Five year results of a randomized Five year results of a randomized Phase III trial of pre-operative Phase III trial of pre-operative vs post-operative radiotherapy in vs post-operative radiotherapy in extremity soft tissue sarcoma extremity soft tissue sarcoma Brian O'Sullivan, Aileen Davis, Robert Brian O'Sullivan, Aileen Davis, Robert Turcotte, Robert Bell, Jay Wunder, Charles Turcotte, Robert Bell, Jay Wunder, Charles Catton, Rita Kandel, Alex Hammond, Carolyn Catton, Rita Kandel, Alex Hammond, Carolyn Freeman, Marc Isler, Karen Goddard, Pierre Freeman, Marc Isler, Karen Goddard, Pierre Chabot, Dongsheng Tu, Joseph Pater Chabot, Dongsheng Tu, Joseph Pater Canadian Sarcoma Group • National Cancer Institute of Canada, Clinical Trials Group / Groupe des assais clinique
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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
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)
HR of post-op to Log-rankpre-op with 95% CI p-value
1.2 (0.4-3.5) 0.76
HR of post-op to Log-rankpre-op with 95% CI p-value
0.96 (0.6-1.6) 0.86
HR of post-op to Log-rankpre-op with 95% CI p-value
1.0 (0.7-1.6) 0.92
HR of post-op to Log-rankpre-op with 95% CI p-value
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
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
CTOS 2004 (Analysis: Dec 2003)
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)
CTOS 2004 (Analysis: Dec 2003)
HR of post-op to Log-rankpre-op with 95% CI p-value
1.2 (0.7-2.0) 0.48
ASCO 2004 (Analysis: Dec 2003)
Overall survival
HR of post-op to Log-rankpre-op with 95% CI p-value
1.2 (0.7-2.0) 0.48
ASCO 2004 (Analysis: Dec 2003)
Overall survival
HR of post-op to Log-rankpre-op with 95% CI p-value
1.2 (0.7-2.0) 0.48
ASCO 2004 (Analysis: Dec 2003)
Overall survival
?
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