Table 7.
Selected trials evaluating total neoadjuvant therapy approaches
| Author | Year | Phase | Stage | n | Ind. CHT | RT dose | Conc. CHT | Cons. CHT | Adj. CHT | pCR (%) | Downst | 3y-DFS | 3y-OS | Tox gr.3+ | Pop. c |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chau [144] | 2006 | II | High risk1 | 105 | 4xCAPOX | 54 | Cap | None | 4xCap | 20 | n.r | 68% | 83% | n.r | n.r |
| Chua [145] | 2010 | ||||||||||||||
| Koeberle [146] | 2008 | II | T3/4 | 60 | 1xXELOX | 45 | Cap/Ox | None | dis | 23 | n.r | n.r | n.r | n.r | n.r |
| Zampino [147] | 2009 | II | T3/4 or N+ | 51 | None | 50,4 | Cap | 2xCap | Cap or CAPOX 6 | 18 | 30%9 | 85%12 | n.r | n.r | n.r |
| Fernandez [148] | 2010 | II | T3/4 or N+ | 108 | None | 50,4 | Cap/Ox | None | 4xCAPOX | 13 | 53%10 | 64%12 | 78%12 | CRT 29%/adj. 54% | 7%21 |
| Fernandez [149] | 2015 | 4xCAPOX | 50,4 | Cap/Ox | None | None | 14 | 35%10 | 62%12 | 75%12 | CRT 23%/ind. 19% | 8%21 | |||
| Nogue [150] | 2011 | II | T3/4 or N+2 | 47 | 4xXELOX/Bev | 50,4 | Cap/Bev | None | rec | 36 | 69%10 | n.r | n.r | n.r | 24%21 |
| Chiorean [151] | 2012 | II | T3/4 or N+ | 22 | 2xCap/Iri | 50,4 | Cap | None | rec | 33 | n.r | 76% | n.r | n.r | n.r |
| Di Petrillo [64] | 2012 | II | T3/4 or N+ | 26 | 2xmFOLFOX6/Bev | 50,4 | 5-FU ci/Ox/Bev | None | 6xmFOLFOX6/Bev | 20 | n.r | 80%13 | 95%13 | n.r | n.r |
| Marechal [152] | 2012 | II | T3/4 | 57 | None | 45 | 5-FU ci | None | dis | 28 | 35%11 | n.r | n.r | CRT 7% | n.r |
| Or T2N+ | 2xmFOLFOX6 | 45 | 5-FU ci | None | dis | 25 | 32%11 | n.r | n.r | CRT 7%/ind. 25% | n.r | ||||
| Dewdney [88] | 2012 | II, r | High risk3 | 165 | 4xCAPOX | 50,4 | Cap | None | CAPOX | 15 | n.r | Not sig | Not sig | n.r | n.r |
| Expert-C | 4xCAPOX/Cet | 50,4 | Cap/Cet | None | CAPOX/Cet | 18 | n.r | Diff | Diff | n.r | n.r | ||||
| Zhu [153] | 2013 | II | T3/4 or N+ | 42 | None | 44 5 | Cap/Ox | 1xCap | 6-8xXELOX | 16 | n.r | 57% | 66% | n.r | n.r |
| Gao [154] | 2014 | II | T3/4 or N+ | 51 | 1xXELOX | 50 | Cap/Ox | 1xXELOX | 4xXELOX | 42 | n.r | n.r | n.r | n.r | 11% |
| Borg [155] | 2014 | II, r | T3 | 91 | 6xFOLFOX/Bev | 45 | 5-FU ci/Bev | None | n.s | 24 | 66%9 | n.r | n.r | 50% | 22% |
| None | 45 | 5-FU ci/Bev | None | n.s | 11 | 55%9 | n.r | n.r | 20% | 22% | |||||
| II | T3/4 or N+ | 259 | None | 50 | 5-FU ci | None | 8xmFOLFOX6 | 18 | n.r | 50%12 | 79%12 | cons. n.a.15,16 | 9% | ||
| Garcia-A [24] | 2015 | 2xmFOLFOX6 | 6xmFOLFOX6 | 25 | n.r | 81%12 | 92%12 | cons. 4%15,16 | 6% | ||||||
| Marco [156] | 2018 | 4xmFOLFOX6 | 4xmFOLFOX6 | 30 | n.r | 86%12 | 88%12 | cons. 18%15,16 | 4% | ||||||
| 6xmFOLFOX6 | 2xmFOLFOX6 | 38 | n.r | 76%12 | 84%12 | cons. 35%15,16 | 9% | ||||||||
| Bujko [157] | 2016 | III | fix. T3 | 515 | None | 5 × 5 | None | 3xFOLFOX | dis | 16 | n.r | 43%26 | 49%26 | 24% | n.r |
| Cisel [20] | or T4 | None | 50.4 | 5-FU/LV/Ox | None | dis | 12 | n.r | 41%26 | 49%26 | 24% | n.r | |||
| Perez [158] | 2017 | II | T3/4 or N+ | 39 | 8xmFOLFOX6 | 50.4 | Cap | None | n.s | 33 | 56%10 | 80%13 | n.r | n.r | 13% |
| Cercek [159] | 2018 | re | T3/4 or N+ | 308 | 5xCAPOX19 | 50–50,4 | 5-FU ci or Cap | None | None | 187 | n.r | n.r | n.r | n.r | n.r |
| 320 | None | 50–50,4 | 5-FU ci or Cap | None | CAPOX20 | 178 | n.r | n.r | n.r | n.r | n.r | ||||
| Fokas [25] | 2019 | II, r | T3/4 or N+ | 306 | 3 × 5-FU/LV/Ox | 50,4 | 5-FU ci/Ox | None | None | 17 | n.r | n.r | n.r | CRT 37%/CHT 22% | 17% |
| ARO-2012 | None | 50.4 | 5-FU ci/Ox | 3 × 5-FU/LV/Ox | None | 25 | n.r | n.r | n.r | CRT 27%/CHT 22% | 16% | ||||
| van der Valk [160] | 2020 | III | High risk4 | 911 | None | 50.4 | Cap | None | Opt.22 | 14 | n.r | 30%14 | 89% | 25%17,23 | 15% |
| Hospers [161] RAPIDO | None | 5 × 5 | None | 6xCAPOX18 | Opt.22 | 28 | n.r | 24%14 | 89% | 48%17,23 | 14% | ||||
| Conroy [162] | 2020 | III | T3/4 | 461 | None | 50,4 | Cap | None | 8xCap24 | 12 | n.r | 69% | 88% | n.r | n.r |
| PRODIGE 23 | 6 × mFOLFIRINOX | 50,4 | Cap | None | 4xCap25 | 28 | n.r | 76% | 91% | n.r | n.r |
n = number of patients, ind.: induction CHT (prior to chemoradiation), RT dose: radiation dose in Gy, conc. CHT: chemotherapy concurrent to radiation, cons. CHT: consolidation chemotherapy (after chemoradiation prior to surgery), adj. CHT: adjuvant chemotherapy after surgery, pCR rate: percentage of patients with pathologic complete regression, downstaging: percentage of patients with major downstaging defined according to study protocol (only listed if combined T and N downstaging was reported), 3y-DFS: 3-year disease free survival, 3y-OS: 3-year overall survival, grade 3+ tox: acute grade 3+ toxicity during chemotherapy and/or chemoradiation (only listed if an overall percentage was reported), pop.c.: postoperative complications grade 3+ (only listed if an overall percentage was reported), r.: randomized, re.: retrospective, fix.: fixed tumors, CAPOX: combination regimen including capecitabine and oxaliplatin, XELOX: combination regimen including capecitabine and oxaliplatin, Bev: Bevacizumab, Cap: Capecitabine, Iri: irinotecan, mFOLFOX6: combination regimen including 5-FU, leucovorine and oxaliplatin, Cet: Cetuximab, 5-FU: 5-fluorouracil, LV: leucovorine, Ox: Oxaliplatin, ci: contineous infusion, b: bolus, FOLFOX: combination regimen including 5-FU, leucovorine and oxaliplatin, dis.: at the discretion of the treating physician, rec.: recommended, n.s.: not specified, opt.: optional, n.r.: not reported, no. sig. diff.: no significant difference between arms, CRT: chemoradiation, n.a.: not applicable, 1: T3c or T4 or MRF+ or N2 orT3 at levator level,: T3 only if distal located or < 2 mm from MRF, 3: T3c or T4 or MRF+ or EVSI or tumor at levator level, 4: T4 or N2 or EVSI or MRF+ or positive lateral nodes, 5: in 20 fractions, 6: if pCR none, if N0 Cap., if N+ CAPOX, 7: 24% of the patients chose non-oprative management due to clinical complete remission, 8: 8% of the patients chose non-oprative management due to clinical complete remission, 9: downstaging defined as lower p vs c stage, 10: downstaging defined as ypstage 0–1, 11: downstaging defined as ypT0-1N0, 12: 5-year rate, 13: estimated from curve, 14: disease-related treatment failure (DrTF), 15: CRT toxicity reported for all groups together (28%), did not significantly differ between the groups, 16: toxicities for adjuvant CHT not reported, significantly less patients received adjuvant chemotherapy in group 1, 17: toxicities reported only for preoperative part of treatment, 18: or 9 × FOLFOX, 19: or 8 × mFOLFOX6, 20 or mFOLFOX6, 21: re-operation rate, 22: predifined strategy by center, either none or 8 × CAPOX or 12 × FOLFOX, 23: 35% for adjuvant chemotherapy, 24: or 12 × mFOLFOX (predefined choice by center), 25: or 6xmFOLFOX6 (predefined choice by center), 26: 8-year rate