Abstract
BackgroundPrevious studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re‐examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS.MethodsData from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low‐, intermediate‐ and high‐risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event‐free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross‐validated results.ResultsThe 5‐year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%).ConclusionsAfter metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.
Highlights
Rhabdomyosarcomas (RMS) constitute 40% of soft tissue sarcomas in children, with an incidence of 4.5 cases per million children and adolescents per year.[1]
The 5‐year event‐free survival (EFS) and overall survival (OS) for patients with localized disease (Group I, II, and III) were 73% and 84% compared to 30% and 42% for patients with metastatic disease (Group IV) (Figure 1; Table 3)
In this large cohort of contemporarily treated patients with RMS, incorporating FOXO1 fusion status into the risk stratification algorithm separated out a small group of patients with an excellent 5‐year EFS of 91%, characterized by favorable site, FOXO1 fusion‐negative status, and clinical group I disease
Summary
Rhabdomyosarcomas (RMS) constitute 40% of soft tissue sarcomas in children, with an incidence of 4.5 cases per million children and adolescents per year.[1]. Analysis of patient and disease characteristics of patients with nonmetastatic RMS treated on the third and fourth Intergroup Rhabdomyosarcoma Studies (IRS‐III and IRS‐IV) identified prognostic significance of histology, stage, clinical group, and primary site. Subsequent clinical studies from 1997 to 2004 divided patients into two low‐risk, one intermediate‐risk, and one high‐risk prognostic subgroups for treatment assignment.[2] Oberlin and colleagues performed a multivariate analysis of risk factors in 788 patients with metastatic RMS treated in nine studies performed by European and American cooperative groups from 1984 to 2000.3 Inferior event‐free survival (EFS) was correlated with age under 1 year or older than 10 years, unfavorable site of primary tumor (defined as extremity and “other” sites), presence of three or more sites of metastatic disease, and presence of bone or bone marrow involvement; histology was not independently associated with outcome. Our findings support incorporation of FOXO1 status in risk stratified clinical trials
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