Table 1. Characteristics of included studies.
| Author | Study/year | N (pts) (exp vs. ctr) | Neoadjuvant RT | Neoadjuvant CT (exp vs. ctr) | Adjuvant therapy | pCR% (exp vs. ctr) | ∆pCR% | 3Y-DFS% (exp-ctr)/∆3yDFS (%) | 5Y-OS% (exp-ctr)/∆5yOS (%) | Median FU (months)/primary endpoint |
|---|---|---|---|---|---|---|---|---|---|---|
| Wong RTOG 0247 | Phase II RCT/2012–2015 | 52 vs. 52 | 50.4 Gy/28 fx | CAPIRI vs. CAPOX | √ | 10.4 vs. 20.8 | 10.4 | 70-62/8 | 59-72/−13 | 3.77–3.97 years/pCR |
| Rodel CAO/ARO/AIO-04 | Phase III/2015 | 613 vs. 623 | 50.4 Gy/28 fx | 5-FU + OXA vs. 5-FU | √ | 17 vs. 13 | 4 | 76-72/4* | 78-80/−2 | 50/DFS |
| Sainato I-CNR-RT | Phase III/2014 | 334 vs. 321 | 45 Gy/25 fx | 5FU + FA bolus gg 1–5, 29–33 (all pts) | Adj vs. no adj CT | 18.6 vs. 17 | 1.6 | 70-70/0 | 66.9-67.9/−1 | 63.7/OS |
| Appelt | Phase III/2013 | 111 vs. 110 | 50 Gy/28 fx + brachi RT boost vs. 50 Gy/28 fx + EBRT boost | Oral UFT + FA | At discretion | 18 vs. 18 | 0 | 62-67&/−5 | 70.6-73.6/3 | 5.4 years/pCR |
| Saglam Istanbul R-01# | Phase II RCT/2014 | 76 vs. 77 | 45 Gy/25 fx | 5FU 225 mg/m2 d ic | Optional | 1.3 vs. 1.3 | 0 | 74-74/0 | 76.5-74.2/2.3 | 56.8–59.3/local recurrences |
| Jeong** | Phase III/2014 | 170 vs. 170 | 45 Gy/25 fx + EBRT boost | CAP or 5FU + FA or UFT + FA or CAPIRI or CAPIRI + cetuximab | √ | NR | NR | 73-78/−5 | 83-88/−5 | 46–48/3Y DFS |
| Bosset EORTC 22921 | Phase III/2006 | 506 vs. 505 | 45 Gy/25 fx | 5FU + FA bolus gg 1–5, 29–33 (only pts in CTRT arms) | Randomization to adjuvant CT | 13.7 vs. 5.3 | 8.4 | NR/– | 64.8-65.8/−1 | 5.4 years/OS |
| Gerard ACCORD 12 | Phase III/2012 | 299 vs. 299 | 45 Gy/25 fx (arm 1) vs. 50 Gy/25 fx (arm 2) | CAP (arm 1) vs. CAPOX (arm 2) | At discretion | 19.2 vs. 13.9 | 5.3 | 72-67.9/4.1 | NR/– | 36.8/pCR |
| Ngan Trans Tansman RTOG 01-04 | Phase III/2012 | 163 vs. 163 | 50.4 Gy/28 fx (arm 1) vs. 25 Gy/5 fx (arm 2) | 5FU 225 mg/m2 d ic (arm 1) | √ | NR | NR | 68-74&&/−6 | 70-74/−4 | 5.9 years/local recurrences |
| Sauer CAO-ARO-AIO-94 | Phase III/2004 | 415^ | 50.5 Gy/28 fx (arm 1) | 5FU 1,000 mg/m2 gg 1–5 week 1 & 5 (arm 1) | √ | 8 | NA | 75/– | 76/– | 45.8/OS |
| Hofheinz | Phase III/2012 | 81 vs. 80^^ | 50.4 Gy/5–6 weeks | CAP vs. 5FU 1,000 mg/m2 gg 1–5 week 1 & 5 | √ | 14 vs. 5 | 9 | 71-63/8 | 66-61/5 | 52/OS |
| Park | Phase III/2011 | 107^^ | 50.4 Gy/25 fx | CAP | √ (+ randomization to adjuvant CTRT) | 17 | NA | 77/NA | 90/NA | 52/3Y DFS |
| Roh NSABP R-03 | Phase III/2009 | 123^^ | 45 Gy/25 fx (+ randomization to adjuvant CTRT) | 5FU + FA bolus x6 weeks → 5FU + FA bolus weeks 1 & 5 |
√ | 15 | NA | 70/NA | 67/NA | NA/DFS & OS |
| Braendengen | Phase III/2008 | 98 vs. 109 | 50 Gy | ± 5FU bolus gg 1,2,11,12,21,22 | 5FU + FA in CTRT arm (permitted in RT arm) | 16 vs. 7 | 9 | 65-48§/13 | 66-53/13 | 61/5Y OS |
| Bujko | Phase III/2006 | 157 vs. 155 | 50 Gy/28 fx (arm 1) vs. 25 Gy/5 fx (arm 2) | 5FU + FA bolus weeks 1 & 5 (arm 1) | Optional | 16.1 vs. 0.7 | 15.4 | 60-63/−3 | NA/– | 48/sphincter preservation |
| Mohiuddin RTOG-0012 | Phase II RCT/2013 | 50 vs. 53 | 45.6 Gy/1.2 Gy fx bid + boost (arm 1) vs. 45 Gy/1.8 Gy fx + boost (arm 2) | 5FU 225 mg/m2 d ic (arm 1) + 5FU 225 mg/m2 d ic + weekly CPT11 (arm 2) | – | 30 vs. 26 | 4 | NA/NA | 61-75/−14 | 6.4–7 years/pCR & toxicity |
| Pach | Phase II RCT/2012 | 77 vs. 77 | 25 Gy/5 fx (random to immediate vs. delayed surgery) | – | – | 10.4 vs. 0 | 10.4 | NA/– | 73-63/10 | 86/recurrences and OS |
| Sebag Montefiore MRC CR07 | Phase III/2009 | 674^^ | 25 Gy/5 fx (+ randomization to adjuvant CTRT) | – | At discretion | NR | – | 70.3/– | 77.5/– | 48/local recurrence |
| Gerard FFCD 9203 | Phase III/2006 | 367 vs. 375 | 45 Gy/25 fx | 5FU + FA bolus weeks 1 & 5 vs. no CT | √ | 11.4 vs. 3.6 | 7.8 | NA&/– | 67.9-67.4/0.5 | 81/OS |
| Glehen Lyons R90-01 | Phase III/2003 | 99 vs. 101 | 39 Gy/13 fx (random to immediate vs. delayed surgery) | – | – | 7 vs. 14 | 7 | NA/– | 69–66/3 | 6.3 years/sphincter preservation & local control |
| Peeters/Kapiteijn TME trial | Phase III/2001–2007 | 924^^ | RT vs. TME surgery alone | – | – | 1 | 1 | NA/– | 64.2/– | 6 years/local control |
| Allegra NSABP R-04 | Phase III/2015 | 1608 | RT 45 Gy/25 fx | 5FU ic or CAP ± OXA | Not known | 19.5 vs. 17.8 | 1.7 | NA/– | 81.3-79/2.3 | NA/locoregional control at 3 y |
| Wong RTOG 0247 | Phase II RCT/2012–2015 | 52 vs. 52 | 50.4 Gy/28 fx | CAPIRI vs. CAPOX | √ | 10.4 vs. 20.8 | 10.4 | 70-62/8 | 66-46/20 | 3.77–3.97 years/pCR |
*, statistically significant; **, randomized to open vs. laparoscopic surgery; #, the study investigated different timing of surgery (4 vs. 8 weeks after neoadjuvant therapy); ^, randomization to neoadjuvant vs. adjuvant therapy but only neoadjuvant arm considered for the purpose of the study; ^^, only neoadjuvant arm; §, time to treatment failure; &&, relapse-free survival; &, progression-free survival. pCR, pathologic complete response; N, number; CT, chemotherapy; RT, radiotherapy; exp, experimental; ctr, control; ∆3yDSF, difference in 3-year disease-free survival rate; ∆5yOS, difference in 5-year overall survival rate; ref, reference; √, offered to all patients ; pts, patients; NA, not applicable for neoadjuvant comparisons; UFT, uracil + tegafur; FA, folinic acid; ic, continuous infusion; 5FU, 5-fluorouracil; CAPOX, capecitabine + oxaliplatin; CAPIRI, capecitabine + irinotecan; OXA, oxaliplatin; d, daily; NR, not reported; 3Y DFS, 3-year disease free survival; 5Y OS, 5-year overall survival; fx, fractions.