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

Risk of radiation-induced sarcoma: Data of a population-Risk of radiation-induced sarcoma: Data of a population-based registry of 29.931 irradiated patientsbased 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 CenterComprehensive Cancer Center Tuebingen and Institute of Biometry, Hanover Medical School

CTOS, Miami 2009

IntroductionIntroduction

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

Catchment AreaCatchment Area

Area: 7500 km²

No. of new referrals per year: 4500-5000

Unterer Neckar

LB

MittlererOberrhein

Franken

Ost-Württemb.

SüdlicherOberrhein

FDS

CW

PF WN

ES GPBB

TÜRT

Donau-IllerBL

Schwarzwald-Baar-Heuberg

Hochrhein-

Bodensee-Oberschwaben

S

Bodensee

11%

5%

5%

1%

7%

4% 14%

5%

0%

17%

10%

2%4%

3%

1%

1%

0%2%

1%

3%

1%

covering the region South West Germany with a population of approximately 3 millions inhabitants.

Selection criteria and statisticsSelection criteria and statisticsFor this analysis patients have been identified using the following selection criteria:

malignant primary tumorradiation within 6 months of primary diagnosissecondary tumor exceeding 1 year after diagnosis

29.931 patients had received radiation therapy between 1/1968 and 12/2006Irrespective of type of treatment (curatve vs. palliative), extent of disease, prognosis.

Statistics: univariate analysisCox proportional hazardcumulative IncidenceLogistic regression analysis

Patients´ characteristics (n=29.931)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 25.8hematologic tumors, NHL, HD 3 354 11.2head and neck 3 045 10.2lung/thoracic 2 621 8.8Gastrointestinal 2 615 8.7female reproductive 2 326 7.7Prostate 1 878 6.3Brain 1 354 4.5genitourinary (other than prostate) 1 135 3.8Endocrine 1 067 3.6Sarcomas 1 016 3.4Cutaneous 735 2.5other malignancies 1 062 3.5

Results: whole populationResults: whole population

36 patients with RIS were identified 1994 through 2006 representing 0.12% of 29.931 irradiated patients.

Median follow up:

96 months (95%CI, 92.9-99.1)

Median age: 59 years (range, 5-74)female to male ratio was 2.3:1 Primary tumors were

breast cancer n=19lymphoma (incl. Hodgkin´s/NHL) n= 9head and neck cancer n= 4tumors of the female reproductive organs n= 2neuroblastoma n= 1seminoma 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).

Patients´characteristics: RIS cohort (n=36)Patients´characteristics: RIS cohort (n=36)

Examples in breast cancer patientsExamples in breast cancer patients

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

Radiation Source N60Cobalt 23Electron 8Not available 5

Mode of Primary Therapy NRadiation alone 25Radiochemotherapy 1Sequential Chemotherapy 5Unknown 5

Results: RIS patientsResults: RIS patientsradiation field and histologyradiation field and histology

The tumors arosewithin the radiation field in 29 caseson the border of the field in 6 casesout of field in a single case

The histologies of RIS werevascular tumors, e.g. angiosarcoma n = 12 pleomorphic sarcoma, not otherwise specified n = 10leiomyosarcoma n = 4fibrosarcoma n = 2osteosarcoma n = 2others n = 6

Significantly, angiosarcoma occurred in breast cancer (p<.01)

Cumulative RIS incidence

Cumulative risks (95%CI) years0.2% (0.00-0.49) 10 0.9% (0.01-1.79) 2016.0% (0.01-33.8) 30

Cum

ulat

ive

1 m

inus

sur

viva

l fun

ctio

n

Cumulative RIS incidence

Primary breast cancer vs. other

Cum

ulat

ive

1 m

inus

sur

viva

l fun

ctio

n

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%)

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)

Results: RIS patientsResults: RIS patients

Factors influencing survival of RISFactors influencing survival of RISHistology: Angiosarcoma vs. otherHistology: Angiosarcoma vs. other

0 10 20 30 40 50 600

25

50

75

100Angiosarkom

Non-Angiosarkom

months

Prop

ortio

n su

rviv

ing

P=0.94

Factors influencing survival of RISFactors influencing survival of RISBreast cancer vs. other primaryBreast cancer vs. other primary

0 10 20 30 40 50 600

25

50

75

100Breast cancer

Non-Breast cancer

months

Prop

ortio

n su

rviv

ing

P=0.50

Factors influencing survival of RISFactors influencing survival of RISCompleteness ofCompleteness of resectionresection

0 10 20 30 40 50 600

25

50

75

100Resektion complete

Resektion incomplete

months

Prop

ortio

n su

rviv

ing

P=0.08

ConclusionsConclusions

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

Conclusions (cont.)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

RIS after Radiation for RIS after Radiation for Breast CancerBreast Cancer, Case , Case CollectionsCollections

Author Year N pts 5y-OS Cum. Incidence of RIS

Zucali et al. [29] 1994 3 - -

Brady et al. [7] 1993 48 29% -

Taghian et al. [9] 1991 11 Med.S. = 2.4 y 0.2% at 10 years

Schulz et al. [15] 1999 3 - -

Yap et al. [18] 2002 87 27-35% 0.09% at 15 years

This series 2008 11 28 0.2% at 10 yrs0.9% at 20 yrs