This non-interventional observational study analyzed data of pediatric patients between 0.5 and 17 years of age who were treated at the Department of Pediatric Hematology and Oncology at the Dr. von Hauner Children’s Hospital, Germany between November 2015 and August 2016 receiving one or more chemotherapy courses for the treatment of hemato-oncological diseases according to pediatric oncology protocols.
The EP of the administered chemotherapeutic agent (in % frequency of emesis in absence of prophylaxis) was defined as: minimal, stage 1 (< 10%) | low, stage 2 (10 - < 30%) | moderate, stage 3 (30–90%) | high, stage 4 (> 90%) . The EP of each chemotherapy course was defined by the administered agent with the highest EP (≥3; compare Table 3).
Inclusion criteria were age at the time of chemotherapy administration between 0.5–17 years, administration of chemotherapy with a moderately or highly emetogenic potential (stage 3–4) during an in-patient stay, antiemetic prophylaxis with ondansetron only or ondansetron plus single-dose fosaprepitant.
Exclusion criteria were vomiting in the 24 h prior to the start of emetogenic chemotherapy, (additional) medication with aprepitant, granisetron, or dexamethasone, allergy to NK1 or 5-HT3-antagonists, congestive heart failure, abnormal liver (AST and ALT > 2.5-fold of the upper normal limit) or kidney (serum creatinine > 2.5-fold of the upper normal limit) function in the 24 h prior to the start of emetogenic chemotherapy, and scheduled hematopoietic stem cell transplantation.
All patients who met the inclusion criteria and received single-dose fosaprepitant and 24-h continuous infusion with ondansetron between November 2015 and August 2016 were consecutively enrolled in the fosaprepitant group (FG; n = 40). All patients who met the inclusion criteria and received CINV prophylaxis with ondansetron only between November 2014 and October 2015 were consecutively enrolled in the control group (CG; n = 39).
The analysis period with fosaprepitant and/or ondansetron included the time between the start of antiemetic prophylaxis until 120 h after starting the first moderately or highly emetogenic agent of each chemotherapy course.
The acute CINV phase of each chemotherapy course was defined as the first 24 h after the first application of a moderately or highly emetogenic agent. The delayed CINV phase was defined as the subsequent 96 h (> 24–120 h after administration of the first moderately or highly emetogenic agent).
Primary endpoints were the assessment of the efficacy (frequency of vomiting, number of patients who experienced vomiting; frequency of administration of antiemetic PRN medication dimenhydrinate) and safety (clinical and laboratory-chemical adverse events) of the prophylaxis regimens.
Ondansetron intravenous administration through a central venous catheter was started at least 30 min prior to the start of the first moderately or highly chemotherapeutic agent of each chemotherapy course at dosages of 8 mg per 24 h in patients ≤15 kg bodyweight, 16 mg per 24 h in patients of > 15–30 kg bodyweight, 24 mg per 24 h in patients of > 30–45 kg bodyweight, and a maximum dose of 32 mg per 24 h in patients with a bodyweight of > 45 kg as a 24-h continuous infusion over the whole time of intravenous chemotherapy administration until 24 h after the administration of the last agent of the respective course. Subsequently, the patients were supplied with ondansetron tablets or orally disintegrating tablets (2 × 2–8 mg per day; adapted to the body surface area).
Fosaprepitant was started at least 1 h prior to the start of the first moderately or highly chemotherapeutic agent of each chemotherapy course as a single dose of 4.0 mg per kg bodyweight (maximum 150 mg) as intravenous infusion through a central venous catheter over 30 min.
Dimenhydrinate was provided as PRN medication through a central venous catheter infusion (1.0 mg per kg BW three times per day, max. 3 × 62 mg short infusion).
Breakthrough CINV was treated with dimenhydrinate (dosage 0.1 mg per kg BW per day as 24 h infusion (max. 0.2 mg/kg per day BW)).
Assessment of safety and tolerance
The toxicity and adverse events grading of this analysis is based on the current United States National Cancer Institute’s Common Terminology Criteria for Adverse Events . Analyses of liver parameters, kidney parameters and electrolytes were performed on the day of in-patient admission before the first chemotherapy course and antiemetic prophylaxis (baseline), at least every other day during antiemetic prophylaxis during the in-patient stay (maximum or minimum), as well as on the day of clinical discharge (end), i.e. during the whole analysis period.
Liver parameters included alanine aminotransferase (ALT, normal range ≤ 39 U/L) and aspartate aminotransferase (AST, normal range ≤ 59 U/L), and the cholestasis parameter total bilirubin (normal range ≤ 1.1 mg/dL). Kidney parameters included serum creatinine (normal range ≤ 0.7 mg/dL) and urea (normal range ≤ 46 mg/dL). Electrolytes included potassium (normal range ≥ 3.4 mmol/L - 4.9 mmol/L), sodium (normal range 134 mmol/L - 145 mmol/L), and calcium (≥2.0 mmol/L - 2.6 mmol/L). Clinically-relevant elevations of > 1.5 and > 2.5 times the normal values of hepatic and kidney parameters, and decreases of potassium values < 3.4 mmol/L or < 2.4 mmol/L, sodium values < 134 mmol/L and calcium values < 2.0 mmol/L were assessed. Maximum (ALT, AST, total bilirubin, creatinine, and urea) or minimum (potassium, sodium, calcium) values during the analysis period were used for comparisons with baseline values. Clinical potentially drug-related adverse events were analyzed during the application of fosaprepitant and compared between the two groups.
Assessment of efficacy
All patients were primarily monitored for the efficacy of the antiemetic prophylaxis regimen during the acute and delayed CINV phase of moderately and highly emetogenic chemotherapy courses. The vomiting frequency of the patients during the acute and delayed CINV phases and the number of administered doses of dimenhydrinate during all chemotherapy courses of both study cohorts was used as the measure for the efficacy analyses of both prophylaxis regimens. The relative number of patients experiencing vomiting and receiving dimenhydrinate was analyzed. The assessed parameters were analyzed and compared between the two study cohorts.
Chi-square-tests (with Yates’ continuity correction) and Fisher’s exact tests were used for 2-sample tests for equality of proportions and applied to the frequencies of clinical parameters in the two treatment groups (FG and CG). In addition, the package rateratio.test of R was used to compare the frequency of the vomiting events between FG and CG .
The statistical comparison of the differences between the results and the normal range values for the liver and kidney parameters, as well as electrolytes, was performed by one-sample t-tests or one sample Wilcoxon signed rank tests (depending on the results of the Shapiro-Wilk normality test), taking into account the 95% confidence intervals (CI).
The inferential statistical analysis between the baseline values, as well as the maximum and minimum values, was performed with the Wilcoxon matched pairs signed rank test. Differences were only considered to be significant if they were clinically relevant, i.e. significantly below (sodium, calcium and potassium) the reference values or above them (all other parameters).
Graphs and statistical tests were created with GraphPad Prism for Windows, version 7 (GraphPad Software Inc., La Jolla, CA, USA), or with R (The R Foundation for Statistical Computing, Institute for Statistics and Mathematics, Wirtschaftsuniversität Wien, Austria). P-values of p < 0.05 (*), p < 0.01(**), p < 0.001 (***), and p < 0.0001 (****) were defined as statistically significant and are illustrated in the bar charts.