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SR-2 Trial (NCIC CTG / CSG)

Five year results of a randomized Phase III trial of pre-operative vs post-operative radiotherapy in extremity soft tissue sarcoma.

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SR-2 Trial (NCIC CTG / CSG)

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  1. 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

  2. CTOS 2004 SR-2 Trial (NCIC CTG / CSG) RANDOMIZATION • Pre-op RT • 50 Gy in 25 fractions • Phase 2 to 66 Gy, if margins positive • 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 Phase 1: 5 cm longitudinal 2 cm axial Phase 2: 2 cm coverage • Post-op RT • 50 Gy in 25 fractions • Phase 2 to 66 Gy, all cases

  3. CTOS 2004 SR-2 Trial • Trial open from late 1994 to late 1997 • 190 patients entered from 10 Canadian centres • 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 addressed

  4. Background Previous Analyses (3.3 years Median FU) • Primary End-point (wound complications) • Twice the rate in pre vs post-op (35 vs 17%) • Confined to the lower extremity • Secondary 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

  5. Background SR-2 Local Control and Survival: First analysis (3.3 yrs median follow up) Lancet 2002;359:2235-2241

  6. CTOS 2004 (Analysis: Dec 2003) • Pre-op Post-op Total • n (%) n (%) n (%) • Total 94 (100) 96 (100) 190 (100) • Gender: Female 42 (45) 44 (46) 86 (45) • Male 52 (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) • Presentation Primary 83 (88) 89 (93) 172 (91) • Recurrent 11 (12) 7 (7) 18 (9) Patient Characteristics Median Follow-up: 6.9 years(range 0 – 8.6 years)

  7. CTOS 2004 (Analysis: Dec 2003) • Pre-op Post-op Total • n (%) n (%) n (%) • Total 94 (100) 96 (100) 190 (100) • Size: ≤ 10 cm 61 (65) 64 (67) 125 (66) • (stratification) > 10 cm 33 (35) 32 (33) 65 (34) • Grade: Low 15 (16) 17 (18) 32 (17) • Interm / High 79 (84) 79 (82) 158 (83) • Histology MFH 29 (31) 23 (24) 52 (27) • Liposarc. 26 (28) 26 (27) 52 (27) • Leiomyos. 10 (11) 9 (9) 19 (10) • Other 29 (31) 38 (40) 67 (35) Tumor Characteristics

  8. Pre-op Post-op Total • n (%) n (%) n (%) • Total 94 (100) 96 (100) 190 (100) • Compartment: Intracompartment 48 (51) 50 (52) 100 (52) • Extra – by growth 29 (31) 26 (27) 55 (29) • Extra - iatrogenic 12 (13) 11 (11) 23 (12) • Extra - de novo 5 (5) 9 (9) 14 (7) • Depth: Deep to fascia 56 (59) 48 (50) 104 (55) • Deep & Superficial 23 (24) 28 (29) 51 (27) • Superficial 15 (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 margins Positive 14 (15) 13 (13) 27 (14) • Negative 80 (85) 83 (87) 163 (86) • * Distal upper includes elbow; Proximal lower includes knee AnatomicCharacteristics

  9. CTOS 2004 (Analysis: Dec 2003) Patient status at last follow-up Pre-op Post-op Total n % n % n % Alive 64 (68) 62 (65) 126 (66.3) Dead 30 (32) 34 (35) 64 (33.7) Cause of death: Disease 24 (80) 26 (76) 50 (78) Non-protocol complication 0 (0) 1 (3) 1 (2) Other 4 (13) 4 (12) 8 (12) Other primary cancer 2 (7) 3 (9) 5 (8) Total 94 (100) 96 (100) 190 (100)

  10. 5 year local control by TumorCharacteristics • Pre-op Post-op • N = 94 N = 96 • Compartment: Intracompartment 92.9% 97.9% • Extra-compartmental 93.0% 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% • Grade Low 86.7% 100% • High 94.5% 90.5%

  11. 5 year local control by prognostic factors • Pre-op Post-op • N = 94 N = 96 • Resection Margins 95.8% 95.0% • 77.1% 73.3% • Treatment Center: PMH 91.7% 92.0% • Other 94.4% 92.7% • Presentation: Primary 93.4% 91.7% • Recurrent 90.0% 100.0% • Age <50 93.0% 97.7% • >=50 93.0% 87.2% • Gender Male 95.4% 96.0% • Female 90.0% 87.9% • Pre-op Post-op • N = 94 N = 96 • Resection Margins Negative 95.8% 95.0% • Positive 77.1% 73.3% • Treatment Center: PMH 91.7% 92.0% • Other 94.4% 92.7% • Presentation: Primary 93.4% 91.7% • Recurrent 90.0% 100.0% Environmental / Treatment Host Factors

  12. Local recurrence free Regional / distant recurrence free HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.4-3.5) 0.76 HR of post-op to Log-rank pre-op with 95% CI p-value 0.96 (0.6-1.6) 0.86 Progression free survival Disease specific survival HR of post-op to Log-rank pre-op with 95% CI p-value 1.0 (0.7-1.6) 0.92 HR of post-op to Log-rank pre-op with 95% CI p-value 1.1 (0.7-2.0) 0.64

  13. CTOS 2004 (Analysis: Dec 2003) Cox regression models with P-Values for Risk Ratios (not shown) for outcomes Local Met Progress Disease Overall Predictor Rec Rec Free surv Spec Surv Survival Pre vs Post 0.56 1.00 0.79 0.49 0.32 Center (PMH vs other) 0.63 0.94 0.73 0.81 0.22 Upper vs Lower Limb 0.92 0.82 0.83 0.90 0.24 Grade (low vs high) 0.52 0.01 0.005 0.02 0.008 Max Baseline tumor size 0.11 0.020.10 0.0005 0.0002 Depth (superficial vs deep) 0.63 0.57 0.91 0.34 0.62 Primary vs Recurrent Pres. 0.88 0.50 0.73 0.94 0.98 Margins (‘pos’ vs ‘neg’) 0.01 NA 0.10 NA NA NA: not applicable (not included in model)

  14. ASCO 2004 (Analysis: Dec 2003) Overall survival HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.7-2.0) 0.48

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

  16. CTOS 2004 (Analysis: Dec 2003) Grade 3 or 4 subcutaneous fibrosis Probability: 3-yr 5-yr Pre-op: 20% 23% Post-op: 26% 36% P=0.02, log rank for equality of groups

  17. CTOS 2004 (Analysis: Dec 2003) Cox regression model for Grade 3 and 4 fibrosis Hazard 95% Hazard Ratio P-Value Variable Ratio Confidence Limits Schedule (pre vs. post-op) 1.084 0.513, 2.291 0.8325 Centre (PMH vs. other) 0.711 0.406, 1.248 0.2350 D max (total dose) 1.037 0.989, 1.087 0.1316 Phase I field size (cm2) 1.002 1.001, 1.003 0.0006

  18. 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 RCT • Very high local control rates (95 % range) are evident with combined Surgery and RT in extremity STS • 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 schedule • New local control techniques or approaches are needed to ameliorate local tissue toxicity (especially fibrosis, and bone later)

  19. ASCO 2004 (Analysis: Dec 2003) Overall survival HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.7-2.0) 0.48

  20. ASCO 2004 (Analysis: Dec 2003) Overall survival HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.7-2.0) 0.48

  21. ASCO 2004 (Analysis: Dec 2003) Overall survival ? HR of post-op to Log-rank pre-op with 95% CI p-value 1.2 (0.7-2.0) 0.48

  22. Brian O’Sullivan, a.k.a. “the Enforcer”, Toronto Maple Leafs, c. 1966-67 1931-32 1941-42 1944-45 1946-47 1947-48 1948-49 1950-51 1961-62 1962-63 1963-64 1966-67

  23. CTOS 2004 (Analysis: Dec 2003) Cox regression model for Local Control Predictor p-value Risk Ratio 95% CI for Risk Ratio Pre vs Post 0.56 0.72 (0.23,2.2) Centre (PMH vs other) 0.63 1.33 (0.41,4.27) Upper vs Lower Limb 0.92 1.08 (0.22,5.25) Grade (low vs high) 0.52 0.60 (0.13,2.79) Max Baseline tumor size 0.11 1.02 (1.00,1.06) Depth (superficial vs deep) 0.63 0.60 (0.07,4.89) Primary vs Recurrent Pres. 0.88 1.18 (0.15,4.54) Margins (‘pos’ vs ‘neg’) 0.014.66 (1.38,15.7)

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