Development and External Validation of a Model to Predict Overall Survival in Patients With Resected Gallbladder Cancer.

OBJECTIVE: The aim of this study was to develop and validate a clinical prediction model to predict overall survival in patients with nonmetastatic, resected gallbladder cancer (GBC). BACKGROUND: Although several tools are available, no optimal method has been identified to assess survival in patients with resected GBC. METHODS: Data from a Dutch, nation-wide cohort of patients with resected GBC was used to develop a prediction model for overall survival. The model was internally validated and a cohort of Australian GBC patients who underwent resection was used for external validation. The performance of the American Joint Committee on Cancer (AJCC) staging system and the present model were compared. RESULTS: In total, 446 patients were included; 380 patients in the development cohort and 66 patients in the validation cohort. In the development cohort median survival was 22 months (median follow-up 75 months). Age, T/N classification, resection margin, differentiation grade, and vascular invasion were independent predictors of survival. The externally validated C-index was 0.75 (95%CI: 0.69-0.80), implying good discriminatory capacity. The discriminative ability of the present model after internal validation was superior to the ability of the AJCC staging system (Harrell C-index 0.71, [95%CI: 0.69-0.72) vs. 0.59 (95% CI: 0.57-0.60)]. CONCLUSION: The proposed model for the prediction of overall survival in patients with resected GBC demonstrates good discriminatory capacity, reasonable calibration and outperforms the authoritative AJCC staging system. This model can be a useful tool for physicians and patients to obtain information about survival after resection and is available from https:// gallbladderresearch.shinyapps.io/Predict_GBC_survival/.

Correction to: Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning.

Tumor budding is a promising and cost-effective biomarker with strong prognostic value in colorectal cancer. However, challenges related to interobserver variability persist. Such variability may be reduced by immunohistochemistry and computer-aided tumor bud selection. Development of computer algorithms for this purpose requires unequivocal examples of individual tumor buds. As such, we undertook a large-scale, international, and digital observer study on individual tumor bud assessment. From a pool of 46 colorectal cancer cases with tumor budding, 3000 tumor bud candidates were selected, largely based on digital image analysis algorithms. For each candidate bud, an image patch (size 256 × 256 µm) was extracted from a pan cytokeratin-stained whole-slide image. Members of an International Tumor Budding Consortium (n = 7) were asked to categorize each candidate as either (1) tumor bud, (2) poorly differentiated cluster, or (3) neither, based on current definitions. Agreement was assessed with Cohen's and Fleiss Kappa statistics. Fleiss Kappa showed moderate overall agreement between observers (0.42 and 0.51), while Cohen's Kappas ranged from 0.25 to 0.63. Complete agreement by all seven observers was present for only 34% of the 3000 tumor bud candidates, while 59% of the candidates were agreed on by at least five of the seven observers. Despite reports of moderate-to-substantial agreement with respect to tumor budding grade, agreement with respect to individual pan cytokeratin-stained tumor buds is moderate at most. A machine learning approach may prove especially useful for a more robust assessment of individual tumor buds.

Low Incidence of Advanced Neoplasia in Serrated Polyposis Syndrome After (Sub)total Colectomy: Results of a 5-Year International Prospective Cohort Study.

INTRODUCTION: Serrated polyposis syndrome (SPS) is accompanied by a substantially increased colorectal cancer (CRC) risk. To prevent or treat CRC in patients with a very high polyp burden, (sub)total colectomy with ileorectal or ileosigmoidal anastomosis is regularly performed. The CRC risk after (sub)total colectomy might be decreased, but evidence is lacking. We aimed to assess the yield of endoscopic surveillance in patients with SPS who underwent (sub)total colectomy. METHODS: For this post hoc analysis, we used prospectively collected data from a large international prospective cohort study. We included patients diagnosed with SPS (World Health Organization type I and/or III) who underwent (sub)total colectomy. Primary endpoint was the cumulative 5-year incidence of CRC and advanced neoplasia (AN). RESULTS: Forty-eight patients (mean age 61 [±7.8]; 52% men) were included and followed up for a median of 4.7 years (interquartile range 4.7-5.1). None of the patients developed CRC during follow-up. Five patients developed AN, corresponding to a cumulative 5-year AN incidence of 13% (95% confidence interval 1.2-23). In 4 patients, AN was diagnosed at the first surveillance endoscopy after study inclusion, and in 1 patient, AN was detected during subsequent rounds of surveillance. The risk of AN was similar for patients with ileorectal and ileosigmoidal anastomosis (logrank P = 0.83). DISCUSSION: (Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS. Advanced neoplasms are mainly detected at the first endoscopy after (sub)total colectomy. Based on these results, after the first surveillance, intervals might be extended beyond the currently recommended 1-2 years.

The impact of mammography screening programmes on incidence of advanced breast cancer in Europe: a literature review.

BACKGROUND: Observational studies have reported conflicting results on the impact of mammography service screening programmes on the advanced breast cancer rate (ABCR), a correlation that was firmly established in randomized controlled trials. We reviewed and summarized studies of the effect of service screening programmes in the European Union on ABCR and discussed their limitations. METHODS: The PubMed database was searched for English language studies published between 01-01-2000 and 01-06-2018. After inspection of titles and abstracts, 220 of the 8644 potentially eligible papers were considered relevant. Their abstracts were reviewed by groups of two authors using predefined criteria. Fifty studies were selected for full paper review, and 22 of these were eligible. A theoretical framework for their review was developed. Review was performed using a ten-point checklist of the methodological caveats in the analysis of studies of ABCR and a standardised assessment form designed to extract quantitative and qualitative information. RESULTS: Most of the evaluable studies support a reduction in ABCR following the introduction of screening. However, all studies were challenged by issues of design and analysis which could at least potentially cause bias, and showed considerable variation in the estimated effect. Problems were observed in duration of follow-up time, availability of reliable reference ABCR, definition of advanced stage, temporal variation in the proportion of unknown-stage cancers, and statistical approach. CONCLUSIONS: We conclude that much of the current controversy on the impact of service screening programmes on ABCR is due to observational data that were gathered and/or analysed with methodological approaches which could not capture stage effects in full. Future research on this important early indicator of screening effectiveness should focus on establishing consensus in the correct methodology.

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis.

OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias.

Childhood neuroendocrine tumours: a descriptive study revealing clues for genetic predisposition.

BACKGROUND: Neuroendocrine tumours (NETs) are rare in children and limited data are available. We aimed to specify tumour and patient characteristics and to investigate the role of genetic predisposition in the aetiology of paediatric NETs. METHODS: Using the Dutch Pathology Registry PALGA, we collected patient- and tumour data of paediatric NETs in the Netherlands between 1991 and 2013 (N=483). RESULTS: The incidence of paediatric NETs in the Netherlands is 5.40 per one million per year. The majority of NETs were appendiceal tumours (N=441;91.3%). Additional surgery in appendiceal NETs was indicated in 89 patients, but performed in only 27 of these patients. Four out of five patients with pancreatic NETs were diagnosed with Von Hippel-Lindau disease (N=2) and Multiple Endocrine Neoplasia type 1 (N=2). In one patient with an appendiceal NET Familial Adenomatous Polyposis was diagnosed. On the basis of second primary tumours or other additional diagnoses, involvement of genetic predisposition was suggestive in several others. CONCLUSIONS: We identified a significant number of patients with a confirmed or suspected tumour predisposition syndrome and show that paediatric pancreatic NETs in particular are associated with genetic syndromes. In addition, we conclude that treatment guidelines for appendiceal paediatric NETs need revision and improved implementation.

Incidence of second tumors after treatment with or without radiation for rectal cancer.

Background: The aim of this study was to analyze the association between radiation therapy (RT) for rectal cancer and the development of second tumors. Patients and methods: Data on all surgically treated non-metastatic primary rectal cancer patients diagnosed between 1989 and 2007 were retrieved from the Netherlands population-based cancer registry. Fine and Gray's competing risk model was used for estimation of the cumulative incidence of second tumors. Multivariable analysis was conducted using Cox regression. Results: The cohort consisted of 29 027 patients of which 15 467 patients had undergone RT. Median follow-up was 7.7 years (range 0-27). Among all 4398 patients who were diagnosed with a second primary tumor, 1030 had one or more pelvic tumors. The standardized incidence risk for any second tumor was 1.16 (95% confidence interval [CI] 1.12-1.19), resulting in 27.7/10 000 excess cancer cases per year in patients treated for rectal cancer compared with the general population. RT reduced the cumulative incidence of second pelvic tumors compared with patients who did not receive RT (subhazard ratio [SHR] 0.77, CI 0.68-0.88). Second prostate tumors were less common in patients who received RT (SHR 0.54, CI 0.46-0.64), gynecological tumors were more frequently observed in patients who received RT (SHR 1.49, CI 1.11-2.00). Conclusions: Patients with previous rectal cancer had a marginally increased risk of a second tumor compared with the general population. Gynecological tumors occurred more often in females who received RT, but this did not result in an overall increased risk for a second cancer. RT even seemed to have a protective effect on the development of other second pelvic tumors, pre-dominantly for prostate cancer. These findings are highly important and can contribute to improved patient counseling.

Prognostic value of BRAF and KRAS mutation status in stage II and III microsatellite instable colon cancers.

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer-specific (CSS) and overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild-type cancers (dWT; i.e., BRAF and KRAS wild-type) had a highly favourable survival with 5-year CSS of 93% (95% CI 84-100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5-year CSS of 76% (95% CI 67-85%). In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.

Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study.

BACKGROUND: Neoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients. METHODS: Data on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5-6 to 13-14 weeks. Kaplan-Meier curves, and logistic regression and Cox regression models were used for data analysis. RESULTS: No significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7-8 weeks, pCR rates in LARC patients were higher after 9-10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03-2.37) and 11-12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15-3.26). Treatment interval did not influence OS in ET or LARC patients. CONCLUSIONS: Treatment intervals of 9-12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response.

A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer.

BACKGROUND: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. METHODS/STUDY DESIGN: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. DISCUSSION: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. TRIAL REGISTRATION: NCT02371304 , registration date: February 2015.

Liver Resection for Metastatic Disease; A Population-Based Analysis of Trends.

OBJECTIVE: The study aims to evaluate all patients who underwent liver resection for metastatic disease for demographics, characteristics of the primary tumor and metastasis, volume of liver resection specimens per pathology laboratory and to describe trends in surgical treatment. METHODS: Data were prospectively collected using the Dutch nationwide pathology network. All pathology reports containing details on liver resections for metastatic disease between January 2001 and December 2010 were evaluated. RESULTS: A total of 3,916 liver resections were performed in 3,699 patients with a median age of 63 years (range 1-91). The primary tumor was mainly colorectal (n = 3,256; 88.0%). The number of 'high volume liver centers' increased from 2 to 12 in the study period, whereas the number of 'low volume centers' decreased. The number of liver resections increased from 224 to 596 per year (p ≤ 0.0001). A significant increase was demonstrated in elderly patients, patients with multiple metastases, liver resections for smaller metastases and minor liver resections. CONCLUSION: Although the majority of patients were young and had solitary metastasis, indications for liver resection are expanding as indicated by increasing numbers of elderly and patients with multiple liver metastases. Patients with non-colorectal liver metastases were seldom candidates for resection.

Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer.

BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1þ) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBþCBM), 0.21; 95% CI, 0.08­0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13­0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2þ PFS HR, 0.67; 95% CI, 0.45­1.00; OS HR, 0.82; 95% CI, 0.52­1.30; VEGF-D 3þ PFS HR, 0.77; 95% CI, 0.50­1.17; OS HR, 1.28; 95% CI, 0.79­2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.

Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial.

BACKGROUND: The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME). PATIENTS AND METHODS: The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 × 5 Gy. Chemoradiotherapy consisted of 25 × 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. RESULTS: Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). CONCLUSION: The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual. REGISTRATION NUMBER: Dutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.

Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study).

BACKGROUND: This prospective multicentre study was performed to quantify the number of patients with minimal residual disease (ypT0-1) after neoadjuvant chemoradiotherapy and transanal endoscopic microsurgery (TEM) for rectal cancer. METHODS: Patients with clinically staged T1-3 N0 distal rectal cancer were treated with long-course chemoradiotherapy. Clinical response was evaluated 6-8 weeks later and TEM performed. Total mesorectal excision was advocated in patients with residual disease (ypT2 or more). RESULTS: The clinical stage was cT1 N0 in ten patients, cT2 N0 in 29 and cT3 N0 in 16 patients. Chemoradiotherapy-related complications of at least grade 3 occurred in 23 of 55 patients, with two deaths from toxicity, and two patients did not have TEM or major surgery. Among 47 patients who had TEM, ypT0-1 disease was found in 30, ypT0 N1 in one, ypT2 in 15 and ypT3 in one. Local recurrence developed in three of the nine patients with ypT2 tumours who declined further surgery. Postoperative complications grade I-IIIb occurred in 13 of 47 patients after TEM and in five of 12 after (completion) surgery. After a median follow-up of 17 months, four local recurrences had developed overall, three in patients with ypT2 and one with ypT1 disease. CONCLUSION: TEM after chemoradiotherapy enabled organ preservation in one-half of the patients with rectal cancer.

Metastatic pattern in colorectal cancer is strongly influenced by histological subtype.

BACKGROUND: Clinical studies regarding colorectal cancer (CRC) have suggested differences in metastatic patterns between mucinous adenocarcinoma (MC), signet-ring cell carcinoma (SRCC) and the more common adenocarcinoma (AC). The current study systematically evaluates metastatic patterns of different histological subtypes in CRC patients and analyzes metastatic disease upon primary tumor localization. PATIENTS AND METHODS: A nationwide retrospective review of pathological records of 5817 patients diagnosed with CRC who underwent an autopsy between 1991 and 2010 was performed. Patients were selected from the Dutch pathology registry (PALGA). To substantiate clinical relevance, metastatic patterns were compared with the prospective randomized multicenter Total Mesorectal Excision (TME) trial, which investigated efficacy of preoperative radiotherapy in rectal cancer patients. RESULTS: In the autopsy study, 1675 patients had metastatic disease. MC and SRCC patients more frequently had metastatic disease (33.9% and 61.2% versus 27.6%; P < 0.0001) and had metastases at multiple sites more often compared with AC patients (58.6% and 70.7% versus 49.9%; P = 0.001). AC predominantly metastasized to the liver, and MC and SRCC more frequently had peritoneal metastases. Metastatic patterns were also related to the primary tumor site, with a high rate of abdominal metastases in colon cancer patients, whereas rectal cancer patients more often had metastases at extra-abdominal sites. Results from the TME trial confirmed findings in rectal cancer patients from the autopsy study. CONCLUSION: There are profound differences in metastatic patterns between histological subtypes and the localization of the primary tumor in CRC. Findings from this study should encourage to take these factors into account for follow-up strategies and future studies.

Predicting lymph node metastases in pT1 rectal cancer.

With the widespread introduction of population screening for colorectal cancer in Europe, the number of early rectal cancers is expected to increase. In the past, approximately 25 % of rectal cancers presented with early disease, defined as stage I disease. First, results from population screening in the UK demonstrate an increase to approximately 50 % stage I for screen-detected carcinomas. In the absence of lymph node metastases, local excision of the tumor might be an attractive option, with considerably less morbidity due to surgery and a lower mortality. This option demonstrates the need for a reliable method of lymph node metastasis prediction in early rectal cancer. The overall risk of lymph node metastasis in pT1 tumors is still considerable, 11.4 %. In order to avoid both under-and overtreatment, we need adequate risk factors.