The Association of Mismatch Repair Status with Microscopically Positive (R1) Margins in Stage III Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND: There is mounting evidence that microscopically positive (R1) margins in patients with colorectal cancer (CRC) may represent a surrogate for aggressive cancer biology rather than technical failure during surgery. However, whether detectable biological differences exist between CRC with R0 and R1 margins is unknown. We sought to investigate whether mismatch repair (MMR) status differs between Stage III CRC with R0 or R1 margins. METHODS: Patients treated for Stage III CRC from January 1, 2016 to December 31, 2019 were identified by using the Danish Colorectal Cancer Group database. Patients were stratified according to MMR status (proficient [pMMR] vs. deficient [dMMR]) and margin status. Outcomes of interest included the R1 rate according to MMR and overall survival. RESULTS: A total of 3636 patients were included, of whom 473 (13.0%) had dMMR colorectal cancers. Patients with dMMR cancers were more likely to be elderly, female, and have right-sided cancers. R1 margins were significantly more common in patients with dMMR cancers (20.5% vs. 15.2%, p < 0.001), with the greatest difference seen in the rate of R1 margins related to the primary tumour (8.9% vs. 4.7%) rather than to lymph node metastases (11.6% vs. 10.5%). This association was seen in both right- and left-sided cancers. On multivariable analyses, R1 margins, but not MMR status, were associated with poorer survival, alongside age, pN stage, perineural invasion, and extramural venous invasion. CONCLUSIONS: In patients with Stage III CRC, dMMR status is associated with increased risks of R1 margins following potentially curative surgery, supporting the use of neoadjuvant immunotherapy in this patient group.

Current treatment of pT1 rectal cancers in Denmark: A retrospective national cohort study.

AIM: Organ preservation strategies for patients with rectal cancer are increasingly common. In appropriately selected patients, local excision (LE) of pT1 cancers can reduce morbidity without compromising cancer-related outcomes. However, determining the need for completion surgery after LE can be challenging, and it is unknown if prior LE compromises subsequent total mesorectal excision (TME). The aim of this study is to describe the current management of patients with pT1 rectal cancers. METHOD: This is a retrospective national cohort study of the Danish Colorectal Cancer Group database, including patients with newly diagnosed pT1 cancers between 2016 and 2020. Patients were stratified according to treatment into LE alone, completion TME after LE or upfront TME. The treatment and outcomes of these groups were compared. RESULTS: A total of 1056 patients were included. Initial LE was performed in 715 patients (67.7%), of whom 194 underwent completion TME (27.1%). The remaining 341 patients underwent upfront TME (32.3%). Patients undergoing LE alone were more likely to be male with low rectal cancers and greater comorbidity. No differences in specimen quality or perioperative outcomes were noted between patients undergoing completion or upfront TME. Eighty-five patients (15.9%) had lymph node metastases (LNM). Pathological risk factors poorly discriminated between patients with and without LNM, with similar rates seen in patients with zero (14.1%), one (12.0%) or two (14.4%) risk factors. CONCLUSION: LE is a key component of the treatment of pT1 rectal cancer and does not appear to affect the outcomes of completion TME. Patient selection for completion TME remains a major challenge, with current stratification methods appearing to be inadequate.

Do differences in surgical quality account for the higher rate of R1 margins to lymph node metastases in right- versus left-sided Stage III colon cancer: A retrospective cohort study.

AIM: Microscopically positive (R1) margins to lymph node metastases (R1LNM) are associated with poorer oncological outcomes in patients with Stage III colon cancer. R1LNM margins are more common in right-sided cancer, although the cause of this phenomenon is unknown. We sought to investigate whether differences in surgical quality account for the higher rate of R1LNM in right-sided cancers. METHOD: Patients treated for Stage III colon cancer from 1 January 2016 to 31 December 2018 were identified using the Danish national cancer registry. Indicators of surgical quality (mesocolic resection grade, median lymph node yield, and length to the distal colonic margin) were compared according to tumour site and margin status. RESULTS: In all, 1765 patients were included, 981 (55.6%) with right-sided cancers. R1LNM margins were more common in right-sided cancers (14.4% vs. 6.1%, P < 0.001). All three surgical quality indicators were higher in patients with right-sided cancers (mesocolic resection planes 81.7% vs. 69.5%, P < 0.001; median lymph node yield 28 vs. 25, P < 0.001; ≥5 cm to the distal colon margin 81.2% vs. 53.6%, P < 0.001). When stratified according to margin status, no differences in mesocolic resection planes or resectate length were noted, whilst median lymph node yield was higher in patients with R1LNM margins (29 vs. 27, P = 0.009). CONCLUSION: Surgical quality does not appear to be poorer in patients undergoing surgery for right-sided versus left-sided colon cancers in Denmark. Suboptimal surgery does not appear to be responsible for R1LNM margins, implying that these margins may be a surrogate for more aggressive biology.

The impact of subdivisions of microscopically positive (R1) margins on patterns of relapse in stage III colorectal cancer - A retrospective cohort study.

AIM: Microscopically positive (R1) margins are associated with poorer outcomes in patients with colorectal cancer. However, the impact of subdivisions of R1 margins, be they to the primary tumour (R1 tumour) or to lymph node metastases (R1LNM), on patterns of relapse is unknown. METHODS: Patients treated for stage III colorectal cancer from 01 January 2016 to 31 December 2019 in four specialist centres were identified from the Danish national cancer registry. Patients were stratified into three groups according to margin status (R0 vs. R1 tumour vs. R1LNM). The primary outcomes were local recurrence-free survival (LRFS), distant metastases-free survival (DMFS) and disease-specific survival (DSS). RESULTS: A total of 1,164 patients were included, with R1 margins found in 237 (20.4%). Irrespective of tumour location, R1 tumour and R1LNM margins were independent prognostic factors for systemic relapse (R1 tumour HR 1.84, CI: 1.17-2.88, p = 0.008; R1LNM HR 1.59, CI: 1.12-2.27, p = 0.009) and disease-related death (R1 tumour HR 2.08, CI: 1.12-3.85, p = 0.020; R1LNM HR 1.84, CI: 1.12-3.02, p = 0.016). Whereas R1 tumour margins were associated with poorer 3-year LRFS in both colon and rectum cancer, R1LNM margins only reduced LRFS in patients with rectal cancer. Patterns of relapse differed between R1 subdivisions, with R1 tumour margins more likely to affect multiple anatomical sites, with a predilection for extra-hepatic/pulmonary metastases. CONCLUSION: Subdivisions of R1 margins have a distinct impact on the oncological outcomes and patterns of disease relapse in patients with stage III colorectal cancer.

The significance of subdivisions of microscopically positive (R1) margins in colorectal cancer: A retrospective study of a national cancer registry.

AIM: Microscopically positive (R1) margins are associated with poorer outcomes in patients with colorectal cancer. However, little is known of the differential impact of subdivisions of R1 margins, be they to the primary tumour (R1tumour) or to lymph node metastases/tumour deposits (R1LNM). METHODS: Patients treated for Stage III colorectal cancer from 1 January 2016 to 31 December 2019 were identified from the Danish national cancer registry. Patients were stratified into three groups according to margin status (R0 vs. R1tumour vs. R1LNM). The primary outcome was overall survival. RESULTS: In all, 4186 patients were included, comprising 3012 patients with colon cancer and 1174 patients with rectal cancer. The R1 resection rates were 16.5% and 18.2% in patients with colon and rectum cancer, respectively. In colon cancers, 3-year overall survival was reduced in patients with R1LNM (65.7%, 95% CI 62.8-68.6) or R1tumour margins (51.8%, 95% CI 47.3-56.3) compared with R0 resections (80.8%, 95% CI 79.9-81.6, P < 0.001). A similar impact on survival was seen in rectal cancers (R0, 84.2%, 95% CI 82.9-85.5; R1LNM, 72.2%, 95% CI 67.8-76.6; R1tumour, 56.6%, 95% CI 50.0-63.2, P < 0.001). Margin status was independently prognostic of survival in both colon (R1tumour, hazard ratio 2.08, 95% CI 1.50-2.89, P < 0.001; R1LNM, hazard ratio 1.48, 95% CI 1.11-1.97, P = 0.008) and rectal cancers (R1tumour, hazard ratio 2.35, 95% CI 1.42-3.90, P < 0.001; R1LNM, hazard ratio 1.54, 95% CI 0.95-2.48, P = 0.077). CONCLUSION: R1 subdivisions have distinct impacts on survival in Stage III colorectal cancer. Further focused research in these patient subgroups is warranted.