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Cancer Pain Relief and Palliative Care Unit, University of Athens, Areteion Hospital, Athens, Greece
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.
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ABSTRACT |
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Key Words. Far advanced cancer • Emesis • Nausea • Vomiting • Tropisetron • Metoclopramide
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INTRODUCTION |
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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 far-advanced 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 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).
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METHODS |
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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 x 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’ 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:
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The patients’ characteristics are presented in Table 2.
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). Patients with metabolic or electrolytic disturbance and central etiology vomiting were excluded from the study. Patients who were under phenobarbital, riphamicin, or 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.
Antiemetic Treatment
The antiemetic treatment schedules were as follows: (A) MET+DEX: 10 mg x 4 p.o. plus 2 mg x 1 p.o.; (B) MET+TRO: 10 mg x 2 p.o. plus 5 mg x 1 p.o., and (C) MET+TRO+DEX: 10 mg x 2 p.o. plus 5 mg x 1 p.o. plus 2 mg x 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.
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:
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:
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.
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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RESULTS |
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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.
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.
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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.
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).
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DISCUSSION |
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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%) 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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ACKNOWLEDGMENT |
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REFERENCES |
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