ORIGINAL ARTICLE. Mirja Sargent & Stefan Boeck & Volker Heinemann & Karl-Walter Jauch & Thomas Seufferlein & Christiane J. Bruns

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1 Langenbecks Arch Surg (2011) 396: DOI /s ORIGINAL ARTICLE Surgical treatment concepts for patients with pancreatic cancer in Germany results from a national survey conducted among members of the Chirurgische Arbeitsgemeinschaft Onkologie (CAO) and the Arbeitsgemeinschaft Internistische Onkologie (AIO) of the Germany Cancer Society (DKG) Mirja Sargent & Stefan Boeck & Volker Heinemann & Karl-Walter Jauch & Thomas Seufferlein & Christiane J. Bruns Received: 6 May 2010 /Accepted: 12 July 2010 /Published online: 15 August 2010 # Springer-Verlag 2010 Abstract Background To date, only limited data are available regarding the routine surgical management of patients with exocrine pancreatic cancer (PC) in German community and university hospitals. Methods With the use of a standardized questionnaire, a national survey on surgical and oncological treatment concepts for PC in Germany was conducted on behalf of the Chirurgische Arbeitsgemeinschaft Onkologie and Arbeitsgemeinschaft Internistische Onkologie. The surgical part of that questionnaire contained 25 questions on criteria regarding resectability, surgical techniques, perioperative Mirja Sargent and Stefan Boeck contributed equally. M. Sargent : S. Boeck : V. Heinemann Department of Internal Medicine III, Klinikum Grosshadern, Ludwig Maximilian University of Munich, Munich, Germany S. Boeck stefan.boeck@med.uni-muenchen.de K.-W. Jauch Department of Surgery, Klinikum Grosshadern, Ludwig Maximilian University of Munich, Marchioninistr. 15, Munich, Germany T. Seufferlein : C. J. Bruns (*) Department of Internal Medicine I, University of Halle, Halle, Germany christiane.bruns@med.uni-muenchen.de patient management, and palliative surgical procedures in advanced PC. Data were collected centrally and analyzed using the SPSS software. Additionally, predefined subgroup analyses, classifying the results by the professional site of the responding physician and the local annual number of treated patients, were carried out. Results One-hundred and two questionnaires on the surgical survey section were returned. For the majority of the survey respondents, arterial infiltration is the most important criterion for non-resectability of PC (common hepatic artery, 69.9%; superior mesenteric artery, 85.3%; celiac trunk, 86.3%), whereas only 17.6% would define nonresectability based on portal vein infiltration; 69.9% consider extrapancreatic tumor manifestations as a criterion of surgical non-resectability. Of the survey participants, 53.9% perform a biliary drainage in case of preoperative cholestasis, whereas 43.1% reject this preoperative endoscopic-interventional approach. For cancers of the pancreatic head, 24.5% of surgical units recommend a classical Kausch Whipple procedure, 52.9% prefer the pylorus-preserving partial pancreatoduodenectomy, and 20.6% use both procedures; 74.5% routinely perform a standard lymphadenectomy, whereas 16.7% prefer an extended procedure. A radical pancreatic resection would be performed by 63.7% of survey respondents also if a single liver metastasis would be found intraoperatively. Conclusion Surgical treatment of PC in Germany is heterogeneous; future efforts to implement an evidence-based and standardized surgical management will be necessary.

2 224 Langenbecks Arch Surg (2011) 396: Keywords Pancreatic cancer. Surgery. Survey Introduction In Germany each year, approximately 12,800 patients are newly diagnosed with exocrine pancreatic cancer (PC). The 5-year survival rate of PC currently is below 5%. This is among the lowest in malignant diseases. According to its high malignancy, incidence and mortality are nearly identical in PC, and long-term survival unfortunately is a rare exception [1 3]. To date, radical surgical tumor resection is regarded as the only viable option for any long-term survival or even cure [2]. The biology and prognosis of PC is significantly affected by its early dissemination [4]. Due to the absence of early symptoms and the resulting late detection, in over 90% of patients the cancer has, at the time of diagnosis, spread beyond the boundaries of the pancreatic tissue [2]. However, as any oncosurgical intervention should be performed with curative intent [5], several questions arise regarding the daily management of patients with PC; for instance, how to uniformly define surgical resectability in PC or how to establish standard surgical procedures for optimal treatment outcome in this patient population. Currently, several fields in the surgical management of patients with PC may be regarded as a matter of scientific debate. These include the value of interventions like preoperative biliary drainage [6 10], the perioperative use of somatostatin analogs [11, 12], the standardization of pathological work-up of resected PC specimens [13, 14], surgical techniques in PC surgery (i.e., lymph node dissection) [15 18], and the importance of surgical treatment options in patients with advanced disease (e.g., palliative surgery, resection of PC metastases) [19 22]. Based on a national survey with standardised questionnaires, this study aimed to evaluate the current daily clinical practise in PC surgery at German community and university hospitals. The results obtained from this multicenter survey were also interpreted within the context of the recently published multidisciplinary S3 guideline on exocrine pancreatic cancer, which was generated as a result of an evidence-based consensus conference, including recommendations for prevention/screening, diagnosis, and treatment of PC [2]. Material and methods Survey design and questionnaire The methods of this multicenter survey have already been published previously [3]. On behalf of the CAO ( Chirurgische Arbeitsgemeinschaft Onkologie ) and AIO ( Arbeitsgemeinschaft Internistische Onkologie ) working groups of the German Cancer Society (DKG), questionnaires regarding the current surgical treatment of PC were sent to members of the CAO and AIO at German community and university hospitals. Responsible for the design of the questionnaire were C. J. Bruns and K. W. Jauch (surgical section) and S. Boeck, T. Seufferlein and V. Heinemann (section for medical oncology). This paper describes the results of the surgical part only, the data regarding the oncological part of the survey have been published separately in 2009 [3]. The questionnaires asked for statistical information about the participating physicians, their respective centers/surgical units (professional site, number of annual patients with PC, and number of PC surgeries per year), local criteria for resectability, pre- and perioperative measures, as well as detailed information about actual surgical procedures. That includes the preferred type of surgical intervention (e.g., extent of lymph node dissection, use of laparoscopy). The surgical section of the study questionnaire consisted of 25 questions, with 6 multiple-choice, 14 yes/no-questions, and 5 open questions. Its main objective was to illustrate the current surgical standard of care for patients with PC in Germany. Participating physicians Between February 2007 and March 2008, 1,130 standardized questionnaires were sent out to all members of the AIO GI cancer study group and all members of the CAO. All participating CAO/AIO physicians were contacted via e- mailing lists. Additionally, members of the project group Gastrointestinal Tumors (chair: C. J. Bruns) of the Tumorzentrum München were contacted via mail and fax, and a participation in the national CAO/AIO survey was offered to each physician registered in this local project group. Furthermore, the questionnaire was published in the journal Z Gastroenterol (2007; 45: ) of the DGVS ( Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten ) encouraging readers to fill out the questionnaire and return it by fax to the study center at the University of Munich. Statistical analyses All returning questionnaires were collected centrally at the University of Munich, and data were entered into an electronic database by one person (M. Sargent). Study data were analyzed using SPSS software (version 16.0) and the Microsoft Office package (Excel database). Pre-defined subgroup analysis was performed by grouping the results of each question with regard to the professional site of the

3 Langenbecks Arch Surg (2011) 396: responding physician (university hospital vs. community hospital) and to the local number of patients treated by year (<5 patients vs patients vs. >30 patients). Results Participants of the survey From the 1,130 questionnaires that were sent out, 102 questionnaires concerning the surgical part of the survey were completed and returned; 32.4% of the responding surgeons/surgical units were located at university hospitals, and 67.6% at community hospitals. Regarding the annual number of patients seen with PC, 6 respondents (5.9%) replied to see less than 5 patients per year; 20.6% see between patients, 18.6% see patients, 14.7% have annual PC patient contacts, 9.8% see between 41 and 50, and 30.4% treat more than 50 patients with PC every year. The number of surgical resections of PC per year was specified by nine surgical units with less than five (8.8%) resections. Of the 42 resections between 11 and 20 patients per year (41.2%), 16 perform resections (15.7%) and 9 survey participants perform resections (8.8 %). Further, 7 respondents (6.9%) carried out resections, and 18 (17.6%) perform more than 50 pancreatic resections annually at their institution. Surgical criteria for resectability Only 7 (6.9%) of the responding surgeons define a pancreatic tumor as non-resectable if imaging modalities suggests a possible regional lymph node infiltration (cn1). An infiltration of the common hepatic artery equals nonresectability in the opinion of 71 (69.9%) respondents. A pancreatic tumor infiltrating the portal vein is regarded as non-resectable by 18 (17.6%), infiltration of the superior mesenteric artery by 87 (85.3%), and infiltration of the celiac trunk by 88 (86.3%). Extrapancreatic manifestations of the tumor are regarded as a criterion for surgical nonresectability by 71 (69.9%) survey participants (see Fig. 1). Perioperative medical procedures Fifty-five surgeons (53.9%) would decide to perform a biliary drainage in case of a significant preoperative cholestasis (defined for this survey as a bilirubin level of 15 mg/dl), whereas 44 (43.1%) reject this preoperative endoscopic-interventional approach. Eighty-three (81.4%) of the respondents would select to place a biliary stent by endoscopic retrograde cholangiopancreatography (ERCP) in order to treat a preoperative malignant bile duct stenosis, whereas 10 (9.8%) would recommend a percutaneous transhepatic cholangio drainage (PTCD). Fifty-two survey participants (51.8%) apply the somatostatin analog octreotide perioperatively; in contrast, 49 (48.0%) do not use octreotide in the perioperative setting in PC surgery. Surgical procedures Resectable pancreatic tumors Carcinomas of the head of the pancreas are treated by 25 survey respondents (24.5%) with a classical Kausch Whipple procedure (partial pancreatoduodenectomy, PPD); 54 (52.9%) prefer the pylorus-preserving partial pancreatoduodenectomy technique according to Traverso/Longmire (PPPD), and 21 (20.6%) use both procedures, depending on the individual case. Seventy-one surgeons (69.6%) support Fig. 1 Selected criteria of surgical non-resectability in PC cn1 by imaging criteria 6,9% Infiltration common hepatic artery 69,6% Portal vein infiltration 17,6% Infiltration superior mesenteric artery 85,3% Celiac trunk infiltration 86,3% Extrapancreatic tumor manifestations 69,6%

4 226 Langenbecks Arch Surg (2011) 396: the statement that the PPPD shows relevant advantages compared to the classical PPD. Explicitly named (free text answer) were the shorter operation time as well as a better digestive passage and less reflux. Twenty-seven participants (26.5%) do not see a superiority of a PPPD compared to the classical Kausch Whipple procedure. Seventy-six physicians (74.5%) routinely perform a standard lymphadenectomy, whereas 17 (16.7%) prefer an extended procedure; 7 colleagues (6.9%) decide the extent of lymphadenectomy individually based on each single case. Adenocarcinomas of the body of the pancreas are treated by 81 surgeons (79.4%) with a distal pancreatectomy, 10 (9.8%) perform an extended Kausch Whipple procedure. In patients with pancreatic tail carcinomas, 98 survey participants (96.1%) would perform a distal pancreatectomy. In both scenarios (pancreatic body and tail tumors), the removal of local lymph nodes and the spleen is performed within an individual case-by-case decision (free text answer). Forty-two respondents (41.2%) use laparoscopic surgical techniques in pancreatic surgery, most of them for staging (45.6%) or diagnostic (21.7%) procedures, i.e., to exclude peritoneal metastasis (15.2%). Fifty-nine centers (57.8%) never apply laparoscopy within their standard procedures. Intraoperative histological evaluation of the resection margins is a mandatory step for 97 (95.1%) of the survey respondents. Only three surgeons (2.9%) do not perform intraoperative frozen section exams to determine the resection margin status. Eighty-six surgeons (84.3%) would also perform multivisceral resections if the tumor infiltrates surrounding organs, whereas 13 (12.7%) would not perform multivisceral surgical resections. Advanced pancreatic tumors If a preoperatively unknown, but technically resectable distant metastasis (e.g., single liver mass) would be found during the surgical exploration and pancreatic resection, 67 surgeons (65.7%) would remove them, whereas 34 colleagues (33.3%) would not resect these metastases. Sixty-five of the responding survey participants (63.7%) would perform a radical pancreatic resection if a single liver metastasis would be found intraoperatively, whereas 30 surgeons (29.4%) would in this case scenario not resect the primary tumor in the pancreas. Palliative surgical procedures, specifically bypass gastroenterostomy and biliodigestive anastomosis, are performed by 51 survey participants (50.0%) in case of jaundice or pyloric/duodenal stenosis. However, 5 colleagues (4.9%) would also perform such palliative surgical procedures in asymptomatic patients (e.g., no bowel obstruction or malignant bile duct stenosis) with non-resectable PC. In asymptomatic PC patients with distant metastases, 16 surgeons (15.7%) would recommend to perform the above-named palliative surgical procedures. Subgroup analyses In PC surgery, large volume centers (defined by >50 patients/year) are mainly located at German university hospitals (72.7% of university surgical units state to see more than 50 PC patients per year, and 54.5% of university centers perform more than 50 pancreatic resections each year, respectively). Most surgical units localized at community hospitals (53.6%) consult with between 11 and 30 patients with PC annually. Influence of the professional site of the responding surgeon on treatment decisions Figure 2 summarizes the criteria for surgical nonresectability split by the professional site of the responding surgeon. Surgeons (53.6%) working in community hospitals use perioperative octreotide treatment, whereas at university centers, 45.5% of survey surgeons apply this somatostatin analog. Standard lymphadenectomy is performed by 73.9% of community-based surgeons and by 75.8% of the university physicians. As shown in Fig. 3, the opinion on surgical removal of intraoperatively detected, technically resectable distant metastasis differed significantly between surgeons at community and university hospitals (resection rate, 58.0% vs. 81.8%). For the other above-named variables, no significant differences were apparent when analyzing the data with regard to the professional site of the responding surgeon (data not shown). Influence of the number of patients treated per year on treatment decisions Figure 4 illustrates the different assessment of nonresectability criteria in PC surgery with regard to the number of patients treated per year. A PPPD approach is, compared to the classical Kausch Whipple procedure, performed more often at high-volume centers (rate of PPPD; <5 patients/year, 16.7%; patients/year, 47.5%; >30 patients/year, 60.7%). The PPPD is also regarded as more advantageous at hospitals with more than 30 patients per year compared to lower volume centers (see Fig. 5). Discussion Radical surgical resection is still regarded as the only valid option for long-term survival in patients with PC. Although

5 Langenbecks Arch Surg (2011) 396: surgical techniques have improved during the last 10 years, the rate of resections in curative intent is still low. It remains unclear as to how many PC patients in Germany are actually treated according to the consensus-based recommendations suggested by the current S3 guidelines [2]. For this national survey, 102 German surgeons from university and community hospitals completed and returned a questionnaire regarding their local standard surgical management of PC. A return rate of 9% (102/1,130) may be regarded as low for a national survey; however, one must consider that most contacted physicians (mainly via the AIO mailing list) were medical oncologists or gastroenterologists [3]. The available CAO mailing list contained 261 surgeons; thus, a theoretical response rate of 102 (39%) may be regarded as more representative. In fact, we cannot rule out that also surgical oncologists that were contacted via the AIO mailing list responded to the survey; however, the authors would assume that this did not confound the results significantly. Moreover, a main limitation of this national CAO/AIO survey arises from the fact that we contacted only physicians that were registered within the CAO or AIO, respectively. This approach may have resulted in a significant selection bias, which also could have influenced the findings obtained from this national survey. Thus, when interpreting the data, one should be aware of these possible confounders. As many low-volume centers (<5 to 10 PC patients per year) were potentially not contacted for this survey, a possible pre-selection of university and higher-volume community hospitals was performed. Therefore, the results may not necessarily reflect the actual surgical treatment of PC in Germany. This national CAO/AIO survey, however, suggests that several aspects of surgical PC management are heterogeneous in Germany. As shown in Figs. 1 and 2, no standardized definitions for a technically unresectable pancreatic tumor exist. On the one hand, this may be based on the fact that the currently available radiological imaging methods (spiral CT, MRI scan, PET-CT) still have several limitations in the preoperative assessment of resectability; on the other hand, the decision for a radical surgical resection may also correlate with the experience of the operating surgeon. However, only 70% of the survey respondents regard extrapancreatic tumor manifestations as an (imaging) criterion for non-resectability. Regarding the perioperative management of PC patients, the role of the endoscopic-interventional treatment (by ERCP or PTCD) of preoperative jaundice is a matter of debate. Based on previous studies, the S3 guideline from 2007 recommends the use of biliary drainage only in case of cholangitis or if surgical resection needs to be delayed [2, 6 8]. Two recently published studies showed that the routine use of preoperative biliary drainage may increase the rate of postpancreatectomy (infectious) complications [9, 10]. However, the authors are aware of the fact that these data were not available when the survey was conducted. Based on our data, the participants could be divided into two nearly equal groups with regard to the use of preoperative biliary drainage (54% vs. 43%). During the last years, several clinical studies and also a meta-analysis have suggested that the use of a PPPD may be at least as effective as the classical Kausch Whipple procedure in carcinomas of the pancreatic head [2, 15]. Our national data show that the majority of German surgical centers (53%) prefer the PPPD, and we also found a correlation between the number of PC patients treated per year and the use of PPPD (Fig. 5). The role of surgical treatment options in patients with advanced PC is currently a matter of scientific debate. The S3 guideline clearly states that in patients with non- Fig. 2 Criteria of surgical non-resectability in PC grouped by professional site of the responding surgeon cn1 by imaging criteria Infiltration common hepatic artery 3,0% 8,7% 75,8% 66,7% Portal vein infiltration 15,2% 18,8% Infiltration superior mesenteric artery 78,8% 88,4% Celiac trunk infiltration 78,8% 89,9% Extrapancreatic tumor manifestations 57,58% 75,4% Community hospital University hospital

6 228 Langenbecks Arch Surg (2011) 396: ,0% Resection yes 81,8% Community hospital 42,0% Resection no University hospital 15,2% Fig. 3 Resection of technically removable distant metastases during PC surgery (grouped by professional site of the responding surgeon) ,3% 67,5% Yes 75,0% < >30 66,7% 27,5% 21,4% Fig. 5 Response to the survey question Does the pylorus-preserving procedure (PPPD) offer advantages compared to the classical Kausch Whipple operation? grouped by number of patients treated per year resectable disease, systemic gemcitabine-based chemotherapy is the treatment of choice [2]. Nevertheless, there is preliminary evidence in surgical literature, provided by high-volume specialized centers, which supports the possible benefit of palliative surgical intervention in (highly) selected patients with locally advanced or metastatic PC [19, 21, 22]. Surprisingly, a significant proportion of survey respondents (66%) would already resect intraoperatively detected and technically resectable distant metastases during a radical PC operation. However, this rate may differ significantly based on the professional site of the responding surgeon (Fig. 3). Based on current scientific evidence, one must clearly state that such an experimental approach is not recommended and should be offered to PC patients only within controlled clinical trials [2]. Furthermore, 64% of the responding physicians would proceed with the radical surgical resection of a pancreatic tumor if they detect a single liver metastasis intraoperatively. Palliative surgical interventions like bypass gastroenterostomy or biliodigestive anastomosis are recommended by 50% of survey participants only in a symptomatic patient (e.g., malignant bowel obstruction or bile duct stenosis). The benefit of a pre-emptive medical treatment with somatostatin analogs is also controversial in PC surgery. A meta-analysis of ten studies suggested a reduction in complications and morbidity [11], whereas another recent meta-analysis with eight studies concluded that there is no significant decrease in postoperative complications [12]. The participants of this survey are equally split in this aspect; 51% do and 48% do not apply octreotide or one of its analogs prior to their surgical intervention. The S3 guideline does not give a clear recommendation in this point and states that a specific group of patients who would benefit from this prophylaxis has not yet been identified [2]. No Fig. 4 Criteria of surgical non-resectability in PC grouped by number of patients per year cn1 by imaging criteria Infiltration common hepatic artery Portal vein infiltration 1,8% 12,5% 16,7% 8,9% 22,5% 50,0% 75,0% 65,0% 66,7% Infiltration superior mesenteric artery Celiac trunk infiltration Extrapancreatic tumor manifestations 80,4% 90,0% 100% 83,9% 87,5% 100% 66,1% 72,5% 83,3% < >30

7 Langenbecks Arch Surg (2011) 396: In conclusion, the results from the surgical section of the national CAO/AIO survey clearly illustrate that the surgical management of PC patients at German community and university hospitals is heterogeneous and that as expected both the professional site and the number of patients treated per year may have an influence on local treatment decisions. Future efforts should focus on the implementation of evidence-based and standardized surgical management procedures at German hospitals which treat patients with PC. Acknowledgements The authors would like to thank all members of the CAO, AIO, DGVS, and of the GI group of the Tumorzentrum München for their active support of this survey. This work is part of the doctoral thesis of Mirja Sargent. Conflicts of interest References None. 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics. 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