Table 4.
Phase I/II trials of neoadjuvant concurrent chemoradiation approaches with the addition of EGFR-pathway targeting agents
| Author | Year | Phase | KRAS | Disease stage | n | RT dose | Conc. CHT | Adj. CHT | pCR rate (%) | downst | tox gr.3+ | postop. c |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Machiels [78] | 2007 | I/II | n.s | T3/4 or N+ | 40 | 45 | Cap + Cet | dis | 5 | 38%7 | n.r | 13% |
| Roedel [79] | 2008 | I/II | n.s | T3/4 or N+ | 60 | 50.4 | Cap + Ox + Cet | n.s | 9 | n.r | n.r | 11%9 |
| Valentini [80] | 2008 | I/II | n.s | T3 or T2N+ | 41 | 50.4 | 5-FU ci + Gef | 5-FU/LV11 | 27 | 73%8 | 41% | 0% |
| Bertolini [81] | 2009 | II | n.s | T3/4 | 40 | 50–50.4 | 5-FU ci + Cet3 | n.s | 8 | 45%8 | n.r | n.r |
| Horisberger [82] | 2009 | II | n.s | T3/4 or N+ | 50 | 50.4 | Cap + Iri + Cet | n.s | 8 | n.r | n.r | n.r |
| Velenik [83] | 2010 | II | n.s | T3/4 or N+ | 37 | 45 | Cap + Cet4 | Cap | 8 | 73%7 | n.r | 5%9 |
| Kim [84] | 2011 | II | n.s | T3/4 or N+ | 40 | 50.4 | Cap + Iri + Cet | 5-FU/LV | 23 | n.r | 18% | 5% |
| Pinto [85] | 2011 | II | n.s | T3N+ or T4 | 60 | 50.4 | 5-FU ci + Ox + Pan | FOLFOX + Pan | 21 | 58%7 | n.r | n.r |
| Sun [86] | 2012 | II | n.s | T3/4 or N+ | 63 | 45 | Cap + Cet | dis | 13 | 78%7 | n.r | n.r |
| Kim [87] | 2012 | Pooled | wt | T3/4 or N+ | 62 | 50.4 | Cap + Iri | 5-FU/LV | 21 | 44%8 | n.r | n.r |
| Cap + Iri + Cet | 5-FU/LV | 28 | 56%8 | n.r | n.r | |||||||
| Dewdney [88] | 2012 | II, rand | n.s | T3c/T41 | 165 | 50.4 | Cap5 | CAPOX | 15 | n.r | n.r | n.r |
| Expert-C | 50.4 | Cap + Cet6 | CAPOX + Cet | 18 | n.r | n.r | n.r | |||||
| Helbling [89] | 2013 | II, rand | wt | T3/4 or N+ | 40 | 45 | Cap + Pan | rec | 10 | n.r | n.r | 18%10 |
| SAKK 41/07 | 28 | 45 | Cap | 18 | n.r | n.r | 15%10 | |||||
| Eisterer [90] | 2014 | II | n.s | T3/4 | 31 | 45 | Cap + Cet | n.s | 0 | n.r | n.r | n.r |
| Mardjuadi [91] | 2015 | II | wt | T3/4 or N+ | 19 | 45 | Pan | n.s | 0 | n.r | n.r | n.r |
| Jin [92] | 2015 | II | n.s | T3/4 or N+ | 23 | 50.4 | Cap + Nim3 | CAPOX | 19 | n.r | n.r | n.r |
| Bazarbashi [93] | 2016 | II | n.s | T3/4 or N+ | 15 | 50.4 | Cap + Cet | 5-FU/LV or Cap | 13 | n.r | n.r | n.r |
| Gollins [94] | 2017 | II | n.s | MRF+ or dis.2 | 82 | 45 | Cap + Iri + Cet | dis | 17 | 49%7 | 59% | n.r |
| Pinto [95] | 2018 | II | wt | T3 or T2N+ | 98 | 50.4 | Pan | FOLFOX | 11 | 46%7 | n.r | n.r |
KRAS: KRAS status of included patients, n: number of patients, RT dose: radiation dose in Gray, conc. CHT: concurrent chemotherapy, adj. CHT: adjuvant chemotherapy, pCR rate: percentage of patients with complete pathologic remission, downst.: percentage of patients with major downstaging according to study protocol (only listed if combined T and N downstaging was reported), tox gr.3+: acute Grade 3+ toxicity during chemoradiation (only listed if an overall percentage was reported), postop. c.: postoperative complications grade 3+ (only listed if an overall percentage was reported), rand.: randomized, n.s.: not specified, wt: wild type, MRF: mesorectal fascia, dis.: distal tumors, Cap: Capecitabine, Cet: Cetuximab, Ox: Oxaliplatin, 5-FU: 5-fluorouracil, ci: contineous infusion, Gef: gefitinib, Iri: Irinotecan, Pan: Panitumumab, Nim: Nimotizumab, CAPOX: combination regimen including capecitabine and oxaliplatin, dis: at the discretion of the treating physician, LV: leucovorine, FOLFOX: combination regimen including 5-FU, leucovorine and oxaliplatin, rec. recommended, bold style indicates significant difference, 1: or threatened mesorectal fascia (< 1 mm) or EVSI or tumor at levator level, 2: MRF+ defined as tumor < 1 mm of mesorectal fascia or involved fascia, 3: 3 times cetuximab mono as induction, 4: 2 weeks capecitabine mono as induction, 5: 4 cycles CAPOX as induction, 6: 4 cycles CAPOX + Cetuximab as induction, 7: downstaging defined as reduction of pathological stage versus clinical stage, 8: downstaging defined as yp stage 0–1, 9: re-operation rate, 10: rate of surgical interventions, 11: if ypN+