Maintenance therapy with low dose cyclophosphamide does not increase the risk of second malignancies: The European...

Survivors of childhood rhabdomyosarcoma (RMS) are at increased risk of second malignant neoplasms (SMNs), influenced by treatment type and genetic predisposition. Recently, the addition of maintenance chemotherapy with low-dose cyclophosphamide and vinorelbine has improved survival outcomes for patients with high-risk disease. However, the potential SMN risk from increased cumulative alkylating agent exposure remains unclear.

The authors analyzed 1633 patients enrolled in the European RMS 2005 trial. Cumulative incidence of SMN was estimated using competing risk methodology. Outcomes were compared between patients who did and did not receive maintenance chemotherapy.

After a median follow-up of 9.3 years (range, 0.6-17.7), 27 patients (1.7%) developed a SMN. Eight had a known cancer predisposition syndrome: Li-Fraumeni syndrome (LFS) in six patients and neurofibromatosis type 1 (NF1) in two patients. Osteosarcoma was the most frequent SMN (n = 6), followed by low-grade glioma (n = 3), hematological malignancies (n = 3), and undifferentiated sarcoma (n = 2). Twenty of 27 patients with SMN received radiotherapy before developing an SMN, including eight who's SMN arose within a previously irradiated field. Three of these eight patients had LFS. The 8-year cumulative incidence of SMN in the entire cohort was 1.3% (95% CI, 0.8-2.0). SMNs occurred in 17 of 1081 patients without maintenance therapy (1.6%) and in nine of 486 patients who received maintenance therapy (1.9%; p = .75).

Maintenance chemotherapy was not associated with increased SMN risk. Genetic predisposition was a major contributor to SMN development, supporting risk-adapted survivorship care. Longer follow-up is required to evaluate late-occurring SMNs.