Table 3.

Prospective Studies on Dose Escalation/Elevated Dose in Non-Operative Management of Esophageal Cancer.

Completed
Study	Patient Population	Treatment	Results	Comments
INT 0123 (Minsky et al., 2002)	Phase III 218 eligible patients T1-T4 N0-1 M0 Adeno: 14% Squamous CC: 86%	RT: 50.4 Gy in 1.8 Gy/fx vs. 64.8 Gy in 1.8 Gy/fx 2D Treatment Chemo: Cisplatin/5-FU	High dose vs standard: MS: 13 mo vs 18.1 mo (NS) 2 yr OS: 31% vs 40% (NS) 2 yr LRF: 56% vs 52% (NS) Distant failure: 9% vs 16% Grade 5 toxicity: 11 pts vs 2 pts	• 7 deaths in high dose arm occurred at or before 50.4 Gy • When early deaths factored out, survival still comparable between high and standard dose arms
RTOG 9207 (Gaspar et al., 2000)	Phase I/II 49 eligible patients T1-2 NX-1 M0 No cervical tumors or within 1 cm GE junction Adeno: 8% Squamous CC: 92%	RT: EBRT: 50 Gy in 2 Gy/fx Brachytherapy boost: LDR: 20 Gy HDR: Initially 15 Gy in 3 fx, later changed 10 Gy in 2 fx Chemo: Cisplatin/5-FU	MS: 11 months “Life threatening” toxicity: 12 pts (24%) Grade 5 toxicity: 5 pts (10%) Esophageal fistula developed in 6 pts (12%)	• Regimen felt not to be feasible due to high rate of toxicity
MD Anderson (Chen et al., 2019)	Phase I/II 46 eligible patients All stages including IV with up to 3 metastatic sites Adeno: 48% Squamous CC: 52%	RT: Simultaneous integrated boost (SIB) 50.4 Gy in 1.8 Gy/fx to PTV 63.0 Gy in 2.25 Gy/fx to IGTV IMRT: 85% IMPT: 15% Chemo: Docetaxel + 5-FU or Capecitabine. Induction allowed but not mandated (37% received) 11% ultimately received surgery	MS: 21.5 months 2 yr OS: 41.3% No difference between histologies 2 yr LR: 33% Grade 3 acute toxicity in 10 pts No Grade 4 or 5 toxicity 17 pts (37%) developed esophageal strictures	• Study compared SIB dose escalated patients to similar institutional patients receiving standard dose RT • SIB showed improved OS (HR 0.66, CI: 0.47 to 0.94) •SIB showed reduced LR (HR 0.49, CI: 0.26 to 0.92)
ESO-Shanghai 1 (Chen et al., 2019)	Phase III 436 eligible patients Stage IIA to IVA (AJCC, 6th) Adeno: 0% Squamous CC: 100%	RT: 61.2 Gy in 1.8 Gy/fx Chemo: Cisplatin/5-FU vs Paclitaxel/5-FU	Cisplatin/5-FU vs Paclitaxel/5-FU 2 yr OS: 61.5% vs 60.6% (NS) Median PFS: 24.3 mo vs 21.0 ms (NS) LR free survival and Metastasis free survival comparable Grade 3+ toxicity: 51.6% vs 48.8% (NS)	• Total doses of 60-64 Gy in 1.8-2 Gy/fx considered standard of care in China per national guidelines [18]

Ongoing
Study	Eligible Patient Population	Treatment	Preliminary Results	Status
CONCORD-PRODIGE 26 Clinicaltrials.gov: NCT01348217	Age ≥ 18 and <75 T1-3 N1-3 M0 Inoperable	Arm A: RT: 40 Gy in 2 Gy/fx + boost 10 Gy in 5 fx (50 Gy total) Chemo: FOLFOX Arm B: RT: 40 Gy in 2 Gy/fx + boost 26 Gy in 13 fx(66 Gy total) Chemo: FOLFOX	196 pts enrolled Preliminary Abstract [13]: 160 pts evaluated IMRT (vs 3DC) in 70% in both arms Standard vs High Dose: Grade 3+ toxicity: Non-heme: 77% vs 86% (NS) Heme: 83% vs 89% (NS)	Completed, Final Results Pending
ARTDECO Netherlands Trial Register ID: 3532	Age > 18 T1-4 N0-3 M0 Inoperable	Arm A: RT: 50.4 Gy in 1.8 Gy/fx Chemo: Carboplatin/paclitaxel Arm B: RT: 50.4 Gy in 1.8 Gy/fx with SIB to 61.6 Gy in 2.2 Gy/fx Chemo: Carboplatin/paclitaxel	Preliminary Abstract [12]: 260 pts eligible 61% with Squamous CC and 39% adenocarcinoma Standard vs High Dose: 3 yr OS: 41% vs 40% (NS) 3 yr LPFS: 70% vs 76% (NS) 3 yr LRPFS: 53% vs 63% (p = 0.08) Grade 4 toxicity: 12% vs 14% Grade 5 toxicity: 4% vs 10%	Completed, Final Results Pending
SCOPE 2 Clinicaltrials.gov: NCT02741856	Age ≥ 17 T1-4 N0 or N+ M0	Arm 1: RT: 50 Gy in 2 Gy/fx Chemo: Carboplatin/paclitaxel Arm 2: RT: 50 Gy in 2 Gy/fx Chemo: Cisplatin/capecitabine Arm 3: RT: 60 Gy in 2.4 Gy/fx Chemo: Carboplatin/paclitaxel Arm 4: RT: 60 Gy in 2.4 Gy/fx Chemo: Cisplatin/capecitabine	None	Recruiting
Washington University Clinicaltrials.gov: NCT04046575	Age ≥ 18 Inoperable Amenable to definitive chemoradiation	Phase I RT: 40.05 Gy in 2.67 Gy/fx to PTV Starting dose boost SIB: 50 Gy in 3.33 Gy/fx Chemo: carboplatin/paclitaxel	None	Recruiting