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Definitive Radiotherapy in Patients with Localized Ewing’s Sarcoma

Definitive Radiotherapy in Patients with Localized Ewing’s Sarcoma. Matthew Krasin, M.D. Assistant Member Department Of Radiation Oncology St. Jude Children’s Research Hospital Memphis, TN. History.

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Definitive Radiotherapy in Patients with Localized Ewing’s Sarcoma

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  1. Definitive Radiotherapy in Patients with Localized Ewing’s Sarcoma Matthew Krasin, M.D. Assistant Member Department Of Radiation Oncology St. Jude Children’s Research Hospital Memphis, TN

  2. History • CH is an otherwise healthy 15-year old male from Kentucky who in Sept. 2002 began experiencing pain localized to the posterior aspect of his neck and upper thoracic spine • Continued until the end of Oct. when he demonstrated, over 2-3 days, • Progressive left upper and lower extremity weakness • Urinary and bowel retention

  3. History • PMH and PSxH – unremarkable • FMH – non-contributory • Soc – 9th grade straight A student. Denies tobacco or alcohol use. • All – Amoxicillin • ROS – otherwise negative

  4. Imaging

  5. Surgery • 11/2/02 • “A lateral mass could be seen destroying the T1 spinous process...” • T1 laminectomy and facetectomy and partial laminectomy of T2 and C7 with a gross total removal of primary tumor involving the T1 lamina and spinous process with cord compression

  6. CD99 Negative for actin, desmin, myogenin, synaptophysin, and neuron specific enolase Thoracic spine, biopsy of tumor: Ewing sarcoma family of tumors

  7. Referral to SJCRH • Mild postoperative pain • Resolution of urinary and bowel retention • Healing incision • Good range of motion of the neck • Improved strength in the left extremities (4+/5)

  8. Work Up • Chest CT (11/8/02) – postoperative changes and otherwise unremarkable • Spine MRI (11/8/02) – removal of the soft tissue tumor with residual tumor present in the body of T1 • Bone scan (11/8/02) – unremarkable • BM aspirates and biopsies (11/11/02) – no evidence of metastasis

  9. Treatment • Chemotherapy • 12 weeks of VAC alternating with IE • Radiotherapy (on RT-SARC) • 54 Gy in 30 fractions from 2/13-3/27/03 • Off cord at 45 Gy • Developed esophagitis and grade II skin reaction

  10. Local Management of Ewing’s Sarcoma • Objectives for session • Review the role of radiotherapy in the management of localized Ewing’s sarcoma and relevant data to support its efficacy • Discuss toxicities of radiotherapy in the local management of Ewing’s sarcoma • Discuss the current status of radiotherapy treatment planning and delivery and its potential to change the toxicity profile for local management of Ewing’s sarcoma.

  11. Current Recommendations for Delivery of Radiation • Volume • Initial - 2 cm treatment margin around the pre-induction therapy bony and soft tissue tumor • Boost - 2 cm treatment margin around the pre-induction therapy bony and post-induction therapy soft tissue tumor • Dose • Initial - 4500 cGy / 180 cGy fxn / 25 fxn delivered daily • Boost - 1080 cGy / 180 cGy fxn / 10 fxn (5580 cGy cumulative) delivered daily

  12. Traditional Treatment Fields and Beam Arrangements

  13. What are the Endpoints to Measure Successful Management • Survival • Straightforward to measure • Limited utility in tumors with high incidence of metastases and moderate levels of survival • Relapse-Free or Event-Free Survival • Straightforward to measure • Only detects effects of local modality if local control is a significant component of failures • Local Control • Measures directly the effects of local treatment • May also measure contribution of systemic therapy • Difficult to measure as is dependent on exam and imaging (unless biopsy obtained)

  14. Defining Local Control • Failure within the treatment field or tumor bed • Measures the effect of treatment actually delivered • Failures outside the treatment field are considered distant • Regional failure • Nodal failure • Marginal failure outside the treated volume • May be considered as local failure if treatment volume is a study question

  15. Local Control in Cooperative Group Studies Study Years Chemotherapy LC Resection IESS II (Burgert, JCO ‘90) 78-82 VACA Non-Pelvis91% 27% Pelvis88% 19% POG 8346 83-88 VACA 77% 26% (Donaldson, IJRO ‘98) SE-91 CNR (Rosito, Ca ‘99) 91-97 VAC-VAI-EI 93% 72% SSG IX (Elomaa, EJC ‘00) 90-99 VAI/PAI 87% 66% POG 8850 (Grier, NEJM ’03) 88-92 VAC/IE 93% 61% EI/CESS 86-99 86-91 VACA/VAIA 90% 76% (Schuck, IJROBP ‘03)

  16. Local Control in Prospective Institutional Studies Study Years Chemotherapy LC Resection NCI-S2-4(Kinsella, IJRO ‘89) 68-80 VC/VAC/VAdrC 84% 0% NCI 86C (Wexler, Ca ‘96) 86-92 VAC-1E 74% ~8% EW 79 (Arai, IJRO ‘91) 78-88 VACA 68% 28% EW 87 (Meyer, JCO ‘92) 87-92 IE-CAdr-AV 76% 20% EW 92 (Marina, JCO ‘99) 92-96 IECAdr-VA-IE-CA 88% 62%

  17. Prognostic Value of Tumor Site and Size Pelvic Site Non-Pelvic Site Study LC LC IESS I 73% 86% POG 8346 44% 69-82% CESS 86 82% 91% ET-1 67% 80% ET-2 21% 71% Study Tumor Size / Volume Local Control POG 8346 8, 10, 12, 15 cm n.s. CESS 86 < 100 cc < n.s. EW 88 (SFOP) < 100 cc < 88% vs 70% NCI 86C cm n.s.. EW 79 < 8 cm < 94% vs 56% EW 92 < 8 cm < n.s.

  18. Local Control by Treatment Modality Study Proportion Pelvic Site POG 8346 Surgery 8% Radiation 20% EI/CESS 81-92 Surgery 12% Radiation 34% SE 91 CNR Surgery 4% Radiation 39% ET-2 Surgery 32% Radiation 71%

  19. Local Control by Treatment Modality Study LC POG 8346 Surgery >85% Radiation 65% CESS 86 Surgery 96% Radiation 74% SE 91 CNR Surgery 93% Radiation 94% ET-2 Surgery 88% Radiation 87%

  20. St. Jude Institutional Experience with Definitive XRT for Localized ESFT (’80-’00) Median age 13.3 yrs. Site Bone 70 Systemic Rx VACA 38 Soft Tissue 12 VAC/IE 44 Site Extremity/H&N 39 RT Dose Low 45 Central 43 Standard 37 Size <8cm 38 ≥8cm 44 Total treated with definitive RT 82 Total localized ESFT treated 157

  21. Local Tumor Control with Definitive XRT 5 yr LTC 70%

  22. Local Tumor Control by Tumor Site Central 76% Ext/H&N 63%

  23. Local Tumor Control by Osseus / Extra-Osseus Primary Site Soft tissue 70% Bone 70%

  24. Local Tumor Control by Initial Tumor Size P=0.004 <8cm 85% ≥8cm 56%

  25. Local Tumor Control by XRT Dose Std Dose (>50Gy) 67% Low Dose (<50Gy) 71%

  26. Local Tumor Control by XRT Dose and Size Std Dose, <8cm 94% P=0.04 Low Dose <8cm 81% Low Dose, ≥8cm 61% Std Dose, ≥8cm 48%

  27. Caveats to Local Tumor ControlQuality Assurance in Radiation Planning and Delivery • Limited numbers of osseous Ewing’s sarcoma preclude a large clinical experience for most radiation oncologists. • 250 cases ESFT / year in U.S. • ~180 cases are localized • ~70 cases require definitive XRT • ~250 COG sites • Treatment planning becomes a greater factor in local control as target volumes decrease in size. • Two studies demonstrate this effect in decreased local control rates.

  28. Quality Assurance in Radiation Planning and Delivery • CESS experience • Local control with radiation alone increased from 50% in CESS 81 to 87% in CESS 86. • Central treatment planning may in part be responsible for this improvement • POG 8346 experience (Donaldson, IJRO ‘98)

  29. Treatment Related Effects of Local Radiotherapy for ESFT • Bone Effects • Growth • Ablation of a non-fused epiphysis • Long bone curvatures • Flat bone volume • Fractures • Soft Tissue Effects • Muscle atrophy or hypoplasia • Secondary Malignancies

  30. Bone Growth Effects • Growth • Long bones • Limb length discrepancy of 3.88 cm in pubertal age children (10-16 yrs.) treated for Ewing’s sarcoma with radiation (Bolek, ‘96) • Treatment volumes often included one or both epiphyses • Spine • Volume of treatment and dose above 33 Gy correlate with stature loss in pediatric Hodgkin’s disease patients • Pre-pubertal children suffered the largest deficits (Willman, ‘93) • Craniofacial Skeleton • Children with NPC and craniofacial RMS were found to significantly smaller craniofacial measurements compared to normal subjects documented by Waitzman (Denys, ‘98)

  31. Fractures Series Pts Dose Fractures U. of Florida (Bolek, ‘96) 31 55-68 Gy 5/31 (16%) St. Jude (Wagner, ‘01) 93 47-68 Gy 9/93 (10%) • Etiology of fractures is multifactorial and relates to location, surgical history, tumor growth, and irradiation.

  32. Soft Tissues • Muscle • NCI review (Jentzsch, ‘81) found 9/22 patients with ESFT to have moderate to severe limitations relating to muscle or soft tissue following radiation to 50 Gy . • Brown (‘87) noted 5/60 patients to have moderate to severe musculoskeletal limitations following radiation for ESFT. • Limited data is available regarding soft tissue toxicity • Historical series include patients with large volume irradiation not clinically relevant compared with the more focal modern techniques

  33. LESG (Tucker, NEJM, ‘87) RR = 649 for patients with Ewing’s sarcoma Increased with dose above 60 Gy CESS (Dunst, IJRO, ‘98) Limited FU Secondary malignancies

  34. Secondary malignancies • NCI/SJ/UF collaborative review (Kuttesch, JCO ‘96) • Dose response for secondary sarcomas at 60 Gy 60 Gy

  35. Methods to Reduce Toxicity Related to Radiotherapy and Maintain Local Control • Modifications in dose • Decreasing dose • Altering fractionation • Modifications in volume • Further reductions in treatment volumes or boost volumes • Increasing conformality with treatment techniques • Combining local modalities • Non-morbid surgery paired with low-dose radiation • Improve local control with aggressive surgery and radiation in patients with tumors in unfavorable sites

  36. Methods to Reduce Toxicity Related to Radiotherapy • Reduction in dose • St. Jude data delivering 36 Gy to patients with tumors <8 cm achieving CR to induction chemotherapy • Response determined by PE, CT and MRI • 81% local control - somewhat lower than anticipated LC with conventional dose radiation • Limited data for this approach • A potential role for PET, DEMRI or other functional imaging to better select responding patients • Potential for reducing dose to areas of microscopic disease

  37. Methods to Reduce Toxicity Related to Radiotherapy • Alterations in volume • Treatment volume determined by local disease extent • Improved tumor definition - accuracy and conformality • Functional imaging evidence of response allowing volume reduction • Functional imaging delineation of tumor activity requiring increased radiation dose for control • Image-guided radiation treatment planning (conformal, intensity-modulated) to reduce high dose treatment volume

  38. Reduction in Treatment VolumeAnatomically constrained target volumes in ESFT of the tibia

  39. Reduction of target volume by chemoreductionPelvic Ewing’s Sarcoma Induction Chemotherapy

  40. Intensity modulated radiotherapy EWS Rib (Askin) Induction Chemotherapy

  41. Definitive Radiation for Ewing’s Sarcoma • Local control rates for radiotherapy alone are high. • Improvements in target delineation, planning and delivery may allow limited reductions in treatment effects. • Greater understanding of normal tissue effects of radiation on the musculoskeletal system will aid in preventing and predicting toxicity • Reductions in dose or more likely irradiated volume will aid in reducing late effects

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