1. Surgical Management of Pulmonary Metastases in Pediatric Patients with Ewing Sarcoma Kevin Hug

2. Case Presentation SM is a previously healthy 18 y/o M FHx: Stage IV tongue cancer in F and prostate cancer in maternal GF. Intermittent L hip pain, for 1 year, worse over previous 2 months. Describes “tingling” in anterior thigh and inability to participate in running sports for 2 months

3. CT Pelvis Operative biopsy is performed revealing Ewing Sarcoma

4. Ewing Sarcoma Part of the Ewing family of tumors along with primitive neuroectodermal tumors (PNET) Malignant small, round blue cell tumors Classically, 11;22 chromosomal translocation (FLI1/EWS fusion gene) Other translocations are t(21;22) and t(7;22) 2 nd most common primary bone tumor in children, male : female ratio of 1.6 to 1 250 cases are diagnosed in the US per year

5. Ewing Sarcoma Most common locations are pelvis, long bone diaphyses, and scapula Plain film imaging: lytic, classic finding of “onion skin” periosteal reaction. Permeative appearance. Isolated 5-year survival is 70%. Metastatic 5- year survival is <20% Metastases primarily to the lungs, bone, bone marrow

6. CT Thorax Innumerable tiny 2-4 mm lower lung nodules scattered in both lung fields predominantly in the lower lobes. No other evidence for metastatic disease

7. Thoracoscopic wedge biopsies, LLL x 2

8. Treatment options in metastatic or recurrent ES In contrast to localized disease, modern chemotherapy is limited to extending progression free survival Overall Survival (OS) of patients with metastatic disease remains at 25%. OS in isolated pulmonary mets vs. osseous mets vs. muti- system mets is 29%, 19%, 8% respectively Chemotherapy

9. Treatment options in metastatic or recurrent ES Controversial and co-morbid therapy, but multiple studies show increased survival German/European Intergroup Cooperative Ewing’s Sarcoma Studies (CESS) showed a benefit in disease free survival and recommended 18-20 Gy irradiation Currently, many protocols reserve WLI for patients with pulmonary metastases who are poor chemotherapy responders Whole Lung Irradiation

10. Treatment options in metastatic or recurrent ES Multiple studies have suggested aggressive pulmonary resection for metastatic osteosarcoma Osteosarcoma and ES have similar presentations, but arise from different cell types and have different biological characteristics This practice in ES is less well studied and perhaps more controversial. Surgery

11. Briccoli et al, European Journal of Cancer Surgery Retrospective review of 496 patients with ES treated at a single institution in Italy between 1972-97 All patients were treated with chemotherapy (5 different protocols) Matched 24 operative patients to 34 non-operative patients by age, gender, tumor location, disease-free interval

12. Briccoli et al, European Journal of Cancer Surgery Mean disease-free interval was 30.3 months in non- op group and 37.4 months in operative group Mean 5 year survival in non-op vs. op groups was 24.2% vs. 55.8% (P = 0.02)

13. Letourneau et al, Journal of Pediatric Surgery, 2011 Retrospective review, patients < 21 y/o treated at a single institution (1990-2006) 80 patients identified, 31 with pulmonary mets Groups: resection alone (5), radiation alone (3), radiation and resection (3), chemotherapy alone (11) Authors do not describe how the treatment decisions were made.

14. Letourneau et al, Journal of Pediatric Surgery, 2011 Hazard ratio, lung resected vs not resected: 15.11 (2.63-86.78)

15. Letourneau et al, Journal of Pediatric Surgery, 2011 5-year survival: Radiation, no resection: 0% No radiation, no resection: 0% Radiation and resection: 65% Resection only: 80%

16. Discussion The small sample size, multivariate care strategies, and major selection biases make these studies suspect. Given the long term f/u of these studies, these procedures were all done with thoracotomies. Due to the reduced morbidity of thoracoscopy, this moderately life-prelonging procedure begins to appear more favorable Higher level clinical studies are likely not feasible, but tumor biology plays a large role in determining which patients may benefit from metastasectomy and can be studied further.

17. References [1] Ludwig JA. Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future. Curr OpinOncol 2008;20:412-8. [2] Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European intergroup cooperative Ewing's sarcoma study group. JClinOncol 2000;18:3108-14. [3] Subbiah V, Anderson P, Lazar AJ, et al. Ewing's sarcoma: standard and experimental options. Curr Treat Options Oncol 2009;10:126-40. [4] Harting MT, Blakely ML, Jaffe N, et al. Long term survival after aggressive resection of pulmonary metastases among children and adolescents with osteosarcoma. J Pediatr Surg 2006;41:194-9. [5] Briccoli A, Rocca M, Ferrari S, et al. Surgery for lung metastases in Ewing's sarcoma of bone. Eur J Cancer Surg 2004;30:63-7. [6] Miser J, Goldsby R, Chen Z, et al. Treatment of metastatic Ewing's sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy—a report from the Children's Oncology Group. Pediatr Blood Cancer 2007;49:894-900. [7] Tronc F, Conter C, Marec-Berard P, et al. Prognostic factors and longterm results of pulmonary metastasectomy for pediatric histologies. Eur J Cardiothorac Surg 2008;34:1240-6. [8] Karnak I, Emin Senocak M, Kutluk T, et al. Pulmonary metastases in children: an analysis of surgical spectrum. Eur J Pediatr Surg 2002;12: 151-8. [9] Paulussen M, Ahrens A, Craft J et al. Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s sarcoma studies patients. J Clin Oncol 1998; 16: 3044-52. [10] Spunt S, McCarville B, Kun L et al. Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Ped Heme/Onc 2001; 23: 93-8. [11] Letourneau P, Shackett B, Xia L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg 2011; 46:332-35