Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Impact of a multidisciplinary training programme on outcome of upper rectal cancer by critical appraisal of the extent of mesorectal excision with postoperative MRI.

BACKGROUND: Optimal management of patients with upper rectal cancer remains unclear. Partial mesorectal excision (PME) without neoadjuvant therapy is currently advocated for the majority of patients. Recent studies, however, reported a high risk of local recurrence and suboptimal surgery. The aim of this study was to evaluate the effects of a quality assurance initiative with postoperative MRI to improve outcomes in these patients. METHODS: Patients who underwent mesorectal excision with curative intent for rectal cancer in 2007-2013 were included. Postoperative MRI of the pelvis was performed 1 year after surgery. In 2011, a multidisciplinary workshop with focus on extent and completeness of surgery was held for training surgeons, pathologists and radiologists involved in treatment planning. Images of residual mesorectum and histopathological reports were reviewed with regard to the distal resection margin. Local recurrence after a minimum of 3 years' follow-up was compared between two cohorts from 2007-2010 and 2011-2013. RESULTS: A total of 627 patients were included; postoperative MRI of the pelvis was done in 381 patients. The 3-year actuarial local recurrence rate in patients with upper rectal cancer improved from 12·9 to 5·0 per cent (P = 0·012). After the workshop, fewer patients with cancer of the upper rectum were selected to have PME (90·8 per cent in 2007-2010 versus 80·2 per cent in 2011-2013; P = 0·023), and fewer patients who underwent PME had an insufficient distal resection margin (61·7 versus 31 per cent respectively; P < 0·001). CONCLUSION: Quality assessment of surgical practice may have a major impact on oncological outcome after surgery for upper rectal cancer.

ANTECEDENTES: El tratamiento óptimo para los pacientes con cáncer del tercio superior de recto no está claro. En este momento, la conducta más empleada es la exéresis parcial del mesorrecto (partial mesorectal excision, PME) sin tratamiento neoadyuvante. Sin embargo, estudios recientes han apuntado que se trata de una cirugía subóptima con un elevado riesgo de recidiva local. El objetivo de este estudio fue evaluar los efectos de una iniciativa de control de calidad con una resonancia magnética (magnetic resonance imaging, MRI) postoperatoria para mejorar los resultados en estos pacientes. MÉTODOS: Se incluyeron los pacientes con cáncer rectal a los que se realizó una exéresis del mesorrecto con intención curativa entre los años 2007 y 2013. Un año después de la cirugía se realizó una MRI de la pelvis. En el 2011, se organizó un taller multidisciplinario para educar a los cirujanos, patólogos y radiólogos involucrados en la planificación del tratamiento, en el que se discutieron la extensión y la radicalidad de la cirugía. Se revisaron las imágenes de mesorrecto residual y los informes histopatológicos respecto al margen de resección distal. Se comparó la recidiva local después de más de 3 años de seguimiento entre dos cohortes temporales, 2007-2010 y 2011-2013, respectivamente. RESULTADOS: Se incluyeron un total de 627 pacientes, en los que en 381 se realizó una MRI postoperatoria de la pelvis. Las tasa actuarial de recidiva local a 3 años en pacientes con cáncer del tercio superior de recto mejoraron del 12,9% al 5,0% (P = 0,012). Después del taller, se realizaron menos PME en pacientes con cáncer del tercio superior de recto (91% versus 80%, P = 0,023) y menos pacientes en los que se realizó una PME presentaron un margen de resección distal insuficiente (62% versus 31%, P < 0,001). CONCLUSIÓN: La evaluación de la calidad de la práctica quirúrgica puede tener un gran impacto en los resultados oncológicos después de la cirugía del cáncer del tercio superior de recto.

Pelvic insufficiency fractures frequently occur following preoperative chemo-radiotherapy for rectal cancer - a nationwide MRI study.

AIM: The aim of this prospective case-control study was to evaluate the rate of pelvic insufficiency fractures (PIFs) in Denmark using MRI at the 3-year follow-up. All patients had rectal cancer and had undergone surgery with or without preoperative chemo-radiotherapy (CRT). METHOD: Patients registered with primary rectal cancer in the Danish Colorectal Cancer Group database, who underwent rectal cancer resection from April 2011 through August 2012, were invited to participate in a national MRI study aiming to detect local recurrence and evaluate quality of the surgical treatment. Pelvic MRI including bone-specific sequences 3 years after treatment was obtained. The primary outcome was the rate of PIFs; secondary outcome was risk factors of PIFs evaluated in multivariate analysis. RESULTS: During the study period, 890 patients underwent rectal cancer surgery. Of these, 403 patients were included in the MRI study and had a 3-year follow-up MRI. PIFs were detected in 49 (12.2%; 95% CI 9.0-15.4) patients by MRI. PIFs were detected in 39 patients (33.6%; 95% CI 24.9-42.3) treated with preoperative CRT compared to 10 (3.5%; 95% CI 1.3-5.6) non-irradiated patients (P < 0.001). In a multivariate analysis female gender (OR = 3.52; 95% CI 1.7-7.5), age above 65 years (OR = 3.20; 95% CI 1.5-6.9) and preoperative CRT (OR = 14.20; 95% CI 6.1-33.1) were significant risk factors for PIFs. CONCLUSION: Preoperative CRT in the treatment of rectal cancer was associated with a 14-fold higher risk of PIFs after 3 years, whereas female gender and age above 65 years each tripled the risk of PIFs.

Neoadjuvant therapy abolishes the functional benefits of a larger rectal remnant, as measured by magnetic resonance imaging after restorative rectal cancer surgery.

BACKGROUND: The combination of advances in surgical technique and neoadjuvant therapy for rectal cancer has resulted in more patients undergoing sphincter-preserving surgery. Unfortunately, numerous patients subsequently experience bowel dysfunction, and may suffer from lifelong severe disability with major impact on their quality of life. The aim of the present study was to investigate whether the risk of severe LARS in patients was associated with the length of remnant rectum. METHODS: A total of 125 patients who underwent sphincter-preserving surgery for rectal cancer were included. Postoperative bowel function was assessed using the low anterior resection syndrome (LARS) score a minimum of one year following surgery. The length of remnant rectum was measured on postoperative MRI of the pelvis and was correlated with the risk of having major LARS. RESULTS: Overall, major LARS was observed in 38 per cent of patients. In the patients who underwent surgery alone, major LARS was reported by 27 per cent, and a larger remnant rectum was associated with a better functional outcome. In contrast, 80 per cent of patients who underwent combined preoperative chemoradiotherapy and surgery reported having major LARS. No association between the length of remnant rectum and the risk of major LARS was observed in patients treated with combined neoadjuvant therapy and surgery. CONCLUSION: Both the length of remnant rectum and preoperative chemoradiotherapy had a major impact on the severity of bowel dysfunction after restorative rectal cancer surgery. No functional benefit from an irradiated rectal remnant was observed.

Suboptimal surgery and omission of neoadjuvant therapy for upper rectal cancer is associated with a high risk of local recurrence.

AIM: The aim of the present study was to estimate the risk of local recurrence in an audited cohort of patients, with a particular focus on patients with upper rectal cancer treated by partial mesorectal excision without neoadjuvant therapy. METHOD: Perioperative clinical data on all patients who underwent mesorectal excision for primary adenocarcinoma of the rectum in the period from 2007 to 2010 were prospectively collected and follow-up data on oncological outcome were retrieved from patient records. Three-year actuarial local recurrence rates were estimated using Kaplan-Meier methods. RESULTS: Local recurrence was diagnosed in 17 of 247 patients treated with curative intent. The 3-year actuarial local recurrence rate was 7.0% (95% CI 4.0-11.8). The risk of local recurrence was negatively associated with tumour stage (P = 0.015), an involved circumferential resection margin (P = 0.007) and tumour height (P = 0.044). The local recurrence rate at 3 years was 13.5% after partial mesorectal excision, 2.9% following total mesorectal excision and 5.7% after extralevator abdominoperineal excision (P = 0.032). CONCLUSION: Tumour stage and an involved circumferential resection margin were the most important predictors of local recurrence. For cancer of the upper rectum, partial mesorectal excision was associated with a high risk of local recurrence.

Extent and completeness of mesorectal excision evaluated by postoperative magnetic resonance imaging.

BACKGROUND: The major advance in rectal cancer management over the past 20 years has been the standardization of mesorectal excision. The aim of this study was to determine the prevalence and localization of inadvertent residual mesorectum detected on magnetic resonance imaging (MRI) after rectal cancer surgery. METHODS: Postoperative T2-weighted MRI of the pelvis was performed on patients following mesorectal excision. A multidisciplinary team radiologist evaluated the images with regard to residual mesorectum and distal margin. Only mesorectum above the level of the anastomosis perpendicular to the bowel was regarded as inadvertent residual mesorectum after partial mesorectal excision. Histopathological records, standardized photographs and clinical records were assessed. The pathology and MRI findings were evaluated independently in a blinded fashion. RESULTS: MRI-detected residual mesorectum was identified in 54 (39·7 per cent) of 136 patients. There was agreement with the pathology findings in 88 patients (64·7 per cent). Residual mesorectum was more frequent in patients treated with partial mesorectal excision (63 per cent) than those who had total mesorectal excision (36 per cent) or abdominoperineal resection (13 per cent) (P < 0·001). Pathology and MRI findings both showed that the distal resection margin after partial mesorectal excision was less than 5 cm in more than three-quarters of patients, and less than 3 cm in more than one-third. CONCLUSION: Inadvertent residual mesorectum was commonly found on postoperative MRI, especially after partial mesorectal excision.