S3-Guideline “Exocrine Pancreatic Carcinoma” 20071 ... - DGVS

S3-Guideline “Exocrine Pancreatic Carcinoma” 2007 1 

Results of an Evidence-Based Consensus Conference 

(13. – 14.10.2006) 

S3-Leitlinie „Exokrines Pankreaskarzinom“ 2007 

Authors G. Adler, T. Seufferlein, S. C. Bischoff, H.-J. Brambs, S. Feuerbach, G. Grabenbauer, S. Hahn, V. Heinemann, 

W. Hohenberger, J. M. Langrehr, M. P. Lutz, O. Micke, H. Neuhaus, P. Neuhaus, H. Oettle, P. M. Schlag, R. Schmid, 

W. Schmiegel, K. Schlottmann, J. Werner, B. Wiedenmann, I. Kopp 

Affiliation Department of Internal Medicine I, University Medical Center Ulm 

Bibliography 

DOI 10.1055/s-2008-1027420 

Z Gastroenterol 2008; 46: 

449 – 482 Georg Thieme 

Verlag KG Stuttgart · New York · 

ISSN 0044-2771 

Correspondence 

Prof. Dr. Guido Adler 

Department of Internal 

Medicine I, University Medical 

Center 

Robert-Koch-St. 8 

89081 Ulm 

Germany 

Tel.: ++ 49/7 31/50 04 45 00 

Fax: ++ 49/7 31/50 04 45 02 

guido.adler@uniklinik-ulm.de 

Introduction: Scope and aim of the 

guideline 

! 

More than 95% of pancreatic carcinomas are 

adenocarcinomas. They develop by malignant 

degeneration of the exocrine part of the pancreas. 

According to current knowledge, the pancreatic 

carcinoma develops from a premalignant 

stage of the epithelium of the pancreatic 

duct system (PanIN: pancreatic intraepithelial 

neoplasia). Cystic tumors that also arise from 

duct cells and acinar cell carcinoma which develops 

from secretory pancreatic parenchyma 

cells are not as common. Even less common 

are endocrine tumors that arise from endocrine 

cells in the islets of Langerhans. 

About 12800 people develop pancreatic carcinoma 

per year in Germany. Men and women are affected 

with about the same frequency. Pancreatic 

carcinoma in men takes 9th place and in women 

7th place in the statistic of newly developed cancer 

in Germany. Most of the people that are affected 

develop the disease at an older age: The mean 

age at which men and women are diagnosed is 68 

and 75 years, respectively. Pancreatic carcinoma 

with 12100 deaths was the 5th most common 

cause of death in the year 2000. Thus, it causes 

about 6% of all cancer deaths. The pancreatic carcinoma 

incidence is very close to its annual mortality 

rate. Long-term survival is the exception. 

1 Commissioned by the German Society for Digestive and 

Metabolic Diseases (DGVS) und the German Cancer Society 

(DKG). In cooperation with the Task Force Radiologic 

Oncology of the German Cancer Society (ARO), 

Pancreatectomy Team e. V., German Society for Surgery 

(DGCH), German Society for Hematology and Oncology 

(DGHO), German Society for Palliative MedicineGerman 

Society for Pathology (DGP), German Society for Radiooncology 

(DEGRO), German Society for Visceral Surgery 

(CAO-V)/Surgical Task Force Oncology (CAO-V), German 

Society for Radiology (DRG), German Joint Societies for 

Clinical Chemistry and Laboratory Medicine (DGKL) 

(Chairmen: G. Adler, T. Seufferlein, I. Kopp) 

Leitlinie 449 

Thus, the 5-year survival rate for pancreatic carcinoma 

of 4% is the lowest of all malignant diseases. 

The reasons are the late diagnosis, the resulting 

low curative resection rate, and the rapid and 

aggressive metastasis. 

In the last few years important progress has been 

made not only in the understanding of pancreatic 

carcinoma development but also in its diagnosis 

and therapy. Therefore, it was in the interest of 

both the DGVS and the German Cancer Society 

to have a high-quality guideline compiled that is 

based on the best available scientific evidence 

and existing clinical experience. 

The aim of the guideline “exocrine pancreatic 

carcinoma” is to ensure an evidence based, comprehensive, 

and optimal care for patients with 

pancreatic cancer. The guideline is meant to accomplish: 

E early diagnosis of pancreatic carcinoma, 

E thus, the possibilty of a higher rate of resections 

with a curative intent, 

E considerably prolonged survival with a good 

quality of life in the palliative situation, 

E prolonged survival with a good quality of life 

in the postoperative situation, 

E strongly improved pain and malnourishment 

reduction during follow-up. 

The guideline addresses anyone involved in the 

diagnosis, therapy, and follow-up of outpatients 

or inpatients. According to the definition of 

guidelines, it is meant to help doctors and patients 

to decide on diagnostic and therapeutic 

procedures. The guideline does not release the 

doctor from his responsibility to individually 

examine the adequate procedure for the overall 

situation of each patient. Reasons should be given 

in case of deviation from the guideline. The 

physician’s task is to continuously ensure the 

quality of curative and palliative treatment. 

This guideline also addresses persons indirectly 

involved e. g. health care providers or medical 

services of the health insurance companies. 

Adler G et al. S3-Guideline “Exocrine Pancreatic… Z Gastroenterol 2008; 46: 449–482 

Downloaded by: Thieme Verlagsgruppe. Copyrighted material.

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Leitlinie 

The methodologic recommendations of the AWMF on the preparation 

of guidelines (http://www.awmf-leitlinien.de), the 

guideline manual of the Medical Center of Quality in Medicine 

(http://www.aezq.de), and the German Instrument on Methodologic 

Guideline Evaluation (http://www.delbi.de) were the 

basis for the organization of the guideline procedure. As is demonstrated 

in the following chapter (guideline report), the 

guideline fulfills the criteria of an evidence and consensusbased 

guideline (S3). 

This guideline is estimated to be valid for 3 years. If during this 

time important changes in care become evident, the coordination 

groups will decide whether individual topics or the complete 

guideline must be updated ahead of time. 

The preparation of the guideline was financially supported by 

the DGVS and the DKG. The work of the participants taking 

part in the consensus process and the resulting recommendations 

were not influenced by this support. 

This manuscript is the English version of the German guidelines 

that were published in the Zeitschrift für Gastroenetrologie 

in June 2007 [1]. 

Organizational procedure and methodologic basis of 

the consensus process (guideline report) 

! 

Following the commission by the DGVS and the DKG, the organizational 

procedure for the guideline preparation was discussed 

with the chairman of the guideline commission, Prof. H.-K. 

Selbmann. Subsequent methodologic supervision was done by 

the vice chairman Dr. Ina Kopp. The guideline project was registered 

at the AWMF on July 4, 2005 (AWMF-Register-No. 032/ 

010). 

Recruitment of participants 

To recruit the members of the steering committee (coordinators) 

presidents of the societies involved in diagnostics, therapy, 

and follow-up of pancreatic carcinoma were asked to 

name two representatives. After voting on the topics, the naming 

and invitation of task force members was performed together 

with the coordinators (l " Table 1). Participants were doctors 

from various care levels who work in hospitals and private 

practices. They represented the key disciplines that are relevant 

for pancreatic carcinoma: internal medicine (gastroenterology, 

hematology-oncology), surgery (visceral surgery), radiooncology, 

pathology, diagnostic radiology, palliative medicine, 

pain therapy, dietary medicine, psychotherapy-psychosomatics, 

laboratory medicine, and epidemiology. The patients’ representative 

was appointed by the Task Force of the Pancreatectomized 

Patients e. V. Dormagen. 

Organizational procedure 

Following the voting on the topics with the coordinators, the 

list of questions was generated and the search terms for the 

literature search were defined (time course l " Table 2). Afterwards 

the list of questions and the search terms were revised 

and amended by the task forces. A systematic literature 

search according to defined search terms was done in 

PubMed/Medline for the period from 1995 to May 2006 (inclusive). 

The search terms that were used are listed in the 

appendix. A total of 42345 citations were viewed (l " Table 3) 

and appendix (l " Table 10). 1409 were chosen according to 

the following criteria: investigations in humans, original arti- 


Table 1 Task forces 

1. Risk factors/screening/risk groups 

chairmen 

S.C. Bischoff Universität Hohenheim, Lehrstuhl für Ernährungsmedizin 

und Prävention, Stuttgart 

S. Hahn Knappschaftskrankenhaus, Medizinische Universitätsklinik, 

Bochum 

R. Schmid Klinikum rechts der Isar der TU, II. Medizinische 

Klinik und Poliklinik, München 

members 

G. Adler Universitätsklinikum, Zentrum für Innere Medizin, 

Klinik für Innere Medizin I, Ulm 

A. Aschoff Universitätsklinikum, Klinik für Diagnostische und 

Interventionelle Radiologie, Ulm 

I. Bergheim Universität Hohenheim, Lehrstuhl für Ernährungsmedizin 

und Prävention, Stuttgart 

T. Gress Universitätsklinikum Giessen und Marburg GmbH, 

Klinik für Innere Medizin, SP Gastroenterologie, 

Endokrinologie und Stoffwechsel, Marburg 

V. Keim Universitätsklinikum, Medizinische Klinik und Poliklinik 

II, Leipzig 

M. Lerch Universitätsklinikum, Klinik und Poliklinik für Innere 

Medizin A, Greifswald 

J. Lüttges Klinikum Saarbrücken, Pathologisches Institut, 

Saarbrücken 

G. Nagel Universität Ulm, Institut für Epidemiologie, Ulm 

H. Rieder Universitätsklinikum, Institut für Humangenetik 

und Anthropologie, Düsseldorf 

2. Diagnostics 

chairmen 

H.-J. Brambs Universitätsklinikum, Klinik für Diagnostische und 


K. Schlottmann Katharinen-Hospital gGmbH, Innere Klinik I, Unna 

B. Wiedenmann CharitØ Universitätsmedizin, CharitØCentrum 13, 

Medizinische Klinik mit SP Hepatologie und Gastroenterologie, 

Campus Virchow, Berlin 

members 

M. Dobritz Klinikum rechts der Isar der TU, Institut für Rçntgendiagnostik, 

München 

P. Mçller Universitätsklinikum, Comprehensive Cancer 

Center, Institut für Pathologie, Ulm 

J. Mçssner Universitätsklinikum, Zentrum für Innere Medizin, 

Medizinische Klinik und Poliklinik II; Gastroenterologie 

und Hepatologie, Leipzig 

S.T. Post Universitätsklinikum gGmbH, Chirurgische Klinik, 

Mannheim 

S.N. Reske Universitätsklinikum, Klinik für Nuklearmedizin, 

Ulm 

J.F.Riemann Klinikum der Stadt Ludwigshafen am Rhein 

gGmbH, Medizinische Klinik C, Ludwigshafen 

T. Rçsch CharitØ Universitätsmedizin, CharitØCentrum 13, 

Medizinische Klinik mit SP Hepatologie und Gastroenterologie, 

Zentrale interdisziplinäre Endoskopie, 

Campus Virchow, Berlin 

A.-O. Schäfer Universitätsklinikum, Radiologische Universitätsklinik, 

Rçntgendiagnostik, Freiburg 

W. Uhl St. Josef-Hospital, Klinikum der Ruhr-Universität, 

Klinik für Chirurgie, Bochum 

C. Wagener Universitätsklinikum, Institut für Klinische Chemie/Zentrallaboratorien, 

Hamburg-Eppendorf 

3. Surgical therapy of pancreatic carcinoma (curative intention) 

chairmen 

J. Werner Universitätsklinikum, Chirurgische Klinik, Klinik 

für Allgemein-, Viszeral- und Transplantationschirurgie, 

Heidelberg 

W. Hohenberger Chirurgische Klinik mit Poliklinik der Friedrich- 

Alexander-Universität Erlangen-Nürnberg, Allgemeine, 

Bauch- und Thoraxchirurgie, Erlangen 


Table 1 (Fortsetzung) 

members 

G. Baretton Universitätsklinikum, Institut für Pathologie, 

Dresden 

R. Bittner Marienhospital, Klinik für Allgemein- und 

Viszeralchirurgie, Stuttgart 

D. Dittert Universitätsklinikum, Institut für Pathologie, 

Dresden 

P. Galle Klinikum der Johannes Gutenberg-Universität, I. 

Medizinische Klinik und Poliklinik, Mainz 

D. Henne-Bruns Universitätsklinikum, Zentrum für Chirurgie, Klinik 

für Allgemein-, Viszeral- und 

Transplantationschirurgie, Ulm 

U.T. Hopt Universitätsklinikum, Chirurgische Universitätsklinik, 

Allgemein- und Viszeralchirurgie, Freiburg 

J. Izbicki Universitätsklinikum, Klinik und Poliklinik für Allgemein-, 

Viszeral- und Thoraxchirurgie, Hamburg- 

Eppendorf 

G. Klçppel Universitätsklinikum Schleswig-Holstein, Institut 

für Pathologie, Campus Kiel 

K.H. Link Asklepios Paulinen Klinik, Chirurgisches Zentrum, 

Wiesbaden 

P. Neuhaus CharitØ Universitätsmedizin, CharitØCentrum 8 

für Chirurgische Medizin, Klinik für Allgemein-, 

Visceral- und Transplantationschirurgie (CVK), 

Berlin 

J. Pelz Chirurgische Klinik mit Poliklinik der Friedrich- 



B. Rau Universitätsklinikum des Saarlandes, Klinik für 

Allgemeine Chirurgie, Viszeral-, Gefäß und Kinderchirurgie, 

Homburg/Saar 

P. Schlag CharitØ Universitätsmedizin, Robert-Rçssle-Klinik, 

Klinik für Chirurgie und Chirurgische Onkologie, 

Campus Berlin-Buch, Berlin 

H.D. Saeger Universitätsklinikum, Klinik und Poliklinik für 

Viszeral-, Thorax- u. Gefäßchirurgie, Dresden 

4. Neoadjuvant and adjuvant non-surgical therapy of pancreatic carcinoma 

chairmen 

J.M. Langrehr CharitØ Universitätsmedizin, CharitØCentrum 8 

für Chirurgische Medizin, Klinik für Allgemein-, 

Visceral- und Transplantationschirurgie (CVK), 

Berlin 

H. Oettle CharitØ Universitätsmedizin, Medizinische Klinik 

m.S. Hämatologie und Onkologie, Campus 

Virchow, Berlin 

W. Schmiegel Knappschaftskrankenhaus, Medizinische Universitätsklinik, 

Bochum 

members 

C. Bokemeyer Universitätsklinikum, II. Medizinische Klinik und 

Poliklinik, Hamburg-Eppendorf 

Th. Brunner University of Oxford, Churchill Hospital, Radiation 

Oncology and Biology; Headington, Oxford 

W. Budach Universitätsklinikum, Klinik und Poliklinik für 

Strahlentherapie und radiologische Onkologie, 

Düsseldorf 

H. Friess Universitätsklinikum, Chirurgische Klinik, Allgemein-, 

Viszeral- und Transplantationschirurgie, 

Heidelberg 

M. Geissler Klinikum Esslingen, Klinik für Onkologie, Gastroenterologie 

und Allgemeine Innere Medizin, 

Esslingen 

T. Meyer Chirurgische Klinik mit Poliklinik der Friedrich- 




A. Reinacher- 

Schick 

Knappschaftskrankenhaus, Medizinische Universitätsklinik, 

Bochum 

H.J. Schmoll Universitätsklinikum, Zentrum für Innere Medizin, 

Universitätsklinik und Poliklinik für Innere Medizin 

IV, Halle (Saale) 

H. Witzigmann Krankenhaus Dresden-Friedrichstadt, Klinik für 

Allgemein- und Abdominalchirurgie, Dresden 

5. Palliative therapy 

chairmen 

G. Grabenbauer Radiologische Gemeinschaftspraxis am Klinikum 

Coburg 

V. Heinemann Universitätsklinikum Großhadern, Medizinische 

Klinik und Poliklinik III, München 

M.P. Lutz Caritasklinik St. Theresia, Medizinische Klinik, 

Saarbrücken 

members 

U.R. Fçlsch Universitätsklinikum, Klinik für Allgemeine Innere 

Medizin, Kiel 

J.T. Hartmann Universitätsklinikum, Medizinische Universitätsklinik, 

Innere Medizin II, Tübingen 

S. Hegewisch- Internistische Gemeinschaftspraxis Eppendorf 

Becker 

F. Kullmann Klinikum der Universität, Klinik und Poliklinik für 

Innere Medizin I, Regensburg 

M. Lçhr Universitätsklinikum, II. Medizinische Universitätsklinik, 

Mannheim 

R. Porschen Klinikum Bremen Ost, Zentrum für Innere Medizin, 

Medizinische Klinik, Bremen 

M. Schilling Universitätsklinikum des Saarlandes, Klinik für 

Allgemeine Chirurgie, Viszeral-,Gefäß- und Kinderchirurgie, 

Homburg/Saar 

T. Seufferlein Universitätsklinikum, Zentrum für Innere Medizin, 

Klinik für Innere Medizin I, Ulm 

6. Supportive therapy and follow-up 

chairmen 

S. Feuerbach Klinikum der Universität, Institut für Rçntgendiagnostik, 

Regensburg 

O. Micke Franziskus Hospital gGmbH, Klinik für Strahlenheilkunde 

und Radioonkologie, Bielefeld 

H. Neuhaus Evangelisches Krankenhaus, Medizinische Klinik, 

Düsseldorf 

members 

C.F. Dietrich Caritas-Krankenhaus, Innere Medizin II, Bad Mergentheim 

A. Feil Arbeitskreis der Pankreatektomierten e.V., Siegen 

U. Graeven Kliniken Mariahilf, Klinik für Hämatologie, Onkologie 

und Gastroenterologie, Mçnchengladbach 

G. Hege-Scheuing 

Universitätsklinikum, Klinik für Anästhesiologie, 

Ulm 

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E. Klar Universitätsklinikum, Abteilung für Allgemeine, 

Thorax-, Gefäß- und Transplantationschirurgie, 

Rostock 

F. Lordick Klinikum rechts der Isar der TU, III. Medizinische 

Klinik, München 

S. Pauls Universitätsklinikum, Klinik für Diagnostische und 


W. Scheppach Universitätsklinikum, Medizinische Klinik und Poliklinik 

I, Würzburg 

J. Weitz Universitätsklinikum, Klinik für Allgemein-, 

Viszeral- und Transplantationschirurgie, Sektion 

Chirurgische Onkologie, Heidelberg 



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Table 2 Time course of consensus process 

category aspect time period 

initiation determination of conference date 1/2006 

choice of conference participants 1/2006 

preparation, revision, and amendment of the questionnaire by the respective task forces (topic 1 – 6) 2 – 3/2006 

literature search determination of search terms for the literature search 4/2006 

systematic literature search 5/2006 

delphi-questionnaire dispatch of final questionnaire including publications from 1995 on mid 5/2006 

response to questionnaire by task forces 6 – 7/2006 

summary/evaluation of results of the questionnaire by coordinators and dispatch with recommendations 

to all consensus conference participants 

9 – 2006 

conference preliminary discussion of consensus conference 

consensus conference: 

12.9.2006 

task force meetings 13.10.2006 

plenary session 13.–14.10.2006 

preparation of manuscript by consensus conference coordinators and chairmen until 2/2007 

decisions on open issues by questioning all concensus conference participants via email 5.4.2007 

dispatch of final manuscript to all conference participants and incorporation of all comments 15.4.2007 

peer review of the manuscript 6.5.2007 

Table 3 Literature search 

topic references initial selected references 

topic 1 16584 258 

topic 2 12419 407 

topic 3 5 994 202 

topic 4 2 739 111 

topic 5 2 241 262 

topic 6 2 368 169 

total 42345 1 409 

Table 4 Basis for evidence level: Center of Evidence Based Medicine Oxford, 

Topics 1, 3, 4, 5, and 6 

recommendation 

grade 

evidence 

level 

A 1 systematic review (SR) with 

homogeneity (no heterogeneity 

with respect to the results of individual 

studies) of randomized 

controlled studies (RCT) 

B 2a 

systematic review with homogeneity 

of cohort studies 

2b 

Individual cohort studies plus 

RCTs of low quality (e. g. followup 

< 80%) 

C 3 systematic reviews with homogeneity 

of case-control-studies as 

well as individual case-controlstudies: 

EL 3 

C 4 case studies and cohort studies as 

well as case-control-studies of low 

quality (i. e. cohorts: no clearly 

defined group for comparison, no 

outcome/exposition assessment 

in experimental and control 

groups, insufficient follow-up; 

case-control-studies: no clearly 

defined group for comparison) 

D 5 expert opinion or inconsistent or 

inconclusive studies of every evidence 

level 


cles, or systematic reviews, and the number of examined or 

treated patients (> 10), no case reports. The literature was 

made available as an Endnote-file. In May 2006 the final 

questionnaires and the abstracts of the citations were sent 

to all members of the guideline process (n = 79). The members 

were requested to evaluate them by the middle of July 

(Delphi-technique). Until the end of August, the coordinators 

of the individual topics summarized the results from the 

task forces and developed recommendations for consensus 

finding. Four weeks before the consensus conference, a preliminary 

discussion took place with the coordinators of the 

individual topics. The evaluation table of the list of questions 

and the methodology for consensus finding during the consensus 

conference were discussed. The documents were sent 

to all participants of the consensus conference by the middle 

of September. 

The consensus conference took place on October 13 th and 14 th , 

2006 in Stuttgart-Hohenheim. On the first day, the suggestions 

for consensus finding for the individual topics were formulated 

within the task forces (nominal group process, n = 7 – 12). 

Dr. Kopp (AWMF) was available for support in methodologic 

questions. On the second day, the consensus suggestions were 

presented, discussed, and if necessary modified in the plenum 

(n = 57). The voting of the evidence level and recommendation 

grade was performed using a TED-system. 

Evidence level and recommendation grade classification 

The evidence level of the relevant studies was defined according 

to the recommendations of the Center for Evidence-Based 

Medicine, Oxford, UK (http://www.cebm.net/) (l " Table 4). During 

the consensus conference preparation, it was discovered 

that these criteria do not apply to individual studies of Topic 

2 (diagnostics). Therefore, a modified classification of the evidence 

level was employed for the evaluation of the literature 

on diagnostics (l " Table 5). For all topics within the group processes 

it was considered whether the results of the studies are 

applicable to the guideline target population in Germany. 

The recommendation grades were assigned based on the evidence 

level. The classification of the recommendation grade is 

shown in (l " Table 6). In most cases the evidence level determines 

the recommendation grade (l " Table 4, 6). In justified 


Table 5 Basis for evidence level: Centre for Evidence-Based Medicine Oxford, 

Topic 2 

recommendation 

grade 

evidence 

level 

A 1a 

Systematic review (SR) with homogeneity 

(no heterogeneity with respect 

to results of individual studies) of level 

1 diagnostic studies. Clinical decision 

rule with 1b studies also from different 

clinical centers? 

1b 

Validating cohort studies (test quality 

of specific tests based on existing evidence, 

no explorative data collection 

with regression analysis) 

1c 

Specificity of diagnostic results that is 

so high (“absolute”) that a positive result 

leads to diagnosis or sensitivity of 

diagnostic results that is so high (“absolute”) 

that a negative result leads to 

exclusion of the diagnosis. 

B 2a 

Systematic review with homogeneity 

of diagnostic studies > level 2 

2b 

Explorative cohort studies with good 

reference basis (i. e. independent of 

test, blinded, or objective for all included 

subjects). 

C 3 systematic overview with homogeneity 

of studies EL3b or better 

C 4 case-control-studies of poor or reference 

standard that is not independent 

D 5 expert opinion without critical discussion 

Table 6 Recommendation grade classification 

A 

B 

C 

D 

consistent studies with evidence level 1 available 

consistent studies with evidence level 2 or 3 or extrapolations of 

studies with evidence level 1 

studies with evidence level 4 or extrapolations of studies with 

evidence level 2 or 3 

expert opinion or inconsistent or inconclusive studies of every 

evidence level 

cases, a deviation from this rule within the consensus conference 

was allowed: 

E consistency and effect size of the studies, 

E consideration of benefits, risks, and side effects, 

E applicability on extended patient groups, on the German 

health care system, or on the availability of resources. 

Consensus degree classification 

The TED-system was used to vote in the plenum of the consensus 

conference. Thus, immediately after the vote on individual 

questions, the absolute or percent approval of the participants 

was shown electronically. This resulted in the classification of 

the consensus magnitude (l " Table 7). 

Guideline implementation 

The quality of the guideline cannot be assessed before it has 

been implemented in the daily health care routine. Aside from 

the present scientific publication, the guideline will be published 

electronically by the AWMF in its information system 

“AWMF online” (http://www.awmf.org/). The German Cancer 

Table 7 Consensus size classification 

strong consensus approval of > 95% of participants 

consensus approval of > 75 – 95% of participants 

majority approval approval of > 50 – 75% of participants 

no consensus approval of < 50% of participants 

Leitlinie 453 

Society and the German Society for Digestive and Metabolic 

Diseases (DGVS) will also make the guideline available electronically. 

Following the publication of the complete version of 

the guideline, a short version and a version for patients will 

be introduced. 

Topic 1: 

Risk factors/screening/risk groups 

! 

Risk factors 

Introduction 

For many years diet has been discussed as a possible risk factor 

for the development of exocrine pancreatic carcinoma. However, 

there are no unanimous recommendations or recommendations 

established in clinical practice as to whether dietary 

procedures are effective in the prevention of pancreatic cancer 

and if so, which dietary factors play a role. Aside from the dietary 

factors, life style and work-related exposure must be discussed 

as possible risk factors for the development of pancreatic 

carcinoma. Finally, it will be discussed whether drug prophylaxis 

can reduce the risk of developing pancreatic carcinoma. 

Diet 

Diet recommendations 

Currently, a specific diet recommendation for the risk reduction 

of pancreatic carcinoma cannot be given. The current diet recommendations 

of the German Society for Nutrition (DGE) should be 

followed to reduce the risk of pancreatic carcinoma. 

Recommendation grade: C, evidence level 2b, strong consensus 

Comments 

Some connection between dietary factors and pancreatic carcinoma 

was considered likely in a comprehensive literature 

review of the World Cancer Research Fund in 1997. However, 

these associations were not rated as convincing [2]. In the last 

12 years, connections between dietary factors and the development 

of pancreatic carcinoma were repeatedly found in original 

publications. They were rated with evidence levels 2b to 

3b [3 – 7]. However, there is also one group of investigators 

who found no association between dietary factors and pancreatic 

carcinoma in their cohort study [8, 9]. Nonetheless, a 

dietary recommendation to reduce pancreatic carcinoma risk 

is indicated, particularly because an association seems plausible 

from a biologic point of view [10]. 

There is no clear relationship between fiber intake and risk of 

pancreatic carcinoma. 

Recommendation grade: C, evidence level 3, strong consensus 

Comments 

The studies on fiber intake are contradictory. A protective effect 

of an increased intake of fiber was described in two case control 

studies [4, 11]. However, this was not confirmed in another 

case control study in men [12]. Due to the overall insufficient 



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studies with contradictory results, a positive recommendation 

cannot be given. 

Recommendation 

An increased intake of legumes cannot be recommended to reduce 

the risk of pancreatic carcinoma. 


Comments 

A protective effect of legumes on the incidence of pancreatic 

carcinoma was found in two cohort studies that were done on 

subpopulations (Adventists) [13, 14]. Since both publications 

included a very special study population a selection bias cannot 

be excluded. Thus, a general recommendation cannot be 

given. 

A benefit of an increased fruit and vegetable intake to reduce 

the risk of pancreatic cancer can currently not be proven. 

Recommendation grade: C, evidence level: 2b, strong consensus 

Comments 

Increased fruit and vegetable consumption reduced the pancreatic 

carcinoma risk in several case control studies [3, 4, 15, 

16]. However, in a cohort study, which is considered more relevant, 

no relationship was observed between fruit and vegetable 

consumption and pancreatic carcinoma risk [17]. Nonetheless, 

a recommendation that encourages eating fruits and 

vegetables is rated as desirable, because regular consumption 

decreases the risk of cancer in general [18]. 


Consuming vitamin C rich foods may help reduce the risk of pancreatic 

carcinoma. 

Recommendation grade: D, evidence level 3, majority approval 

Comments 

Two case control studies indicate a protective relationship between 

the consumption of vitamin C rich foods and pancreatic 

carcinoma [4, 19]. However, the recommendation grade is restricted 

by limitations of both studies. Parameters such as age 

and smoking are not sufficiently taken into account by Lin et al. 

[19] and the population size is too small. Ji et al. [4] only found 

a significant association between vitamin C rich food and the 

risk of pancreatic carcinoma in men. 

A low-fat diet does not help reduce pancreatic carcinoma risk. 

Recommendation grade: B, evidence level 2b, consensus 

Comments 

An increased consumption of saturated fats was associated with 

a higher pancreatic carcinoma risk in a cohort study with male 

smokers [20]. This result is consistent with an ecologic study 

[21]. However, in other cohort studies there was no relationship 

[7], and in a study with an Asian population an inverse association 

was even described [4]. 

A low-cholesterol diet does not help reduce the risk of pancreatic 

carcinoma. 

Recommendation grade: B, evidence level 2b, strong consensus 


Comments 

In a case control study an increased pancreatic carcinoma risk 

was seen in the group with a high cholesterol diet [19]. However, 

this observation could not be confirmed in a cohort study 

[8]. 

The reduction of red meat consumption does not help reduce 



Comments 

The studies on this topic are contradictory. The consumption of 

red meat was connected with an increased risk of pancreatic 

carcinoma in a cohort study [7]. However, it remained unclear 

whether the red meat itself or the way it was prepared was responsible 

for the risk association [22]. No relationship between 

the consumption of red meat and the risk of pancreatic carcinoma 

was found in two other studies of which one was a cohort 

study by Michaud et al. [4, 8]. Therefore, it must be assumed 

that the positive association described by Nothlings [7] 

is most likely caused by the way the meat was prepared rather 

than by the consumption of the meat itself. This leads to the 

overall evaluation that reducing red meat consumption is not 

associated with a reduced pancreatic carcinoma risk. 

A relationship between the preferred consumption of white 

meat and pancreatic carcinoma risk cannot be reported. 


Comments 

There are two studies that deal with this topic. Both found no 

association between the consumption of white meat and pancreatic 

carcinoma risk [7, 22]. 

The consumption of smoked/grilled food may be associated 

with an increased risk of pancreatic carcinoma. 

Recommendation grade: C, evidence level 3, majority approval 

Comments 

Three studies show that the consumption of smoked/grilled 

foods is associated with a higher pancreatic carcinoma risk 

[22 – 24]. However, all three studies are merely case control 

studies so that an evidence level of 3 can be given. 

An increased consumption of fish should not be recommended 

to decrease the risk of pancreatic carcinoma. 


Comments 

Two cohort studies [7, 8] showed no relationship between fish 

consumption and pancreatic carcinoma risk. Thus, two case control 

studies that showed a protective effect are less important [5, 

25]. 

A general recommendation to reduce the consumption of 

sugar cannot be given. 


Comments 

There is evidence that the consumption of sugar is associated 

with an increased risk of pancreatic carcinoma [24, 26, 27]. 


However, a possible statistically significant relationship was 

reported only in women [28]. 

An increased consumption of milk and milk products does not 

lead to a risk reduction of pancreatic carcinoma. 


Comments 

A connection between milk and cheese consumption and the 

risk of pancreatic carcinoma was ruled out [7]. However, a protective 

effect against pancreatic carcinoma was reported for 

fermented milk products [11]. Since these data pertain only to 

certain milk products and not to milk and all milk products, a 

general recommendation cannot be given for this food group. 

The protective effect of fermented milk products has so far 

only been proven in a single study. 

Giving up excessive alcohol consumption may be recommended 

to reduce the risk of pancreatic carcinoma. 


Comments 

Numerous studies showed no connection between moderate alcohol 

consumption and pancreatic carcinoma [29 –32]. However, 

several studies indicate that very high alcohol consumption 

or binge-drinking may be associated with an increased pancreatic 

carcinoma risk [32 – 34]. Therefore, it is recommended that 

alcohol consumption should be limited to a moderate quantity. 

This is especially the case because increased alcohol consumption 

may be connected to the pathogenesis of other malignant 

diseases. It may also result in chronic pancreatic and hepatic diseases. 

A general renouncement of coffee cannot be recommended. 


Comments 

High consumption of coffee (more than three cups per day) was 

associated with an increased risk of pancreatic carcinoma in several 

case control studies [35– 37]. This could not be confirmed in 

several other cohort studies [29, 30, 40] with the exception of 

two [38, 39]. 

An increased consumption of tea to reduce the pancreatic 

carcinoma risk cannot be recommended. 


Comments 

In general, there is no connection between tea consumption and 

pancreatic carcinoma risk [38, 41]. Green tea may possibly have 

a protective effect on the development of pancreatic carcinoma 

[4]. In contrast, a cohort study that was done in Japan did not 

show such a connection [42]. These data may only apply to Europe. 

Life style 

Recommendations 

Recommendations on life style are indicated to reduce the risk of 



Leitlinie 455 

Comments 

Results from family studies show that aside from a genetic component 

certain life styles are associated with a higher risk of developing 

pancreatic carcinoma [43, 44]. Especially smoking and 

obesity have been proven as risk factors for pancreatic carcinoma 

[45]. This will be described in the following in more detail. 

Obesity is associated with an increased risk of pancreatic 

carcinoma. Therefore, excess weight should be avoided. 

Recommendation grade: A, evidence level 2a, strong consensus 

Comments 

A meta-analysis [46], as well as five cohort studies [47 –51], and 

one case control study [52] found that various obese populations 

(BMI > 30) had an increased pancreatic carcinoma risk. Thus, a 

clear connection can be assumed. 

A general recommendation to encourage exercise to control 

weight can be given. 

Recommendation grade: C, evidence level 2b, consensus 

Comments 

The results from cohort studies [47, 51, 53] and a case control 

study [54] indicate a protective effect of exercise on the risk of 

pancreatic carcinoma. Particularly overweight persons seem to 

benefit from exercise [47]. However, a detailed recommendation 

cannot be given, because contradictory results were also 

found [48], and not all observations and associations were significant 

[51] or consistent [47]. 

Avoiding tobacco consumption is recommended to reduce 


Recommendation grade: A, evidence level 2b, strong consensus 

Comments 

Smoking tobacco doubles the risk of pancreatic carcinoma. This 

relationship is consistently proven by cohort studies [39, 50, 

55–57] and case control studies [58, 59]. Individual genetic 

factors seem to influence the degree of association [60 – 62]. A 

connection was found even between passive smoking and risk 

of pancreatic carcinoma [63]. 

Work-related risk factors 


Contact with pesticides, herbicides, and fungicides may increase 

the risk of pancreatic carcinoma. Other potential risk factors 

may be chlorinated hydrocarbons, chromium and chromium 

compounds, electromagnetic fields, and fuel fumes. 

Recommendation grade: C, evidence level 2b–3, consensus 

Comments 

Some occupational and work areas seem to be associated with 

a slightly increased disease risk [64 – 66]. The abovementioned 

chemicals may possibly represent particular risk factors [67– 

73]. 

Drug prophylaxis 


There is at present no drug prophylaxis to reduce the risk of pancreatic 

carcinoma. 

Recommendation grade: B, evidence level 2a, consensus 



456 

Leitlinie 

Comments 

Neither the supplementation with antioxidants [74, 75] nor the 

intake of non-steroidal antirheumatics [76–78] leads to a reduction 

of pancreatic carcinoma risk. 

Screening of asymptomatic population 


A screening of asymptomatic persons with CA19–9 for early diagnosis 

should not be done. 

Recommendation grade: B, evidence level 3, strong consensus 

Comment 

Two studies with large study populations show that screening 

of asymptomatic persons is not sensible due to the low positive 

predictive value [79, 80]. 


Molecular biologic screening methods such as mutation analysis 

to screen the asymptomatic normal population are currently not 

recommended. 

Recommendation grade: A, evidence level 5, strong consensus 

Comment 

There is currently no scientific evidence which warrants the 

screening of the asymptomatic normal population with molecular 

biologic methods. 


Imaging techniques to screen the asymptomatic normal population 

can currently not be recommended. 


Comment 

Currently, there is no scientific evidence that mandates the 

screening of the asymptomatic normal population with imaging 

techniques [79]. 

Risk group – identification and monitoring 

Sporadic pancreatic carcinoma in the family (sporadic 

pancreatic cancer kindred: SPC) 


Compared to the normal population, first degree relatives of patients 

with pancreatic carcinoma have an increased risk of also 

developing pancreatic cancer. 

Evidence level 2b, consensus 

Comments 

The risk is twice as high for first degree relatives of patients 

with pancreatic carcinoma. If the patient is under 60 years of 

age, the risk is 3 times as high [81, 82]. Second and third degree 

relatives are not suitable as index patients to define an individually 

increased pancreatic carcinoma risk. If pancreatic 

carcinoma occurs in two or more first degree relatives in one 

family, this family fulfills the currently valid criteria of “familial 

pancreatic carcinoma”. Thus, it does not belong to the group 

of sporadic pancreatic carcinoma. 


A recommendation for primary prevention for relatives of pancreatic 

carcinoma patients which differs from that for the normal 

population cannot be given. 

Recommendation grade: D, evidence level 5, strong consensus 


Comment 

In general, the recommendation for the normal population can 

also be applied to relatives of pancreatic carcinoma patients. 

There is currently no scientific evidence that supports a benefit 

of deviating procedures. 

Familial pancreatic carcinoma 

(familial pancreatic cancer kindred: FPC) 

An increased pancreatic carcinoma risk was observed in several 

hereditary syndromes. In these cases, pancreatic carcinoma 

is not considered a leading clinical/phenotypic form (see below). 

Today, familial pancreatic carcinoma (FPC) is differentiated 

from these syndromes. FPC is always assumed if at least 

two first degree relatives (independent of age) in one family 

have pancreatic carcinoma and the family does not fulfill the 

clinical or familial anamnestic criteria of other hereditary syndromes 

(see below). FPC-tumors cannot be histologically differentiated 

from sporadic tumors. A prospective study from 

Germany showed that between 1 – 3% of all pancreatic carcinoma 

patients fulfill the FPC-criteria. Thus, FPC has a similar 

frequency to other hereditary tumor diseases [83]. The mean 

age of onset of FPC is not significantly different from sporadic 

cases (€ 62 years). However, preliminary data seem to indicate 

that offspring of FPC-patients may develop pancreatic carcinoma 

up to 10 years earlier (anticipation) [84]. As for all hereditary 

diseases, relatives from FPC-families should be referred to 

genetic consultation. A specific gene defect for FPC was found 

for only a small subgroup (about 10%). This is why predictive 

gene diagnostics outside of clinical studies cannot be recommended 

at this time. 

Compared to the normal population, family members with at 

least two first degree relatives who have pancreatic carcinoma 

(independent of the patient’s age) have a highly increased risk 

of also developing pancreatic carcinoma. 


Comments 

The risk of a first degree relative to develop pancreatic carcinoma 

is 18 times as high if two family members have this disease. 

It can increase up to 57 times if three or more persons are 

affected. However, these numbers are based only on one prospective 

study [85]. Therefore, they must be interpreted with 

caution. 


A recommendation for primary prevention for relatives of FPC-families 

which differs from that for the normal population cannot be 

given. 

Recommendation grade: C, evidence level 3, consensus 

Comments 

In general, the recommendations for the normal population 

can also be applied to relatives of pancreatic carcinoma patients. 

There is currently no scientific evidence that supports 

a benefit of deviating procedures. Recently, data on preliminary 

screening tests using imaging techniques for families at 

risk were published [86 – 88]. However, they have not been 

confirmed by independent studies. Therefore, based on the 

current data a general recommendation of screening tests 

such as endosonography, ERCP, or MRCP for high risk groups 

are not recommended outside of controlled studies because 

of the high risk of false positive results. 


Other diseases/syndromes which are associated with an 

increased pancreatic carcinoma risk 

Patients with Peutz-Jeghers-Syndrome have a 36 to 42% lifetime 

risk of developing pancreatic carcinoma. 

Evidence level 2a, strong consensus 

Comments 

Two studies prove the much higher risk of developing pancreatic 

carcinoma for patients with Peutz-Jeghers-Syndrome [89, 90]. 

Patients with B-K mole-syndrome (including pancreatic-carcinoma-melanoma-syndrome) 

have an up to 17% lifetime risk 

of developing pancreatic carcinoma. 

Evidence level 2b, strong consensus 

Comments 

Several studies in FAMMM or families with pancreatic-carcinoma-melanoma-syndrome 

prove a much higher risk of pancreatic 

carcinoma [83, 91–93]. 

Patients and relatives of patients with hereditary breast or 

ovarian cancer have a higher risk of contracting pancreatic 

carcinoma. 

Evidence level 2a, consensus 

Comments 

There are only few systematic studies on the pancreatic carcinoma 

risk in families with hereditary breast or ovarian cancer. 

These are usually based on families with known germ line mutations 

in the BRCA 1 and 2 genes. The pancreatic carcinoma 

risk seems to be 2 to 6 times as high in these families [94 – 96]. 

Patients and relatives of patients with HNPCC may have a 

higher risk of developing pancreatic carcinoma. 

Evidence level 3, consensus 

Comment 

The data available are very sparse and point towards a possible 

risk increase [97, 98]. 

Patients and their relatives with ataxia teleangiectasia do not 

have an increased pancreatic carcinoma risk. 


Comment 

It is difficult to evaluate the data on pancreatic carcinoma risk 

of ataxia teleangiectasia patients, because of the few numbers 

of cases. A higher risk of pancreatic carcinoma does not seem 

to be evident [99]. 

Patients with FAP and their relatives have an increased risk of 



Comments 

One study reports an increased relative risk of 4.5 for pancreatic 

carcinoma [100]. 

Patients with cystic fibrosis probably have no increased risk 

for pancreatic carcinoma. 


Comment 

There are no definite statements in the literature on this subject. 

Patients with Li-Fraumeni-syndrome and their relatives 

may also have an increased risk of developing pancreatic 

carcinoma. 


Leitlinie 457 

Comment 

Data are sparse on this subject and further studies are necessary 

[97]. 

Other diseases that may be associated with a higher risk of 

pancreatic carcinoma 

Patients with von Hippel’s disease and Fanconi’s anemia may have 

an increased risk of pancreatic carcinoma while patients with neurofibromatosis 

do not. 

Evidence level 4 

Comments 

One study reported an association of pancreatic carcinoma with 

von Hippel’s disease [97]. Furthermore, gene mutations in the 

FANCC and FANCG genes were determined in patients with pancreatic 

carcinoma. A loss of heterozygosity was found in resected 

tumors. These data suggest that patients with mutations in the 

FANCC gene as is the case in Fanconi’s anemia may have a predisposition 

for pancreatic carcinoma. The relative and life time risks 

are not known [101]. 


In general, the recommendation for the normal population to reduce 

the risk of pancreatic carcinoma also applies to relatives of 

the abovementioned pancreatic carcinoma patients with hereditary 

disease. There is currently no scientific evidence that supports 

a benefit of deviating procedures (see also FPC). This recommendation 

applies only to the pancreatic carcinoma risk and not to deviating 

recommendations on screening/monitoring of the corresponding 

hereditary disease. 

Recommendation grade: D, evidence level 4, consensus 

Patients with hereditary pancreatitis 

Patients with hereditary pancreatitis have a highly increased risk 

of pancreatic carcinoma. 


Comment 

The cumulative risk of developing pancreatic carcinoma by the 

age of 70 is between 40 and 44% in this group [102, 103]. 


Imaging techniques can currently not be recommended to monitor 

patients with hereditary pancreatitis. 


Comments 

Prospective screening of families at risk was performed at two 

institutions (Johns Hopkins University and University of Seattle). 

Johns Hopkins recommends an annual screening and the Seattle-program 

a screening every two to three years. Lesions that 

are typical for chronic pancreatitis and unexpectedly frequent 

IPMNs were found using endosonography and ERCP. The value 



458 

Leitlinie 

of these results is not known. Therefore, this type of monitoring 

should only be done under study conditions [86 – 88, 104]. 

Chronic pancreatitis 

Patients with many years of chronic pancreatitis have an increased 

risk of developing pancreatic carcinoma. 


Comments 

The data on the relative risk are heterogeneous and vary from 

2.3 to 18.5. The cumulative incidence is reported to be 1.1% after 

5 years, 1.8% after 10 years, and 4% after 20 years [105 – 109]. 

Type 2 diabetes mellitus 

Patients with type 2 diabetes mellitus have an increased risk for 



Comments 

About 1% of diabetics age 50 years and younger develop pancreatic 

carcinoma in the following 3 years. That is equal to an 

about 8-fold higher risk [110]. Further studies show a risk that 

is lower [50, 111 – 118]. It must be taken into account that diabetes 

can be caused by pancreatic carcinoma [119, 120]. 

Recommendation on genetic consultation 

The genetic consultation of patients with genetic syndromes and 

their relatives is performed according to the directives of the German 

Medical Association. 

Recommendation grade: A, consensus 

Topic 2: 

Diagnostics 

! 

Diagnostics in case of newly occurring symptoms 


Newly occurring pain in the epigastric region and back should 

result in tests for diagnosing pancreatic carcinoma. 


Comments 

In general, newly occurring pain in the epigastric region or 

back which could be caused by pancreatitis or pancreatic carcinoma 

mandate further diagnostics. No literature is available 

that states for which symptoms alone or in combination and 

from which age pancreatic carcinoma should be considered. 

The diagnostics alone or in combination that are necessary to 

exclude pancreatic tumors have also not been reported. Newly 

occurring back pain alone which cannot be explained by alterations 

of the musculoskeletal system should not result in 

testing for pancreatic carcinoma. 

l " Table 8 suggests an age and suspicion level adapted procedure 

which is based on expert opinion. 


A newly occurring or manifest type 2 diabetes mellitus with no further 

pancreatic carcinoma symptoms should not lead to pancreatic 

carcinoma diagnostic testing. 



Table 8 Diagnostic procedures adapted to age and suspicion level for newly 

occurring pain of the epigastric region and back 

suspicion 

level 

age 

(years) 

symptoms procedure 

low < 50 just pain1 sonography in case of 

persisting symptoms 

intermediate 

50 justpain1 sonography, if necessary CT 

pain plus2 sonography, if necessary CT 

high > 50 pain plus sonography, if necessary CT/ 

endosonography 

1 Newly occurring pain that radiates localized/belt-like to the back and that 

is perceivable during the night should be clarified further regardless of age. 

If the suspicion level is high or if the ultrasound is negative, complementary 

CT, or endosonography should be implemented. 

2 Pain plus other symptoms (inappetence, weight loss, weakness). 

Comment 

According to current studies, there is only a moderate connection 

between type 2 diabetes and pancreatic carcinoma [110, 

112, 115]. This and the few possibilities for early pancreatic carcinoma 

diagnosis currently available, make diagnostic testing 

for pancreatic cancer not useful for type 2 diabetes mellitus patients 

without further symptoms. 


Newly occurring painless jaundice should result in diagnostic testing 



Comment 

Pancreatic and bile duct carcinoma are the most frequent cause 

(20%) for newly occurring jaundice in patients over 60 years of 

age [121 –123]. 


In certain cases (patients > 50 years with primary “idiopathic” 

pancreatitis), acute pancreatitis of unknown etiology should result 

in additional procedures for the diagnosis of pancreatic carcinoma. 


Comments 

The pancreatic carcinoma incidence seems to be higher in patients 

with acute pancreatitis and even more so in patients 

with an acute episode of chronic pancreatitis. However, they 

do not exceed 1 – 2% of all pancreatic carcinoma cases or a maximum 

of 5% of idiopathic forms. There are only few systematic 

studies on this topic, especially on the idiopathic forms. Data 

using endosonography in this context are well documented. 

Thus, the primary recommendation is endoscopic ultrasound, 

which should be done during the symptom-free interval following 

acute pancreatitis. MD-CT examinations are an alternative. 

If the endoscopic ultrasound is negative, a clarification of the 

ducts should be considered. However, only data on ERCP are 

available, which has the risk of post-ERCP-pancreatitis. By analogy, 

MRCP is recommended [124, 125]. 

In general, CA 19–9-assessment should not be done to diagnose 

pancreatic carcinoma. Algorithms or diagnostic procedures are 

also not recommended to clarify an increased CA 19–9-value. 


Although pancreatic carcinoma may also develop before the 

age of 50, the age dependent incidence curve does not show 

an increase until after the age of 50 [122]. Therefore, diagnostic 

testing should be done in patients age 50 years and older. 

Imaging techniques for primary diagnostics 


Different procedures such as sonography, endosonography, multidetector-CT, 

MRT with MRCP or ERCP are suitable to confirm suspected 

tumors. 

Recommendation grade: B, evidence level 2, consensus 

Comments 

The abovementioned procedures are not always available. 

Therefore, they cannot be implemented in an algorithm defined 

for every situation. It was agreed that initially an ultrasound 

examination of the epigastric region should be done. 

This would allow a tentative diagnosis of pancreatic carcinoma 

and perhaps also diagnosis of metastases. The diagnosis 

of pancreatic carcinoma is also possible with all other procedures. 

However, ERCP alone is not sufficient to diagnose ductal 

pancreatic carcinoma, because it depicts only the ductal 

changes and not the lesion itself [126, 127]. 

Computed tomography (multi-detector-CT) should be done 

using a biphasic contrast medium protocol (pancreas parenchyma 

phase and portal venous phase). The section thickness 

should be £ 3 mm. The MRT/MRCP should be done with a field 

strength of at least 1.5 tesla and standard weighting (T1 and T2 

including MRCP). The section thickness should be 5 – 7 mm. 

The endoscopic ultrasound may be done with a mechanical radial 

scanner as well as an electronic endosonography device. 

However, the published data are based on mechanical radial 

scanners. Although the electronic endosonography most likely 

has a better local resolution, it has not been investigated whether 

carcinomas can be identified with a higher sensitivity with 

this device. 


Sonography of the epigastric region, endosonography, multi-detector-CT, 

as well as MRT in combination with MRCP are first choice 

diagnostic procedures to detect pancreatic carcinoma. 


Comments 

According to the literature multi-detector-CT and MRT in combination 

with MRCP are the most sensitive procedures for the 

detection of pancreatic carcinoma. If used by specialists, endosonography 

may partly be even more sensitive. A clear recommendation 

for or against one of these procedures cannot be given. 

The procedure for which there is the most expertise in the 

facility should be used. Different complementary procedures 

may also have to be implemented. 

Cytologic and laboratory diagnostics 


If pancreatic carcinoma is suspected, brush cytology from the bile 

ducts is not sensitive enough. It is also not recommended to use 

brush cytology from the pancreas duct to detect pancreatic carcinoma. 

Therefore, an ERCP for tissue diagnostics is not indicated. 


Leitlinie 459 

Comments 

The literature does not allow for an adequate statement on the 

abovementioned question. Brush techniques in pancreas as well 

as in the bile duct system are risky and not useful. 

Laboratory tests 


If there is a pancreatic lesion, CA 19–9-testing should be done. 

Recommendation grade: C, evidence level 2a, majority approval 

Comments 

CA 19–9 laboratory tests may be used in individual cases for 

differential diagnostics. Potential resectability detected with 

imaging techniques and a very high preoperative CA 19–9-value 

may make staging laparoscopy necessary. In such cases the tumor 

load is often greater than expected from the imaging technique 

e. g. a disseminated tumor. However, so far there are no 

cost-benefit analyses which support the use of this test [128– 

131]. 

Tissue diagnostics: procedure in case of pancreatic lesion 


Initially a resection should be done if there is a potentially resectable 

lesion in the pancreas that may be a tumor. An endosonographic 

guided biopsy may be done if differential diagnostic 

indications are present that would change the procedure e. g. if 

metastases are suspected because of an earlier malignancy. 


Comments 

The endosonographically guided fine needle puncture is sensitive 

and highly specific for histologic or cytologic diagnosis of 

pancreatic carcinoma [132–134]. However, in most cases it is 

unnecessary, because if resectable, lesions of unclear dignity 

should also be operated on. Therefore, for a potentially resectable 

lesion, a preoperative biopsy to confirm the diagnosis of 

pancreatic cancer is not necessary. 


If nonetheless a biopsy is done for differential diagnostics, biopsies 

should be preferably taken from those lesions that have the 

lowest risk of complications. 



A biopsy to confirm a diagnosis is mandatory before specific palliative 

therapy is initiated independently of whether the pancreatic 

tumor is locally advanced, inoperable, or metastatic. 

Recommendation grade: B, evidence level 2a, strong consensus 

Comment 

The diagnosis must be cytologically or histologically confirmed 

before palliative chemotherapy is started to exclude false treatment 

due to other differential diagnoses [135]. 


The lesion that is easiest to reach and that has the lowest risk is 

biopsied independently of whether it is the primary tumor or a 

metastasis. 




460 

Leitlinie 

Preoperative staging 


Preoperatively, multi-detector-CT and endosonography should be 

preferred to evaluate local tumor spread or resectability. 

Recommendation grade: A, evidence level 1a, consensus 

Comments 

The standard procedure to evaluate the size of primary tumors 

and the local tumor spread is a CT. A combination of transabdominal 

and endoscopic ultrasound can give similar diagnostic 

results. However, the image documentation of sonographic procedures 

is often insufficient from a surgeon’s point of view. The 

sonographic and endosonographic procedures are dependent on 

who performs them. If sufficient multi-detector-CTs and MRIs 

are available preoperatively, no other procedures are necessary. 

Because of the high costs, an MRI is not always done for primary 

evaluation of local tumor spreading [136]. 


Abdominal sonography is mandatory to assess systemic tumor 

spreading. If no systemic metastases were detected using abdominal 

sonography or if a study protocol requests imaging according 

to RECIST-criteria (Response-Evaluation-Criteria in Solid Tumors), 

then abdominal multi-detector-CT is mandatory. 

X-ray thorax examinations are part of the tumor staging. 

MRT as well as thoracic-CT are assessed as optional for the evaluation 

of systemic tumor spread. Endosonography, ERCP, MRCP, 

and bone scans are not used for tumor staging. 

Currently, FDG-PET examinations as well as micrometastasis diagnostics 

from whole blood do not play a role in preoperative diagnostics. 

Recommendation grade: D, evidence level 2b, consensus 

Comments 

A comparison of the literature on preoperative staging of pancreatic 

carcinoma demonstrated a slightly higher sensitivity of 

endoscopic ultrasound versus computed tomography. However, 

when the studies were compared they revealed a high heterogeneity 

with regard to design, quality, results, as well as methodologic 

weaknesses [137]. Literature on MRT showed a high 

sensitivity and specificity for the detection of biliary obstruction, 

but not a high sensitivity for the differentiation between 

benign or malignant causes of the obstruction [138]. However, 

this study only took publications into account that were published 

until the end of 2003. PET-studies are too complex and 

expensive even though their potency was shown to be similar 

to other methods. The significance of the new PET-CT-procedure 

must be evaluated in future studies [139]. 


Staging-laparoscopy is optional. 

Recommendation grade: D, evidence level 2b, consensus 

Comments 

Staging-laparoscopy is of particular interest if e. g. due to excessively 

high CA 19–9-values or ascites there is suspicion of peritoneal 

carcinosis which is not visible by imaging techniques. 

Findings in up to one third of those patients exclude curative 

resection [140, 141]. 


Cystic processes 


To differentiate cystic processes epigastric ultrasound, multi-detector-CT, 

MRT with MRCP, endosonography, and ERCP are principally 

implemented. 


Comments 

None of the methods that are mentioned allows a definite diagnosis. 

At most a robust conclusion can be made if they are combined 

with the below mentioned procedures and in connection 

with the individual clinical constellations. 


An endosonographically guided biopsy should be performed if a 

cyst is considered to be suspicious. 


The tumor markers CA19–9 and CEA as well as cytology can be 

determined in aspirates. 

Recommendation grade: D, evidence level 2a, consensus 

Comments 

The abovementioned procedures are based on one original article. 

Further prospective multi-center trials are necessary to validate 

the recommendation [142]. 

Therapy evaluation in the palliative situation 


An epigastric ultrasound should always be done to examine the 

course of a tumor response during palliative chemotherapy. CT 

should only be done if the study conditions demand it (RECISTcriteria) 

or if the epigastric ultrasound does not give information 

on the course of the response. 

Recommendation grade: D, consensus 

Topic 3: 

Surgical therapy of pancreatic carcinoma 

(curative intention) 

! 

Introduction 

The following describes the surgical procedure for pancreatic 

tumors. In particular criteria are defined that make resectability 

of tumors with curative intent possible. Aside from the perioperative 

patient management, the topics that are dealt with 

are surgical techniques, surgical tactics for different tumor entities, 

disease stages, as well as preparation of surgical specimens 

that are relevant for prognosis. The data from the literature 

can be applied to the conditions in Germany. They are the 

basis for the evidence and recommendation grades of the individual 

topics. 

Criteria for irresectability from the patient’s perspective 


Age should not be a criterion to exclude a patient from pancreatic 

carcinoma resection. 


Comorbidity may be a criterion against resection. 



Comment 

Due to the demographic development the population will become 

older in the next decades. Therefore, the number of elderly 

patients (> 75 years) with pancreatic carcinoma will rise. 

Already today, different reports show that chronologic age is 

not a contraindication for pancreatic surgery, because the operative 

results for younger patient groups are comparable 

[143 –145]. In contrast to chronologic age, major visceral surgery 

may be contraindicated if comorbidities are present. It is 

not possible to specify individual clinical scenarios based on 

the literature. However, it is known that up to 30% of all perioperative 

complications and up to 50% of all postoperative 

deaths have cardiac causes. In addition, patients with chronic 

respiratory diseases or liver cirrhosis have an increased risk of 

developing perioperative complications. The decision whether 

pancreatic surgery is beneficial and safe for these risk patients 

must be carefully considered. Furthermore, an interdisciplinary 

evaluation of the complete constellation must be performed 

before surgery. The treatment alternatives and the patient’s 

wishes should also be taken into consideration [146]. 

Criteria for irresectability due to the tumor 

Extrapancreatic tumor manifestation 


Pancreatic carcinoma in healthy patients may be resectable even 

if it has infiltrated neighboring organs. 


Infiltration of Haller’s tripod and the superior mesenteric 

artery 


If Haller’s tripod and the superior mesenteric artery are infiltrated 

in healthy patients, a resection is rarely possible. 


Infiltration of the portal vein and the superior mesenteric 

vein 


The infiltration of the portal vein should not be a contraindication 

for resection. If the superior mesenteric vein is infiltrated, the possiblity 

of resection is less likely than if the portal vein is infiltrated. 


Comments 

The aim of pancreatic surgery is an R 0 resection independently 

of the location of the tumor [147]. Locally advanced carcinomas 

should be resected if necessary en bloc with the neighboring 

organs, because the prognosis for extended R 0 resection is 

identical to standard resections [148 –152]. 

Resection of the portal vein and the superior mesenteric vein 

should be performed during pancreatic surgery if it makes an 

R0 resection possible. A systematic review shows that in a high 

percentage of these patients the lymph nodes are already infiltrated 

[153]. Many series from pancreas centers demonstrate 

that the morbidity and the mortality of an en bloc resection of 

pancreas and portal vein (or superior mesenteric vein) and the 

patient’s long-term prognosis are comparable to that of patients 

without portal vein resection if their disease stages correspond 

[147, 149, 151, 154 –156]. 

The infiltration of Haller’s tripod and the superior mesenteric 

artery rarely allows resections in healthy patients. A recommendation 

on the extent of the vessel infiltration is deliberate- 

Leitlinie 461 

ly not made. The resection of tumor infiltrated arteries during 

pancreas resection is technically possible, but should currently 

be viewed as experimental [150, 152, 157, 158]. 

Preoperative cholestasis 


Preoperative drainage of bile using stents should not be generally 

done. It should be performed only if cholangitis is present or if 

an operation cannot take place immediately. 


Comments 

In 73% of the cases an infection is seen after ERCP and stent 

placement [159]. Infections of the biliary system at the time 

of pancreas resection are associated with an increased morbidity. 

Therefore, a stent should not be placed if an operation 

can be done quickly [160 – 163]. If cholangitis is present or the 

operation cannot be done right away e.g. due to neoadjuvant 

therapy, a stent should be placed. 

Perioperative antibiotic prophylaxis 


A perioperative antibiotic prophylaxis should always be done. 

Recommendation grade: A, evidence level 1c, strong consensus 

There should be no difference in the prophylaxis of patients with 

and without stents. 

Recommendation grade: C, consensus 

Comments 

Antibiotic prophylaxis should always be done during hepatobiliary 

surgery, because it significantly reduces postoperative infections 

including wound infections [164]. It should not be maintained 

postoperatively, because there is no advantage. However, 

there is a higher risk of complications including development of 

resistances and allergies [165]. If cholangitis is present, an antibiotic 

therapy should be done. 

Perioperative somatostatin prophylaxis 


A reduction of pancreas-specific complications by perioperative 

somatostatin prophylaxis is supported by a meta-analysis of randomized 

studies. However, the prophylaxis with somatostatin cannot 

be recommended for all patients, because existing studies define 

pancreas fistula differently. This could lead to differences in 

the classification of postoperative complications. 

Recommendation grade: C, evidence level 1a, consensus 

Comments 

The studies are heterogeneous with respect to the benefit of 

somatostatin prophylaxis. None of the studies showed a difference 

in postoperative mortality. However, a meta-analysis 

of 1918 patients and 10 randomized studies shows that somatostatin 

significantly reduces the morbidity and pancreas-specific 

complications including the frequency of biochemically 

detectable fistula [166]. Further differentiation of the resection 

methods in subgroup analyses shows no benefit of somatostatin 

prophylaxis. Therefore, the patient group that benefits 

from a perioperative inhibition of secretion using somatostatin 

can currently not be identified. 

At present there is no uniform definition of a pancreatic fistula. 

This complicates the evaluation of the efficacy of somatostatin 

prophylaxis and may lead to differences in the classification of 



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postoperative complications. Therefore, the comparison of published 

data is difficult. A new classification of pancreatic fistulas 

was developed at a consensus conference in 2005 [167]. This is 

an attempt to make an internationally accepted and comparable 

definition of fistulas in future publication possible. Therefore, a 

general recommendation on the perioperative application of somatostatin 

cannot be given. 

Objectives for intraoperative resection margins 


There are no definite data on necessary safety margins when resecting 

pancreatic carcinoma. Macroscopically assessed resection 

margins for curative resection (R0) can be deduced from practical 

experience. They should be as follows: 

E in pancreas tissue: 10 mm, 

E for bile ducts: 10 mm, 

E at the stomach/pylorus: 10 mm. 

For anatomic reasons, no objectives can be given for R 0 resections 

in the area of the retroperitoneum. 


Intraoperative sonography of the liver 


An intraoperative sonography is not necessary if the preoperative 

abdominal CT is inconspicuous. 


If the results of abdominal sonography or CT are not clear, a clarification 

should be attempted prior to surgery. In unclear cases an 

intraoperative sonography can lead to further clarification. 


Comments 

The quality of the new generation of multi-detector-CT is so 

high that if metastases were not detected using preoperative 

CT diagnostics, an intraoperative sonography would give no 

further information. Therefore, if a preoperative CT is inconspicuous, 

an intraoperative sonography is not necessary [168]. 

If the preoperative clarification of changes in the liver is still 

unclear, an intraoperative sonography may be useful to assess 

the operability of pancreatic tumors. If the resectability of the 

pancreatic tumor was assessed laparoscopically, an intraoperative 

sonography can replace the palpation and add to the mere 

inspection of the liver surface [169]. 

Intraoperative peritoneal lavage/cytology 


Intraoperative peritoneal lavages have no therapeutic consequences. 

Therefore, there is no indication for a peritoneal lavage with 

cytology. 


Comments 

Most patients have a relapse after curative resection of pancreatic 

carcinoma. It is speculated that this is due to micrometastases 

in the peritoneum which are not detectable at the 

time of surgery [170]. Even though peritoneal micrometastases 

could be detected in peritoneal lavages, a prognostic relevance 

of positive cytologic results was not found. Therefore, 

micrometastases are not an exclusion criterion for radical resection, 

and a peritoneal lavage is not necessary [171, 172]. 


Extent of resection/surgical technique/preferred 

anastomosis technique 


The aim of pancreatic surgery is an R0 resection independently of 

the location of the tumor. 

Pancreas head carcinoma 


The resection of the pancreas head tumors usually includes the 

partial duodenopancreatectomy with or without pylorus preservation. 

In rare cases a total pancreatectomy may be necessary if 

the carcinoma has spread. If neighboring organs and other structures 

are infiltrated, the resection should be extended. 

Recommendation grade: A, evidence level 1c, consensus 

Classic Whipple versus pp-Whipple 


Both procedures (pylorus preserving [pp] versus stomach resecting 

partial duodenopancreatectomy [classic]) are comparable with respect 

to postoperative complications and oncologic long-term results 

(1a). 


Comment 

A meta-analysis of the literature on pylorus preserving and classic 

duodenopancreatectomy demonstrated no relevant differences 

between both procedures with respect to patient mortality, 

morbidity, and survival. However, the studies that were analyzed 

were very heterogeneous [173]. 

Carcinoma of the pancreatic tail 


The surgical procedure for pancreas tail carcinomas is left-sided 

pancreatic resection. The abovementioned criteria on the surgical 

expansion apply [174 –176]. 

Recommendation grade: A, evidence level 3, consensus 

Pancreatic body cancer 


In general a subtotal left-sided pancreatic resection or if necessary 

a total duodenopancreatectomy is indispensable for pancreas body 

cancer [174–176]. 


Tumor adherence to surrounding organs 


An R0 resection can be performed even if the neighboring organs 

are infiltrated (extrahepatic local manifestations). The goal of every 

resection must be an R0 resection [148–152]. 


Radical extension of lymphadenectomy 


So far, a benefit of extended lymph node resections was not observed. 


Comments 

A standardized lymphadenectomy during pancreas head cancer 

surgery according to Whipple should be performed as follows: 

complete and circular dissection of the lymph nodes of the hepatoduodenal 

ligament as well as around the common hepatic 


artery and the portal vein and the cranial part of the superior 

mesenteric artery. Furthermore, lymph nodes at the right side 

of the celiac trunk and the lymph nodes at the right hemicircumference 

of the superior mesenteric artery stem should be 

dissected. 

The term “radical extension of lymphadenectomy” includes different 

degrees of dissection. The number of removed lymph 

nodes and the additional time needed for an extended lymphadenectomy 

differ significantly between the 4 randomized studies 

on this topic [177–179]. Consistently all 4 studies from 

Europe, Japan, and the USA showed no additional benefit with 

respect to long-term survival after extended radical dissection 

of the lymph nodes compared to standard dissection (definition 

see above). Thus, so far no benefit was shown for the extended 

resection. 

Operative strategy for IPMT/cystic pancreatic tumors 


All potentially malignant tumor entities of the pancreas are primarily 

resected with the same goal and to the same extent as the 

ductal pancreatic carcinoma. 


Comments 

Cystic pancreatic tumors have a wide spectrum of histologic 

characteristics including inflammatory (pseudocysts) and benign 

(serous) cysts as well as cysts of unknown or malignant 

origin (IPMT, mucinous) [180]. A definite differentiation between 

benign and malignant is not possible with modern CT or 

MRT examinations. Endosonographic and cytologic differentiation 

of cystic contents are not as good as differentiation using 

CEA values of cystic contents and, thus, not definite [181, 182]. 

If the operative risk is justifiable, resection is recommended, 

because it is not possible to differentiate benign and malignant 

cystic lesions preoperatively [183–185]. However, for high risk 

patients and patients with small serous tumors without symptoms 

a resection can be sustained. In this case, a close monitoring 

of the pancreas is useful [184]. A limited resection (segmental 

resection, enucleation) for serous cystic adenoma and the 

early stages of IPMT of the collateral duct are sufficient [180, 

185]. All potentially malignant tumor entities should primarily 

be operated with the same goal and to the same extent of resection 

as the ductual pancreatic carcinoma, because the prognosis 

of advanced IPMT and mucinous cystic adenocarcinoma is identical 

to ductual adenocarcinoma. 

Therapeutic procedures for distant metastases 


Resection of distant metastases of ductal pancreatic cancer (organ 

metastases, peritoneal carcinosis, lymph node metastases that are 

defined as distant metastases) does not improve the prognosis and, 

thus, should usually be avoided. 


Resection of intraoperatively detectable distant metastases 


Even if the tumor is resectable, a resection should not be done if 

distant metastases are only detectable intraoperatively. 


Leitlinie 463 

Comments 

In high volume centers, the morbidity of pancreatic surgery is 

markedly reduced and the mortality is under 5%. If metastases 

have been detected and the complication rate is acceptable, 

pancreas resection can lead to excellent pain control. In 

several publications it was already considered to be an alternative 

to palliative double bypass surgery. However, despite 

the progress in adjuvant therapy, so far no survival advantage 

has been shown for resection of metastatic pancreatic cancer 

[186–188]. 

Laparoscopic surgical techniques 


Pancreatic cancer is an indication for laparoscopic tumor staging. 

However, laparoscopic surgery of pancreatic carcinoma is currently 

not recommended. 


Comments 

In about 20% of the cases a curative resection is not possible 

despite standardized preoperative staging of pancreatic cancer 

using modern imaging techniques. This is due to local tumor 

spreading or peritoneal carcinosis or liver metastasis that is 

only detectable intraoperatively [189]. In this case patients 

can benefit from diagnostic laparoscopy, as a minimal invasive 

technique. It can complete the staging (see also Topic 2) 

[189, 190]. A diagnostic laparoscopy is especially useful for 

the staging of cancer in the pancreatic body and tail, because 

of the late development of symptoms compared to pancreatic 

head carcinomas. In contrast, laparoscopically performed oncologic 

pancreatic resections, although possible, are experimental 

[191]. 

Intraoperative frozen section examination 


Pancreas and if applicable bile duct resection margins should be 

tested by frozen section analysis independently of frozen section 

testing for the diagnosis of distant metastases [192]. In addition, 

putative liver metastases and possibly peritoneal carcinosis should 

be assessed. Lymph nodes and the retroperitoneal margin do not 

have to be evaluated. 


Intraoperative needle or incision biopsies of the primary pancreatic 

tumor should not be done to clarify its dignity. 


Histologic evaluation of resected tumors 


Criteria for the R0 resection are tumor-free margins at the hepatic 

duct, the pancreas resection area, as well as the circumferential 

inclusive retroperitoneal margin. An additional prerequisite is 

that no distant metastases (organs, peritoneum, lymph nodes) remain 

[193, 194]. 


The specimen should be prepared using ink to mark the retroperitoneal 

margin [193, 194]. 


Necessary information from the pathologist: 

a) pT-classification 


b) pN-classification 




464 

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c) Number of lymph nodes examined 


d) Lymph node micrometastases 


e) R-classification 


f) Status at the resection area of the remaining pancreas 


g) Status at the retropancreatic resection area 


h) Lymph vessel invasion 


i) Blood vessel invasion 

Recommendation grade: B, evidence level 3; strong consensus 

j) Nerve sheath invasion 


Comments 

A recommendation by the UICC is only available on the least 

number of lymph nodes that should be removed. To determine 

pN0 at least 10 lymph nodes should be examined. This number 

is not supported by data in the literature. The number of examined 

lymph nodes should be documented in the histopathologic 

report. 

The UICC-definition (0.2 – 2 mm) should be applied for the identification 

of lymph node micrometastases. This does not include 

so-called disseminated tumor cells [195]. 


The histologic results are most important for the frozen section 

analysis. Histology and perhaps immunohistology are necessary 

for paraffin embedded tissue [193, 194]. 


Topic 4: 

Adjuvant and neoadjuvant non-surgical therapy of 


! 

The only curative therapy option for pancreatic carcinoma is surgical 

therapy. However, the long-term survival after resection is 

still under 20%. Local relapse as well as distant metastases play a 

role in recurrence. 

The curative intended pancreatic resection is a prerequisite for 

adjuvant therapy (R0/R1). Following surgery, the tumor should 

be histopathologically staged. It is especially important to pay 

attention to the resection margins, particularly the retroperitoneal 

margins. This should be documented (see also Topic 3 surgical 

therapy). 


Following R0 resection of pancreatic carcinoma, adjuvant chemotherapy 

is indicated for UICC-stage I-III. 

Recommendation grade: A, evidence level 1b, consensus 

Comments 

Adjuvant chemotherapy should be done after R0 resection (primary 

tumor-M0). An advantage in the disease-free survival was 

shown in two randomized phase-III studies and a meta-analysis 

[196 –198]. However, this may not mean an improved overall 

survival [196]. Frequently, the patient’s quality of life rapidly 

worsens if pancreatic carcinoma recurs. Therefore, to delay re- 


lapse an adjuvant therapy is recommended for all patients after 

R0 resection if no distant metastases are present. If possible, 

patients should be included in clinical trials to assess the optimal 

duration and type of adjuvant therapy. If a patient is treated 

outside of clinical studies, the patient’s disease course should 

be documented with respect to relapse, survival, and side effects 

as part of the tumor documentation/quality assurance. 


Adjuvant/additive chemotherapy can be done after R 0 resection of 

metastases. 


Comments 

Currently, the importance of additive chemotherapy after R 0 

resection of metastases cannot be conclusively evaluated. Similar 

to the role of metastasis resection, the role of additive 

chemotherapy also cannot be evaluated with the data available. 

As already shown in Chapter 3, outside of clinical trials 

pancreatic cancer should generally not be resected if distant 

metastases are detectable even if it were possible. 


Tumor associated risk factors (e.g. G 3-, T 4-stage) are not important 

for the decision to initiate adjuvant chemotherapy. 


Comments 

Currently, no differentiated procedures can be derived from the 

studies available for the adjuvant situation based on pancreatic 

carcinoma grading and staging [196, 197]. General contraindications 

for adjuvant therapy are summarized in l " Table 9. 

Table 9 Contraindications of adjuvant chemotherapy for pancreatic carcinoma 

general condition of health poorer than ECOG 2 

uncontrolled infections 

liver cirrhosis Child B and C 

severe coronary heart disease; heart failure (NYHA III and IV) 

preterminal and terminal kidney failure 

restricted bone marrow function 

inability to have regular follow-up examinations 


There is no general restriction with respect to age for the implementation 

of adjuvant chemotherapy. 


Comments 

Patients that were over 80 years of age were also included in 

the published trials. An unfavorable side effect profile was not 

observed for this age group [196, 197]. 


Adjuvant chemotherapy should be done for ECOG-status 0 – 2. 


Comments 

This recommendation follows the general practical experience. 

Patients with a Karnofsky-performance-status of ‡ 50% (corresponding 

to maximum ECOG 3) were also included in the CON- 


KO1-study [196]. The study by Neoptolemos et al. does not mention 

the performance status of the patients that were included. 

Therefore, the indication for adjuvant chemotherapy can be assessed 

individually for ECOG-stage 3. 


The following adjuvant chemotherapy protocols can be implemented: 

a) 5-FU/folinic acid (Mayo-protocol) 

Recommendation grade: none, evidence level 2b, consensus 

Comments 

The study by Neoptolemos et al. was evaluated by the group 

as an RCT of low quality with 2b because of its methodologic 

weakness (method of randomization, quality control of surgical 

and radiation therapy) [198]. 

b) 5-FU/folinic acid (AIO-scheme) 


Comment 

Although there are no studies available on infusional 5-FU-protocols 

for adjuvant pancreatic carcinoma therapy, if 5-FU is chosen, 

all 5-FU-protocols were considered possible. 

c) Gemcitabine 


Comment 

The largest controlled, randomized study is presently available 

for gemcitabine [196]. 

d) Loco-regional chemotherapy 

Recommendation grade: none, evidence level 5, consensus 

Comment 

A recommendation cannot be given, because sufficient data are 

not available. 


Adjuvant chemotherapy should last 6 months. 


Comment 

This recommendation is based on the treatment duration that 

was selected in the randomized studies [196, 198]. For pancreatic 

carcinoma there are no studies that have compared the effect 

of long-term versus short-term adjuvant therapy. 


If possible, adjuvant chemotherapy should be initiated within 

6 weeks after surgery. 


Comment 

There are no systematic investigations on the best time to begin 

adjuvant chemotherapy after pancreatic resection. The recommendation 

is based on the procedure used in the available 

studies (therapy start 10 – 42 days after surgery [196] or start 

of therapy median 46 days after surgery [198]). 

Leitlinie 465 


An additive chemotherapy should be performed for R1 resected 


Recommendation grade: B, evidence level 3, majority consensus 

Comment 

This recommendation is based on a subgroup analysis of the 

CONKO1-study in which 61 patients with R1 resection were 

treated either with placebo (n = 27) or gemcitabine (n = 34). Patients 

treated with gemcitabine demonstrated a significantly 

better disease-free survival and a better overall survival than 

the placebo treated group [196]. 


The additive therapy with gemcitabine should be performed for 6 

months. 

Recommendation grade: A, evidence level 3, majority consensus 

Comment 

A similar therapy duration as for the adjuvant situation applies. 

Following an R0 resection for pancreatic carcinoma, there is 

no indication for an adjuvant radiochemotherapy outside of 

clinical trials. 


Comment 

A current meta-analysis [197] as well as the ESPAC-1-study 

[198] show no benefit of adjuvant radiochemotherapy for pancreatic 

carcinoma. 


Additive radiochemotherapy for pancreatic carcinoma cannot be 

generally recommended after R1 resection. For individual cases 

it may be an option that should be individually discussed. Ideally 

these patients should be treated as part of randomized, controlled 

study protocols. 


Comment 

Currently, only few data are available on the efficacy of radiochemotherapy 

following R1 resection. There is no direct comparison 

between the efficacy of chemotherapy and radiochemotherapy 

[199]. The distinct side effects of radiochemotherapy 

compared to chemotherapy have to be considered. A continuous 

infusion of 5-FU is recommended after R1 resection if additive 

radiochemotherapy is done outside of trials followed by treatment 

with gemcitabine as monotherapy. Preferably the treatment 

should be done as part of a clinical trial. 


Surgery is the only curative therapeutic procedure for pancreatic 

cancer. Chemotherapy, radiochemotherapy, or radiation therapy 

without surgery are not indicated if the intention is curative. 



Neoadjuvant radiation therapy, radiochemotherapy, or chemotherapy 

are presently not indicated for pancreatic carcinoma outside of 

clinical trials. This applies to patients with locally advanced, inoperable 

tumors as well as for patients with T4-tumors. 




466 

Leitlinie 

Comment 

Currently, the available data are not sufficient for this kind of 

treatment. It should only be done as part of a clinical trial. 


There is no indication for intraoperative radiation therapy for pancreatic 

carcinoma. 



Targeted therapies and immunotherapeutic approaches do not 

play a role in adjuvant or neoadjuvant therapies for pancreatic 

carcinoma. 


Comment 

Currently, a recommendation cannot be given, because the published 

data are insufficient. 

All the data from the literature on this topic are applicable to 

Germany. 

Topic 5: 

Palliative therapy 

! 

Introduction 

Since the studies of Mallinson [200], Palmer [201], and Glimelius 

[202], chemotherapy in the palliative situation has been 

shown to be better than the best supportive therapy with respect 

to survival and quality of life. This is confirmed by a recent 

Cochrane-analysis [203]. Gemcitabine was established as 

standard in palliative chemotherapy for pancreatic carcinoma 

by the Burris trial [204]. The role of new combination therapies 

was investigated in several phase-III studies, and the role 

of molecular therapies (“targeted therapies”) was and is being 

established in phase-III studies. Most of the completed trials 

have not been published in journals. They are only available 

as conference presentations or abstracts. 

Indication for chemotherapy 


Metastatic pancreatic cancer is an indication for palliative chemotherapy. 


Comment 

Palliative chemotherapy leads to longer survival, an improvement 

of quality of life, and “clinical benefit” i. e. especially use 

of less pain medication and less weight loss [200–202, 204]. 


Chemotherapy should be immediately initiated after metastases 

have been detected. It should not be postponed until tumor size 

progression, metastasis-induced symptoms, or other complications 

have developed. 



Weight course, serum albumin, CA 19–9-value, hemoglobin value, 

and tumor differentiation grade at diagnosis do not influence the 

decision for or against chemotherapy. 



Comment 

The benefit of chemotherapy is questionable for patients in poor 

general condition (KI < 70% ECOG > 2) [196, 205 –207]. This is 

confirmed by a subgroup analysis of a phase-III study that so 

far is only available in abstract form [208]. 


Patients with locally advanced, inoperable pancreatic carcinoma 

should also be treated from the time of diagnosis. 


Comments 

In the subgroup of patients with locally advanced, inoperable 

pancreatic carcinoma current phase-III studies demonstrate a 

similar benefit of chemotherapy as for the metastatic situation 

[204, 206, 207, 209, 210]. 

Drugs for palliative first line therapy 


Data from several phase-III studies establish gemcitabine as a 

standard first line therapy for systemic palliative treatment. 


Comments 

This recommendation is based among others on several phase- 

III studies that show a consistent 1-year survival of 18 – 20% 

with gemcitabine therapy [204, 206, 207, 209, 210]. 


Gemcitabine should be given in conventional doses (1000 mg/m 2 

over 30 minutes). 


Comments 

There is a pharmacokinetic rationale for protracted infusion of 

gemcitabine as a so-called fixed-dose-rate-infusion (10 mg/ 

m 2 /min over 150 min; FDR). There is one published randomized 

phase-II study on this topic, which was negative in its 

primary endpoint (time to treatment failure) [211]. A phase-III 

study that compares the conventional gemcitabine therapy 

with FDR-infusion is only preliminary. However, it does not 

show a significant advantage of FDR-infusion [212]. 


5-FU/folinic acid is not recommended as a standard therapy. 


Comments 

Only phase-II data are available on protracted infusion of 5-FU 

for pancreatic carcinoma and these show inconsistent results. 

A direct comparison with gemcitabine in a phase-III study is 

missing [213–215]. 


Currently, combination chemotherapies with gemcitabine cannot 

be generally recommended as standard first line therapies for metastatic 

or locally advanced, inoperable pancreatic carcinoma. 


This is explained for individual combinations in the following in 

more detail. 


Gemcitabine/oxaliplatin or gemcitabine/cisplatin 


This combination should not be used as standard. 


Comments 

There are 2 randomized, controlled studies on the combination 

of gemcitabine with oxaliplatin. Both show a benefit with respect 

to tumor response and a consistent trend towards longer survival 

for the combination therapy. However, the difference in survival 

did not reach significance in either study. The combination therapy, 

however, has a higher rate of side effects [206 –212]. 

There are 2 randomized, controlled studies on the combination 

of gemcitabine with cisplatin. They demonstrate a consistent 

trend towards longer survival. However, these studies also 

show no statistically significant difference in survival. Clearly 

more side effects were seen than with the monotherapy [207, 

216]. 

5-FU/oxaliplatin 


This combination should not be used as standard treatment. 

Recommendation grade: A, evidence level 2a, strong consensus 

Comment 

There is only one small phase-II study with few numbers of patients 

that show an advantage of a combination of 5-FU and 

oxaliplatin compared to monotherapy with 5-FU or oxaliplatin 

[217]. 

Gemcitabine/capecitabine or gemcitabine/5-FU 


The combination gemcitabine and capecitabine or 5-FU is not recommended 

as standard therapy until definite publications are 

available. 


Comments 

The combination of gemictabine and oral fluoropyrimidin capecitabine 

was investigated in 2 randomized, controlled studies. 

A significantly better median and 1-year survival of the 

total population was shown for the combination in only one 

study [208, 218]. So far, these studies have merely been published 

as abstracts. Randomized, controlled studies on the combination 

of 5-FU and gemcitabine showed no significant difference 

in survival [209, 219, 220]. 

Gemcitabine/erlotinib 


A statistically significant difference in survival was demonstrated 

in favor of the combination of gemcitabine and the EGF-receptor 

tyrosine kinase inhibitor erlotinib [221]. The difference in median 

survival is about 2 weeks. The 1-year survival is 24% for the group 

receiving the combination therapy compared to 19% for the group 

receiving gemcitabine monotherapy. 


Comments 

An evaluation of the study that was published online by the 

CHMP of EMEA shows that there is a 22% increase in the median 

survival of patients with metastatic pancreatic carcinoma 

Leitlinie 467 

receiving gemcitabine plus erlotinib compared to gemcitabine 

plus placebo. However, the survival of patients with locally advanced, 

inoperable pancreatic carcinoma did not differ between 

both arms of the trial. Thus, the EMEA recommended the approval 

of a combination of gemcitabine and erlotinib for the indication 

“metastastic pancreatic carcinoma”. Particularly patients 

receiving a combination therapy with erlotinib who have 

a skin reaction (‡ grade 2) after 4 – 8 weeks seem to benefit. For 

patients who do not develop skin rash within the first 8 weeks 

of treatment, therapy with erlotinib should be reconsidered if 

there is no tumor response detectable with imaging techniques 

(i. e. mere stabilization of the disease, no partial or complete remission). 

Gemcitabine/bevacizumab 


This combination is not recommended. 


Comments 

In a phase-II study it was shown that a combination of gemcitabine 

and the VEGF-antibody bevacizumab was beneficial. 

However, the toxicity was increased [222]. A current prematurely 

terminated phase-III study did not show a better survival 

of the combination treatment compared to monotherapy. 

So far the study is only available as an abstract [223]. 

Capecitabine/oxaliplatin 


The data available for the combination of capecitabine and oxaliplatin 

is insufficient. 

Recommendation grade: B, evidence level 2b, strong consensus. 


Patients with a good Karnofsky-index (‡ 90% or ECOG 0 – 1) may 

benefit more from a therapy with gemcitabine/oxaliplatin, gemcitabine/cisplatin, 

or gemcitabine/capecitabine than from monotherapy. 


Comment 

Subgroup analyses of phase-III-studies demonstrate that patients 

with KPS ‡ 90% who receive combination therapy have 

a greater survival advantage [206 – 208]. 

Other drugs 

Drugs such as mitomycin C (recommendation grade: A, evidence 

level 1) [213], a combination of cisplatin, epirubicine, 5-FU, and 

gemcitabine (PEFG) (recommendation grade: A, evidence level 

2) [224], and a combination of gemcitabine and docetaxel (recommendation 

grade: B, evidence level 2b) [225 –228] are not 

important in first line therapy of metastatic or locally advanced, 

inoperable pancreatic carcinoma. 

Second line treatment 


If the first line therapy fails, a second line therapy can be done. 

This is especially true if the patient is in good general health, it 

is the patient’s wish, pretreatment was insufficient, or there is a 

good tumor response during first line therapy. 




468 

Leitlinie 

Comments 

Several studies, mostly phase-II, show the efficacy of second 

line therapy for metastatic pancreatic carcinoma with respect 

to tumor response. Treatments with 5-FU, capecitabine, or raltitrexed, 

also in combination with oxaliplatin, docetaxel, or irinotecan 

are possible [229 – 235]. 

Palliative therapy algorithms 


Palliative chemotherapy should be started with gemcitabine. 


Comment 

There are no studies that investigate the sequential palliative 

therapy of pancreatic carcinoma. It is recommended to start 

treatment with gemcitabine. An alternative for metastatic pancreatic 

carcinoma is a combination of gemcitabine and erlotinib. 

For patients with locally advanced, inoperable tumors and very 

good performance-status a combination of gemcitabine with a 

platinum analogue or capecitabine is possible (see above). 


Standard practice is continuous treatment until progression. 


Comment 

So far, this problem has not been formally investigated. The current 

data available do not yet allow a change of the present practice 

of continuous therapy. 

Clinical efficacy of chemotherapy 


Remission behavior, clinical benefit, or a combination of both are 

used to evaluate the clinical efficacy. 


Comment 

These parameters are based on standard clinical practice which 

is supported by phase-II studies [204]. 

Palliative radiation therapy 


Indications for palliative radiation therapy are limited to symptomatic 

metastases (especially skeletal and cerebral metastases). 


Radiation therapy alone of a locally advanced, inoperable pancreatic 

tumor is not indicated. 


[236] 

Radiochemotherapy for locally advanced, inoperable 

tumors 


If radiation therapy is performed for locally advanced, inoperable 

pancreatic carcinoma, radiochemotherapy should be done. 


Comment 

In several (mostly older) studies radiochemotherapy is better 

than radiation therapy alone for locally advanced, inoperable 

pancreatic carcinoma [237 –241]. However, the data are inconsistent. 



Radiochemotherapy is currently not standard for locally advanced, 

inoperable pancreatic carcinoma. It may benefit patients with 

questionable resectable pancreatic carcinoma. 

Consensus 

In 5 randomized radiochemotherapy studies (randomized phase- 

II-studies) a median survival of 10.3 and 13.2 months was reported 

[242–246]. 

Recommendation grade: C, evidence level 3 

Comparable survival times of 8.7 to 11.7 months were reported for 

locally advanced, inoperable pancreatic carcinoma in 4 randomized 

phase-III-studies on chemotherapy [206, 207, 210, 247]. 


Comment 

Older randomized phase-II-studies [239, 242], which directly 

compare radiochemotherapy and chemotherapy show no difference 

or a small advantage of radiochemotherapy. A recent abstract 

of a phase-III study shows a slight disadvantage of radiochemotherapy 

[248]. The current Cochrane-review reports that 

a better survival can be reached with radiochemotherapy compared 

to the best supportive therapy or radiation therapy alone. 

However, radiochemotherapy is associated with higher toxicity. 

The review concludes that currently there is not enough evidence 

to recommend radiochemotherapy as a better alternative 

to chemotherapy alone for patients with locally advanced, inoperable 

pancreatic carcinoma [203]. 

Problematic for the radiochemotherapy concept is the fast development 

of metastases of some patients with pancreatic carcinoma. 

This is taken into consideration by a concept of the 

French GERCOR-group. A retrospective analysis showed that 

patients with locally advanced, inoperable pancreatic carcinoma 

who do not progress after 3 months of chemotherapy with 

respect to metastases benefit more from radiochemotherapy 

that is subsequently performed than from chemotherapy alone 

[249]. This concept should be tested in a prospective study. 


Radiochemotherapy is not indicated for metastastic pancreatic 

carcinoma. 


If radiochemotherapy is performed for locally advanced, inoperable 

pancreatic carcinoma, it should be conventionally fractionated 

and three-dimensionally planned (single dose 1.8 – 2 Gy; total 

dose 50 – 54 Gy) so as not to increase the toxicity [243–246]. 



Surgery should be considered after pertinent staging (if necessary 

also by laparoscopy) if there is a clear response of the locally advanced 

pancreatic tumor to radiochemotherapy and if potential 

resectability is reached. 


Comment 

A secondary resectability can be reached in about 10% of patients 

who have undergone RCT [250]. 


If radiochemotherapy is performed outside of clinical trials, it 

should be done with infusional 5-FU. 



Comment 

The largest amount of data are available for continuous infusion 

of the radiosensitizer 5-FU [243, 244, 246, 251, 252]. It has an acceptable 

side effect profile. 


A combination of 5-FU/mitomycin C during radiochemotherapy 

should not be used outside of clinical trials because of increased 

hematologic toxicity [241, 253]. 


Gemcitabine or a combination of gemcitabine and cisplatin should 

also not be used outside of clinical trials because of increased toxicity 

[245, 246, 254–257]. 


Importance of targeted-therapy approaches 


Molecular therapy strategies such as marimastat (recommendation 

grade: A, evidence level 1), tanomastat (recommendation 

grade: A, evidence level 1), tipifarnib (recommendation grade: 

A, evidence level 1), and cetuximab (recommendation grade: C, 

evidence level 3) currently do not play a role in the palliative 

therapy of pancreatic cancer [210, 222, 258–260]. 

Consensus 

Intra-arterial chemotherapy 


Intra-arterial chemotherapy does not play a role in palliative 

treatment of pancreatic carcinomas [261, 262]. 


Immunotherapeutic/gene therapeutic approaches 


E Immunotherapeutic or gene therapeutic approaches 

Recommendation grade: C, evidence level 2b, consensus. 

E or hyperthermia € radiation therapy/radiochemo- or chemotherapy 

Recommendation grade: C, evidence level 4, consensus. 

currently do not play a role in palliative treatment of pancreatic 

carcinomas. 

Comment 

These therapeutic approaches are currently experimental and 

should not be used outside of clinical trials, because insufficient 

study data are available [263]. 

Radiofrequency thermoablation 


Radiofrequency thermoablation does not play a role in the palliative 

treatment of pancreatic carcinomas. 


Topic 6: 

Supportive therapy and follow-up 

! 

Pain therapy 


The standard rules for tumor pain therapy apply for the treatment 

of pain in patients with pancreatic carcinoma. The WHO’s pain ladder 

is suitable for pain therapy of pancreatic carcinoma. Other procedures 

against pain are currently not available [264 – 266]. 

Leitlinie 469 

It should be taken into account that the severity and the development 

of pain during pancreatic carcinoma can depend on the diet. 

The treatment procedure should be adapted accordingly (possible 

additional dose). Invasive neuroablative procedures (especially celiac 

blockade) also play a role in pancreatic carcinoma [267–269]. 



There are no specific criteria that influence the drug selection for 

pancreatic tumor pain therapy. This is true for non-opioids (NSAR, 

COXIBE, metamizol, paracetamol). 

Recommendation grade: D, evidence level: 4 

This recommendation also applies to the use and selection of 

opioids. There is no evidence of superiority of certain substances. 


Comments 

Two reviews of studies on tumor pain treatment concluded 

that a meta-analysis is not possible for methodologic reasons. 

This is due to the heterogeneity of the methods and the completely 

different tools that were used to evaluate the results. 

Based on these restricted data, NSAR was superior to placebo. 

Only in a few studies the combination of NSAR and opioids 

was slightly better than each drug alone. Nonetheless, the difference 

was significant [270, 271]. 


A certain application route (oral or transdermal) for opioids should 

not be preferred for pancreatic carcinoma. Possible gastrointestinal 

problems, especially constipation, which can be caused by motility 

disorders must be taken into account [272, 273]. 



Adjuvants should be used according to the WHO-pain ladder. There 

are no specific recommendations for the use of adjuvants such as 

anti-emetica for pancreatic carcinoma [268, 274]. 



Invasive treatment methods (preferably subcutaneous or intravenous 

application of opioids, if necessary application near the spine) 

can be indicated if pain cannot be sufficiently controlled using the 

WHO-pain ladder [275]. 



Celiac blockade can principally be indicated for pancreatic carcinoma 

in some patients [276]. 


Comments 

There is a meta-analysis on the topic of celiac blockade which 

takes 59 publications into account [277]. However, only 24 report 

on 2 or more patients. Thus, more than half are case studies. 

21 have retrospective character. 63% use a celiac blockade 

for pancreatic carcinoma. The methods used were definitely not 

in line with present standards in all cases. In 32% no radiologic 

control of the alcohol application was done. Only 2 studies that 

were taken into account dealt with pain quality. The pain characteristics 

were also not considered. In summary, in 70 – 90% it 



470 

Leitlinie 

was concluded that the method has a good long-term effect, 

side effects are transient and harmless, and severe complications 

are rare. Another publication [278] (evidence level 3) hypothesizes 

that the plexus blockade with concomitant administration 

of opioids improves pain therapy and survival. This is a 

double-blind, randomized study where patients receiving systemic 

therapy had a plexus blockade with alcohol or a “sham”plexus 

blockade. Furthermore, the quality of life (QoL) was taken 

into account. 100 patients with non-resectable pancreatic 

carcinoma and pain were included in the study. The plexus 

blockade significantly improved the pain reduction compared 

to systemic therapy alone. However, it did not affect the patients’ 

survival and had no effect on the opioid dose. 


The data available on the optimal time of celiac blockade are insufficient. 



A certain method representing an optimal technical procedure for 

celiac blockade should not be preferred. 


Comments 

Radiologic procedures (fluoroscopy or CT) were not implemented 

in 32% in a meta-analysis by Eisenberg et al. [277]. There are 

no studies that compare the advantage and disadvantage of different 

methods (CT, fluoroscopy, US, EUS). There are no studies 

that compare various painkillers for the blockade. Also, different 

amounts of alcohol and local anesthetics were used. 


The role of thoracoscopic splanchniectomy for pain therapy of pancreatic 

carcinoma cannot be definitely evaluated. This is a reserve 

procedure because of its invasiveness. 


Comments 

A retrospective analysis of 59 patients compares videothoracoscopic 

splanchniectomy and percutaneous celiac blockade in 

patients with inoperable pancreatic carcinoma with respect to 

pain reduction, quality of life, and opioid dose administered. 

Improvement of quality of life and a pronounced pain reduction 

was seen for both methods. Quality of life was slightly better for 

patients who received a plexus blockade. The amount of opioid 

that was necessary was reduced using both methods. Therefore, 

videothoracoscopic splanchniectomy is recommended as a reserve 

procedure, because the plexus blockade is less invasive 

and still as effective [279]. 


Radiation therapy with the sole aim of pain therapy is an exception 


Recommendation grade: D, consensus 

Comments 

The indication of radiation therapy for pain treatment is the exception, 

because of the immediate effect of e.g. a plexus blockade. 

Comparative studies are not available. 



Pancreas enzymes are not suited for pain therapy of pancreatic 

carcinoma. 



Psycho-oncologic support may be useful to ease pain of patients 

with pancreatic carcinoma. 


Diet and tumor cachexia 

Enteral diet 


There are no specific diet recommendations for patients with metastatic 

pancreatic carcinoma. In general, it should be kept in mind 

that patients with malignant tumors need a diet with sufficient 

calories because of progressive weight loss. 

A supportive or total enteral diet can help minimize weight loss 

if spontaneous food intake is insufficient [280]. 



There are no specific diet recommendations for patients with pancreatic 

carcinoma during radiation therapy. The guideline “enteral 

diet” of the DGEM 2003 states: “According to the data presently 

available a routine enteral diet is not indicated after radiation in 

the abdomen” [281]. 


Vitamins, minerals and micronutrients 


At physiologic concentrations, vitamins, minerals, and other micronutrients 

that are contained in food are important components 

of a balanced diet. There are no indications that taking 

vitamins, minerals, and other micronutrients in so-called pharmacologic 

doses is useful. Also, there is no proof of its harmlessness 

[281]. 


Comment 

A recently published meta-analysis on the supplementation of 

anti-oxidants in primary and secondary prevention demonstrated 

that supplementation of the diet with beta-carotene, vitamin 

A, and vitamin E may increase the death rate instead of reducing 

it [282]. 

Diet following pancreatectomy or during pancreatic duct 

obstruction 


The consequences of exocrine and endocrine pancreas insufficiency 

have to be kept in mind when recommending a diet for 

patients after pancreatectomy or for patients with long-term 

pancreas duct obstruction. When treating exocrine pancreas insufficiency 

an adequate amount of pancreas enzymes must be 

given at meals. If pancreoprive diabetes is present, the patient 

should be treated with insulin according to standard principles. 

There are no further diet specific recommendations. 



Drugs to stimulate appetite against tumor cachexia 


Although there are individual positive studies on several drugs, e. g. 

ibuprofen, megesterolacetate, steroids, thalidomide, and cannabinoids, 

the clinical role of appetite stimulating drug therapy for patients 

with metastatic pancreatic carcinoma with tumor cachexia 

cannot be definitely evaluated [283–286]. 

Recommendation grade: D, evidence level 1b–3, strong consensus 

Comment 

The studies on individual substances are of different quality. 

Some are poor while others such as a controlled, randomized 

trial which compares treatment of dronabinol, megesterolacetate, 

and the combination of both for patients with tumor cachexia 

are fairly sound. This study shows that megesterolacetate 

monotherapy is superior. However, a placebo arm is missing, 

only about 1/3 of the patients had gastrointestinal tumors, and 

the number of patients with pancreatic carcinoma is not reported 

[285]. 

Supportive therapy for further symptoms of advanced 



An important goal of supportive therapy is the maintenance or 

improvement of the quality of life. The patient should be specifically 

asked about uncomfortable symptoms (e.g. fatigue, itching, 

diarrhea, constipation). These symptoms should be treated. 


Procedures for tumor-induced cholestasis 

Tumor-induced cholestasis is a frequent symptom which makes 

palliative therapy necessary for pancreatic carcinoma patients. 

Stents 


Metal stents are the therapy of choice. If the survival time is expected 

to be < 3 months, plastic stents should be used. 


Comments 

A meta-analysis based on 21 studies compares surgical procedures 

to stent-methods and metal stents to plastic ones. The studies 

included 1454 patients. Stent-techniques have a lower complication 

rate compared to surgery. However, they also have a 

higher relapse rate with respect to obstruction. There was a tendency 

for the group that had surgery to have a higher 30-day 

mortality. There was no difference in the technical and therapeutic 

success. Metal stents have a lower re-occlusion rate than 

plastic ones. There was no difference in the technical success, the 

primary therapeutic success, the complications, or the 30-day 

mortality. Overall, metal stents are recommended as first choice 

therapy [287]. 


If metal mesh stents are used, they do not have to be polyurethane 

coated. 

Recommendation grade: B, evidence level 2b, majority consensus 

Comments 

Two studies deal with polyurethane-coated stents [288, 289]. 

The results of a one-arm study on polyurethane-coated stents 

including 30 patients correspond to those reported in the literature 

for non-coated metal stents [288]. Thus, there is no 

benefit of the coated stents. A second study with 112 patients 

compares the polyurethane-coated stents with self-expanding 

metal stents. It reports a significantly higher openness rate of 

distal bile duct stenoses for the former, because the coating 

prevents tumor infiltration. However, there was no difference 

in the survival between the groups. The group that received 

the coated stents demonstrated a higher rate of cholecystitis 

and pancreatitis [289]. 


Percutaneous transhepatic cholangiodrainage, PTCD, is sensible 

for palliative therapy of pancreatic carcinoma if endoscopic therapy 

(e. g. due to tumor-induced duodenal stenoses) is not possible. 

PTCD is also indicated if endoscopic therapy is not effective. 


Comment 

The literature on PTCD is “historic” [290]. There are no recent 

studies that compare the percutaneous application of metal 

stents with endoscopic access using the same stent design. 

Biliodigestive anastomosis 


Surgery with the only goal of placing a biliodigestive anastomosis 

is surely the exception. However, the placement is indicated if the 

tumor turns out to be non-resectable during curative intended surgery 

and if cholestasis is present and survival time is expected to be 

longer. It must be differentiated between patients with peritoneal 

spreading or liver metastases. 



Choledochojejunostomy should be preferred over other bypass procedures 

if a biliodigestive anastomosis is done in the palliative situation 

[291–293]. 


Relapsing cholangitis after biliodigestive anastomosis 


Before therapeutic intervention a drainage blockade must be excluded. 

If a mechanical hindrance is present necessary steps should 

be taken. Then long-term antibiotic treatment can be attempted. 


Comment 

There is no special literature on this topic. 

Leitlinie 471 

Tumor-induced stenoses of the upper gastrointestinal 

tract 


A drug therapy attempt for tumor-induced functional pyloric stenosis 

is justified. The drugs metoclopramide and erythromycin 

should be preferred. Endoscopic stent placement and surgical intervention 

are not recommended. 




472 

Leitlinie 

Comment 

There is no special literature on this topic. The recommendations 

are based on experience in standard clinical practice. 


Principally there are two palliative therapeutic procedures available 

for obstruction of the duodenum: an endoscopic stent placement 

or a surgical gastroenterostomy. The literature that is available 

does not demonstrate a superiority of one of the methods. 


Comment 

The data published are mainly monocentric case study collections 

of patients with duodenal obstruction of different origins 

[294, 295]. There are no randomized prospective studies that 

compare endoscopic stenting and surgical gastroenterostomy. 

Prophylactic gastroenterostomy 


According to the current data it seems sensible to perform a prophylactic 

gastroenterostomy if irresectability is diagnosed during 

surgery. 


Comment 

The publication on this topic, a monocentric, prospective, randomized 

study shows that a prophylactic gastrojejunostomy 

for non-resectable periampullary carcinoma significantly reduces 

the future development of pyloric stenosis [145]. 

Importance of hematopoetic growth factors for locally 

advanced pancreatic carcinoma 


Granulocyte-stimulating growth factors (G-CSF or GM-CSFs) are 

not important for the supportive therapy of locally advanced pancreatic 

carcinoma. 


Comment 

Chemotherapy that is so aggressive that the administration of 

granulocyte-stimulating growth factors is necessary is not recommended 

for palliative treatment of locally advanced or metastatic 

pancreatic carcinoma. Refer to the current guidelines of 

ASCO on the use of growth factors [296]. 


Erythrocyte-stimulating growth factors (erythropoietin) can under 

certain circumstances play a role. 


Comment 

Also, refer to the current guidelines of ASCO [297] or EORTC 

[298]. 


Role of cytoprotectives/radical scavengers during 

chemotherapy and/or radiation therapy of pancreatic 

carcinoma 


Amifostin or other cytoprotectives do not play a role in chemotherapy 

and/or radiation therapy of pancreatic carcinoma. 


Comment 

This recommendation follows the meta-analysis of the chemotherapy 

and radiation therapy expert panel of the ASCO [299]. 

Evaluation of pancreatic carcinoma patients’ quality of 

life 


QLQ-C30 and the related specific pancreas module QLQ-PAN 26 offer 

suitable tools for the assessment of quality of life. 


Comment 

The routine implementation of QLQ-C30 and QLQ-PAN 26 are 

only reasonable for clinical studies. 

Follow-up 

Follow-up program after curative resection 


A structured follow-up program cannot be recommended independent 

of the pancreatic carcinoma stage. 


Comments 

There is no scientific proof that structured follow-up with regular 

staging examinations leads to an improvement of the survival 

of patients with pancreatic cancer. 

Medical history and a physical examination are necessary if exocrine 

or endocrine insufficiency is suspected. The examination 

can be performed regularly by a general practitioner. 

Rehabilitation following curative pancreatic carcinoma resection 


For individual patients rehabilitation may be useful under certain 

conditions. This should be coordinated with the family. 


Comment 

There is no assessable literature on the role of rehabilitation 

after pancreatic carcinoma resection with curative intent. 

Acknowledgements 

! 

We would like to thank the staff of the Clinic for Internal Medicine 

I, University of Ulm, T. Locher, R. Lorenz, M. Porzner, I. Rueß, 

A. Stein, E. Thanner, and Christian Aslan for the support in preparing 

and implementing the consensus conference. 


Appendix 

! 

Table 10 Search terms for the literature search: search level 1: all task forces: pancreatic cancer | pancreatic neoplasm | pancreatic carcinoma | ductal adenocarcinoma 

of the pancreas; task force-specific search levels 2 – 5: task force 

search level 2 

topic 1 

risk factors 

search level 3 search level 4 search level 5 

risk factor nutrition * | dietary fibre | fiber | 

legume|fruit|vegetables 

vitaminc|fat|cholesterol| 

red meat | white meat | barbecued 

| 

grilled | nitrate | nitrite | fish 

sugar | saccharide | milk | milk 

produce | alcohol | coffee | tea 

lifestyle 

occupational risks 

| *exercise | sports | physical activity 

| weight | obesity | nicotine 

| weight | obesity | nicotine | 

prophylaxis | 

vitamins | 

prevention 

NSAID 

screening CA19–9 | genomic analysis | genetic 

analysis | DNA array tool | 

technique | method 

Cost-effectiveness 

risk group 

* | prevention | propyhlaxis tool | technique | method | genetic analysis 

sporadic 

screening | surveillance 

CA19–9 | 

pancreatic juice 

(k-ras/p16) 

risk group 

* | familial pancreatic | hereditary * | genetic consultant 

genetic analysis 

hereditary 

pancreatic cancer | prevention | tool | technique | method 

(k-ras/p16) 

prophylaxis | 

CA19–9 | 

genetic consultation 

surveillance 

pancreatic juice 

Peutz-Jeghers Syndrome | FAMMM 

Syndrome | pancreatic cancer 

melanoma syndrome | Hereditary 

breast/ovarian cancer (BRCA2) | 

HNPCC | Ataxia teleangiectasia | 

FAP 

Cystic fibrosis | Li-Fraumeni syndrome 

| Lindau’s disease | Neurofibromatosis 

| Fanconi’s anemia | 

Seattle family X | Familial fibrocystic 

pancreatic atrophy | 

Hereditary pancreatitis 

risk group chronic pancreatitis 

diabetes 

topic 2 

diagnostics 

diagnosis abdominal pain| back ache |back 

pain | hyperglycemia | diabetes | 

jaundice | 

acute pancreatitis 

ERCP | ultrasound | MRI | 

endoscopic ultrasound | 

computed tomography | MRCP 

therapy | pancreatectomy 

surveillance | CA 19–9 

age 

supposed malignancy | 

elevated CA19–9 | 

sensitivity 

cytology | aspirate 

laboratory test | serum marker 

bile duct | pancreatic duct 

pancreatic tumor | lesion biopsy | surgery solitary | curative | 

size | localisation | 

technique | 

palliative | 

metastatic 

cystic | pseudocyst | 

serous | mucinous 

resection | biopsy | aspirate 

Leitlinie 473 



474 

Leitlinie 


search level 2 search level 3 search level 4 search level 5 

biopsy pathological finding | 

content | criteria | 

histological report 

pathological report 

pancreatectomy 

preoperative 

ultrasound | computer 

diagnostic | 

tomography | ct | mri | 

staging | 

bone scan | chest x-ray | 

topic 3 

response to chemotherapy 

endoscopic ultrasound | 

ercp | mrcp | pet | 

micrometastases | 

laparoscopy | 

surgical treatment of pancreatic carcinoma (curative intention) 

surgery inoperable | nonresectable age | elderly | 

Celiac artery | 

comorbidity | 

truncus coeliacus | 

infiltration 

Superior mesenteric artery | 

Superior mesenteric vein | 

Liver/hepatic vein 

cholestasis 

resection margins 

preoperative stent | 

ERCP 

inoperative ultrasonography | 

peritoneal lavage 

cytologic examination 

perioperative antibiotics | 

somastatin | 

octreotide 

stent 

tumor of the head | pylorus preserving 

| tumor of the tail | tumor 

ofthebody|locallyadvanced 

growth | extended lymphadenectomy 

| cystic tumors of the 

pancreas | intracuctal papillary 

mucinous tumor | metastatic | 

metastases | laparoscopic | frozen 

section | rapid section | 

R0 resection 

pancreatic fistula 

topic 4 

adjuvant and neoadjuvant non-surgical therapy of pancreatic carcinoma 

adjuvant 

chemotherapy 

adjuvant chemoradiation | chemoradiotherapy 

| radiochemotherapy 

radiotherapy | 

radiation 

chemoradiation | 

chemoradiotherapy | radiochemotherapy 

histology | pathology |criteria 

inflammation | neoplastic 

curative resection | R0 resection differentiation | locally 

advanced |mircometastases 

Age | elderly | ECOG | 5-FU/folinic 

acid (Mayo) | 5-FU/folinic acid 

(AIO) | Gemcitabine | CapecetabineRegional|Start|timeaftersurgery 

| postoperative begin | R 1 

resection 

R0 resection | UICC | 

risk factors 

5-fluorouracil continuous infusion 

| 5-fluorouracil | Mitomycin | 

Gemcitabine | age | elderly | 

ECOG | R 1 resection 

curative intention 

curative intention 

chemotherapy curative intention 

neoadjuvant 


neoadjuvant 

radiation 

locally advanced | inoperable | T 4 

| protocol | duration | dosis | 

technique | chemotherapy 


differentiation | 

locally advanced | 

micrometastases 





downsizing | 

locally advanced | T4 | 

surgery 

chemoradiation | 

tumor mass reduction | 

inoperable 

radiochemotherapy | 

chemoradiotherapy 

stable disease 

neoadjuvant 

radiochemotherapy 

intraoperative radiation | 

intraoperative radiotherapy 

adjuvant therapy | 

neoadjuvant therapy 

locally advanced | 

inoperable 

surgery | radiochemotherapy 

UICC | risk factors differentiation | locally 

advanced | micrometastases 

targeted therapies 

topic 5 

palliative chemotherapy and radiationtherapy 

palliative chemotherapy * | metastases | metastatic | progressive 

| size | prognostic factors 

symptoms | locally advanced | inoperable 

| first line | 

gemcitabine 

5-fluorouracil/folinic acid (AIO) | 

gemcitabine/oxaliplatin | 

gemcitabine/cisplatin | 

oxaliplatin/5-fluorouracil/folinic 

acid | 

gemcitabine/capecitabine | gemcitabine/erlotinib 

| 

gemcitabine/bevacizumab| 

capecitabine/oxaliplatin 

polychemotherapy 

second line 

Karnofski | ECOG | albumin | 

CA19–9 | differentiation | 

hemoglobin 

fixed dose rate | infusion 

*|indication| 

5-FU/folinic acid (Mayo) | 

5-fluorouracil continuous 

infusion | 

oxaliplatin/5-fluorouracil/ 

folinic acid | 

capectiabine mono | 

capecitabine/oxaliplatin 

third line * | inidcation | 

oxaliplatin/5-fluorouracil/ 

folinic acid | 

5-fluorouracil/mitomycin | 

capecitabine/mitomycin 

sequence | order | 

duration | time | 

surveillance | efficacy 

palliative radiotherapy locally advanced | inoperable | 

metastatic | symptoms | protocoll 

|chemotherapy 

* | 5-fluorouracil continous 

infusion | 

5-fluorouracil/mitomycin | 

gemcitabine 

palliative therapies targeted therapy marimastat | tanomastat | 

tipifamib | bevacizumab | 

cetuximab 

topic 6 

supportive therapy 

intra-arterial chemotherapy 

immunotherapy | gene therapy | 

hyperthermia | radiofrequency 

thermoablation 

* | indication 

palliation pain therapy * | WHO | non-opioids | 

opioids 

nmda antagonists | 

celiac plexus block | 

pancreatic enzymes | 

thorascoscopic splanchnicectomy 

| radiotherapy | radiation 

application | antiemetics | constipation 

nutrition metastatic | cachexia nutrition | vitamins 

Leitlinie 475 



476 

Leitlinie 



radiotherapy | radiation | 

pancreatectomy 

supplements 

appetite corticosteroids | dronabinol | megestrol 

acetate | growth hormone 

| Eicosapentaenoic acid | probiotics 

| ibuprofen 

symptoms fatigue | pruritus | constipation | 

diarrhea | pleural effusion 

cholestatsis stent | stenting 

PTCD 

plastic | metal 

biliodigestive anastomosis cholangitis 

gastric outlet obstruciton drug therapy 

stent | stenting | surgery 

erythromycin | 

metoclopramide 

duodenal obstruction 

palliative surgery 

stent | stenting | surgery 

hematopoietic growth factors * | granulocytes | erythrocytes 

cytoprotective agents * | amifostine 

pancreatic enzymes pancreatectomy 

follow-up | 

after-care 

curative resection rehabilitation 

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