Table 2.
Landmark chemotherapy studies in locally advanced rectal cancer
| Ref. | Study type | Treatment | Outcomes | Comments |
| TIMING Garcia-Aguilar et al[22] | Phase II n = 144 | All treated with CRT If evidence of response, given 2 cycles upfront FOLFOX6 then TME If no response, proceed to TME 6 wk after CRT | 70 patients treated with upfront FOLFOX6 74 patients proceeded directly to TME pCR 25% vs 18% (P > 0.05) | No difference in toxicities |
| MSKCC Cercek et al[23] | Retrospective n = 61 | Upfront FOLFOX (median 7 cycles) followed by CRT | Patients with TME (49): 100% R0 resections pCR 27% | Non-randomized, retrospective data |
| Calvo et al[24] | Prospective non-randomized n = 116 | Upfront FOLFOX-4 (2 cycles) followed by CRT compared to historical controls treated with CRT | 52 patients treated with upfront FOLFOX pCR 29% vs 8% (P = 0.006) | 3 patients in FOLFOX had grade 3-4 toxicities (vs 0). No difference in surgical complications |
| Chau et al[25] | Prospective non-randomized n = 77 | Upfront CAPOX (4 cycles) followed by CRT with TME 6 wk later | R0 resections in all but 1 patient pCR 24%, additional 48% with only microscopic tumor foci | 10% with cardiac or thromboembolic toxicity during CAPOX. 12% with grade 3-4 diarrhea during CAPOX |
| Schou et al[26] | Prospective non-randomized n = 84 | Upfront CAPOX (2 cycles) followed by CRT with TME 6 wk later | 94% R0 resections pCR 23% 5-yr DFS 63%, 5-yr OS 67% | Grade 3-4 toxicities in 18% |
| Marechal et al[27] | Phase II, randomized n = 57 | Randomized to preoperative CRT followed by TME vs upfront FOLFOX followed by CRT and TME | ypT0-1N0 34.5% vs 32.1% (P = 0.85) pCR 28% vs 25% (P = 0.92) | A pre-planned interim analysis no difference in primary endpoints; study closed prematurely for futility |
| STAR-01 Aschele et al[11] | Phase III n = 747 | Preoperative CRT with fluorouracil ± oxaliplatin | pCR 16% vs 16% (P = 0.904) | Oxaliplatin group had more grade 3-4 adverse events (24% vs 8% P < 0.001) |
| ACCORD12/0405-Prodige 2 Gérard et al[12] | Phase III n = 598 | Preoperative CRT with capecitabine ± oxaliplatin | pCR 19.2 vs 13.9% (P = 0.09) | Oxaliplatin group had more grade 3-4 adverse events (25% vs 1%, P < 0.001) |
| NSABP R-04 O’Connell et al[9] | Phase III n = 1608 | Preoperative CRT with fluorouracil ± oxaliplatin vs Preoperative CRT with capecitabine ± oxaliplatin | FU vs Cap: pCR 17.8% vs 20.7% (P = 0.14) Oxaliplatin vs No Oxaliplatin: pCR 19.5% vs 17.8% (P = 0.42) | Patients treated with oxaliplatin experienced significantly more grade 3 or 4 diarrhea (P < 0.001) |
| PETACC-6 Schmoll et al[13] | Phase III n = 1094 | Preoperative CRT with capecitabine ± oxaliplatin (adjuvant chemo same drugs as preoperative) | pCR 11.3% vs 13.3% (P = 0.31) | Patients treated with preoperative oxaliplatin had significant more grade 3-4 adverse events (36.7% vs 15.1%) |
| German CAO/ARO/AIO-04 Rodel et al[15] | Phase III n = 1236 | Preoperative CRT with fluorouracil ± oxaliplatin (adjuvant chemo same drugs as preoperative) | pCR 17% vs 13% (P = 0.038) | Different fluorouracil dosing/schedule and different number of adjuvant cycles used across the arms |
| 3-yr DFS 75.9% vs 71.2% | ||||
| EORTC 22921 Bosset et al[19] | Phase III n = 1011 | Preoperative RT + adjuvant FU/L vs preoperative RT vs CRT with adjuvant FU/L vs CRT | 10-yr LR 14.5% vs 22.4% vs 11.7% vs 11.8% (P = 0.0017)a 10-yr DR 35.9% vs 39.6% vs 34.1% vs 33.4% (P = 0.52) | Any chemotherapy (neoadjuvant only, adjuvant only, or both) had significant reduction in local recurrence, but no difference in OS. Used concomitant bolus FU dosing not commonly utilized in the United States, and only four cycles of adjuvant chemotherapy |
a
P < 0.01 any chemo vs no chemo. LR: Local recurrence; DR: Distant recurrence; TME: Total mesorectal excision; CRT: Chemotherapy radiation therapy.