Table 1.
Summary of randomized controlled trials included in trial and treatment arm level analyses.
| Trial | Inclusion criteria | Primary endpoint | Median FU (month) | No. | Treatment | pCR (%) | R0 (%) | PFS | OS | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | Median (month) | 1-y (%) | 2-y (%) | 3-y (%) | 5-y (%) | HR | Median (month) | 5-y (%) | ||||||||
| NCRT + surgery vs. surgery alone (n = 8) | ||||||||||||||||
| NEOCRTEC5010 (Yang, 2018) (11) | SCC; age 18-70; T1-4N1M0 and T4N0M0; KPS ≥ 90 | OS | 40.8 | 224 | NCRT + surgery | 43.2* | 98.4* | 0.58*P (DFS) | 100.1* | 85.1 | 77.8 | 70.9 | 63.1 | 0.71*P | 100.1* | 60.8 |
| 34.8 | 227 | Surgery | NA | 91.2* | 41.8* | 75.1 | 60 | 52.1 | 45.8 | 66.5* | 51.1 | |||||
| CROSS (Shapiro, 2015) (12) | SCC and AC; age ≤ 75; T1N1M0 and T2-3N0-1M0; PS ≤ 2 | OS | 84 | 178 | NCRT + surgery | NA | 92* | 0.64*P | 37.7* | 71* | 60* | 51* | 44* | 0.68*P | 48.6* | 47* |
| 188 | Surgery | NA | 69* | 16.2* | 54* | 41* | 35* | 27* | 24* | 33* | ||||||
| FFCD 9901 (Mariette, 2014) (13) | SCC and AC; age ≤ 75; T1-2N0-1M0 and T3N0M0; PS 0-1 | OS | 93.6 | 98 | NCRT + surgery | 33.3* | 93.8* | 0.92*N (DFS) | 27.8* | 71.2 | 51.8 | 40.8 | 35.6* | 0.99*N | 31.8* | 41.1* |
| 97 | Surgery | NA | 92.1* | 27.8* | 75.3 | 58.7 | 44.7 | 27.7* | 41.2* | 33.8* | ||||||
| Lv, 2010 (14) | SCC; Age ≥ 40; stage II-III | PFS | 45.6 | 80 | NCRT + surgery | NA | 97.4* | NA | 46.5* | 89.3* | 75.0 | 61.3* | 37.5 | NA | 53.0* | 43.5* |
| 78 | Surgery + CRT | NA | 78.2* | NA | 45* | 89.1* | 74.9 | 61.1* | 37.2* | NA | 48* | 42.3* | ||||
| 80 | Surgery | NA | 80* | 32.5* | 84.5* | 60.6 | 49.3* | 25.9* | 36* | 33.8* | ||||||
| Burmeister, 2005 (15) | SCC and AC; T1-3N0-1M0; PS ≤ 1 | PFS | 64.8 | 128 | NCRT + surgery | 16 | 80 | 0.82*N | 16.0* | 55.7 | 39.1 | 32.5 | 30.7 | 0.89*N | 22.2* | 26.6 |
| 128 | Surgery | NA | 59 | 12* | 50.1 | 33.8 | 26.3 | 23.2 | 19.3* | 23.4 | ||||||
| Urba, 2001 (16) | SCC, AC and adenosquamous carcinoma; age ≤ 75; resectable; KPS ≥ 60 | NA | 98.4 | 50 | NCRT + surgery | 28* | 97.8 | NA | 9.84 (DFS) | 47.1 | 32.7 | 28* | 25.4 | 0.73*N | 16.9* | 20.3 |
| 50 | Surgery | NA | 97.8 | 9.7 | 46.9 | 22.7 | 16* | 11.6 | 17.6* | 10.1 | ||||||
| Bosset, 1997 (17) | SCC; age ≤ 70; T1-3N0M0 and T1-2N1M0; PS ≤ 2 | OS | 55.2 | 143 | NCRT + surgery | 26* | 81.2 | 0.6*P
(DFS) |
19.7 | 63.7 | 44.5 | 40 | 31.4 | 1*N | 18.6* | 25.2 |
| 139 | Surgery | NA | 68.6 | 8.4 | 44.9 | 32.2 | 27.3 | 24.7 | 18.6* | 24.1 | ||||||
| Walsh, 1996 (18) | AC; age ≤ 76; TanyNanyM0; PS ≤ 2 | OS | 9.6 | 58 | NCRT + surgery | 25* | NA | NA | NA | NA | NA | NA | NA | NA | 16.0* | NA |
| 8.4 | 55 | Surgery | NA | NA | NA | NA | NA | NA | NA | 11.0* | NA | |||||
| NCT + surgery vs. surgery alone (n = 5) | ||||||||||||||||
| Boonstra, 2011 (19) | SCC; T1-3NanyM0; M1a (distal); age < 80; KPS > 70 | OS | 15.6 | 85 | NCT + surgery | NA | 71* | 0.72*P
(DFS) |
5.4 | 46.5 | 38.8 | 32.5 | 28.1 | 0.71*P | 16.0* | 26* |
| 14.4 | 84 | Surgery | NA | 57* | NA | 29.5 | 19.1 | 17.8 | 13.4 | 12* | 17* | |||||
| Ychou, 2011 (20) | AC; age 18-75; PS ≤ 2 | OS | 68.4 | 113 | NCT + surgery | NA | 87* | 0.65*P (DFS) | 20.0 | 67.9 | 46.8 | 40.0 | 34* | 0.69*P | 31.6 | 38* |
| 111 | Surgery | NA | 74* | 12.2 | 49.2 | 30.8 | 25.1 | 19* | 22.3 | 24* | ||||||
| OEO2 (Allum, 2009) (21) | SCC, AC and undifferentiated; resectable | OS | 70.8 | 400 | NCT + surgery | NA | 60* | 0.82*P (DFS) | 7.0 | 42.0 | 29.6 | 24.1 | 19.8 | 0.84*P | 17.8 | 23* |
| 73.2 | 402 | Surgery | NA | 54* | NA | 31.8 | 21.9 | 17.4 | 14.4 | 14.5 | 17.1* | |||||
| RTOG 8911 (Kelsen, 2007) (22) | SCC and AC; age ≥ 18; T1-3NanyM0 | OS | 105.6 | 213 | NCT + surgery | 2.5* | 62* | 0.95N (DFS) | NA | 38.9 | 22 | 16.6 | 14.4 | 1.07*N | 14.9* | 20.6 |
| 227 | Surgery | NA | 59* | NA | 28.9 | 20.4 | 16.5 | 14.3 | 16.1* | 21.8 | ||||||
| Law, 1997 (23) | SCC; TanyNanyM0 | OS | 16.8 | 74 | NCT + surgery | 6.7* | NA | NA | 8.0* | NA | NA | NA | NA | NA | 16.8* | NA |
| 73 | Surgery | NA | NA | 9.7* | NA | NA | NA | NA | 13.0* | NA | ||||||
| NCT vs. postoperative CT (n = 2) | ||||||||||||||||
| JCOG9907 (Ando, 2012) (24) | SCC; Age ≤ 75; stage II-III (excluding T4); PS ≤ 2 | PFS | 61.2 | 164 | NCT + surgery | 2.4* | 94* | 0.84*N | 35.8 | 70.7 | 57.5 | 49.5 | 44* | 0.73*P | NA | 55* |
| 166 | Surgery + CT | NA | 91* | 23.5 | 66.6 | 48.3 | 42.1 | 39* | 36.8 | 43* | ||||||
| NCT01225523 (Zhao, 2015) (25) | SCC; age ≥ 18; resectable; PS ≤ 1 | RFS | 60 | 175 | NCT + surgery + CT | NA | NA | 0.62*P (RFS) | 23.0* | 75.0 | 47.4 | 40.5 | 35* | 0.79*P | 29.04* | 38* |
| 171 | NCT + surgery | NA | NA | 15* | 64.3 | 32.0 | 24.5 | 19.1* | 22.0* | 22* | ||||||
| Induction CT + NCRT/NCT vs. NCRT/NCT (n =2) | ||||||||||||||||
| NCT00525915 (Ajani, 2013) (26) | SCC and AC; T1N+M0 and T2–3NanyM0; age ≤ 75; PS ≤ 1 | pCR | NA | 54 | Induction CT + NCRT + surgery | 26* | NA | NA | NA | NA | NA | NA | NA | NA | 43.68* | 48.4 |
| 55 | NCRT + Surgery | 13* | NA | NA | NA | NA | NA | NA | 45.6* | 45.4 | ||||||
| POET (Stahl, 2017) (27) | AC; T3-4; PS ≤ 1 | OS | 126 | 60 | Induction CT + NCRT + surgery | 14.3* | 88* | 0.64*N | NA | NA | NA | NA | NA | 0.65*N | 30.8* | 39.5* |
| 59 | NCT + Surgery | 1.9* | NA | NA | NA | NA | NA | NA | 21.1* | 24.4* | ||||||
| NCRT vs. NCT (n =1) | ||||||||||||||||
| NCT01362127 (von Döbeln, 2019) (28) | SCC and AC; T1N1 or T2-3N0-1 and M0-1a; age ≤ 75; PS ≤ 1 | pCR | NA | 90 | NCRT + surgery | 28 | 87 | 1.02*N | 24 | 65 | 50.6 | 44* | 38.9* | 1.09*N | 31.4* | 42.2* |
| 91 | NCT + surgery | 9 | 74 | 20.0 | 64.8 | 48.7 | 44* | 33* | 36* | 39.6* | ||||||
| Different NCT regimens (n =2) | ||||||||||||||||
| OE05 (Alderson, 2017) (29) | AC; T1-2N1M0 and T3-4N0-1M0; age ≤ 75; PS ≤ 1 | OS | 76.8 | 446 | ECX + surgery | 7* | 66* | 0.84*N | 21.4* | NA | NA | NA | NA | 0.9*N | 26.2* | 31.7 |
| 451 | CF + surgery | 1* | 59* | 18.4* | NA | NA | NA | NA | 23.4* | 28.9 | ||||||
| OGSG1003 (Yamasaki, 2017) (30) | SCC; T1-4aNanyM0-1LYM(supraclavicular); age ≥ 20; PS ≤ 1 | RFS | 34.8 | 81 | DCF + surgery | NA | 96.2* | 0.53*P (RFS) | NA | 73.0 | 64.1* | 62.1 | NA | 0.62N | NA | NA |
| 34.8 | 81 | ACF + surgery | NA | 95.9* | 10.8 | 47.1 | 42.9* | 41.5 | NA | NA | NA | |||||
| Conventional chemotherapy + targeted drugs (n =2) | ||||||||||||||||
| SAKK 75/08 (Ruhstaller, 2018) (31) | SCC and AC; T2N1-3M0 and T3-4aNanyM0; age 18-75; PS ≤ 1 | PFS | 48 | 149 | Cetuximab + induction CT + NCRT + surgery | 37* | 95* | 0.79*N | 34.8* | 74* | 58* | 50* | 46.4 | 0.73*N | 61.2* | 52.4 |
| 151 | Induction CT + NCRT + surgery | 33* | 97* | 24* | 73* | 50* | 41* | 35.5 | 36* | 41.5 | ||||||
| NCT00450203 (Cunningham, 2017) (32) | AC; resectable; age ≥ 18; PS ≤ 1 | OS | 39.6 | 530 | Bevacizumab + perioperative CT + surgery | 3* | 61* | 1.05*N | NA | NA | NA | NA | NA | 1.09*N | 33.6 | 35.6 |
| 36 | 533 | Perioperative CT + surgery | 5* | 64* | NA | NA | NA | NA | NA | 33.5 | 40.2 | |||||
| Minimally invasive surgery vs. open surgery (n = 2) | ||||||||||||||||
| ROBOT (van der Sluis, 2019) (33) | SCC and AC; T1-4aN0-3M0; age 18-80; PS ≤ 2 | Postoperative complication | 39.6 | 54 | NCRT/NCT + RAMIE surgery | NA | 93* | 0.99N (DFS) | 28.0* | 65.5 | 54.0 | 48.7 | 48.7 | 1.05N | NA | 49.1 |
| 55 | NCRT/NCT + open surgery | NA | 96* | 28.0* | 68.5 | 51.1 | 48.4 | NA | NA | NA | ||||||
| TIME (Straatman, 2017) (34) | SCC and AC; T1-3N0-1M0; age 18-75; PS ≤ 2 | DFS | 27.6 | 59 | NCRT/NCT + MIE | NA | 91.5* | 0.69*N
(DFS) |
17.0 | 70.4 | 43.6 | 40.2* | 31.9 | 0.88*N | 27 | 37.5 |
| 21.6 | 56 | NCRT/NCT + open surgery | NA | 83.9* | 16.9 | 54.7 | 40.3 | 35.9* | 25.4 | 21.8 | 30 | |||||
The standard arm is labeled in bold. *Represents data directly reported in the full text. “P” and “N” in the top right of the HR indicate positive and negative result, respectively. AC, adenocarcinoma; ACF, cisplatin, fluorouracil and adriamycin; CF, cisplatin and fluorouracil; CT, chemotherapy; DCF, cisplatin, fluorouracil and docetaxel; DFS, disease-free survival; ECX, epirubicin, cisplatin and capecitabine; FU, follow-up; HR, hazard ratio; KPS, Karnofsky performance score; MIE, minimally invasive esophagectomy; NA, not available; NCRT, neoadjuvant chemoradiotherapy; NCT, neoadjuvant chemotherapy; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival; PS, performance score; RAMIE, robot-assisted minimally invasive thoracolaparoscopic esophagectomy; RFS, relapse-free survival; SCC, squamous cell carcinoma.