Maintenance low-dose chemotherapy prolongs survival of children with high-risk rhabdomyosarcoma
Data of a phase III study, presented during the plenary sessions at ASCO 2018, demonstrate that adding maintenance metronomic chemotherapy after standard chemotherapy improves survival of patients with high-risk non-metastatic rhabdomyosarcoma (RMS). In fact, adding 6 months of low-dose maintenance chemotherapy after initial treatment significantly increased the 5-year overall survival (OS) rate from 73.7% to 86.5% (HR[95%CI]: 0.52[0.32-0.86]; p=0.0111). Tumour recurrence after 5 years is very rare in patients with RMS, indicating that with the maintenance therapy almost 9 out of 10 patients are cured.
RMS originates in the muscle tissue and can occur in any part of the body. Most often RMS is found in the head, neck, pelvis, or the abdomen. RMS is rare and accounts for approximately 4% of all childhood cancers. The prognosis for RMS patients is generally good as 70 to 80% of children can be cured with the current treatment strategy, including high-dose chemotherapy, radiation, and surgery. However, among children who have metastasis at diagnosis or a recurrence after initial treatment, only 20-30% can be cured.
The study at hand tested whether adding maintenance metronomic chemotherapy after standard chemotherapy would improve the survival of patients with non-metastatic RMS defined as high-risk according to the European paediatric Soft tissue sarcoma Study Group (EpSSG) criteria. In total, 670 patients between 6 months and 21 years old were enrolled in the study. In order to be eligible for the study patients had to have a N0 alveolar RMS or incompletely resected (Group II or III) embryonal RMS arising in an unfavourable primary site and/or N1 in complete remission after standard treatment. This standard treatment consisted of 9 cycles of ifosfamide, vincristine and actinomycin D with or without doxorubicin, surgery and/or radiotherapy. Patients in the study were randomly assigned to stop treatment or receive maintenance chemotherapy consisting of 6 28-day cycles of intravenous vinorelbine (25 mg/m2 on days 1, 8 and 15 of each cycle) and continuous daily oral cyclophosphamide (25 mg/m2). Overall, 67% of patients in the study had embryonal RMS while 33% had alveolar RMS. One-fifth of patients were older than 10 years, 86% was classified as IRS Group III and 16% had N1 disease. The most common primary tumour site was parameningeal (32%).
At five years from diagnosis, the disease-free survival (DFS, defined as five years without tumour recurrence or death from any cause) was 69.8% in the standard treatment group as compared to 77.6% in the maintenance group (HR[95%CI]: 0.68[0.45-1.02]; p=0.0613). The 5-year OS rate was significantly higher in the maintenance arm compared to the standard group: 86,5% vs. 73.7%. This corresponds to a 48% reduction in the risk of death for patients treated with maintenance chemotherapy (HR[95%CI]: 0.52[0.32-0.86]; p=0.0111).
The most common side effect in the maintenance group was low blood cell count, though it was usually mild. High-grade febrile neutropenia (grade 3/4) occurred in 25% of patients. Infection rates were lower with maintenance treatment than after initial standard chemotherapy (29.4% vs. 56.4%), and neurologic side effects resolved after treatment ended (grade 4 neurotoxicity seen in 1.1% of patients). However, as with most kinds of chemotherapy, long-term side effects are still possible, and patients will continue to be monitored.
In summary, maintenance therapy represents a novel, well-tolerated and effective strategy in patients with high risk RMS. As such, this study establishes the new standard treatment for patients with high-risk RMS.
Bisogno G, et al. Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Presented at ASCO 2018; Abstract LBA2.