K. Mystakidou, S. Befon, J. Trifyllis, C. Liossi and J ...

Tropisetron versus Metoclopramide in the Control of Emesis in Far-Advanced Cancer K. Mystakidou, S. Befon, J. Trifyllis, C. Liossi and J. Papadimitriou The Oncologist 1997, 2:319-323.

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Tropisetron versus Metoclopramide in the Control of Emesis in Far-Advanced Cancer K. MYSTAKIDOU, S. BEFON, J. TRIFYLLIS, C. LIOSSI, J. PAPADIMITRIOU Cancer Pain Relief and Palliative Care Unit, University of Athens, Areteion Hospital, Athens, Greece Key Words. Far advanced cancer · Emesis · Nausea · Vomiting · Tropisetron · Metoclopramide

A BSTRACT plus TRO plus DEX. Patient diary cards were used to assess nausea and vomiting. By the end of day 15, total control of vomiting was achieved in 24% of MET plus DEX patients, in 84% of MET plus TRO patients, and in 92% of MET plus TRO plus DEX patients. Total control of nausea was achieved in 18% of MET plus DEX patients, in 74% of MET plus TRO patients, and in 87% of MET plus TRO plus DEX patients. All antiemetic treatments were similarly well tolerated. TRO in combination with either MET or MET and DEX produced the best control of both nausea and vomiting. The Oncologist 1997;2:319-323

INTRODUCTION Nausea and vomiting are common complaints of cancer patients, whether related to active treatment with chemotherapy or radiotherapy or arising at the terminal stage of the disease. Relatively little data exist on the overall incidence patterns of nausea and vomiting in patients with far-advanced cancer. Such information as is available suggests that nausea occurs in 60% of terminal cancer patients [1]. Vomiting is less common, occurring in about 30% of patients [2]. Nausea and vomiting are upsetting and distressing to the patient, have great clinical importance, and require immediate treatment. Patients with uncontrolled emesis are not able to take their analgesic medication. Dehydration, malnutrition, and electrolytic disturbance appear quickly, and this in turn results in exacerbation of emesis. There are many potential causes of emesis which impinge on a complex physiological process and lead to great difficulties in both treatment and research. It may be due to gastrointestinal causes (e.g., gastric stasis, bowel obstruction), cranial causes (e.g., intracranial metastases), electrolytic disturbance,

metabolic causes (e.g., uremia, hypercalcemia), or drug intake (e.g., opioids) [3]. Conventional antiemetics when used in high dose or in combination may alleviate nausea and vomiting in faradvanced cancer [4]. A high dose of metoclopramide and a corticosteroid often combined with a tranquilizer or sedative form the basis of many antiemetic cocktails. However, the use of higher doses or combinations of drugs is associated with a greater incidence of side effects and a greater complexity of administration. For example, at high dose, metoclopramide (MET) is a far more effective antiemetic and is thought to act by blocking both dopamine and 5-hydroxytryptamine (5-HT3) receptors. However, at high dose, the incidence of extrapyramidal effects increases [5]. Recently, much attention has been given to the mechanisms and management of cytotoxic- and radiotherapy-induced emesis, but more study, evaluation of, and intervention in nausea and vomiting associated with terminal illness is required. The development of 5-HT3-receptor antagonists such as tropisetron (TRO) has provided clinicians with better means for controlling nausea and vomiting induced in patients by

Correspondence: Kyriaki Mystakidou, M.D., Ph.D., Cancer Pain Relief and Palliative Care Unit, University of Athens, Areteion Hospital, Vas. Sofias 76, 11528 Athens, Greece. Telephone: 30-1-94-334330; Fax: 30-1-7286248. Accepted for publication July 16, 1997. ©AlphaMed Press 1083-7159/97/$5.00/0

The Oncologist 1997;2:319-323 1997;2:


The present study was conducted to assess the optimum treatment for nausea and vomiting in patients with far advanced cancer. More specifically, we studied patients with cancers that were too far advanced to benefit from chemotherapy or radiotherapy and whose nausea and vomiting were not due to drug intake, cranial, electrolytic, or metabolic causes. One hundred twenty patients who were under antiemetic medication with metoclopramide (MET) and suddenly presented with uncontrolled nausea and vomiting were randomized to three different therapeutic regimens: MET plus dexamethasone (DEX), MET plus tropisetron (TRO), and MET

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METHODS After obtaining approval from the ethics committee of our institute and written informed consent from the patients, a single-institution, prospective, randomized study was carried out to compare TRO and MET in the control of the nausea and vomiting of far-advanced cancer. The study was conducted in accordance with the Helsinki Declaration. Recommendations for the conduct of clinical trials of antiemetics determined the design and implementation of our study, which therefore had clearly predefined endpoints, a prospective parallel group-design, a proven antiemetic for comparison, a homogeneous study population, groups balanced for important variables, and patient participation in an evaluation of efficacy and tolerability [6]. Therefore, this comparative study was prospective, randomized, and consisted of parallel groups. One hundred twenty patients took part in this study. These patients were under opioid administration for pain control (Table 1) and on a low dose of MET (10 mg × 2) to avoid opioid-induced nausea and vomiting. All patients were under total emesis control for a long period of time (x = 38 days, range 23-57 days). No alterations were made in patients’ Table 1. Patient medication before and during the study Drug

Dose

Dihydrocodeine p.o.

120 mg - 240 mg

Morphine

60 mg - 300 mg 10 mg - 90 mg 1.5 mg - 12 mg 1 mg - 5 mg

p.o. s.c. epidural intrathecal

Metoclopramide Anti-inflammatory

10 mg × 2/day

analgesic and/or other medication. Suddenly, they experienced vomiting and nausea. Patients entered the study the second day after the appearance of these symptoms. The 120 patients were randomized to one of three treatment groups. There were no significant differences in patients’ medical and demographic characteristics. More specifically, for: A) Age—an f test was conducted (for the individual comparisons MET+DEX/MET+TRO f = 0.20//p = NS, MET+DEX/MET+DEX+TRO f = 0.81//p = NS, and MET+TRO/MET+TRO+DEX f = 0.13//p = NS); B) Sex—an x2 test was conducted (p = NS for all the individual comparisons MET+DEX/MET+TRO, MET+ DEX/ MET+DEX+TRO, MET+TRO/MET+TRO+ DEX), and C) Primary location—an x2 test was conducted (p = NS for all the individual comparisons MET+DEX/MET+TRO, MET+ DEX/MET+DEX+TRO, MET+TRO/MET+TRO+ DEX). (NS = not significant) The patients’ characteristics are presented in Table 2. Inclusion criteria for entry to the study were: patients with faradvanced cancer who, even though they were well controlled with their antiemetic medication, (MET: 10 mg × 2 p.o.) suddenly started having nausea and vomiting (three or more vomiting or retching events per day). All patients were receiving standard analgesic medication, were free of pain, and had no alteration to their medication prior to the onset of emesis (Table 1). Patients with metabolic or electrolytic disturbance and central etiology vomiting were excluded from the study. Patients who were under phenobarbital, riphamicin, or Table 2. Patient characteristics at entry to the study Treatment Group Characteristic Age Median Range SD (Standard deviation)

MET+DEX MET+TRO MET+TRO+DEX n = (40) n = (40) n = (40) 55 36-75 9.06

61 41-78 7.4

59 37-72 9.4

Sex Male Female

22 18

17 23

19 21

Primary diagnosis– type of cancer Colon, rectum Ovary Uterus, cervix Pancreas Stomach Abdominal sarcoma Cholangiocarcinoma Lung

12 9 7 3 4 2 2 1

9 8 8 2 4 4 3 2

8 7 10 4 3 4 2 2


emetogenic chemotherapy and radiotherapy. However, even though the advantages of the 5-HT3-receptor antagonists over traditional antiemetic combination therapy are now generally acknowledged in this type of emesis, it is of interest to study their efficacy in emesis associated with far-advanced cancer. Thus, the purpose of the present study was to assess the optimum treatment for nausea and vomiting in advanced cancer patients who, even though they were on antiemetic medication, suddenly experienced nausea and vomiting. The patients’ nausea and vomiting were not due to cranial, electrolytic, or metabolic causes, drug intake, chemotherapy, or radiotherapy. This treatment is the first of its kind that uses a 5-HT3 antagonist in the control of emesis associated with far-advanced cancer. Three antiemetic treatments were compared: metoclopramide plus dexamethasone (MET+DEX), metoclopramide plus TRO (MET+TRO), and metoclopramide plus TRO plus dexamethasone (MET+TRO+DEX).

Tropisetron versus Metoclopramide for Controlling Emesis

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phenylbutazone were also excluded from the study. All patients were (x > 32 days) from chemotherapy or radiotherapy. None of the patients had a nasogastric tube and all were treated at home.

Assessments The criteria used in the analysis of the study results are particularly important. Different criteria have been used by different investigators to assess the efficacy and tolerability of the different 5-HT3 receptor antagonists in chemotherapy- or radiotherapy-induced emesis. Hence, terminology has become confusing. It is believed that the objective of antiemetic therapy must be the complete abolition of both nausea and vomiting. The purpose of this study was to achieve complete control of nausea and vomiting in the shortest possible time. This is why the most stringent evaluation criteria have been used and have defined total control as the complete absence of nausea or vomiting. Nausea was measured as the duration of this reaction in hours, rounded to the nearest quarter. Vomiting was measured in single events (one vomit or retch). Patient diary cards provided the data on these parameters. Nausea control on a particular day was classified as: • Total control • Major control • Minor control • No control

No nausea < 4 hours > 4 hours to < 8 hours > 8 hours

In the absence of reliable methods of quantifying this reaction, no analysis was made of the severity of nausea. Vomiting control on a particular day was classified as: • Total control • Major control • Minor control • No control

No vomiting 1 vomiting event 2 vomiting events 3 or more vomiting events

Our criteria for gauging tolerability included the occurrence of adverse reactions (constipation, anorexia, dizziness, extrapyramidal symptoms). Data concerning adverse reactions were also collected from patient diaries.

RESULTS For all the tables, the Pearson Chi square was statistically significant and the residual tables (observed minus expected frequencies) indicated that the MET+DEX combination gave the worst response in total control of both nausea and vomiting, with MET+TRO being second, and MET+TRO+DEX being the most effective in providing total control of both nausea and vomiting. The magnitude of all of the differences was quite high. Day 1 Nausea and Vomiting Total control of nausea was not achieved in any of the patients receiving MET+DEX. When TRO was given in combination with MET the control rate improved to 2.5%. TRO together with MET and DEX prevented nausea in 7.5% of patients. Similarly for vomiting, the combination of TRO with either MET (7.5%) or MET and DEX (15%) provided the best control. The combination of MET and DEX did not provide total control in any of the patients. Day 3 Nausea and Vomiting Total control of nausea was achieved in 10% of patients receiving MET+DEX. When TRO was given in combination with MET, the control rate improved to 35%. TRO+MET+DEX prevented nausea in 55% of patients. Similarly for vomiting, the combination of TRO with either MET (65%) or MET+DEX (75%) provided the best control. The combination of MET+DEX provided total control of vomiting in approximately 5% of patients. Day 7 Nausea and Vomiting Total control of nausea was achieved in 16% of patients receiving MET+DEX. When TRO was given in combination with MET, the control rate improved to 53%. TRO together with MET and DEX prevented nausea in 72% of patients. Similarly for vomiting, the combination of TRO with either MET (71%) or MET and DEX (82%) provided the best control. The combination of MET+DEX provided total control of vomiting in approximately 21% of patients.


Antiemetic Treatment The antiemetic treatment schedules were as follows: (A) MET+DEX: 10 mg × 4 p.o. plus 2 mg × 1 p.o.; (B) MET+TRO: 10 mg × 2 p.o. plus 5 mg × 1 p.o., and (C) MET+TRO+DEX: 10 mg × 2 p.o. plus 5 mg × 1 p.o. plus 2 mg × 1 p.o. Patients were monitored for 15 days in order to evaluate not only the efficacy of the drug combinations, as far as total emesis control and time of achievement are concerned, but also the preservation of the results in time. The evaluation of vomiting and nausea took place 24 h after the commencement of therapy, and on days 3, 7, and 15 of treatment.

Statistical Analysis The analysis was performed using the Basic Statistics/ Tables and banners module of the STATISTICA/w v. 5.1 statistical package. A standard crosstabulation approach was employed, and the Pearson Chi square and Maximum Likelihood indexes were calculated. For the purposes of this report, the Pearson Chi square will be used throughout. Once statistical significance was observed, residual analysis was used to interpret the tables.

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Adverse Effects The antiemetic treatments were generally well tolerated. Side effects were not significant and did not cause the discontinuance of therapy in any patient. The percentage of patients experiencing adverse events was similar among treatment groups. The pattern of adverse events also was similar among the groups, and there were no statistically significant differences in the incidence of any individual adverse event (Table 5).

Table 3. Vomiting control versus time (two patients from MET+DEX, two from MET+TRO and one from MET+TRO+DEX were excluded from the study after day 3 because of minor vomiting control) MET+DEX

MET+TRO

MET+DEX

MET+TRO

MET+TRO+DEX

15.00% 70.00% 15.00% 0.00%

0.00% 25.00% 70.00% 5.00%

2.50% 25.00% 62.50% 10.00%

7.50% 40.00% 50.00% 2.50%

65.00% 30.00% 5.00% 0.00%

75.00% 22.50% 2.50% 0.00%

Day 3 Control Total Major Minor No

10.00% 60.00% 25.00% 5.00%

35.00% 60.00% 5.00% 0.00%

55.00% 42.50% 2.50% 0.00%

21.05% 78.95%

71.05% 28.95%

82.05% 17.95%


15.79% 68.42% 15.79%

52.63% 47.37% 0.00%

71.79% 28.21% 0.00%

23.68% 76.32%

84.21% 15.79%

92.31% 7.69%


18.42% 71.05% 10.53%

73.68% 26.32% 0.00%

87.18% 12.82% 0.00%

0.00% 30.00% 65.00% 5.00%

7.50% 40.00% 52.50% 0.00%


5.00% 50.00% 40.00% 5.00%


Table 4. Nausea control versus time (two patients from MET+TRO and one from MET+TRO+DEX were excluded from the study after day 3 because of minor nausea control) 24 Hours Control Total Major Minor No

24 Hours Control Total Major Minor No


DISCUSSION The present study was carried out to assess the optimum treatment for nausea and vomiting in patients with far-advanced cancer. The emesis was not due to drug intake, cranial, electrolytic, or metabolic causes, and the cancers were too far advanced for chemotherapy or radiotherapy. Patients were under standard analgesic and antiemetic medication and suddenly presented uncontrolled nausea and vomiting. Until now, the so-called cocktails seemed to have a good but insufficient efficacy in the treatment of persistent emesis due to far advanced cancer. Therefore, the primary objective of the present study was to compare the efficacy of three antiemetic regimens, namely MET+DEX, MET+TRO, MET+TRO+DEX, in preventing the persistent nausea and vomiting of far-advanced cancer. The results of the present study show that the combinations of TRO A) with MET and B) with MET+DEX are superior to the combination of MET+DEX in controlling both nausea and vomiting. The combination of TRO with MET was effective even under the stringent response criteria applied in this study. However, for those patients not fully controlled with TRO+MET, the addition of DEX to the regimen was beneficial. The data collected during this study indicate that by day 15 of treatment, the majority of patients (74%) experienced total control of nausea with the combination of TRO+MET. The addition of DEX increased total control to 87%. These data also indicate that the majority of patients (84%)

MET+TRO+DEX


Day 15 Nausea and Vomiting Total control of nausea was achieved in 18% of patients receiving MET+DEX. When TRO was given in combination with MET, the control rate improved to 74%. TRO together with MET and DEX prevented nausea in 87% of patients. Similarly for vomiting, the combination of TRO with either MET (84%) or MET+DEX (92%) provided the best control. The combination of MET and DEX provided total control of vomiting in approximately 24% of patients. Nausea and vomiting control data during day 15 of the study are presented in Tables 3 and 4, respectively. No difference in antiemetic treatment compliance was observed among the groups. The number of patients withdrawing from the study was similar among the groups: only five of the patients discontinued treatment on day 3 due to poor antiemetic efficacy and were administered antiemetics intravenously.

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323

Table 5. Adverse effects during the study MET+DEX MET+TRO MET+TRO+DEX Dizziness

1

2

1

Constipation

1

8

6

Extrapyramidal symptoms

0

0

0

12

8

2

Weakness

ACKNOWLEDGMENTS We gratefully acknowledge the financial support of Sandoz Pharma Ltd., Athens, Greece. We also thank Miss Popi Chalkidou for her skillful secretarial assistance.

R EFERENCES 1 Twycross R. Symptom Management in Advanced Cancer. Oxford and New York: Radcliffe Medical Press, 1995;168. 2 Reuben DB, Mar V. Nausea and vomiting in terminal cancer patients. Arch Intern Med 1983;146:2021-2023. 3 Allan SG. Nausea and vomiting. In: Doyle D, Hanks GW, MacDonald N, eds. Oxford Textbook of Palliative Medicine. Oxford: Oxford University Press, 1996;282-290. 4 Bruere E, Seifert L. Chronic nausea in advanced cancer patients: a retrospective assessment of a MET-based antiemetic regimen. J Pain Symptom Manage 1996;11:147-153 5 Kris MG, Leslie B, Tyson LB et al. Extrapyramidal reactions with high-dose metoclopramide. New Engl J Med (Letter) 1983;7:433.

6 McVie JG, de Bruijn KM. Methodology of antiemetic trials. Drugs 1992;43(suppl 3):1-5. 7 Lee CR, Plosker GL, McTavish D. Tropisetron. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993;46:925-943. 8 Higgins GA, Kilpatrick GJ, Bunce KT et al. 5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin induced emesis in the ferret. Br J Pharmacol 1989;97:247-255 9 Richardson BP, Engel G, Donatsh P et al. Identification of serotonin-M receptor sub-types and their specific blockade by a new class of drugs. Nature 1985;316:126-131.


experienced total control of vomiting with the combination of TRO+MET. The addition of DEX increased total control to 92%. Moreover, the combinations MET+TRO and MET+TRO+DEX succeeded in providing total control of nausea and vomiting in the majority of patients after day 1 of treatment, which has great clinical significance. More specifically, for the MET+TRO and MET+TRO+DEX group, there were not statistically significant differences between day 3 and day 15 on total nausea and total vomiting control. For the MET+ DEX group, there were no statistically significant differences between days 7 and 15 on total nausea and vomiting control. Antiemetic agents block activity at one or more of various receptor types (muscarinic, dopamine D2, histamine H1, serotonin 5-HT3). Serotonin (5-HT) receptors, specifically the 5-HT3 subtype, are regarded as particularly important in nausea and vomiting and also in gastrointestinal mobility. TRO is a specific 5-HT3 receptor antagonist. It is considered to exert its action by interrupting the vomiting reflex in two ways: by blocking the emetogenic information transfer reaching the vomiting center via the vagal nerve and by reducing the detection and integration of incoming information in the vomiting center [7]. As stated, the patients were in terminal stages of the disease. In Table 2, it is shown that 66 patients had primary cancer location in the gastrointestinal system. The primary location of the other 49 patients was in the abdomen, and the tumor growth could affect the gastrointestinal function. The five patients with lung cancer had liver metastasis. For all

these patients mechanical factors such as tumor growth, external pressure (ascites, abnormal liver growth), gastric distention, and stomach evacuation delay are partly responsible for nausea and vomiting in this case without causing complete gastrointestinal obstruction. Nausea and vomiting are due to irritation A) of nociceptors in the gastric wall (vagus nerve) and B) of sympathetic afferents. It is also known that in this stage, the circulation of “putative toxins” stimulates the chemoreceptor trigger zone. The role of 5-HT3 receptors in the area postrema in emesis is known [8], as is their role in gastric emptying inhibition (5-HT3 receptors have been found on vagal afferent terminals) [9]. This is why inhibition of 5-HT3 receptors by TRO in combination with MET (binding of the dopamine receptors in the chemoreceptor trigger zone and stimulation of the gastrointestinal mobility) seems to have such good results in the control of nausea and vomiting. Data presented here demonstrated that effective antiemetic control can be achieved without the sedation or extrapyramidal effects associated with prolonged administration of high-dose MET. In addition, the simplicity and convenience of TRO administration contribute to an improved quality of life for the cancer patient. As far as cost is concerned, the use of TRO is much more expensive than that of conventional antiemetics, and, therefore, is not suggested as a first-line treatment. However, in cases where conventional antiemetics prove to be unsuccessful, the use of TRO is cost effective since it can provide very good emesis control. In conclusion, the use of TRO offers clear advantages over conventional antiemetics in the control of persistent emesis due to far-advanced cancer.

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