Five year results of a randomized Phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma Brian O'Sullivan, Aileen.

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Five year results of a randomized Phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma Brian O'Sullivan, Aileen Davis, Robert Turcotte, Robert Bell, Jay Wunder, Charles Catton, Rita Kandel, Alex Hammond, Carolyn Freeman, Marc Isler, Karen Goddard, Pierre Chabot, 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) 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 R A N D O M IZ A TI O N 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 1:5 cm longitudinal 2 cm axial Phase 2: 2 cm coverage

SR-2 Trial Trial open from late 1994 to late 1997Trial open from late 1994 to late patients entered from 10 Canadian centres190 patients entered from 10 Canadian centres Sample size to detect 15% difference in wound complications (80% power)Sample size to detect 15% difference in wound complications (80% power) Closed after a planned interim analysis showed significant difference between two arms for the primary end-point, and no value in continuing after primary question addressedClosed after a planned interim analysis showed significant difference between two arms for the primary end-point, and no value in continuing after primary question addressed CTOS 2004

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%) –Confined to the lower extremity Secondary End-pointsSecondary End-points –QoL and function similar after 1 year –Survival advantage favoring pre-op RT O’Sullivan et al, Lancet 2002 Davis et al, JCO 2002 Background

SR-2 Local Control and Survival: First analysis (3.3 yrs median follow up) Lancet 2002;359: Background

Pre-opPost-opTotal n (%)n (%) n (%) Total94(100)96(100) 190(100) Gender:Female42 (45) 44(46)86(45) Male52(55)52 (54)104(55) Age:<50 32 (34) 45(47)77(41) ≥50<70 39 (42)34 (36)73(38) ≥70 23 (24)17 (18)40(21) PresentationPrimary83(88)89(93)172(91) Recurrent11(12)7(7)18(9) Patient Characteristics CTOS 2004 (Analysis: Dec 2003) Median Follow-up: 6.9 years (range 0 – 8.6 years)

Pre-opPost-opTotal n (%)n (%) n (%) Total94(100)96(100) 190(100) Size:≤ 10 cm 61 (65) 64(67)125(66) (stratification)> 10 cm33(35)32 (33)65(34) Grade:Low 15 (16) 17(18)32(17) Interm / High 79 (84)79 (82)158(83) HistologyMFH29(31)23(24)52(27) Liposarc.26(28)26(27)52(27) Leiomyos.10(11)9(9)19(10) Other29(31)38(40)67(35) Tumor Characteristics CTOS 2004 (Analysis: Dec 2003)

Pre-opPost-opTotal n (%)n (%) n (%) Total94(100)96(100) 190(100) Compartment:Intracompartment 48 (51) 50(52)100(52) Extra – by growth29(31)26 (27)55(29) Extra - iatrogenic12(13)11 (11)23(12) Extra - de novo 5(5) 9 (9)14(7) Depth:Deep to fascia56 (59) 48(50)104(55) Deep & Superficial 23 (24)28 (29)51(27) Superficial15(16)20(21)35(18) Site *Upper:Proximal 11(12)12(13)23(12) Distal 10(11)8(8)20(11) Lower: Proximal 47(50)56(58)103(54) Distal 26(28)20(21)46(24) Resection marginsPositive14(15)13(13)27(14) Negative80(85)83(87)163(86) * Distal upper includes elbow; Proximal lower includes knee Anatomic Characteristics

Pre-op Post-opTotal n %n%n% Alive64(68)62(65)126 (66.3) Dead30(32)34(35)64(33.7) Cause of death: Disease24(80)26(76)50 (78) Non-protocol complication0(0)1(3)1(2) Other4(13)4(12)8(12) Other primary cancer2(7)3(9)5(8) Total94(100)96(100)190 (100) Patient status at last follow-up CTOS 2004 (Analysis: Dec 2003)

Pre-opPost-op N = 94N = 96 Compartment:Intracompartment 92.9% 97.9% Extra-compartmental93.0%85.7% Depth:Superficial 100.0% 95.0% Deep 91.5% 91.6% Anatomic Site Upper Limb 95.2% 94.7% Lower Limb 92.3% 91.7% Tumor Size <=10 cm 98.1% 92.1% >10 cm 83.6% 92.6% GradeLow86.7% 100% High94.5% 90.5% 5 year local control by Tumor Characteristics

Environmental / Treatment 5 year local control by prognostic factors Pre-opPost-op N = 94N = 96 Resection Margins95.8% 95.0% 77.1% 73.3% Treatment Center:PMH 91.7% 92.0% Other94.4%92.7% Presentation:Primary 93.4% 91.7% Recurrent 90.0% 100.0% Age < % 97.7% >=5093.0% 87.2% GenderMale95.4% 96.0% Female90.0% 87.9% Pre-opPost-op N = 94N = 96 Resection MarginsNegative95.8% 95.0% Positive77.1% 73.3% Treatment Center:PMH 91.7% 92.0% Other94.4%92.7% Presentation:Primary 93.4% 91.7% Recurrent 90.0% 100.0% Host Factors

HR of post-op to Log-rank pre-op with 95% CIp-value 1.2 ( )0.76 HR of post-op to Log-rank pre-op with 95% CIp-value 0.96 ( )0.86 HR of post-op to Log-rank pre-op with 95% CIp-value 1.0 ( )0.92 HR of post-op to Log-rank pre-op with 95% CIp-value 1.1 ( )0.64 Local recurrence freeRegional / distant recurrence free Progression free survivalDisease specific survival

Cox regression models with P-Values for Risk Ratios (not shown) for outcomes LocalMetProgressDiseaseOverall Predictor RecRecFree survSpec SurvSurvival Pre vs Post Center (PMH vs other) Upper vs Lower Limb Grade (low vs high) Max Baseline tumor size Depth (superficial vs deep) Primary vs Recurrent Pres Margins (‘pos’ vs ‘neg’)0.01NA0.10NANA CTOS 2004 (Analysis: Dec 2003) NA: not applicable (not included in model)

HR of post-op to Log-rank pre-op with 95% CIp-value 1.2 ( )0.48 ASCO 2004 (Analysis: Dec 2003) Overall survival

Late Subcutaneous Fibrosis (RTOG/EORTC) Grade 0NoneGrade 0None Grade 2slight induration (fibrosis) and loss of subcutaneous fatGrade 2slight induration (fibrosis) and loss of subcutaneous fat Grade 3severe induration and loss of subcutaneous tissue; field contracture >10% linear measurementGrade 3severe induration and loss of subcutaneous tissue; field contracture >10% linear measurement Grade 4necrosisGrade 4necrosis

Probability: 3-yr5-yr Pre-op:20%23% Post-op:26%36% P=0.02, log rank for equality of groups CTOS 2004 (Analysis: Dec 2003) Grade 3 or 4 subcutaneous fibrosis

Cox regression model for Grade 3 and 4 fibrosis Hazard 95% Hazard RatioP-Value Variable Ratio Confidence Limits Schedule (pre vs. post-op) , Centre (PMH vs. other) , D max (total dose) , Phase I field size (cm 2) , CTOS 2004 (Analysis: Dec 2003)

Summary and Conclusions No differences in cancer-specific outcomes between Pre-op vs. Post- op RT with the protocols used in this RCTNo differences in cancer-specific outcomes between Pre-op vs. Post- op RT with the protocols used in this RCT Very high local control rates (95 % range) are evident with combined Surgery and RT in extremity STSVery high local control rates (95 % range) are evident with combined Surgery and RT in extremity STS Morbidity profiles differ between both approaches:Morbidity profiles differ between both approaches: –Acute complications: significantly greater in pre-op (recoverable) –Late tissue effects: significantly greater in post-op (likely permanent) Local anatomic factors and wound reconstruction should dictate the choice of radiotherapy scheduleLocal anatomic factors and wound reconstruction should dictate the choice of radiotherapy schedule New local control techniques or approaches are needed to ameliorate local tissue toxicity (especially fibrosis, and bone later)New local control techniques or approaches are needed to ameliorate local tissue toxicity (especially fibrosis, and bone later) CTOS 2004 (Analysis: Dec 2003)

HR of post-op to Log-rank pre-op with 95% CIp-value 1.2 ( )0.48 ASCO 2004 (Analysis: Dec 2003) Overall survival

HR of post-op to Log-rank pre-op with 95% CIp-value 1.2 ( )0.48 ASCO 2004 (Analysis: Dec 2003) Overall survival

HR of post-op to Log-rank pre-op with 95% CIp-value 1.2 ( )0.48 ASCO 2004 (Analysis: Dec 2003) Overall survival ?

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

Cox regression model for Local Control Predictor p-value Risk Ratio95% CI for Risk Ratio Pre vs Post (0.23,2.2) Centre (PMH vs other) (0.41,4.27) Upper vs Lower Limb (0.22,5.25) Grade (low vs high) (0.13,2.79) Max Baseline tumor size (1.00,1.06) Depth (superficial vs deep) (0.07,4.89) Primary vs Recurrent Pres (0.15,4.54) Margins (‘pos’ vs ‘neg’) (1.38,15.7) CTOS 2004 (Analysis: Dec 2003)