Drugs 43 (Suppl. 3): 23-26, 1992 0012-6667/92/0300-0023/$2.00/0 © Adis International Limited. All rights reserved. DRSUP3388
Prevention of Chemotherapy-Induced Nausea and Emesis in Patients Responding Poorly to Previous Antiemetic Therapy
Comparing Tropisetron with Optimised Standard Antiemetic Therapy U. Bruntsch, I S. Drechsler.t E. Hiller,3 W. Biermann;" A.H. Tulusan,5 M. Buhner.i R. Hartensteinf H.J. Koenig! and W.M. Gallmeiert 15th Med. Department, City Hospital, Nuremberg, Federal Republic of Germany 2 Clinical Research, Sandoz AG, Nuremberg, Federal Republic of Germany 3 3rd Med. Department, University of Munich, Grosshadern, Federal Republic of Germany 4 Gynaecology Department, University of Munich, Grosshadern, Federal Republic of Germany 5 Gynaecology Department, University of Erlangen, Erlangen, Federal Republic of Germany 6 Community Hospital, Munich-Harlaching, Federal Republic of Germany 7 Ist Med. Department, University of Erlangen, Erlangen, Federal Republic of Germany
Summary
In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (~ 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p < 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p < 0.0l) and was less severe (p < 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.
The primary objective of this study was to compare the efficacyand tolerability oftropisetron (ICS205-930; Navoban'P, Novaban'P) with standard antiemetic therapy in the prophylaxis of chemotherapy-induced nausea and vomiting. The patients studied had experienced insufficient control of emesis with standard anti-emetic therapy during 1 or 2 previous courses of chemotherapy. The study was conducted as a cooperative trial at 6 German
hospitals, including 2 gynaecological departments, and was approved by the ethical committee of the study chairman's institution (City Hospital, Nuremberg).
1. Patients and Study Design Patients aged> 18 years with proven malignant disease were eligible to enter the study if they had experienced at least 3 emetic episodes within 24
Drugs 43 (Suppl. 3) 1992
24
hours during 1 or 2 previous cycles of chemotherapy and if at least 1 further identical course of therapy was planned. Patients were considered ineligible if they had severe renal, hepatic, or cardiac failure, suffered from nausea or vomiting unrelated to chemotherapy or were receiving concurrent antiemetic therapy with the exception of a mild sedative at night. All patients gave informed consent before randomisation. 78 patients (61 female, 17 male) with various malignancies and a median age of 47 years (range 19 to 75 years), who were treated with a variety of different chemotherapeutic regimens, were included. 46 patients had received 1 and 32 patients 2 prior cycles of cytotoxic treatment. Patient characteristics in the 2 treatment arms did not differ with respect to gender, age, tumour type, number of previous courses of chemotherapy, or degree of emesis during these treatment cycles. The study was of open randomised design (fig. 1). According to the randomisation code, patients were treated with either tropisetron or 'standard' antiemetic drugs. After the first study course, all patients chose whether to be treated with tropisetron or other drugs in subsequent courses. Tropisetron 5mg once daily was started the evening before chemotherapy and continued for at least 5 more days. If chemotherapy lasted 5 days, tropisetron treatment was continued for another 2 days. The drug was given orally on an empty stomach except on the days of chemotherapy, when it was infused intravenously in 250ml of normal saline over 15 minutes before chemotherapy was begun. No attempt was made to standardise the referPoor control of emesis during prior chemotherapy with standard antiemetics according to institutional policies
+
"" " Randomise
Tropisetron
"-
Standard antiemetics
Patients' choice of antiemetic therapy
Fig. 1. Study scheme.
Table I. Changes from previous antiemetic regimen made for the first study course to optimise therapy for the 38 patients receiving standard treatment
No. of pts (%) No change Change in dose Drugs added Antiemetic cocktail changed
9 6 19 4
(24) (16) (50) (10)
ence antiemetic therapy; treatment was given according to the usual practice of the participating institutions. 82% of the 38 patients in this group received a dopamine antagonist, 55% triflupromazine, 47% tranquillisers and 18% glucocorticoids. Also, the antiemetic therapy did not have to be the same as that used in the previous treatment cycle. As patients were selected for this study on the basis of previous insufficient antiemetic control, it was considered unethical to make no attempt to improve the antiemetic regimen. Changes made to optimise antiemetic therapy for the first study course are listed in table I. The duration of antiemetic therapy was different in the 2 treatment groups. Mean treatment time with tropisetron was 5.5 days (range 1 to 7 days) versus 2.2 days (range 1 to 5 days) for standard treatments.
2. Methods
0/ Evaluation
To determine the efficacy of antiemetic therapy 2 parameters were evaluated: emesis and nausea. The numbers of emetic episodes in each 24-hour period during all days of chemotherapy and the following day were recorded for all treatment courses. Control of emesis was considered complete if there were no episodes of vomiting or retching during 24 hours, partial if 1 to 4 episodes occurred and a failure if more than 4 episodes occurred. Nausea was recorded for the same time-periods by the patients in a diary chart (table II). They scored the degree of nausea on a 4-point scale from o to 3, representing no, mild, moderate, or severe nausea, and were also asked to record the duration of each period of different intensity. Multiplying
25
Tropisetron vs Standard Antiemetic Therapy
the degree of nausea (0 to 3) by its duration (in hours) produces a score for this symptom that we thought would reflect the amount of discomfort the patients suffered. The theoretical range of this score is from 0 to 72. At the end of each treatment cycle, patients were also asked to give their overall assessment of the efficacyand tolerability of the treatment, rated from very good to very poor on a 5-point scale. Measurements of vital signs, detailed laboratory investigations and physical examinations were used to monitor the safety of treatment. Patients were repeatedly questioned about possible adverse effects.
100
l
90 80 70 60
C
50
CIl
.!!!
~
o o
Tropisetron (n • 40) Standard (n = 38)
40
30 20
10 Complete (no emesis)
Partial (1-4 episodes)
Failure
(> 4 episodes)
Fig. 2. Control of emesis during the 24 hours after the beginning of chemotherap y (first course).
3. Results All 78 patients randomised were evaluable for efficacy and tolerability. 40 were treated with tropisetron and 38 with standard antiemetic therapy. The median number of emetic episodes during the first 24 hours after the start of chemotherapy during the first study course was 3.5 for patients receiving tropisetron and 10.0 for those in the standard antiemetic group (p < 0.002; Wilcoxon-V-test). The difference between the 2 treatment groups with regard to the proportion of patients with complete control (42% for tropisetron vs 8% for standard therapy) was also statistically significant [fig. 2 (p < 0.001; Wilcoxon-V-test)]. The lower failure rate in the tropisetron group also indicates better control of emesis. These differences could also be seen, but to a lesser extent, on the last day of, and on the first day after, chemotherapy, but not on the following days. In patients treated with tropisetron during repeated cycles, the average number of -emetic events remained unchanged in later cycles, i.e. efficacy was maintained. Table II. Criteria lor the evaluation 01 nausea Degree graded by the patient on a scale from 0 to 3, representing no, mild, moderate or severe nausea Duration given in hours Severity given as a score, calculated by multiplying the degree by the duration of nausea (theoretical range 0 to 72)
16 patients randomised to standard antiemetic therapy chose to be treated with tropisetron in subsequent cycles of chemotherapy. In these 16 patients, it was thus possible to directly compare the emetic episodes of the 2 treatment modalities . A marked reduction in the median number of vomiting episodes from 13.2 to 4.6 was recorded. Duration and severity of nausea differed significantly in the 2 treatment groups during the first 24 hours after the beginning of chemotherapy (fig. 3). The time with nausea was 3.4 hours shorter in patients treated with tropisetron than in those
20 -
0 Tropisetron (n = 40) Standard (n = 38)
o
15
10 -
5 p
Duration (hours)
< 0.01
p
< 0.005
Seventy score
Fig. 3. Duration and severit y of nausea during the 24 hours after the beginning of chemotherapy (first course).
26
Drugs 43 (Suppl. 3) 1992
Table III. Efficacy of antiemetic treatment according to the patients' judgement (first course)
Evaluation
No. of judgements tropisetron (39 courses)
Very good Good Fair Poor Very poor
14 14
7 2 2
standard antiemetics (38 courses) 1
7
16 10 4
in the standard treatment arm. Total control of nausea was achieved in 18% and 5% of patients receiving tropisetron and standard therapy, respectively. Patients treated with standard antiemetics during the first study course and with tropisetron thereafter experienced a reduction in the time with nausea of 5 hours and a decrease in severity score of 8 points. The superiority of control of nausea with tropisetron was marked only on the first day of chemotherapy. On the following days the difference between treatments became less pronounced and was no longer statistically significant. At the end of the first treatment cycle, 72% of patients in the tropisetron group and 21% in the standard therapy group considered the overall efficacy of antiemetic treatment to be good or very good (table III). Conversely, 10%of the tropisetron group and 37% of patients receiving standard antiemetic therapy judged the result as poor or very poor. No serious adverse event likely to be related to the experimental drug was recorded. One patient had an allergic reaction after intravenous infusion of tropisetron, with itching and reddening of the skin that resolved within 30 minutes of the patient being treated with an antihistamine and glucocorticoids. A causal relationship to tropisetron was considered likely but not proven.
4. Discussion In this study, the efficacy of tropisetron was tested in patients who had previously experienced insufficient control of emesis with standard anti-
emetic drugs during chemotherapy. The standard antiemetic regimens, which were also used in the control arm of this randomised study, did not contain other 5-hydroxytryptamine type 3 (serotoninj) [5-HT3l-receptor antagonists, as none were marketed at the beginning of the study. Patients treated with tropisetron had markedly better results in terms of frequency of emesis as well as duration and severity of nausea during the first 24 hours after the beginning of chemotherapy. Complete control of emesis was attained in 42% of patients treated with tropisetron but in only 8% of those treated with standard antiemetic drugs. The better control of emesis produced by tropisetron was pronounced during all days of chemotherapy and also on the first day after the end of cytostatic treatment. Improved control of nausea, however, was much less evident after the first day of chemotherapy. The differences between treatment groups in duration and severity of nausea werethen no longer statistically significant or clinically relevant. The therapeutic effect of tropisetron was maintained during repeated cycles of chemotherapy. Patients who were treated with standard regimens during the first study course and who were then changed to tropisetron showed markedly improved symptom control in the following courses, in which the number of emetic episodes during 24 hours was lowered from 13.2 to 4.6 and the duration of nausea was reduced by 5 hours. As with other 5-HT3-receptor antagonists, tropisetron controls acute nausea and emesis more effectively than the delayed symptoms. This is quite obvious in this study in which treatment with tropisetron was given for 5 days or longer, whereas the mean treatment time with the standard antiemetics lasted only 2.2 days. It is unlikely that higher doses of tropisetron or longer treatment times will solve this problem. Delayed emesis and nausea are probably due to a mechanism different from that of the acute symptoms and different neurotransmitters may be involved. Further improvement in antiemetic therapy may therefore be possible with combination treatment. Such studies are in progress. Correspondence and reprints: Dr U. Bruntsch, 5. Med. Klinik, F1urstrasse 17, 8500 Nurnberg 90, Federal Republic of Gerrnany.
Prevention of Chemotherapy-Induced Nausea and Emesis in Patients Responding Poorly to Previous Antiemetic Therapy
Comparing Tropisetron with Optimised Standard Antiemetic Therapy U. Bruntsch, I S. Drechsler.t E. Hiller,3 W. Biermann;" A.H. Tulusan,5 M. Buhner.i R. Hartensteinf H.J. Koenig! and W.M. Gallmeiert 15th Med. Department, City Hospital, Nuremberg, Federal Republic of Germany 2 Clinical Research, Sandoz AG, Nuremberg, Federal Republic of Germany 3 3rd Med. Department, University of Munich, Grosshadern, Federal Republic of Germany 4 Gynaecology Department, University of Munich, Grosshadern, Federal Republic of Germany 5 Gynaecology Department, University of Erlangen, Erlangen, Federal Republic of Germany 6 Community Hospital, Munich-Harlaching, Federal Republic of Germany 7 Ist Med. Department, University of Erlangen, Erlangen, Federal Republic of Germany
Summary
In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (~ 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p < 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p < 0.0l) and was less severe (p < 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.
The primary objective of this study was to compare the efficacyand tolerability oftropisetron (ICS205-930; Navoban'P, Novaban'P) with standard antiemetic therapy in the prophylaxis of chemotherapy-induced nausea and vomiting. The patients studied had experienced insufficient control of emesis with standard anti-emetic therapy during 1 or 2 previous courses of chemotherapy. The study was conducted as a cooperative trial at 6 German
hospitals, including 2 gynaecological departments, and was approved by the ethical committee of the study chairman's institution (City Hospital, Nuremberg).
1. Patients and Study Design Patients aged> 18 years with proven malignant disease were eligible to enter the study if they had experienced at least 3 emetic episodes within 24
Drugs 43 (Suppl. 3) 1992
24
hours during 1 or 2 previous cycles of chemotherapy and if at least 1 further identical course of therapy was planned. Patients were considered ineligible if they had severe renal, hepatic, or cardiac failure, suffered from nausea or vomiting unrelated to chemotherapy or were receiving concurrent antiemetic therapy with the exception of a mild sedative at night. All patients gave informed consent before randomisation. 78 patients (61 female, 17 male) with various malignancies and a median age of 47 years (range 19 to 75 years), who were treated with a variety of different chemotherapeutic regimens, were included. 46 patients had received 1 and 32 patients 2 prior cycles of cytotoxic treatment. Patient characteristics in the 2 treatment arms did not differ with respect to gender, age, tumour type, number of previous courses of chemotherapy, or degree of emesis during these treatment cycles. The study was of open randomised design (fig. 1). According to the randomisation code, patients were treated with either tropisetron or 'standard' antiemetic drugs. After the first study course, all patients chose whether to be treated with tropisetron or other drugs in subsequent courses. Tropisetron 5mg once daily was started the evening before chemotherapy and continued for at least 5 more days. If chemotherapy lasted 5 days, tropisetron treatment was continued for another 2 days. The drug was given orally on an empty stomach except on the days of chemotherapy, when it was infused intravenously in 250ml of normal saline over 15 minutes before chemotherapy was begun. No attempt was made to standardise the referPoor control of emesis during prior chemotherapy with standard antiemetics according to institutional policies
+
"" " Randomise
Tropisetron
"-
Standard antiemetics
Patients' choice of antiemetic therapy
Fig. 1. Study scheme.
Table I. Changes from previous antiemetic regimen made for the first study course to optimise therapy for the 38 patients receiving standard treatment
No. of pts (%) No change Change in dose Drugs added Antiemetic cocktail changed
9 6 19 4
(24) (16) (50) (10)
ence antiemetic therapy; treatment was given according to the usual practice of the participating institutions. 82% of the 38 patients in this group received a dopamine antagonist, 55% triflupromazine, 47% tranquillisers and 18% glucocorticoids. Also, the antiemetic therapy did not have to be the same as that used in the previous treatment cycle. As patients were selected for this study on the basis of previous insufficient antiemetic control, it was considered unethical to make no attempt to improve the antiemetic regimen. Changes made to optimise antiemetic therapy for the first study course are listed in table I. The duration of antiemetic therapy was different in the 2 treatment groups. Mean treatment time with tropisetron was 5.5 days (range 1 to 7 days) versus 2.2 days (range 1 to 5 days) for standard treatments.
2. Methods
0/ Evaluation
To determine the efficacy of antiemetic therapy 2 parameters were evaluated: emesis and nausea. The numbers of emetic episodes in each 24-hour period during all days of chemotherapy and the following day were recorded for all treatment courses. Control of emesis was considered complete if there were no episodes of vomiting or retching during 24 hours, partial if 1 to 4 episodes occurred and a failure if more than 4 episodes occurred. Nausea was recorded for the same time-periods by the patients in a diary chart (table II). They scored the degree of nausea on a 4-point scale from o to 3, representing no, mild, moderate, or severe nausea, and were also asked to record the duration of each period of different intensity. Multiplying
25
Tropisetron vs Standard Antiemetic Therapy
the degree of nausea (0 to 3) by its duration (in hours) produces a score for this symptom that we thought would reflect the amount of discomfort the patients suffered. The theoretical range of this score is from 0 to 72. At the end of each treatment cycle, patients were also asked to give their overall assessment of the efficacyand tolerability of the treatment, rated from very good to very poor on a 5-point scale. Measurements of vital signs, detailed laboratory investigations and physical examinations were used to monitor the safety of treatment. Patients were repeatedly questioned about possible adverse effects.
100
l
90 80 70 60
C
50
CIl
.!!!
~
o o
Tropisetron (n • 40) Standard (n = 38)
40
30 20
10 Complete (no emesis)
Partial (1-4 episodes)
Failure
(> 4 episodes)
Fig. 2. Control of emesis during the 24 hours after the beginning of chemotherap y (first course).
3. Results All 78 patients randomised were evaluable for efficacy and tolerability. 40 were treated with tropisetron and 38 with standard antiemetic therapy. The median number of emetic episodes during the first 24 hours after the start of chemotherapy during the first study course was 3.5 for patients receiving tropisetron and 10.0 for those in the standard antiemetic group (p < 0.002; Wilcoxon-V-test). The difference between the 2 treatment groups with regard to the proportion of patients with complete control (42% for tropisetron vs 8% for standard therapy) was also statistically significant [fig. 2 (p < 0.001; Wilcoxon-V-test)]. The lower failure rate in the tropisetron group also indicates better control of emesis. These differences could also be seen, but to a lesser extent, on the last day of, and on the first day after, chemotherapy, but not on the following days. In patients treated with tropisetron during repeated cycles, the average number of -emetic events remained unchanged in later cycles, i.e. efficacy was maintained. Table II. Criteria lor the evaluation 01 nausea Degree graded by the patient on a scale from 0 to 3, representing no, mild, moderate or severe nausea Duration given in hours Severity given as a score, calculated by multiplying the degree by the duration of nausea (theoretical range 0 to 72)
16 patients randomised to standard antiemetic therapy chose to be treated with tropisetron in subsequent cycles of chemotherapy. In these 16 patients, it was thus possible to directly compare the emetic episodes of the 2 treatment modalities . A marked reduction in the median number of vomiting episodes from 13.2 to 4.6 was recorded. Duration and severity of nausea differed significantly in the 2 treatment groups during the first 24 hours after the beginning of chemotherapy (fig. 3). The time with nausea was 3.4 hours shorter in patients treated with tropisetron than in those
20 -
0 Tropisetron (n = 40) Standard (n = 38)
o
15
10 -
5 p
Duration (hours)
< 0.01
p
< 0.005
Seventy score
Fig. 3. Duration and severit y of nausea during the 24 hours after the beginning of chemotherapy (first course).
26
Drugs 43 (Suppl. 3) 1992
Table III. Efficacy of antiemetic treatment according to the patients' judgement (first course)
Evaluation
No. of judgements tropisetron (39 courses)
Very good Good Fair Poor Very poor
14 14
7 2 2
standard antiemetics (38 courses) 1
7
16 10 4
in the standard treatment arm. Total control of nausea was achieved in 18% and 5% of patients receiving tropisetron and standard therapy, respectively. Patients treated with standard antiemetics during the first study course and with tropisetron thereafter experienced a reduction in the time with nausea of 5 hours and a decrease in severity score of 8 points. The superiority of control of nausea with tropisetron was marked only on the first day of chemotherapy. On the following days the difference between treatments became less pronounced and was no longer statistically significant. At the end of the first treatment cycle, 72% of patients in the tropisetron group and 21% in the standard therapy group considered the overall efficacy of antiemetic treatment to be good or very good (table III). Conversely, 10%of the tropisetron group and 37% of patients receiving standard antiemetic therapy judged the result as poor or very poor. No serious adverse event likely to be related to the experimental drug was recorded. One patient had an allergic reaction after intravenous infusion of tropisetron, with itching and reddening of the skin that resolved within 30 minutes of the patient being treated with an antihistamine and glucocorticoids. A causal relationship to tropisetron was considered likely but not proven.
4. Discussion In this study, the efficacy of tropisetron was tested in patients who had previously experienced insufficient control of emesis with standard anti-
emetic drugs during chemotherapy. The standard antiemetic regimens, which were also used in the control arm of this randomised study, did not contain other 5-hydroxytryptamine type 3 (serotoninj) [5-HT3l-receptor antagonists, as none were marketed at the beginning of the study. Patients treated with tropisetron had markedly better results in terms of frequency of emesis as well as duration and severity of nausea during the first 24 hours after the beginning of chemotherapy. Complete control of emesis was attained in 42% of patients treated with tropisetron but in only 8% of those treated with standard antiemetic drugs. The better control of emesis produced by tropisetron was pronounced during all days of chemotherapy and also on the first day after the end of cytostatic treatment. Improved control of nausea, however, was much less evident after the first day of chemotherapy. The differences between treatment groups in duration and severity of nausea werethen no longer statistically significant or clinically relevant. The therapeutic effect of tropisetron was maintained during repeated cycles of chemotherapy. Patients who were treated with standard regimens during the first study course and who were then changed to tropisetron showed markedly improved symptom control in the following courses, in which the number of emetic episodes during 24 hours was lowered from 13.2 to 4.6 and the duration of nausea was reduced by 5 hours. As with other 5-HT3-receptor antagonists, tropisetron controls acute nausea and emesis more effectively than the delayed symptoms. This is quite obvious in this study in which treatment with tropisetron was given for 5 days or longer, whereas the mean treatment time with the standard antiemetics lasted only 2.2 days. It is unlikely that higher doses of tropisetron or longer treatment times will solve this problem. Delayed emesis and nausea are probably due to a mechanism different from that of the acute symptoms and different neurotransmitters may be involved. Further improvement in antiemetic therapy may therefore be possible with combination treatment. Such studies are in progress. Correspondence and reprints: Dr U. Bruntsch, 5. Med. Klinik, F1urstrasse 17, 8500 Nurnberg 90, Federal Republic of Gerrnany.
