Mortality After Apparent Cure of Soft Tissue Sarcoma Using Combined Modality Therapy Ballo MT, Zagars GK, Strom SS, Pisters PW, Patel SR, Feig BW, Cormier JN, Hunt KK, Pollack RE, & Benjamin RS

Purpose Determine the incidence of treatment-related mortality in long- term survivors of STS

Hypothesis 1. Survival of patients cured of STS will be equivalent to that of the general population. 2. No patient, tumor, or treatment characteristic will be associated with survival.

Patients & Methods 1,435 patients with STS1,435 patients with STS Surgery and XRT +/- ChemotherapySurgery and XRT +/- Chemotherapy Examined only 640 patients ostensibly cured of disease.Examined only 640 patients ostensibly cured of disease. IRB approved retrospective reviewIRB approved retrospective review

Patients & Methods 640 cured patients640 cured patients –512 patients alive and well –128 patients dead (20%) Confirmed using Social Security Death IndexConfirmed using Social Security Death Index –Cause of death determined Medical informaticsMedical informatics Death certificateDeath certificate Communication with local physicianCommunication with local physician Communication with family membersCommunication with family members –Median follow-up: 11 years (2 to 41 years)

Patients & Methods Actuarial methodActuarial method –Examined overall survival –Subgroup analysis –Examined specific causes of death Person-years method using US population dataPerson-years method using US population data –Examined overall survival –Subgroup analysis –Examined specific causes of death versus expected

Patient Characteristics SexRaceGradeSizeSiteChemo XRT Timing MaleFemaleWhiteBlackLowIntHigh  5 cm >5 cm ExtremityNon-ExtremityNoYes Post op Pre op Characteristic n

87% 70% 58%

Results: Univariate Analysis SexRaceGradeSizeSiteChemo XRT Timing MaleFemaleWhiteBlackLowIntHigh  5 cm >5 cm ExtremityNon-ExtremityNoYes Post op Pre op 72%69%71%67%71%72%69%73%68%73%60%69%76%70%70% Characteristic 20-year OS P value

Results: Multivariate analysis Only significant Factor was:Only significant Factor was: Non-extremity site (p = 0.01) Controlled for: Age (p < as a continuous variable)

73% 60% P=0.05

Specific Causes of Death 40 pts 37 pts 40 pts 11 pts

P = 0.9

P = 0.2

P = 0.03

Results: Standardized Mortality Ratios Confirmatory SMR analysis US male/female age-specific mortality data US race-specific mortality data US cause specific mortality data –“Heart Disease” (non-PVD, CVD, PE) –“Malignant Neoplasm” (non-skin) All published in 10-year intervals

Results: Standardized Mortality Overall:Cardiac:Cancer:Cancer:ExtremityNon-extremity / /37.637/30.523/23.814/ Categoryn Person-years O/ESMR 95% CI

Perspective 7 additional cancer deaths 923 total deaths 7 additional cancer deaths 1,435 total patients 1,435 total patients = 0.8% = 0.5%

Conclusions No increased overall, cancer or cardiac- related mortality for all patients after combined modality therapy for STS.No increased overall, cancer or cardiac- related mortality for all patients after combined modality therapy for STS. Patients with non-extremity site primaries are at risk of death from second cancers.Patients with non-extremity site primaries are at risk of death from second cancers.

Conclusions Confirms the known carcinogenic effects of radiation.Confirms the known carcinogenic effects of radiation. Illustrates a preferential carcinogenic effect on tissues of epithelial origin:Illustrates a preferential carcinogenic effect on tissues of epithelial origin: –After extremity irradiation the only tissues at risk are mesenchymal = STS –After axial site irradiation the tissues at risk are epithelial = lung, GI, etc…

Conclusions Benefits of XRT need to outweight the risks.Benefits of XRT need to outweight the risks. –True for extremities. –What about retroperitoneum, H/N or trunk? We should decrease XRT dose to non-target tissues as much as possible.We should decrease XRT dose to non-target tissues as much as possible. –Protons?

Specific Causes of Death: work in progress 40 pts 37 pts 40 pts 11 pts Malignancies Bladder - 2 Breast - 1 Colon - 3 Esophagus - 2 Gastric - 2 Glioma - 3 H/N - 3 Liver - 1 Lung - 9 Pancreas - 5 Prostate - 3 Sarcoma - 3