5-year Event-free Survival For Patients Research Articles

LMIC-15. OUTCOMES OF PEDIATRIC MEDULLOBLASTOMA IN LOW- AND MIDDLE-INCOME COUNTRIES: A REPORT OF 330 PATIENTS FROM 8 COUNTRIES

Abstract BACKGROUND AND AIMS Reports from low-and middle-income countries (LMICs) indicate lower survival in medulloblastoma (MB), though these studies are mainly from single institutions. This multi-institutional, retrospective study aimed to analyze the outcomes for MB in 9 centers in 8 LMICs. METHODS Patients <18 years old with newly diagnosed MB, treated from January 2014 to December 2018 in Egypt, El Salvador, Malaysia, Mexico, Pakistan, Peru, Philippines, and Uruguay were included. Data on demographics, clinical presentation, treatment and biological characteristics were collected. Factors associated with patient outcomes were analyzed. RESULTS The study included 330 patients with a median age of 7.7 years. Of these, 49 patients (15%) were <3 years old and 212 (64%) were male. Eighty-eight patients (26%) had experienced symptoms for >3 months at diagnosis. Gross total resection was achieved in 153 (47%) patients. Sixty-three patients (19%) experienced post-operative infections. Eighty-four patients (24%) had metastatic disease at diagnosis. The histologic subtype was not specified in 98 cases (30%), and 25 patients (7%) had molecular subgroups identified. Radiotherapy was administered to 216 patients (64%). The median number of chemotherapy cycles was 8 (range 0-14). There were 64 patients (19%) who abandoned treatment, and 24 patients (7%) died due to treatment-related toxicity. The 5-year event-free survival (EFS) was 44±4%, while the 5-year overall survival was 58±4%. The 5-year EFS for patients <3 years was 42±9%, while 44±4% for older patients (p=0.49). The 5-year EFS for patients with metastasis was 38±7%, while it was 46±4% for patients without metastasis (p=0.13). CONCLUSIONS This large, multinational cohort of MB in LMICs describes poor outcomes, which may be attributed to delays in care, high abandonment rate, surgical complications, treatment-related mortality and a low fraction of patients receiving radiotherapy. Interventions to build care capacity can be prioritized based on these data.

Relative Wash-In Rate in Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a New Prognostic Biomarker for Event-Free Survival in 82 Patients with Osteosarcoma: A Multicenter Study.

The decreased perfusion of osteosarcoma in dynamic contrast-enhanced (DCE) MRI, reflecting a good histological response to neoadjuvant chemotherapy, has been described. In this study, we aim to explore the potential of the relative wash-in rate as a prognostic factor for event-free survival (EFS). Skeletal high-grade osteosarcoma patients, treated in two tertiary referral centers between 2005 and 2022, were retrospectively included. The relative wash-in rate (rWIR) was determined with DCE-MRI before, after, or during the second cycle of chemotherapy (pre-resection). A previously determined cut-off was used to categorize patients, where rWIR < 2.3 was considered poor and rWIR ≥ 2.3 a good radiological response. EFS was defined as the time from resection to the first event: local recurrence, new metastases, or tumor-related death. EFS was estimated using Kaplan-Meier's methodology. Multivariate Cox proportional hazard model was used to estimate the effect of histological response and rWIR on EFS, adjusted for traditional prognostic factors. Eighty-two patients (median age: 17 years; IQR: 14-28) were included. The median follow-up duration was 11.8 years (95% CI: 11.0-12.7). During follow-up, 33 events occurred. Poor histological response was not significantly associated with EFS (HR: 1.8; 95% CI: 0.9-3.8), whereas a poor radiological response was associated with a worse EFS (HR: 2.4; 95% CI: 1.1-5.0). In a subpopulation without initial metastases, the binary assessment of rWIR approached statistical significance (HR: 2.3; 95% CI: 1.0-5.2), whereas its continuous evaluation demonstrated a significant association between higher rWIR and improved EFS (HR: 0.7; 95% CI: 0.5-0.9), underlining the effect of response to chemotherapy. The 2- and 5-year EFS for patients with a rWIR ≥ 2.3 were 85% and 75% versus 55% and 50% for patients with a rWIR < 2.3. The predicted poor chemo response with MRI (rWIR < 2.3) is associated with shorter EFS even when adjusted for known clinical covariates and shows similar results to histological response evaluation. rWIR is a potential tool for future response-based individualized healthcare in osteosarcoma patients before surgical resection.

Intensive chemotherapy with dual induction and ALL-like consolidation for childhood acute myeloid leukemia: a respective report from multiple centers in China.

Pediatric acute myeloid leukemia (AML) has poor prognosis and high rate of relapse and mortality, and exploration of new treatment options is still critically needed. To summarize the outcome of our new treatment strategies for pediatric AML, which is characterized by dual induction and acute lymphoblastic leukemia (ALL) elements consolidation. Retrospective, single-arm study. From July 2012 to December 2019, an intensive chemotherapy protocol was used for newly diagnosed children with AML, which contains dual induction, three courses of consolidations based on high-dose cytarabine, and two courses of consolidations composed of high-dose methotrexate, vincristine, asparaginase, and mercaptopurine (ALL-like elements). Blasts were monitored by bone marrow smears at intervals, and two lumbar punctures were performed during chemotherapy. We retrospectively analyzed the efficacy and safety of this study. The last follow-up was on 26 May 2023. A total of 70 pediatric AMLs were included. The median age at diagnosis was 6.7 (0.5-16.0) years. The median initial WBC count was 23.74 × 109/L, 11 of whom ⩾100 × 109/L. After dual induction, there were 62 cases of complete remission (CR), 5 cases of partial remission, and 3 cases of nonremission. The CR rate was 88.57%. The median follow-up time was 5.8 (0.2-9.4) years, the 5-year overall survival was 78.2% ± 5%, the event-free survival (EFS) was 71.2% ± 5.6%, and the cumulative recurrence rate was 27.75%. The 5-year EFS of patients with initial WBC < 100 × 109/L (n = 59) and ⩾100 × 109/L (n = 11) were 76.4% ± 5.7% and 45.5% ± 15% (p = 0.013), respectively. A total of 650 hospital infections occurred. The main causes of infection were respiratory tract infection (26.92%), septicemia (18.46%), stomatitis (11.85%), and skin and soft-tissue infection (10.46%). This intensive treatment protocol with dual induction and ALL-like elements is effective and safe for childhood AML. Initial WBC ⩾ 100 × 109/L was the only independent risk factor in this cohort. It is a retrospective study, and no registration on ClinicalTrials.gov.

Variant histology of pediatric nodular lymphocyte-predominant Hodgkin lymphoma with IgD and CD30 expression.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), recently known as nodular lymphocyte-predominant B-cell lymphoma (NLPBL), accounts for 5%-10% of Hodgkin lymphoma (HL). Different morphologic patterns of NLPBL are identified and categorized as typical patterns (type A and B) and variant histologic patterns (types C, D, E, and F). We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. Forty-six (53%) of the patients exhibited a typical histologic pattern, whereas the remaining (47%) exhibited variant histologic pattern. Variant histology is associated with unfavorable clinical characteristics, such as advanced stages, B-symptoms, and extranodal involvements, particularly bone marrow and bone infiltration, with p-values of .06, .05, and 0.01%, respectively. Additionally, 39% of patients with variant histology experienced disease progression or relapse, compared to only 15.2% of patients with typical patterns (p=.009). Types C and D are related to decreased event-free survival (EFS), as shown by a p-value of .05. The 5-year EFS for patients with variant histology was 94.4% for the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (RCHOP) versus 33.3% for the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). IgD expression in lymphocyte-predominant (LP) cells was detected in 44 (50%) patients, while CD30 expression in LP cells was found in 39 (44%) patients. Variant histology of NLPBL was associated with advanced disease stages and a poor prognosis, while expression of IgD and CD30 in LP cells was not. The poor outcome of variant histology improved with the RCHOP regimen.

Metabolic tumor parameters complement clinicopathological factors in prognosticating advanced stage Hodgkin Lymphoma.

Advanced Hodgkin Lymphoma has a higher probability of relapse and recurrence. Classical clinicopathological parameters including the International Prognostic Score (IPS) have not been reliable in predicting prognosis or tailoring treatment. Since FDG PET/CT is the standard of care in staging Hodgkin Lymphoma, this study attempted to evaluate the clinical utility of baseline metabolic tumor parameters in a cohort of advanced Hodgkin lymphoma (stage III and IV). Histology-proven advanced Hodgkin Patients presenting to our institute between 2012-2016 and treated with chemo-radiotherapy (ABVD / AEVD) were followed up till 2019. Quantitative PET/CT and clinicopathological parameters were used to estimate the Event Free Survival (EFS) in 100 patients. Kaplan-Meier method with log-rank test was used to compare the survival times of prognostic factors. At a median follow-up of 48.83 months (IQR:33.31-63.05 months), the five-year-EFS was 81%. Of the 100 patients, 16 had relapsed (16%) and none died at the last follow-up. On Univariate analysis, among non-PET parameters bulky disease (P=0.03) and B-symptoms (P=0.04) were significant while among PET/CT parameters SUVmax (p=0.001), SUVmean (P=0.002), WBMTV2.5 (P<0.001), WBMTV41% (P<0.001), WBTLG2.5 (P<0.001) and WBTLG41% (P <0.001) predicted poorer EFS. 5-year EFS for patients with low WBMTV2.5 [<1038.3 cm3] was 89% and 35% for patients with high WBMTV2.5 [≥1038.3 cm3] (p <0.001). In a multivariate model, only WBMTV2.5 (P=0.03) independently predicted poorer EFS. PET-based metabolic parameter (WBMTV2.5) was able to prognosticate and complement the classical clinical prognostic factors in advanced Hodgkin Lymphoma. This parameter could have a surrogate value for prognosticating advanced Hodgkin lymphoma. Better prognostication at baseline translates to tailored or risk-modified treatment and hence higher survival.

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia with High Tumor Burden Treated with BFM95-Based Protocol Combining Rituximab: A Report from Shanghai, China

The Berlin-Frankfurt-Münster (BFM) based protocols have been wildly used in children with non-Hodgkin lymphoma (NHL) and leukemia for more than ten years in China. At the same time, rituximab has become a standard medicine in the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) and relapsed or refractory B-cell NHL. In this study, we explored the efficacy of rituximab in childhood CD20 positive B-NHL and B-cell acute leukemia (B-AL).To explore the effect of rituximab in mature B-cell lymphoma (B-NHL)/mature B-cell leukemia ((B-AL) in children, this study included children and adolescents aged younger than 18 years with newly diagnosed CD20 positive, stage III/IV B-NHL/B-AL for treatment combining NHL-BFM95-based protocol with rituximab. A total of 4 injections with 375 mg/m2 rituximab each were administered intravenously after prephase V course at one day before the following 4 course of chemotherapy. Retrospective cases diagnosed with stage III/IV B-NHL/B-AL in our center were used as historical control. All of these patients were treated under NHL-BFM90 based protocol. Patient characteristics, event free survival (EFS), recurrence and mortality were analyzed.From April 2009 to December 2015, 46 patients were recruited and treated with rituximab combining BFM95-based protocol (R+BFM95 protocol). 23 cases diagnosed with stage III/IV B-NHL/B-AL from January 2005 to March 2009 treated with BFM90-based protocol. All patients followed till December 31, 2016. This study recruited 35 males and 11 females with an average age of 6.9 years who were treated with R+BFM95 protocol. Among the historical control of 23 patients treated with BFM90-based chemotherapy, 18 were males and 5 were females and the average age of our historical control was 7.2 years. Among patients treated with R+BMF95 protocol, the average duration of continuous complete remission (CR) was 3.6 years. Compared with patients treated with BFM90-based protocol, the 5-year event free survival (EFS) of patients under R+BMF95 was higher (83.7±5.7% vs 69.6%±9.6% in R+BMF95 and BFM90 respectively), however the difference was not statistically significant (P=0.1062). Among subgroups of our patients between patients treated with R+BMF95 and BFM90, the 5-year EFS of patients with stage III disease was 87.3±6.1% vs 77.8±9.8% (P=0.2998), stage IV subgroup was 72.7%±13.4% vs 40.0±21.9% (P=0.0878), respectively. Among patients whose LDH level were below 500 U/L at diagnosis, R+BFM95 protocol achieved 100% EFS during our follow-up, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3±7.4%, P=0.2994). Among patients had LDH >500 U/L at diagnosis, the 5-year EFS in R+BFM95 group was 77.2±7.7% and significantly higher than that of BFM90 group (40.0±15.5%, P=0.0048). In the patient group treated with R+BFM95, there were 2 (2/46, 4.3%) did not achieve CR. During the follow-up, recurrence occurred in 5 patients (5/46, 10.9%) including 2 partial remission (PR). Early death occurred in 1 patient (1/46, 2.2%) in the first course due to tumor lysis syndrome. Two cases with recurrence were treated with R-ICE regimen however remission did not occur. All patients with recurrent disease died. In the control patients treated with BFM90-based protocol, there were 3 (3/23, 13.0%) did not achieve CR. One patient did not respond to chemotherapy therefore received second-look operation however the pathology was positive and he died of disease progression. The other 2 patients give up treatment after 2 courses of chemotherapy. One patient (1/23, 4.3%) died in the first course because of sepsis. One patient with relapsed disease received R-ICE treatment however not achieved remission again. All patients with recurrent disease also died in BFM90 group.To summarize, our study demonstrated the feasibility of rituximab for Chinese children with B-NHL/B-AL. Rituximab improved the prognosis of Chinese B-NHL/B-AL children, especially among patients with LDH >500U/L. However, the limited number of patients and retrospective study design suggested further randomized trial with larger number of patients to confirm the efficacy, as well as cost-effectiveness of rituximab in childhood B-NHL/B-AL in China. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Stratified treatment of non-distant metastatic rhabdomyosarcoma in children: an analysis of its efficacy and prognostic factors

Objective To assess the efficacy of stratified treatment of pediatric non-distant metastatic rhabdomyosarcoma (RMS). Methods A retrospective review was conducted in 129 pediatric patients with non-distant metastatic RMS between January 2005 and December 2016 at Shanghai Children′s Medical Center Affiliated to Shanghai Jiaotong University School of Medicine.According to their pathological types, TNM stages and postoperative pathologic staging, the 129 patients were grouped a low-risk group, an intermediate-risk group and a high-risk group.Multimodality therapies were applied to all patients including chemotherapy, surgery and radiotherapy.The overall survival (OS) and event-free survival (EFS) rates were analyzed by using the Kaplan-Meier method. Results Of 129 patients, 119 cases were included in this study.In 119 patients, the age of onset for the RMS ranged from 7 to 191 months, with the median onset age of 48 months.The median follow-up time was 40 months for event-free patients with RMS, and 36 months for all the 119 patients.The 5-year OS and EFS for all patients were (92.1±2.9)% and (76.5±4.4)%, respectively.While the 5-year EFS for patients in the low-risk group, intermediate-risk group and high-risk group were all above 70%, and the difference among the three groups was not statistically significant (χ2=2.679, P=0.262). A subsequent univariate analysis revealed that the onset age for RMS (≤1 year old or≥10 years old), TNM stage and postoperative pathologic stage were important predictors of EFS with statistical significance (all P 0.05). The 5-year EFS of RMS patients with Forkhead Box Protein O1(FOXO1)-positive was significantly lower than that of FOXO1-negative patients [(56.3%±14.8)% vs.(83.3±15.2)%], and the difference was statistically significant (χ2=4.588, P=0.028). Conclusions It is important that the stratification treatment should be strictly implemented on RMS patients.First, further improvement is necessary for the treatment of patients in the low-risk group due to their poorer prognosis compared to that of their intermediate-risk counterparts, for whom one feasible option is to reduce the dose of chemotherapy drug.Furthermore, FOXO1 can be used as an indicator for poor prognosis, where stratified treatment is necessary for pediatric patients with RMS. Key words: Rhabdomyosarcoma; Stratification treatment; Prognosis; Child

Improved Outcome of Newly Diagnosed Childhood Mature B-Cell Lymphoma/Leukemia With High Tumor Burden Treated With BFM95-based Protocol Combining Rituximab: A Report From Shanghai, China.

In this study we evaluated children with newly diagnosed advanced (stage III and stage IV) mature B-cell non-Hodgkin lymphoma (B-NHL) or mature B-cell acute leukemia (B-AL), who were treated with Berlin-Frankfurt-Münster (BFM)95-based protocol combined with rituximab (R+BFM95). Our study recruited 46 patients who were treated with BFM95 protocol combined with rituximab. There are 23 patients as the historical control treated with BFM90 protocol. Compared with patients treated with BFM90 protocol, the 5-year event-free survival (EFS) rate of patients under R+BFM95 was higher (83.7%±5.7% vs. 69.6%±9.6%; P=0.1062). Among subgroups of our patients, the 5-year EFS of patients with stage III was 87.3%±6.1% vs. 77.8%±9.8% (P=0.2998), stage IV/B-AL was 72.7%±13.4% versus 40.0%±21.9% (P=0.0878) between patients treated with R+BFM95 and BFM90, respectively. Among patients whose lactate dehydrogenase (LDH) level were <500 U/L at diagnosis, R+BFM95 protocol reached 100% survival, nevertheless the 5-year EFS of patients in this group was not statistically different from that of patients treated with BFM90 (92.3%±7.4%; P=0.2994). Among patients had LDH≥500 U/L at diagnosis, the 5-year EFS in R+BFM95 group was 77.2%±7.7% (32 patients) and significantly higher than that of BFM90 group (40.0%±15.5%, 10 patients; P=0.0048). We found that rituximab has improved the EFS of childhood B-NHL/B-AL with LDH≥500U/L. Our results require validation from future studies with large cohort.

Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma

AbstractIn the present study, we evaluated the efficacy and safety of rituximab in combination with standard doxorubicin, bleomycin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lymphoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m2 weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respectively. The 5-year EFS for patients with stage III/IV cHLwas 82%. Furthermore, the 5-year EFS for patients with an International Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in patients with advanced-stage cHL. These data are currently being confirmed in a multicenter randomized trial. This trial has been completed and is registered with www.clinicaltrials.gov as NCT00504504.

Final Report of a Phase-II Study of Rituximab Plus ABVD for Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma.: Results of Long Follow up and Comparison to Institutional Historical Data.

Abstract 1680Poster Board I-706We previously reported (Wedgwood et al, ASH, 2007) improvement in event free survival (EFS) using Rituximab+ABVD (RABVD) in newly diagnosed patients with advanced stage classical Hodgkin lymphoma (HL) when compared to the previously published historical data from the International Prognostic Score (IPS) project using standard ABVD (Hasenclever et. Al, NEJM, 1998). The purpose of this report is to provide a final update on the EFS with long term follow up of patients who received RABVD. In addition, because of the potential difference in the EFS reported by the IPS project and a single institution results, we provide a new analysis comparing our RABVD data to that of historical data from our institution. After IRB approval, we conducted a retrospective data analysis on patients with advanced HL treated at our center with ABVD from February 1996 to May 2006. Information was collected for the IPS factors: age, stage, gender, hemoglobin, white blood cell count, albumin, and lymphocyte count. 104 consecutive patients who met the eligibility criteria for the RABVD study were identified, and were evaluable for response with at least 2 year follow up. Median age was 35 years old, 48 were female and 56 male. 23 (22%) had stage II disease, 12 of these with bulky disease, 45 (43%) stage III and 36 (35%) with stage IV. 65 (63%) had IPS 0-2 and 39 (37%) had IPS >2. The institutional 5-year EFS for ABVD patients regardless of IPS was 66%. For those with IPS 0-2 the institutional EFS was 71% compared with 74% reported by the IPS project. The institutional 5 year EFS for patients treated with ABVD with IPS >2 was 55%, compared with 55% reported by the IPS project. With a median of 5 year follow up (6-94 months) the projected EFS for RABVD is 87% which is significantly better than institutional results with ABVD (p=0.0036). Improvement in EFS was observed with RABVD in patients with IPS 0-2 (EFS 89% vs. 71%, p=0.0248); and those with IPS >2 (80% vs. 55%; p=0.0532). In conclusion, this long term follow up data confirms the superiority of RABVD to ABVD in patients with advanced stage classical HL in all risk groups. This data serves as the rationale for a multicenter randomized trial comparing ABVD with RABVD in newly diagnosed patients with classical HL with stage III and IV and IPS >2. The study is currently enrolling patients. DisclosuresOff Label Use: Rituximab in Hodgkin lymphoma. Younes:Genentech: Honoraria, Research Funding.

Secondary Cytogenetic Abnormalities and Outcome in Children with TEL-AML1-Positive Acute Lymphoblastic Leukemia.

The t(12;21) translocation, which results in the fusion of the TEL (ETV6) and AML1 (RUNX1) genes, is present in ~25% of pediatric B-precusor acute lymphoblastic leukemia (ALL) patients. Although initially thought to be a favorable prognostic indicator, the t(12;21) was associated with a similar rate of relapse as t(12;21)-negative pre-B ALL in subsequent studies. While secondary cytogenetic abnormalities are often present, their prognostic significance is unknown. The objective of this study is therefore to examine the type, frequency and prognostic impact of secondary cytogenetic abnormalites in t(12;21)-positive blasts of children with ALL. We studied retrospectively 56 patients diagnosed with t(12;21)-positive ALL at the Hospital for Sick Children between 2000–2005. The mean age at diagnosis was 4.9 years (range <1 to 12 years). Nine patients (16%) presented with a white blood cell count of greater than 50 × 109/L. Cytogenetic studies consisted of a combination of FISH, G-banding and spectral karyotyping. The most frequent secondary cytogenetic changes in patients with t(12;21)-positive ALL were: the deletion of the non-translocated TEL allele (38%), an extra copy of the TEL-AML1 fusion gene (14%). Additional numerical abnormalities were seen in approximately one-third of the cases, with the most common being a gain of chromosome 21(13%). Recurrent deletions of chromosomal regions 6q and 11q were observed (14%). A surprising degree of karyotypic complexity was noted. Three or more additional chromosome abnormalities, two abnormal clonal lines, and complex structural rearrangements involving TEL-AML1 were detected in 28%, 21%, and 9% of patients, respectively. Five children (9%) in this cohort have developed a relapse of ALL. The 5-year event-free survival (EFS) was 83±7%. The 5-year EFS for patients with a deleted second TEL allele or an extra TEL-AML1 fusion was not statistically different. Of note, 4 of the children who relapsed had high-risk features at presentation (NCI criteria). All were treated with chemotherapy protocols developed for lower risk ALL. The realization that TEL-AML1 does not always predict excellent prognosis indicates that an on-going study of patients and their survival, with detailed analysis of complex genetic changes, is necessary for a reliable assessment of the prognostic value of the t(12;21) in pediatric ALL.

A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346

Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewing’s sarcoma. Methods and Materials: Between 1983 and 1988, 184 children with Ewing’s sarcoma were enrolled onto Pediatric Oncology Group 8346 (POG 8346). A total of 178 (97%) met eligibility criteria; 6 had pathology other than Ewing’s sarcoma. Induction chemotherapy of cyclophosphamide/doxorubicin (adriamycin )(C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy and C/A, dactinomycin, and vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. Forty patients were randomized to receive SF, whole bone radiation to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy, and the remainder were assigned to IF radiation. Results: Of 178 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases at presentation. Their 5-year EFS was 51% (SE 5%) and 23% (SE 7%) respectively. The response rate to induction chemotherapy was 88% (28% complete, 60% partial), but after radiotherapy the response rate increased to 98%. Thirty-seven of the localized patients underwent resection, of whom 16 (43%) required postoperative radiotherapy; the 5-year EFS of these surgical patients was 80% (SE 7%). The remaining 104 localized patients were eligible for randomization or assignment to receive radiotherapy; the 5-year EFS of these patients was 41% (SE 5%), with no significant difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5-year EFS: distal extremity 65% (SE 8%), central 63% (SE 10%), proximal extremity 46% (SE 8%), and pelvic–sacral 24% (SE 10%) ( p = 0.004). Initial tumor size did not correlate significantly with EFS. Patterns of failure among the 141 localized patients revealed 23% of patients experienced a local failure, while 40% had a systemic failure. The 5-year local control rate for the surgical patients +/- postoperative radiotherapy was 88% (SE 6%), while for the patients undergoing radiotherapy alone it was 65% (SE 7%). There was no difference in local control between those randomized to SF vs. IF. The 5-year local control rate for the patients with pelvic–sacral tumors was 44% (SE 15%), significantly worse than the local control rates for those with central tumors 82% (SE 8%), distal extremity 80% (SE 8%), or proximal extremity 69% (SE 9%) ( p = 0.023). However, quality of radiotherapy correlated with outcome. Patients who had appropriate radiotherapy had a 5-year local control of 80% (SE 7%), while those with minor deviations had 5-year local control of 48% (SE 14%), and those with major deviations had a local control of only 16% (SE 15%) ( p = 0.005). The local failure was within an irradiated volume in 62% of patients, outside the irradiated volume in 24% of cases, while the precise location could not be determined in the remaining 14%. Conclusions: As most failures in Ewing’s sarcoma are systemic, improved EFS requires more effective systemic chemotherapy. Adequate IF radiotherapy requires treatment to appropriate volumes as defined by MRI imaging and full radiation doses. Pretreatment review of radiologic images with a musculoskeletal radiologist to determine appropriate tumor volumes, as well as use of conformal radiotherapy techniques are important for improved outcome.