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Ewing Sarcoma - new classification and Management.pptx

Management of Ewing Sarcoma (including New Classification) Ewing Sarcoma is a high-grade, undifferentiated small round cell tumor, primarily affecting children and young adults. In the 2020 WHO Classification of Soft Tissue and Bone Tumors, the term “Ewing Family of Tumors” has been retired. Instead, tumors are classified based on molecular alterations, specifically EWSR1/FUS::ETS fusion-positive sarcomas, primarily EWSR1::FLI1. Other tumors previously grouped under the ESFT umbrella (e.g., Ewing-like sarcomas with CIC or BCOR alterations) are now considered distinct entities due to their differing biology and clinical behavior. Management of Ewing Sarcoma is stage-dependent and requires a multimodal strategy: Localized Disease: Standard treatment begins with neoadjuvant chemotherapy, typically the VDC/IE regimen (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide). Following tumor shrinkage, local control is achieved through surgical resection when anatomically feasible, or radiotherapy if surgery poses significant morbidity. Adjuvant chemotherapy continues post-local therapy. With current strategies, 5-year survival exceeds 70% in localized cases. Metastatic Disease: Prognosis is poorer, particularly with bone or combined lung and bone metastases. Treatment mirrors that for localized disease, but may include whole-lung irradiation (for isolated lung metastasis) or intensified systemic therapy. High-dose chemotherapy with autologous stem cell rescue may be considered in selected patients. Recurrent Disease: Prognosis remains guarded. Salvage regimens include high-dose ifosfamide, topotecan/cyclophosphamide, or irinotecan/temozolomide. The rEECur trial supports high-dose ifosfamide as the preferred second-line agent. Molecularly targeted agents like cabozantinib and regorafenib have shown modest efficacy in phase II trials. Enrollment in clinical trials evaluating new modalities (e.g., PARP inhibitors, GD2-targeted therapies, immune checkpoint inhibitors) is encouraged. Advances in molecular diagnostics and risk stratification are driving more personalized therapeutic approaches. The revised classification underscores the need for accurate molecular testing to guide diagnosis and trial eligibility. Future efforts aim to integrate genomic profiling and immunotherapeutic strategies to improve outcomes in high-risk and relapsed patients.

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DR SUMIT KUMAR Assistant professor I ECMO NEIGRIHMS, Shillong No more ESFT, ASKIN, pPNET SECOND LINE CHEMO THIRD LINE CHEMO FURTHER LINE CHEMO
• Ewing Sarcoma is a malignant small round cell tumor. • It is defined by EWSR1 gene fusions, usually with FLI1. • The most common translocation is t(11;22)(q24;q12) (~85% of cases). • Rare fusions involve ERG, ETV1, ETV4, FEV, or FUS. • CD99 (MIC2) shows strong membrane expression in most cases. • Molecular testing is essential for diagnosis and classification. Introduction
• Mainly affects adolescents and young adults (AYA). • Incidence is about 1 case per 1.5 million annually. • Common sites: pelvis, femur, chest wall; often diaphyseal bone. • Extraosseous tumors occur in ~20% of cases. • Patients present with pain, swelling, and sometimes fever or fatigue. • Lab findings may show elevated LDH and leukocytosis. Introduction
• Prognosis is influenced by tumor location, size, metastasis, and treatment response. • Metastatic disease at diagnosis is the strongest negative predictor. Prognostic Factors in Ewing Sarcoma Favourable Factors Unfavourable Factors Peripheral/distal tumor site Axial (spine, sacrum) or pelvic location Tumor volume < 100 mL Tumor size > 8 cm No metastasis at diagnosis Metastases to bone or combined lung + bone ≥90% necrosis post-chemotherapy Poor histologic response (<90% necrosis) Normal LDH at baseline Elevated LDH Early, appropriate local therapy Delayed local treatment, adult age, low SES
️ 🖼️Essential Imaging Modalities MRI (Primary site) Best for assessing local extent Shows marrow infiltration, soft tissue mass, skip lesions CT Chest Detects lung metastases (commonest site) Used for baseline and restaging FDG-PET/CT (Preferred) Whole-body staging High sensitivity (96–100%) and Diagnostic Workup – Imaging Approach specificity (92–96%) May replace bone scan and bone marrow biopsy Bone Scan (if PET/CT not available) Identifies skeletal metastasis Shows increased uptake in involved bone MRI of Spine/Pelvis Alternative to PET for marrow evaluation Detects occult spinal/pelvic marrow disease
🔬 Histology & Immunohistochemistry (IHC) •Biopsy: Small round blue cell tumor •CD99: Strong membranous positivity (sensitive, not specific) •NKX2.2: Highly specific for Ewing Sarcoma •WT1/ETV4: Suggests CIC-rearranged sarcoma •BCOR/SATB2: Suggests BCOR-rearranged sarcoma ️ 🎞️Diagnostic Workup – Pathology & Molecular Testing Test Purpose / Target FISH Detects EWSR1 rearrangement RT-PCR Confirms EWSR1::FLI1, EWSR1::ERG fusions RNA Fusion Panel / NGS Detects rare fusions: CIC::DUX4, BCOR::CCNB3, EWSR1::NFATc2 CGP For fusion-negative or atypical cases 🧬 Molecular Testing (WHO 2020/2024)
Feature Pre-2020 2020 WHO 2024 WHO Classification Approach Morphology-based (CD99, histology) Molecular + histology Emphasis on NGS/RNA-seq Main Grouping Ewing Sarcoma Family of Tumors (ESFT) Term abolished Confirmed as obsolete Ewing Sarcoma Bone/soft tissue/pPNET/Askin variants Unified as one entity with EWSR1/FUS- ETS Same; fusion confirmation is essential Use of "Askin"/"pPNET" Commonly used Discouraged Officially obsolete Fusion Testing Not routine Recommended (FISH, RT-PCR) Strongly encouraged (NGS preferred) Evolution of WHO Classification – General Overview
Entity Pre-2020 2020 WHO 2024 WHO CIC-Rearranged Sarcoma Misclassified as Ewing New distinct subtype More data: WT1, ETV4 markers highlighted BCOR-Altered Sarcoma Not recognized Newly defined (BCOR::CCNB3) Broadened: includes MAML3, ITD, YWHAE fusions EWSR1-non-ETS Fusion Tumors Grouped under ESFT Identified separately (e.g., NFATc2, PATZ1) Further subclassified; distinct from Ewing Adamantinoma-like Ewing Variant of Ewing Included Now proposed as separate entity Round Cell Sarcoma (RCS) Broad label Interim term pending molecular results Not a final diagnosis – genetics mandatory Emerging Subtypes & Diagnostic Advances
Aspect Pre-2020 2020 WHO 2024 WHO Terminology Consistency Variable (Ewing, pPNET, Askin) Unified under “Ewing Sarcoma” Cleaner, location- based preferred Diagnostic Accuracy Prone to overlap/misdiagnosis Improved via fusion detection refined by adding epigenetic insights Treatment Implications Often same approach for all More precise due to distinct biology Distinct subtypes --- future therapy Research & Registry Clarity Difficult to compare studies Molecular criteria enable consistency Global classification Educational Value Confusing with overlapping terms Simplified aids training standardizes reporting Clinical and Practical Impact of the Changes
Subtype Chemo Sensitivity Prognosis Treatment Direction Ewing Sarcoma High (VDC/IE) Good– Intermediate Standard chemo + research on IGF1R/PARP inhibitors CIC-rearranged Sarcoma Low Poor Clinical trials, novel agents, immune therapy BCOR-altered Sarcoma Variable Intermediate Possibly chemo + future epigenetic/targeted therapy EWSR1-non-ETS Sarcoma Uncertain Varies Personalized therapy based on fusion Adamantinoma-like Ewing Unknown/low Unclear May need surgical-first or carcinoma-like approach Summary Table of Treatment Implications
AJCC staging
EWING SARCOMA - MANAGEMENT LOCALISED METASTATIC RECURRENT
•Total Duration: ~8–12 months •Goal: Multimodal cure – systemic + local therapy Ewing Sarcoma – Non-Metastatic: Standard Treatment Neoadjuvant Chemo (6 cycles VDC/IE, q2wk, ~9 weeks) Local Control: Surgery ± RT (45–55.8 Gy) Adjuvant Chemo: Continue VDC/IE to 14–17 cycles
Ewing sarcoma- Historical Timeline of Treatment Evolution 1921 🔹 Ewing Sarcoma first described by Dr. James Ewing 1950s–60s 🔹 Radiation therapy alone used 1981 🔹 CESS-81 Addition of ➤ doxorubicin (VACA regimen); improved survival 1977 🔹 CESS-77 (Germany) ➤ First multi- agent chemo (VA) + local control attempted 1988 🔹 INT-0091 (POG/CCG, USA) (📖 published 2003) VDC/IE alternating ➤ regimen → 5-yr EFS: 69% vs 54% ➤ Established VDC/IE as new standard of care 1992 🔹 EICESS-92 (Europe) (📖 2001) Added etoposide ➤ to VAIA → improved survival, reduced toxicity 2012 🔹 Euro-EWING 2012 (EE2012) (interim results ongoing) ➤ VIDE → VAI vs VDC/IE; compares efficacy, toxicity, and QoL 2001 🔹 AEWS0031 (COG) (📖 2009) ➤ Dose-dense VDC/IE (q2wk) vs standard q3wk → 3- yr EFS: 77% vs 65% 2020s–Present 🔹 Targeted therapy & Immunotherapy trials IGF-1R inhibitors, ➤ PARP inhibitors, and CAR-T under investigation 2015 🔹 AEWS1031 (📖 ~2021) Added ➤ topotecan/cyclophosp hamide → no additional benefit
Trial (Group) Treatment Arms Results / Impact IESS-I (USA, 1970s) VAC vs VAC + Dactinomycin Dactinomycin addition improved 5-yr survival significantly IESS-II (USA, 1980s) VAC + RT vs VAC + Act-D + RT Adding doxorubicin improved survival and local control CESS-81 (Germany) VAIA vs VAIA + high-dose Ifosfamide Intensified alkylator dose improved EFS and OS CESS-86 (Germany) Early local therapy vs delayed local therapy Delayed surgery allowed better response assessment; similar survival EICESS-92 (Europe) VAIA vs VAIA + Etoposide Etoposide addition improved 5-yr EFS and OS; became standard part of regimens INT-0091 (COG, USA) VDC vs alternating VDC/IE VDC/IE improved 5-yr EFS from 54% to 69%, now standard backbone AEWS0031 (COG, USA) VDC/IE q3wk vs q2wk (dose-dense) Dose-dense chemo improved 3-yr EFS from 65% to 77% without extra toxicity Chemotherapy Trials in Non-Metastatic Ewing Sarcoma
Trial (Group) Treatment Arms Results / Impact Euro-EWING99-R1 (Europe) VIDE → VAI vs VIDE → VAI + Busulfan/Melphalan High-dose consolidation improved survival in high-risk patients EE2012 (Europe) VIDE → VAI vs VDC/IE (American protocol) Ongoing trial comparing toxicity and efficacy; aims to maintain outcomes with less toxicity AEWS1031 (COG, USA) VDC/IE vs VDC/IE + Topotecan/Cyclophosphamide Experimental arm showed no improvement in EFS or OS INT-0154 (COG, USA) Standard chemo vs intensified ifosfamide doses Intensification showed no survival benefit IESS-III (USA) VAC + Dactinomycin + Doxorubicin + Ifosfamide Early trial supporting multi-agent chemo approach Chemotherapy Trials in Non-Metastatic Ewing Sarcoma
N Engl J Med 2003 Study: INT-0091 (CCG-7881/POG-8850) – Children’s Cancer Group & Pediatric Oncology Group Population: •Age ≤ 30 years. •Newly diagnosed Ewing Sarcoma or PNET of bone •N = 518 (398 non-metastatic, 120 metastatic) Arms: •Standard: VDC/AD (Vincristine, Doxorubicin, Cyclophosphamide ± Dactinomycin) •Experimental: VDC/AD alternating with Ifosfamide + Etoposide (IE) •Chemotherapy :- every three weeks for a total of 17 courses. •The duration of chemotherapy :---49 weeks. •Local Therapy:---at week 12
Parameter Standard Arm IE Arm (Ifosfamide + Etoposide) P-value Non-Metastatic Patients (n=398) 5-year Event-Free Survival (EFS) 54% 69% 0.005 5-year Overall Survival (OS) 61% 72% 0.01 Local Recurrence Rate 15% 5% <0.001 Systemic Recurrence Rate 21% 20% NS Metastatic Patients (n=120) 5-year Event-Free Survival (EFS) 22% 22% 0.81 5-year Overall Survival (OS) 35% 34% 0.43
Final Comment: •Non-Metastatic Ewing Sarcoma: IE significantly improves survival and local control but with increased toxicity and hospital stay. •Metastatic Ewing Sarcoma: No survival benefit from IE addition; prognosis remains poor.
EURO EWING 2012 Lancet 2022;400:1513-1521
Objective: To compare European (VIDE) vs. U.S. (VDC/IE) regimens in newly diagnosed Ewing Sarcoma patients across the U.S. and Europe. Design: •Type: Randomized controlled trial •Patients: 640 (ages 2–49 years) Outcome Arm A (VIDE) Arm B (VDC/IE) 3-year EFS 61% 67% Overall Survival Inferior Superior Grade 3–5 Febrile Neutropenia 74% 58% Final Comment: The VDC/IE regimen (U.S.) demonstrated superior efficacy in EFS and OS compared to the European VIDE regimen. Despite differing toxicity patterns, overall tolerability was comparable, favoring wider adoption of the VDC/IE protocol in Ewing Sarcoma
© 2008 by American Society of Clinical Oncology
Outcome VACA VAIA 3-year EFS (%) 73% 74% 5-year EFS (%) 67% 68% 3-year OS (%) 90% 86% 5-year OS (%) 82% 84% Standard-Risk (SR)Group Purpose: To evaluate if cyclophosphamide can replace ifosfamide in SR Ewing sarcoma patients. •Standard-risk: Localized disease, tumor volume ≤100 mL •Randomized Phase III trial…Sample size: 155 SR patients (VAIA: 76, VACA: 79) Interpretation: Survival outcomes were similar between both regimens, with no significant difference in event- free or overall survival. However, VACA was associated with increased grade 3–4 toxicity, including leukocytopenia, thrombocytopenia, mucositis, and infection. Ifosfamide remains preferable due to better tolerability.
Outcome EVAIA VAIA 3-year EFS (%) 52% 47% 5-year EFS (%) 52% 44% 3-year OS (%) 62% 59% 5-year OS (%) 57% 53% High-Risk Group Purpose:To assess if adding etoposide improves outcomes in high-risk (HR) Ewing sarcoma patients. Population & Design: High-risk: Metastatic disease and/or tumor volume >100 mL •Randomized Phase III trial………….Sample size: 492 HR patients (VAIA: 240, EVAIA: 252) Interpretation: EVAIA showed a modest improvement in both event-free and overall survival compared to VAIA. The benefit appeared more pronounced in non-metastatic patients. However, toxicity was higher in the EVAIA arm, with significantly increased rates of hematologic and mucosal side effects. Benefit-risk balance supports consideration of etoposide in selected high-risk patients.
Purpose: To evaluate whether VAC (cyclophosphamide-based) is non-inferior to VAI (ifosfamide-based) consolidation chemotherapy after good response to VIDE induction in standard-risk localized Ewing sarcoma. Study Type: Phase III, randomized, non-inferiority trial. •Patients: 856 total •Included: Localized Ewing sarcoma with good histologic response •Excluded: Metastatic or high-risk patients 2014 by American Society of Clinical Oncology
Outcome VAC VAI 3-year EFS (%) 75.4 78.2 3-year OS (%) 88.4 88.8 Local recurrence Similar Similar Secondary metastases Lower Higher Secondary malignancy Lower Higher Severe thrombocytopenia (%) 45 35 Renal toxicity (G2–4) Lower Higher Interpretation: VAC was statistically non-inferior to VAI. VAC had more hematologic toxicity, while VAI had more renal toxicity.
2018 by American Society of Clinical Oncology Objective: Evaluate whether consolidation with high-dose chemotherapy + autologous stem cell transplant (BuMel + ASCT) improves survival in high-risk localized Ewing Sarcoma. High-Risk Criteria for Randomization: •Poor histologic response (≥10% viable cells after induction) •Tumor volume ≥200 mL (unresected or resected) •Age < 50 years Study Design: •Induction: 6 cycles (VIDE) •Consolidation:BuMel + ASCT (n = 122)..Standard VAI x7 (n = 118) Enrollment Summary: •Total screened: 716…Randomized: 240 •78% enrolled due to poor histologic response
Outcome BuMel + ASCT VAI (Standard) 3-year EFS 69.0% 56.7% 8-year EFS 60.7% 47.1% 3-year OS 78.0% 72.2% 8-year OS 64.5% 55.6% Events 45 60 Deaths 37 53 Key Findings: •BuMel + ASCT significantly improved EFS and OS •Benefit mostly due to reduced distant metastases •Increased acute toxicity with BuMel (3 treatment-related deaths) •No major benefit variation by age, tumor site, or volume Conclusion: BuMel with ASCT offers a survival advantage in high-risk localized ES and may be a consolidation standard in selected patients.
🔍 Why Local Therapy is Critical •Microscopic disease often remains despite radiologic complete response. •Pathologic response can only be confirmed with resection. •Omission of local therapy increases risk of relapse (EURO-EWING 99, INT-0091). 🕒 When to Deliver Local Therapy •After neoadjuvant chemotherapy (typically 6 cycles of VIDE/VIDE-like regimen). •Typically between weeks 12–16 after starting systemic therapy. Local Therapy in Ewing Sarcoma – Rationale & Timing
🔧 Surgery •Preferred for resectable tumors with acceptable morbidity. •Common for extremity, chest wall, and pelvic sites. •Offers histological grading of response. •May be followed by RT if margins are inadequate or response is poor. Modalities of Local Therapy 📡 Radiotherapy •Indicated when surgery is not feasible (e.g., spine, sacrum, skull base). •Dose: • Definitive RT: 55.8–60 Gy • Post-op RT: 45–50.4 Gy •Pre-op RT (45 Gy) may improve resectability in borderline tumors.
📍 Indications for Post-op RT •Inadequate surgical margins (R1 or close margins). •Poor histologic response (≥10% viable tumor cells). •Intraoperative tumor spill or piecemeal excision. •Chest wall tumors (high local recurrence risk). 📖 Supporting Evidence •CESS/EICESS & EURO-EWING 99: Higher local failure without RT in above settings. •Children’s Oncology Group (COG) studies support RT in poor responders or marginal excision. •Retrospective studies: Surgery + RT → lower local failure than RT alone. Post-operative Radiotherapy – Indications & Evidence
Indication Rationale References Unresectable tumor at diagnosis Shrink tumor, enable limb-sparing or safer surgery Paulussen M et al., J Clin Oncol, 2008 Tumor in anatomically complex site (e.g., spine, pelvis, chest wall) Achieve negative margins, preserve function Puri A et al., J Bone Joint Surg Br, 2007 Close relationship to critical structures (e.g., vessels, nerves) Reduce size for safe dissection Ladenstein R et al., Lancet Oncol, 2010 Large tumor volume where resection could lead to major morbidity Downstage tumor, reduce surgical morbidity Grier HE et al., NEJM, 2003 Plan to avoid postoperative RT in case of good margins post-surgery Preop RT may avoid need for postop RT if R0 achieved EURO-EWING 99 Protocol Preoperative Radiotherapy in Ewing Sarcoma
Study Modality Compared Local Control Rate 5-yr EFS Key Findings CESS 86 Surgery vs RT vs Surgery+RT 100% / 86% / 95% No OS diff Surgery had better local control, but no OS benefit due to distant relapse. INT-0091 Surgery vs RT vs Surgery+RT 75% / 75% / 89.5% 42% / 52% / 47% Surgery+RT ↓ local failure, but no significant EFS/OS difference. CESS 81/86/EICESS Surgery±RT vs Definitive RT 92.5% vs 73.7% — Significantly lower local failure with surgery±RT (P = 0.001). COG analysis Definitive RT vs Surgery+RT 75% vs 93.7% — Higher risk of local failure with RT alone. EURO-EWING 99 With vs Without Local Therapy — 3-yr EFS: 45% vs 18% Omission of local therapy in metastatic disease ↓ survival. Local Therapy Outcomes in Ewing Sarcoma Conclusion: Surgery with or without RT offers superior local control. Definitive RT is effective in non-resectable sites but associated with higher local failure risk.
2023 by American Society of Clinical Oncology Design: Randomized, multicenter phase III trial Participants: 568 patients with newly diagnosed localized Ewing sarcoma Treatment Arms: •Standard-Timing Chemotherapy (STC): Vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) every 3 weeks •Interval-Compressed Chemotherapy (ICC): Same regimen administered every 2 weeks
Parameter ICC (Intensive Compressed) STC (Standard Timing) 10-Year Event-Free Survival (EFS) 70% 61% 10-Year Overall Survival (OS) 76% 69% Second Malignant Neoplasms (SMNs) 3.2% 4.2% Relapse/Progression (Years 6–10) 4 (out of 8 events) 4 (out of 8 events) Benefit in Large Tumors (≥200 mL) Yes (RHR = 0.45) No (RHR = 1.2) Benefit in Small Tumors (<200 mL) No significant benefit Histologic Response Subgroup No significant interaction Patients ≥18 Years Poor outcome despite ICC 10-Year EFS in NVT + ICC subgroup 91% post-local therapy – AEWS0031 Trial Results: ICC vs. STC (10-Year Follow-Up)
📌 Notes: •ICC involved more compressed cycles of VAC/IE compared to STC. •ICC particularly benefited patients with large tumor volumes (≥200 mL). •Second cancers (SMNs) occurred at similar rates across both groups. •Subgroup analysis revealed limited benefit in older patients (≥18 years), despite ICC.
•Micrometastases common at diagnosis → Not visible on scans •Surgery treats only local disease → High relapse without systemic therapy •Historical 5-year survival (surgery alone): <20% •With multiagent chemo: 5-year survival >70% •Chemo eradicates residual disease → Essential in multimodal treatment 💡 Systemic disease needs systemic therapy 🚫 No RCTs of surgery vs. surgery + chemo ✅ Strong historical + trial evidence supports chemo necessity 🧬 Why Surgery Alone Is Not Enough in Ewing Sarcoma
.Metastatic at diagnosis in ~25–30% of Ewing cases •Median age: 17 years •Most common metastatic sites: • Lung – 49.1% • Bone – 37.5% • Others: lymph nodes (7%), liver (3.8%), brain (2.7%) •95.3% received chemotherapy •3-year cause-specific survival (CSS): 56.1% Metastatic Ewing Sarcoma (De Novo Stage IV)
Factor Outcome Impact Bone metastasis ↓ CSS (HR 1.90, P = .002) Age ≥ 25 ↓ CSS (HR 2.21, P < .001) Lung metastasis No significant effect on CSS Multiple sites Worse 3-year CSS: 42.3% Single site Better 3-year CSS: 60.3% Prognostic Factors (Survival Impact) 🧬 Bone-only metastasis had significantly worse survival than lung-only 3-year CSS: 47.1% (bone) vs. 69.1% (lung)
•Bone metastasis = high-risk group → needs intensive therapy •Lung metastasis = relatively favorable → consider whole lung irradiation (WLI) •Age and number of metastatic sites are key risk stratifiers •Use metastatic site pattern for risk-based treatment planning and counseling 📌 Future research needed for site-adapted and biologically tailored therapies Clinical Implications & Takeaways
Induction chemotherapy (VDC/IE – ~6 cycles) Local control: • Surgery/RT of primary site • WLI for lung metastases Consolidation: chemo ± high-dose chemo + ASCT (select centers) Treatment Strategies in Metastatic Ewing Sarcoma •Total treatment duration: ~10–12 months 🔬 Trials ongoing for targeted agents & immunotherapy in high-risk subgroups
Study / Trial (yr) Intervention Key Findings / Impact EORTC-SIOP (1988) Chemo ± WLI No OS benefit in osteosarcoma; later reviews suggest selective benefit of WLI in Ewing sarcoma. EICESS-92 (1998) Chemotherapy ± WLI Patients receiving WLI showed a 12% improvement in 5- year overall survival. INT-0091 / CCG-7881 (2003) VAC vs. VAC/IE VAC/IE better for localized disease; metastatic subgroup trends favored VAC/IE. Euro-EWING 99 (2010) Induction chemo → HDCT + auto-SCT vs. standard chemo HDCT showed improved EFS; SCT is considered in select high-risk or metastatic cases. AEWS0031 (2012) Compressed vs. standard interval VAC/IE Compressed schedule improved event-free survival; now standard backbone. Systematic Review on WLI (2015) Chemo + WLI vs. Chemo alone Benefit of WLI in pulmonary metastases; especially post- chemotherapy responders. NCCN Guidelines (2022–2023) Surgery, RT, Chemo (28–49 weeks), WLI, SBRT Recommends multimodal treatment; WLI and SBRT for pulmonary/oligo-mets based on response. rEECur Trial (2023) Topotecan/cyclophosphamide vs. other agents Helped identify more effective salvage regimens for relapsed/metastatic Ewing sarcoma. Ongoing Trials (2020s) IGF-1R mAbs, CDK4/6 inhibitors, CAR-T, PARP inh. Early-phase results; promising for patients with relapsed or nonresponsive metastatic disease. 📊 Evidence in Metastatic Ewing Sarcoma
💨 Pulmonary Metastases: Whole Lung Irradiation (WLI) •Indicated for good responders to chemo. •EICESS-92: WLI + chemo = 12% OS gain •Dose: 15–18 Gy in 10–12 fx Radiation Therapy in Metastatic Ewing Sarcoma 🧩 Primary Tumor Local Control •RT is essential if surgery is not feasible. •Dose: 55.8–60 Gy in definitive cases. •Postoperative RT: For positive margins, poor response, or spillage. 🎯 Metastatic Site Control •Oligometastatic Disease: • SBRT/SRS offers high precision for lung, bone, soft tissue mets. • Dose: 24–40 Gy in 3–5 fx •Polymetastatic Disease: • Palliative RT for pain/neuro symptoms. • Dose: 20–30 Gy in 5–10 fx
Site RT Modality Dose Indication Primary tumor 3DCRT/IMRT/VMAT 55.8–60 Gy Inoperable or post-op positive margins Bone mets (oligo) SBRT 24–30 Gy in 3–5 fx Local control Bone mets (palliation) EBRT 20–30 Gy in 5–10 fx Symptom relief Lung mets WLI 15–18 Gy in 10–12 fx Chemo responder with good lung reserve CNS/Soft tissue mets SRS/SBRT 18–24 Gy in 1–3 fx Symptomatic or oligometastatic Spinal compression EBRT 8 Gy ×1 or 20–30 Gy/5– 10 Emergency decompression Practical RT Approach in Metastatic Ewing
Strahlenther Onkol 2008 · No. 4
EICESS-92 evaluated Whole Lung Irradiation (WLI) in Ewing tumor patients with exclusively pulmonary metastases. .99 patients (1990–1999), all with lung-only metastases at diagnosis •Treated with polychemotherapy (VAIA or EVAIA), local therapy, ± WLI •70 patients received WLI (dose: 12–21 Gy); 13 also received a thoracic boost (up to 54 Gy) Key Results: •5-year Overall Survival (OAS): • WLI group: 61% • No WLI group: 49% (p = 0.36) •5-year Event-Free Survival (EFS): • WLI: 39% • No WLI: 37% •Conclusion: Trend toward survival benefit with WLI, though not statistically significant •Pulmonary relapses: Not significantly different
Pulmonary Function Tests (PFTs) after WLI: •Out of 28 patients (no thoracic boost): • Normal: 43% • Mild impairment: 29% • Moderate: 21% • Severe: 7% •Patients with thoracic surgery had more lung toxicity (mean PFT grade: 1.3 vs. 0.6) Clinical Takeaways: ✅ WLI is safe and tolerable in most cases ✅ Best used in patients with good chemo response and no extrapulmonary disease Thoracic surgery and pre-existing lung issues may increase late pulmonary toxicity ⚠️ Should remain standard for patients with 🩺 exclusive lung mets WLI Toxicity & Clinical Implications (EICESS-92)
Relapsed or Refractory Disease in Ewing Sarcoma: 🧬 Relapse Incidence: •30–40% in initially localized cases •60–80% in metastatic disease at diagnosis 📉 Prognosis After Relapse: Generally poor •Favorable prognosis associated with: • Late relapse (≥ 2 years) • Lung-only metastases • Local recurrence amenable to surgery • Intensive chemotherapy ⚠️Adverse Prognostic Factors: •Early relapse (< 2 years from diagnosis) •Local + distant recurrence •Elevated LDH at initial diagnosis •Distant metastatic relapse
Relapsed or Refractory Disease in Ewing Sarcoma: 📊 Post-Relapse Survival Rates: • Local relapse: ~55% 5-year survival • Distant relapse: ~22% 5-year survival • Late relapse → better outcomes • Early relapse → worse outcomes 📌 Relapse Patterns: • ~70% of relapses are early • Two-thirds of early relapses at distant sites (lungs, bones) •Initial disease extent impacts pattern: • Localized → more local relapse • Metastatic → more distant relapse
Trial / Regimen Phase Drug(s) Key Outcome rEECur Trial II/III Ifosfamide vs. TC Ifosfamide had better EFS and OS than TC. Elraglusib Trial I/II Elraglusib ± Chemo 62% disease control; 2 CR Irinotecan + Temozolomide Retrospective Irinotecan + Temozolomide ORR 63%; TTP 8.3 months. Cyclophosphamide + Topotecan Retrospective Cyclophosphamide + Topotecan ORR 44%; 26% long-term remission. Vincristine + Irinotecan + Temozolomide Retrospective VIT ORR 68%; well-tolerated. Etoposide + Platinum Agent Retrospective Etoposide + Cis/Carboplatin Promising; further study suggested. HDT/HCT Single-center High-dose Chemo + Transplant Improved survival in select cases. CABONE Trial II Cabozantinib ORR 26%; OS 10.2 mths; PFS 4.4 mths. SARC024 Trial II Regorafenib PFR 63% at 8 weeks; OS 53 weeks. Docetaxel + Gemcitabine Retrospective Docetaxel + Gemcitabine ORR 29%; response ~5 months. ICE Regimen I/II Ifosfamide + Carboplatin + Etoposide ORR 51%. Lurbinectedin Study II Lurbinectedin ORR 14.3%; resp. duration 4.2 mths Relapsed/Refractory Ewing Sarcoma: Trial
2022 ASCO Annual Meeting II Regimen Outcome Summary IFOS Best EFS (5.7 mo) and OS (16.8 mo); favorable in <14 yrs TC (Topotecan + Cyclo) EFS 3.7 mo, OS 10.4 mo; more neutropenia, fewer renal AEs IT (Irinotecan + Temozolomide) Dropped early due to lower response and EFS GD (Gemcitabine + Docetaxel) Dropped early due to poor objective response and EFS Purpose: Identify the most effective chemotherapy regimen for RR-ES by comparing four commonly used options. .451 patients (age 4–50), median age 19 •Disease status: 18% refractory, 66% first relapse, 17% ≥2 relapses
Outcome Result Design Phase II, single-arm 6-month ORR (primary) 26% (partial only) Median PFS 4.4 months Median OS 10.2 months Metabolic Response 42% Common G3/4 AEs ↓Phos, ↑AST, HFS, pneumothorax, neutropenia Purpose: Evaluate cabozantinib in relapsed/refractory Ewing sarcoma. 39 patients, age ≥12, progressive disease, ECOG 0–1.
Lancet Oncol 2020
Purpose: To evaluate the efficacy and safety of regorafenib in patients with advanced Ewing sarcoma. 30 patients with metastatic Ewing family sarcomas, aged ≥18 years, ECOG performance status 0– 2, who had received at least one prior line of therapy and experienced disease progression within 6 months before enrollment. Key Results: •Median PFS: 14.8 weeks (95% CI: 7.3–15.9 weeks) •8-Week Progression-Free Rate (PFR): 63% (95% CI: 46–81%) •ORR: 10% •Median OS: 53 weeks (95% CI: 37–106 weeks) •Common Grade ≥3 Adverse Events: Hypophosphatemia, hypertension, elevated ALT levels •Conclusion: Regorafenib demonstrated modest activity in patients with advanced Ewing sarcoma, with a manageable safety profile. Further studies are warranted to explore its potential in this setting.
Cancer Med 2022 Aug 10
Purpose: Improve outcomes in first relapse or refractory setting. Population: Patients post first-line therapy (VDC/IE or similar). 🔹 Standard Regimens: •Topotecan + Cyclophosphamide (TC) – Widely used; ORR ~35–44%, median EFS ~3.7 mo •Irinotecan + Temozolomide (IT) – ORR ~63%, TTP ~8.3 mo •High-Dose Ifosfamide (IFOS) – Superior to TC in rEECur trial: Median OS: 16.8 mo (vs. TC 10.4 mo) ➤ Median EFS: 5.7 mo ➤ 🧪 Recommendation: IFOS preferred over TC based on rEECur Phase III trial. Second-Line Treatment in Ewing Sarcoma (RR-ES)
Indication: Progression after 2 prior lines. 🔹 VIT Regimen (Vincristine, Irinotecan, Temozolomide) – ORR: 68% (retrospective), well tolerated 🔹 Topotecan + Cyclophosphamide (if not used earlier) 🔹 Docetaxel + Gemcitabine (GD) – ORR: 29%, duration ~5 months 🔹 ICE (Ifosfamide, Carboplatin, Etoposide) – ORR: 51%, used selectively 🔍 Strategy: Try non-cross-resistant chemo combinations, consider prior toxicity. Third-Line Treatment Options
Indication: Refractory disease after ≥3 lines 🔬 Targeted & Experimental Therapies: •Cabozantinib (CABONE trial) – ORR: 26%, PFS: 4.4 mo, OS: 10.2 mo •Regorafenib (SARC024 trial) – PFR at 8 weeks: 63%, OS: 53 weeks •Lurbinectedin – ORR: 14.3%, Duration: ~4.2 mo 🧪 HDT + HCT (High-dose chemo + transplant) – Consider in select responsive cases 📌 Clinical Trial Enrollment Highly Recommended Further-Line & Investigational Therapies
.Classified as undifferentiated small round cell sarcoma (WHO 2020) •Defined by EWSR1::FLI1 or similar fusions •Localized: Neoadjuvant chemo → surgery ± RT → adjuvant chemo •Metastatic: Systemic chemo; lung mets better prognosis than bone/other sites •Recurrent: Options include high-dose ifosfamide, cabozantinib, regorafenib •Trials ongoing for targeted agents and immunotherapy •Treatment guided by risk, site, and response Ewing Sarcoma – Summary
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Ewing Sarcoma - new classification and Management.pptx

  • 1.
    DR SUMIT KUMAR Assistantprofessor I ECMO NEIGRIHMS, Shillong No more ESFT, ASKIN, pPNET SECOND LINE CHEMO THIRD LINE CHEMO FURTHER LINE CHEMO
  • 2.
    • Ewing Sarcomais a malignant small round cell tumor. • It is defined by EWSR1 gene fusions, usually with FLI1. • The most common translocation is t(11;22)(q24;q12) (~85% of cases). • Rare fusions involve ERG, ETV1, ETV4, FEV, or FUS. • CD99 (MIC2) shows strong membrane expression in most cases. • Molecular testing is essential for diagnosis and classification. Introduction
  • 3.
    • Mainly affectsadolescents and young adults (AYA). • Incidence is about 1 case per 1.5 million annually. • Common sites: pelvis, femur, chest wall; often diaphyseal bone. • Extraosseous tumors occur in ~20% of cases. • Patients present with pain, swelling, and sometimes fever or fatigue. • Lab findings may show elevated LDH and leukocytosis. Introduction
  • 4.
    • Prognosis isinfluenced by tumor location, size, metastasis, and treatment response. • Metastatic disease at diagnosis is the strongest negative predictor. Prognostic Factors in Ewing Sarcoma Favourable Factors Unfavourable Factors Peripheral/distal tumor site Axial (spine, sacrum) or pelvic location Tumor volume < 100 mL Tumor size > 8 cm No metastasis at diagnosis Metastases to bone or combined lung + bone ≥90% necrosis post-chemotherapy Poor histologic response (<90% necrosis) Normal LDH at baseline Elevated LDH Early, appropriate local therapy Delayed local treatment, adult age, low SES
  • 5.
    ️ 🖼️Essential Imaging Modalities MRI(Primary site) Best for assessing local extent Shows marrow infiltration, soft tissue mass, skip lesions CT Chest Detects lung metastases (commonest site) Used for baseline and restaging FDG-PET/CT (Preferred) Whole-body staging High sensitivity (96–100%) and Diagnostic Workup – Imaging Approach specificity (92–96%) May replace bone scan and bone marrow biopsy Bone Scan (if PET/CT not available) Identifies skeletal metastasis Shows increased uptake in involved bone MRI of Spine/Pelvis Alternative to PET for marrow evaluation Detects occult spinal/pelvic marrow disease
  • 6.
    🔬 Histology &Immunohistochemistry (IHC) •Biopsy: Small round blue cell tumor •CD99: Strong membranous positivity (sensitive, not specific) •NKX2.2: Highly specific for Ewing Sarcoma •WT1/ETV4: Suggests CIC-rearranged sarcoma •BCOR/SATB2: Suggests BCOR-rearranged sarcoma ️ 🎞️Diagnostic Workup – Pathology & Molecular Testing Test Purpose / Target FISH Detects EWSR1 rearrangement RT-PCR Confirms EWSR1::FLI1, EWSR1::ERG fusions RNA Fusion Panel / NGS Detects rare fusions: CIC::DUX4, BCOR::CCNB3, EWSR1::NFATc2 CGP For fusion-negative or atypical cases 🧬 Molecular Testing (WHO 2020/2024)
  • 7.
    Feature Pre-2020 2020WHO 2024 WHO Classification Approach Morphology-based (CD99, histology) Molecular + histology Emphasis on NGS/RNA-seq Main Grouping Ewing Sarcoma Family of Tumors (ESFT) Term abolished Confirmed as obsolete Ewing Sarcoma Bone/soft tissue/pPNET/Askin variants Unified as one entity with EWSR1/FUS- ETS Same; fusion confirmation is essential Use of "Askin"/"pPNET" Commonly used Discouraged Officially obsolete Fusion Testing Not routine Recommended (FISH, RT-PCR) Strongly encouraged (NGS preferred) Evolution of WHO Classification – General Overview
  • 8.
    Entity Pre-2020 2020WHO 2024 WHO CIC-Rearranged Sarcoma Misclassified as Ewing New distinct subtype More data: WT1, ETV4 markers highlighted BCOR-Altered Sarcoma Not recognized Newly defined (BCOR::CCNB3) Broadened: includes MAML3, ITD, YWHAE fusions EWSR1-non-ETS Fusion Tumors Grouped under ESFT Identified separately (e.g., NFATc2, PATZ1) Further subclassified; distinct from Ewing Adamantinoma-like Ewing Variant of Ewing Included Now proposed as separate entity Round Cell Sarcoma (RCS) Broad label Interim term pending molecular results Not a final diagnosis – genetics mandatory Emerging Subtypes & Diagnostic Advances
  • 10.
    Aspect Pre-2020 2020WHO 2024 WHO Terminology Consistency Variable (Ewing, pPNET, Askin) Unified under “Ewing Sarcoma” Cleaner, location- based preferred Diagnostic Accuracy Prone to overlap/misdiagnosis Improved via fusion detection refined by adding epigenetic insights Treatment Implications Often same approach for all More precise due to distinct biology Distinct subtypes --- future therapy Research & Registry Clarity Difficult to compare studies Molecular criteria enable consistency Global classification Educational Value Confusing with overlapping terms Simplified aids training standardizes reporting Clinical and Practical Impact of the Changes
  • 11.
    Subtype Chemo Sensitivity Prognosis Treatment Direction EwingSarcoma High (VDC/IE) Good– Intermediate Standard chemo + research on IGF1R/PARP inhibitors CIC-rearranged Sarcoma Low Poor Clinical trials, novel agents, immune therapy BCOR-altered Sarcoma Variable Intermediate Possibly chemo + future epigenetic/targeted therapy EWSR1-non-ETS Sarcoma Uncertain Varies Personalized therapy based on fusion Adamantinoma-like Ewing Unknown/low Unclear May need surgical-first or carcinoma-like approach Summary Table of Treatment Implications
  • 12.
  • 16.
    EWING SARCOMA -MANAGEMENT LOCALISED METASTATIC RECURRENT
  • 17.
    •Total Duration: ~8–12months •Goal: Multimodal cure – systemic + local therapy Ewing Sarcoma – Non-Metastatic: Standard Treatment Neoadjuvant Chemo (6 cycles VDC/IE, q2wk, ~9 weeks) Local Control: Surgery ± RT (45–55.8 Gy) Adjuvant Chemo: Continue VDC/IE to 14–17 cycles
  • 18.
    Ewing sarcoma- HistoricalTimeline of Treatment Evolution 1921 🔹 Ewing Sarcoma first described by Dr. James Ewing 1950s–60s 🔹 Radiation therapy alone used 1981 🔹 CESS-81 Addition of ➤ doxorubicin (VACA regimen); improved survival 1977 🔹 CESS-77 (Germany) ➤ First multi- agent chemo (VA) + local control attempted 1988 🔹 INT-0091 (POG/CCG, USA) (📖 published 2003) VDC/IE alternating ➤ regimen → 5-yr EFS: 69% vs 54% ➤ Established VDC/IE as new standard of care 1992 🔹 EICESS-92 (Europe) (📖 2001) Added etoposide ➤ to VAIA → improved survival, reduced toxicity 2012 🔹 Euro-EWING 2012 (EE2012) (interim results ongoing) ➤ VIDE → VAI vs VDC/IE; compares efficacy, toxicity, and QoL 2001 🔹 AEWS0031 (COG) (📖 2009) ➤ Dose-dense VDC/IE (q2wk) vs standard q3wk → 3- yr EFS: 77% vs 65% 2020s–Present 🔹 Targeted therapy & Immunotherapy trials IGF-1R inhibitors, ➤ PARP inhibitors, and CAR-T under investigation 2015 🔹 AEWS1031 (📖 ~2021) Added ➤ topotecan/cyclophosp hamide → no additional benefit
  • 19.
    Trial (Group) TreatmentArms Results / Impact IESS-I (USA, 1970s) VAC vs VAC + Dactinomycin Dactinomycin addition improved 5-yr survival significantly IESS-II (USA, 1980s) VAC + RT vs VAC + Act-D + RT Adding doxorubicin improved survival and local control CESS-81 (Germany) VAIA vs VAIA + high-dose Ifosfamide Intensified alkylator dose improved EFS and OS CESS-86 (Germany) Early local therapy vs delayed local therapy Delayed surgery allowed better response assessment; similar survival EICESS-92 (Europe) VAIA vs VAIA + Etoposide Etoposide addition improved 5-yr EFS and OS; became standard part of regimens INT-0091 (COG, USA) VDC vs alternating VDC/IE VDC/IE improved 5-yr EFS from 54% to 69%, now standard backbone AEWS0031 (COG, USA) VDC/IE q3wk vs q2wk (dose-dense) Dose-dense chemo improved 3-yr EFS from 65% to 77% without extra toxicity Chemotherapy Trials in Non-Metastatic Ewing Sarcoma
  • 20.
    Trial (Group) TreatmentArms Results / Impact Euro-EWING99-R1 (Europe) VIDE → VAI vs VIDE → VAI + Busulfan/Melphalan High-dose consolidation improved survival in high-risk patients EE2012 (Europe) VIDE → VAI vs VDC/IE (American protocol) Ongoing trial comparing toxicity and efficacy; aims to maintain outcomes with less toxicity AEWS1031 (COG, USA) VDC/IE vs VDC/IE + Topotecan/Cyclophosphamide Experimental arm showed no improvement in EFS or OS INT-0154 (COG, USA) Standard chemo vs intensified ifosfamide doses Intensification showed no survival benefit IESS-III (USA) VAC + Dactinomycin + Doxorubicin + Ifosfamide Early trial supporting multi-agent chemo approach Chemotherapy Trials in Non-Metastatic Ewing Sarcoma
  • 21.
    N Engl JMed 2003 Study: INT-0091 (CCG-7881/POG-8850) – Children’s Cancer Group & Pediatric Oncology Group Population: •Age ≤ 30 years. •Newly diagnosed Ewing Sarcoma or PNET of bone •N = 518 (398 non-metastatic, 120 metastatic) Arms: •Standard: VDC/AD (Vincristine, Doxorubicin, Cyclophosphamide ± Dactinomycin) •Experimental: VDC/AD alternating with Ifosfamide + Etoposide (IE) •Chemotherapy :- every three weeks for a total of 17 courses. •The duration of chemotherapy :---49 weeks. •Local Therapy:---at week 12
  • 22.
    Parameter Standard ArmIE Arm (Ifosfamide + Etoposide) P-value Non-Metastatic Patients (n=398) 5-year Event-Free Survival (EFS) 54% 69% 0.005 5-year Overall Survival (OS) 61% 72% 0.01 Local Recurrence Rate 15% 5% <0.001 Systemic Recurrence Rate 21% 20% NS Metastatic Patients (n=120) 5-year Event-Free Survival (EFS) 22% 22% 0.81 5-year Overall Survival (OS) 35% 34% 0.43
  • 23.
    Final Comment: •Non-Metastatic EwingSarcoma: IE significantly improves survival and local control but with increased toxicity and hospital stay. •Metastatic Ewing Sarcoma: No survival benefit from IE addition; prognosis remains poor.
  • 24.
  • 25.
    Objective: To compare European(VIDE) vs. U.S. (VDC/IE) regimens in newly diagnosed Ewing Sarcoma patients across the U.S. and Europe. Design: •Type: Randomized controlled trial •Patients: 640 (ages 2–49 years) Outcome Arm A (VIDE) Arm B (VDC/IE) 3-year EFS 61% 67% Overall Survival Inferior Superior Grade 3–5 Febrile Neutropenia 74% 58% Final Comment: The VDC/IE regimen (U.S.) demonstrated superior efficacy in EFS and OS compared to the European VIDE regimen. Despite differing toxicity patterns, overall tolerability was comparable, favoring wider adoption of the VDC/IE protocol in Ewing Sarcoma
  • 26.
    © 2008 byAmerican Society of Clinical Oncology
  • 27.
    Outcome VACA VAIA 3-yearEFS (%) 73% 74% 5-year EFS (%) 67% 68% 3-year OS (%) 90% 86% 5-year OS (%) 82% 84% Standard-Risk (SR)Group Purpose: To evaluate if cyclophosphamide can replace ifosfamide in SR Ewing sarcoma patients. •Standard-risk: Localized disease, tumor volume ≤100 mL •Randomized Phase III trial…Sample size: 155 SR patients (VAIA: 76, VACA: 79) Interpretation: Survival outcomes were similar between both regimens, with no significant difference in event- free or overall survival. However, VACA was associated with increased grade 3–4 toxicity, including leukocytopenia, thrombocytopenia, mucositis, and infection. Ifosfamide remains preferable due to better tolerability.
  • 28.
    Outcome EVAIA VAIA 3-yearEFS (%) 52% 47% 5-year EFS (%) 52% 44% 3-year OS (%) 62% 59% 5-year OS (%) 57% 53% High-Risk Group Purpose:To assess if adding etoposide improves outcomes in high-risk (HR) Ewing sarcoma patients. Population & Design: High-risk: Metastatic disease and/or tumor volume >100 mL •Randomized Phase III trial………….Sample size: 492 HR patients (VAIA: 240, EVAIA: 252) Interpretation: EVAIA showed a modest improvement in both event-free and overall survival compared to VAIA. The benefit appeared more pronounced in non-metastatic patients. However, toxicity was higher in the EVAIA arm, with significantly increased rates of hematologic and mucosal side effects. Benefit-risk balance supports consideration of etoposide in selected high-risk patients.
  • 30.
    Purpose: To evaluate whetherVAC (cyclophosphamide-based) is non-inferior to VAI (ifosfamide-based) consolidation chemotherapy after good response to VIDE induction in standard-risk localized Ewing sarcoma. Study Type: Phase III, randomized, non-inferiority trial. •Patients: 856 total •Included: Localized Ewing sarcoma with good histologic response •Excluded: Metastatic or high-risk patients 2014 by American Society of Clinical Oncology
  • 31.
    Outcome VAC VAI 3-yearEFS (%) 75.4 78.2 3-year OS (%) 88.4 88.8 Local recurrence Similar Similar Secondary metastases Lower Higher Secondary malignancy Lower Higher Severe thrombocytopenia (%) 45 35 Renal toxicity (G2–4) Lower Higher Interpretation: VAC was statistically non-inferior to VAI. VAC had more hematologic toxicity, while VAI had more renal toxicity.
  • 32.
    2018 by AmericanSociety of Clinical Oncology Objective: Evaluate whether consolidation with high-dose chemotherapy + autologous stem cell transplant (BuMel + ASCT) improves survival in high-risk localized Ewing Sarcoma. High-Risk Criteria for Randomization: •Poor histologic response (≥10% viable cells after induction) •Tumor volume ≥200 mL (unresected or resected) •Age < 50 years Study Design: •Induction: 6 cycles (VIDE) •Consolidation:BuMel + ASCT (n = 122)..Standard VAI x7 (n = 118) Enrollment Summary: •Total screened: 716…Randomized: 240 •78% enrolled due to poor histologic response
  • 33.
    Outcome BuMel +ASCT VAI (Standard) 3-year EFS 69.0% 56.7% 8-year EFS 60.7% 47.1% 3-year OS 78.0% 72.2% 8-year OS 64.5% 55.6% Events 45 60 Deaths 37 53 Key Findings: •BuMel + ASCT significantly improved EFS and OS •Benefit mostly due to reduced distant metastases •Increased acute toxicity with BuMel (3 treatment-related deaths) •No major benefit variation by age, tumor site, or volume Conclusion: BuMel with ASCT offers a survival advantage in high-risk localized ES and may be a consolidation standard in selected patients.
  • 34.
    🔍 Why LocalTherapy is Critical •Microscopic disease often remains despite radiologic complete response. •Pathologic response can only be confirmed with resection. •Omission of local therapy increases risk of relapse (EURO-EWING 99, INT-0091). 🕒 When to Deliver Local Therapy •After neoadjuvant chemotherapy (typically 6 cycles of VIDE/VIDE-like regimen). •Typically between weeks 12–16 after starting systemic therapy. Local Therapy in Ewing Sarcoma – Rationale & Timing
  • 35.
    🔧 Surgery •Preferred forresectable tumors with acceptable morbidity. •Common for extremity, chest wall, and pelvic sites. •Offers histological grading of response. •May be followed by RT if margins are inadequate or response is poor. Modalities of Local Therapy 📡 Radiotherapy •Indicated when surgery is not feasible (e.g., spine, sacrum, skull base). •Dose: • Definitive RT: 55.8–60 Gy • Post-op RT: 45–50.4 Gy •Pre-op RT (45 Gy) may improve resectability in borderline tumors.
  • 36.
    📍 Indications forPost-op RT •Inadequate surgical margins (R1 or close margins). •Poor histologic response (≥10% viable tumor cells). •Intraoperative tumor spill or piecemeal excision. •Chest wall tumors (high local recurrence risk). 📖 Supporting Evidence •CESS/EICESS & EURO-EWING 99: Higher local failure without RT in above settings. •Children’s Oncology Group (COG) studies support RT in poor responders or marginal excision. •Retrospective studies: Surgery + RT → lower local failure than RT alone. Post-operative Radiotherapy – Indications & Evidence
  • 37.
    Indication Rationale References Unresectabletumor at diagnosis Shrink tumor, enable limb-sparing or safer surgery Paulussen M et al., J Clin Oncol, 2008 Tumor in anatomically complex site (e.g., spine, pelvis, chest wall) Achieve negative margins, preserve function Puri A et al., J Bone Joint Surg Br, 2007 Close relationship to critical structures (e.g., vessels, nerves) Reduce size for safe dissection Ladenstein R et al., Lancet Oncol, 2010 Large tumor volume where resection could lead to major morbidity Downstage tumor, reduce surgical morbidity Grier HE et al., NEJM, 2003 Plan to avoid postoperative RT in case of good margins post-surgery Preop RT may avoid need for postop RT if R0 achieved EURO-EWING 99 Protocol Preoperative Radiotherapy in Ewing Sarcoma
  • 38.
    Study Modality Compared LocalControl Rate 5-yr EFS Key Findings CESS 86 Surgery vs RT vs Surgery+RT 100% / 86% / 95% No OS diff Surgery had better local control, but no OS benefit due to distant relapse. INT-0091 Surgery vs RT vs Surgery+RT 75% / 75% / 89.5% 42% / 52% / 47% Surgery+RT ↓ local failure, but no significant EFS/OS difference. CESS 81/86/EICESS Surgery±RT vs Definitive RT 92.5% vs 73.7% — Significantly lower local failure with surgery±RT (P = 0.001). COG analysis Definitive RT vs Surgery+RT 75% vs 93.7% — Higher risk of local failure with RT alone. EURO-EWING 99 With vs Without Local Therapy — 3-yr EFS: 45% vs 18% Omission of local therapy in metastatic disease ↓ survival. Local Therapy Outcomes in Ewing Sarcoma Conclusion: Surgery with or without RT offers superior local control. Definitive RT is effective in non-resectable sites but associated with higher local failure risk.
  • 39.
    2023 by AmericanSociety of Clinical Oncology Design: Randomized, multicenter phase III trial Participants: 568 patients with newly diagnosed localized Ewing sarcoma Treatment Arms: •Standard-Timing Chemotherapy (STC): Vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) every 3 weeks •Interval-Compressed Chemotherapy (ICC): Same regimen administered every 2 weeks
  • 40.
    Parameter ICC (IntensiveCompressed) STC (Standard Timing) 10-Year Event-Free Survival (EFS) 70% 61% 10-Year Overall Survival (OS) 76% 69% Second Malignant Neoplasms (SMNs) 3.2% 4.2% Relapse/Progression (Years 6–10) 4 (out of 8 events) 4 (out of 8 events) Benefit in Large Tumors (≥200 mL) Yes (RHR = 0.45) No (RHR = 1.2) Benefit in Small Tumors (<200 mL) No significant benefit Histologic Response Subgroup No significant interaction Patients ≥18 Years Poor outcome despite ICC 10-Year EFS in NVT + ICC subgroup 91% post-local therapy – AEWS0031 Trial Results: ICC vs. STC (10-Year Follow-Up)
  • 41.
    📌 Notes: •ICC involvedmore compressed cycles of VAC/IE compared to STC. •ICC particularly benefited patients with large tumor volumes (≥200 mL). •Second cancers (SMNs) occurred at similar rates across both groups. •Subgroup analysis revealed limited benefit in older patients (≥18 years), despite ICC.
  • 42.
    •Micrometastases common atdiagnosis → Not visible on scans •Surgery treats only local disease → High relapse without systemic therapy •Historical 5-year survival (surgery alone): <20% •With multiagent chemo: 5-year survival >70% •Chemo eradicates residual disease → Essential in multimodal treatment 💡 Systemic disease needs systemic therapy 🚫 No RCTs of surgery vs. surgery + chemo ✅ Strong historical + trial evidence supports chemo necessity 🧬 Why Surgery Alone Is Not Enough in Ewing Sarcoma
  • 43.
    .Metastatic at diagnosisin ~25–30% of Ewing cases •Median age: 17 years •Most common metastatic sites: • Lung – 49.1% • Bone – 37.5% • Others: lymph nodes (7%), liver (3.8%), brain (2.7%) •95.3% received chemotherapy •3-year cause-specific survival (CSS): 56.1% Metastatic Ewing Sarcoma (De Novo Stage IV)
  • 44.
    Factor Outcome Impact Bonemetastasis ↓ CSS (HR 1.90, P = .002) Age ≥ 25 ↓ CSS (HR 2.21, P < .001) Lung metastasis No significant effect on CSS Multiple sites Worse 3-year CSS: 42.3% Single site Better 3-year CSS: 60.3% Prognostic Factors (Survival Impact) 🧬 Bone-only metastasis had significantly worse survival than lung-only 3-year CSS: 47.1% (bone) vs. 69.1% (lung)
  • 45.
    •Bone metastasis =high-risk group → needs intensive therapy •Lung metastasis = relatively favorable → consider whole lung irradiation (WLI) •Age and number of metastatic sites are key risk stratifiers •Use metastatic site pattern for risk-based treatment planning and counseling 📌 Future research needed for site-adapted and biologically tailored therapies Clinical Implications & Takeaways
  • 46.
    Induction chemotherapy (VDC/IE – ~6cycles) Local control: • Surgery/RT of primary site • WLI for lung metastases Consolidation: chemo ± high-dose chemo + ASCT (select centers) Treatment Strategies in Metastatic Ewing Sarcoma •Total treatment duration: ~10–12 months 🔬 Trials ongoing for targeted agents & immunotherapy in high-risk subgroups
  • 47.
    Study / Trial(yr) Intervention Key Findings / Impact EORTC-SIOP (1988) Chemo ± WLI No OS benefit in osteosarcoma; later reviews suggest selective benefit of WLI in Ewing sarcoma. EICESS-92 (1998) Chemotherapy ± WLI Patients receiving WLI showed a 12% improvement in 5- year overall survival. INT-0091 / CCG-7881 (2003) VAC vs. VAC/IE VAC/IE better for localized disease; metastatic subgroup trends favored VAC/IE. Euro-EWING 99 (2010) Induction chemo → HDCT + auto-SCT vs. standard chemo HDCT showed improved EFS; SCT is considered in select high-risk or metastatic cases. AEWS0031 (2012) Compressed vs. standard interval VAC/IE Compressed schedule improved event-free survival; now standard backbone. Systematic Review on WLI (2015) Chemo + WLI vs. Chemo alone Benefit of WLI in pulmonary metastases; especially post- chemotherapy responders. NCCN Guidelines (2022–2023) Surgery, RT, Chemo (28–49 weeks), WLI, SBRT Recommends multimodal treatment; WLI and SBRT for pulmonary/oligo-mets based on response. rEECur Trial (2023) Topotecan/cyclophosphamide vs. other agents Helped identify more effective salvage regimens for relapsed/metastatic Ewing sarcoma. Ongoing Trials (2020s) IGF-1R mAbs, CDK4/6 inhibitors, CAR-T, PARP inh. Early-phase results; promising for patients with relapsed or nonresponsive metastatic disease. 📊 Evidence in Metastatic Ewing Sarcoma
  • 48.
    💨 Pulmonary Metastases:Whole Lung Irradiation (WLI) •Indicated for good responders to chemo. •EICESS-92: WLI + chemo = 12% OS gain •Dose: 15–18 Gy in 10–12 fx Radiation Therapy in Metastatic Ewing Sarcoma 🧩 Primary Tumor Local Control •RT is essential if surgery is not feasible. •Dose: 55.8–60 Gy in definitive cases. •Postoperative RT: For positive margins, poor response, or spillage. 🎯 Metastatic Site Control •Oligometastatic Disease: • SBRT/SRS offers high precision for lung, bone, soft tissue mets. • Dose: 24–40 Gy in 3–5 fx •Polymetastatic Disease: • Palliative RT for pain/neuro symptoms. • Dose: 20–30 Gy in 5–10 fx
  • 49.
    Site RT ModalityDose Indication Primary tumor 3DCRT/IMRT/VMAT 55.8–60 Gy Inoperable or post-op positive margins Bone mets (oligo) SBRT 24–30 Gy in 3–5 fx Local control Bone mets (palliation) EBRT 20–30 Gy in 5–10 fx Symptom relief Lung mets WLI 15–18 Gy in 10–12 fx Chemo responder with good lung reserve CNS/Soft tissue mets SRS/SBRT 18–24 Gy in 1–3 fx Symptomatic or oligometastatic Spinal compression EBRT 8 Gy ×1 or 20–30 Gy/5– 10 Emergency decompression Practical RT Approach in Metastatic Ewing
  • 50.
  • 51.
    EICESS-92 evaluated WholeLung Irradiation (WLI) in Ewing tumor patients with exclusively pulmonary metastases. .99 patients (1990–1999), all with lung-only metastases at diagnosis •Treated with polychemotherapy (VAIA or EVAIA), local therapy, ± WLI •70 patients received WLI (dose: 12–21 Gy); 13 also received a thoracic boost (up to 54 Gy) Key Results: •5-year Overall Survival (OAS): • WLI group: 61% • No WLI group: 49% (p = 0.36) •5-year Event-Free Survival (EFS): • WLI: 39% • No WLI: 37% •Conclusion: Trend toward survival benefit with WLI, though not statistically significant •Pulmonary relapses: Not significantly different
  • 52.
    Pulmonary Function Tests(PFTs) after WLI: •Out of 28 patients (no thoracic boost): • Normal: 43% • Mild impairment: 29% • Moderate: 21% • Severe: 7% •Patients with thoracic surgery had more lung toxicity (mean PFT grade: 1.3 vs. 0.6) Clinical Takeaways: ✅ WLI is safe and tolerable in most cases ✅ Best used in patients with good chemo response and no extrapulmonary disease Thoracic surgery and pre-existing lung issues may increase late pulmonary toxicity ⚠️ Should remain standard for patients with 🩺 exclusive lung mets WLI Toxicity & Clinical Implications (EICESS-92)
  • 53.
    Relapsed or RefractoryDisease in Ewing Sarcoma: 🧬 Relapse Incidence: •30–40% in initially localized cases •60–80% in metastatic disease at diagnosis 📉 Prognosis After Relapse: Generally poor •Favorable prognosis associated with: • Late relapse (≥ 2 years) • Lung-only metastases • Local recurrence amenable to surgery • Intensive chemotherapy ⚠️Adverse Prognostic Factors: •Early relapse (< 2 years from diagnosis) •Local + distant recurrence •Elevated LDH at initial diagnosis •Distant metastatic relapse
  • 54.
    Relapsed or RefractoryDisease in Ewing Sarcoma: 📊 Post-Relapse Survival Rates: • Local relapse: ~55% 5-year survival • Distant relapse: ~22% 5-year survival • Late relapse → better outcomes • Early relapse → worse outcomes 📌 Relapse Patterns: • ~70% of relapses are early • Two-thirds of early relapses at distant sites (lungs, bones) •Initial disease extent impacts pattern: • Localized → more local relapse • Metastatic → more distant relapse
  • 55.
    Trial / RegimenPhase Drug(s) Key Outcome rEECur Trial II/III Ifosfamide vs. TC Ifosfamide had better EFS and OS than TC. Elraglusib Trial I/II Elraglusib ± Chemo 62% disease control; 2 CR Irinotecan + Temozolomide Retrospective Irinotecan + Temozolomide ORR 63%; TTP 8.3 months. Cyclophosphamide + Topotecan Retrospective Cyclophosphamide + Topotecan ORR 44%; 26% long-term remission. Vincristine + Irinotecan + Temozolomide Retrospective VIT ORR 68%; well-tolerated. Etoposide + Platinum Agent Retrospective Etoposide + Cis/Carboplatin Promising; further study suggested. HDT/HCT Single-center High-dose Chemo + Transplant Improved survival in select cases. CABONE Trial II Cabozantinib ORR 26%; OS 10.2 mths; PFS 4.4 mths. SARC024 Trial II Regorafenib PFR 63% at 8 weeks; OS 53 weeks. Docetaxel + Gemcitabine Retrospective Docetaxel + Gemcitabine ORR 29%; response ~5 months. ICE Regimen I/II Ifosfamide + Carboplatin + Etoposide ORR 51%. Lurbinectedin Study II Lurbinectedin ORR 14.3%; resp. duration 4.2 mths Relapsed/Refractory Ewing Sarcoma: Trial
  • 56.
    2022 ASCO AnnualMeeting II Regimen Outcome Summary IFOS Best EFS (5.7 mo) and OS (16.8 mo); favorable in <14 yrs TC (Topotecan + Cyclo) EFS 3.7 mo, OS 10.4 mo; more neutropenia, fewer renal AEs IT (Irinotecan + Temozolomide) Dropped early due to lower response and EFS GD (Gemcitabine + Docetaxel) Dropped early due to poor objective response and EFS Purpose: Identify the most effective chemotherapy regimen for RR-ES by comparing four commonly used options. .451 patients (age 4–50), median age 19 •Disease status: 18% refractory, 66% first relapse, 17% ≥2 relapses
  • 57.
    Outcome Result Design PhaseII, single-arm 6-month ORR (primary) 26% (partial only) Median PFS 4.4 months Median OS 10.2 months Metabolic Response 42% Common G3/4 AEs ↓Phos, ↑AST, HFS, pneumothorax, neutropenia Purpose: Evaluate cabozantinib in relapsed/refractory Ewing sarcoma. 39 patients, age ≥12, progressive disease, ECOG 0–1.
  • 58.
  • 59.
    Purpose: To evaluatethe efficacy and safety of regorafenib in patients with advanced Ewing sarcoma. 30 patients with metastatic Ewing family sarcomas, aged ≥18 years, ECOG performance status 0– 2, who had received at least one prior line of therapy and experienced disease progression within 6 months before enrollment. Key Results: •Median PFS: 14.8 weeks (95% CI: 7.3–15.9 weeks) •8-Week Progression-Free Rate (PFR): 63% (95% CI: 46–81%) •ORR: 10% •Median OS: 53 weeks (95% CI: 37–106 weeks) •Common Grade ≥3 Adverse Events: Hypophosphatemia, hypertension, elevated ALT levels •Conclusion: Regorafenib demonstrated modest activity in patients with advanced Ewing sarcoma, with a manageable safety profile. Further studies are warranted to explore its potential in this setting.
  • 60.
  • 61.
    Purpose: Improve outcomesin first relapse or refractory setting. Population: Patients post first-line therapy (VDC/IE or similar). 🔹 Standard Regimens: •Topotecan + Cyclophosphamide (TC) – Widely used; ORR ~35–44%, median EFS ~3.7 mo •Irinotecan + Temozolomide (IT) – ORR ~63%, TTP ~8.3 mo •High-Dose Ifosfamide (IFOS) – Superior to TC in rEECur trial: Median OS: 16.8 mo (vs. TC 10.4 mo) ➤ Median EFS: 5.7 mo ➤ 🧪 Recommendation: IFOS preferred over TC based on rEECur Phase III trial. Second-Line Treatment in Ewing Sarcoma (RR-ES)
  • 62.
    Indication: Progression after2 prior lines. 🔹 VIT Regimen (Vincristine, Irinotecan, Temozolomide) – ORR: 68% (retrospective), well tolerated 🔹 Topotecan + Cyclophosphamide (if not used earlier) 🔹 Docetaxel + Gemcitabine (GD) – ORR: 29%, duration ~5 months 🔹 ICE (Ifosfamide, Carboplatin, Etoposide) – ORR: 51%, used selectively 🔍 Strategy: Try non-cross-resistant chemo combinations, consider prior toxicity. Third-Line Treatment Options
  • 63.
    Indication: Refractory diseaseafter ≥3 lines 🔬 Targeted & Experimental Therapies: •Cabozantinib (CABONE trial) – ORR: 26%, PFS: 4.4 mo, OS: 10.2 mo •Regorafenib (SARC024 trial) – PFR at 8 weeks: 63%, OS: 53 weeks •Lurbinectedin – ORR: 14.3%, Duration: ~4.2 mo 🧪 HDT + HCT (High-dose chemo + transplant) – Consider in select responsive cases 📌 Clinical Trial Enrollment Highly Recommended Further-Line & Investigational Therapies
  • 64.
    .Classified as undifferentiatedsmall round cell sarcoma (WHO 2020) •Defined by EWSR1::FLI1 or similar fusions •Localized: Neoadjuvant chemo → surgery ± RT → adjuvant chemo •Metastatic: Systemic chemo; lung mets better prognosis than bone/other sites •Recurrent: Options include high-dose ifosfamide, cabozantinib, regorafenib •Trials ongoing for targeted agents and immunotherapy •Treatment guided by risk, site, and response Ewing Sarcoma – Summary
  • 65.