ARTDECO
Randomized Study on Dose Escalation in Definitive Chemoradiation for Locally Advanced Esophageal Cancer
Hulshof et al.
Journal of Clinical Oncology 2021
Background
- Standard dose of 50 Gy with concurrent chemotherapy is standard for definitive chemoradiation (dCRT) in esophageal cancer
- Previous RTOG INT 0123 trial showed no benefit of 64.8 Gy vs 50.4 Gy
- Study hypothesis: Modern techniques and improved chemotherapy could allow safe dose escalation
- Primary endpoint: Local progression-free survival
Methods
- Phase 3 randomized trial in 16 Dutch centers
- Inclusion: T1-4N0-3M0 or M1 (supraclavicular nodes only)
- Medically inoperable, technically unresectable, or patient preference
- Randomized between:
- Standard dose (SD): 50.4 Gy in 28 fractions
- High dose (HD): 61.6 Gy to tumor, 50.4 Gy to nodes in 28 fractions
- All patients received weekly carboplatin/paclitaxel x 6 weeks
Patient Characteristics
- 260 patients enrolled (130 per arm)
- Well-balanced baseline characteristics:
- Median age: 70.5 years
- 62% squamous cell carcinoma, 38% adenocarcinoma
- 70% T3 disease
- 74% node positive
- 39% lower thoracic location
- Main reasons for dCRT: Medical unfit (28%), proximal location (20%), extensive nodes (13%)
Radiation Planning Details
Target Volumes
- GTV: Primary tumor + involved nodes
- CTV: GTV + 3cm superior/inferior margin
- Node regions included:
- Periesophageal tissue
- Bilateral supraclavicular
- Aortopulmonary window
- Subcarinal area
- PTV: CTV + 1cm all directions
Dose Constraints
- Lung V20 < 30%
- Mean lung dose ≤ 16 Gy
- Heart V45 < 50%
- Spinal cord max < 50 Gy
Technical Details
- IMRT or VMAT allowed
- Minimum weekly verification
- ≥ 6 MV photons
ART DECO
Schema
Randomization (N=260)
Standard Dose (n=130)
↓
50.4 Gy/28 fx
Weekly carboplatin (AUC 2) + paclitaxel (50 mg/m2)
↓
RT completed: 96%
Chemo completed: 69%
High Dose (n=130)
↓
61.6 Gy/28 fx tumor
50.4 Gy/28 fx nodes
Weekly carboplatin (AUC 2) + paclitaxel (50 mg/m2)
↓
RT completed: 92%
Chemo completed: 59%
Primary Outcome
- 3-year progression-free survival:
- Standard dose: 70% (95% CI: 62-81%)
- High dose: 73% (95% CI: 64-83%)
- No significant difference (p=0.62)
- No difference by histology:
- SCC: 75% vs 79% (SD vs HD)
- Adenocarcinoma: 61% vs 61%
Primary Outcome
- 3-year progression-free survival:
- Standard dose: 70% (95% CI: 62-81%)
- High dose: 73% (95% CI: 64-83%)
- No significant difference (p=0.62)
- No difference by histology:
- SCC: 75% vs 79% (SD vs HD)
- Adenocarcinoma: 61% vs 61%
- SCC appear to do better but due to way the analyzed this it was not statistically significant
Secondary Outcomes
-
3-year overall survival:
- Standard dose: 42% (95% CI: 34-52%)
- High dose: 39% (95% CI: 31-49%)
- No significant difference (p=0.22)
- 3-year locoregional PFS:
- Standard dose: 52%
- High dose: 59%
- p=0.08
Secondary Outcomes
- 3-year overall survival:
- Standard dose: 42% (95% CI: 34-52%)
- High dose: 39% (95% CI: 31-49%)
- No significant difference (p=0.22)
-
3-year locoregional PFS:
- Standard dose: 52%
- High dose: 59%
- p=0.08
Pattern of Failure Analysis
Site of First Failure
- No Progression: 46.2%
- Locoregional Only: 25.3%
- Distant Only: 19.1%
- Both: 9.2%
Location of Local Failure
- Primary Tumor Only: 62.4%
- Primary + Nodes: 17.2%
- In-field Nodes Only: 8.6%
- Out-of-field Nodes: 11.8%
Key Observations:
- Most failures occur at primary tumor site despite dose escalation
- Similar pattern between standard and high-dose arms
- Low rate of isolated nodal failures
- Almost half of patients remain progression-free
Treatment Compliance & Toxicity
- Radiation completion:
- Standard dose: 96%
- High dose: 92%
- Chemotherapy completion (6 cycles):
- Standard dose: 69%
- High dose: 59%
- Grade 4-5 toxicity:
- Standard dose: 16% (grade 4: 13%, grade 5: 3%)
- High dose: 22% (grade 4: 14%, grade 5: 8%)
- Most common grade 5: bleeding, fistula
Strengths and Limitations
- Strengths:
- Large, well-designed phase 3 trial
- Long follow-up (median 50 months)
- Modern radiation techniques
- Well-balanced arms
- Limitations:
- Higher grade 5 toxicity in HD arm may have affected results
- Weekly setup verification only required (though many centers used daily)
- Selected population (62% SCC)
- No quality of life data
Conclusions
- Dose escalation to 61.6 Gy did not improve local control or survival compared to 50.4 Gy
- Results consistent with RTOG INT 0123 despite:
- Modern radiation techniques
- Less toxic chemotherapy regimen
- Integrated boost approach
- 50.4 Gy remains the standard dose for definitive chemoradiation
- Higher radiation doses may not be feasible due to esophageal toxicity
Dose Escalation Trials in Esophageal Cancer
|
Trial |
N |
Population |
Treatment Arms |
Key Outcomes |
Notable Findings |
|---|---|---|---|---|---|
|
ARTDECO |
260 |
T2-4N0-3M0/M1 supraclav |
50.4 Gy vs 61.6/50.4 Gy SIB |
3-yr LPFS: 70% vs 73% |
No benefit with modern techniques |
|
CONCORDE |
109 |
Unresectable |
40 Gy + 10 Gy boost vs |
2-yr LRPFS: 43-44% |
IMRT improved outcomes: |
|
INT 0123 |
236 |
Inoperable |
50.4 Gy vs 64.8 Gy |
2-yr OS: 31% vs 40% |
Closed early for toxicity |
- Three randomized trials consistently show no benefit to dose escalation above 50.4 Gy
- Modern RT techniques (IMRT/VMAT) may improve outcomes independent of dose
- Weekly carbo/taxol appears better tolerated than older cisplatin-based regimens
- Toxicity may limit ability to safely escalate dose beyond current standards