Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide in Pediatric Intermediate-Risk Rhabdomyosarcoma


Key Points

  • VAC/VI did not improve event-free or overall survival vs VAC.
  • VAC was associated with more severe hematologic toxicity.

In a phase III Children’s Oncology Group study reported in the Journal of Clinical Oncology, Hawkins et al found that substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses did not improve event-free survival in pediatric intermediate-risk rhabdomyosarcoma but was associated with less hematologic toxicity.

In the study, 448 evaluable patients with nonmetastatic, unresected embryonal rhabdomyosarcoma with an unfavorable primary site or nonmetastatic alveolar rhabdomyosarcoma were randomized between December 2006 and December 2012 to receive VAC (n = 222; cumulative cyclophosphamide dose = 16.8 g/m2) or VAC/VI (n = 226; cumulative cyclophosphamide dose = 8.4 g/m2) for 42 weeks of therapy. During the first 12 weeks of treatment, the two groups received the same treatment, with the exception of substituting irinotecan for dactinomycin and cyclophosphamide at week 4 and for cyclophosphamide at weeks 7 and 10 in the VAC/VI group. During the next 30 weeks, irinotecan replaced dactinomycin and cyclophosphamide at weeks 16, 19, 25, 31, and 37 in the VAC/VI group. Radiation therapy began at week 4.

The primary endpoint was event-free survival. Most patients were male (54%), aged 1 to 10 years (61%), and white (71%); 53% had embryonal rhabdomyosarcoma, and 91% had stage II or III disease.

Survival Outcomes and Toxicity

At a median follow-up of 4.8 years, 4-year event-free survival was 59% in the VAC/VI group vs 63% in the VAC group (P = .51), and 4-year overall survival was 72% vs 73% (P = .80). No differences in 4-year event-free or overall survival were found in the alveolar rhabdomyosarcoma (51% vs 58%, P = .25; 66% vs 68%, P = .59) or embryonal rhabdomyosarcoma subgroups (64% vs 66%, P = .85; 76% vs 77%; P = .96).

Overall, grade 3 or 4 hematologic toxicity was less common with VAC/VI. Grade 3 or 4 anemia (27.5% vs 8.9%; 28.0% vs 8.9%) and thrombocytopenia (31.4 vs 11.8%; 32.6% vs 6.8%) were significantly (all P < .001) more common with VAC vs VAC/VI in weeks 16–30 and 31–43. Diarrhea was more common with VAC/VI vs VAC during weeks 1–15 and 16–30, oral mucositis was more common with VAC/VI vs VAC during weeks 1–15, and febrile neutropenia was more common with VAC vs VAC/VI during weeks 16–30.

The instigators concluded, “The addition of VI to VAC did not improve [event-free or overall survival] for patients with intermediate-risk [rhabdomyosarcoma]. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk [rhabdomyosarcoma].”

The study was supported by Children’s Oncology Group grants and the St. Baldrick’s Foundation.

Douglas S. Hawkins, MD, of Seattle Children’s Hospital, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.