Japanese Journal of Clinical Oncology

INTRODUCTION

Chemotherapy-induced emesis is one of the major problems observed during the treatment of childhood malignancies and it also has great clinical importance since it can considerably limit the administration of cytotoxic chemotherapy regimens. Because of 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 greater patient morbidity, difficulties in adaptation to chemotherapy regimens and increased length of time spent in the hospital.

Blocking of the 5-HT3 receptors in the proximal gastrointestinal tract, along the vagus nerve and in the area postrema of the brain stem, is an important measure to prevent chemotherapy-induced emesis (1). Tropisetron is one of a family of highly specific antagonists to this subtype of serotonin receptor (2).

We aimed to assess the potency and efficacy of tropisetron, a 5-HT3 receptor antagonist, in the prevention of nausea and emesis observed in the pediatric patient population taking various chemotherapy protocols in the Pediatric Hematology and Oncology Department, Cerrahpasa Medical Faculty, University of Istanbul.

PATIENTS AND METHODS

Between July 1995 and July 1998, a total of 100 patients receiving cancer chemotherapy in the Pediatric Hematology and Oncology Department were enrolled in the study. The study respected the guidelines of the Helsinki Declaration concerning medical research in humans.

Patients with gastrointestinal obstruction or paralytic ileus, 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 (maximum 5 mg) was administered intravenously by 30 min infusion in 100 ml/m² normal saline before the start of chemotherapy on day 1 and intravenously or orally on subsequent days of each course. It was taken as a single morning dose, orally. The contents of a 5 mg/5 ml ampoule were also taken, undiluted or mixed with orange juice. The duration of treatment was as that of the chemotherapy course.

Chemotherapy regimens with and without cisplatin were completed to 5 and 2 days, respectively. A group of patients given cisplatin-containing chemotherapy were randomized to receive or not receive dexamethasone concurrently. Dexamethasone was administered at 20 mg/m² diluted in 50 ml D5W intravenously by 30 min infusion, 1 h before the cisplatin infusion on day 1.

A grading-scale based on a combined measure of nausea and vomiting was used to assess the efficacy of tropisetron. This was a scale that had been used in previous studies (3,4). The response per 24 h period on the first five days of each course of chemotherapy was graded as: complete (no nausea or vomiting), partial (1-4 vomits and/or <5 h of nausea) or failure (more than four vomits and/or at least 5 h of nausea). The nurses and the parents of the patients recorded data concerning nausea, emesis, appetite and adverse effects daily.

Chemotherapy courses were grouped by emetic grade (1-4) of chemotherapy (Table 1). The grade of a chemotherapy course was determined by the highest emetic grade of each agent at the dose used. Chemotherapy regimens containing at least two days of grade 2 or grade 3 were upgraded.

Table 1. Criteria for emetic grade of chemotherapy courses (dose in mg/m²)

Grade 1	Grade 2	Grade 3*	Grade 4*
Amsacrine	Cisplatin <20	Cisplatin [ge]20	Cisplatin [ge]60
Asparaginase	Carboplatin <150	Carboplatin [ge]150	Dactinomycin [ge]0.45
Bleomycin	Dactinomycin <0.3	Dactinomycin [ge]0.3	Cyclophosp. [ge]1000
Etoposide	Carmustine <75	Carmustine [ge]75	Cytarabine [ge]1000
Fluorouracil	Chlormethine <6	Chlormethine [ge]6	Ifosfamide [ge]3000
Mercaptopurine	Cyclophosp. <300	Cyclophosp. [ge]300
Methylgag	Cytarabine <150	Cytarabine [ge]150
Mitomycin	Dacarbazine <100	Dacarbazine [ge]100
Mitoxantrone	Daunorubicin <45	Daunorubicin [ge]45
Procarbazine	Doxorubicin <45	Doxorubicin [ge]45
Teniposide	Epirubicin <75	Epirubicin [ge]75
Thioguanine	Ifosfamide <1000	Ifosfamide [ge]1000
Vinorelbine	Methotrexate <3000	Methotrexate [ge]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.

Chi-squared, Student's t-test and Mantel-Haenszel methods were used for statistical analysis.

RESULTS

A total of 100 children (62 boys and 38 girls) under chemotherapy for malignant disease were enrolled in this study. Their median age was 4 years (range 6 months to 15 years); 14 children were under 2 years of age. The patients received 350 chemotherapy courses with an average of three courses per patient. The most frequent diagnosis in our study group was ALL (40%), followed by lymphoma (15%), neuroblastoma (10%), rhabdomyosarcoma (10%), AML (6%) and PNET (4%). Other solid tumors (osteogenic sarcoma, Ewing sarcoma, Wilms tumor, nasopharyngeal cancer, retinoblastoma, hepatoblastoma and germ cell tumor) accounted for the remaining 15% of the cases.

Of the chemotherapy courses, 60% were of emetic grade 4, 20% of grade 3 and 20% of grade 2. The patients received chemotherapy exclusively by vein in 235 of the courses (67%) and chemotherapy was administered both intravenously and intrathecally in 115 of the courses (33%).

Overall response rates to tropisetron were 79% complete, 18% partial and 3% failure (Table 2). On day 1 of the first course of chemotherapy, 70% complete, 24% partial response and 6% failure rates were obtained and in the second course 75% complete, 21% partial response, 4% failure rates were obtained (Table 3). In the worst day analysis of the first chemotherapy course, the complete response rates according to the emetic grade of the chemotherapy regimen received were 50, 60 and 100% for the emetic grades 4, 3 and 2, respectively (Table 4). Corticosteroids were part of the chemotherapy regimens in 34% of the patients. In these courses, 85% complete response, 12% partial response and 3% failure rates were obtained while 73% complete response, 24% partial response and 3% failure rates were obtained with regimens lacking corticosteroids (p < 0.001) (Table 2).

Table 2. Response rates to tropisetron in regimens containing and lacking corticosteroids (%)

Regimen	Complete	Partial	Failure
Containing corticosteroids	85	12	3
Lacking corticosteroids	73	24	3
All	79	18	3

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.

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.

Fifteen of the patients received cisplatin-containing regimens. Forty (11%) of the 350 chemotherapy courses included cisplatin. In courses with cisplatin-containing regimens, 50% complete response rate was obtained in the tropisetron monotherapy group while 65% complete response rate were observed in the tropisetron + dexamethasone group (Trop + Dex). We compared the number of daily vomiting episodes between the Trop + Dex and the tropisetron groups. In Table 5 it can be seen that on days 1, 2 and 3, the mean ± SD episodes of vomiting were 0.60 ± 1.35, 0.55 ± 1.15 and 0.65 ± 1.23, respectively, for the Trop + Dex group and 1.95 ± 2.16, 1.75 ± 1.92 and 1.40 ± 1.57, respectively, for the tropisetron group. The mean number of episodes of vomiting was lower in the Trop + Dex group (p < 0.05) (Table 5).

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.

Adverse effects attributable to tropisetron such as headache (five courses), diarrhea (three courses) and loss of appetite (one course) were observed in nine courses (2.5%).

DISCUSSION

Nausea and vomiting caused by anticancer chemotherapy are a major problem in children as in adults. Additionally, the side-effects of traditional antiemetics are found to be more pronounced in children. Before the introduction of the 5-HT3 receptor antagonists, traditional antiemetic agents and cocktails were inadequate for the prevention of nausea and vomiting induced by highly emetogenic cytostatic agents (3-7).

Our results are in agreement with those reported in previous studies with tropisetron in pediatric oncology. We administered tropisetron to 100 children with a median age of 4 years (range 6 months to 15 years) for 350 chemotherapy courses. In the study of Benoit et al. (3), 131 children with a median age of 5 years (range 10 weeks to 21 years) received tropisetron for 455 chemotherapy courses. Our study is the second large series study with tropisetron. Benoit et al.'s report was the first study on the use of tropisetron in infants suffering from malignancy. In our study, we administered tropisetron to three children under 1 year and 14 children under 2 years of age.

Another important point is that in the first course of chemotherapy 84% of our patients had highly emetogenic chemotherapy (emetogenic grades 3-4), whereas in the study of Benoit et al. (3) 68% of the patients received highly emetogenic chemotherapy (emetogenic grades 3-4) in the first course.

On the first day of the first course of chemotherapy, our complete response rate for nausea and vomiting was 70%, whereas Benoit et al. (3) and Gershanovich et al. (5) reported this rate as 70 and 69%, respectively. In the second course using tropisetron the response rates were similar to the first, suggesting consistency in response over multiple chemotherapy courses.

Fifteen of the patients received cisplatin-containing regimens. Forty (11%) of the 350 chemotherapy courses included cisplatin. In cisplatin-containing regimens a 50% complete response rate to nausea and vomiting was achieved in the tropisetron monotherapy group whereas with the addition of dexamethasone the response rate was found to be 65% in the Trop + Dex group (p < 0.05). Berberoglu (7) in Turkey administered tropisetron to 15 children with a median age of 13 years (range 6 months to 17 years) for cisplatin-containing chemotherapy courses. Berberoglu reported a complete response rate of 62% with tropisetron alone whereas we achieved that rate with the aid of dexamethasone. The combination of tropisetron with dexamethasone is highly effective antiemetic prophylaxis for patients receiving high-dose cisplatin chemotherapy.

In corticosteroid-containing chemotherapy courses the patients had a 85% complete response rate to tropisetron whereas in corticosteroid-lacking courses the complete response rate was 73% (p < 0.001). Many investigators have reported that in the control of nausea and vomiting with 5-HT3 receptor antagonists, the addition of a corticosteroid might improve the efficacy of tropisetron in anticancer chemotherapy (8-12).

In conclusion, tropisetron is safe, effective and 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 corticosteroid in patients receiving highly emetogenic cancer chemotherapy.