Feasibility of relatively low neoadjuvant radiation doses for locally advanced rectal cancer: A propensity score-matched analysis.

Neoadjuvant chemoradiation therapy is part of the standard treatment of locally advanced rectal cancer (LARC). Although various options for modifying preoperative radiotherapy protocols have been researched and proposed, there is still no consensus as to the most appropriate dose regimen of neoadjuvant therapy for this disease. To evaluate the effects of relatively low-dose radiation regimens on tumor regression and clinical outcomes in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. We retrospectively analyzed patients with LARC who underwent neoadjuvant concurrent chemoradiation (CCRT) in our hospital from June 2010 to December 2015. A total of 259 consecutive patients were enrolled, receiving 42 to 44 Gy (RLD, n = 31), 46 Gy (SD1, n = 69), or 50 Gy (SD2, n = 159) of CRT, combined with either capecitabine/oxaliplatin or capecitabine only or mFOLFOX6, followed by total mesorectal excision. A 1:4 propensity score matching was employed, and all patients in the RLD group were matched with 124 patients in the SD2 group. Rates of pCR, 3-year local/regional recurrence (LRR), overall survival (OS), and disease-free survival (DFS) in the RLD group were all not significantly different (0.313 for pCR; 0.884 for LRR; and 0.762 for OS; 0.101 for DFS) from those in SD1 and SD2 groups. The RLD group showed a lower incidence of grade 3 to 4 hematologic toxicity than SD2 group (0.019). A propensity score analysis demonstrated no significant differences in the pCR rates and 3-year outcomes between the RLD and SD2 group. Relatively low-dose regimen (≤44 Gy) of neoadjuvant CRT combined with standard concurrent chemotherapy appears to be both safe and effective in Chinese patients with LARC. Further testing by prospective randomized trials is needed.

Ye W ，Shi L ，Qian L ，Sun Y ，Sun X ... -  《Cancer Reports》

NORAD01-GRECCAR16 multicenter phase III non-inferiority randomized trial comparing preoperative modified FOLFIRINOX without irradiation to radiochemotherapy for resectable locally advanced rectal cancer (intergroup FRENCH-GRECCAR- PRODIGE trial).

Brouquet A ，Bachet JB ，Huguet F ，Karoui M ，Artru P ，Sabbagh C ，Lefèvre JH ，Vernerey D ，Mariette C ，Vicaut E ，Benoist S ，on behalf the FRENCH , GRECCAR, PRODIGE study groups ... -  《BMC CANCER》

Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study.

This trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications. Patients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin). Patients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70-1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75-1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70-1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68-1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively. The superiority of preoperative short-course/CCT over chemoradiation was not demonstrated. The trial is registered as ClinicalTrials.gov number NCT00833131.

Ciseł B ，Pietrzak L ，Michalski W ，Wyrwicz L ，Rutkowski A ，Kosakowska E ，Cencelewicz A ，Spałek M ，Polkowski W ，Jankiewicz M ，Styliński R ，Bębenek M ，Kapturkiewicz B ，Maciejczyk A ，Sadowski J ，Zygulska J ，Zegarski W ，Jankowski M ，Las-Jankowska M ，Toczko Z ，Żelazowska-Omiotek U ，Kępka L ，Socha J ，Wasilewska-Tesluk E ，Markiewicz W ，Kładny J ，Majewski A ，Kapuściński W ，Suwiński R ，Bujko K ，Polish Colorectal Study Group ... -  《-》

Clinical Analysis of the Efficacy and Safety of Different Neoadjuvant Strategies in the Treatment of Locally Advanced Rectal Cancer.

Chen W ，Wang W ，Huang S ，Zhou L ，Wang G ，Chen W ... -  《-》

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial.

Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. German Cancer Aid (Deutsche Krebshilfe).

Rödel C ，Graeven U ，Fietkau R ，Hohenberger W ，Hothorn T ，Arnold D ，Hofheinz RD ，Ghadimi M ，Wolff HA ，Lang-Welzenbach M ，Raab HR ，Wittekind C ，Ströbel P ，Staib L ，Wilhelm M ，Grabenbauer GG ，Hoffmanns H ，Lindemann F ，Schlenska-Lange A ，Folprecht G ，Sauer R ，Liersch T ，German Rectal Cancer Study Group ... -  《-》