Oncological outcome after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer Trial.

BACKGROUND: It is not clear whether all patients with rectal cancer need chemoradiotherapy. A restrictive use of neoadjuvant chemoradiotherapy (nCRT) based on MRI findings for rectal cancer was investigated in this study. METHODS: This prospective multicentre observational study included patients with stage cT2-4 rectal cancer, with any cN and cM0 status. Carcinomas in the middle and lower third that were 1 mm or less from the mesorectal fascia, all cT4 tumours, and all cT3 tumours of the lower third were classified as high risk, and these patients received nCRT followed by total mesorectal excision (TME). All other carcinomas with a minimum distance of more than 1 mm from the mesorectal fascia and those in the upper third were classified as low risk; these patients underwent TME alone (no nCRT). Patients were followed for at least 3 years. Outcomes were the rates of local recurrence, distant metastasis and survival. RESULTS: Among 545 patients included, 428 were treated according to the study protocol: 254 (59·3 per cent) had TME alone and 174 (40·7 per cent) received nCRT and TME. Median follow-up was 60 months. The 3- and 5-year local recurrence rates were 1·3 and 2·7 per cent respectively, with no differences between the two treatment protocols. Patients with disease requiring nCRT had higher 3- and 5-year rates of distant metastasis (17·3 and 24·9 per cent respectively versus 8·9 and 14·4 per cent in patients who had TME alone; P = 0·005) and worse disease-free survival compared with that in patients who did not need nCRT (3- and 5-year rates 76·7 and 66·7 per cent, versus 84·9 and 76·0 per cent in the TME-alone group; P = 0·016). CONCLUSION: Restriction of nCRT to high-risk patients achieved good results.

Session 1: The surgeon as a prognostic factor in colon and rectal cancer?

The impact of quality of surgery, colorectal surgical specialization, training and expertise has been far greater on survival outcomes than adjuvant and neoadjuvant therapies. The review of the evidence by Professor Martling and expert discussion addresses the evidence base and the crucial importance of the surgeon as a prognostic factor, and how this has been relatively neglected in comparison to other resources invested in improving the treatment of colorectal cancer.

[Quality indicators of diagnosis and therapy in MRI-based neoadjuvant radiochemotherapy for rectal cancer - interim analysis of a Prospective Multicentre Observational Study (OCUM)]. / Qualitätsindikaktoren der Diagnose und Therapie bei MRT-basierter neoadjuvanter Radiochemotherapie des Rektumkarzinoms - Interimsanalyse einer prospektiven, multizentrischen Beobachtungsstudie (OCUM).

BACKGROUND: The interim analysis of a prospective multicentre observational study of selective neoadjuvant chemoradiotherapy (OCUM) in patients with rectal cancer should evaluate the quality of diagnosis and therapy as a prerequisite for continuation of the study. PATIENTS AND METHODS: 230 patients with the clinical stage cT2 - 4, each cN, M0 with radical tumour resection were enrolled until now. The values of 13 quality indicators were compared with the target values formulated by the workflow of the Working Group rectal cancer II and the German Cancer Society and were also compared with the results of the certified bowel centres of Germany 2010. RESULTS: The target values were fulfilled to a high degree regardless of caseload. 83 % of parameters have been fully achieved and 14 % nearly achieved. In primary surgery the proportion of patients with 12 or more histologically examined lymph nodes was 99.2 %, after neoadjuvant chemoradiotherapy 90 %. A R0 resection was performed in 98.3 % and a resection of TME in muscularis propria plane only in 2.2 %. The rate of positive circumferential resection margins (pCRM + ) was 5.7 % only. CONCLUSIONS: The high quality of rectal surgery justifies the concept and the continuation of the study.

Use of Preoperative Magnetic Resonance Imaging to Select Patients with Rectal Cancer for Neoadjuvant Chemoradiation--Interim Analysis of the German OCUM Trial (NCT01325649).

INTRODUCTION: Introduction of total mesorectal excision (TME) surgery for rectal cancer decreased local recurrence dramatically. Additional neoadjuvant chemoradiation (nCR) is frequently given in UICC II and III tumors based on TNM staging which is of limited accuracy. We aimed to evaluate determination of circumferential margin by magnetic resonance imaging (mrCRM) as an alternative criterium for nCR. METHODS: Multicenter prospective cohort study which enrolled 642 patients in 13 centers with non-metastasized rectal adenocarcinoma. Patients with T4 tumors or patients with a mrCRM of 1 mm or less were treated by neoadjuvant chemoradiation. All others proceeded directly to surgery when inclusion criteria and no exclusion criteria were met. Quality of TME and accuracy of mrCRM determination were assessed during pathology workup. RESULTS: TME was complete in 381 of 389 patients after surgery without nCR (97.9%) and in 245 of 253 patients (96.8%) after nCR. Negative pathology circumferential margins (pCRM) were seen in 97.4% without nCR and in 89% of patients after nCR. Negative pCRM was predicted by negative mrCRM in 98.3% of rectal cancers. NCR was given to 253 of 642 patients (39.5%). Lymph node count was 23 (range 7-79; median/range) for surgery without nCR and 19 (range 2-56) for surgery after nCR. CONCLUSIONS: Surgical quality determined by pathology workup of specimen was very good in this study. Magnetic resonance imaging guided indication for nCR allows to achieve superb results concerning surrogate parameters for good oncological outcome. Thus, use of neoadjuvant chemoradiation with its potential detrimental side effects may be substantially reduced in selected patients.

[Lymph node dissection after primary surgery and neoadjuvant radiochemotherapy of rectal cancer. Interim analysis of a multicenter prospective observational study (OCUM)]. / Lymphknotendissektion nach primärer Chirurgie und neoadjuvanter Radiochemotherapie des Rektumkarzinoms. Interimsanalyse einer multizentrischen prospektiven Beobachtungsstudie (OCUM).

INTRODUCTION: The OCUM trial (NCT01325649) aims to clarify whether low rates of local recurrence are also achieved when the indications for neoadjuvant radiochemotherapy are not based on the clinical TNM staging but on preoperative magnetic resonance imaging with measurement of the tumor distance to the circumferential resection margin. In this interim analysis the lymph node status in OCUM patients was investigated as a surrogate parameter for quality of surgery and histopathological work-up. MATERIAL AND METHODS: Until now a total of 560 patients have been included in this study. Total mesorectal excision (TME) without pretreatment was undertaken in 338 patients (60.4 %) and neoadjuvant radiochemotherapy was administered in 222 (39.6 %) patients. The histological work-up was performed according to the guidelines of the German Association of Pathologists. Data are given as median values and ranges in brackets. RESULTS: The lymph node yield was 24 (7-79) in 338 patients undergoing primary TME surgery without pretreatment, while 20 (3-56) lymph nodes were identified in patients after neoadjuvant radiochemotherapy (p = 0.001). A minimum of 12 lymph nodes were analyzed in 335 out of 338 patients (99.1 %) and in 209 out of 222 patients (94.1 %) following neoadjuvant radiochemotherapy (p = 0.001). Lymph node metastasis was identified (p = 0.362) in 116 out of 338 patients without pretreatment (34.3 %) and in 71 out of 222 patients after neoadjuvant radiochemotherapy (32.0 %). Patient age did not influence the number of identified lymph nodes or rate of lymph node metastasis. CONCLUSION: In this trial the number of identified lymph nodes suggests that the quality of surgery and histopathological work-up were adequate compared to the standards defined by national guidelines. Neoadjuvant radiochemotherapy led to a reduced lymph node yield compared to surgery without pretreatment; however, this did not influence the rate of lymph node metastasis.

[Spincter preservation after selective chemoradiotherapy of rectal cancer. Interim results of the OCUM study]. / Spinktererhalt nach selektiver Radiochemotherapie des Rektumkarzinoms. Zwischenergebnisse der OCUM-Studie.

BACKGROUND: In a prospective multicenter observational study (OCUM) neoadjuvant chemoradiotherapy (nRCT) was selectively administered depending on the risk of local recurrence and based on the distance between tumor and mesorectal fascia in pretherapeutic high-resolution magnetic resonance imaging (MRI). OBJECTIVE: Frequency and quality of abdominoperineal excision (APE) and sphincter preserving operations. PATIENTS AND METHODS: Of 642 patients treated in 13 hospitals 389 received surgery alone and 253 nRCT followed by surgery. By univariate and multivariate analysis risk factors for APE were determined. Quality parameters were the quality grade of mesorectal excision, the pathohistological involvement of the circumferential resection margin and intraoperative local dissemination of tumor cells. RESULTS AND DISCUSSION: In 12.8 % of the patients APE was performed. Independent risk factors for APE were tumor location in the lower third of the rectum and the individual hospitals, where APE varied between 0 and 32 %. This variation was chiefly caused by the different case mix. Hospitals with a high APE rate (> 30 %) treated significantly more patients with very low lying carcinomas (< 3 cm above the anal verge) and more advanced tumors. The median height of the tumor in cases of APE was nearly equal in all participating hospitals. Independent on the number of cases the quality of rectal surgery was high. Within the patient groups of primary surgery and nRCT the oncological quality parameter did not significantly differ between sphincter preservation and APE. As far as sphincter preservation is concerned the results justify a selective application of nRCT in patients with rectal carcinoma. The long-term results still have to be awaited.

Oncological short-term effects and adverse events of MRI-guided selective neoadjuvant radiochemotherapy for rectal cancer.

AIM: To investigate the oncological short-term effects and acute side-effects of magnetic resonance imaging (MRI)-guided selective neoadjuvant radiochemotherapy (nRCT) for rectal cancer. PATIENTS AND METHODS: In a prospective multicenter cohort study of 230 patients with rectal cancer stage II or III, nRCT was applied in the following situations (n=96) only: cT4 tumors, cT3 tumors of the distal rectum or tumors leaving a circumferential resection margin (CRM) of ≤1 mm between the tumor and the mesorectal fascia (mrCRM+). Pre-therapeutical tumor stage and involvement of mesorectal fascia were assessed by MRI and were compared with the pathological findings of the rectal specimens. Furthermore, tumor regression grades, acute side-effects, and surgical complications were analysed. RESULTS: Using selective nRCT, 62 out of 72 patients (86%) with mrCRM+ had tumor-negative pathological CRM. Reduction of T category was observed in 62% and of N category in 88% of patients. Lymph node metastasis was found by pathology in only 21% of all irradiated patients. Histologically complete tumor regression (ypT0ypN0) was observed in 15% and intermediate regression (more than 25%, but not complete) in 67% of patients. Fifteen percent of patients suffered from grade 3 toxicity, but no grade 4 toxicity occurred. nRCT did not adversely influence surgical morbidity. CONCLUSION: Despite the negative selection of locally advanced rectal cancer cases for nRCT, impressive rates of tumor down-staging and eradication of tumor from the mesorectal fascia were achieved. The rate of complete regression is comparable to that in the literature. Moreover, the selective use of nRCT spared a considerable percentage of patients with stage II/III rectal cancer severe irradiation toxicity.

Whole-body MR imaging versus sequential multimodal diagnostic algorithm for staging patients with rectal cancer: cost analysis.

PURPOSE: To compare the direct costs of two diagnostic algorithms for pretherapeutic TNM staging of rectal cancer. MATERIALS AND METHODS: In a study including 33 patients (mean age: 62.5 years), the direct fixed and variable costs of a sequential multimodal algorithm (rectoscopy, endoscopic and abdominal ultrasound, chest X-ray, thoracic/abdominal CT in the case of positive findings in abdominal ultrasound or chest X-ray) were compared to those of a novel algorithm of rectoscopy followed by MRI using a whole-body scanner. MRI included T 2w sequences of the rectum, 3D T 1w sequences of the liver and chest after bolus injection of gadoxetic acid, and delayed phases of the liver. The personnel work times, material items, and work processes were tracked to the nearest minute by interviewing those responsible for the process (surgeon, gastroenterologist, two radiologists). The costs of labor and materials were determined from personnel reimbursement data and hospital accounting records. Fixed costs were determined from vendor pricing. RESULTS: The mean MRI time was 55 min. CT was performed in 19/33 patients (57%) causing an additional day of hospitalization (costs 374 euro). The costs for equipment and material were higher for MRI compared to sequential algorithm (equipment 116 vs. 30 euro; material 159 vs. 60 euro per patient). The personnel costs were markedly lower for MRI (436 vs. 732 euro per patient). Altogether, the absolute cost advantage of MRI was 31.3% (711 vs. 1035 euro for sequential algorithm). CONCLUSION: Substantial savings are achievable with the use of whole-body MRI for the preoperative TNM staging of patients with rectal cancer.

Optimised surgery (so-called TME surgery) and high-resolution MRI in the planning of treatment of rectal carcinoma.

BACKGROUND: Since November 1998, we have applied the concept of total mesorectal excision (TME) to rectal carcinoma together with a standardised pathological quality assessment. Participation in the European MERCURY study [The MERCURY Study Group Radiology (in press), 2006] required us to establish the indication for neoadjuvant radiochemotherapy on the basis of an magnetic resonance imaging (MRI) scan. The aim of the present retrospective study is to evaluate the quality of the surgery, the efficacy of the MRI and the oncological outcomes achieved. MATERIALS AND METHODS: Between November 2001 and October 2005, 68 out of 109 patients with carcinoma of the rectum were submitted to radical surgery in curative intent and 23/68 (34%) were given neoadjuvant therapy. In an interdisciplinary study group, each patient was evaluated pre-operatively and post-operatively using standardised MRI and histopathological methods. RESULTS: The quality of surgery was established on the basis of the pathological examination of the surgical specimen. The rates of incomplete mesorectal excision, intra-operative tumour cell dissemination and positive circumferential margins were all low at 4%, 7% and 3%, respectively. The effectiveness of MRI proved to be greatest in predicting the tumour status at the circumferential resection margin: in the admittedly limited number of patients it proved possible to correctly predict the tumour status for every patient. The assessment of the anatomic extent of the primary tumour and of the regional lymph node metastasis according to the TNM system, in contrast, was considerably less successful at 73% and 75%, and 37% and 57%, respectively. CONCLUSION: By applying the TME concept and MRI-based therapy planning, excellent results can be achieved and, at the same time, the number of patients requiring neoadjuvant treatment is considerably reduced.

[Quality indicators for diagnostic and therapy of rectal carcinoma]. / Qualitätsindikatoren bei Diagnostik und Therapie des Rektumkarzinoms.

Diagnostic and treatment of rectal cancer need a continuous quality assessment. Indicators of quality were compiled as indicator profile for a summarizing evaluation. The indicators selected should potentially show an appreciable variation of the quality target and in addition should be decisive for the outcome. For the evaluation of the clinical diagnostic the frequency of the determination of the pretherapeutic T, N and M categories and the proportion of pT 1-tumors were chosen, for the pathological diagnostic the number of histologically examined lymph nodes and the proportion of lymphnode positive patients. Process quality of treatment was defined by the following indicators: proportion of tumor excision, of definite therapy by local tumor removal, of neo-adjuvant long-term radiochemotherapy, of adjuvant treatment in patients not selected for neoadjuvant therapy, of total / partial mesorectal excision, of abdomino-perineal resection, postoperative mortality, frequency of clinically apparent anastomotic leakage, and of neurogenic bladder dysfunction at hospital discharge. The indicators for the quality of the performance of treatment were differentiated between surrogate indicators that can be determined immediately after accomplishment of primary surgical therapy giving strong clues for the further course of disease at an early date, and definite indicators. Important surrogate indicators comprise the occurrence of intraoperative local tumor cell dissemination, R 1 / 2-resection, pathohistologically CRM-positive tumor resection, and the quality of mesorectal excision (proportion of incomplete mesorectal excision). The definite indicators include the 5-year local recurrence rate and the 5-year overall survival rate. The corresponding quantifying parameters for the individual indicators are specified in this paper with precise figures.

[Report on the workshop "workflow rectal cancer II" in Burghausen]. / Bericht über den Workshop "Workflow Rektumkarzinom II" am 10. / 11.11.2006 in Burghausen.

The task force "workflow rectal cancer II" defined operative techniques in lower rectal cancer, especially the total mesorectal excision and an improved technique of abdominalperineal resection. New aspects for treatment of rectal cancer with primary distant metastases are described. Due to newer publications a concept of bidirectional procedure with surgery and radiochemotherapy is recommended, where the operation must not be inevitably the first step. In anastomoses below 6 cm of the anocutaneous verge a reservoir should be performed on principle due to better functional results. The colon-j-pouch with a maximal loop length of 6 cm is best investigated under these conditions, the other procedures should be further evaluated.

The need for future surgical low rectal cancer studies.

Optimal surgery remains the mainstay of best outcome for rectal cancer. The demonstration, during the 3rd Annual Pelican Surgical Workshop Symposium, of an abdomino-perineal excision (APE) performed in the 'Berlin position', further added to the debate on optimal surgical technique. Much interest was created at the 1st Pelican symposium with the demonstration, by the Swedish surgeon Dr Torbjorn Holm, of a prone APE and the delivery of a 'cylindrical' specimen and the potential to reduce local recurrence using this approach. The high rates of local recurrence following APE and the discussions as to optimal technique have led to the development of a proposed MERCURY Study Group study to assess the benefit of a radical APE, with careful assessment of the impact that this operation may have on morbidity. A German study has also been proposed adopting the UK's multidisciplinary team approach. It aims at targeting preoperative chemoradiotherapy at those patients in whom a radical APE or total mesorectal excision is likely to result in an involved surgical resection margin. In this article we review the evidence for improving the surgical technique for low rectal cancer. We believe improvements may be best achieved through continued European prospective, multi-centre, multidisciplinary studies.

Bacterial biofilm within diseased pancreatic and biliary tracts.

BACKGROUND: Bacterial community structures in human pancreatic and biliary tracts were evaluated. METHODS: Gall bladder stones from 153 patients, 20 gall bladder walls, six common duct stones, 52 biliary stents, 21 duodenal biopsies, nine pancreatic duct biopsies, and five bile ducts were investigated using fluorescence in situ hybridisation (FISH) with ribosomal RNA targeted Cy3/Cy5 (carbocyanine) labelled oligonucleotide probes. RESULT: Duodenal, gall bladder, and bile duct walls were free of bacteria. A dense multispecies bacterial biofilm was present within the pancreatic duct of patients with calcific pancreatitis and within biliary stents, irrespective of diagnosis. The concentration, density, and amenability of the biofilm to FISH and DNA staining declined progressively with the grade of stent occlusion. The lowest detectable bacterial concentrations were found by FISH in completely occluded stents and brown/mixed gall stones. Bacteria were not detectable with FISH in cholesterol gall stones. CONCLUSIONS: A wide range of different branches and groups of bacteria participate in the development of biofilms on the surfaces of foreign bodies, such as biliary stents, mixed gall stones, or calcific pancreatic ducts, but not on the surface of pure cholesterol gall stones. Occlusion of stents leads to progressive extinction of the biofilm and mummification of its components. Deposition of cholesterol or other substances within the biofilm matrix may be a novel mechanism of host defence against bacteria present in these biofilms.

Magnetic resonance imaging in rectal cancer: the MERCURY experience.

Eleven European clinics, well experienced in a multidisciplinary approach to rectal cancer therapy, were testing magnetic resonance imaging (MRI) as a preoperative tool for staging of unselected rectal cancer patients. Aims and preliminary results of the study are presented. The way of using MRI for patient selection for neoadjuvant therapy is demonstrated from Berlin-Friedrichshain.