SCOPE 2 Trial Overview
SCOPE2 is a UK-based phase II/III randomized trial evaluating radiotherapy dose escalation in oesophageal cancer, building upon the SCOPE-1 trial which tested definitive chemoradiotherapy with or without cetuximab. 1, 2
Trial Design and Objectives
SCOPE2 specifically investigates whether escalating radiotherapy doses improves outcomes in oesophageal cancer patients receiving definitive chemoradiotherapy (dCRT). 1 This trial represents the next generation of UK oesophageal cancer research following SCOPE-1, which closed early in February 2012 after demonstrating that adding cetuximab to conventional dCRT resulted in greater toxicity and worse survival outcomes. 2
Key Findings from SCOPE-1 (The Predecessor Trial)
The SCOPE-1 trial provides critical context for understanding SCOPE2's rationale:
258 patients were randomized between February 2008 and February 2012 to receive cisplatin 60 mg/m² (day 1) and capecitabine 625 mg/m² twice daily (days 1-21) for four cycles, with or without cetuximab. 2
Radiotherapy consisted of 50 Gy in 25 fractions given concurrently with cycles 3 and 4. 2
Median overall survival was 34.5 months (95% CI: 24.7-42.3) in the dCRT arm versus 24.7 months (95% CI: 18.6-31.3) in the dCRT plus cetuximab arm (HR=1.25, P=0.137). 2
The dCRT regimen demonstrated useful survival outcomes despite being used predominantly in patients who were unfit for surgery or had inoperable disease, with 72.9% having squamous cell histology. 2
Multivariable analysis identified earlier stage, full-dose radiotherapy, and higher cisplatin dose intensity as factors associated with improved overall survival. 2
SCOPE2 Radiotherapy Quality Assurance Program
The SCOPE2 trial implemented a comprehensive radiotherapy quality assurance (RTQA) program consisting of pre-accrual and on-trial components, revealing substantial challenges in protocol adherence despite detailed guidance. 1
Pre-Accrual Requirements
Acceptable submission of 3D ± 4D benchmark contouring exercises and a high-dose planning case were mandatory before site activation. 1
Only 47% (30/64) of pre-accrual contouring submissions were approved on initial review. 1
59% (38/64) contained ≥1 unacceptable target volume variation from protocol, most commonly in CTVB (clinical target volume B) and ITV (internal target volume). 1
21% (6/28) of organ-at-risk contours contained ≥1 unacceptable variation, most frequently in heart and spinal cord delineation. 1
On-Trial Quality Assurance
Prospective reviews were required for each center's first 3D ± 4D patient and all high-dose cases prior to formal safety review, with additional reviews at the RTQA team's discretion. 1
65% (82/126) of on-trial contouring submissions were approved initially, representing significant improvement over pre-accrual performance (p=0.016). 1
37% (47/126) still contained ≥1 target volume unacceptable variation, most commonly in CTVB, GTV (gross tumor volume), and ITV. 1
24% (30/126) contained ≥1 organ-at-risk unacceptable variation, most frequently in heart and lung contours. 1
Planning Quality Assurance
79% (32/43) of pre-accrual plans were approved, with unacceptable cases due to PTV (planning target volume) coverage or conformity issues. 1
98% (118/120) of on-trial plans were approved, with the two unacceptable cases also related to PTV coverage/conformity. 1
No unacceptable variations in organ-at-risk dose constraints were observed in the planning phase. 1
All on-trial submissions were ultimately approved following resubmission where necessary. 1
Critical Lessons and Implications
Despite providing a radiotherapy planning guidance document (RPGD), contouring atlas, and similar protocols from preceding trials, SCOPE2 demonstrated a persistently high frequency of unacceptable variations, particularly in target volume delineation. 1 This finding has profound implications:
CTVB contouring remains the most challenging aspect, appearing as the most common source of unacceptable variation in both pre-accrual and on-trial submissions. 1
The learning curve effect is real but incomplete: on-trial submissions showed statistically significant improvement over pre-accrual (p=0.016), yet more than one-third still contained protocol violations. 1
Planning quality exceeded contouring quality, with 98% of on-trial plans approved versus only 65% of contours, suggesting that dose optimization is more standardizable than anatomical delineation. 1
Future Directions: PROTIEUS Trial
The SCOPE2 RTQA findings directly inform recommendations for PROTIEUS, the next UK trial in oesophageal radiotherapy. 1 The persistent challenges in achieving protocol compliance despite extensive quality assurance measures underscore the need for enhanced training, potentially more prescriptive contouring guidance, and consideration of centralized contouring or real-time expert review for complex anatomical regions like CTVB. 1
The competing risks of systemic and local failure identified in SCOPE-1's mature analysis support SCOPE2's focus on radiotherapy dose escalation, as future studies must continue optimizing both local control and systemic therapy. 2