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Division of Colorectal Surgery, Department of Surgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
© 2019 The Korean Society of Coloproctology
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
Study | Design | No. of patients | CRT regimen | NAC regimen | Adjuvant CTx | pCR rate (%) | Compliance | R0 resection rate (%) | Surgical complication rate (%) | Survival outcome |
---|---|---|---|---|---|---|---|---|---|---|
Garcia-Aguilar et al. [43] | Phase II nonrandomized | 259 | CRT+5FU | None | mFOLFOX (8×) | 18 | Not reported | 98 | 15 | Not reported |
4-arm | CRT+5FU | mFOLFOX6 (2×) | mFOLFOX (6×) | 25 | 82% completed NAC | 100 | 6 | Not reported | ||
CRT+5FU | mFOLFOX6 (4×) | mFOLFOX (4×) | 30 | 81% completed NAC | 96 | 4 | Not reported | |||
CRT+5FU | mFOLFOX6 (6×) | mFOLFOX (2×) | 36 | 77% completed NAC | 100 | 9 | Not reported | |||
Polish II trial [45] | Phase III randomized 2-arm | 515 | RT (5 × 5 Gy) | FOLFOX4 (3 cycles) | Not reported | 16 | 63% completed NAC | 77 | 29 | 3-yr DFS, 53%; 3-yr OS, 73% |
CRT + 5FU/Leucovorin/oxaliplatin | None | Not reported | 12 | 66% completed CRT | 71 | 25 | 3-yr DFS, 52%; 3-yr OS, 65% | |||
Gao et al. [46] | Prospective single-arm | 36 | CRT + CAPOX | CAPOX (1×) | Not reported | 36 | 94% completed NAC | 100 | 36 | Not reported |
Zhu et al. [47] | Phase II single-arm | 42 | CRT + CAPOX | Cape (1×) | CAPOX (6–8×) | 17 | 100% completed NAC | 92 | 16 | 3-yr DFS, 57%; 3-yr OS, 66% |
CRT, chemoradiotherapy; NAC, neoadjuvant chemotherapy; CTx, chemotherapy; pCR, pathologic complete response; RT, radiotherapy; 5-FU, 5-fluorouracil; Cape, capecitabine; CAPOX, capecitabine/oxaliplatin; DFS, disease-free survival; mFOLFOX6, modified 5-fluorouracil, leucovorin, and oxaliplatin; Gy, gray; OS, overall survival; R0, microscopically clear resection.
Study | No. of patients | Surveillance protocol | Follow-up time (mo) |
---|---|---|---|
Smith et al. [50] | 32 | 1st year | 28 (9–70) |
-every 3 months: DRE and sigmoidoscopy | |||
2nd year | |||
-every 4 to 6 months: DRE and sigmoidoscopy | |||
Habr-Gama et al. [53] | 90 | 1st year | 60 (12–233) |
-every 1 to 2 months: DRE and sigmoidoscopy | |||
-every 2 to 3 months: serum CEA | |||
-every 6 months: C/A/P CT scan, pelvic MRI and/or TRUS | |||
2nd year | |||
-every 3 months: DRE, sigmoidoscopy, serum CEA | |||
-annual: C/A/P CT scan, pelvic MRI and/or TRUS | |||
Lai et al. [55] | 16 | 1st year | 46 (14–80) |
-every 3 months: DRE, sigmoidoscopy, serum CEA | |||
2nd year | |||
-every 3 months: DRE and sigmoidoscopy, serum CEA | |||
Pelvic MRI, TRUS, A/P CT scan, chest X-ray 6 months after nCRT and annually thereafter | |||
Renehan et al. [56] | 129 | 1st and 2nd year | 33 (19–43) |
-every 4 to 6 months: DRE, examination under anesthesia or endoscopy, C/A/P CT scan, serum CEA, Pelvic MRI | |||
Vaccaro et al. [57] | 23 | 1st year | 46 (10–119) |
-every month: DRE, sigmoidoscopy | |||
2nd year | |||
-every 2 months: DRE and sigmoidoscopy | |||
-every 3 to 6 months: pelvic MRI, C/A/P CT scan | |||
In some patients, PET scan was included. | |||
Appelt et al. [58] | 40 | 1st year | 24 (8–49) |
-every 2 months: DRE, sigmoidoscopy | |||
-every 4 months: PET scan | |||
2nd year | |||
-every 3 months: DRE, sigmoidoscopy | |||
-every 6 months: PET scan |
TNT type | Trial | Design | No. of patients | Arms | 1° endpoint | 2° endpoint |
---|---|---|---|---|---|---|
Consolidation | RAPIDO trial [82] (NCT01558921) | Phase III RCT | 842 | Standard long course CRT → surgery → optional adjuvant CAPOX (8×) | 3-yr DFS | Toxicity, R0 resection rate, pCR, QoL, functional outcome, OS |
SC-RT (5 Gy × 5) → CAPOX (6×) → surgery | ||||||
Consolidation | TRIGGER trial [65] (NCT02704520) | Phase III RCT | 633 | Refer to Fig. 1 | The rate of patient recruitment and randomization | Rate of unit recruitment, toxicity, reproducibility of mrTRG reporting, surgical morbidity, pCR, residual tumor density, surgical quality rates |
Consolidation or induction | Smith et al. [82] (NCT02008656) | Phase II RCT | 202 | Induction CTx + CRT | 3-yr RFS | Organ preservation rate, compliance, toxicity, functional outcome, QoL |
CRT + consolidation CTx | ||||||
Consolidation | KONCLUDE [83] (NCT02843191) | Phase III RCT | 358 | Standard CRT→ surgery → mFOLFOX6 (8×) | pCR, 3-yr DFS | Toxicity, R0 resection rate, tumor response rate, postoperative morbidity, peripheral neuropathy at 3 years after surgery |
Standard CRT → mFOLFOX6 (3×) → surgery → mFOLFOX (5×) | ||||||
TNT without RT | PROSPECT [84] (NCT01515787) | Phase III RCT | 1,060 | 5-FU +CRT → surgery → FOLFOX (8×) | R0 rate, DFS, LRR | pCR, OS, toxicity, rate of CRT |
FOLFOX (6×) → tumor response assessment → TME or CRT | ||||||
Adjuvant therapy if | ||||||
R0 → FOLFOX (6×) | ||||||
R1+ → FOLFOX (4×) + CRT | ||||||
TNT without RT | BACCHUS [85] (NCT01650428) | Phase II RCT | 60 | FOLFOX + bev | pCR rate | Response rate; CRM negative resection; T and N downstaging; PFS, DFS, OS, LRR; 1-yr colostomy rate; toxicity, compliance |
FOLFOXIRI + bev | ||||||
TNT with or without RT | FOWARC [86] (NCT01211210) | Phase II RCT | 495 | Standard CRT | 3-yr DFS | pCR, R0, LRR, OS; predictive biomarkers; QoL, toxicity |
FOLFOX + CRT | ||||||
FOLFOX alone |
TNT, total neoadjuvant therapy; RCT, randomized controlled trial; CRT, chemoradiotherapy; CTx, chemotherapy; SC-RT, short-course radiotherapy; Gy, gray; CAPOX, capecitabine/oxaliplatin; 5-FU, 5-fluorouracil; Cape, capecitabine; FOLFOXIRI, oxaliplatin/5-FU/irinotecan; bev, bevacizumab; DFS, disease-free survival; mFOLFOX6, modified 5-fluorouracil, leucovorin, and oxaliplatin; OS, overall survival; mrTRG, magnetic resonance tumor regression grade; PFS, progression free survival; LRR, local recurrence rate; R0, microscopically clear resection; QoL, quality of life.
Study | Design | No. of patients | CRT regimen | NAC regimen | Adjuvant CTx | pCR rate (%) | Compliance | R0 resection rate (%) | Surgical complication rate (%) | Survival outcome |
---|---|---|---|---|---|---|---|---|---|---|
Garcia-Aguilar et al. [43] | Phase II nonrandomized | 259 | CRT+5FU | None | mFOLFOX (8×) | 18 | Not reported | 98 | 15 | Not reported |
4-arm | CRT+5FU | mFOLFOX6 (2×) | mFOLFOX (6×) | 25 | 82% completed NAC | 100 | 6 | Not reported | ||
CRT+5FU | mFOLFOX6 (4×) | mFOLFOX (4×) | 30 | 81% completed NAC | 96 | 4 | Not reported | |||
CRT+5FU | mFOLFOX6 (6×) | mFOLFOX (2×) | 36 | 77% completed NAC | 100 | 9 | Not reported | |||
Polish II trial [45] | Phase III randomized 2-arm | 515 | RT (5 × 5 Gy) | FOLFOX4 (3 cycles) | Not reported | 16 | 63% completed NAC | 77 | 29 | 3-yr DFS, 53%; 3-yr OS, 73% |
CRT + 5FU/Leucovorin/oxaliplatin | None | Not reported | 12 | 66% completed CRT | 71 | 25 | 3-yr DFS, 52%; 3-yr OS, 65% | |||
Gao et al. [46] | Prospective single-arm | 36 | CRT + CAPOX | CAPOX (1×) | Not reported | 36 | 94% completed NAC | 100 | 36 | Not reported |
Zhu et al. [47] | Phase II single-arm | 42 | CRT + CAPOX | Cape (1×) | CAPOX (6–8×) | 17 | 100% completed NAC | 92 | 16 | 3-yr DFS, 57%; 3-yr OS, 66% |
Study | No. of patients | Surveillance protocol | Follow-up time (mo) |
---|---|---|---|
Smith et al. [50] | 32 | 1st year | 28 (9–70) |
-every 3 months: DRE and sigmoidoscopy | |||
2nd year | |||
-every 4 to 6 months: DRE and sigmoidoscopy | |||
Habr-Gama et al. [53] | 90 | 1st year | 60 (12–233) |
-every 1 to 2 months: DRE and sigmoidoscopy | |||
-every 2 to 3 months: serum CEA | |||
-every 6 months: C/A/P CT scan, pelvic MRI and/or TRUS | |||
2nd year | |||
-every 3 months: DRE, sigmoidoscopy, serum CEA | |||
-annual: C/A/P CT scan, pelvic MRI and/or TRUS | |||
Lai et al. [55] | 16 | 1st year | 46 (14–80) |
-every 3 months: DRE, sigmoidoscopy, serum CEA | |||
2nd year | |||
-every 3 months: DRE and sigmoidoscopy, serum CEA | |||
Pelvic MRI, TRUS, A/P CT scan, chest X-ray 6 months after nCRT and annually thereafter | |||
Renehan et al. [56] | 129 | 1st and 2nd year | 33 (19–43) |
-every 4 to 6 months: DRE, examination under anesthesia or endoscopy, C/A/P CT scan, serum CEA, Pelvic MRI | |||
Vaccaro et al. [57] | 23 | 1st year | 46 (10–119) |
-every month: DRE, sigmoidoscopy | |||
2nd year | |||
-every 2 months: DRE and sigmoidoscopy | |||
-every 3 to 6 months: pelvic MRI, C/A/P CT scan | |||
In some patients, PET scan was included. | |||
Appelt et al. [58] | 40 | 1st year | 24 (8–49) |
-every 2 months: DRE, sigmoidoscopy | |||
-every 4 months: PET scan | |||
2nd year | |||
-every 3 months: DRE, sigmoidoscopy | |||
-every 6 months: PET scan |
TNT type | Trial | Design | No. of patients | Arms | 1° endpoint | 2° endpoint |
---|---|---|---|---|---|---|
Consolidation | RAPIDO trial [82] (NCT01558921) | Phase III RCT | 842 | Standard long course CRT → surgery → optional adjuvant CAPOX (8×) | 3-yr DFS | Toxicity, R0 resection rate, pCR, QoL, functional outcome, OS |
SC-RT (5 Gy × 5) → CAPOX (6×) → surgery | ||||||
Consolidation | TRIGGER trial [65] (NCT02704520) | Phase III RCT | 633 | Refer to Fig. 1 | The rate of patient recruitment and randomization | Rate of unit recruitment, toxicity, reproducibility of mrTRG reporting, surgical morbidity, pCR, residual tumor density, surgical quality rates |
Consolidation or induction | Smith et al. [82] (NCT02008656) | Phase II RCT | 202 | Induction CTx + CRT | 3-yr RFS | Organ preservation rate, compliance, toxicity, functional outcome, QoL |
CRT + consolidation CTx | ||||||
Consolidation | KONCLUDE [83] (NCT02843191) | Phase III RCT | 358 | Standard CRT→ surgery → mFOLFOX6 (8×) | pCR, 3-yr DFS | Toxicity, R0 resection rate, tumor response rate, postoperative morbidity, peripheral neuropathy at 3 years after surgery |
Standard CRT → mFOLFOX6 (3×) → surgery → mFOLFOX (5×) | ||||||
TNT without RT | PROSPECT [84] (NCT01515787) | Phase III RCT | 1,060 | 5-FU +CRT → surgery → FOLFOX (8×) | R0 rate, DFS, LRR | pCR, OS, toxicity, rate of CRT |
FOLFOX (6×) → tumor response assessment → TME or CRT | ||||||
Adjuvant therapy if | ||||||
R0 → FOLFOX (6×) | ||||||
R1+ → FOLFOX (4×) + CRT | ||||||
TNT without RT | BACCHUS [85] (NCT01650428) | Phase II RCT | 60 | FOLFOX + bev | pCR rate | Response rate; CRM negative resection; T and N downstaging; PFS, DFS, OS, LRR; 1-yr colostomy rate; toxicity, compliance |
FOLFOXIRI + bev | ||||||
TNT with or without RT | FOWARC [86] (NCT01211210) | Phase II RCT | 495 | Standard CRT | 3-yr DFS | pCR, R0, LRR, OS; predictive biomarkers; QoL, toxicity |
FOLFOX + CRT | ||||||
FOLFOX alone |
CRT, chemoradiotherapy; NAC, neoadjuvant chemotherapy; CTx, chemotherapy; pCR, pathologic complete response; RT, radiotherapy; 5-FU, 5-fluorouracil; Cape, capecitabine; CAPOX, capecitabine/oxaliplatin; DFS, disease-free survival; mFOLFOX6, modified 5-fluorouracil, leucovorin, and oxaliplatin; Gy, gray; OS, overall survival; R0, microscopically clear resection.
DRE, digital rectal examination; CEA, carcinoembryonic antigen; C/A/P CT, chest/abdomen/pelvis computed tomography; MRI, magnetic resonance imaging; TRUS, transrectal ultrasonography; nCRT, neoadjuvant chemoradiation therapy; PET, positron emission tomography.
TNT, total neoadjuvant therapy; RCT, randomized controlled trial; CRT, chemoradiotherapy; CTx, chemotherapy; SC-RT, short-course radiotherapy; Gy, gray; CAPOX, capecitabine/oxaliplatin; 5-FU, 5-fluorouracil; Cape, capecitabine; FOLFOXIRI, oxaliplatin/5-FU/irinotecan; bev, bevacizumab; DFS, disease-free survival; mFOLFOX6, modified 5-fluorouracil, leucovorin, and oxaliplatin; OS, overall survival; mrTRG, magnetic resonance tumor regression grade; PFS, progression free survival; LRR, local recurrence rate; R0, microscopically clear resection; QoL, quality of life.