Drugs 43 (Suppl. 3): 33-39, 1992 0012-6667/92/0300-0033/$3.50/0
© Adis International Limited. All rights reserved. DRSUP3387
Tropisetron, a New 5-HT3-Receptor Antagonist, in the Prevention of Radiation-Induced Nausea, Vomiting and Diarrhoea Bengt Sorbe and Anne-Marie Berglind Department of Gynecologic Oncology, Orebro Medical Center Hospital, Orebro, Sweden
Summary
Oral tropisetron, a 5-hydroxytryptamine type 3 (serotoninj) [5-HT3l-receptor antagonist, at a dose of 5mg daily was evaluated as antiemetic prophylaxis during postoperative abdominal irradiation. 20 women with International Federation of Gynecology and Obstetrics (FIGO) stage I to III ovarian carcinoma were included. 12 women received irradiation of whole abdominal fields and 8 of lower abdominal/pelvic fields. Efficacy and adverse events were recorded by the patients in diary-form booklets. The cumulative weekly incidence of patients with nausea, which was generally mild and of short duration, increased from 30% at the start of radiotherapy to 54% at the end of treatment. Episodes of vomiting occurred in less than 10%of the patients. Diarrhoea was common towards the end ofthe radiotherapy courses, and the proportion of patients needing extra antidiarrhoeal medication (loperamide) increased from 38% during the first week to 100% at the end of the radiotherapy course. Mean weight loss was 1.2kg during the 5- to 6-week course. Overall ratings for quality of life were excellent or good in 75 to 85% of patients. Tropisetron seems to be a promising and well tolerated drug in conjunction with extended radiotherapy of abdominal fields. This was an open study, establishing the methodology for long term follow-up of patients during fractionated radiotherapy.
Irradiation of abdominal fields for the treatment of cancer is associated with nausea, vomiting, anorexia, and diarrhoea. Total-body irradiation and irradiation of the upper parts of the abdomen are also associated with these side effects, whereas during irradiation of the pelvic region alone nausea and vomiting are not a frequent clinical problem (Krook et al. 1991). Previous reports have indicated that emesis occurs in approximately 50% of patients receiving fractionated radiotherapy of the whole abdomen (Priestman & Priestman 1984)and in over 80% when single treatments are given (Danjoux et al. 1979). Nutritional problems involving bodyweight loss, electrolyte disturbances and deteriorated quality of life develop. No effec-
tive prophylaxis or treatment has hitherto been available (Reyntjens 1979). The introduction of the new group of5-hydroxytryptamine type 3 (serotoninj) [5-HT3]-receptor antagonists has changed the therapeutic situation regarding antiemetic therapy in oncology (Cunningham et al. 1987). The superiority of these drugs in the treatment of chemotherapy-induced emesis is well documented (Marty et al. 1990). As with chemotherapy, radiation may induce nausea and vomiting by triggering 5-HT3 receptors in the gut wall. Thus, 5-HT3-receptor antagonists should also be effective as antiemetics in radiotherapy. In addition, a known side effect of 5-HT3-receptor ant-
Drugs 43 (Suppl. 3) 1992
34
Table I. Characteristics of 20 women with ovarian carcinoma treated with postoperative irradiation and tropisetron Patient characteristics [mean ± SO (range)) Age (years) 56.5 ± 13.5 (26-77) Weight (kg) 68.2 ± 12.8 (46-101) Height (em) 162.5 ± 5.0 (151-170) FIGO stage [no. (%)) I II III
12 (60) 6 (30) 2 (10)
Abbreviations: FIGO = International Federation of Gynecology and Obstetrics.
agonists, constipation, might be helpful in preventing radiation-induced diarrhoea. Clinical experience of the use of 5-HT3-receptor antagonists in radiotherapy is sparse, however, especially with regard to long term administration, and no methodology exists for evaluating efficacy and adverse events. The purpose of this pilot study was to develop such a methodology and to test it for the evaluation of the antiemetic and antidiarrhoeal efficacy and safety of tropisetron (Navoban®, Novaban'P; Sandoz Pharma Ltd, Basel, Switzerland) [Richardson & Buchheit 1988] when administered orally at a dose of 5mg once daily for 5 to 6 weeks in conjunction with abdominal/pelvic irradiation.
1. Patients and Methods During the period March 1 to December 15, 1990, 20 consecutive women with ovarian carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stages I to III] who were scheduled for postoperative irradiation of whole abdominal or lower abdominal/pelvic fields were included in a pilot study to evaluate the efficacy and safety of the 5-HT3-receptor antagonist tropisetron in the prevention of radiation-induced nausea or vomiting and diarrhoea. All patients were treated at the Department of Gynecologic Oncology, Orebro Medical Center Hospital, Orebro, Sweden. The mean age of the patients was 56.5 (range 26 to 77) years (table I). All tumours were diagnosed and
staged at primary laparotomy (table I). In all patients, total abdominal hysterectomy and bilateral salpingo-oophorectomy and omentectomy were initially performed and no apparent residual tumour was left at laparotomy. Two patients with stage III disease also received 4 courses of chemotherapy [doxorubicin (adriamycin)-cisplatin] in addition to radiotherapy and subsequently underwent secondlook laparotomy. 12 patients with potential tum" our spread to the whole abdominal cavity received postoperative irradiation to whole abdominal/pelvic fields and 8 patients with localised disease to lower abdominal/pelvic fields. The upper limits of the whole abdominal fields were set lcm cranial to the diaphragmatic domes during expiration, the lateral borders lcm outside the iliacal spinae, and the lower limits below the obturator foramina. The upper limits of the lower abdominal fields were set Table II. Questionnaire for quality of life assessment Structured interview During the last week: 1. Have you felt queasy? 2. Have you had a dry mouth? 3. Have you had palpitations? 4. Have you had tingling sensations in your hands or feet? 5. Have you felt stiff in your arms, legs, or jaws? 6. Have you felt tense or 'wound up'? 7. Have you felt ill? 8. Have you been bothered by dizziness? 9. Have you felt unusually tired or sleepy? 10. Have you had problems concentrating? 11. Have you suffered forgetfulness? 12. Have you suffered from headache? 13. Have you slept normally? 14. Could you eat and drink normally? Code: 0= not at all 1 = a little bit 2 = quite a bit 3 = very much 15. How would you rate your overall quality of life? Code: o = terrible 1 fair 2 = good 3 = excellent Problems related to radiotherapy (apart from gastrointestinal symptoms)?
=
35
Tropisetron and Radiation-Induced Emesis
100
;e
.. ..
o o
Whole abdominal f,eld Lower abdominal field
80
~ Q)
en ::>
60 42
c:
s
.~
.
40
>-
c
38
31
24
en
20 0
o 6
2 Weeks
Fig. 1. The ratio of days with nausea (any intensity and duration within a 24-hour period) to the total number of days of treatment per week for patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8).
at a line between the third (LJ) and the fourth (L4) lumbar vertebrae. The lateral and the lower borders were the same as for the whole abdominal field. No shielding was employed in the treatment fields. The target dose per fraction was 1.0Gy 5 times a week for 4 weeks (total dose 20.0Gy) to the whole abdominal field, followed by. 1.7Gy per fraction , 5 times a week for 2 weeks to the lower abdominal/ pelvic fields (boost to total dose of 40.0Gy). When only the lower abdominal/pelvic fields were treated, the dose per fraction was 1.7Gy, given 5 times a week for 5 weeks (total dose 40.0Gy). The treatments were given using 10 or 18 MeV linear accelerators and both anterior and posterior fields were treated each day. Prophylactic antiemetic medication was given every morning in the form of an oral capsule containing 5mg of tropisetron, and this was continued during the whole course of radiotherapy (5 or 6 weeks), including weekends. The patients were instructed to take a capsule 2 hours before the first meal of the day. Treatment efficacy (nausea, vomiting and diarrhoea) and tolerability (adverse events) were recorded in diary-form booklets by the patients themselves . A 0 to 100mm visual analogue scale (VAS) was used to assess the intensity of nausea . The number of vomiting episodes and the number of bowel movements were re-
corded . The requirement for antidiarrhoeal medication [the number of 2mg loperamide capsules (lmodium, Janssen Pharmaceutica, Beerse, Belgium) used per week) was also recorded . Once a week, a research nurse checked the booklets and completed a quality of life questionnaire (table II). Bodyweight was recorded every week at follow-up visits. ECG, haematology and blood chemistry tests were performed before the start and immediately after the end of treatment. A routine physical examination and a gynaecological examination under anaesthesia were performed before treatment, and a second physical examination was made before the patient left the clinic. The patients were then to be followed up in conformity with the routine of the clinic, i.e. every third month for the first year, every fourth month for the second and third years, every sixth month until the sixth year, and then annually up to 10 years. No patients have been lost to follow-up to date, and all are scheduled for 10 years of follow-up. Abnormal haematology and blood chemistry results were repeated at follow-up visits until normal.
2. Results In the whole study group, the frequency of nausea , calculated as cumulative incidence of
36
Drugs 43 (Suppl. 3) 1992
patients with nausea per week, regardless of duration and intensity, ranged between 30 and 54% during the whole course of radiotherapy. The percentage of days with nausea per week of treatment increased from 13%during the first 2 weeks to 32% during the sixth week of radiotherapy. The median for the whole period of treatment was 22%. The incidence of nausea was higher during weeks 3 to 6 for the patients who received irradiation of whole abdominal/pelvic fields compared with those receiving irradiation of only lower abdominal/pelvic fields (fig. 1). For those who experienced nausea, the median intensity, measured on the VAS, was 23mm during the first week of treatment, 32mm during the second week, and 9mm during the last week. The median value was 20mm for the whole period of treatment. There was no difference in the maximum recorded intensity of nausea between treatment of the whole abdomen and treatment of the lower abdomen and pelvis. Vomiting associated with irradiation was infrequent. In the complete series, the cumulative incidence of patients with vomiting ranged from 5 to 10% per week of treatment. Vomiting was slightly more common among women receiving irradiation of the whole abdomen (8 to 17%) than among those receiving irradiation of a lower abdominal field (0 to 13%) [fig. 2). The median weekly number of bowel movements increased from 8 during the first week of
o o
100
~
C>
therapy to 15 to 17 during the last two-thirds of the treatment course. During the whole study period, treatment of lower abdominal/pelvic fields was associated with more frequent bowel movements than treatment of the whole abdomen. The percentage of patients using loperamide increased from 0% during the first week to 50% during the fifth week of therapy when recorded for all women. During whole abdominal/pelvic irradiation the use ofloperamide was lower (0 to 25%of patients) than during lower abdominal/pelvic irradiation (38 to 100% of patients) [fig. 3]. Quality of life was assessed once a week throughout the course of radiotherapy. The proportion of the complete group that rated overall quality oflife as good or excellent (75 to 85%) was constant throughout all 6 weeks of treatment (table III). Patients receiving irradiation of the whole abdomen had a slightly higher quality of life during the first 3 'weeks of therapy (83 to 92% good or excellent) than the group receiving lower abdominal/pelvic irradiation (63 to 75%). During the following weeks there was no difference in quality of life in relation to the sizes of the fields irradiated. All patients recruited for the study completed the whole treatment period of 5 or 6 weeks. Tropisetron was well tolerated. Side effects possibly associated with the drug were reported by 5 to 30% of the patients per week. The majority of these patients reported headache; one patient com-
Whole abdom inal field Lower abdom inal field
80
'Eo
E 60 0 >
'0
>-
.,c:
0
.,
40
::J
0-
u:
20 0
0 Weeks
Fig. 2. Cumulative frequency of patients with vomiting (%) per week of treatment (regardless of the number of vomiting episodes) for patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8).
37
Tropisetron and Radiation-Induced Eme sis
o o
100
~ .,
"0
'e os 8.Q '0
.,
100
.....--
Whole abdominal lield Lower abdominal field
88
.....--
63 .....--
60 38
40
r-
25
.----
!/)
:::>
.----
75
80
20 8
0
0
0
0
r-
0
3
2
5
4
18
I
6
Weeks Fig. 3. Cumulative use of loperamide per week of treatment by patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8); a highly significant difference was dete cted with regard to the dose per fractio n ( 1.7 vs l.OGy) and type of field irra diated.
3. Discussion
plained of abdominal pain. Queasiness of the stomach was recorded by 15 to 69% of patients but this was probabl y related to the irradiation per se (table IV). No serious advers e events were recorded , despite long term medication. The mean ± SD weight of the whole group of patients decreased from 69.0 ± 12.6kg at the start of treatment to 67.8 ± 12.8kg at the end of radiotherapy. No significant ECG changes occurred . Haematology and blood chemistry revealed changes normally seen during and after radiotherapy of whole abdominal or lower abdominal/pelvic fields (table
Nausea du ring radiotherapy is common, especially when the upper parts of the abdomen or the whole abdomen are irradiated (Danjoux et al. 1979; Priestman & Priestman 1984). Most interest in antiemetic treatment during radiotherapy has focused on whole body irradiation, which induces nausea of shorter duration (Danjou x et al. 1979; Reyntjens 1979). The main aim of the present study was to develop methodology for evaluating prevention and treatment of nausea, vomiting, and diarrhoea occurring during fractionated radiotherapy over 5 or 6 weeks. The new 5-HT3-receptor antagonist tropisetron was found to be effective and was well tolerated during long term radiotherapy. When nausea occurred (in 30 to 50% of the patients), it was gen-
V ).
According to the overall evaluation made by the investigator at the end of the course of treatment, the efficacy of the drug was excellent or good in 80% of patients and the tolerability of the drug was excellent or good in 85% of patients.
Table III. Overall.quality of life assessments in 20 women with ovarian carcinoma who were treated with postoperative irradiation and tropisetron Ratings
Number 01 patients (%) week 01 treatment 2
Excellent Good
Fair Terrible
13 3 1 3
(65) (15) (5) (15)
14 2 3 1
3 (70) (10) (15) (5)
11 6 2 1
4 (55) (30) (10) (5)
11 6 2 1
5 (55) (30) (10) (5)
11 4 3 2
6 (55) (20) (15) (10)
7 (54) 4 (31) 2 (15) 0(0)
Drugs 43 (Suppl. 3) 1992
38
Table IV. Patients reporting adverse effects possibly associated with tropisetron treatment
Symptoms
Number of patients (%) week of treatment 2 2 2 1 3
Headache Constipation Colicky pain Queasy stomach
(10) (10) (5) (15)
1 1 1 11
3 (5) (5) (5) (55)
erally of mild intensity and short duration. This cumulative frequency of nausea was in the same range as that found in a recent study of ondansetron (Franzen et al. 1990). Vomiting was rare in the present study, with less than 10% of patients suffering from this adverse effect. Both nausea and vomiting were slightly more common in the group receiving whole abdominal irradiation than in those receiving irradiation to only the lower part of the abdomen and the pelvis. On the other hand, the intensity of the nausea was not influenced by the size of the irradiated field. An increased number of bowel movements and diarrhoea were common during treatment of the lower parts of the abdomen (1.7Gy per fraction) and this was less well prevented by tropisetron. 38
Table V. Haematology and blood chemistry before and after radiotherapy (RT) in 20 women with ovarian carcinoma
Before RT
After RT
Haemoglobin (gIL) Leucocytes (10 9/L) Platelets (10 9/LJ
131 7.9 294
127 4.8 209
Sodium (mmoI/L) Potassium (mmoI/L) Calcium (mmoI/L) Gamma-GT (/lkat/L) Creatinine (/lmoI/L) Bilirubin (/lmoI/L) AST (/lkat/L) ALT (/lkat/L) Alkaline phosphatase (/lkat/L)
138 4.0 2.37 0.57 79 7.40 0.35 0.31 3.50
137 3.8 2.30 0.85 70 7.71 0.50 0.53 4.42
3 1 1 13
(15) (5) (5) (65)
4
5
6
4 (20) 0(0) 1 (5) 13 (65)
5 (25) 0(0) 1 (5) 11 (55)
4 (31) 0(0) 1 (5) 9 (69)
to 100% of this group needed extra antidiarrhoeal medication with loperamide. The size of the radiation dose per fraction had an important influence on this adverse effect. This is probably related to the degree to which the intestinal mucosal cells are destroyed and which parts of the small gut and colon are irradiated. Tropisetron was not found to be very effective as an antidiarrhoeal agent. The mean bodyweight loss of 1.2kg during a 5to 6-week course of radiotherapy was surprisingly low, and the quality of life assessments also showed excellent or good ratings in 75 to 85% of the cases throughout the course of treatment. Therefore, it seems reasonable to ascribe a positive effect to tropisetron. The drug was very well tolerated and no serious adverse events were recorded despite long term treatment. Headache and abdominal cramps were noted in less than 10%of the patients. All the patients and the research nurses taking part in this study were very satisfied with the drug and regarded it as a therapeutic improvement for this type of radiotherapy. To further and more definitively evaluate the 5-HT3-receptor antagonists as antiemetics during radiotherapy, prospective randomised placebo-controlled studies are needed. Other treatment schedules (e.g. on-demand medication) should also be considered. This was a feasibility study. The methodology of assessment with the VAS was powerful, simple to use and to analyse. The patients' diary-form booklets worked well for long term follow-up and seemed to give reliable data for efficacy and tolerability. For future prospective studies, we have learnt that stratification for type of field irradiated is mandatory and that the 5-HT3-receptor antag-
Tropisetron and Radiation-Induced Emesis
onists are of limited value as antidiarrhoeal medication during radiotherapy.
References Cunningham D, Pople A, Ford HT, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5 HT3 receptor antagonist. Lancet I: 1461-1463, 1987 Danjoux CE, Rider WD, Fitzpatrick PJ. The acute radiation syndrome: a memorial to William Michael Court-Brown. Clinical Radiology 30: 581-584, 1979 Franzen L, Lomberg H, Israelsson G, et al. Ondansetron-Nytt antiemetikum mot illamaende i samband med stralterapi. Svenska Lakarsallskapets Handlingar Hygiea 99: 255-256, 1990 Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. New England Journal of Medicine 324: 709-715, 1991 Marty M, Pouillart P, Scholl S, Droz JP, Azab M, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist
39
ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. New England Journal of Medicine 322: 816-821, 1990 Priestman T, Priestman S. An initial evaluation of nabilone in the control of radiotherapy-induced nausea and vomiting. Clinical Radiology 35: 265-266, 1984 Reyntjens A. Domperidone as an anti-emetic: summary of research reports. Postgraduate Medical Journal 55 (Suppl. I): 5054, 1979 Richardson BP, Buchheit KH. The pharmacology, distribution and function of 5-HT3 receptors. In Osborne NN & Hamon M (Eds) Neuronal serotonin, pp. 465-504, Wiley and Sons Ltd, London, 1988
Correspondence and reprints: Dr Bengt Sorbe, Department of Gynecologic Oncology, Orebro Medical Center Hospital, S-701 85 Orebro, Sweden.
© Adis International Limited. All rights reserved. DRSUP3387
Tropisetron, a New 5-HT3-Receptor Antagonist, in the Prevention of Radiation-Induced Nausea, Vomiting and Diarrhoea Bengt Sorbe and Anne-Marie Berglind Department of Gynecologic Oncology, Orebro Medical Center Hospital, Orebro, Sweden
Summary
Oral tropisetron, a 5-hydroxytryptamine type 3 (serotoninj) [5-HT3l-receptor antagonist, at a dose of 5mg daily was evaluated as antiemetic prophylaxis during postoperative abdominal irradiation. 20 women with International Federation of Gynecology and Obstetrics (FIGO) stage I to III ovarian carcinoma were included. 12 women received irradiation of whole abdominal fields and 8 of lower abdominal/pelvic fields. Efficacy and adverse events were recorded by the patients in diary-form booklets. The cumulative weekly incidence of patients with nausea, which was generally mild and of short duration, increased from 30% at the start of radiotherapy to 54% at the end of treatment. Episodes of vomiting occurred in less than 10%of the patients. Diarrhoea was common towards the end ofthe radiotherapy courses, and the proportion of patients needing extra antidiarrhoeal medication (loperamide) increased from 38% during the first week to 100% at the end of the radiotherapy course. Mean weight loss was 1.2kg during the 5- to 6-week course. Overall ratings for quality of life were excellent or good in 75 to 85% of patients. Tropisetron seems to be a promising and well tolerated drug in conjunction with extended radiotherapy of abdominal fields. This was an open study, establishing the methodology for long term follow-up of patients during fractionated radiotherapy.
Irradiation of abdominal fields for the treatment of cancer is associated with nausea, vomiting, anorexia, and diarrhoea. Total-body irradiation and irradiation of the upper parts of the abdomen are also associated with these side effects, whereas during irradiation of the pelvic region alone nausea and vomiting are not a frequent clinical problem (Krook et al. 1991). Previous reports have indicated that emesis occurs in approximately 50% of patients receiving fractionated radiotherapy of the whole abdomen (Priestman & Priestman 1984)and in over 80% when single treatments are given (Danjoux et al. 1979). Nutritional problems involving bodyweight loss, electrolyte disturbances and deteriorated quality of life develop. No effec-
tive prophylaxis or treatment has hitherto been available (Reyntjens 1979). The introduction of the new group of5-hydroxytryptamine type 3 (serotoninj) [5-HT3]-receptor antagonists has changed the therapeutic situation regarding antiemetic therapy in oncology (Cunningham et al. 1987). The superiority of these drugs in the treatment of chemotherapy-induced emesis is well documented (Marty et al. 1990). As with chemotherapy, radiation may induce nausea and vomiting by triggering 5-HT3 receptors in the gut wall. Thus, 5-HT3-receptor antagonists should also be effective as antiemetics in radiotherapy. In addition, a known side effect of 5-HT3-receptor ant-
Drugs 43 (Suppl. 3) 1992
34
Table I. Characteristics of 20 women with ovarian carcinoma treated with postoperative irradiation and tropisetron Patient characteristics [mean ± SO (range)) Age (years) 56.5 ± 13.5 (26-77) Weight (kg) 68.2 ± 12.8 (46-101) Height (em) 162.5 ± 5.0 (151-170) FIGO stage [no. (%)) I II III
12 (60) 6 (30) 2 (10)
Abbreviations: FIGO = International Federation of Gynecology and Obstetrics.
agonists, constipation, might be helpful in preventing radiation-induced diarrhoea. Clinical experience of the use of 5-HT3-receptor antagonists in radiotherapy is sparse, however, especially with regard to long term administration, and no methodology exists for evaluating efficacy and adverse events. The purpose of this pilot study was to develop such a methodology and to test it for the evaluation of the antiemetic and antidiarrhoeal efficacy and safety of tropisetron (Navoban®, Novaban'P; Sandoz Pharma Ltd, Basel, Switzerland) [Richardson & Buchheit 1988] when administered orally at a dose of 5mg once daily for 5 to 6 weeks in conjunction with abdominal/pelvic irradiation.
1. Patients and Methods During the period March 1 to December 15, 1990, 20 consecutive women with ovarian carcinoma [International Federation of Gynecology and Obstetrics (FIGO) stages I to III] who were scheduled for postoperative irradiation of whole abdominal or lower abdominal/pelvic fields were included in a pilot study to evaluate the efficacy and safety of the 5-HT3-receptor antagonist tropisetron in the prevention of radiation-induced nausea or vomiting and diarrhoea. All patients were treated at the Department of Gynecologic Oncology, Orebro Medical Center Hospital, Orebro, Sweden. The mean age of the patients was 56.5 (range 26 to 77) years (table I). All tumours were diagnosed and
staged at primary laparotomy (table I). In all patients, total abdominal hysterectomy and bilateral salpingo-oophorectomy and omentectomy were initially performed and no apparent residual tumour was left at laparotomy. Two patients with stage III disease also received 4 courses of chemotherapy [doxorubicin (adriamycin)-cisplatin] in addition to radiotherapy and subsequently underwent secondlook laparotomy. 12 patients with potential tum" our spread to the whole abdominal cavity received postoperative irradiation to whole abdominal/pelvic fields and 8 patients with localised disease to lower abdominal/pelvic fields. The upper limits of the whole abdominal fields were set lcm cranial to the diaphragmatic domes during expiration, the lateral borders lcm outside the iliacal spinae, and the lower limits below the obturator foramina. The upper limits of the lower abdominal fields were set Table II. Questionnaire for quality of life assessment Structured interview During the last week: 1. Have you felt queasy? 2. Have you had a dry mouth? 3. Have you had palpitations? 4. Have you had tingling sensations in your hands or feet? 5. Have you felt stiff in your arms, legs, or jaws? 6. Have you felt tense or 'wound up'? 7. Have you felt ill? 8. Have you been bothered by dizziness? 9. Have you felt unusually tired or sleepy? 10. Have you had problems concentrating? 11. Have you suffered forgetfulness? 12. Have you suffered from headache? 13. Have you slept normally? 14. Could you eat and drink normally? Code: 0= not at all 1 = a little bit 2 = quite a bit 3 = very much 15. How would you rate your overall quality of life? Code: o = terrible 1 fair 2 = good 3 = excellent Problems related to radiotherapy (apart from gastrointestinal symptoms)?
=
35
Tropisetron and Radiation-Induced Emesis
100
;e
.. ..
o o
Whole abdominal f,eld Lower abdominal field
80
~ Q)
en ::>
60 42
c:
s
.~
.
40
>-
c
38
31
24
en
20 0
o 6
2 Weeks
Fig. 1. The ratio of days with nausea (any intensity and duration within a 24-hour period) to the total number of days of treatment per week for patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8).
at a line between the third (LJ) and the fourth (L4) lumbar vertebrae. The lateral and the lower borders were the same as for the whole abdominal field. No shielding was employed in the treatment fields. The target dose per fraction was 1.0Gy 5 times a week for 4 weeks (total dose 20.0Gy) to the whole abdominal field, followed by. 1.7Gy per fraction , 5 times a week for 2 weeks to the lower abdominal/ pelvic fields (boost to total dose of 40.0Gy). When only the lower abdominal/pelvic fields were treated, the dose per fraction was 1.7Gy, given 5 times a week for 5 weeks (total dose 40.0Gy). The treatments were given using 10 or 18 MeV linear accelerators and both anterior and posterior fields were treated each day. Prophylactic antiemetic medication was given every morning in the form of an oral capsule containing 5mg of tropisetron, and this was continued during the whole course of radiotherapy (5 or 6 weeks), including weekends. The patients were instructed to take a capsule 2 hours before the first meal of the day. Treatment efficacy (nausea, vomiting and diarrhoea) and tolerability (adverse events) were recorded in diary-form booklets by the patients themselves . A 0 to 100mm visual analogue scale (VAS) was used to assess the intensity of nausea . The number of vomiting episodes and the number of bowel movements were re-
corded . The requirement for antidiarrhoeal medication [the number of 2mg loperamide capsules (lmodium, Janssen Pharmaceutica, Beerse, Belgium) used per week) was also recorded . Once a week, a research nurse checked the booklets and completed a quality of life questionnaire (table II). Bodyweight was recorded every week at follow-up visits. ECG, haematology and blood chemistry tests were performed before the start and immediately after the end of treatment. A routine physical examination and a gynaecological examination under anaesthesia were performed before treatment, and a second physical examination was made before the patient left the clinic. The patients were then to be followed up in conformity with the routine of the clinic, i.e. every third month for the first year, every fourth month for the second and third years, every sixth month until the sixth year, and then annually up to 10 years. No patients have been lost to follow-up to date, and all are scheduled for 10 years of follow-up. Abnormal haematology and blood chemistry results were repeated at follow-up visits until normal.
2. Results In the whole study group, the frequency of nausea , calculated as cumulative incidence of
36
Drugs 43 (Suppl. 3) 1992
patients with nausea per week, regardless of duration and intensity, ranged between 30 and 54% during the whole course of radiotherapy. The percentage of days with nausea per week of treatment increased from 13%during the first 2 weeks to 32% during the sixth week of radiotherapy. The median for the whole period of treatment was 22%. The incidence of nausea was higher during weeks 3 to 6 for the patients who received irradiation of whole abdominal/pelvic fields compared with those receiving irradiation of only lower abdominal/pelvic fields (fig. 1). For those who experienced nausea, the median intensity, measured on the VAS, was 23mm during the first week of treatment, 32mm during the second week, and 9mm during the last week. The median value was 20mm for the whole period of treatment. There was no difference in the maximum recorded intensity of nausea between treatment of the whole abdomen and treatment of the lower abdomen and pelvis. Vomiting associated with irradiation was infrequent. In the complete series, the cumulative incidence of patients with vomiting ranged from 5 to 10% per week of treatment. Vomiting was slightly more common among women receiving irradiation of the whole abdomen (8 to 17%) than among those receiving irradiation of a lower abdominal field (0 to 13%) [fig. 2). The median weekly number of bowel movements increased from 8 during the first week of
o o
100
~
C>
therapy to 15 to 17 during the last two-thirds of the treatment course. During the whole study period, treatment of lower abdominal/pelvic fields was associated with more frequent bowel movements than treatment of the whole abdomen. The percentage of patients using loperamide increased from 0% during the first week to 50% during the fifth week of therapy when recorded for all women. During whole abdominal/pelvic irradiation the use ofloperamide was lower (0 to 25%of patients) than during lower abdominal/pelvic irradiation (38 to 100% of patients) [fig. 3]. Quality of life was assessed once a week throughout the course of radiotherapy. The proportion of the complete group that rated overall quality oflife as good or excellent (75 to 85%) was constant throughout all 6 weeks of treatment (table III). Patients receiving irradiation of the whole abdomen had a slightly higher quality of life during the first 3 'weeks of therapy (83 to 92% good or excellent) than the group receiving lower abdominal/pelvic irradiation (63 to 75%). During the following weeks there was no difference in quality of life in relation to the sizes of the fields irradiated. All patients recruited for the study completed the whole treatment period of 5 or 6 weeks. Tropisetron was well tolerated. Side effects possibly associated with the drug were reported by 5 to 30% of the patients per week. The majority of these patients reported headache; one patient com-
Whole abdom inal field Lower abdom inal field
80
'Eo
E 60 0 >
'0
>-
.,c:
0
.,
40
::J
0-
u:
20 0
0 Weeks
Fig. 2. Cumulative frequency of patients with vomiting (%) per week of treatment (regardless of the number of vomiting episodes) for patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8).
37
Tropisetron and Radiation-Induced Eme sis
o o
100
~ .,
"0
'e os 8.Q '0
.,
100
.....--
Whole abdominal lield Lower abdominal field
88
.....--
63 .....--
60 38
40
r-
25
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75
80
20 8
0
0
0
0
r-
0
3
2
5
4
18
I
6
Weeks Fig. 3. Cumulative use of loperamide per week of treatment by patients receiving irradiation of the whole abdomen (n = 12) or of the lower abdomen and pelvis (n = 8); a highly significant difference was dete cted with regard to the dose per fractio n ( 1.7 vs l.OGy) and type of field irra diated.
3. Discussion
plained of abdominal pain. Queasiness of the stomach was recorded by 15 to 69% of patients but this was probabl y related to the irradiation per se (table IV). No serious advers e events were recorded , despite long term medication. The mean ± SD weight of the whole group of patients decreased from 69.0 ± 12.6kg at the start of treatment to 67.8 ± 12.8kg at the end of radiotherapy. No significant ECG changes occurred . Haematology and blood chemistry revealed changes normally seen during and after radiotherapy of whole abdominal or lower abdominal/pelvic fields (table
Nausea du ring radiotherapy is common, especially when the upper parts of the abdomen or the whole abdomen are irradiated (Danjoux et al. 1979; Priestman & Priestman 1984). Most interest in antiemetic treatment during radiotherapy has focused on whole body irradiation, which induces nausea of shorter duration (Danjou x et al. 1979; Reyntjens 1979). The main aim of the present study was to develop methodology for evaluating prevention and treatment of nausea, vomiting, and diarrhoea occurring during fractionated radiotherapy over 5 or 6 weeks. The new 5-HT3-receptor antagonist tropisetron was found to be effective and was well tolerated during long term radiotherapy. When nausea occurred (in 30 to 50% of the patients), it was gen-
V ).
According to the overall evaluation made by the investigator at the end of the course of treatment, the efficacy of the drug was excellent or good in 80% of patients and the tolerability of the drug was excellent or good in 85% of patients.
Table III. Overall.quality of life assessments in 20 women with ovarian carcinoma who were treated with postoperative irradiation and tropisetron Ratings
Number 01 patients (%) week 01 treatment 2
Excellent Good
Fair Terrible
13 3 1 3
(65) (15) (5) (15)
14 2 3 1
3 (70) (10) (15) (5)
11 6 2 1
4 (55) (30) (10) (5)
11 6 2 1
5 (55) (30) (10) (5)
11 4 3 2
6 (55) (20) (15) (10)
7 (54) 4 (31) 2 (15) 0(0)
Drugs 43 (Suppl. 3) 1992
38
Table IV. Patients reporting adverse effects possibly associated with tropisetron treatment
Symptoms
Number of patients (%) week of treatment 2 2 2 1 3
Headache Constipation Colicky pain Queasy stomach
(10) (10) (5) (15)
1 1 1 11
3 (5) (5) (5) (55)
erally of mild intensity and short duration. This cumulative frequency of nausea was in the same range as that found in a recent study of ondansetron (Franzen et al. 1990). Vomiting was rare in the present study, with less than 10% of patients suffering from this adverse effect. Both nausea and vomiting were slightly more common in the group receiving whole abdominal irradiation than in those receiving irradiation to only the lower part of the abdomen and the pelvis. On the other hand, the intensity of the nausea was not influenced by the size of the irradiated field. An increased number of bowel movements and diarrhoea were common during treatment of the lower parts of the abdomen (1.7Gy per fraction) and this was less well prevented by tropisetron. 38
Table V. Haematology and blood chemistry before and after radiotherapy (RT) in 20 women with ovarian carcinoma
Before RT
After RT
Haemoglobin (gIL) Leucocytes (10 9/L) Platelets (10 9/LJ
131 7.9 294
127 4.8 209
Sodium (mmoI/L) Potassium (mmoI/L) Calcium (mmoI/L) Gamma-GT (/lkat/L) Creatinine (/lmoI/L) Bilirubin (/lmoI/L) AST (/lkat/L) ALT (/lkat/L) Alkaline phosphatase (/lkat/L)
138 4.0 2.37 0.57 79 7.40 0.35 0.31 3.50
137 3.8 2.30 0.85 70 7.71 0.50 0.53 4.42
3 1 1 13
(15) (5) (5) (65)
4
5
6
4 (20) 0(0) 1 (5) 13 (65)
5 (25) 0(0) 1 (5) 11 (55)
4 (31) 0(0) 1 (5) 9 (69)
to 100% of this group needed extra antidiarrhoeal medication with loperamide. The size of the radiation dose per fraction had an important influence on this adverse effect. This is probably related to the degree to which the intestinal mucosal cells are destroyed and which parts of the small gut and colon are irradiated. Tropisetron was not found to be very effective as an antidiarrhoeal agent. The mean bodyweight loss of 1.2kg during a 5to 6-week course of radiotherapy was surprisingly low, and the quality of life assessments also showed excellent or good ratings in 75 to 85% of the cases throughout the course of treatment. Therefore, it seems reasonable to ascribe a positive effect to tropisetron. The drug was very well tolerated and no serious adverse events were recorded despite long term treatment. Headache and abdominal cramps were noted in less than 10%of the patients. All the patients and the research nurses taking part in this study were very satisfied with the drug and regarded it as a therapeutic improvement for this type of radiotherapy. To further and more definitively evaluate the 5-HT3-receptor antagonists as antiemetics during radiotherapy, prospective randomised placebo-controlled studies are needed. Other treatment schedules (e.g. on-demand medication) should also be considered. This was a feasibility study. The methodology of assessment with the VAS was powerful, simple to use and to analyse. The patients' diary-form booklets worked well for long term follow-up and seemed to give reliable data for efficacy and tolerability. For future prospective studies, we have learnt that stratification for type of field irradiated is mandatory and that the 5-HT3-receptor antag-
Tropisetron and Radiation-Induced Emesis
onists are of limited value as antidiarrhoeal medication during radiotherapy.
References Cunningham D, Pople A, Ford HT, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5 HT3 receptor antagonist. Lancet I: 1461-1463, 1987 Danjoux CE, Rider WD, Fitzpatrick PJ. The acute radiation syndrome: a memorial to William Michael Court-Brown. Clinical Radiology 30: 581-584, 1979 Franzen L, Lomberg H, Israelsson G, et al. Ondansetron-Nytt antiemetikum mot illamaende i samband med stralterapi. Svenska Lakarsallskapets Handlingar Hygiea 99: 255-256, 1990 Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. New England Journal of Medicine 324: 709-715, 1991 Marty M, Pouillart P, Scholl S, Droz JP, Azab M, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist
39
ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. New England Journal of Medicine 322: 816-821, 1990 Priestman T, Priestman S. An initial evaluation of nabilone in the control of radiotherapy-induced nausea and vomiting. Clinical Radiology 35: 265-266, 1984 Reyntjens A. Domperidone as an anti-emetic: summary of research reports. Postgraduate Medical Journal 55 (Suppl. I): 5054, 1979 Richardson BP, Buchheit KH. The pharmacology, distribution and function of 5-HT3 receptors. In Osborne NN & Hamon M (Eds) Neuronal serotonin, pp. 465-504, Wiley and Sons Ltd, London, 1988
Correspondence and reprints: Dr Bengt Sorbe, Department of Gynecologic Oncology, Orebro Medical Center Hospital, S-701 85 Orebro, Sweden.
