Development of an algorithm combining blood-based biomarkers, fecal immunochemical test, and age for population-based colorectal cancer screening.

BACKGROUND AND AIMS: Implementation of screening modalities have reduced the burden of colorectal cancer (CRC), but high false positive rates pose a major problem for colonoscopy capacity. We aimed to create a tailored screening algorithm that expands the fecal immunochemical test (FIT) with a blood specimen and current age to improve selection of individuals for diagnostic colonoscopy. METHODS: In this prospective multi-center study, eight blood-based biomarkers (CEA, Ferritin, hsCRP, HE4, Cyfra21-1, Hepsin, IL-8 and OPG) were investigated in 1,977 FIT positive individuals from the Danish national CRC screening program undergoing follow-up colonoscopy. Specimens were analyzed on ARCHITECT i2000®, ARCHITECT c8000® or Luminex xMAP® machines. FIT analyses and blood-based biomarker data were combined with clinical data (i.e., age and colonoscopy findings) in a cross-validated logistic regression model (algorithm) benchmarked against a model solely using the FIT result (FIT model) applying different cutoffs for FIT positivity. RESULTS: The cohort included individuals with CRC (n = 240), adenomas (n = 938) or no neoplastic lesions (n = 799). The cross-validated algorithm combining the eight biomarkers, quantitative FIT result and age performed superior to the FIT model in discriminating CRC versus non-CRC individuals (AUC 0.77 versus 0.67, p < 0.001). When discriminating individuals with either CRC or high- or medium-risk adenomas versus low-risk adenomas or clean colorectum, the AUCs were 0.68 versus 0.64 for the algorithm and FIT model, respectively. CONCLUSIONS: The algorithm presented here can improve patient allocation to colonoscopy, reducing colonoscopy burden without compromising cancer and adenomas detection rates or vice versa.

Impact of Whole Genome Doubling on Detection of Circulating Tumor DNA in Colorectal Cancer.

OBJECTIVE: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. METHODS: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. RESULTS: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12-2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22-5.03) and Stage II (OR = 1.76, 95%CI: 1.11-2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44-1.53) patients. CONCLUSION: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell.

Diagnostic performance of MRI and endoscopy for assessing complete response in rectal cancer after neoadjuvant chemoradiotherapy: a systematic review of the literature.

BACKGROUND: The diagnostic performance of magnetic resonance imaging (MRI) modalities and/or endoscopy for assessing complete response in rectal cancer after neoadjuvant chemoradiotherapy (nCRT) is unclear. PURPOSE: To summarize existing evidence on the diagnostic performance of diffusion-weighted MRI, perfusion-weighted MRI, T2-weighted MR tumor regression grade, and/or endoscopy for assessing complete tumor response after nCRT. MATERIAL AND METHODS: MEDLINE and Embase databases were searched. The PRISMA guidelines were followed. Sensitivity, specificity, negative predictive, and positive predictive values were retrieved from included studies. RESULTS: In total, 81 studies were eligible for inclusion. Evidence suggests that combined use of MRI and endoscopy tends to improve the diagnostic performance compared to single imaging modality. The positive predictive value of a complete response varies substantially between studies. There is considerable heterogeneity between studies. CONCLUSION: Combined re-staging tends to improve diagnostic performance compared to single imaging modality, but the vast majority of studies fail to offer true clinical value due to the study heterogeneity.

Training of radiology specialists in local staging of primary rectal cancer on MRI: a prospective intervention study exploring the impact of various educational elements on the interpretive performance.

BACKGROUND: MRI interpretation and accurate radiological staging are crucial to the important treatment decisions and a consequent successful patient outcome in rectal cancer. AIMS: To investigate the effect of intensive training on rectal cancer MRI staging performance of radiologists and the impact of different course elements on learning outcomes. METHODS: In this prospective intervention study, 17 radiology specialists and 1 radiology registrar participated in a training programme including a 6-hour imaging workshop, a 3-hour session of individual feedback and independent MRI readings of primary rectal cancer cases. Their rectal MRI interpretive performance was evaluated through repeated readings of 30 training cases before and after each course element and a time interval with no educational intervention. A proforma template for MRI staging of primary rectal cancer was used and the results were compared with a reference standard of an expert panel. Participants repeatedly reported on confidence scores and self-assessed learning outcome. Outcomes were analysed using mixed-effects models. RESULTS: At baseline the quality of rectal MRI assessment varied significantly, with a higher interpretive performance among participants with shorter radiological experience (10.2 years vs 19.9 years, p=0.02). The ability to perform correct treatment allocation improved from 72% to 82% (adjusted OR=2.36, 95% CI 1.64 to 3.39). The improvement was largely driven by the participants with lower performance at baseline and by prevention of overstaging. Individual feedback had a significant impact on the improved interpretive performance (adjusted OR=1.82, 95% CI 1.27 to 2.63), whereas no significant change was seen after workshop or case readings only. Confidence scores increased significantly during training. CONCLUSIONS: Targeted and individualised training improves the rectal cancer MRI interpretive performance essential to successful patient treatment, especially among radiology specialists with lower performance at baseline.

Postoperative MRI Findings Following Conventional and Extralevator Abdominoperineal Excision in Low Rectal Cancer.

Aim: The disparity in outcomes for low rectal cancer may reflect differences in operative approach and quality. The extralevator abdominoperineal excision (ELAPE) was developed to reduce margin involvement in low rectal cancers by widening the excision of the conventional abdominoperineal excision (c-APE) to include the posterior pelvic diaphragm. This study aimed to determine the prevalence and localization of inadvertent residual pelvic diaphragm on postoperative MRI after intended ELAPE and c-APE. Methods: A total of 147 patients treated with c-APE or ELAPE for rectal cancer were included. Postoperative MRI was performed on 51% of the cohort (n = 75) and evaluated with regard to the residual pelvic diaphragm by a radiologist trained in pelvic MRI. Patient records, histopathological reports, and standardized photographs were assessed. Pathology and MRI findings were evaluated independently in a blinded fashion. Additionally, preoperative MRIs were evaluated for possible risk factors for margin involvement. Results: Magnetic resonance imaging-detected residual pelvic diaphragm was identified in 45 (75.4%) of 61 patients who underwent ELAPE and in 14 (100%) of 14 patients who underwent c-APE. An increased risk of margin involvement was observed in anteriorly oriented tumors with 16 (22%) of 73 anteriorly oriented tumors presenting with margin involvement vs. 7 (9%) of 74 non-anteriorly oriented tumors (p = 0.038). Conclusion: Residual pelvic diaphragm following abdominoperineal excision can be depicted by postoperative MRI. Inadvertent residual pelvic diaphragm (RPD) was commonly found in the series of patients treated with the ELAPE technique. Anterior tumor orientation was a risk factor for circumferential resection margin (CRM) involvement regardless of surgical approach.

Cancer of the upper rectum.

Rectal cancer constitutes one-third of all colorectal cancers, and the incidence in Denmark increasing. In 2012, 1.400 cases were registered, and of these 38% were located in the upper rectum. There have been several key advances in the optimal management of rectal cancer during the past decades, primarily by standardisation and improvement of the surgical procedure. There is now general agreement that the optimal surgical treatment involves the concept of total mesorectal excision and that a resection with tumour-free margins is crucial. Controversy exists as to whether total mesorectal excision (TME) is necessary for upper rectal cancers or if a partial mesorectal excision (PME) with mesorectal transection 5 cm below the tumour is adequate. Furthermore, there is no agreement as to whether surgery alone is sufficient or whether neoadjuvant radio- and/or chemotherapy should be administered for tumours of the upper rectum. This thesis aims to discuss aspects of the treatment of rectal cancer with regard to the adequacy of mesorectal excision and oncological outcome with a particular focus on cancer of the upper rectum. In study I, the extent and completeness of mesorectal excision was estimated by postoperative magnetic resonance imaging of the pelvis in patients with primary surgery for rectal cancer. In the 136 patients with post-operative MRI, inadvertent residual mesorectal tissue was evident in 40%, especially following PME, suggesting suboptimal surgery performed. Additionally in patients who had PME, the distal margin was found to be less than 3 cm in more than 50% of patients, suggesting a discrepancy between guidelines and the actual surgery performed. In study II, we estimated the risk of local recurrence in the previously audited cohort of patients, with a particular focus on patients with upper rectal cancer treated by PME and without neo-adjuvant therapy as standard. Using Kaplan-Meier analysis, the total three-year local recurrence rate was 7% with tumour stage and an involved circumferential margin as the most important predictors of local recurrence. The local recurrence rate after PME was significantly higher than for TME (14% vs. 3%; p=0.032), and were diagnosed earlier (p=0.001). In all cases with local recurrence following PME there was evidence of either inadvertent residual mesorectum and/or an insufficient distal resection margin. In study III, we investigated the length of the distal resection margin and degree of tissue shrinkage after surgical removal and fixation by using MRI of the fresh and fixed specimen. We found that the length of the specimen and the distal margin was reduced by 30% after surgical removal and fixation. If a 5-cm distal margin below the luminal level of the primary tumour on the fresh specimen is the objective for advanced cancer of the upper rectum treated with PME surgery, a margin of at least 3.5 cm of mesorectum on the fixed specimen should be attained for the pathologist to accurately establish distal radicality.

Objective measurement of the distal resection margin by MRI of the fresh and fixed specimen after partial mesorectal excision for rectal cancer: 5 cm is not just 5 cm and depends on when measured.

BACKGROUND: Most studies have directly established the optimal perioperative in situ clearance margin in surgery for rectal cancer from the histologically observed extent of distal spread, neglecting the tissue variability that occurs after resection and fixation of the rectal specimen. PURPOSE: To measure the length of the distal resection margin in the fresh and fixed specimen following partial mesorectal excision for rectal cancer using magnetic resonance imaging (MRI) to document tissue shrinkage after surgical removal and fixation. MATERIAL AND METHODS: The length of the distal resection margin was measured by MRI of the fresh and fixed specimen and at histopathological examination of the fixed specimen in 10 patients who underwent surgery for upper rectal cancer. In addition, tissue shrinkage was estimated by measuring the total length of the fresh and fixed specimen and distance from the peritoneal reflection anteriorly to the distal cut edge of the specimen. RESULTS: Measured by MRI, the distal resection margin was in the range of 0.6-10.2 cm (mean, 4.6 cm) in the fresh specimen, and 0.5-6.2 cm (mean, 3.2 cm) in the fixed specimen. The tissue shrinkage ratio was a mean of 69% (interquartile range, 61-77%). Taking all ratios from MRI and histopathological examination of tissue shrinkage into account, the collective tissue shrinkage ratio was 70% (95% confidence interval, 67-73%) CONCLUSION: The length of the distal resection margin was reduced by 30% after surgical removal and fixation of the specimen.