Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO) RAPIDO collaborative investigators; Bahadoer

4006 Background: Local control in locally advanced rectal cancer (LARC) has improved. However, systemic relapses remain high even with postoperative chemotherapy, possibly due to low compliance. Short-course radiotherapy (SCRT) followed by delayed surgery with, in the waiting period, chemotherapy, may lead to better compliance, downstaging and fewer distant metastases. The main objective of the international multicenter phase III RAPIDO trial is to decrease Disease-related Treatment Failure (DrTF), defined as locoregional failure, distant metastasis, a new primary colon tumor or treatment-related death, by reducing the risk of systemic relapse without compromising local control. Methods: MRI-diagnosed LARC patients with either cT4a/b, extramural vascular invasion, cN2, involved mesorectal fascia or enlarged lateral lymph nodes considered to be metastatic were randomly assigned to SCRT (5x5 Gy) 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). Results: Between June 2011 and June 2016, 920 patients were randomized. Pathological complete response rates were 27.7% vs 13.8% (OR 2.40 [1.70 – 3.39]; p < 0.001) in the experimental and standard arms, respectively. 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). Probability at three years of distant metastasis and locoregional failure were, in the experimental and standard arms, 19.8% vs 26.6% (HR 0.69 [0.53 – 0.89]; p = 0.004) and 8.7% vs 6.0% (HR 1.45 [0.93 – 2.25]; p = 0.10), respectively. No differences in DrTF between hospitals with or without policy for postoperative chemotherapy were found (p = 0.37). Overall health ( p = 0.192), quality of life ( p = 0.125) and low anterior resection syndrome score ( p = 0.136) were comparable between the two treatment arms. Conclusions: A lower rate of DrTF, as a result of a lower rate of distant metastases, in high-risk LARC patients can be achieved with preoperative short-course radiotherapy, followed by chemotherapy and TME than by conventional chemoradiotherapy. In addition, the high pCR rate, achieved with the experimental treatment regimen can contribute to organ preservation. This treatment can be considered as a new standard of care. Clinical trial information: NCT01558921 .

To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years. Background: Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial. Methods: A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed. Results: Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively (P = 0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy (P = 0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P = 0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P = 0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P = 0.29]. Conclusions: The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated.

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Objectives To identify the main problem areas in the applicability of the current TNM staging system (8th ed.) for the radiological staging and reporting of rectal cancer and provide practice recommendations on how to handle them. Methods A global case-based online survey was conducted including 41 image-based rectal cancer cases focusing on various items included in the TNM system. Cases reaching < 80% agreement among survey respondents were identified as problem areas and discussed among an international expert panel, including 5 radiologists, 6 colorectal surgeons, 4 radiation oncologists, and 3 pathologists. Results Three hundred twenty-one respondents (from 32 countries) completed the survey. Sixteen problem areas were identified, related to cT staging in low-rectal cancers, definitions for cT4b and cM1a disease, definitions for mesorectal fascia (MRF) involvement, evaluation of lymph nodes versus tumor deposits, and staging of lateral lymph nodes. The expert panel recommended strategies on how to handle these, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define MRF involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes. Conclusions The recommendations derived from this global survey and expert panel discussion may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting. Key Points • Via a case-based online survey (incl. 321 respondents from 32 countries), we identified 16 problem areas related to the applicability of the TNM staging system for the radiological staging and reporting of rectal cancer. • A multidisciplinary panel of experts recommended strategies on how to handle these problem areas, including advice on cT-stage categorization in case of involvement of different layers of the anal canal, specifications on which structures to include in the definition of cT4b disease, how to define mesorectal fascia involvement by the primary tumor and other tumor-bearing structures, how to differentiate and report lymph nodes and tumor deposits on MRI, and how to anatomically localize and stage lateral lymph nodes. • These recommendations may serve as a practice guide and support tool for radiologists (and other clinicians) involved in the staging of rectal cancer and may contribute to improved consistency in radiological staging and reporting.