Rodeberg, David A.

10012 Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]

10554 Background: Age at diagnosis is a prognostic factor in patients with RMS. We sought to determine whether AYA with metastatic alveolar (ARMS) or embryonal (ERMS) RMS had a different failure-free survival (FFS) compared to younger patients, and to identify treatment related factors that may be associated with outcome. Methods: COG ARST0431 patients were reviewed. The incidence of toxicities (AE, grade3/4 using CTCAEv3) by age was determined in 4 reporting periods (RP: wks 1-6; RP2:7-19; RP3: 20-34; RP4: 35-54). The AEs in younger patients (<=13 years) were compared with those in AYA. Fisher’s exact test was used to compare differences between the groups. Results: Of 109 patients, 60 (55%) were AYA. In RP1, they were more likely to have nausea/vomiting (4.1 vs. 16.9%, p=0.06), pain (6.1 vs. 20.3%, p=0.05), and metabolic disturbances (4.1 vs. 20.3%, p=0.02) compared to younger patients. In RP4, older patients trended to have less infection (15.8 vs. 30.1, p=0.07). All other toxicities were similar between the two age cohorts in the other RPs. AYA were less likely to complete therapy (52 vs. 73%, p=0.03) and more likely (in RP 4) to have unplanned dose modifications (outside of protocol guidelines) (23 vs. 2.7%). Of patients that completed therapy, there was no age-related difference in the time to completion. As shown in the table, younger patients had better 3-yr FFS, driven by a lower FFS for AYA with ARMS. Conclusions: This evaluation suggests that AYA with RMS were less likely to complete therapy and experienced a higher prevalence of pain and nausea compared to younger patients; the role of reporting bias and reasons for treatment discontinuation need further study. Children were more likely than AYA to have infection. Inferior FFS was only seen in AYA with ARMS suggesting a clear need for novel therapies for these patients. This study may be underpowered to demonstrate significant differences in other toxicities or in FFS among ERMS patients. [Table: see text]

Abstract Background Previous 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. Methods Data 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. Results The 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%). Conclusions After 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.

Background The objective of this study was to evaluate local control for patients with intermediate‐risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. Methods This study analyzed 424 patients with intermediate‐risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate‐risk study, D9803. Results For patients with group I/II alveolar RMS (n = 55), the 5‐year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% ( P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 ( P = .02). After adjustments for clinical prognostic factors, event‐free survival and overall survival were worse on ARST0531 ( P = .004 and P = .05, respectively). Conclusions Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m 2 ) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m 2 ) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.

AbstractBackgroundVaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed.ProcedureFrom 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty‐eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG).ResultsTen‐year event‐free (EFS) and overall survival (OS) were 74% (95% CI, 67–79%) and 92% (95% CI, 88–96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty‐one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery.ConclusionsAbout half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.

Purpose Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. Patients and Methods Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). Results One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. Conclusion Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.