Tropisetron (Navoban®) in the Control of Nausea and Vomiting Induced by Combined Cancer Chemotherapy in Children

Jpn J Clin Oncol1999;29(2)92-95

Alp Ozkan, Inci Yildiz, Lebriz Yuksel, Hilmi Apak and Tiraje Celkan

Cerrahpasa Medical Faculty, Department of Pediatric Hematology-Oncology, University of Istanbul, Istanbul, Turkey

Background: We aimed to assess the potency and efficacy of tropisetron, a 5-HT3 receptor Downloaded from https://academic.oup.com/jjco/article/29/2/92/1048971 by guest on 24 September 2021 antagonist, in the prevention of nausea and emesis observed in the pediatric patient population taking various chemotherapy protocols. Methods: Tropisetron (Navoban'[) was given to 100 children (62 boys and 38 girls aged 6 months to 15 years) with various malignancies. Patients received tropisetron during one or more courses of emetogenic chemotherapy for a total of 350 courses administered intravenously or intravenously and intrathecally. Tropisetron (0.2 mg/kg/day, maximum: 5 mg/day) was adminis tered as a single intravenous dose slowly, before the start of chemotherapy on day 1 and intravenously or by mouth on subsequent days (median treatment duration: 5 days). Results: The patients receiving cytotoxic chemotherapy had a 70% complete response rate and a 24% partial response rate during the first 24 h period of the first course. We observed headache (five courses), diarrhea (three courses) and loss of appetite (one course) as side-effects (2.5%). Conclusion: Tropisetron is safe, effective, easy to use, has no serious side-effects and can be recommended for pediatric patients. The efficacy of tropisetron may be enhanced by the addition of corticosteroids in patients receiving highly emetogenic cancer chemotherapy.

Key words: tropisetron - serotonin antagonist -dexamethasone - vomiting - children

INTRODUCTION We aimed to assess the potency and efficacy of tropisetron, a 5-HT3 receptor antagonist, in the prevention of nausea and Chemotherapy-induced emesis is one of the major problems emesis observed in the pediatric patient population taking various observed during the treatment of childhood malignancies and it chemotherapy protocols in the Pediatric Hematology and Onco also has great clinical importance since it can considerably limit the logy Department, Cerrahpasa Medical Faculty, University of administration of cytotoxic chemotherapy regimens. Because of Istanbul. appetite loss and acute disturbances of nutritional and electrolyte balance leading to dehydration, emesis and nausea are more hazardous in children than adults. All these issues can lead to PATIENTS AND METHODS greater patient morbidity, difficulties in adaptation to chemother Between July 1995and July 1998, a total of 100patients receiving apy regimens and increased length of time spent in the hospital. cancer chemotherapy in the Pediatric Hematology and Oncology Blocking of the 5-HT3 receptors in the proximal gastrointesti Department were enrolled in the study. The study respected the nal tract, along the vagus nerve and in the area postrema of the guidelines of the Helsinki Declaration concerning medical brain stem, is an important measure to prevent chemotherapy research in humans. induced emesis (1). Tropisetron is one of a family of highly Patients with gastrointestinal obstruction or paralytic ileus, specific antagonists to this subtype of serotonin receptor (2). CNS tumors or brain metastasis and patients given prior antiemetic therapy during the preceding 24 h were excluded from the study. A single daily dose of tropisetron of 0.2 mg/kg Received September 16, 1998; accepted November 11, 1998 (maximum 5 mg) was administered intravenously by 30 min infusion in 100 ml/m2 normal saline before the start of For reprints and all correspondence: Alp Ozkan, Suadiye Kavisli Sokak, Fidan Apt. No. 15/13, 81070-Istanbul, Turkey chemotherapy on day 1and intravenously or orally on subsequent days of each course. It was taken as a single morning dose, orally. Abbreviations: 5-HT3, 5-hydroxytrptamine 3; eNS, central nervous The contents of a 5 mg/5 ampoule were also taken, undiluted system; ALL, acute lymphocytic leukemia; AML, acute myelocytic m1 leukemia; PNET, primitive neuroectodermal tumors; Trop + Dex, or mixed with orange juice. The duration of treatment was as that tropisetron and dexamethasone. of the chemotherapy course.

Table 1. Criteria for emetic grade of chemotherapy courses (dose in mg/m-)

Grade I Grade 2 Grade 3* Grade 4* Amsacrine Cisplatin <20 Cisplatin ~20 Cisplatin ~60 Asparaginase Carboplatin <150 Carboplatin ~150 Dactinomycin ~O.45 Bleomycin Dactinomycin <0.3 Dactinomycin ~O.3 Cyclophosp. ~ I000 Etoposide Carmustine <75 Carmustine ~75 Cytarabine ~1000 Fluorouracil Chlormethine <6 Chlormethine ~6 Ifosfamide ~3000 Mercaptopurine Cyclophosp. <300 Cyclophosp. ~300 Methylgag Cytarabine <150 Cytarabine ~ 150 Mitomycin Dacarbazine <100 Dacarbazine ~100 Downloaded from https://academic.oup.com/jjco/article/29/2/92/1048971 by guest on 24 September 2021 Mitoxantrone Daunorubicin <45 Daunorubicin ~45 Procarbazine Doxorubicin <45 Doxorubicin ~45 Teniposide Epirubicin <75 Epirubicin ~75 Thioguanine Ifosfamide <1000 Ifosfamide ~1 000 Vinorelbine Methotrexate <3000 Methotrexate ~3000 Vindesine Vinblastine Vincristine

*Chemotherapy regimens containing at least two drugs of grade 2 were considered as grade 3. Chemotherapy of grade 3 was considered as grade 4 when combined with grade 2 or grade 3 chemotherapy.

Chemotherapy regimens with and without cisplatin were (10%), AML (6%) and PNET (4%). Other solid tumors completed to 5 and 2 days, respectively. A group of patients given (osteogenic sarcoma, Ewing sarcoma, Wilms tumor, nasopharyn cisplatin-containing chemotherapy were randomized to receive geal cancer, retinoblastoma, hepatoblastoma and germ cell or not receive dexamethasone concurrently. Dexamethasone was tumor) accounted for the remaining 15% of the cases. administered at 20 mg/m? diluted in 50 ml D5W intravenously by Of the chemotherapy courses, 60% were of emetic grade 4, 30 min infusion, 1 h before the cisplatin infusion on day 1. 20% of grade 3 and 20% of grade 2. The patients received A grading-scale based on a combined measure of nausea and chemotherapy exclusively by vein in 235 of the courses (67%) vomiting was used to assess the efficacy of tropisetron. This was and chemotherapy was administered both intravenously and a scale that had been used in previous studies (3,4). The response intrathecally in 115 of the courses (33%). per 24 h period on the first five days of each course of Overall response rates to tropisetron were 79% complete, 18% chemotherapy was graded as: complete (no nausea or vomiting), partial and 3% failure (Table 2). On day 1 of the first course of partial (1-4 vomits and/or <5 h of nausea) or failure (more than chemotherapy, 70% complete, 24% partial response and 6% four vomits and/or at least 5 h of nausea). The nurses and the failure rates were obtained and in the second course 75% parents of the patients recorded data concerning nausea, emesis, complete, 21% partial response, 4% failure rates were obtained appetite and adverse effects daily. (Table 3). In the worst day analysis of the first chemotherapy Chemotherapy courses were grouped by emetic grade (1-4) of course, the complete response rates according to the emetic grade chemotherapy (Table 1).The grade of a chemotherapy course was of the chemotherapy regimen received were 50, 60 and 100% for determined by the highest emetic grade of each agent at the dose the emetic grades 4,3 and 2, respectively (Table 4). Corticoster used. Chemotherapy regimens containing at least two days of oids were part of the chemotherapy regimens in 34% of the grade 2 or grade 3 were upgraded. patients. In these courses, 85% complete response, 12% partial Chi-squared, Student's t-test and Mantel-Haenszel methods response and 3% failure rates were obtained while 73% complete were used for statistical analysis. response, 24% partial response and 3% failure rates were obtained with regimens lacking corticosteroids (P < 0.001) (Table 2). RESULTS Table 2. Response rates to tropisetron in regimens containing and lacking A total of 100 children (62 boys and 38 girls) under chemotherapy corticosteroids (%) for malignant disease were enrolled in this study. Their median age was 4 years (range 6 months to 15 years); 14 children were Regimen Complete Partial Failure under 2 years of age. The patients received 350 chemotherapy Containing corticosteroids 85 12 3 courses with an average of three courses per patient. The most Lacking corticosteroids 73 24 frequent diagnosis in our study group was ALL (40%), followed 3 by lymphoma (15%), neuroblastoma (10%), rhabdomyosarcoma All 79 18 3 94 Tropisetron in pediatric oncology

Table 3. Response rates to tropisetron on the observation days of the first and second courses of chemotherapy

Course Day 1 Day 2 Day 3 Day 4 Day 5 Course 1 (n* = 100) Complete response 70 (70%) 75 (75%) 80 (80%) 82 (82%) 85 (85%) Partial response 24 (24%) 21 (21%) 18 (18%) 17 (17%) 15 (15%)

Failure 6 (6%) 4 (4%) 2 (2%) 1 (1%) 0 Course 2 (n = 100) Complete response 75 (75%) 80 (80%) 80 (80%) 82 (82%) 85 (85%) Partial response 21 (21%) 16 (16%) 18 (18%) 18 (18%) 15 (15%)

Failure 4 (4%) 4(4%) 2 (2%) 0 0

*n = Number of patients. Downloaded from https://academic.oup.com/jjco/article/29/2/92/1048971 by guest on 24 September 2021

Table 4. Complete response rates by emetic grade on the five observation days of the first and second courses of chemotherapy

Course Grade Day 1 Day 2 Day 3 Day 4 Day 5 Course 1 2 (n* = 16) 16 (100%) 16 (100%) 16 (100%) 16 (100%) 16 (100%) 3 (n =23) 14 (60%) 17(74%) 18 (79%) 19 (83%) 20 (87%) 4 (n = 61) 30 (50%) 30 (50%) 37 (61%) 39 (64%) 43 (70%) Course 2 2(n= 18) 18 (100%) 18 (100%) 18 (100%) 18 (100%) 18 (100%) 3 (n =28) 19 (68%) 22 (79%) 23 (82%) 24 (86%) 25 (89%) 4(n=54) 31 (57%) 32 (59%) 31 (57%) 33 (61%) 36 (67%)

*n =Number of patients.

Table 5. Comparison of the daily number of episodes (mean ± SD) of vomiting between the Trop + Dex and the tropisetron groups in cisplatin-containing regimens

Day 1 Day 2 Day 3 Day 4 Day 5 Trop + Dex (n* =20) 0.60 ± 1.35 0.55 ± 1.15 0.65 ± 1.23 0.65 ± 1.23 0.55 ± 1.00 Trop (n =20) 1.95 ± 2.16 1.75 ± 1.92 1.40 ± 1.57 0.95 ± 1.28 0.75 ± 1.02 P <0.05 <0.05 <0.05 >0.05 >0.05

*n =Number of courses.

Fifteen of the patients received cisplatin-containing regimens. DISCUSSION Forty (11%) of the 350 chemotherapy courses included cisplatin. In courses with cisplatin-containing regimens, 50% complete Nausea and vomiting caused by anticancer chemotherapy are a response rate was obtained in the tropisetron monotherapy group major problem in children as in adults. Additionally, the while 65% complete response rate were observed in the side-effects of traditional antiemetics are found to be more tropisetron + dexamethasone group (Trop + Dex). We compared pronounced in children. Before the introduction of the 5-HT3 the number of daily vomiting episodes between the Trop + Dex receptor antagonists, traditional antiemetic agents and cocktails and the tropisetron groups. In Table 5 it can be seen that on days were inadequate for the prevention of nausea and vomiting 1, 2 and 3, the mean ±SD episodes of vomiting were 0.60 ± 1.35, induced by highly emetogenic cytostatic agents (3-7). 0.55 ± 1.15 and 0.65 ± 1.23, respectively, for the Trop + Dex Our results are in agreement with those reported in previous group and 1.95 ± 2.16,1.75 ± 1.92 and lAO ± 1.57, respectively, studies with tropisetron in pediatric oncology. We administered for the tropisetron group. The mean number of episodes of tropisetron to 100 children with a median age of 4 years (range 6 vomiting was lower in the Trop + Dex group (P < 0.05) (Table 5). months to 15 years) for 350 chemotherapy courses. In the study Adverse effects attributable to tropisetron such as headache of Benoit et al. (3), 131 children with a median age of 5 years (five courses), diarrhea (three courses) and loss of appetite (one (range 10 weeks to 21 years) received tropisetron for 455 course) were observed in nine courses (2.5%). chemotherapy courses. Our study is the second large series study Jpn J Clin Oncol1999;29(2) 95

with tropisetron. Benoit et al.'s report was the first study on the In conclusion, tropisetron is safe, effective and easy to use, has use of tropisetron in infants suffering from malignancy. In our no serious side-effects and can be recommended for pediatric study, we administered tropisetron to three children under 1 year patients. The efficacy of tropisetron may be enhanced by the and 14 children under 2 years of age. addition of corticosteroid in patients receiving highly emetogenic Another important point is that in the first course of chemother cancer chemotherapy. apy 84% of our patients had highly emetogenic chemotherapy (emetogenic grades 3-4), whereas in the study of Benoit et al. (3) References 68% of the patients received highly emetogenic chemotherapy 1. Andrews PLR, Rapeport WG, Sanger GJ. Neuropharmacology of emesis (emetogenic grades 3-4) in the first course. induced by anticancer chemotherapy. Trends Phannacol Sci 1988;9:334-41. On the first day of the first course of chemotherapy, our 2. Richardson BP, Engel G, Donatsch P,Stadler PA. Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. complete response rate for nausea and vomiting was 70%, Nature 1985;316:126.

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