A course of low-dose maintenance chemotherapy administered after standard-of-care intensive chemotherapy led to significant improvements in disease-free and overall survival in pediatric rhabdomyosarcoma.
Practice-changing findings were reported for pediatric rhabdomyosarcoma at the 2018 ASCO Annual Meeting Sunday. Investigators said a course of low-dose maintenance chemotherapy administered after standard-of-care intensive chemotherapy led to significant improvements in disease-free (DFS) and overall survival (OS).
The findings from the decade-long trial were hailed as 1 of the 4 most important clinical developments to emerge from the 5800 abstract presentations at the ASCO meeting.
Patients receiving maintenance therapy had a 5-year DFS advantage of 77.6% versus 69.8% in the standard arm (HR = 0.68; 95% CI, 0.45-1.02; P = .0613). Low-dose maintenance therapy following initial treatment increased the 5-year OS from 73.7% to 86.5% in pediatric cases (HR = 0.52; 95% CI, 0.32-0.86; P = .0111).1,2
“At the end of this long, but not easy, study, we concluded that maintenance is an effective and well-tolerated treatment for children with high risk rhabdomyosarcoma and our group decided this is the new standard treatment for patients—at least, in Europe we will keep standard intensive chemotherapy and then we’ll continue with 6 more months of low-dose chemotherapy,” said lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova in Italy and Chair of the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG).
Bisogno added that this maintenance approach can potentially be applied to other pediatric tumors.
The standard intensive therapy course is a 6- to 8-month regimen that includes 9 cycles of high-dose chemotherapy, radiotherapy, and surgery. Patients up to the age of 21 with no evidence of metastasis were enrolled in the study following standard treatment, and were randomized to either stop treatment or continue with maintenance therapy for 6 additional months. Treatment in the experimental arm included 6 cycles of intravenous vinorelbine at 25 mg/m2 on days 1, 8, and 15 of each 28-day cycle; and continuous daily oral cyclophosphamide at 25 mg/m2. Standard treatment included 9 cycles of ifosfamide, vincristine, and actinomycin D, plus or minus doxorubicin, surgery, and/or radiotherapy.
Those enrolled were considered at high risk of recurrence due to having large tumors in hard-to-treat locations. After completing standard treatment, 371 patients aged 6 months to 21 years (79% 10 years or younger) were randomized to standard (n = 186) or maintenance care (n = 185).
In addition to prolonged survival rates, there were no cardiac, hepatic, gastrointestinal, or renal toxicities. “Treatment toxicities were much lower in comparison with what we usually see with standard chemotherapy,” Bisogno said. ‘We have less anemia, less neutropenia, less thrombocytopenia. We had fewer episodes of infection and we didn’t see any important organ dysfunction.”
Low blood cell counts were the most common adverse event in the maintenance arm, although generally mild. Febrile neutropenia occurred in 25% of patients, and infections were lower in the maintenance arm (29.4%) than what is generally seen with standard therapy. Grade 4 neurotoxicity occurred in 1.1% of patients.
Grade 3/4 hematological toxicities in the maintenance arm included neutropenia (80.6%), leukopenia (73.9%), anemia (8.9%), and low platelet counts (0.6%).
Rhabdomyosarcoma is a rare soft tissue cancer that is diagnosed in 350 children in the United states and 320 in the European Union each year; 40% of all rhabdomyosarcoma diagnoses occur in adults. Modern treatment enables the cure of 70% to 80% of children, and children who are alive at 5 years are considered cured, as recurrence is low.
However, standard of care in this disease has not changed in 30 years, Bisogno said.
“At the end of standard treatment more than 90% of children have no evidence of tumor, but we know that after 1 year or 2 years, one-third of these children relapse and most of them die,” Bisogno said, explaining the decision to initiate the trial of maintenance therapy.
ASCO expert Warren Chow, MD, a specialist in the treatment of sarcomas, described the EpSSG study as a model for how to conduct large and important trials in rare diseases. The trial took 10 years to complete partly because of the rarity of the disease and the challenges in reaching the enrollment goal.
Because there are slight differences in the way rhabdomyosarcoma is treated in the United States, there will need to be further tests with US protocols before these new findings become standard of care, Chow said. Also, it will need to be determined whether these results are applicable to patients older than 21 years of age, he said. “Even with these caveats, this is the most significant treatment advance in this disease in more than 30 years.”