Preoperative, Adaptive Radiotherapy Concomitant to Chemotherapy for Rectal Adenocarcinoma (Adaptive Rectal Cancer Trial 02). An Interventional Study.

Background and rational

Preoperative radiochemotherapy (RCT) has a beneficial impact on loco-regional control, improves pathological complete response (pCR) rate and has been considered a standard therapeutic option in advanced, resectable, rectal adenocarcinoma. In the last years, three phase III trials using total neoadjuvant therapy (TNT), that is radiotherapy and all cycles of chemotherapy before surgery, or intensified preoperative chemotherapy have changed this standard.

The RAPIDO trial included MRI-diagnosed LARC patients with either cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia or enlarged lateral lymph nodes considered to be metastatic. Patients were randomized to short course radiotherapy (SCRT), 5Gyx5 fractions, with subsequent six cycles of CAPOX or nine cycles of FOLFOX4 followed by total mesorectal excision (TME) (experimental arm) or capecitabine-based chemoradiotherapy (25-28 x 2.0-1.8 Gy) followed by TME and optional, predefined by hospital policy, postoperative eight cycles of CAPOX or twelve cycles of FOLFOX4 (standard arm). The main end point was to decrease Disease-related Treatment Failure (DrTF), defined as locoregional failure, distant metastasis, a new primary colorectal tumor or treatment-related death. 920 patients were enrolled. At three years, cumulative probability of DrTF was 23.7% in the experimental arm and 30.4% in the standard arm (HR 0.76 [0.60 - 0.96]; p = 0.02). ypT0N0 rate was 28% in TNT arm and 14% in standard arm (p<0.0001). The 3-years probability of distant metastasis was 20.0% in the experimental group and 26.8% in standard group (p=0.0048). The 3-years probability of locoregional failure was 8.3% and 6.0% in experimental and standard groups, respectively (P=0.12) (1).

The UNICANCER-PRODIGE 23 Trial randomized 461 patients staged cT3 (considered at risk of local recurrence and for which a multidisciplinary board recommended chemoradiotherapy) or cT4 to either neoadjuvant chemotherapy consisting of six cycles of folfirinox, chemoradiotherapy and surgery (experimental arm), or chemoradiotherapy followed by surgery (standard arm). Adjuvant chemotherapy consisted of modified Folfox6 for 6 cycle or 4 cycles of capecitabine months for experimental arm and 12 cycles of modified Folfox6 or 8 cycles of capecitabine for standard arm. Main end point was 3-years DFS. At a median follow up of 46.5 months, 3-years DFS were 76% in experimental arm and 69% in standard arm (p=0.034). ypT0N0 rates was significantly increased in experimental arm, 28% vs 12%, p<0.0001. 3-years metastasis free survival was 79% in the experimental group and 72% in the standard group (p=0.017). No difference in locoregional control was seen in the two groups (4% vs 6%) (2).

The STELLAR Trial enrolled cT3, cT4 or N positive stage and randomized them to short course RT (5x5Gy) followed by 4 cycles of Capox, the TNT arm (n=302 patients) or chemoradiotherapy, the standard arm, (n=297 patients). After total mesorectal excision, TNT arm receive 2 cycles of adjuvant Capox, the standard arm 6 cycles of Capox. Primary end point was 3-years DFS. At a median follow up of 35 months, 3-years DFS were 64.5% and 62.3 in TNT and standard arm, respectively (p<0.01). ypT0N0 or sustained cCR were 21.8 % in TNT arm and 12.3% in standard arm, p=0.002). There was no significant difference in metastasis free survival and locoregional relapse between the two groups (3).