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Maintenance chemotherapy improves OS in rhabdomyosarcoma
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CHICAGO — Maintenance chemotherapy after standard intensive therapy improved DFS and OS rates among children with rhabdomyosarcoma, according to study results presented during the plenary session of the ASCO Annual Meeting.
“Maintenance therapy represents a novel well-tolerated effective strategy in patients with high-risk rhabdomyosarcoma,” Gianni Bisogno, MD, PhD, professor in the department of women's and children's health, hematology/oncology division at Padova University Hospital in Padova, Italy, said during a press conference. “This study establishes the new standard of treatment for patients with high-risk rhabdomyosarcoma, at least in the European Union.”
Rhabdomyosarcoma — a rare tumor of mesenchymal origin — is diagnosed in approximately 350 children in the United States and 320 children in the European Union annually.
“It is a very aggressive tumor but, with modern intensive treatment, 70% to 80% of children can be cured,” Bisogno said.
Bisogno and colleagues from European pediatric Soft tissue sarcoma Study Group, or EpSSG, randomly assigned patients aged 6 months to 21 years with high-risk rhabdomyosarcoma to standard intensive therapy (n = 186) or standard intensive therapy followed by maintenance chemotherapy (n = 185).
Standard intensive therapy included nine cycles of high-dose chemotherapy (ifosfamide, vincristine, actinomycin, with or without doxorubicin), radiotherapy and surgery for 6 to 8 months.
Maintenance chemotherapy included six 28-day cycles of 25 mg/m2 IV vinorelbine on days 1, 8 and 15 of each cycle and continuous daily oral 25 mg/m2 cyclophosphamide.
Clinical characteristics of the patients were similar between the groups. Incomplete resected embryona disease occurred in 67% of patients; 33% had alveolar disease; 21% were aged 10 years or older; and the most common primary tumor site was parameningeal (32%) followed by other sites (23%).
Researchers defined DFS as 5 years without tumor recurrence or mortality from any cause.
At 5 years, the DFS was 77.6% (70.6-83.2) among patients in the standard and maintenance therapy group compared with 69.8% (62.2-76.2) in the standard therapy only group, for a HR of 0.68 (95% CI, 0.45-1.02).
More patients treated with maintenance therapy achieved 5-year OS than patients who underwent standard therapy (86.5% vs. 73.7%; HR = 0.52; 95% CI, 0.32-0.86).
Toxicities were manageable among patients who underwent maintenance therapy. Twenty-five percent of patients experienced grade 3 or 4 febrile neutropenia. Grade 4 neurotoxicity occurred in 1.1% of patients.
Maintenance therapy led to fewer occurrence of anemia, febrile neutropenia, thrombocytopenia, and infectious episodes than occurred during standard treatment, Bisogno noted. Further, no cardiac, hepatic, gastrointestinal or renal toxicities were observed.
“The same approach is worthwhile to be investigated in other solid tumors of childhood,” Bisogno said. – by Melinda Stevens
Reference:
Bisogno G, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Bisogno reports a consultant/advisory role with Clinigen Group and travel expenses, accommodations or other expenses from Jazz Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Alberto Pappo, MD
The results of this study are very encouraging, and the investigators should be congratulated on the successful completion of such a large trial.
Based on my reading of the abstract, I could not recommend this regimen as being the standard of care for patients with intermediate-risk rhabdomyosarcoma. Although innovative, the concept of maintenance chemotherapy was piloted several decades ago by investigators of the Intergroup Rhabdomyosarcoma Study Group, where patients with high-risk disease received oral cyclophosphamide for up to 2 years.
This trial uses a shorter course of chemotherapy compared with the U.S. trials (27 weeks vs. 40-42 weeks) and review of the results from the COG D9803 trial show similar rates of survival between the arms. In addition, the latter study included 10% of patients with metastatic disease and a higher number of patients with unfavorable features, such as alveolar histology and age older than 10 years.
Reference:
Arndt CAS, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2009.22.3768.
Perspective
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Margaret von Mehren, MD
In this disease, where many are cured, the focus has been to adjust therapy based on risk. This study focuses on high-risk patients who are at greater risk for dying of their disease. We see meaningful improvements with maintenance therapy. An important question not yet answered is the long-term effects of maintenance cyclophosphamide and vinorelbine. In particular, cyclophosphamide is associated with risk for leukemia and myelodysplastic syndrome. There are data on cardiac toxicities, as well, with cyclophosphamide, although mostly in patients with pre-existent cardiac disease. Although this is unlikely for the patients in this study — who were all 21 aged years or younger — there remains a question of whether they will be at risk for greater issues as they age and develop problems with hypertension or related cardiac issues.
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