Ewings sarcoma - Dr. Vandana


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Identified in 1921 by James Ewing
2nd most common bone tumor in children
Ewing’s Sarcoma Family of tumors:
Ewing’s sarcoma (Bone –87%)
Extraosseous Ewing’s sarcoma (8%)
Peripheral PNET(5%)
Askin’s tumor

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Ewings sarcoma - Dr. Vandana

  1. 1. Dr. VandanaDept of Radiotherapy,CSMMU, Lucknow
  2. 2.  Identified in 1921 by James Ewing 2nd most common bone tumor in children Ewing’s Sarcoma Family of tumors: ◦ Ewing’s sarcoma (Bone –87%) ◦ Extraosseous Ewing’s sarcoma (8%) ◦ Peripheral PNET(5%) ◦ Askin’s tumor 2
  3. 3. Epidemiology 2% of cancer childhood malignancy Occurs most commonly in 2nd decade ◦ 80% occur between ages 5 and 25 M:F 1.3:1 < 10 yrs 1.6:1 > 10 yrs Rare in African-Americans and Asians
  4. 4.  One of many ‘small round blue cell’ tumors seen in pediatrics Poorly differentiated tumor Unknown origin, Thought to be of neural crest progenitor cells origin
  5. 5.  Consistent cytogenetic abnormality, t(11;22)(q24;q12) present in 90-95% ◦ resultant fusion gene is EWS/FLI-1 Also seen: ◦ t(21;22)(q22;q12)  5-10% EWS/ERG ◦ t(7;22) and t(17;22)  the remainder EWS/ETV1 and EWS/E1AF respectively ◦ t(1;16)(q21;q13) present along with t(11;22) The c-myc protooncogene is frequently expressed in Ewing’s. CD 99 ( MIC2) PAS +ve
  6. 6. 1
  7. 7.  Pain & swelling of affected area May also have systemic symptoms: ◦ Fever ◦ Anemia ◦ Weight loss ◦ Elevated WBC & ESR,LDH Longest lag time in diagnosis for any pediatric solid tumor (mean of 146 days) Pathological fracture
  8. 8. Skull(3.8%) Scapula (3.8%) more common in diaphysis or metadiaphysis central axis (47%): ◦ pelvis, chest wall, spine, head & neck extremities (53%)
  9. 9.  direct extension into adjacent bone or soft tissue. Metastases generally spread through bloodstream 25% present with metastatic disease ◦ Lungs (38%) ◦ Bone (31%) ◦ Bone Marrow (11%) Nearly all pts. have micromets at diagnosis, so all Need chemo. Lung 13% Bone/BM 7 % Lu+Bone/BM 4 % Other 1 % No mets 75%
  10. 10.  No uniform staging system. The AJCC staging systems for bone or soft-tissue sarcomas may be used.
  11. 11. Primary tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Tumor 8 cm or less in greatest dimensionT2 Tumor more than 8 cm in greatest dimensionT3 Discontinuous tumors in the primary bone siteRegional lymph nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasisNote: Because of the rarity of lymph node involvement in bone sarcomas, thedesignation NX may not be appropriate and cases should be considered N0 unlessclinical node involvement is clearly evident.Distant metastasis (M)M0 No distant metastasisM1 Distant metastasisM1a LungM1b Other distant sites
  12. 12. IA T1 N0 M0 G1,2 low grade, GXIB T2 N0 M0 G1,2 low grade, GX T3N0 M0 G1,2 low grade, GXIIA T1 N0 M0 G3, 4 high gradeIIB T2 N0 M0 G3, 4 high gradeIII T3 N0 M0 G3, 4IVA Any T N0 M1a any GIVB Any T N1 any M any G Any T any N M1b any G
  13. 13. Disease factors Favorable prognosis Unfavorable prognosisSite Distal extremity (tibia, Central lesions (especially pelvic fibula, radius, ulna, bones) less favorable: proximal hands, feet) extremity (humerus, femur), ribsSize <8 cm in greatest Larger tumors diameter or <200 mL estimated volumeSoft tissue Absence of Presence of soft tissue extension byextension radiographically radiograph or significant extension identifiable soft tissue by computed tomography extensionExtent of Localized MetastaticdiseaseSite of Lung Bone / bone marrowMetastasis Both Lung and BoneResponse to CT Responsive Unresponsive
  14. 14. 14
  15. 15. Primary StagingHistory & Physical ExaminationHisto-pathology -Biopsy -Bone Marrow -Genetics -IHCImaging -X-ray -CT Thorax -CT scan -Bone scan -MRI -PET scanLab Test - Renal – RFT - Cardiac – 2D-ECHO
  16. 16.  Confirmation of diagnosis: ◦ biopsy and histopathologic examination  core needle / open Inx biopsy ◦ Cytogenetics and IHC
  17. 17.  X-RAY ◦ Moth eaten lesion ◦ Lytic or mixed lytic-sclerotic areas present ◦ Multi-Layered subperiosteal reaction (onion skinning) ◦ Lifting of perioteum (codman’s triangle) CT SCAN: bone destruction best seen  Intramedullary space  extraosseous involvement
  18. 18. 18
  19. 19.  Involvement detected by MRI extends beyond the anticipated area seen on plain X-ray Intra-medullary extent Soft tissue extension Skip lesions Relation Adjacent structures, vessels , nerves Multi-planar
  20. 20.  Bone scan: ◦ To detect polyostotic involvement ◦ to detect bone metastasis Bone marrow biopsy CXR/CT of chest: lung mets
  21. 21. Bone Scan: Ewing Sarcoma of Left Humerus demonstrates Intense UptakeFig: bone scan shows increased Gross Pathology: Ewing Sarcoma ofactivity in the distal femur. Metadiaphysis of Proximal Humerus. (Top arrow) Permeative Marrow Lesion. (Bottom arrow) Surrounding Soft Tissue Mass
  22. 22.  newer technique Under evaluation to detect ◦ local and distal extent, ◦ Predictor of outcome and recurrence
  23. 23.  Laboratory tests: ◦ CBC, Alkaline phosphatase, liver/kidney function tests, ◦ LDH:  useful as gauge of tumor burden  Falls with effective therapy and rises with disease recurrence
  24. 24.  Multidisciplinary approach ◦ Chemotherapy: control of micrometasis ◦ Surgery: local control where possible ◦ Radiotherapy: local control where surgery not possible or . incomplete 24
  25. 25.  Effective local and systemic chemotherapy necessary for cure. Induction chemotherapy preferred over starting the systemic and local therapy Advantage of this approach: ◦ Evaluation of effectiveness of the regimen ◦ Decreases the vol. of local therapy for surgery or RT ◦ Some bone healing occurs during CT, diminish the risk of pathological fracture
  26. 26. Local Control Maintenance Induction • Surgery • ChemotherapyChemotherapy • Radiotherapy
  27. 27. 27
  28. 28.  All patients require chemotherapy ◦ Induction chemotherapy ◦ Maintenance chemotherapy Effective chemotherapy has improved local control rates achieved with radiation to 85-90% 28
  29. 29.  First Line therapy: ◦ VAC/IE  Vincristine 2.0 mg/m2 on D1  Adriamycin 75 mg/m2 on D1  Cyclophosphamide 1.2 gm/m2 on D1  Ifosphamide 1.8 gm/m2 on D1-5  Etoposide 100 mg/m2 on D1-5 ◦ **Substitute adriamycin with dactinomycin (1.2 mg/m2 on D1) after 375 mg/m2 ◦ VAI (Vincristine, Adriamycin, Ifosphamide) ◦ VIDE ( Vincristine, ifosphamide, Doxorubicin, Etoposide) 29
  30. 30.  Cyclophosphamide (250 mg/m2)and topotecan(0.75 mg/m2) D1-D5 Temozolomide and irinotecan Ifosfamide and etoposide Ifosfamide ,etoposide and carboplatin Docetaxel and gemcitabine
  31. 31.  IESS-1and IESS-2 showed 4 drug regimen VACD is superior to 3 drug VAC in terms of RFS and OS. INT-OO91:Adding IE improved 5-year OS (61→72%) for localized disease, but not for metastatic disease (25%).
  32. 32.  Induction Multiagent chemotherapy for at least 12- 24 weeks prior to local therapy. Maintenance (adjuvant chemotherapy) with or without Radiotherapy is recommended following local control treatment and the duration of chemotherapy should be between 28-49 weeks.**NCCN guidelines version 2.2012
  33. 33. 34
  34. 34.  Development of Innovative Surgical Techniques: Limb preservation & Structural bone function preservation Chemo - cytoreduction makes resection possible Local failure rates with RT in historical series : 9 - 25% * Concern over second malignancies* Horonitz et al, Pediatr Clin Nor Am, 1991 35
  35. 35.  Surgical Indications ◦ Expendable bone (fibula, rib, clavicle) ◦ Bone defect able to be reconstructed with modest loss of function ◦ May consider amputation if considerable growth remaining ◦ After pre-op RT Limb-salvage surgery is preffered. Curative surgery requires wide local excision and negative margin ◦ Bony margins of at least 1 cm, with a 2 to 5 cm margin recommend. ◦ Soft tissue at least 5mm in fat or muscle , with 2mm through fascial planes. 36
  36. 36. 37
  37. 37.  radiation responsive tumor. There are no randomized trials that have directely compared Radiotherapy to surgery for local control of Ewing’s sarcoma. Radiotherapy can, in combination with chemotherapy, achieve local control, but complete surgery when feasible has to be regarded as the first choice of local therapy.****ESMO clinical practice Guidelines for diagnosis, treatment and follow-up for Bone sarcomas. Ref. Annals of Oncology 21 (Supplement 5) 13,2010
  38. 38.  Patient may be treated in supine ,prone, or lateral position site dependent. 6MV of energy used For limb, opposing fields normally used. Tailored portals for every patient. Field should not cross joints unless essential. Entire Medullary cavity need not be included in the RT portal. Try and spare a strip(1-2cm) of normal tissue for lymph drainage. 39
  39. 39. FIG. Changes in treatment volume. (A) Fieldencompassing the entire length of the medullary cavityfor a tumor involving the proximal left humerus. (B)Tailored field encompassing only the proximal aspect ofthe leg for a limited tumor of the left tibia.
  40. 40.  Definitive Radiation Therapy: ◦ Tumors where Resection is Impossible ◦ For skull, face, vertebra, or pelvic primary ◦ where only an intra-lesional resection is achievable ◦ Patient with poor Surgical risk ◦ Patient refusing surgery Note: Surgery is the preferred arm where wide or marginal resection is possible 42
  41. 41.  Pre-operative Radiation Therapy ◦ Indicated when narrow resection margins are expected ◦ Principle :  To sterilize the tumor compartment before surgery & to potentially reduce the risk of dissemination during surgery ◦ Local recurrence with pre-op RT  <5% EI-CESS-92 : Schuck et al – IJROBP-1998 & 2003 43
  42. 42.  Post-operative Radiation Therapy ◦ For gross or microscopic positive margin ◦ For marginal Resection ◦ For wide-resection with Poor Histological response to Neo- adjuvant Chemotherapy  (>10% viable tumor cells in the specimen) Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003 44
  43. 43.  Definitive RT ◦ Phase 1:  Gross tumor in bone and soft tissue (pre chemo ) + 2-4 cm longitudinal margins + 2 cm lateral margins.  Dose:45 Gy/180cGy/# ◦ Boost phase :  Reduced 1-2 cm margins(bone and residual tissue)  Up to total dose of 55.8Gy.Note: - In case of no soft tissue involvement, the proximal and distal margins in bone are not changed. 45
  44. 44. Figure: Schematic depiction of GTV1 (pre-induction bone and pre- induction soft tissue extent) and GTV2 (pre-induction and post- induction soft tissue extent)Pre-chemotherapy tumor Post-chemotherapy tumor
  45. 45.  Pretreatment gross tumor volume +surgical scar+2cm margin(45 Gy) boost to post op residual +2cm margin. Dose: ◦ MICROSCOPIC DISEASE- 45 Gy ◦ MACROSCOPIC RESIDUAL – 55.8Gy Pre op RT 45 Gy to original bone and soft tissue 47
  46. 46.  For rib primary ,with pleural effusion, RT to hemithorax For lung mets ,whole lung RT(15-18 Gy) or consider resection if< 4 mets. Pain palliation– advanced disease. Isolated bone secondaries. 48
  47. 47. Clinical Situation Total Dose (%) Dose per Fraction (%)Gross disease (afterbiopsy only or intralesionalresection) 1. Treatment once a Initial Field 45 1.8 day Boost field 10.8 1.8After marginal resection or 41.4 – 45 1.8poor histologic response atsurgeryPreoperative radiotherapy: 45 1.8 49
  48. 48.  If disease extension into pre-formed body cavities e.g. lung & pelvis, radiotherapy volume includes post induction volume with 2cm margin in order to reduce treatment related toxicity. Lesion of vertebral body treated with 45Gy to 50.4Gy More than 20 Gy can prematurely close epiphysis. 20–30 Gy usually can be given to entire circumference of an extremity, doesn’t cause lymphedema.
  49. 49. Physical Exam, Local and ChestImaging:• Every 2- 3 months• Increase interval after 24 months• Annually after 5 years indefinitelyCBC and other lab studies asindicatedConsider Bone Scan or Pet scan 51
  50. 50.  30-40% of patients develop relapse with <20% survival Early relapse – less than 2 years:  Consider Changing Chemotherapy Late relapse – more than 2 years:  Continue the previously used chemotherapy 52
  51. 51.  Functional results : Of all the patient’s treated with RT ◦ 60 % have good functional activity ◦ 20 % have mild morbidities ◦ 20 % have significant morbidities Risk for Post treatment Fractures Lymphedema Dermatitis; recall reaction may occur with doxo, dactinomycin. Adriamycin cardiomyopathy. Ifosphamide renal toxicity. 53
  52. 52.  Second malignancy after RT ◦ Cumulative risk at 15yrs = 6 – 6.7% ( CESS-81 & CESS-86; IJROBP:1997; 39) ◦ No secondary sarcomas seen at doses <48 Gy ( Kutterch et al; JCO:1996, 14 ) ◦ Risk increased by anthracycline and alkylating agent chemotherapy ◦ Osteosarcoma most common. ◦ Leukemia can also occur. 54
  53. 53.  Use of 3D-CRT / IMRT as a standard protocol Incorporation of functional imaging modalities e.g. PET- CT / PET-MRI for Target Volume delineation, Boost treatment and IMRT TARGATED therapy :Molecular agents like Apoptosis directed targeted therapies e.g. TRAIL therapy (TNF Related Apoptosis Inducing Ligand),anti IGF-1R antibodies…etc 55
  54. 54.  Second most common childhood bone tumor. Small round cell tumor with CD99 (MIC2), PAS positive Lytic lesion with onion peel appearance on X-Ray Overall survival with localized disease (55%) and metastatic disease 22% Multimodal treatment approach Induction Chemotherapy for 3-6 cycles and another 6- 10 cycles for maintenance. Surgery when feasible first choice of local therapy Radiation responsive tumor There are no randomized trials that have directely compared Radiotherapy to surgery for local control of Ewing’s sarcoma.