Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

[Benefit assessment of operative interventions from the perspective of surgical research]. / Nutzenbewertung operativer Maßnahmen aus der Perspektive der chirurgischen Forschung.

The benefit assessment of surgical procedures serves as the basis for the concept of evidence-based surgery. However, especially in the field of surgery, many interventions are lacking assessment in high-quality clinical trials. Therefore, a well-structured benefit assessment of surgical interventions in the future is imperative. Considering the different perspectives, e.g. of the patients, surgeons, industry or health care investors, the implications of the benefits and risks of a procedure can differ significantly. Researchers have to abide by different regulations, depending on the type of intervention being evaluated in a surgical trial. Furthermore, the benefit assessment of surgical procedures poses specific challenges, from the choice of a relevant endpoint to issues concerning the standardization of the interventions and the impact of learning curves. The IDEAL concept, which was established by a group of international experts in 2009, serves as a framework for the future development and assessment of innovations in the field of surgery. For example, the SDGC (Study Center of the German Society of Surgery) and CHIR-Net (Surgical Studies Network) indicate that such collaborations of clinicians and methodologists can lead to the creation of a qualified structure for the effective benefit assessment of surgical procedures. In the future, the aforementioned evidence gaps must be eliminated and innovations evaluated efficiently by the work of such networks.

[Clinical trials in surgery. On the way towards evidence-based surgery]. / Klinische Studien in der Chirurgie. Auf dem Weg zur evidenzbasierten Chirurgie.

The Study Centre of the German Surgical Society (SDGC) aims at a sustainable support of clinical trials in surgery. The SDGC focuses especially on the development and conducting of clinical trials in university and non-academic hospitals. This article outlines current fields of action and future perspectives of the SDGC.

[Contribution of the Study Center of the German Surgical Society to evidence based surgery]. / Beitrag des Studienzentrums der Deutschen Gesellschaft für Chirurgie zur evidenzbasierten Chirurgie.

Since the Study Center of the German Surgical Society (SDGC) was established in 2003 it has been supporting surgeons to implement their ideas for multicenter randomized studies. Assistance is provided for development (sample size calculation, protocol, funding application) implementation (submission to ethics committee, data management, monitoring) and analysis (statistical analysis, publication) in close collaboration with biometricians and data managers. Currently more than 2,500 patients have been included in 11 trials. The most complex SDGC study (SYNCHRONOUS) so far with up to 80 participating centers has been activated in September 2011. Furthermore, there is an increasing relevance for systematic reviews and meta analyses with regard to the development of studies and aggregation of results. For this reason a systematic review working group was established within the SDGC. To date 13 publications have been completed and 8 more are underway.

[Clinical trials beyond the German Drug Law. Clinical trials in surgery]. / Klinische Studien ausserhalb des Arzneimittelgesetzes. Klinische Studien in der Chirurgie.

Proof of safety and effectiveness of surgical procedures follows the same scientific principles as for drugs. Control of bias and chance when evaluating new operations has to be considered and should generally be followed using randomized controlled trials (RCT). The expenditure for study design, execution and analysis can be substantial due to specific characteristics of surgical treatments. The largest challenges represent the maintenance of comparable treatment and assessment within and between the study groups of a RCT, such as, blinding of surgeons, learning curves, standardization of procedures, and monitoring interventions to ensure execution according to protocol. This evaluation is made even more difficult due to lack of broadly accepted definitions of surgically relevant endpoints in daily practice and research. Since 2004, new methods and procedures are being tested to demonstrate the feasibility of surgical RCTs through a grant program for surgical clinical trial centers in Germany. In six surgical trial centers, a number of surgical RCTs have been designed and conducted. The first results of high-quality surgical RCTs are described.

DISPACT trial: a randomized controlled trial to compare two different surgical techniques of DIStal PAnCreaTectomy - study rationale and design.

BACKGROUND: Surgery is of increasing importance in the treatment and outcome of diseases of the pancreas worldwide. The incidence of pancreatic cancer (7-11/ 100,000 per year) has risen over the last years and surgical resection remains the only option for definite cure. Twenty-five percent of all resections are left of the superior mesenteric vein (distal pancreatectomy) and the appropriate closure technique for the pancreatic remnant remains unclear. Pancreatic fistulas are the most common (0-40%) and relevant postoperative complication. The optimal surgical strategy for pancreatic resection needs to be identified from the large number of surgical procedures available today. PURPOSE: To evaluate the effectiveness of the two most common surgical techniques for distal pancreatectomy: stapler versus hand-sewn closure of the pancreatic remnant. METHODS: In order to account for the uncertainty and clinical heterogeneity in the management of the pancreatic remnant following distal pancreatectomy, a study protocol is developed on the basis of a retrospective survey of patients in a center of excellence for pancreatic surgery and a systematic review with meta-analysis. RESULTS: The DISPACT trial is a multicentered, randomized, controlled and patient-and observer-blinded trial using a two-group parallel group-sequential superiority design to compare the two techniques mentioned above. It will include approximately 336 randomized patients at up to 20 centers of excellence in pancreatic surgery, who are undergoing elective distal pancreatectomy for resectable benign, malign, and neuroendocrine tumors, chronic pancreatitis and pseudocysts of the pancreatic body and tail. The combination of the rate of postoperative pancreatic fistula and mortality will be evaluated as the primary endpoint. In addition, a set of general and surgical parameters will be analyzed. Pre-specified treatment manuals and continuous intra-operative (photo-documentation of surgical procedures and blinded evaluation thereafter) and on-site monitoring will assure that the treatment of the study patients conforms to protocol and will minimize clinical heterogeneity. Due to uncertainties about the effect sizes of the primary endpoint, an a priori planned interim analysis of the primary endpoint will be conducted after 224 evaluable patients are selected in order to reassess the initially planned sample size. LIMITATIONS: Since pre-existing evidence was limited our initial sample size calculation is based on uncertain assumptions and may need to be modified in a planned interim analysis. Moreover, since surgical experience remains a potential confounder in surgical trials, learning curve bias has to be taken into account when analyzing the results. Given the participating trial sites, standardization of peri-and postoperative treatment represents a major issue of trial conduct. CONCLUSIONS: A group-sequential study design accounts for the uncertainty of pre-existing evidence. Also, standardization of surgical and postoperative care and blinded outcome assessment as well as adjustment for varying surgical expertise will contribute to a high validity and generalizability of the results.

[Consequences of the 12th AMG amendment on the conduct of non-commercial clinical trials]. / Auswirkungen der 12. AMG-Novelle auf die Durchführung von nichtkommerziellen klinischen Studien.

In 2004, the German Drug Law was reformed substantially putting into effect the European directive 2001/20/EG on Good Clinical Practice (GCP). Investigator initiated trials have to comply with the same requirements as clinical trials for drug development. When registered drugs are used in non-commercial clinical trials some simplifications are possible.Currently, all essential elements of GCP, such as financing of the trial, laying-down of sponsor responsibilities, establishing an extensive quality assurance system as well as immediate reporting of unexpected serious drug reactions, are stipulated by law. Since regulatory authorities and ethics committees have to approve every clinical trial, surveillance is reinforced. The new requirements cannot be met without sufficient financing, qualified personnel and professional structures for clinical trials. Compared to European partners, the research location Germany is at a disadvantage due to high administrative workload and costs.

[Results of resection and adjuvant therapy of liver metastases of primary colorectal tumors--a review of the literature]. / Ergebnisse der Resektion und adjuvanten Therapie von Lebermetastasen kolorektaler Primärtumoren--eine Literaturübersicht.

Natural history of patients with colorectal liver metastases is not significantly changed even by curative resection. The majority unfortunately relapse. The results of adjuvant treatment after resection were evaluated by analysis of 17 publications as well as by own data (60 patients). 340 patients were either treated by intraarterial (n = 201), systemic (n = 82), intraportal (n = 29) or intraperitoneal (n = 28) chemoinfusion (5-Fluorouracil or Floxuridine). An alternative approach was the treatment with specific immunotherapy using tumor vaccination (n = 35) or monoclonal antibodies (n = 20). Morbidity of adjuvant treatment includes local (chemical hepatitis, biliary sclerosis) and systemic (diarrhea, stomatitis) side effects. Technical complications could reach a level of up to 50% in case of local administration. With exception of 6 studies no comparison with a resection only group was performed. Despite postulated increase of survival and recurrence free time with historical controls the results of current ongoing studies are needed before general use of adjuvant treatment can be recommended.