Evolution of clinical nature, treatment and survival of locally recurrent rectal cancer: Comparative analysis of two national cross-sectional cohorts.

BACKGROUND: In the Netherlands, use of neoadjuvant radiotherapy for rectal cancer declined after guideline revision in 2014. This decline is thought to affect the clinical nature and treatability of locally recurrent rectal cancer (LRRC). Therefore, this study compared two national cross-sectional cohorts before and after the guideline revision with the aim to determine the changes in treatment and survival of LRRC patients over time. METHODS: Patients who underwent resection of primary rectal cancer in 2011 (n = 2094) and 2016 (n = 2855) from two nationwide cohorts with a 4-year follow up were included. Main outcomes included time to LRRC, synchronous metastases at time of LRRC diagnosis, intention of treatment and 2-year overall survival after LRRC. RESULTS: Use of neoadjuvant (chemo)radiotherapy for the primary tumour decreased from 88.5% to 60.0% from 2011 to 2016. The 3-year LRRC rate was not significantly different with 5.1% in 2011 (n = 114, median time to LRRC 16 months) and 6.3% in 2016 (n = 202, median time to LRRC 16 months). Synchronous metastasis rate did not significantly differ (27.2% vs 33.7%, p = 0.257). Treatment intent of the LRRC shifted towards more curative treatment (30.4% vs. 47.0%, p = 0.009). In the curatively treated group, two-year overall survival after LRRC diagnoses increased from 47.5% to 78.7% (p = 0.013). CONCLUSION: Primary rectal cancer patients in 2016 were treated less often with neoadjuvant (chemo)radiotherapy, while LRRC rates remained similar. Those who developed LRRC were more often candidate for curative intent treatment compared to the 2011 cohort, and survival after curative intent treatment also improved substantially.

Relief of Obstruction in Left-Sided Obstructive Colon Cancer: Nationwide Analysis of Applied Treatment in the Palliative Setting.

BACKGROUND: For relief of bowel obstruction in left-sided obstructive colon cancer (LSOCC), a self-expandable metal stent (SEMS) or decompressing stoma (DS) can be placed. In a curative setting, these two strategies have been extensively studied as a bridge to elective resection. Guidelines recommend SEMS as the preferred option in the palliative setting, but adherence in daily practice is unknown. Therefore, this study aimed to gain more insight into patients with LSOCC who received palliative treatment with SEMS or DS at a national level. METHODS: A retrospective population-based cohort study was conducted in the Netherlands. Data from the Netherlands Cancer Registry (NCR) on all patients with LSOCC treated with DS or SEMS not followed by resection of the primary tumour between January 1, 2015, and December 31, 2019, were analysed. Type of treatment (DS or SEMS) for different clinical scenarios, was the main outcome of this study, and was also evaluated over the years (2015-2019). RESULTS: Palliative treatment with SEMS or DS for LSOCC was performed in 1077 patients, of whom 79.2% had metastatic disease (M1). Patients without metastatic disease (M0) were older (≥ 80 years M0 67.4%, M1 25.3%, P < 0.001), had a worse clinical condition (ASA III 51.4% versus 36.37%, ASA IV-V 13.3% versus 4.0% P < 0.001) and presented with higher tumour stage (cT4 55.4% versus 33.5%, % P < 0.001). DS was performed in 91.5% of the patients and SEMS in 8.5%. The proportion of DS did not significantly differ between patients with M1 and M0 (91.8% vs. 90.2% respectively, P = 0.525). No increase in SEMS application was observed over the years, with a stable overall proportion of DS of 91-92% per year. In the multivariable analyses, ninety-day mortality and overall survival were not significantly different between SEMS and DS. CONCLUSIONS: This study revealed that DS was the primary treatment modality for palliative management of LSOCC in the Netherlands between 2015 and 2019, while the guidelines recommended SEMS as preferred treatment. For patients with LSOCC eligible for stenting in the palliative setting, SEMS placement should become more available and accessible as the preferred treatment option, to avoid a stoma in the terminal phase of life.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Cost-effectiveness of selective decontamination of the digestive tract to decrease infectious complications in colorectal cancer surgery: An analysis of the SELECT trial.

INTRODUCTION: Selective decontamination of the digestive tract (SDD) is effective in reducing infectious complications in elective colorectal cancer (CRC) surgery. However, it is unclear whether SDD is cost-effective compared to standard antibiotic prophylaxis. MATERIAL & METHODS: Economic evaluation alongside multicenter randomized controlled trial, the SELECT-trial, from a healthcare perspective. Patients included underwent elective surgery for non-metastatic CRC. The intervention group received oral non-absorbable colistin, tobramycin and amphotericin B (SDD) next to standard antibiotic prophylaxis. Both groups received a single shot intravenous cefazolin and metronidazole preoperatively as standard prophylaxis. Occurrence of postoperative infectious complication in the first 30 postoperative days was extracted from medical records, Quality-Adjusted Life-Years (QALYs) based on the ED-5D-3L, and healthcare costs collected from the hospital's financial administration. RESULTS: Of the 455 patients, 228 were randomly assigned to intervention group and 227 patients to the control group. SDD significantly reduced the number of infectious complications compared to control (difference = -0.13, 95 % CI -0.05 to -0.20). No difference was found for QALYs (difference = 0.002, 95 % CI -0.002 to 0.005). Healthcare costs were statistically significantly lower in the intervention group (difference = -€1258, 95 % CI -2751 to -166). The ICER was -9872 €/infectious complication prevented and -820,380 €/QALY gained. For all willingness-to-pay thresholds, the probability that prophylactic SDD was cost-effective compared to standard prophylactic practice alone was 1.0. CONCLUSION: The addition of SDD to the standard preoperative intravenous antibiotic prophylaxis is cost-effective compared to standard prophylactic practice from a healthcare perspective and should be considered as the standard of care.

Deep endometriosis muscular infiltration of the bowel wall: correlation between MRI and histopathology.

AIM: To assess the correlation between magnetic resonance imaging (MRI) and histopathology for predicting muscular infiltration of endometriosis in the bowel wall in patients undergoing colorectal resection. MATERIALS AND METHODS: All consecutive patients who underwent colorectal surgery for deep endometriosis (DE) with a preoperative MRI in a single tertiary care referral hospital between 2001 and 2019 were included in a prospective cohort. MRI images were revised by a single blinded radiologist. The MRI results regarding the infiltration depth (serosal, muscular, submucosal, or mucosal) and lesion expansion of DE were compared to histopathology. RESULTS: A total of 84 patients were eligible for evaluation. A sensitivity of 89% and positive predictive value of 97% was shown for predicting muscular involvement of the bowel wall. CONCLUSION: This study showed that MRI is valuable in predicting the involvement of the muscular layer of the colorectal wall. Therefore, in patients with symptomatic pelvic bowel endometriosis MRI is a useful tool in guiding the extent of colorectal surgery.

Perioperative Systemic Therapy Versus Cytoreductive Surgery and HIPEC Alone for Resectable Colorectal Peritoneal Metastases: Patient-Reported Outcomes of a Randomized Phase II Trial.

BACKGROUND: As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored. PATIENTS AND METHODS: Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS-HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm. RESULTS: Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue [mean difference (MD) + 14, p = 0.001], loss of appetite (MD + 15, p = 0.003), hair loss (MD + 18, p < 0.001), and loss of taste (MD + 27, p < 0.001) after neoadjuvant treatment. Except for loss of appetite, these PROs returned to baseline at 3 or 6 months postoperatively. CONCLUSIONS: In patients with resectable CPM randomized to perioperative systemic therapy or CRS-HIPEC alone, PROs were comparable between arms and returned to baseline postoperatively. Together with the trial's previously reported feasibility and safety data, these findings show acceptable tolerability of perioperative systemic therapy in this setting.

Long-term oncological outcomes after local excision of T1 rectal cancer.

BACKGROUND: A growing proportion of patients with early rectal cancer is treated by local excision only. The aim of this study was to evaluate long-term oncological outcomes and the impact of local recurrence on overall survival for surgical local excision in pT1 rectal cancer. METHODS: Patients who only underwent local excision for pT1 rectal cancer between 1997 and 2014 in two Dutch tertiary referral hospitals were included in this retrospective cohort study. The primary outcome was the local recurrence rate. Secondary outcomes were distant recurrence, overall survival and the impact of local recurrence on overall survival. RESULTS: A total of 150 patients (mean age 68.5 ± 10.7 years, 57.3% males) were included in the study. Median length of follow-up was 58.9 months (range 6-176 months). Local recurrence occurred in 22.7% (n = 34) of the patients, with a median time to local recurrence of 11.1 months (range 2.3-82.6 months). The vast majority of local recurrences were located in the lumen. Five-year overall survival was 82.0%, and landmark analyses showed that local recurrence significantly impacted overall survival at 6 and 36 months of follow-up (6 months, p = 0.034, 36 months, p = 0.036). CONCLUSIONS: Local recurrence rates after local excision of early rectal cancer can be substantial and may impact overall survival. Therefore, clinical decision-making should be based on patient- and tumour characteristics and should incorporate patient preferences.

Required distal mesorectal resection margin in partial mesorectal excision: a systematic review on distal mesorectal spread.

BACKGROUND: The required distal margin in partial mesorectal excision (PME) is controversial. The aim of this systematic review was to determine incidence and distance of distal mesorectal spread (DMS). METHODS: A systematic search was performed using PubMed, Embase and Google Scholar databases. Articles eligible for inclusion were studies reporting on the presence of distal mesorectal spread in patients with rectal cancer who underwent radical resection. RESULTS: Out of 2493 articles, 22 studies with a total of 1921 patients were included, of whom 340 underwent long-course neoadjuvant chemoradiotherapy (CRT). DMS was reported in 207 of 1921 (10.8%) specimens (1.2% in CRT group and 12.8% in non-CRT group), with specified distance of DMS relative to the tumor in 84 (40.6%) of the cases. Mean and median DMS were 20.2 and 20.0 mm, respectively. Distal margins of 40 mm and 30 mm would result in 10% and 32% residual tumor, respectively, which translates into 1% and 4% overall residual cancer risk given 11% incidence of DMS. The maximum reported DMS was 50 mm in 1 of 84 cases. In subgroup analysis, for T3, the mean DMS was 18.8 mm (range 8-40 mm) and 27.2 mm (range 10-40 mm) for T4 rectal cancer. CONCLUSIONS: DMS occurred in 11% of cases, with a maximum of 50 mm in less than 1% of the DMS cases. For PME, substantial overtreatment is present if a distal margin of 5 cm is routinely utilized. Prospective studies evaluating more limited margins based on high-quality preoperative magnetic resonance imaging and pathological assessment are required.

The awareness of radiologists for the presence of lateral lymph nodes in patients with locally advanced rectal cancer: a single-centre, retrospective cohort study.

OBJECTIVES: Enlarged lateral lymph nodes (LLNs) are associated with increased (lateral) local recurrence rates. Size and anatomical location should therefore always be reported by radiologists and discussed during multidisciplinary meetings. The objective was to investigate how often LLNs are mentioned in MRI reports in a tertiary referral centre. METHODS: A single - centre, retrospective study of 202 patients treated for primary rectal cancer between 2012 and 2020, with at least a T2 tumour located within 12cm of the anorectal junction. The radiology reports were written by 30-40 consultant radiologists. MRI scans were independently re-assessed by an expert radiologist. The primary outcome was how often the presence or absence of LLNs was mentioned in the initial report. RESULTS: Primary MRI reports explicitly mentioned the presence or absence of LLNs in 89 (44%) cases. Of the 43 reports with present LLNs, only one (1%) reported on all features such as size, location or malignant features. Expert review revealed 17 LLNs which were ≥ 7 mm (short-axis); two of these were not mentioned in the original reports. In 14/43 (33%) cases, LLNs were discussed during the primary multidisciplinary meeting, while 17/43 (40%) restaging MRI reports failed to report on the previously visible LLN. Reporting LLNs increased significantly with higher N-stage (p = .010) and over time (p = .042). CONCLUSIONS: Though improving with time, there is still limited consistency in reporting LLNs. Only 44% of primary MRI reports mentioned LLNs and relevant features of those LLNs were seldomly reported. Given the importance of this information for subsequent treatment; increased awareness, proper training and the use of templates are needed. KEY POINTS: • Comprehensive reporting of lateral lymph nodes in primary MRI reports was limited to less than 50%. • Lateral lymph nodes are not always discussed during primary multidisciplinary meetings or mentioned in restaging reports. • Improvements in the awareness and knowledge of lateral lymph nodes are needed to ensure adequate multidisciplinary treatment decisions.

Local recurrence at the site of the Lone Star device through implantation of exfoliated cells during local excision for early rectal cancer: A case report.

INTRODUCTION: Invasive procedures for colorectal cancer can cause iatrogenic tumor cell seeding. Implantation of these exfoliated cells in the surrounding tissue can result in locoregional cancer recurrence. This has been described in endoscopic procedures and major surgical resections, however recurrence in iatrogenic lesions of the anal canal during minimal invasive rectal surgery has not been shown in literature yet. This is the first reported case of recurrent rectal cancer that developed into an anal metastasis at the site where hooks of the Lone Star Retractor disrupted the epithelial lining of the anal canal during a local excision of early rectal cancer using TAMIS. PRESENTATION OF CASE: A 57 year old male was diagnosed with a high risk early stage rectal adenocarcinoma. He was treated with transanal minimally invasive surgery (TAMIS) with the use of a Lone Star retractor and he received subsequent chemo-radiotherapy. 23 months later the patient developed a bleeding mass bulging out of the anus. A true cut and incision biopsy was performed and the pathology report revealed localization of adenocarcinoma at the anal canal which was similar to the earlier diagnosed rectal carcinoma. The patient underwent an abdominal perineal resection and left-sided lymph node dissection. DISCUSSION AND CONCLUSION: This shows that local recurrence through implantation of exfoliated tumor cells can occur in iatrogenic lesions of the anal canal not only in major but also in minimal invasive rectal surgery. Careful tissue handling and rectal washout may reduce the chance of this implantation metastasis.

Laparoscopic Versus Robot-Assisted Versus Transanal Low Anterior Resection: 3-Year Oncologic Results for a Population-Based Cohort in Experienced Centers.

BACKGROUND: Laparoscopic, robot-assisted, and transanal total mesorectal excision are the minimally invasive techniques used most for rectal cancer surgery. Because data regarding oncologic results are lacking, this study aimed to compare these three techniques while taking the learning curve into account. METHODS: This retrospective population-based study cohort included all patients between 2015 and 2017 who underwent a low anterior resection at 11 dedicated centers that had completed the learning curve of the specific technique. The primary outcome was overall survival (OS) during a 3-year follow-up period. The secondary outcomes were 3-year disease-free survival (DFS) and 3-year local recurrence rate. Statistical analysis was performed using Cox-regression. RESULTS: The 617 patients enrolled in the study included 252 who underwent a laparoscopic resection, 205 who underwent a robot-assisted resection, and 160 who underwent a transanal low anterior resection. The oncologic outcomes were equal between the three techniques. The 3-year OS rate was 90% for laparoscopic resection, 90.4% for robot-assisted resection, and 87.6% for transanal low anterior resection. The 3-year DFS rate was 77.8% for laparoscopic resection, 75.8% for robot-assisted resection, and 78.8% for transanal low anterior resection. The 3-year local recurrence rate was in 6.1% for laparoscopic resection, 6.4% for robot-assisted resection, and 5.7% for transanal procedures. Cox-regression did not show a significant difference between the techniques while taking confounders into account. CONCLUSION: The oncologic results during the 3-year follow-up were good and comparable between laparoscopic, robot-assisted, and transanal total mesorectal technique at experienced centers. These techniques can be performed safely in experienced hands.

Long-term stoma-related reinterventions after anterior resection for rectal cancer with or without anastomosis: population data from the Dutch snapshot study.

BACKGROUND: The aim of this study was to analyze the stoma-related reinterventions, complications and readmissions after an anterior resection for rectal cancer, based on a cross-sectional nationwide cohort study with 3-year follow-up. METHODS: Rectal cancer patients who underwent a resection with either a functional anastomosis, a defunctioned anastomosis, or Hartmann's procedure (HP) with an end colostomy in 2011 in 71 Dutch hospitals were included. The primary outcome was number of stoma-related reinterventions. RESULTS: Of the 2095 patients with rectal cancer, 1400 patients received an anterior resection and were included in this study; 257 received an initially functional anastomosis, 741 a defunctioned anastomosis, and 402 patients a HP. Of the 1400 included patients, 62% were males, 38% were females and the mean age was 67 years (SD 11.1). Following a primary functional anastomosis, 48 (19%) patients received a secondary stoma. Stoma-related complications occurred in six (2%) patients, requiring reintervention in one (0.4%) case. In the defunctioned anastomosis group, stoma-related complications were present in 92 (12%) patients, and required reintervention in 23 (3%) patients, in 10 (1%) of these more than 1 year after initial resection. Stoma-related complications occurred in 92 (23%) patients after a HP, and required reintervention in 39 (10%) patients in 17 (4%) of cases more than 1 year after initial resection. The permanent stoma rate was 11% and 20%, in the functional anastomosis and the defuctioned anastomosis group, respectively. The end colostomy in the HP group was reversed in 4% of cases. CONCLUSIONS: Construction of a stoma after resection for rectal cancer with preservation of the sphincter is accompanied with long-term stoma-related morbidity. Stoma complications are more frequent after a HP. Even after 1 year, a significant number of reinterventions are required.

Comparison of laparoscopic versus robot-assisted versus transanal total mesorectal excision surgery for rectal cancer: a retrospective propensity score-matched cohort study of short-term outcomes.

BACKGROUND: Laparoscopic total mesorectal excision (TME) surgery for rectal cancer has important technical limitations. Robot-assisted and transanal TME (TaTME) may overcome these limitations, potentially leading to lower conversion rates and reduced morbidity. However, comparative data between the three approaches are lacking. The aim of this study was to compare short-term outcomes for laparoscopic TME, robot-assisted TME and TaTME in expert centres. METHODS: Patients undergoing rectal cancer surgery between 2015 and 2017 in expert centres for laparoscopic, robot-assisted or TaTME were included. Outcomes for TME surgery performed by the specialized technique in the expert centres were compared after propensity score matching. The primary outcome was conversion rate. Secondary outcomes were morbidity and pathological outcomes. RESULTS: A total of 1078 patients were included. In rectal cancer surgery in general, the overall rate of primary anastomosis was 39.4, 61.9 and 61.9 per cent in laparoscopic, robot-assisted and TaTME centres respectively (P < 0.001). For specialized techniques in expert centres excluding abdominoperineal resection (APR), the rate of primary anastomosis was 66.7 per cent in laparoscopic, 89.8 per cent in robot-assisted and 84.3 per cent in TaTME (P < 0.001). Conversion rates were 3.7 , 4.6 and 1.9 per cent in laparoscopic, robot-assisted and TaTME respectively (P = 0.134). The number of incomplete specimens, circumferential resection margin involvement rate and morbidity rates did not differ. CONCLUSION: In the minimally invasive treatment of rectal cancer more primary anastomoses are created in robotic and TaTME expert centres.

The results of this study showed similar and acceptable short-term results for laparoscopic, robot-assisted and transanal total mesorectal excision performed in expert centres. In centres with robot-assisted or transanal technique, more primary anastomoses were made.

Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes.

BACKGROUND: In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. METHODS: Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. RESULTS: More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease. CONCLUSION: Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.

Detection of colorectal cancer in urine using DNA methylation analysis.

Colorectal cancer (CRC) is the second leading cause for cancer-related death globally. Clinically, there is an urgent need for non-invasive CRC detection. This study assessed the feasibility of CRC detection by analysis of tumor-derived methylated DNA fragments in urine. Urine samples, including both unfractioned and supernatant urine fractions, of 92 CRC patients and 63 healthy volunteers were analyzed for DNA methylation levels of 6 CRC-associated markers (SEPT9, TMEFF2, SDC2, NDRG4, VIM and ALX4). Optimal marker panels were determined by two statistical approaches. Methylation levels of SEPT9 were significantly increased in urine supernatant of CRC patients compared to controls (p < 0.0001). Methylation analysis in unfractioned urine appeared inaccurate. Following multivariate logistic regression and classification and regression tree analysis, a marker panel consisting of SEPT9 and SDC2 was able to detect up to 70% of CRC cases in urine supernatant at 86% specificity. First evidence is provided for CRC detection in urine by SEPT9 methylation analysis, which combined with SDC2 allows for an optimal differentiation between CRC patients and controls. Urine therefore provides a promising liquid biopsy for non-invasive CRC detection.

Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

BACKGROUND: There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS: We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS: CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p < 0.001). The observed differential gene expression between cancer stages is at least partly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated (r = 0.77, p < 0.001). CMS4 cancers showed an increased progression rate to more advanced stages (CMS4 compared to CMS2: 1.25, 95% CI: 1.08-1.46). Patients with a CMS4 cancer had worse survival in the high-risk stage II tumors compared to the total stage II cohort (5-year DFS 41.7% versus 100.0%, p = 0.008). CONCLUSIONS: Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, might also reflect distinct biological disease entities. These insights can potentially be utilized to optimize identification of high-risk stage II colon cancers.