Mortality After Apparent Mortality After Apparent Cure of Soft Tissue Sarcoma Cure of Soft Tissue Sarcoma Using Combined Modality Using Combined Modality

TherapyTherapy

Ballo MT, Zagars GK, Strom SS, Ballo MT, Zagars GK, Strom SS,

Pisters PW, Patel SR, Feig BW, Pisters PW, Patel SR, Feig BW,

Cormier JN, Hunt KK, Pollack RE, & Cormier JN, Hunt KK, Pollack RE, &

Benjamin RS Benjamin RS

PurposePurpose

Determine the incidence of Determine the incidence of

treatment-related mortality in long-treatment-related mortality in long-term survivors of STSterm survivors of STS

HypothesisHypothesis

1. Survival of patients cured of STS will be 1. Survival of patients cured of STS will be equivalent to that of the general population.equivalent to that of the general population.

2. No patient, tumor, or treatment 2. No patient, tumor, or treatment characteristic will be associated with characteristic will be associated with survival.survival.

Patients & MethodsPatients & Methods

• 1,435 patients with STS1,435 patients with STS• 1960-20001960-2000• Surgery and XRT +/- ChemotherapySurgery and XRT +/- Chemotherapy

• Examined only Examined only 640 patients640 patients ostensibly cured of ostensibly cured of disease.disease.

• IRB approved retrospective reviewIRB approved retrospective review

Patients & MethodsPatients & Methods

• 640 cured patients640 cured patients– 512 patients alive and well512 patients alive and well

– 128 patients dead (20%) 128 patients dead (20%) • Confirmed using Social Security Death IndexConfirmed using Social Security Death Index

– Cause of death determinedCause 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)Median follow-up: 11 years (2 to 41 years)

Patients & MethodsPatients & Methods

• Actuarial method Actuarial method – Examined overall survivalExamined overall survival– Subgroup analysis Subgroup analysis – Examined specific causes of deathExamined specific causes of death

• Person-years method using US population dataPerson-years method using US population data– Examined overall survivalExamined overall survival– Subgroup analysisSubgroup analysis– Examined specific causes of deathExamined specific causes of death

versus expected

Patient CharacteristicsPatient Characteristics

SexSex

RaceRace

GradeGrade

SizeSize

SiteSite

ChemoChemo

XRT TimingXRT Timing

MaleMaleFemaleFemaleWhiteWhiteBlackBlackLowLowIntIntHighHigh5 cm5 cm>5 cm>5 cmExtremityExtremityNon-ExtremityNon-ExtremityNoNoYesYesPost opPost opPre opPre op

CharacteristicCharacteristic31231232832859159149494949184184407407279279349349467467173173444444196196416416224224

nn

87%

70%

58%

Results: Univariate AnalysisResults: Univariate Analysis

SexSex

RaceRace

GradeGrade

SizeSize

SiteSite

ChemoChemo

XRT TimingXRT Timing

MaleMale

FemaleFemale

WhiteWhite

BlackBlack

LowLow

IntInt

HighHigh

5 cm5 cm

>5 cm>5 cm

ExtremityExtremity

Non-ExtremityNon-Extremity

NoNo

YesYes

Post opPost op

Pre opPre op

72%72%

69%69%

71%71%

67%67%

71%71%

72%72%

69%69%

73%73%

68%68%

73%73%

60%60%

69%69%

76%76%

70%70%

70%70%

0.10.1

0.30.3

0.90.9

0.060.06

0.050.05

0.50.5

0.70.7

CharacteristicCharacteristic 20-year OS20-year OS P valueP value

Results: Multivariate analysisResults: Multivariate analysis

• Only significant Factor was:Only significant Factor was:

Non-extremity site (p = 0.01)Non-extremity site (p = 0.01)

Controlled for:Controlled for:

Age (p < 0.001 - as a continuous variable)Age (p < 0.001 - as a continuous variable)

73%

60%

P=0.05

Specific Causes of Death

40 pts37 pts

40 pts

11 pts

P = 0.9

P = 0.2

P = 0.03

Results: Results: Standardized Mortality RatiosStandardized 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 MortalityResults: Standardized Mortality

Overall:Overall:

Cardiac:Cardiac:

Cancer:Cancer:

Cancer:Cancer:

ExtremityExtremity

Non-extremityNon-extremity

640640

640640

640640

467467

173173

79667966

79667966

79667966

60726072

18931893

128/115.6128/115.6

40/37.640/37.6

37/30.537/30.5

23/23.823/23.8

14/6.614/6.6

1.111.11

1.061.06

1.211.21

0.970.97

2.112.11

0.92-1.320.92-1.32

0.76-1.440.76-1.44

0.86-1.670.86-1.67

0.61-1.450.61-1.45

1.15-3.541.15-3.54

CategoryCategory nnPerson-Person-yearsyears O/EO/E SMRSMR 95% CI95% CI

PerspectivePerspective

7 additional cancer deaths7 additional cancer deaths

923 total deaths923 total deaths

7 additional cancer deaths7 additional cancer deaths

1,435 total patients1,435 total patients

= 0.8%

= 0.5%

ConclusionsConclusions

• No increased overall, cancer or cardiac-No increased overall, cancer or cardiac-related mortality for related mortality for all patientsall patients after after combined modality therapy for STS.combined modality therapy for STS.

• Patients with Patients with non-extremity site primariesnon-extremity site primaries are at risk of death from second cancers.are at risk of death from second cancers.

ConclusionsConclusions

• Confirms the known carcinogenic effects of Confirms the known carcinogenic effects of radiation.radiation.

• Illustrates a preferential carcinogenic effect on Illustrates a preferential carcinogenic effect on tissues of epithelial origin:tissues of epithelial origin:– After extremity irradiation the only tissues at risk After extremity irradiation the only tissues at risk

are mesenchymal = STSare mesenchymal = STS– After axial site irradiation the tissues at risk are After axial site irradiation the tissues at risk are

epithelial = lung, GI, etc…epithelial = lung, GI, etc…

ConclusionsConclusions

• Benefits of XRT need to outweight the risks.Benefits of XRT need to outweight the risks.– True for extremities.True for extremities.– What about retroperitoneum, H/N or trunk?What about retroperitoneum, H/N or trunk?

• We should decrease XRT dose to non-target We should decrease XRT dose to non-target tissues as much as possible.tissues as much as possible.– Protons?Protons?

Specific Causes of Death:work in progress

40 pts37 pts

40 pts

11 pts

MalignanciesBladder - 2Breast - 1Colon - 3Esophagus - 2Gastric - 2Glioma - 3H/N - 3Liver - 1Lung - 9Pancreas - 5Prostate - 3Sarcoma - 3