Original Paper Oncology 1992;49:479-483

N. Tsavaris E. Tsaroucha-Noutsou C. Bacoyannis N. Mylonakis P. Valilis D. Kozatsani-Halividi H. Tsoutsos S. Droufakou P. Kosmidis

Antiemetic Efficacy of High-Dose Metoclopramide and Dexamethasone in Patients Receiving Cisplatin Chemotherapy: A Randomized Trial

Keywords Metoclopramide Dexamethasone Cisplatin Antiemetics Chemotherapy

Abstract In a prospective randomized trial we compared the antiemetic efficacy of metoclopramide (MCP) and dexamethasone (DXM). A total of 172 patients receiving chemotherapy based on cisplatin 100 mg/m2/day were randomly allo­ cated to four groups. CP was administered in 5 doses of 1.5 mg/kg (group A). 2 mg/kg (group C), or combined with 4 doses of DXM 4 mg/6 h (MCP: 1.5 mg/kg in group B; 2 mg/kg in group D). Vomiting was decreased in the DXM groups compared to groups A and C ( p < 0.002), and the duratoin of nausea was greater in group A than in group D (P < 0.004). A greater distur­ bance in appetite was observed in group A compared to groups B (p< 0.028), D(p < 0.001) and C (p < 0.045). Activity problems were greater in group A than in C ( p < 0.003) and D (p < 0.005). We noticed that a small increase in MCP (0.5 mg/kg) did not influence the antiemetic effect. The addition of DXM did not significantly alter the antiemetic results at the lower MCP dose, but im­ proved them when MCP was slightly increased. We conclude that DXM slightly improves the antiemetic effect of M CP and the effects are related to the MCP dose.

Introduction

Therefore, the prevention of chemotherapy-induced nausea and vomiting is of paramount importance. Stan­ dard antiemetic treatment is of limited value. Consequent­ ly, antiemetic therapy has been empirical, leading to the testing of agents whose mechanism of action is poorly un­ derstood. Metoclopramide (MCP) is a commonly used antiemetic drug which acts on the brain in the chemoreceptor trigger zone by blocking dopamine receptors [2], It is also a cholinergic stimulant acting peripherally on the musculature of the proximal gut [2], The antiemetic ef-

Nausea and vomiting are frequent, serious, and cause acutely detrimental adverse effects in patients receiving cancer chemotherapy. They may in fact be the limiting fac­ tor of chemotherapy [1-4], Fear of these side effects can result in the rejection of potentially curative or effectively palliative chemotherapy [1,5], In addition, some patients may be unable to tolerante the cycles necessary to com­ plete their course of chemotherapy [ 1].

N. Tsavaris Department of Pathologic Physiology University of Athens School of Medicine *Laiko” Hospital, Athens 11527 (Greece)

100,000/mm3, serum creatinine < 1.4 mg/dl, and serum bilirubin < 1.0 mg/dl (table 1). Pretreatment evaluation included a complete history and physi­ cal examination, blood counts, 12-channel biochemical profile, serum electrolytes and creatinine (creatinine clearance), electro­ cardiogram and chest roentgenogram. Follow-up biochemical and hematologic tests were performed twice a week during the first week of treatment and weekly therafter. Chest roentgenogram and creati­ nine clearance were obtained monthly. Age. sex, Karnofsky index and the site of primary cancer did not differ significantly between the four groups (table 1). All patients were hospitalized to receive cisplatin at a dose of 100 mg/nr of body surface area in a 30-min intravenous infusion. Cisplatin treatment followed intravenous hydration with manitol diuresis. Patients with non small cell lung cancer also received vin­ blastine (6 mg/nr) or vinblastine (6 mg/nr) plus mitomycin, agents that generally do not induce emesis. Patients with ovarian cancer also received doxorubicin, cyclophosphamide and etoposide; those with head and neck cancer received 5-fluorouracil; those with mesoth­ elioma received vinblastine, those with testicular cancer received vepesid and bleomycin. We tested two drugs in two combinations administered as fol­ lows: MCP was given at a dose of 1.5 mg/kg (group A) or 2 mg/kg (group B) every 2 h for five intravenous doses. The first dose was given 30 min prior to cisplatin and then at 1-5,3-5,5-5 and 7-5 h after cisplatin. Intravenous doses of MCP were diluted in 50 ml of 0.9%

480

sodium chloride and infused in 15 min; DXM was given every 6 h for four intravenous doses. The first dose of 4 mg was given intrave­ nously 30 min prior to cisplatin, and then at 5-5,11 -5 and 17-5 h after cisplatin. The two drugs were combined as follows: group A, MCP 1.5 mg/kg alone; group B, MCP 1.5 mg/kg plus DXM; group C, MCP 2 mg/kg alone, and group D. MCP 2 mg/kg plus DXM. The patients were first randomly allocated to one of the two MCP regimens, and then between groups A and B. and groups C and D. Group A included 40, group B 44, group C 40 and group D 48 pa­ tients. The patients received the particular antiemetic treatment once only. Nausea and vomiting were evaluated by the medical personnel for 24 h following cisplatin infusion by interviewing the patients. Vomiting with gastric content was graded as 0 (none), 1(< 5 vom­ iting episodes), 2 (6 10 episodes), and 3 (> 10 episodes). Vomiting without gastric content was evaluated the same way. Nausea was ev­ aluated according to its duration. Nausea and vomiting together were evaluated according to the WHO classification (table 2). Factors that influence antiemetic activity such as stress, depres­ sion, degree of family support, weight loss > 10% during the previous 2 months, and a confronted psychological condition were also evaluated and they did not differ between the four groups. Side effects of antiemetic treatment were also directly observed and recorded (table 3). Sedative effects were evaluated as follows: 0 (none), 1 (mild, patient lethargic but wakened by verbal stimuli and completely oriented with regard to time, place, and persons when aw­ ake), 2 (moderate, patient wakened only by physical stimuli but com­ pletely oriented when awake), and 3 (marked, patient wakened only by physical stimuli and disoriented when awake). The influence on

Table 1. Patients' clinical characteristics

Characteristic

Patient group A

B

C

D

Number of patients

40

44

40

48

Median age. years Age range, sex years

56 39-65

55 31-68

58 39-65

54 41-69

Sex Male

27

34

24

31

Female

13

10

16

17

16 13 11

22 19 11

15 12 17

16 22 27

24 6 3 11

29 0 6 9

17 6 4 13

27 4 10 7

0 0 6 21

0 0 7 27

0 0 5 24

0 0 8 29

Karnofsky performance status 9 0 -100 80 70 Type of cancer Lung Ovarian Head and neck Others Previous chemotherapy Previous antivomiting therapy Previous radiotherapy Stress (Hamilton test)

Tsavaris/Tsaroucha-Noutsou/Bacoyannis/ Mylonakis/Valilis/Kozatsani-Halividi/ Tsoutsos/Droufakou/Kosmidis

Antienetic Effects of Metoclopramide and Dexamethasone

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ficacy of high-dose MCP has been shown in several wellcontrolled studies, and many investigators consider the drug to be a very useful agent against the nausea and vomiting associated with chemotherapy [6-9]. In order to potentiate the efficacy of antiemetic drugs, adjuvant drugs have been used, such as antidopaminergic, anticholinergic and antihistaminic agents, glucocorticosteroids, benzodiazepines, marijuana, and nabilone either alone or in combination [10-12], According to the literature, combinations of MCP and dexamethasone (DXM) may be superior to MCP alone [11-14], but the mechanism of action of corticosteroids in nausea and vomiting is still unknown. Both high-dose methylprednisone [15, 16] and DXM [12, 17-22], have been used in this situation to good effect. We initiated this study to investigate the effectiveness of DXM. The aim was first to compare the efficacy of MCP alone or in combination with DXM, and second to study the interaction between DXM and MCP at different doses. The study was prospective and randomized.

Table 4. Side effects

Table 2. Results of antiemetic treatment

Patient group

Grade Patient group II

0 1 2 3 4

10 15 10 5 0

22 19 1 2 0

13 24 1 1 0

26 10 2 0 0

Vomiting without gastric content

0 1 2 3

7 9 18 6

4 11 23 6

9 17 8 6

9 21 II 7

Nausea and vomiting according to the WHO classification

0 1 2 3 4

9 7 10 12 2

9 12 16 6 1

10 9 12 8 1

12 18 II 7 0

Nausea

no yes

6 34

3 41

7 33

6 42

262 0-600

212 0 500

Duration of nausea, min Mean Range

206 120-780

160 0-1.000

Table 3. Side effects

Grade

Chills Hallucinations and diaphoresis Headache Dizziness Hypotensive symptoms Ataxia Extrapyramidal episodes Mouth dryness

2 16

3 18

4 15

0 16

14 5 1 1 4 8

10 11 1 0 7 15

12 6 1 0 4 14

8 10 2 0 6 10

the patients’ appetites was graded as follows: 0 (normal appetite), 1 (mild impairment due to symptoms). Activity during the trial was graded as follows: 0 (normal), 1 (mild impairment), 2 (moderately severe impairment). Diarrhea during the trial was graded as follows: 0 (none), 1 (< 3 episodes), 2 (3-6 episodes), 3 (> 6 episodes, intoler­ able requiring therapy). Patients were assessed for some other side effects of antiemetics such as chills, diaphoresis, hallucination, headache, dizziness, hyp­ otensive symptoms, ataxia, extrapyramidal manifestation, mouth dryness or any other symptoms (table 4). Patients were awakened if necessary and side effects were assessed before each dose of antiemetic medication, at the end of the 24-hour observation period, and at least every 3 during the trial. For statistical analysis, Pearson’s yj test was used to compare fre­ quencies.

Patient group D A B C (n = 40) (n = 44) (n = 40) (n = 48)

Sedative effects

0 1 2 3

29 11 0 0

37 4 2 i

33 7 0 0

38 8 2 0

Appetite

0 1 2 3

12 13 9 6

24 15 3 2

15 19 4 1

28 18 2 0

Activity

0 1 2 3

16 11 13 3

24 9 10 1

26 12 2 0

25 19 2 2

Diarrhea

0 1 2 3

22 15 3 0

28 5 7 4

26 8 6 0

35 4 8 1

Results Factors that influenced antiemetic activity were similar in the four groups (table 2). As can be seen in table 2, we found differences for vom­ iting with gastric content and duration of nausea. Table 5 shows an increased number of patients without vomiting in group D in comparison with groups C and A (p < 0.002). Duration of nausea was longer in group A (p< 0.004), probably B (p < 0.10) and C (p < 0.07) in comparison with group D. No other significant differences were noted in table 2. With other side effects table 3) we only found differen­ ces for appetite and activity. There was a greater distur­ bance (grades 2 and 3) in appetite (table 5) for group A in comparison with groups B (p< 0.028) and D (p< 0.001); there was also a difference between groups A and C (p < 0.045). The least problemas with appetite were found

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Vomiting with gastric content

B D A C (n = 40) (n = 44) (n = 40) (n=48)

D OO

A B C (n = 40) (n = 44) (n = 40)

Group

Vomiting1 Duration grade 0 of nausea

Appetite grades 2 + 3

Activity grades 2 + 3

A vs. B Cvs. D A vs. C B vs. D B vs. C A vs. D

0.2 0.002 0.1 0.2 0.2 0.002

0.028 0.2 0.045 0.2 0.8

0.2 0.5 0.003 0.067 0.03 0.005

0.2 0.07 0.32 0.1 0.78 0.004

0.001

See tables 2 and 3 for patient numbers. 1 Vomiting with gastric content.

in group D. For activity grades 2 and 3 there were more patients in group A than in groups C (p< 0.003), and D (p< 0.005), and there was probably a difference between groups Band D ( p < 0.067). We noticed no other differences in the parameters ex­ amined (table 4).

Discussion Cisplatin (cis-diamminedichloroplatinum), an agent highly effective against a variety of cances, produces the most severe nausea and emesis of any chemotherapeutic agent [1,14]. Nausea and vomiting have been the most common de­ vastating acute side effects of cisplatin-based chemo­ therapy. Many trials have been undertaken during the last 10 years which have shown that different groups of drugs can ameliorate chemotherapy-induced emesis. Among these drugs high-dose MCP is the most widely used. To try to increase the antiemetic efficacy of MCP, ad­ juvant drugs such as corticosteroids, phenothiazines, and benzodiazepines have been added in different combina­ tions to the principle drugs and seem to contribute to the antiemetic effect [8-13]. It has been established that com­ bination antiemetic therapy offers the best protection against emesis [8-13]. In our trial we tried to examine how DXM interacted with MCP in an antivomiting schedule. It is known that the effective regimens currently available contain MCP and DXM [13,17,18], with or without other agents [ 10,13]. So in our study we kept the quantity of DXM constant, and increased the amount of MCP slightly, using usual

482

therapeutic doses, to try to study the interaction between the two agents. A relative lack of dose-response relationship to DXM was noted in patients receiving cisplatin [23]. We kept the quantity of DXM constant because a total dose of 16-20 mg is adequate to prevent emesis [14], So the ef­ ficacy that was demonstrated in our study of an adequate dose of DXM over high-dose MCP could be attributed to the dose of MCP used. This is in contrast to the Ibrahim [23] study. The mechanism of action of corticosteroids remains unclear, although an antiprostaglandin effect has been suggested [24] and 20% of patients may benefit from them [13,16]. Several investigators have reported improved antiemetic efficacy of MCP plus DXM compared to MCP alone [13,14], In our study we noticed that a small increase in MCP (0.5 mg/kg, group C vs. A) did not influence the antiemetic effect. The addition of DXM did not significantly alter the results. The antiemetic efficacy was significantly increased in group D (absence of vomiting, shorter duration of nausea, better appetite and activity) when MCP was in­ creased. The difference between group D and groups A and C was the addition of DXM, while the difference bet­ ween groups D and B was the increase in MCP. So we con­ clude that the improvements found by adding DXM are also influenced by the amount of MCP. Because an MCP dose of 2 mg/kg and a total DXM dose of 20 mg are opti­ mal, the high effectiveness of the combination was expect­ ed in group D. So, an adequate amount of MCP and DXM are needed in order to have satisfactory effects. Recent investigations have revealed that selective an­ tagonists of serotonin S3 receptors prevent the vomiting induced by cisplatin. Promising results have been obtained in clinical trials, [25], but DXM would remain an adjuvant drug for this new agent. In conclusion DXM is a useful adjuvant antiemetic drug when it is added to MCP in appropriate doses.

Tsavaris/Tsaroucha-Noutsou/Bacoyannis/ Mylonakis/Valilis/Kozatsani-Halividi/ Tsoutsos/Droufakou/Kosmidis

Antiemetic Effects of Metoclopramide and Dexamethasone

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Table 5. Probabilities in group comparisons for vomiting, nausea, appetite and activity

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Antiemetic efficacy of high-dose metoclopramide and dexamethasone in patients receiving cisplatin chemotherapy: a randomized trial.

In a prospective randomized trial we compared the antiemetic efficacy of metoclopramide (MCP) and dexamethasone (DXM). A total of 172 patients receivi...
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