Hartmann JT, Hecker H, Kopp HG, Mayer F, Classen J, Königsrainer A, Wallwiener D, Bamberg M

1. Risk of radiation-induced sarcoma: Data of a population-based registry of 29.931 irradiated patients Hartmann JT, Hecker H, Kopp HG, Mayer F, Classen J, Königsrainer A, Wallwiener D, Bamberg M Medical Center, Radiooncology, General-, Visceral Surgery and Transplantation, Gynecology Interdisciplinary Sarcoma Center Comprehensive Cancer Center Tuebingen and Institute of Biometry, Hanover Medical School CTOS, Miami 2009

2. Introduction • Radiation-induced sarcoma (RIS) is a rare complication of radiation therapy for any cause • With increasing numbers of patients receiving radiotherapy, data concerning the incidence and treatment outcome of RIS are urgently needed • The Surveillance, Epidemiology, and End Results Program of the South West German Comprehensive Cancer Center, Tuebingen University registry, was sreened for patients with RIS

3. Unterer Neckar 0% Franken 2% Mittlerer Oberrhein 1% LB PF WN 3% Ost-Württemb. 1% 2% 1% S 4% CW BB ES GP 11% 1% 5% 7% FDS TÜ RT 17% 4% 14% Südlicher Oberrhein BL Donau-Iller 10% Schwarzwald- Baar-Heuberg 5% Bodensee- Oberschwaben Bodensee Hochrhein- 5% 3% Catchment Area Area: 7500 km² No. of new referrals per year: 4500-5000 covering the region South West Germany with a population of approximately 3 millions inhabitants.

4. Selection criteria and statistics • For this analysis patients have been identified using the following selection criteria: • malignant primary tumor • radiation within 6 months of primary diagnosis • secondary tumor exceeding 1 year after diagnosis • 29.931 patients had received radiation therapy between 1/1968 and 12/2006 • Irrespective of type of treatment (curatve vs. palliative), extent of disease, prognosis. • Statistics: • univariate analysis • Cox proportional hazard • cumulative Incidence • Logistic regression analysis

5. Patients´ characteristics (n=29.931) • median age was 58 years (SD, ±16; range, 0-98) • Gender: male/female: 46 / 54% • Irradiated tumor types: N pts % • breast cancer 7 723 25.8 • hematologic tumors, NHL, HD 3 354 11.2 • head and neck 3 045 10.2 • lung/thoracic 2 621 8.8 • Gastrointestinal 2 615 8.7 • female reproductive 2 326 7.7 • Prostate 1 878 6.3 • Brain 1 354 4.5 • genitourinary (other than prostate) 1 135 3.8 • Endocrine 1 067 3.6 • Sarcomas 1 016 3.4 • Cutaneous 735 2.5 • other malignancies 1 062 3.5

6. Results: whole population Median follow up: 96 months (95%CI, 92.9-99.1) 36 patients with RIS were identified 1994 through 2006 representing 0.12% of 29.931 irradiated patients.

7. Patients´characteristics: RIS cohort (n=36) • Median age: 59 years (range, 5-74) • female to male ratio was 2.3:1 • Primary tumors were • breast cancer n=19 • lymphoma (incl. Hodgkin´s/NHL) n= 9 • head and neck cancer n= 4 • tumors of the female reproductive organs n= 2 • neuroblastoma n= 1 • seminoma n= 1 • median of delivered total radiation dose per patient was 50 Gy (range, 35 to 72 Gy). • median time interval from start of irradiation to detection of RIS was 137 mos (CI95%, 105-169).

8. Examples in breast cancer patients

9. Results RIS patients (n=36)mode of primary therapy, including radiation source

10. Results: RIS patientsradiation field and histology • The tumors arose • within the radiation field in 29 cases • on the border of the field in 6 cases • out of field in a single case • The histologies of RIS were • vascular tumors, e.g. angiosarcoma n = 12 • pleomorphic sarcoma, not otherwise specified n = 10 • leiomyosarcoma n = 4 • fibrosarcoma n = 2 • osteosarcoma n = 2 • others n = 6 • Significantly, angiosarcoma occurred in breast cancer (p<.01)

11. Cumulative RIS incidence Cumulative 1 minus survival function Cumulative risks (95%CI) years 0.2% (0.00-0.49) 10 0.9% (0.01-1.79) 20 16.0% (0.01-33.8) 30

12. Cumulative RIS incidence Primary breast cancer vs. other Cumulative 1 minus survival function • Latency period • breast RIS: 100 mos (CI95%, 69-131) • Non-breast cancer RIS: 224 mos (CI95%, 99-349) • p<.01 • 19 of 7.716 cases (0.246%) • 17 of 22.215 cases (0.076%)

13. Results: RIS patients • Latency period • Breast vs. non-breast cancer: 100 mos (CI95%, 69-131) vs 224 mos, (CI95%, 99-349), p<.01 • age <49 year with 224 mos (95%CI, 107-341) vs age 50-69 years with 100.0 months (95%CI, 67-133), (p<.0001) • trend: men, 255 mos (95%CI, 108-402) vs women, 114 mos (91-137) p=.058 • Factors predicting RIS occurrence (logistic regression): • age >70 years: HR: 3.04 (95%CI, 1.58-5.85, p=.001) • breast cancer: HR: 2.17 (95%, 1.11-4.21, p=.02) • RIS treatment and outcome analysis: • Most cases in a localized stage (34 out of 36) • complete surgical removal 59% (n=19), R I n=8, R II n=4. • 13 patients free of disease during median f/u period of 11 mos (range, 0-51)

14. Factors influencing survival of RISHistology: Angiosarcoma vs. other P=0.94

15. Factors influencing survival of RISBreast cancer vs. other primary P=0.50

16. Factors influencing survival of RISCompleteness ofresection P=0.08

17. Conclusions • Radiation induced secondary sarcoma (RIS) is a rare event within a 20-year period • 10- and 20-year cumulative incidence of RIS were below 1% • Risk is steadily increasing 20 years after application of radiation • Age (>70 years) at the time of the first cancer diagnosis and breast cancer primary associated with elevated RIS risk • Women (e.g. breast cancer patients) and elderlies had shorter latency period

18. Conclusions (cont.) • Angio- or pleomorphic sarcomas, NOS, are the most common RIS subentities • With lag period between initial treatment and RIS occurrence, the need for long-term follow-up becomes evident • Follow-up of previously irradiated breast cancer patients include examination of irradiated regions with a high level of suspicion if cutaneous atypical vascular lesions • Factor associated with outcome for RIS is a early stage disease • RIS is treated the same as non-radiation induced sarcoma

19. RIS after Radiation for Breast Cancer, Case Collections