Methods
Search Strategy
Eligibility Criteria
Study Selection
Risk of Bias Assessment
Data Extraction
Data Analysis
Results
Eligible Studies
Risk of Bias
Characteristics of Included Studies
Source | Study protocol | |||||||||
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Author Year Country | Study ID | Period | Study design | Tumor stage | Number of arms | Number of patients | Neoadjuvant chemotherapy | Neoadjuvant radiotherapy total dose (Gy) (number of fractions × fraction dose) | Adjuvant treatment | Interval to surgery (weeks) |
Fluoropyrimidine-based chemoradiotherapy versus multiagent chemoradiotherapy | ||||||||||
Deng19 2016 China | FOWARC | 2010–2015 | Phase III | Stage II (cT3–4N0) and stage III (cT1–4N1–2) | 3 | 165 | 5FU | 46–50.4 Gy (23–28 × 1.8–2) | 7 cycles 5FU | 4–6 |
165 | mFOLFOX6 | 46–50.4 Gy (23–28 × 1.8–2) | 7 cycles mFOLFOX6 | |||||||
165 | mFOLFOX6 | Before or after surgery at physician discretion | 6–8 cycles mFOLFOX6 | |||||||
Gerard25 2010 France | ACCORD 12/0405-Prodige 2 | 2005–2008 | Phase III | cT2 in the anterior and lower rectum, cT3 or resectable cT4 | 2 | 293 | Capecitabine | 45 Gy (25 × 1.8) | Decision left to institution | 6 |
291 | Capecitabine + oxaliplatin | 50 Gy (25 × 2) | ||||||||
Jiao26 2015 China | – | 2007–2010 | Phase III | clinical stage II/III (cT2 in distal anterior or lower rectum, any cT3, resectable cT4, or cN1–2) | 2 | 103 | Capecitabine | 50 Gy (25 × 2) | 6–8 cycles FOLFOX | 6–10 |
103 | Capecitabine + oxaliplatine | 50 Gy (25 × 2) | ||||||||
Jung29 2015 South Korea | 2009–2011 | Phase II | cT3–4 or any cN | 2 | 71 | 5FU | 45–50.4 Gy + 4.5–9.0 Gy (25–28 × 1.8) | 4 cycles 5FU | 4–8 | |
70 | Irinotecan + S-1 | 45–50.4 Gy + 4.5–9.0 Gy (25–28 × 1.8) | ||||||||
Mohiuddin30 2013 USA | RTOG-0012 | 2001–2003 | Phase II | cT3–4 | 2 | 50 | 5FU | 45.6 Gy + 9.6 Gy for cT3/14.4 Gy for cT4 (19 × 1.2 b.i.d.) | Recommended for patients with residual disease | 4–10 |
53 | 5FU + Irinotecan | 45 Gy + 5.4 Gy for cT3/9 Gy for cT4 (25 × 1.8) | ||||||||
O’Connel l27 2014 USA | NSABP R-04 | 2004–2010 | Phase III | Stage II–III (cT3–4N0 or T1–4N1–2) | 4 | 477 | 5FU | 45 Gy + 5.4 Gy for cT3/10.8 Gy for cT4 (25 × 1.8) | Decision left to institution | 6–8 |
329 | 5FU + oxaliplatin | 45 Gy + 5.4 Gy for cT3/10.8 Gy for cT4 (25 × 1.8) | ||||||||
472 | Capecitabine | 45 Gy + 5.4 Gy for cT3/10.8 Gy for cT4 (25 × 1.8) | ||||||||
330 | Capecitabine + oxaliplatin | 45 Gy + 5.4 Gy for cT3/10.8 Gy for cT4 (25 × 1.8) | ||||||||
Rodel28 2015 Germany | CAO/ARO/AIO-04 | 2006–2010 | Phase III | Any cT3–4 or cN1–2 | 2 | 623 | 5FU | 50.4 Gy (28 × 1.8) | 4 cycles 5FU | 5–6 |
613 | 5FU + oxaliplatin | 50.4 Gy (28 × 1.8) | 8 cycles 5FU-OX | |||||||
Valentini60 2008 Italy | 2002–2005 | Phase II | cT3N0–2 | 2 | 83 | 5FU + Cisplatin | 50.4 Gy (25 × 1.8 + 5.4) | Recommended for ypN + , regimen depended on physician preference | 6–8 | |
81 | Raltitrexed + oxaliplatin | 50.4 Gy (25 × 1.8 + 5.4) | ||||||||
Salazar23 2015 Spain | 2009–2011 | Phase II | Stage II–III | 2 | 46 | Capecitabine | 45 Gy (25 × 1.8) | Administered at the investigators’ discretion | 6–8 | |
44 | Capecitabine + bevacizumab | 45 Gy (25 × 1.8) | ||||||||
Induction chemotherapy and chemoradiotherapy versus standard fluoropyrimidine-based chemoradiation | ||||||||||
Borg32 2014 France | INOVA | 2007–2010 | Phase II | cT3N0–2 in the lower rectum, cT3N0 in the midrectum or cT3N1–2 | 2 | 45 | 5FU + bevacizumab | 45 Gy (25 × 1.8) | Left to the investigators’ discretion | 6–8 |
46 | Induction: Bevacizumab + FOLFOX4 CRT: 5FU + bevacizumab | 45 Gy (25 × 1.8) | ||||||||
Fernandez-Martos33 2015 Spain | GCR-3 | 2006–2007 | Phase II | < 2 mm from MRF, ≤ 6 cm from anal verge, cT3, resectable cT4, or any cT3N+ | 2 | 52 | Capecitabine + oxaliplatin | 50.4 Gy (28 × 1.8) | 4 cycles CAPOX | 5–6 |
56 | Induction Capecitabine + oxaliplatin CRT: Capecitabine + oxaliplatin | 50.4 Gy (28 × 1.8) | – | |||||||
Marechal34 2012 Belgium | Phase II | cT2–4 N+ | 2 | 29 | 5FU | 45 Gy (25 × 1.8) | 6–8 | |||
28 | Induction: mFOLFOX6 CRT: 5FU | 45 Gy (25 × 1.8) | ||||||||
Rouanet36 2017 France | GRECCAR-4 | 2011–2014 | Phase II | cT3–4; CRM ≤ 1 mm, inferior tumor margin ≥ 1 cm from anal verge | 4 | 11 | FOLFIRINOX | None | Left to the investigators’ discretion. Advise: ypT0–1N0 no adjuvant treatment. ypT ≥ 2 or ypN ≥ 1: 6 cycles FOLFOX | NR |
19 | Induction FOLFIRINOX CRT: Capecitabine | 50 Gy (25 × 2) | ||||||||
52 | Induction FOLFIRINOX CRT: Capecitabine | 50 Gy (25 × 2) | ||||||||
51 | Induction FOLFIRINOX CRT: Capecitabine | 60 Gy (30 × 2) | ||||||||
Fokas37 2019 Germany | CAO/ARO/AIO-12 | 2015–2018 | Phase II | cT3 < 6 cm from anal verge, cT3b in midrectum (≥ 6 to 12 cm), cT4, or any N+ | 2 | 156 | Induction: 5FU + oxaliplatin CRT: 5FU + oxaliplatin | 50.4 Gy (28 × 1.8) | Not recommended | 6–12 |
150 | CRT: 5FU + Oxaliplatin Consolidation: 5FU + oxaliplatin | 50.4 Gy (28 × 1.8) | ||||||||
Chemoradiotherapy and consolidation chemotherapy versus standard fluoropyrimidine-based chemoradiation | ||||||||||
Kim38 2018 South Korea | KCSG CO 14-03 | 2014–2016 | Phase II | cT3–4 | 2 | 55 | Capecitabine | 50.4 Gy (28 × 1.8) | ypStage 0–1: 6 cycles CAP ypStage II–III: 6 cycles CAPOX | 6–10 |
53 | CRT: Capecitabine Consolidation: Capecitabine + oxaliplatin | 50.4 Gy (28 × 1.8) | 8–10 | |||||||
Moore39 2017 Australia | WAIT | 2012–2014 | Phase III | NS | 2 | 24 | 5FU | 45 Gy + 5.4 Gy (25 × 1.8) | 10 | |
25 | CRT: 5FU Consolidation: 5FU | 45 Gy + 5.4 Gy (25 × 1.8) | ||||||||
SCRT-delay versus CRT | ||||||||||
Latkauskas24 2016 Lithuania | 2007–2013 | Phase III | Stage II–III (T3–4N0 or N +) | 2 | 68 | None | 25 Gy (5 × 5) | 4 cycles 5FU | 6 | |
72 | 5FU | 50 Gy (25 × 2) |
Author year | Treatment summary (CT, RT, adjuvant treatment) | Included cT4 (%) | Included cN + (%) | NCRT | Any ≥ grade 3 CT/CRT toxicitya | Full CT dose | N
surgery
b
| Weeks to surgeryc | Surgical complicationsd | PCR | R0 resection | 3-Year LRe | 3-Year DFSe | 3-Year OSe |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Fluoropyrimidine-based chemoradiotherapy versus multiagent chemoradiotherapy | ||||||||||||||
Deng19 2016 | 5FU 46–50.4 Gy Adj. 7 × 5FU | 34.5 | 77.6 | 155 | CTC 3.0 49 (31.6) | 88.4% | 141 | 7.6 | NR | 20 (14.2) | 128 (90.8) | NR | NR | NR |
FOLFOX6 46–50.4 Gy Adj. 7 × FOLFOX6 | 33.9 | 81.8 | 158 | 87 (55.1) | 94.9% | 149 | 7.4 | 41 (27.5) | 134 (89.9) | |||||
FOLFOX6 No RT Adj. 6–8 × FOLFOX6 | 30.3 | 72.1 | 163 | 40 (24.5) | 94.5% | 152 | 7.4 | 10 (6.6) | 136 (89.5) | |||||
2010 | CAP 45 Gy Adj.: decision left to institute | 5.1 | 70.7 | 293 | CTC 3.0 32 (10.9) | 97.2% | 282 | 6 | 37 (13.1) | 40 (14.2) | 131f | 6.1% | 67.9% | 87.6% |
CAPOX 50 Gy Adj.: decision left to institute | 6.5 | 73 | 291 | 74 (25.4) | 91.2% | 283 | 6 | 36 (12.7) | 55 (19.4) | 131f | 4.4% | 72.7% HR 0.88 [0.65; 1.18] | 88.3% HR 0.94 [0.59; 1.48] | |
Jiao26 2015 | CAP 50 Gy Adj. 6 − 8 × FOLFOX | 37.9 | 77.7 | 103 | CTC 3.0 11 (10.7) | 85.4% | 103 | 7.4 | NR | 20 (19.4) | 98 (95.1) | NR | 69.9% | 86.4% |
CAPOX 50 Gy Adj. 6 − 8 × FOLFOX | 34.0 | 78.6 | 103 | 22 (21.4) | 81.5% | 103 | 8 | 24 (23.3) | 100 (97.1) | 80.6% | 90.3% | |||
Jung29 2015 | 5FU 50.4 Gy Adj. 4 × 5FU | 19.7 | 88.7 | 71 | CTC 4.0 0 | 71 (100%) | 67 | NR | 11 (16.4) | 11 (16.4) | 65 (98.5) | 4.5% | 79.7% | NR |
Irinotecan-S1 45–50.4 Gy Adj. 4 × 5FU | 21.4 | 90 | 70 | 8 (11.4) | S-1 90% Irinotecan 87.4% | 67 | 12 (17.9) | 17 (25.4) | 65 (97) | 4.2% | 76.6% | |||
2013 | 5FU 45.6 Gy + 9.6/14.4 Adj.: advised for residual disease | 32 | 38 | 50 | CTC NS 20 (40.0) | NR | 46 | 8.1 | NR | 15 (32.6) | NR | 5-Year 16% | 5-Year DSS 78% [66–90%]g | 5-Year OS 61% [47–74%] |
5FU-Irinotecan 45 Gy + 5.4/9 Adj.: advised for residual disease | 26.4 | 38 | 53 | 26 (49.1) | 50 | 6.9 | 14 (28.0) | 5-Year 17% | 5-Year DSS 85% [75–95%]g | 5-Year OS 75% [61–85%] | ||||
O’Connell27 2014 | 5FU 45 Gy + 5.4/10.8 Adj.: decision left to institution | NR | 42.1 | 477 | CTC 4.0 129 (27.0) | NR | 636 | NR | 158 (33.1) | 113 (17.8) (FU/CAP)h | NR | NR | NR | NR |
5FU-OX 45 Gy + 5.4/10.8 Adj.: decision left to institute | NR | 38.3 | 329 | 129 (39.2) | 640 | 116 (35.3) | 125 (19.5) (FU/CAP)h | |||||||
CAP 45 Gy + 5.4/10.8 Adj.: decision left to institute | NR | 42.6 | 472 | 153 (32.4) | 159 (33.7) | |||||||||
CAPOX 45 Gy + 5.4/10.8 Adj.: decision left to institute | NR | 38.5 | 330 | 135 (40.9) | 125 (37.9) | |||||||||
Rodel28 2015 | 5FU 50.4 Gy Adj. 4 × 5FU | 8 | 72.4 | 623 | CTC 3.0 128 (20.5) | 79% | 615 | 6 | 272 (44.2) | 81 (13.2) | 584 (95.0) | 4.6% | 71.2% [67.6–74.9] | 88.0% [85.3–90.7] |
5FU-OX 50.4 Gy Adj. 8 × 5FU-OX | 6.7 | 73.7 | 613 | 144 (23.5) | (85% | 596 | 6 | 291 (48.8) | 104 (17.4) | 567 (95.1) | 2.9% | 75.9% [72.4–79.5] HR 0.79 [0.64; 0.98] | 88.7% [86.0–91.3] HR 0.96 [0.72; 1.26] | |
Valentini60 2008 | Cisplatin-5FU 50.4 Gy Adj.: physician dependent | 0 | 67.5 | 83 | RTOG 6 (7.1) | NR | 83 | NR | 15 (18.1) | 18 (21.7) | NR | NR | NR | NR |
Raltitrexed-OX 50.4 Gy Adj.: physician dependent | 0 | 63 | 81 | 13 (16.4) | 81 | 8 (9.9) | 23 (28.4) | |||||||
Chemoradiotherapy versus chemoradiotherapy + targeted therapy | ||||||||||||||
Salazar23 2015 | CAP 45 Gy Adj.: physician dependent | 15.2 | 89.1 | 46 | CTC 3.0 6 (13.0) | 93.5% | 46 | 7.3 | NR | 5 (10.9) | – | NR | NR | NR |
CAP-BEV 45 Gy Adj.: physician dependent | 22.7 | 84.1 | 44 | 7 (16.0) | CAP 95.5% BEV 97.7% | 43 | 7.3 | 7 (16.3) | – | |||||
Induction chemotherapy and chemoradiotherapy versus standard fluoropyrimidine-based chemoradiation | ||||||||||||||
Borg32 2014 | BEV-5FU 45 Gy Adj.: physician dependent | 0 | 82.2 | 45 | CTC 3.0 9 (20.0) | 100% | 44 | NR | 15 (34.1) (≥ gr. 3) | 5 (11.4) | 43 (97.8) | NR | NR | NR |
Ind.: BEV-FOLFOX4 CRT: BEV-5FU 45 Gy Adj.: physician dependent | 0 | 78.3 | 46 | Overall 23 (50.0) | 93.5% | 42 | 14 (33.3) | 9 (21.4) | 41 (97.6) | |||||
2015 | CAPOX 50.4 Gy Adj. 4 × CAPOX | 5.8 | NR | 52 | CTC 3,0 15 (30.6)* | 93.9% | 46 | NR | 21 (45.7) | 7 (15.2) | 45 (97.8) | 5-Year 2% [0–10.2%] | 5-Year DFS 64% [49.5–75.8%] | 5-Year OS 78% [63.6–87.1%] |
Ind.: CAPOX CRT: CAPOX 50.4 Gy Adj.: – | 13.5 | NR | 56 | Induction 10 (18.5) CRT 12 (22.6) | Induction 94.4% CRT 77.8% | 54 | 27 (50.0) | 8 (14.8) | 48 (88.9) | 5-Year 5% [1.1–14.8%] | 5-Year DFS 62% [48–73.4%] | 5-Year OS 75% [61–84.1%] | ||
Marechal34 2012 | 5FU 45 Gy Adj.: – | 10.3 | 86.2 | 29 | CTC 3.0 2 (6.9) | 97% | 28 | NR | 9 (32.1) | 8 (28.6) | NR | NR | NR | NR |
Ind.: FOLFOX6 CRT 5FU 45 Gy Adj.: – | 7.1NR | 92.9 | 28 | Induction 8 (28.6) CRT 2 (7.1) | Induction 96% CRT 86% | 27 | 7 (25.9) | 7 (25.9) | ||||||
Rouanet36 2017 | FOLFIRINOX No RT Adj.: ypT ≥ 2/ypN ≥ 1: 6 × FOLFOX | 0 | 81.8 | 11 | CTC 4.0 7 (63.6) | Induction 73% | 11 | 4.4 | 5 (50.0) | 1 (9.1) | 10 (90.9) | NR | NR | NR |
Ind.: FOLFIRINOX CRT: CAP 50 Gy Adj.: ypT ≥ 2/ypN ≥ 1: 6 × FOLFOX | 0 | 73.7 | 19 | Induction 8 (42.1) CRT 5 (26.3) | Induction 68% | 19 | 7.6 | 8 (42.1) | 11 (57.9) | 19 (100) | ||||
Ind. FOLFIRINOX CRT: CAP 50 Gy Adj.: ypT ≥ 2/ypN ≥ 1: 6 × FOLFOX | 23.1 | 96.2 | 52 | Induction 19 (36.5) CRT 11 (21.2) | Induction 73% | 52 | 7 | 16 (31.4) | 7 (13.5) | 43 (82.7) | ||||
Ind. FOLFIRINOX CRT: CAP 60 Gy Adj.: ypT ≥ 2/ypN ≥ 1: 6 × FOLFOX | 25.5 | 98 | 51 | Induction 8 (15.7) CRT 12 (23.5) | Induction 86% | 51 | 7 | 23 (53.5) | 9 (17.6) | 43 (84.3) | ||||
Fokas37 2019 | Ind.: 5FU-OX CRT: 5FU-OX 50.4 Gy Adj.: – | 11.5 | 85.9 | 156 | CTC 4.0 Induction: 34 (21.8) CRT: 56 (35.9) | 78% | 142 | 6.4 | 59 (41.6) | 27 (19.0) | 130 (91.5) | NR | NR | NR |
CRT: 5FU-OX Cons.: 5FU-OX 50.4 Gy Adj.: – | 18 | 90 | 150 | CRT: 41 (27.3) Cons.: 30 (20.0) | 76% | 142 | 12.9 | 47 (33.1) | 38 (26.8) | 128 (90.1) | ||||
Chemoradiotherapy and consolidation chemotherapy versus standard fluoropyrimidine-based chemoradiation | ||||||||||||||
Kim38 2018 | CAP 50.4 Gy Adj.: ypStage 0–1: 6 × CAP, ypStage II–III: 6 × CAPOX | 18.2 | 92.7 | 52 | CTC 4.0 Overall 2 (3.8) | NR | 52 | 7.6 | NS | 3 (5.8) | 52 (100) | NR | NR | NR |
CRT: CAP Cons.: CAPOX 50.4 Gy Adj.: ypStage 0–I: 6 × CAP, ypStage II–III: 6 × CAPOX | 17 | 92.5 | 44 | Overall 5 (11.4) | 44 | 8.8 | 6 (13.6) | 39 (88.6) | ||||||
Moore39 2017 | 5FU 45 Gy + 5.4 Adj.: – | 20.8 | 91.7 | 24 | NR | NR | 24 | 10.6 | 10 (41.7) | 6 (25.0) | 22 (91.7) | NR | NR | NR |
CRT: 5FU Cons.: 5FU 45 Gy + 5.4 Adj.: – | 4 | 100 | 25 | 25 | 10.9 | 13 (52.0) | 4 (16.0) | 23 (92.0) | ||||||
SCRT-delay versus CRT | ||||||||||||||
Latkauskas24 2016 | No CT 25 Gy Adj.: 4 × 5FU | NR | 76.5 | 68 | NR | NR | 68 | 6.9 | 24 (35.3) | 3 (4.4) | 57 (83.8) | 3.1% | 59% HR 1.93 [1.08–3.43] | 78% HR 1.64 [0.8–3.43] |
5FU 50 Gy Adj.: 4 × 5FU | NR | 79.2 | 72 | 72 | 6.7 | 19 (26.8) | 8 (11.1) | 64 (88.9) | 5.6% | 75.1% | 82.4% |