE.
COMPARISON OF ANTIEMETIC ACTIVITY OF CHLOROPROMAZINE AND HIGH DOSES OF METOCLOPRAMIDE IN CISPLATIN-BASED CHEMOTHERAPY N. B. TSAVARIS, D. PAPAIOANNOU, D. BELDECOS,S. KAKOLIRIS, N. MYLONAKIS, N. KARVOUNIS, P. KOMITSOPOULOU, P. KARAGIAOURIS, J. SARMAS,I. TZANNOU,C. BACOYANNIS and P. KOSMIDIS
Abstract High dose metoclopramide and different phenothiazines are widely used antiemetics in cancer patients receiving Chemotherapy. In a prospective randomized study we compared the antiemetic efficacy of high dose metoclopramide (M) and chloropromazine (C). We also tested the role of dexamethazone (D) when combined with either of these drugs. A total of 165 patients were randomly allocated to 5 groups with 33 patients in each group. Group A received only M, group B: M + D , group C: C + D , group D: M + D + C and group E M + C. All patients received combination chemotherapy with cisplatin for the first time and were evaluated only once in order to exclude anticipatory nausea and vomiting. Patients in group C had less antiemetic protection than the other groups (p < 0.001). Groups A, B, D, E, had more or less equal antiemetic efficacy, although the efficacy in group B was somewhat better; this difference was not statistically significant. Side-effects were minimal. Chloropromazine seemed to protect patients who received metoclopramide from extrapyramidal manifestations. In conclusion the results suggest that high dose metoclopramide has a better antiemetic effect than chloropromazine, dexamethazone is a helpful adjuvant drug when used in combination with an effective antiemetic agent, and chloropromazine and dexamethazone may prevent the extrapyramidal sideeffects that can occur when metoclopramide is used as single antiemetic drug. Key words: Cancer, chemotherapy, cisplatin, metoclopramide, chloropromazine, antiemetic effect.
Nausea and vomiting are frequent and serious sideeffects in patients receiving cancer chemotherapy and may sometimes be the limiting factor of chemotherapy (1 -4). Fear of these side-effects can result in rejection of potentially curative or effective palliative chemotherapy (1, 5).
In addition, some patients may be unable to tolerate the number of cycles necessary to complete their course of chemotherapy (1). Prevention of chemotherapy-induced nausea and vomiting is therefore important. Standard antiemetic treatment is of limited value. The most commonly used antiemetic drugs are metoclopramide and phenothiazines. Metoclopramide like phenothiazines acts on the brain in the chemoreceptor trigger zone by blocking dopamine receptors (2). In contrast to the phenothiazines, which have anticholinergic effects, metoclopramide is a cholinergic stimulant acting peripherally on the musculature of the proximal gut (2). The antiemetic efficacy of metoclopramide has been shown in several well controlled studies, and many investigators consider the drug to a very useful agent against nausea and vomiting associated with chemotherapy (6-9). Corticosteriods have been used in combination with these two drugs and seem to improve the antiemetic effect (10- 13). In order to investigate the effectiveness of these drugs in different combinations, we compared the efficacy of metoclopramide alone with the following four combinations: metoclopramide + dexamethazone, chloropromazine +corticosteriods, metoclopramide + cloropromazine dexamethazone, and metoclopramide + chloropromazine in cancer patients receiving cisplatin-containing chemotherapy. The study was prospective and randomized.
+
Submitted 18 October 1989. Accepted for publication 24 March 1990.
1005
1006
N. B. TSAVARIS ET AL.
Material and Methods From January 1986 to June 1988, 165 patients with histologically confirmed cancer were entered into this study (Table 1). Only Patients < 70 years old who had not previously received chemotherapy and with a Karnofsky index of >60% were included in the trial. All patients received combination chemotherapy with cisplatin. As required for the concurrent chemotherapy protocols, each patient had a leukocyte count above 4 OOO/mm3, a platelet count above 100 OOO/mm3,serum creatinine below 14 mg/l, and serum bilirubin below 10 mg/l. Pretreatment evaluation included complete history and physical examination, blood counts, 12-channel biochemical profile, serum electrolytes and creatinine (creatinine clearance), electrocardiogram and chest roentgenogram. Follow-up biochemical and hematologic tests were performed twice a week during the first week of treatment and weekly thereafter; chest roentgenogram and creatinine clearance were obtained monthly. Age, sex, Karnofsky index and site of primary cancer did not differ significantly between the five groups. All patients were hospitalized to receive cisplatin at a dose of 100 mg/m2 of body surface area in 30 min intravenous infusion. Cisplatin treatment followed intravenous hydration with mannitol diuresis. Patients with non-small cell lung cancer received also vinblastine (6mg/m2) or vinblastine (6 mg/m2) plus mitomycin, agents that generally do not induce emesis. Patients with ovarian cancer also received doxorubicin, cyclophosphamide, and etoposide.
We tested three antiemetic drugs in five combinations. The drugs were administered as follows: Metoclopramide was given at a dose of 1.5 mg/kg every 2 h for five intravenous doses. The first dose was given 30 min prior to cisplatin and then at 1 1/2, 3 1/2, 5 1/2 and 7 1/2 h after cisplatin. Intravenous doses of metoclopramide were diluted in 50ml of 0.9% sodium chloride and infused in 15 min. Dexamethazone was given at a dose of 8 mg, every 6 h, for four intravenous doses. The first dose was given 30 min prior to cisplatin, and then at 5 1/2, 11 1/2, and 17 1/2 h after cisplatin. Chloropromazine was given at a dose of 12.5 mg, every 6 h, for four intravenous doses. The first dose was given 30 min prior to cisplatin, and then 5 1/2, 11 1/2 and 17 1/2 h after cisplatin. The three drugs were combined in 5 different ways: Group A: Metoclopramide alone. Group B: Metoclopramide plus dexamethazone. Group C: Chloropromazine plus dexamethazone. Group D: Metoclopramide plus chloropromazine plus dexamethazone. Group E: Metoclopramide plus chloropromazine. Food or liquids by mouth were restricted during the 24 h of the trial; only 400 ml of water and 3 pieces of fried bread were allowed. The patients were randomly allocated to one of these 5 groups and each group included 33 patients. The patients received the paticular antiemetic treatment only once.
Table 1 Patieni characteristics
Group Antiemetic drugs
A M
B M+D
C C+D
D M+C+D
E M+C
Total
Number of patiens Median age (years) Range Sex Males Females Performance status Karnofsky 90-100 80 70 Type of cancer Lung cancer Ovarian cancer Soft tissue sarcoma Head and neck tumors Melanoma Others (germ cell testicular, uterus cancer and mesothelioma)
33 56 (39-79)
33 58.2 (37-70)
33 54.3 (24-68)
33 53.2 (23-70)
33 56.9 (40-69)
165 55.7 ( 24-70)
21 12
22 11
19 14
22 11
23 10
107 58
4 17 12
3 16 14
9 11 13
4 18 11
4 19 10
24 81 60
21 5
23 4 0 2 1 3
15 6 1 3 7
1
23 5 0 2 0 3
100 25 3 11
1
18 5 1 4 4
I 0 4 2
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
10 16
1007
ANTIEMETIC EFFECT OF METOCLOPRAMIDE AND CHLOROPROMAZINE
Nausea and vomiting were evaluated by the medical personnel for 24 h following cisplatin infusion by interviewing the patients. Vomiting was graded as 0 (none, absent), 1 ( < 5 vomiting episodes), 2 (6-10 episodes), 3 ( > 10 episodes). Nausea was graded as follows: 0 (none), 1 (mild, no interference with activity), 2 (moderate, interference with activity), 3 (severe, bedridden for over 2 h). Side-effects of treatment were also directly observed and recorded. Activity during the trial was graded as follows: 0 (normal activity), 1 (mild impairment of activity), 2 (moderately severe impairment of activity). The influence on the patients appetite was graded as follows: 0 (normal appetite), 1 (mild impairment due to symptoms). Any sedative effect was evaluated as follows: 0 (none), 1 (mild, patient lethargic but wakened by verbal stimuli and completely oriented as to time, place, and persons when awake), 2 (moderate, patient wakened only by physical stimuli but completely oriented when awake), and 3 (marked, patient wakened only by physical stimuli and disoriented when awake). Diarrhea during the tiral was
graded as follows: 0 (none), 1 ( < 3 episodes), 2 (3-6 episodes), 3 ( >6 episodes, intolerable requiring therapy). Patients were assessed for the side-effect of antiemetics such as: chills diaphoresis, diarrhea, headache, dizziness, hypotensive symptoms, ataxia, hallucination, euphoria, extrapyramidal manifestation or any other symptoms. Patients were awakened if necessary and side-effects assessed before each dose of antiemetic medications, at the end of the 24-h observation period, and at least every 3 h during the trial. For statistical analysis Pearson’s X2-test was used to compare frequencies.
Results As is seen in Table 2 the least antinausea and antivomiting effect was noticed in group C (p c 0.001). Group B had the highest antinausea and antivomiting protection but it was not statistically significant from groups A, D, and E. Regarding toxicity, sedation was slightly more prominent in groups C , D, and E, i.e. patients who received
Table 2 Evaluation of side-effects. The grading systems used are described in ihe test. The WHO recommendations were used for grading of vomiiing and nausea
Side-effects
Grading
Group
D (M+C+D)
E (M+C)
5 22
3 3
8 18 6 1
12 11 8 2
19 6 4 4
15
19
11 I
13 1 0
17 14 2 0
9 24
16 17
18 15
3
21 10 2
20 10
27 5
25 8 0 0
A (M)
B (M+D)
C (D+C)
0 1 2
5 15 10
3
3
6 24 2 1
12 6 12
0 1 2
12 7 8 6
17 9 5 2
6 4 7 16
24 9 0 0
26 7 0 0
0
14 19
18 15
17 9
26 7 0
16 14
Vomiting 3
Nausea
3
Sedative effects 0 1 2
3
Appetite 0
1
Activity 0
I 2
7
3
Diarrhea 0 1 2
3
22 9 2 0
26 6
I 0
33 0 0 0
1 0
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
1008
N. B. TSAVARIS ET AL
Table 3 Other side-effects among the 33 patients in each group
Side-effects
Chills Diaphoresis Headache Dizziness Hypotensive symptoms Ataxia Hallucinations Euphoria Extrapyramidal manifestation Insomnia Mouth dryness
Group A (M)
B (M+D)
C (D+C)
D (M+D+C)
E (M+C)
0 6 8 7 2 0 0 0 6 2 10
4 8 12 3 1 0 0 6 2 3 12
0 6 26 29 0 0 0 0 0 0 6
3 4 19 23 1 0 0 1 0 0 18
0 0 21 26 4 0 0 0 0 0 12
Abbreviations: M = metoclopramide, C = chloropromazine, D = dexamethazone
chloropromazine, whereas diarrhea was completely absent only in group C. Headache and dizziness were significantly more common in groups C, D, and E. Extrapyramidal manifestation appeared in a few patients of groups A and B but was absent in group E. All results are presented in detail in Tables 2 and 3.
Discussion Nausea and vomiting have been the most common devastating acute side-effects of cisplatin-based chemotherapy. Many trials undertaken during the last 8 years have shown different groups of drugs to ameliorate chemotherapy-induced emesis. Among these drugs high dose metoclopramide and phenothiazines are the most widely used. Corticosteroids have been added in different combinations to the principle drugs and seem to contribute to the antiemetic effect (10-13). In our trial, patients who had no metoclopramide in their combination presented the least antiemetic effect, which was statistically significant when compared with the other groups. In all the other groups the antiemetic protection was more or less equal and all patients in these groups had received high doses of metoclopramide. It is interesting to note that the addition of chloropromazine to the combination metoclopramide and dexamethazone did not potentiate the antiemetic effect in our trial. However, we have to recognize that the number of patients in each group was small, which means that the statistical power of the study was low. Metoclopramide in large doses sometimes causes extrapyramidal symptoms, and some such cases were also observed in the present trial. However, no case of extrapyramidal side-effects was observed in the groups which also received chloropromazine suggesting a preventive effect of this drug.
Toxicities in the groups which received metoclopramide alone and metoclopramide plus dexamethazone were mild and well tolerated. They consisted mainly of diarrhea and, in a few patients, extrapyramidal manifestations attributable to metoclopramide. Sedation, dizziness and headache were the most prominent side-effects in the groups which received chloropromazine-containing combinations. Our study suggests that metoclopramide in high doses is a better antiemetic agent for patients who receive cisplatinbased chemotherapy than chloropromazine and that the addition of dexamethazone improves the antiemetic efficacy. Chloropromazine does not seem to potentiate the effectiveness of high dose metoclopramide. Higher doses of metoclopramide are used today with perhaps better efficacy and reduced frequency of administrations. The new drug G R 38032F (GR), a selective serotonine type 3 (5HT,) receptor antagonist, and similar drugs have demonstrated complete efficacy in preventing cisplatin-induced emesis without side-effects in clinical trials (14, 15). These new drugs will probably replace both metoclopramide and all phenothiazine substances within the next few years. Request for reprints: Dr N. B. Tsavaris, Second Department of Medical Oncology, ‘METAXA Cancer Hospital, 56 Botassi Street, Piraeus 18537, Greece.
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