SR-2 Trial (NCIC CTG / CSG)

Five year results of a randomized Phase III Five year results of a randomized Phase III trial of pre-operative vs post-operative trial of pre-operative vs post-operative

radiotherapy in extremity soft tissue sarcoma radiotherapy in extremity soft tissue sarcoma

Brian O'Sullivan, Aileen Davis, Robert Turcotte, Robert Bell, Brian O'Sullivan, Aileen Davis, Robert Turcotte, Robert Bell, Jay Wunder, Charles Catton, Rita Kandel, Alex Hammond, Jay Wunder, Charles Catton, Rita Kandel, Alex Hammond,

Carolyn Freeman, Marc Isler, Karen Goddard, Pierre Chabot, Carolyn Freeman, Marc Isler, Karen Goddard, Pierre Chabot, Dongsheng Tu, Joseph Pater Dongsheng Tu, Joseph Pater

Canadian Sarcoma Group • National Cancer Institute of Canada, Clinical Trials Group / Groupe des assais clinique

SR-2 Trial (NCIC CTG / CSG)SR-2 Trial (NCIC CTG / CSG)

• Extremity Soft tissue sarcoma (appropriate histology)

• No chemotherapy

• Any T,N0,M0

• Any grade

• Combined modality treatment needed:

→ Surgical and Radiation Oncology opinion

• Stratification at 10 cm cut-point

RANDOMIZATION

Pre-op RT • 50 Gy in 25 fractions• Phase 2 to 66 Gy, if

margins positive

Post-op RT • 50 Gy in 25 fractions• Phase 2 to 66 Gy, all

cases

CTOS 2004

Phase 1:Phase 1: 5 cm longitudinal 5 cm longitudinal 2 cm axial2 cm axial

Phase 2: 2 cm coveragePhase 2: 2 cm coverage

SR-2 TrialSR-2 Trial

• Trial open from late 1994 to late 1997Trial open from late 1994 to late 1997

• 190 patients entered from 10 Canadian centres190 patients entered from 10 Canadian centres

• Sample size to detect 15% difference in wound Sample size to detect 15% difference in wound complications (80% power)complications (80% power)

• Closed after Closed after a planned interim analysisa planned interim analysis showed showed significant difference between two arms for the significant difference between two arms for the primary end-point, and primary end-point, and no value in continuing after no value in continuing after primary question addressedprimary question addressed

CTOS 2004

Previous Analyses (3.3 years Median FU)Previous Analyses (3.3 years Median FU)

• Primary End-point (wound complications)Primary End-point (wound complications) – Twice the rate in pre vs post-op (35 vs 17%)Twice the rate in pre vs post-op (35 vs 17%)– Confined to the lower extremityConfined to the lower extremity

• Secondary End-pointsSecondary End-points– QoL and function similar after 1 yearQoL and function similar after 1 year– Survival advantage favoring pre-op RTSurvival advantage favoring pre-op RT

O’Sullivan et al, Lancet 2002 O’Sullivan et al, Lancet 2002 Davis et al, JCO 2002Davis et al, JCO 2002

Background

SR-2 Local Control and Survival: SR-2 Local Control and Survival: First analysis (3.3 yrs median follow up)First analysis (3.3 yrs median follow up)

Lancet 2002;359:2235-2241 Lancet 2002;359:2235-2241

Background

Pre-opPre-op Post-opPost-op TotalTotaln n (%)(%) n n (%) (%) n n (%)(%)

TotalTotal 9494 (100)(100) 9696 (100) (100) 190190 (100)(100)

Gender:Gender: FemaleFemale 42 42 (45) (45) 4444 (46)(46) 8686 (45)(45)MaleMale 5252 (55)(55) 52 52 (54)(54) 104104 (55) (55)

Age:Age: <50 <50 32 32 (34) (34) 4545 (47)(47) 7777 (41)(41)≥≥50<70 50<70 39 39 (42)(42) 34 34 (36)(36) 7373 (38)(38)≥≥70 70 23 23 (24)(24) 17 17 (18)(18) 4040 (21)(21)

PresentationPresentation PrimaryPrimary 8383 (88)(88) 8989 (93)(93) 172172 (91)(91)RecurrentRecurrent 1111 (12)(12) 77 (7)(7) 1818 (9)(9)

Patient CharacteristicsPatient Characteristics

CTOS 2004 (Analysis: Dec 2003)

Median Follow-up: 6.9 years (range 0 – 8.6 years)

Pre-opPre-op Post-opPost-op TotalTotaln n (%)(%) n n (%) (%) n n (%)(%)

TotalTotal 9494 (100)(100) 9696 (100) (100) 190190 (100)(100)

Size:Size: ≤ ≤ 10 cm 10 cm 61 61 (65) (65) 6464 (67)(67) 125125 (66)(66)(stratification)(stratification) > 10 cm> 10 cm 3333 (35)(35) 32 32 (33)(33) 6565 (34) (34)

Grade:Grade: Low Low 15 15 (16) (16) 1717 (18)(18) 3232 (17)(17)Interm / Interm / HighHigh 79 79 (84)(84) 79 79 (82)(82) 158158 (83)(83)

HistologyHistology MFHMFH 2929 (31)(31) 2323 (24)(24) 5252 (27)(27)Liposarc.Liposarc. 2626 (28)(28) 2626 (27)(27) 5252 (27)(27)Leiomyos.Leiomyos. 1010 (11)(11) 99 (9)(9) 1919 (10)(10)OtherOther 2929 (31)(31) 3838 (40)(40) 6767 (35)(35)

Tumor CharacteristicsTumor Characteristics


Pre-opPre-opPost-opPost-op TotalTotal

n n (%)(%) n n (%) (%) n n (%)(%)

TotalTotal 9494 (100)(100) 9696 (100) (100) 190190 (100)(100)

Compartment:Compartment: Intracompartment Intracompartment 48 48 (51) (51) 5050 (52)(52) 100100 (52)(52)Extra – by growthExtra – by growth 2929 (31)(31) 26 26 (27)(27) 5555 (29) (29) Extra - iatrogenicExtra - iatrogenic 1212 (13)(13) 11 11 (11)(11) 2323 (12) (12) Extra - Extra - de novode novo 5 5 (5)(5) 9 9 (9)(9) 1414 (7) (7)

Depth:Depth: Deep to fasciaDeep to fascia 56 56 (59) (59) 4848 (50)(50) 104104 (55)(55)Deep & Superficial Deep & Superficial 23 23 (24)(24) 28 28 (29)(29) 5151 (27)(27)SuperficialSuperficial 1515 (16)(16) 2020 (21)(21) 3535 (18)(18)

Site *Site * Upper:Upper: Proximal Proximal 1111 (12)(12) 1212 (13)(13) 2323 (12)(12)Distal Distal 1010 (11)(11) 88 (8)(8) 2020 (11)(11)

Lower: Lower: Proximal Proximal 4747 (50)(50) 5656 (58)(58) 103103 (54)(54)Distal Distal 2626 (28)(28) 2020 (21)(21) 4646 (24)(24)

Resection marginsResection margins PositivePositive 1414 (15)(15) 1313 (13)(13) 2727 (14)(14)NegativeNegative 8080 (85)(85) 8383 (87)(87) 163163 (86)(86)

* Distal upper includes elbow; Proximal lower includes knee* Distal upper includes elbow; Proximal lower includes knee

AnatomicAnatomic CharacteristicsCharacteristics

Pre-op Pre-op Post-opPost-op TotalTotal

n n %% nn %% nn %%

AliveAlive 6464 (68)(68) 6262 (65)(65) 126 126 (66.3)(66.3)

DeadDead 3030 (32)(32) 3434 (35)(35) 6464 (33.7)(33.7)Cause of death:Cause of death:

DiseaseDisease 2424 (80)(80) 2626 (76)(76) 50 50 (78)(78)

Non-protocol complicationNon-protocol complication 00 (0)(0) 11 (3)(3) 11 (2)(2)

OtherOther 44 (13)(13) 44 (12)(12) 88 (12)(12)

Other primary cancerOther primary cancer 22 (7)(7) 33 (9)(9) 55 (8)(8)

TotalTotal 9494 (100)(100) 9696 (100)(100) 190 190 (100)(100)

Patient status at Patient status at last follow-uplast follow-up


Pre-opPre-opPost-opPost-op

N = 94N = 94 N = 96N = 96

Compartment:Compartment: Intracompartment Intracompartment 92.9% 92.9% 97.9%97.9%Extra-compartmentalExtra-compartmental 93.0%93.0% 85.7%85.7%

Depth:Depth: Superficial Superficial 100.0% 100.0% 95.0%95.0%Deep Deep 91.5% 91.5% 91.6%91.6%

Anatomic Site Anatomic Site Upper Limb Upper Limb 95.2% 95.2% 94.7%94.7%Lower Limb Lower Limb 92.3% 92.3% 91.7%91.7%

Tumor Size Tumor Size <=10 cm <=10 cm 98.1% 98.1% 92.1%92.1%>10 cm >10 cm 83.6% 83.6% 92.6%92.6%

GradeGrade LowLow 86.7% 86.7% 100%100%HighHigh 94.5% 94.5% 90.5%90.5%

5 year local control by Tumor5 year local control by Tumor CharacteristicsCharacteristics

Environmental / TreatmentEnvironmental / Treatment

5 year local control by prognostic factors5 year local control by prognostic factors


N = 94N = 94 N = 96N = 96

Resection MarginsResection Margins 95.8% 95.8% 95.0%95.0%77.1% 77.1% 73.3%73.3%

Treatment Center:Treatment Center: PMH PMH 91.7% 91.7% 92.0%92.0%OtherOther 94.4%94.4% 92.7%92.7%

Presentation:Presentation: Primary Primary 93.4% 93.4% 91.7%91.7%Recurrent Recurrent 90.0% 90.0% 100.0% 100.0%

Age Age <50 <50 93.0% 93.0% 97.7%97.7%>=50>=50 93.0% 93.0% 87.2%87.2%

GenderGender MaleMale 95.4% 95.4% 96.0%96.0%FemaleFemale 90.0% 90.0% 87.9%87.9%


N = 94N = 94 N = 96N = 96

Resection MarginsResection Margins NegativeNegative 95.8% 95.8% 95.0%95.0%PositivePositive 77.1% 77.1% 73.3%73.3%

Treatment Center:Treatment Center: PMH PMH 91.7% 91.7% 92.0%92.0%OtherOther 94.4%94.4% 92.7%92.7%

Presentation:Presentation: Primary Primary 93.4% 93.4% 91.7%91.7%Recurrent Recurrent 90.0% 90.0% 100.0%100.0%

Host FactorsHost Factors

HR of post-op to Log-rankpre-op with 95% CI p-value

1.2 (0.4-3.5) 0.76


0.96 (0.6-1.6) 0.86


1.0 (0.7-1.6) 0.92


1.1 (0.7-2.0) 0.64

Local recurrence free Regional / distant recurrence free

Progression free survival Disease specific survival

Cox regression models with P-Values Cox regression models with P-Values for Risk Ratios (not shown) for outcomesfor Risk Ratios (not shown) for outcomes

LocalLocal MetMet ProgressProgress DiseaseDisease OverallOverall

Predictor Predictor RecRec RecRec Free survFree surv Spec SurvSpec Surv SurvivalSurvival

Pre vs PostPre vs Post 0.560.56 1.001.00 0.790.79 0.490.49 0.320.32

Center (PMH vs other)Center (PMH vs other) 0.630.63 0.940.94 0.730.73 0.810.81 0.220.22

Upper vs Lower LimbUpper vs Lower Limb 0.920.92 0.820.82 0.830.83 0.900.90 0.240.24

Grade (low vs high)Grade (low vs high) 0.520.52 0.010.01 0.0050.005 0.020.02 0.0080.008

Max Baseline tumor size Max Baseline tumor size 0.110.11 0.020.02 0.100.10 0.00050.0005 0.00020.0002

Depth (superficial vs deep)Depth (superficial vs deep) 0.630.63 0.570.57 0.910.91 0.340.34 0.620.62

Primary vs Recurrent Pres.Primary vs Recurrent Pres. 0.880.88 0.500.50 0.730.73 0.940.94 0.980.98

Margins (‘pos’ vs ‘neg’)Margins (‘pos’ vs ‘neg’) 0.010.01 NANA 0.100.10 NANA NANA


NA: not applicable (not included in model)


1.2 (0.7-2.0) 0.48

ASCO 2004 (Analysis: Dec 2003)

Overall survival

Late Subcutaneous Fibrosis Late Subcutaneous Fibrosis (RTOG/EORTC)(RTOG/EORTC)

• Grade 0Grade 0 NoneNone• Grade 2Grade 2 slight induration (fibrosis) slight induration (fibrosis)

and loss of and loss of subcutaneous fatsubcutaneous fat

• Grade 3Grade 3 severe induration and loss severe induration and loss of of subcutaneous tissue; field subcutaneous tissue; field

contracture >10% contracture >10% linear linear measurementmeasurement

• Grade 4Grade 4 necrosisnecrosis

Probability: 3-yr 5-yr Pre-op: 20% 23%Post-op: 26% 36%

P=0.02, log rank for equality of groups


Grade 3 or 4 subcutaneous fibrosis

Cox regression model for Grade 3 and 4 fibrosisCox regression model for Grade 3 and 4 fibrosis

Hazard Hazard 95% Hazard Ratio95% Hazard Ratio P-P-ValueValue

Variable Variable Ratio Ratio Confidence LimitsConfidence Limits

Schedule (pre vs. post-op) Schedule (pre vs. post-op) 1.084 1.084 0.513, 0.513, 2.2912.291 0.83250.8325

Centre (PMH vs. other) Centre (PMH vs. other) 0.711 0.711 0.406, 0.406, 1.248 1.248 0.23500.2350

D max (total dose) D max (total dose) 1.037 1.037 0.989, 0.989, 1.0871.087 0.13160.1316

Phase I field size (cmPhase I field size (cm2)2) 1.002 1.002 1.001, 1.001, 1.003 1.003 0.00060.0006


Summary and ConclusionsSummary and Conclusions

• No differences in cancer-specific outcomes between Pre-op vs. Post-op RT with No differences in cancer-specific outcomes between Pre-op vs. Post-op RT with the protocols used in this RCTthe protocols used in this RCT

• Very high local control rates (95 % range) are evident with combined Surgery and Very high local control rates (95 % range) are evident with combined Surgery and RT in extremity STSRT in extremity STS

• Morbidity profiles differ between both approaches:Morbidity profiles differ between both approaches:

– Acute complications: significantly greater in pre-op (recoverable)Acute complications: significantly greater in pre-op (recoverable)

– Late tissue effects: significantly greater in post-op (likely permanent) Late tissue effects: significantly greater in post-op (likely permanent)

• Local anatomic factors and wound reconstruction should dictate the choice of Local anatomic factors and wound reconstruction should dictate the choice of radiotherapy scheduleradiotherapy schedule

• New local control techniques or approaches are needed to ameliorate local tissue New local control techniques or approaches are needed to ameliorate local tissue toxicity (especially fibrosis, and bone later) toxicity (especially fibrosis, and bone later)



1.2 (0.7-2.0) 0.48


Overall survival


1.2 (0.7-2.0) 0.48


Overall survival


1.2 (0.7-2.0) 0.48


Overall survival

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Brian O’Sullivan, a.k.a. “the Enforcer”, Brian O’Sullivan, a.k.a. “the Enforcer”, Toronto Maple Leafs, c. 1966-67Toronto Maple Leafs, c. 1966-67

1931-321941-421944-451946-471947-481948-491950-511961-621962-631963-641966-67

Cox regression model for Local ControlCox regression model for Local Control

PredictorPredictor p-valuep-value Risk RatioRisk Ratio 95% CI for Risk 95% CI for Risk RatioRatio

Pre vs PostPre vs Post 0.560.56 0.720.72 (0.23,2.2)(0.23,2.2)

Centre (PMH vs other)Centre (PMH vs other) 0.630.63 1.331.33 (0.41,4.27) (0.41,4.27)

Upper vs Lower LimbUpper vs Lower Limb 0.920.92 1.081.08 (0.22,5.25)(0.22,5.25)

Grade (low vs high)Grade (low vs high) 0.520.52 0.600.60 (0.13,2.79)(0.13,2.79)

Max Baseline tumor size Max Baseline tumor size 0.110.11 1.021.02 (1.00,1.06)(1.00,1.06)

Depth (superficial vs deep)Depth (superficial vs deep) 0.630.63 0.600.60 (0.07,4.89)(0.07,4.89)

Primary vs Recurrent Pres.Primary vs Recurrent Pres. 0.880.88 1.181.18 (0.15,4.54) (0.15,4.54)

Margins (‘pos’ vs ‘neg’)Margins (‘pos’ vs ‘neg’) 0.010.01 4.664.66 (1.38,15.7)(1.38,15.7)


Documents

SR-2 Trial (NCIC CTG / CSG)