Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee

Abstract

Background: Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions.

Methods: AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years.

Results: In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P < .0001), thrombocytopenia (OR, 0.41; P < .0001), anemia (OR, 0.34; P < .0001), and infection (OR, 0.41; P < .0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P < .0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males.

Conclusions: Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary.

Figure 1. Treatment Plan for IRS-IV Patients

Mesna 360 mg/m²/dose was given 15 minutes before I or 450 mg/m²/dose before C and then every 3 hours 3 × 3 after each I or C. Chemotherapy doses were reduced by 50% in patients younger than 1 year, if tolerated (nadir absolute neutrophil count < 500 neutrophils/mL and platelet count > 50,000 platelets/mL), increased to 75% and then 100%. Abbreviations: V, vincristine 1.5 mg/m² (2-mg maximum); A, dactinomycin 0.015 mg/kg/d (0.5-mg maximum daily dose), days 0–4; C, cyclophosphamide 2.2 mg/m², day 0; I, ifosfamide 1.8 mg/m²/d, days 0–4; E, etoposide 100 mg/m²/d, days 0–4. *No radiation for stage 1/2, group I, and all group II; randomized to 50.4 Gy conventional v 59.4 Gy hyperfractionated for group III. **No radiation for group I; 41.4 Gy conventional to group II.