Maintenance Therapy Improves Outcomes in Rhabdomyosarcoma

Maintenance Therapy Improves Outcomes in Rhabdomyosarcoma

Dr. Gianni Bisogno
Dr. Douglas S. Hawkins
Adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma, according to the results of the RMS2005 maintenance study from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) presented during the Plenary Session, on June 3 (Abstract LBA2).

Both 5-year disease-free survival (DFS) and 5-year overall survival (OS) increased with the use of the maintenance regimen.

“Maintenance therapy is effective and well tolerated. The study establishes, at least for our group, the new standard of care for patients with high-risk rhabdomyosarcoma,” Gianni Bisogno, MD, of the University Hospital of Padova, Italy, said.

Rhabdomyosarcoma is a tumor of mesenchymal origin found primarily in children, although it can occur in adults. It is rare, Dr. Bisogno said, with only about 350 children diagnosed in the United States and 320 in the European Union each year. Although the tumor is aggressive, approximately 70% to 80% of children achieve complete remission with intensive treatment, including high-dose chemotherapy, radiation, and surgery.

If patients have a recurrence after initial treatment, however, most cannot be cured. Dr. Bisogno explained that in patients with no radiologic evidence of tumor after intensive therapy, 60% to 70% will go on to be long-term survivors, but 30% to 40% relapse, mostly in the first year, and many of these patients will die. This trial was undertaken to improve outcomes for these high-risk patients, Dr. Bisogno said.

The investigators designed the trial to determine whether maintenance metronomic chemotherapy would improve survival for patients with nonmetastatic rhabdomyosarcoma, defined as high-risk based on EpSSG stratification. Previously untreated patients age 0 to 21 with pathologically proven high-risk rhabdomyosarcoma with no evidence of metastasis were enrolled at 108 centers in 14 countries. After standard intensive therapy, including nine cycles of high-dose chemotherapy, radiotherapy, and surgery, if there was no radiologic evidence of tumor, patients were randomly assigned to stop treatment or to continue with 6 months of maintenance therapy.

The low-dose maintenance therapy included six 28-day cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15 of each cycle, plus daily oral cyclophosphamide 25 mg/m2. The primary endpoint was DFS, and the secondary endpoint was OS.

Of the 670 patients assessed for eligibility, 371 were randomly assigned to the standard treatment arm (186 patients) or the maintenance arm (185 patients). In the maintenance arm, fewer instances of anemia and thrombocytopenia were seen than with standard intensive therapy, Dr. Bisogno said. There were fewer infections in the maintenance arm than during intensive therapy and no cardiac, hepatic, or renal toxicity.

Dr. Bisogno pointed out that 120 families declined to participate in the trial. “You can understand how difficult it is to propose to these families 6 more months of treatment after 6 or 8 months of intensive treatment,” he said. Of the patients assigned to maintenance, 91% completed the maintenance regimen.

Five-year DFS was 77.6% in the maintenance group and 69.8% in the standard treatment group (HR 0.68, 95% CI [0.45, 1.02]; p = 0.0613). Five-year OS was 86.5% in the maintenance group and 73.7% in the standard treatment group (HR 0.52, 95% CI [0.32, 0.86]; p = 0.0111). The differences amounted to increases of approximately 8% in DFS and approximately 13% in OS over standard treatment with the maintenance regimen, Dr. Bisogno said.

Discussant Douglas S. Hawkins, MD, of Seattle Children’s Hospital, University of Washington, Fred Hutchinson Cancer Research Center, congratulated the EpSSG investigators for the persistence they demonstrated in designing and conducting a prospective randomized trial in this extremely rare cancer. He noted that this is only the third positive randomized trial published in rhabdomyosarcoma.

Dr. Hawkins’s discussion centered on two questions: Why did this maintenance therapy regimen work, and who should get it? Regarding the first question, he said it was unlikely the low-dose cyclophosphamide was the main driver of the result, as randomized addition of cyclophosphamide in previous trials did not improve outcomes for patients with completely resected tumors. It is more likely the inclusion of vinorelbine, which has shown high single-agent activity in recurrent/refractory rhabdomyosarcoma but has never before been incorporated into frontline therapy for the disease. The maintenance regimen included 18 doses of vinorelbine. Duration of therapy might be another factor in the success of the regimen.

Regarding the second question, Dr. Hawkins noted that the EpSSG and Children’s Oncology Group risk stratifications do not completely overlap; comparisons are possible but will require adjustments. He said maintenance chemotherapy has modest toxicity, and its use should be considered standard for EpSSG high-risk patients after complete remission. The role of maintenance therapy for other populations requires further investigation.

–Tim Donald, ELS