Methods/design
Trial design and randomisation
The SYNCHRNOUS trial is a randomised, controlled, multicentre, confirmatory study comparing resection of the primary tumour versus no resection prior to systemic therapy in patients with colon cancer and synchronous metastases not amenable to curative therapy.
After screening for eligibility and informed consent is obtained, patients are randomised in a 1:1 ratio into one of the following study arms:
• Resection of the primary tumour followed by systemic therapy (experimental arm)
• Systemic therapy alone (control arm)
Patients are randomised stratified for centre using a web-based, central randomisation and registration system
http://www.randomizer.at.
Treatment according to randomisation, i.e. resection of the primary tumour or first cycle of systemic therapy must be carried out within 14 days after randomisation.
Trial organisation
The SYNCHRONOUS trial will be conducted as an intergroup trial of the Study Centre of the German Surgical Society (SDGC), the German Surgical Network of Clinical Studies (CHIR-Net) together with the Colorectal Study Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO) of the German Cancer Society and the Association of Certified Intestinal Centres (Arbeitsgemeinschaft Zertifizierter Darmzentren). The SDGC is responsible for the project management of the trial. Patient recruitment will take place at more than 60 trial centres throughout Europe that will be chosen out of a total of more than 100 institutions with interest in participation in the study.
Trial population and patient recruitment
At each participating centre all consecutive patients with the new diagnosis of colon cancer and synchronous, unresectable metastases will be screened for eligibility to be enrolled in the SYNCHRONOUS trial. An interdisciplinary team at each trial centre including a surgeon and a medical oncologist/gastroenterologist determines, if patients are not amenable to curative therapy and may thus be considered for inclusion in the SYNCHRONOUS trial.
Inclusion criteria
• Newly diagnosed, histologically confirmed colon cancer
• Synchronous metastases not amenable to curative therapy:
Assessment by an interdisciplinary team at each trial centre including a surgeon and a medical oncologist or gastroenterologist.
• Resectable primary tumour
• ECOG performance status of 0, 1, or 2
• Patient considered to tolerate surgery and chemotherapy by the local interdisciplinary team
• ≥ 18 years of age
• Written informed consent
Exclusion criteria
• Rectal cancer (tumour up to 12 cm from the anal verge)
• Tumour-related symptoms or diagnostic findings requiring urgent surgery
Definition of tumour-related symptoms: e.g. lower gastrointestinal bleeding requiring transfusion, bowel obstruction, tumour perforation or intractable pain at site of primary tumour.
Definition of diagnostic findings: e.g. obstructing tumour that cannot be passed by colonoscope.
• Patients not eligible for surgery (ASA ≥ IV)
• Unequivocal extensive peritoneal metastases
• Chemo- or radiotherapy during the past 6 months
• History of another primary cancer
Exceptions: curatively treated in situ cervical cancer, curatively resected non-melanoma skin cancer or other primary solid tumour curatively treated with no known active disease present and no treatment administered for ≥ 5 years prior to randomisation.
• Expected lack of compliance
Trial interventions
Experimental arm: resection of the primary tumour prior to systemic therapy
Patients in the experimental arm will undergo resection of the primary tumour prior to receiving systemic chemotherapy. Surgery has to be performed within 14 days after randomisation. Systemic therapy should be started within 8 weeks after surgery.
The type of surgical procedure depends on the location of the tumour and is thus performed as (extended) right hemicolectomy, (extended) left hemicolectomy, rectosigmoid resection or subtotal colectomy. In certain cases surgeons may perform a segmental colonic resection, if considered adequate by the executing surgeon. If possible and considered safe for the patient, resections should be performed with adequate local lymphadenectomy as it is associated with low additional morbidity [
19]. However, the decision to perform a lymphadenectomy is left at the discretion of the executing surgeon and is documented in the CRF. A complete (R0) resection of the tumour should be performed. However, if a R0 resection is not considered to be safe and adequate (e.g. due to involvement of adjacent structures such as the ureter, stomach, pancreas etc.) surgeons may perform a R2 resection. The kind of resection should be documented in the case report forms (CRF).
The executing surgeon may also decide whether to perform a primary anastomosis or to create a stoma after colonic resection. Open and laparoscopic colectomy may be performed.
The principles of systemic therapy in the experimental arm are identical to those for the control arm.
Control arm: systemic therapy without previous resection of the primary tumour
Patients in the control arm receive primary systemic chemotherapy without previous resection of the primary tumour. Systemic therapy has to start within 14 days after randomisation. There is no predefined protocol of systemic therapy. The executing medical oncologist determines patients' treatment. Chemotherapy according to local practice and/or current guidelines is recommended (e.g. the German S3-guideline for colorectal cancer [
20]). Examples for such chemotherapy regimens are (oral) fluoropyrimidin-based combination therapy with Oxaliplatin or Irinotecan such as FOLFOX-4, FOLFOX-6, FOLFIRI, CAPOX, XELOX with or without targeted therapy such as Bevacizumab or Cetuximab for K-ras wild-type tumours). However, as actually administered therapy depends on various factors (e.g. patients' comorbidities, development of toxicities) and may change over time due to emerging evidence, the administered systemic therapy is documented carefully for each patient in both study arms and is considered as a covariate in multivariate analysis (in addition to centre as factor in multivariate analysis). At each follow-up visit documentation of systemic therapy includes the administered agents (protocol), possible dose reductions and delays of planned chemotherapy cycles. Dose adjustment, duration and termination of systemic therapy are at the discretion of the executing medical oncologist. In case of progression systemic therapy may be switched to a second (and third) line regimen. The choice of the second and third line regimen is also at the discretion of the executing medical oncologist.
Patients may also discontinue systemic therapy in the following instances:
• Occurrence of adverse events, if discontinuation is desired or considered necessary by the patient and/or the medical oncologist
• Request by the patient
• Occurrence of pregnancy during treatment
• Lack of subject compliance
In case of adverse events requiring discontinuation, systemic therapy may be restarted, if considered appropriate by the executing medical oncologist.
Patients may be enrolled in further chemotherapy trials.
Additional treatments
Owing to the palliative situation, patients in both treatment arms may receive any concomitant medications or treatments deemed necessary to provide adequate supportive care. In particular, patients may receive analgetic and antiemetic therapy for relief of symptoms directly related to the disease and/or chemotherapy.
Based on data of randomised phase III trials 6-10% of patients with colorectal cancer and unresectable metastases may become operable after treatment with modern chemotherapy regimens and subsequently undergo surgery with curative attempt [
13,
21]. Patients who become operable during chemotherapy may undergo treatment of the primary tumour (patients in the control arm) or metastases (patients in the experimental and control arm) with curative intent. In this scenario, patients may also undergo radiofrequency ablation (RFA) of metastatic lesions with curative attempt. The decision to initiate curative therapy has to be made by the members of the interdisciplinary team at the recruiting institution. These patients will be included in the intention-to-treat analysis.
Patients randomised to the control arm may, moreover, undergo interventional therapy for local complications (e.g. colonic stents, laser therapy). However, development of local complications will be documented as a secondary endpoint as will be the need for interventions. The decision to refer patients in the control arm for palliative tumour resection due to local complications is at the discretion of the multidisciplinary team at the recruiting institution.
The duration of treatment breaks before and after interventional procedures is at the discretion of the multidisciplinary team at the recruiting site according to the actual extent of the procedure.
Study objectives and endpoints
The primary objective of the present trial is to investigate, whether resection of the primary tumour prolongs survival of patients with colon cancer and synchronous metastases not amenable to curative therapy. The primary hypothesis is that resection of the primary tumour prolongs survival from 20 to 26 months compared to systemic therapy without prior tumour resection.
It is the secondary objective of the trial to evaluate short- and long-term safety of both treatment strategies as well as subsequent curative procedures, the course of tumour markers and patients' quality of life.
Primary endpoint
The primary efficacy endpoint is overall survival, defined as time from randomisation date to date of death due to any reason. After randomisation patients will be followed up at intervals of three months for a minimum duration of 36 months or until death. Patients who have not died by the end of follow-up will be censored at their last contact date, as will be those patients who will be withdrawn from the study for a reason other than death (e.g. loss to follow-up).
Secondary endpoints
-
Time-to-development of primary tumour related local symptoms (control arm):
Time from randomisation date to date of first appearance of tumour related local symptoms requiring hospitalisation and/or therapy (except for use of laxatives)
-
Primary tumour complications (control arm):
Frequency and kind of local complications related to the primary tumour:
-
Lower gastrointestinal bleeding: Evidence of lower gastrointestinal bleeding such as positive Haemoccult test or apparent blood that is not attributable to other causes (e.g. haemorrhoids), results in a drop of systemic haemoglobin and requires transfusion or interventional therapy (e.g. endoscopic control of haemorrhage)
-
Bowel obstruction: Symptoms of ileus/subileus, i.e. abdominal pain and absence of bowel movement together with evidence of bowel obstruction from abdominal x-ray or CT scan that require hospitalisation and/or interventional therapy (e.g. stent placement, laser recanalisation, operation with bowel resection, creation of a stoma or bypass)
-
Tumour perforation: Clinical symptoms suspicious of intestinal perforation (e.g. abdominal pain and tenderness, fever, elevated infectious parameters) together with evidence of bowel perforation by imaging (free air on abdominal x-ray, CT scan) or on laparotomy.
-
Intervention due to primary tumour complication (control arm):
-
Frequency and kind of operative or non-operative interventional therapy for complications of the primary tumour:
-
Operation with colonic resection
-
Operation with creation of a stoma
-
Operation with creation of an intestinal bypass
-
Endoscopic placement of a stent
-
Endoscopic recanalisation (e.g. by laser)
-
Endoscopic control of haemorrhage (e.g. clips, submucosal injections)
-
Administration of systemic therapy (experimental and control arm):
Proportion of patients, who actually receive systemic therapy. Furthermore, the administered agents (i.e. chemotherapy protocol), dose reductions and delays of chemotherapy cycles are documented for both study arms.
-
Peri-operative morbidity (experimental arm):
Frequency and kind of peri-operative complications after resection of the primary tumour until post-operative day 30 (Visit 2a). Complications are graded according to the Dindo classification (
see Additional file
1
: Appendix A).
The diagnosis of anastomotic leakage after colonic resection is made considering the proposed definition of anastomotic leakage after rectal resection [
22]: Defect of the intestinal wall integrity at the anastomotic site leading to a communication between the intra- and extraluminal compartments (detection by imaging or on re-laparotomy). An abscess close to the anastomosis is also considered as anastomotic leakage. The severity of an anastomotic leakage is graded as follows:
Grade A: Anastomotic leakage requiring no active therapeutic intervention.
Grade B: Anastomotic leakage requiring active therapeutic intervention but manageable without re-laparotomy.
Grade C: Anastomotic leakage requiring re-laparotomy.
Obstructive symptoms after surgery (e.g. abdominal distension, vomiting) with the need to stop food intake and/or insert a gastric tube. Radiological confirmation by plain abdominal x-ray or CT scan is required.
-
Surgical site infection (CDC-Definition, see Additional file
1 : Appendix B)
-
Intraabdominal Abscess
Intraabdominal collection of purulent or infected fluid (confirmed by culture) confirmed by interventional drainage or on surgical re-intervention.
Drop of systemic haemoglobin ≥ 3 g/dl compared to postoperative baseline level and/or need for transfusion of > 2 units of packed red blood cells due to intra-abdominal haemorrhage as indicated by blood loss via the abdominal drains and/or free abdominal fluid/hematoma on imaging/re-operation.
Clinical evidence (e.g. painful, swollen, warm, livid leg) of a deep thrombosis located in a leg or pelvic vein confirmed by duplex sonography or CT-angiography, which was not
previously known.
Clinical (e.g. tachycardia, dyspnoea) suspicion of pulmonary embolism confirmed by spiral computed tomography or lung perfusion scintigraphy.
At least 3 of 4 of the following: temperature > 37.5°C, purulent tracheal secretion, white blood count > 12 000 or < 4,500/ml, elevated CRP level together with radiological evidence of pulmonary infection.
Postoperative doubling of pre-operative serum creatinine level or need for dialysis or hemofiltration (in patients who were not on dialysis pre-operatively).
Clinical symptoms suspicious of an (ischemic or non-ischemic) cerebrovascular event with confirmation by CT or MRT.
Electrocardiogram (NSTEMI or STEMI) and enzyme (Troponin I) changes suggestive of myocardial infarction or evidence of myocardial infarction on coronary angiogram.
The length of hospital stay registered from the first day after the operation until the day of discharge.
-
Peri-operative mortality (experimental arm):
30-day mortality or in-hospital mortality during initial hospital stay for resection of the primary tumour (i.e. deaths occurring after patients' discharge from the hospital but within 30 days after resection of the primary tumour are documented as peri-operative mortality).
-
Interventions with curative intent (experimental and control arm):
Frequency and kind of interventions performed with curative intent:
-
Potentially curative resection of the primary tumour and metastases (control arm)
-
Potentially curative resection of metastases (experimental arm).
-
Radiofrequency ablation (RFA) of metastases
The decision for an intervention with curative intent is made by the members of the interdisciplinary team at the participating institution.
-
Course of tumour markers:
The course of the tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 will be monitored in both study arms during the course of therapy. It is a secondary objective to evaluate the influence of primary tumour resection on the circulating levels of these tumour markers.
-
Quality of Life:
Quality of life is measured using the EQ-5D™ questionnaire of the EuroQol Group. In addition, the EORTC QLQ-C30 instrument and the specific colorectal module CR29 is used.
Trial implementation
There are 14 pre-specified study visits (V1 - V14) within the SYNCHRONOUS trial. In V1 patients will be screened according to the eligibility criteria and asked for written informed consent. Within V1 participating patients are also asked to complete the first quality-of-life form.
After enrolment into the study patients will be allocated randomly to either study arm (V2). The protocol requires that the actual start of therapy (i.e. resection of the primary tumour or first cycle of systemic therapy) is carried out within 2 weeks after randomisation to ensure comparable follow-up periods within and between both study arms. An additional visit (Visit 2a) will be performed in patients allocated to the experimental arm to assess early postoperative outcomes until post-operative day 30 (± 7 days). After randomisation patients will be followed-up every 3 months (± 7 days) in both study arms. The frequency and scope of study visits are in line with routine clinical care of patients with metastatic colon cancer. In these study visits (V3 - V14) data on the primary endpoint and secondary endpoints are documented including data on safety, complications, administered therapies (chemotherapy protocols, interventional therapies and surgical procedures) and tumour markers. In addition, quality of life will be assessed on V3 (3 months after V2), V4 (6 months after V2) and then every 6 months (i.e. on V6, V8, V10, V12, V14). V14 is the end-of-study visit, which will take place at a maximum of 36 months follow-up after V2. Peri-operative laboratory tests and those during chemotherapy cycles will be performed at discretion of the executing investigator based on local standards. Table
1 summarises the intended frequency and scope of study visits.
Table 1
Investigation scheme in the SYNCHRONOUS trial
Eligibility criteria |
X
| | | | |
Baseline data, demographics |
X
| | | | |
Laboratory analyses |
X
| | | | |
Tumor markers |
X
| | |
X
|
X
|
Randomization | |
X
| | | |
Administered therapies | | |
X
|
X
|
X
|
Chronic use of analgetic medication |
X
| | |
X
|
X
|
Assessment of com-plications & safety | | |
X
|
X
|
X
|
Primary endpoint | | |
X
|
X
|
X
|
Secondary endpoints | | | X |
X
|
X
|
Quality of life |
X
| | |
X
2)
|
X
|
Sample size
Based on the results obtained from a literature search, a median overall survival time of 20 months is expected for the control group (Fuchs et al. [
12], Saltz et al. [
13], Van Cutsem et al. [
23], Souglakos et al. [
21], Seymour et al. [
11]). An improvement to 26 months by the surgical intervention is considered to be clinically relevant and achievable (Flanigan et al. [
6], Ruo et al. [
14], Tebbutt et al. [
15]). For exponentially distributed survival times, this treatment group difference corresponds to a hazard ratio of 1.3. The accrual period amounts to 24 months and the follow-up period to 36 months. To detect a hazard ratio of 1.3 with a two-sided test for treatment effect at a significance level of 5% within a Cox model without covariates with a power of 85%, 694 patients (347 per group) have to be included in the analysis, leading to a total number of events of 522. These calculations are based on the formula for the log-rank test [
24] and were performed with ADDPLAN 5.0. Due to the asymptotic equivalence of the test statistic of the Cox model without covariates and the log-rank test statistics under the assumed model, the sample size calculation holds also true for the unadjusted Cox model. It can be expected that inclusion of the covariates centre, age, and administered systemic therapy in the analysis will further increase the power as compared to the above calculations that are based on the Cox model without covariates.
Based on the current knowledge about the treatments under investigation, it could not be ruled out that the experimental intervention may show no effect or even a negative effect in the early part of the follow-up as compared to the control group, and that its advantage becomes clear later on. To assess the robustness of the study power, simulations were performed for various parameter scenarios reflecting this situation. A linear increase of the mortality in the control group and an instantaneous increase in the experimental group by rates between 5% and 10% during the first three months of the follow-up were considered. Crossing of the survival curves was assumed to occur after three months and exponential survival thereafter leading overall to the same median survival times as specified above. For the sample size of 694 patients, the resulting power for the two-sided test for treatment effect within the Cox model without covariates varied between 84.5% and 90.3% thus demonstrating robustness of the study power to the assumptions made with respect to the course of the survival curves (simulations performed in SAS, version 9.1; 100,000 replications were performed for each parameter scenario). We repeated these simulations, but now applying the robust test proposed by Lin and Wei [
25] which will be applied in the analysis. For the robust test, power values in the range from 84.6% to 90.5% were obtained. Furthermore, considering the same scenarios we performed simulations under the null hypothesis. The estimated type I error rate for a nominal two-sided significance level of 5% were between 4.95% and 5.08% for the standard Cox model and between 4.78% and 4.98% for the robust approach. It can be concluded that the robust test leads to virtually the same power in the realistic scenarios we considered in our simulations while at the same time assuring appropriate type I error rate even if the proportional hazards assumption is violated.
The loss-to-follow up rate can be assumed to be very low (less than 1% in Van Cutsem et al. [
23]). However, it is expected that in the experimental group a number of patients will not receive standard systemic treatment after resection of the primary colon tumour (about 20%; see Ruo et al. [
14]). Furthermore, some patients will stop standard systemic treatment early due to lack of tolerability (about 20%; see Saltz et al. [
13]). Although these patients will be included in the intention-to-treat analysis, there might be some dilution of the treatment effect due to these protocol violations. This is accounted for by randomising further 15% of the calculated number of patients, i.e., a total of 800 patients (400 per group). It is assumed that further 100 patients will have to be screened to achieve this number of randomised patients.
Statistical analysis
Confirmatory analysis
The confirmatory analysis of the primary efficacy endpoint will be conducted according to the intention-to-treat principle, i.e., all randomised patients will be included and will be analysed in the treatment group where they were allocated to by randomisation. The test for treatment group difference will be performed at the two-sided type I error rate 5% within a Cox proportional hazards model that takes into account the covariates centre, age, and administered systemic therapy. The robust sandwich estimate of the covariance matrix proposed by Lin and Wei [
25] is used for the test for treatment effect. As shown in [
25], this test allows valid statistical inference also in situations where the proportional hazards assumption is violated, which may be the case in the current trial. Drop-out and lost-to-follow-up as well as non-occurrence of death within the follow-up period are treated as censoring events. Overall survival will be displayed for each intervention group based on the Kaplan-Meier estimates as well as on the estimates obtained from the Cox regression model, and the corresponding two-sided 95% confidence interval for the hazard ratio will be calculated.
No interim analysis is planned for this trial. As the follow-up for the primary endpoint is 36 months, and the planned recruitment time 24 months, the results of an interim analysis would arise after completion of the recruitment and treatment period. Accordingly, an interim analysis could not cause a reduction in sample size and was therefore not implemented.
Further analyses
Descriptive methods will be used for the analysis of the secondary outcomes. Time-to-event endpoints will be analysed as described for the primary endpoint. Binary secondary endpoints will be analysed using logistic regression models. Appropriate summary measures of the empirical distributions as well as descriptive p-values will be calculated. Graphical methods will be applied to visualise the findings of the study. Additionally, sensitivity analyses will be conducted for different populations (per protocol population of those patients that show no relevant protocol violations, appropriate subgroups). The safety analysis will be based on all randomised patients who were treated with any of the interventions under investigation. The analysis will include calculation and comparison of the rates of complications and serious adverse events as well as graphical display of the time-course. All analyses will be done using SAS version 9.1 or higher.
Data management and quality assurance
The investigator or a designated representative must enter all protocol-required information in the electronic case report form (eCRF). Any entry and correction in the Remote Data Entry System will be documented automatically in an audit file. Once the documentation of a patient is completed and checked for plausibility the investigator is asked to date and sign it via electronic identification. Documentation of quality of life questionnaires will be done on paper based questionnaires.
Control of data consistency
Automatic checks for data completeness, validity and plausibility will be programmed by the data management group of the Institute of Medical Biometry and Informatics (IMBI), University of Heidelberg, and queries will be generated. The investigator or the designated representatives are obliged to clarify or explain the queries. If no further corrections are to be made in the database, it will be closed and used for statistical analysis. All data management procedures will be carried out according to the current Standard Operating Procedures (SOPs) of the IMBI.
Quality control and monitoring
Clinical monitoring will be performed by the Coordination Centre for Clinical Trials (KKS) Heidelberg, an institution which is independent from other trial staff. Monitoring procedures will be adapted to the study specific risk for the patients. Interpretation of standard operating procedures (SOP) of the KKS to ensure patients' safety and integrity of the clinical data, e.g. primary endpoint in adherence to study protocol. Pre-study visits will be performed in centres interested to participate in the study, to ensure high compliance quality of the participating centres concerning e.g. patient recruitment and documentation.
External monitoring of entries in the electronic CRF will be done by independent monitors from KKS Heidelberg. Regular on-site monitoring visits are planned at all sites depending on the recruitment rate and quality of the data. Monitoring strategy and extent of source data verification (SDV) are described in a trial specific monitoring manual.
Ethical and legal considerations
The SYNCHRONOUS trial is conducted in line with either the Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) or the laws and regulations of the country, whichever provides the greatest protection of the patient.
The trial protocol, patient information and informed consent sheets have been approved by the independent ethics committee of the University of Heidelberg, Medical School (S-073/2011) and by the competent ethics committees of all participating trial centres. The SYNCHRONOUS trial has been registered at the ISRCTN database (ISRCTN30964555;
http://www.isrctn.org).
All patients will be informed of the aims of the study, the possible adverse events, the procedures and possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. Furthermore, it is the responsibility of the investigator to explain patients their duties within the trial. They will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorised individuals other than their treating physician. An example of a patient informed consent statement is given as an appendix to this protocol.
During the trial, patients will be identified solely by means of their year of birth and individual identification code (screening number, randomisation number). Trial findings will be stored in accordance with local data protection law/ICH GCP-Guidelines and will be handled in strictest confidence. For protection of these data, organisational procedures are implemented to prevent distribution of data to unauthorised people.
The SYNCHRONOUS trial is sponsored by the Universitätsklinikum Heidelberg, represented by the Commercial Director. The trial is funded exclusively by the Deutsche Forschungsgemeinschaft (WE 3548/5-1).
Current status
The trial protocol has been approved by the independent ethics committee of the University of Heidelberg, Medical School. At the time of manuscript preparation applications have been sent to the majority of the affiliated local ethics committees of the participating institutions.
Prior to the start of the study, all participating centres were trained and introduced into all study specific procedures. For this purpose an investigator's meeting was held in Heidelberg in October 2011. During this two-day workshop investigators and study nurses from the participating institutions were instructed in the general principles of clinical trials (day one) and the study specific implementation of the SYNCHRONOUS trial (day two). The commitment of all participating institutions to include patients in this important trial was strengthened and the participants used the opportunity to discuss protocol specific subjects and exchanged their experience from previous randomized controlled trials. As recruitment of patients was considered a critical point of the study, the participants expressed their strong will to ensure sufficient recruitment of patients and discussed strategies to optimize patient recruitment.
Acknowledgements
We would like to thank the following centres for their commitment for SYNCHRONOUS trial.: Klinikum Ansbach, Meyer, Prof. Dr. T.; Klinikum Aschersleben-Staßfurt, Grunewald, Dr. M.; Gemeinschaftspraxis Bad Soden, Seipelt, PD Dr. G., Seelig, PD Dr. M.; Berlin, Charité Campus Mitte, Neudecker Dr. J., Müller, Prof. Dr. J.; Berlin, Charité Campus Virchow, Guckelberger, PD. Dr. O.; Berlin, Park-Klinik-Weissensee, Schernikau, Dr. U.; Berlin-Tempelhof, St. Joseph Krankenhaus, Schwarz, Dr. E.; Berlin, Sana Klinikum Lichtenberg, Inderhees, Dr. S.; Universitätsklinik Knappschaftskrankenhaus Bochum, Reinacher-Schick, PD. Dr. A.; Bonn, Johanniterkrankenhaus, Ko, Prof. Dr. Y.; Städt. Klinikum Braunschweig, Lordick, Prof. Dr. F.; Ev. Diakonie-Krankenhaus Bremen, Pflüger, Prof. Dr. K.H.; Fürst - Stirum Klinik Bruchsal, Ihle, Dr. I.; St. Rochus Hospital Castrop-Rauxel, Hilburg-Eull, Dr. N.; Böhner, Dr. H.; St. Vincenz - Krankenhaus Datteln, Becker, Dr. J.; Dortmund-West, Kath. Krankenhaus, Flenker, Prof. Dr. I.; Klinikum Dortmund, Jürgens, Dr. C.; Dortmund, Knappschaftskrankenhaus, Bauer, PD Dr. K.H.; Dortmund-Hörde, St. Josefs-Hospital, Stern, Prof. Dr. J.E.; Kath. Krankenhaus Dortmund West, Flenker, Prof. Dr. I.; St. Josef Krankenhaus, Essen, Friedrich, Dr. J.; Uniklinikum Frankfurt/Main, Bechstein, Prof. Dr. W.O.; Agaplesion Markus Krankenhaus Frankfurt/Main, Bolling, Dr. C.; Uniklinik Freiburg, Chirurgische Klinik, Thomusch, Prof. Dr. O.; Illerhaus, Dr. G.; Klinik am Eichert Göppingen, Riedl, Prof. Dr. S.; Hamburg UKE, Izbicki, Prof. Dr. J.R.; AK Harburg, Hamburg, Kallinowski, Prof. Dr. F.; Vinzenz Krankenhaus Hannover, Kappelmann, Dr. G.; Heidelberg Krankenhaus Salem, von Frankenberg, PD Dr. M.; Klinikum Heidenheim, Imdahl, Prof. Dr. A; SLK-Kliniken Heilbronn, Huber, Dr. J.; Klinikum Herford, Winde, Prof. Dr. G.; Klinikum Ingolstadt, Darmzentrum, Menzel, Prof. Dr. J.; Chirurgische Klinik, Klinikum Kaufbeuren, Tietze, Dr. M.; Köln, Onkologische Gemeinschaftspraxis, Schmitz, Dr. S.; Köln, Krankenhaus Porz, Kroesen, PD Dr. A. J.; Köln, Krankenhaus Merheim, Bulian, Dr. D.; Köln, Krankenhaus Holweide, Hügle, Dr. U.; Köln, Heilig Geist Krankenhaus, Eypasch, Prof. Dr. E.; Uniklinik Köln, Mönig, Prof. Dr. S.; Uniklinik Leipzig, Chirurgische Klinik, Jonas, Prof. Dr. S.; Helmut G. Walter Klinikum Lichtenfels, Greger, PD Dr. B.; Linz, Krankenhaus Barmherzige Schwestern, Rumpold, Dr. H.; Klinikum Lüdenscheid, Güngär, Dr. K.; Klinikum Ludwigshafen, Klippel, Dr. S.; Klinikum Magdeburg, Krüger, Dr. M.; Uniklinikum Mannheim, Kienle, Prof. Dr. P.; Chirurgische Uniklinik Marburg, Riera-Knorrenschild, Dr. J.; Moers, Fachübergreif. Gemeinschaftspraxis, Wiegand, Dr. J.; Bethanien Krankenhaus Moers, Zachert, Dr. H.-R.; St. Josef Krankenhaus Moers, Lippitz, Dr. C.; Evangelisches Krankenhaus Mülheim, Simon, Dr. M.; München Klinikum Bogenhausen, Mühl, Dr. S.; München, TU, Klinik rechts der Isar, Rosenberg, PD Dr. R; Raphaelsklinik Münster, Kratz-Albers, Dr. K.; St. Franziskus Hospital Münster, Engels, Dr. W.; Universitätsklinikum Münster, Engels, Dr. W.; Anthoni, Dr. C.; Stauferklinikum Mutlangen, Hebart, Prof. Dr. H.; Kliniken Nagold, Benz, Prof. Dr. S..;
Klinikum Neumarkt, Hemmel, Dr. M.; Krankenhaus Hetzelstift, Neustadt/Weinstr., Bauer, Dr. W.; Klinikum Nürnberg, Link, Dr. K.; Klinikum Offenbach Wauer, Dr. U.; Marienhospital Osnabrück, Meyer, Dr. M.; St. Vincenz-Krankenhaus, Schmidt, Prof. Dr. R.; Klinikum Passau, Suednoff, Prof. Dr. T.; Klinikum Pinneberg, Nahrstedt, Dr.U.; Prosper Hospital, Recklinghausen, Höhler, Prof. Dr. T.; RoMed Klinikum Rosenheim, Hertreiter Dr. J.; Diakonie-Klinikum Schwäbisch Hall, Golling, Prof. Dr. M.; Helios Klinikum Siegburg, Fronhoffs Dr. S.; St.-Marien-Krankenhaus Siegen; Willeke Prof. Dr. F.; Krankenhaus Sinsheim, Löffler, Dr. T.; Diakonissen-Stiftungs Krankenhaus, Speyer, Fußer Dr. M.; Klinikum St. Elisabeth Straubing, Haberl, Prof. Dr. C.; Stuttgart, Katharinenhospital, Köninger, Prof. Dr. J.; Medizinische Klinik Tübingen, Königsrainer, Prof. Dr. A.; Krankenhaus der Barmherzigen Brüder Trier, Ockert, Prof. Dr. D.; Darmzentrum Klinikum Uelzen, Kather Dr. R.; Uniklinik Ulm, von Wichert, Prof. Dr. G.; Joseph-Hospital, Arndt, Prof. Dr. M.; Bundeswehrkrankenhaus Ulm, Benesch, Dr. S.; Westerstede, Ammerland Klinik, Kohl, Dr. D.; Klinikum Weimar, Hoffmann, Dr. T.; Mittelhessisches Darmzentrum Wetzlar, Schaefer, Dr. O.; Uniklinik Wien, Chirurgische Klinik, Grünberger, Prof. Dr. T.; Uniklinik Mainz, Klinik für Allgemein- und Abdominalchirurgie, Jansen-Winkeln, Dr. B.; Stiftung Juliusspital Würzburg, Breunig, Dr. E.; Helios Klinikum Wuppertal, Schmalz, Dr. O.;