10. Quality indicators – Pancreatic Cancer

Version 3.0 · March 2024 · AWMF 032/010OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

Quality indicators are measured variables that are used to assess the quality of the underlying structures, processes or results. Quality indicators are an important quality management tool. The aim of their use is the continuous improvement of care by presenting the results of care, critically reflecting on them, and improving them if necessary. The present selection of quality indicators was created according to the methodology of the Oncology Guidelines Program [814]. For the derivation process, a “Quality Indicators Working Group” (WG QI) was constituted. This group created the final set of quality indicators based on the existing quality indicators of the Guidelines for Pancreatic Cancer 2013, the new strong recommendations (“shall“) of the updated Guidelines for Pancreatic Cancer, the results of the existing quality indicators from the certified pancreatic cancer centers of the German Cancer Society as well as the results of the search for existing national and international quality indicators. The exact procedure and composition of the WG QI are outlined in the Guidelines report see (https://www.leitlinienprogramm-onkologie.de/leitlinien/pankreaskarzinom/).

After two online meetings of this WG, two new quality indicators (QIs) were adopted, so that the final set consists of 7 QIs.

Based on the recommendations and quality indicators of the Guidelines and building on the preliminary work of the European Joint Action Innovative Partnership for Action Against Cancer (iPAAC), a patient pathway was developed via the Certification Commission of the DKG e.V., to be used in pancreatic cancer centers. The pathway can be adapted and technically implemented According to local conditions and the desired level of digital support. (https://www.krebsgesellschaft.de/zertdokumente.html → Visceral Oncology Centers).

R0 resection (since 2013)

Numerator

Patients of the denominator with R0 resection

Denominator

All patients with initial diagnosis of pancreatic cancer and resection.

Quality target / reference range

a) Quality objective

Highest possible rate of local R0 resections

b) Evidence baseLoE
1a-

Reference recommendations

6.7 · Evidence-based Recommendation 2024

The goal of resection for pancreatic cancer shall be no residual tumor (R0).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1a
Consensus: Strong consensus
References: [272] [273] [274] [275] [276] [277] [278] [279] [280] [281] [282] [283] [284]

Recommendation in chapter

LN- Removal (since 2013, modified in 2021)

Numerator

Patients of the denominator with removal of at least 12 lymph nodes.

Denominator

All patients with initial diagnosis of pancreatic cancer (excluding NEC/NET) and surgical resection.

Quality target / reference range

a) Quality objective
Minimum of 12 regional lymph nodes in the surgical preparation
Note:
Surgical resection: pancreatic head resection, left resection, pancreatectomy

Notes

Surgical resection: pancreatic head resection, left resection, pancreatectomy.

Reference recommendations

6.28 · Evidence-based Recommendation · modified 2024

When resecting a pancreatic carcinoma, a standardized lymphadenectomy shall be performed.

An extended lymphadenectomy shall not be performed.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1
Consensus: Strong consensus
References: [418] [419] [420] [421] [422] [423] [424] [425] [426] [427] [428] [429]

Recommendation in chapter

Content Pathology Reports (modified in 2021)

Numerator

Patients of the denominator with reports of findings indicating: - pT, pN, M - Tumor grading - Ratio of affected to removed lymph nodes

Denominator

All patients with pancreatic cancer and tumor resection

Quality target / reference range

a) Quality objective
Complete pathology reports as often as possible.

b) Evidence baseLoE
2b

Notes

Reference recommendations

6.30 · Evidence-based Recommendation · checked 2024

For resection of pancreatic cancer, the ratio of affected to total lymph nodes removed shall be reported in the pathological histology report.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2b
Consensus: Strong consensus
References: [341] [342] [344] [345] [348] [430] [431] [432] [433] [434] [435] [436] [437] [438] [439] [440] [441] [442] [443]

Recommendation in chapter

6.36 · Evidence-based Recommendation · checked 2024

The indication of pT, pN, and M category as well as tumor grading shall be indicated in the pathology report.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2b
Consensus: Consent
References: [341] [343] [430] [432] [433] [434] [435] [436] [437] [439] [441] [443] [495] [496] [497] [498]

Recommendation in chapter

Adjuvant chemotherapy (modified in 2021)

Numerator

Patients of the denominator with adjuvant chemotherapy

Denominator

All patients with initial diagnosis of pancreatic cancer UICC stage I-III (without NET/NEC) and R0 resection

Quality target / reference range

a) Quality objective
Adjuvant chemotherapy as often as possible
Evidence base LoE 1b

Reference recommendations

7.1 · Evidence-based Recommendation · checked 2021

Adjuvant chemotherapy shall be given after R0 resection of UICC stage I pancreatic cancer–III.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1b
Consensus: Strong consensus
References: [521] [522] [523] [524] [525] [526] [527] [528] [529]

Evidence tables (3)

Oettle, H. et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA - Journal of the American Medical Association. 310. 1473-1481. 2013; Conroy, Thierry et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. The New England journal of medicine. 379. 2395-2406. 2018; Neoptolemos, J. P. et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. The Lancet. 389. 1011-1024. 2017

Recommendation in chapter

Palliative chemotherapy (modified in 2021)

Numerator

Patients of the denominator with palliative chemotherapy

Denominator

All patients - with initial diagnosis of pancreatic cancer (without NET/NEC), ECOG 0-2, M0 and M1, without tumor resection and - with pancreatic cancer (without NET/NEC), ECOG 0-2, with secondary metastasis (M1) without metastasectomy

Quality target / reference range

a) Quality objective
Palliative chemotherapy for metastatic or locally advanced pancreatic cancer ECOG 0-2 as often as possible
b) Evidence baseEK

Reference recommendations

8.1 · Evidence-based Recommendation · modified 2021

In metastatic or locally advanced pancreatic cancer, palliative chemotherapy shall be offered to patients with an ECOG Performance Status of 0 to 2 to improve quality of life, clinical benefit and survival.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 5
Consensus: Strong consensus
References: [622]

Recommendation in chapter

No primary resection for metastatic pancreatic cancer (new in 2021)

Numerator

Patients of the denominator with primary resection of the tumor

Denominator

All patients with initial diagnosis of pancreatic ductal carcinoma (without NET/NEC) with distant metastases (= organ metastases, peritoneal carcinomatosis, lymph node metastases considered as distant metastases (M1)).

Quality target / reference range

a) Quality objective

No primary tumor resection for pancreatic ductal carcinoma with proven distant metastases.

b) Evidence base

LoE 1 and 4

Reference recommendations

6.16 · Evidence-based Recommendation · modified 2021

Primary resection of the tumor shall not be performed for proven distant metastases of pancreatic ductal carcinoma (organ metastases, peritoneal carcinomatosis, lymph node metastases considered distant metastases).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1
4
Consensus: Strong consensus
References: [326] [327] [328] [329] [330] [331] [332] [333] [334] [335] [336] [337] [338] [339] [340] [341] [342] [343] [344] [345] [346] [347]

Evidence tables (12)

Agalianos, C. et al. Positive para-aortic lymph nodes following pancreatectomy for pancreatic cancer. Systematic review and meta-analysis of impact on short term survival and association with clinicopathologic features. HPB. 18. 633-641. 2016; Cao, F. et al. Prognostic significance of positive peritoneal cytology in resectable pancreatic cancer: A systemic review and metaanalysis. Oncotarget. 8. 15004-15013. 2017; Crippa, S. et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy?. European Journal of Surgical Oncology. 42. 1533-1539. 2016; Gebauer, F. et al. [Oligometastasis in pancreatic cancer : Current state of knowledge and spectrum of local therapy]. Oligometastasierung beim Pankreaskarzinom : Aktueller Kenntnisstand und Spektrum der Lokaltherapie. 89. 510-515. 2018; Hempel, S. et al. Para-aortic lymph node metastases in pancreatic cancer should not be considered a watershed for curative resection. Scientific reports. 7. 7688. 2017; Klaiber, U. et al. Prognostic Factors of Survival After Neoadjuvant Treatment and Resection for Initially Unresectable Pancreatic Cancer. Annals of surgery. . . 2019; Liu, X. et al. Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. BMC Gastroenterology. 18. 168. 2018; Lowder, C. Y. et al. Clinical Implications of Extensive Lymph Node Metastases for Resected Pancreatic Cancer. Annals of Surgical Oncology. 25. 4004-4011. 2018; Philips, Prejesh et al. The role of hepatic artery lymph node in pancreatic adenocarcinoma: prognostic factor or a selection criterion for surgery. HPB : the official journal of the International Hepato Pancreato Biliary Association. 16. 1051-1055. 2014; Shi, H. J. et al. Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability. World Journal of Gastroenterology. 22. 10024-10037. 2016; Tachezy, Michael et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery (United States). 160. 136-144. 2016; Kim, Y. et al. Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma. HPB. 18. 325-331. 2016

Recommendation in chapter

Second-line therapy (new in 2021)

Numerator

Patients of the denominator with second-line therapy

Denominator

All patients with pancreatic cancer (without NET/NEC), ECOG 0-2 and progression on palliative first-line therapy

Quality target / reference range

a) Quality objective
Second-line therapy as often as possible in case of progression under first-line therapy and ECOG ≤ 2

b) Evidence base
EC

Reference recommendations

8.25 · Evidence-based Recommendation · modified 2021

Second-line therapy shall be offered for progression on first-line therapy with an ECOG ≤ 2.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 5
Consensus: Strong consensus
References: [207]

Recommendation in chapter

Evidence tables

Oettle, H. et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA - Journal of the American Medical Association. 310. 1473-1481. 2013
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 2 Study type: RCT, multizentrisch (88 Kliniken und Onkologische Praxen), Deutschland, Österreich Number of Patient: n=354 Gesamtpopulation n=179 adjuvante Chemotherapie (A) n=175 keine adjuvante Therapie (B) Recruitung Phase: 07/1998-12/2004 Inclusion Criteria: 1. Stadium T1-4N0-1M0 2. histologisch bestätigt 3. makroskopisch vollständig reseziertes Pankreaskarzinom 4. Alter ≥18 Jahre 5. Karnofsky Performance Status ≥50% 6. adäquate Knochenmarkfunktion 7. Erwartete Einhaltung der Therapie 8. Einhaltung der Follow-Up Termine bis mind. 2 Jahre nach der OP Exclusion Criteria: 1. neoadjuvante Therapie 2. aktive Infektion 3. eingeschränkte Koagulation 4. Dysfuntion der Organe 5. weitere maligne Erkrankungen (außer Carcinoma in situ oder behandeltes Basalzellkarzinom) 6. Tumormarker (post-operativ) CEA/CA19-9 <2,5 x oberes normales Limit 7. Schwangere bzw. Stillende	Intervention: Adjuvante Chemotherapie (A) 6 Zyklen Gemcitabin, 1 Zyklus besteht aus 4 Wochen, 3 Wochen 1000mg/m2 Gemcitabin (Infusion), 1 Woche Pause, Über einen Zeitraum von 6 Monaten Comparison: Keine adjuvante Therapie, Beobachtung (B)	Primary: Krankheitsfreies Überleben Secondary: Gesamtüberleben Results: Follow-Up: Median 136 Monate (IQR 104-144 Monate) Krankheitsfreies Überleben A vs. B Statistisch signifikant länger bei A A: 13,4 Monate (95% CI 11,6-15,3) B: 6,7 Monate (95% CI 6,0-7,5) HR: 0,55 (95% CI 0,44-0,69) p < 0,001 Gesamtüberleben A vs. B statistisch signifikant länger bei A A: 22,8 Monate (95% CI 18,5-27,2) B: 20,2 Monate (95% CI 17,7-22,8) HR 0,76 (95% CI 0,61-0,95) p=0,1 Author's Conclusion: The CONKO-001 data show that among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation resulted in increased overall survival as well as disease-free survival. These findings support the use of gemcitabine in this setting.
Methodical Notes
Funding Sources: This trial was supported in part by a grant from Lilly Germany. The study was further supported by the German Cancer Society (section AIO) and promoted by a research grant from the Charité–Universitätsmedizin Berlin. COI: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Oettle reported receiving honoraria for contributions to advisory boards or oral presentations from Roche Pharma, Cellgene, and Fresenius. Dr Riess reported receiving honoraria for contribution to advisory boards or oral presentations from Bayer Vital, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche Pharma, and sanofi-aventis. Dr Arning reported that he is a former employee of Eli Lilly & Co (until 2006) and owns Lilly stock. No other authors reported disclosures. Randomization: Patients were randomized between adjuvant chemotherapy and observation in a 1:1 ratio using computer-generated random numbers generated at the study coordination center at the Charite–Universitätsmedizin Berlin, Berlin, Germany. At randomization, the patients were stratified according to tumor stage (T1-2 vs T3-4), nodal status (N0 vs N1), and resection status (R0 vs R1), based on the TNM classification. Blinding: keine Verblindung (open-label) Dropout Rate/ITT-Analysis: As defined in the protocol, all survival-type analyses presented were based on the intention-to-treat population, which included all eligible patients enrolled in the study. Patients lost to follow-up were censored on the date of last follow-up. Notes: Gesamtqualität: ausreichend Studiendesign: RCT PICO Frage: ja Randomisiert: ja Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Conroy, Thierry et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. The New England journal of medicine. 379. 2395-2406. 2018

Conroy, Thierry et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. The New England journal of medicine. 379. 2395-2406. 2018
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 2 Study type: RCT, Phase III, multizentrisch (58 Zentren), Frankreich + Canada Number of Patient: n=493 Gesamtpopulation (randomisiert) ITT-Population: n=247 mFOLFIRINOX n=246 Gemcitabin Safety Population n=238 mFOLFIRINOX n=243 Gemcitabin Recruitung Phase: 4/2012 – 10/2016 Inclusion Criteria: 1. Alter 18-79 Jahre 2. Histologisch bestätigtes PDAC 3. Vollständige R0/R1 Resektion 4. Keine Metastasen 5. Kein maligner Aszites 6. Kein Pleuraerguss 7. Vollständige Erholung nach der OP 8. WHO Performance Status 0-1 9. Adäquate hämatologische Funktion (Absolute Neutrophilenzahl ≥1500 pro Kubikmillimeter; Thrombozyten ≥100,000 pro Kubikmillimeter; Hämoglobin ≥10 g pro Deziliter) 10. Adäquate Leberfunktion (Serum Bilirubin, ≤1.5 x oberes normales Limit) 11. Adäquate Nierenfunktion (Kreatin-Clearance, ≥50 ml/Min) Exclusion Criteria: 1. Nicht-duktale Karzinome 2. R2-Resektion 3. CA 19-9 >180 U/ml CA 19-9 innerhalb von 21 Tagen vor der Randomisierung 4. Bereits Bestrahlung oder Chemotherapie bekommen 5. Symptomatische Herzinsuffizienz 6. Symptomatische koronare Herzerkrankung	Intervention: Modified FOLFIRINOX (mFOLFIRINOX) Oxaliplatin 85 mg/m2 2 Stunden intravenöse Infusion direkt gefolgt von: Leucovorin 400 mg/m2 2 Stunden intravenöse Infusion nach 30 min gefolgt von Irinocetan 180 mg/m2 90 min intravenöse Infusion direkt gefolgt von Fluorouracil (ohne Bolus) 2400 mg/m2 46 Stunden kontinuierliche intravenöse Infusion Alle 14 Tage über 24 Wochen – 12 Zyklen Nach 162 Patienten wurde die Dosis Irinocetan auf 150mg reduziert aufgrund von Nebenwirkungen Bei febriler Neutropenie oder Verzögerung der Behandlung durch Neutropenie, G-CSF empfohlen für die folgenden Zyklen Comparison: Gemcitabin Monotherapie (Gemcitabin) 1000 mg/m2 Körperoberfläche 30 min. intravenöse Infusion Tag 1,8 und 15 alle 28 Tage über 24 Wochen 6 Zyklen	Primary: Krankheitsfreies Überleben Secondary: Gesamtüberleben Metastasenfreies Überleben Krebsspezifisches Überleben Toxizitäten Results: Follow-Up: Median 33,6 Monate (95% CI 30,3-36,0) Krankheitsfreies Überleben mFOLFIRINOX vs. Gemcitabin Statistisch signifikant länger bei mFOLFIRINOX mFOLFIRINOX: 21,6 Monate (95% CI 17,7-27,6) Gemcitabin: 12,8 Monate (95% CI 11,7-15,2) HR 0,58 (95% CI 0,46-0,73) p<0,001 1-Jahres-krankheitsfreies Überleben mFOLFIRINOX: 69% Gemcitabin: 53,7% 2-Jahres-krankheitsfreies Überleben mFOLFIRINOX: 47,0% Gemcitabin: 30,7% 3-Jahres-krankheitsfreies Überleben mFOLFIRINOX: 39,7% Gemcitabin: 21,4% Gesamtüberleben mFOLFIRINOX vs. Gemcitabin Statistisch signifikant länger bei mFOLFIRINOX mFOLFIRINOX: 54,4 Monate (95% CI 41,8- not reached) Gemcitabin: 35,0 Monate (95% CI 28,7-43,9) HR 0,64 (95% CI 0,48-0,86) p=0,0003 Metastasenfreies Überleben mFOLFIRINOX vs. Gemcitabin statistisch signifikant länger bei mFOLFIRINOX mFOLFIRINOX: 30,4 Monate (95% CI 21,7 – not reached) Gemcitabin: 17,7 Monate (95% CI 14,2-21,5) HR 0,59 (95% CI 0,46-0,75) p<0,001 Krebsspezifisches Überleben mFOLFIRINOX vs. Gemcitabin statistisch signifikant länger bei mFOLFIRINOX mFOLFIRINOX: Median nicht erreicht (95% CI 47,3 bis not reached) Gemcitabin: 36.4 Monate (95% CI 30,9-46,2) HR 0,63 (95% CI 0,47-0,85) p=0,003 Toxizitäten Grad 3/4 mFOLFIRINOX vs. Gemcitabin Keine Angaben zur statistischen Signifikanz mFOLFIRINOX: 180 (75,9%) Gemcitabin: 128 (52,9%) Grad 4 mFOLFIRINOX vs. Gemcitabin Keine Angaben zur statistischen Signifikanz mFOLFIRINOX: 29 (12,2%) Gemcitabin: 29 (12,0%) 1 Patient im Gemcitabin-Arm starb an den Folgen der Therapie (interstitielle Pneumonitis). Alle toxischen Effekte waren reversibel. Außer die Oxaliplatin-induzierten neurotoxischen Nebenwirkungen. Sie waren nach 3 Jahren bei 2 Patienten des mFOLFIRINOX-Arms immer noch persistent. Author's Conclusion: In conclusion, among patients who underwent complete resection of pancreatic cancer, adjuvant chemotherapy with a modified FOLFIRINOX regimen led to significantly longer disease-free survival and overall survival than adjuvant chemotherapy with gemcitabine. The incidence of toxic effects was higher with the modified FOLFIRINOX regimen than with gemcitabine therapy.
Methodical Notes
Funding Sources: PRODIGE (Partenariat de Recherche en Oncologie Digestive) 24 was supported by R&D Unicancer (which received a grant from Chugai Pharmaceutical), by a Clinical Research Hospital Program grant (PHRC11-006) from the French Ministry of Health and the Institut National du Cancer, and by the French National League against Cancer. The Canadian Cancer Trials Group pancreatic Adenocarcinoma (CCTG PA.6) part of the trial was supported by a Program Grant (704970) from the Canadian Cancer Society and by grants from 7 Days in May COI: Dr. Conroy reports receiving travel support from Roche; Dr. Hammel, receiving grant support, consulting fees, and travel support from Celgene; Dr. Ben Abdelghani, receiving fees for providing expert testimony and travel support from Amgen, Bayer, Merck, Sanofi, and Ipsen; Dr. Wei, receiving consulting fees from Celgene, Shire, Ethicon, and Ipsen and travel support from Bayer; Dr. Raoul, receiving fees for serving on an advisory board from Bayer, Bristol-Myers Squibb, BTG, Ipsen, AstraZeneca, and Terumo Medical; Dr. Francois, receiving consulting fees and travel support from Roche, Merck, and Servier and personal fees from Amgen, Sanofi, Lilly, Novartis, and Bayer; Dr. Ychou, receiving grant support, paid to his institution, and fees for serving as a board member from Bayer, Servier, and Amgen, and grant support, paid to his institution, from Roche; Dr. Di Fiore, receiving fees for a meeting presentation from Celgene; Dr. Bouhier-Leporrier, receiving consulting fees and travel support from Ipsen and Novartis, fees for serving on a speakers’ bureau from Amgen and MSD, and travel support from Bayer; Dr. Khemissa-Akouz, receiving personal fees from Sanofi and Ipsen and personal fees and travel support from Roche; Dr. Legoux, receiving consulting fees and travel support from Novartis, travel fees from Ipsen and Merck Serono, lecture fees and travel support from Servier, and grant support from Sanofi; Dr. Malka, receiving lecture fees and travel support from Amgen and Sanofi, lecture fees, consulting fees, and travel support from Bayer, Merck Serono, and Roche, consulting fees from Merck and Shire, and lecture fees and consulting fees from Servier and HalioDx; and Dr. Bachet, receiving consulting fees and lecture fees from Amgen, Bayer, Merck Serono, and Servier and lecture fees from Celgene, Roche, and Sanofi. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Randomization: Randomization at a 1:1 ratio was performed centrally with the use of an independent Web-based system, with stratification according to trial center, lymph-node status (pN0 [no lymph-node involvement] or pN1 [lymph-node involvement]), resection status (R0 vs. R1), and CA 19-9 level (≤90 U per milliliter vs. 91 to 180 U per milliliter). Randomization of patients with pN0 status was also stratified according to the number of lymph nodes examined (<12 vs. ≥12). Blinding: keine Verblindung (open-label) Dropout Rate/ITT-Analysis: All the analyses were performed on an intention-to-treat basis, except for the safety analyses, which included only the treated patients. Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: RCT PICO Frage: ja Randomisiert: ja Gruppen vergleichbar: ja Gruppen gleichbehandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Neoptolemos, J. P. et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. The Lancet. 389. 1011-1024. 2017

Neoptolemos, J. P. et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. The Lancet. 389. 1011-1024. 2017
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 2 Study type: RCT, Phase III, multizentrisch (92 Kliniken), international (England, Schottland, Wales, Deutschland, Frankreich, Schweden) Number of Patient: n=732 Gesamtpopulation (randomisiert) ITT-Population n=366 Gem n=364 GemCap Safety-Population n=366 Gem n=359 GemCap Recruitung Phase: 11/2008 – 09/2014 Inclusion Criteria: 1. Alter ≥18 Jahre 2. Histologisch bestätigtes PDAC 3. Vollständige R0 oder R1 Resektion 4. kein maligner Aszites 5. Keine Lebermetastasen 6. Keine peritonealen oder Lebermetastasen 7. Keine entfernte intra- oder extra abdominale Ausbreitung 8. Vollständige Erholung von der OP 9. WHO Performance-Status ≤2 10. Kreatinin Clearance ≥50 ml/min 11. Lebenserwartung >3 Monate Exclusion Criteria: 1. Neoadjuvante Chemotherapie oder andere vorrangegangene Chemotherapie 2. R2 Resektion 3. pankreatisches Lymphom 4. TNM Stadium IV	Intervention: Gemcitabin + Capectiabin (GemCap) Gemcitabin 1000 mg/m2 intravenöse Infusion 1x pro Woche über 3 Wochen 1 Woche Pause Zyklus: 4 Wochen 6 Zyklen Capecitabin 1660 mg/m2 oral pro Tag 21 Tage 7 Tage Pause 6 Zyklen Comparison: Gemicitabin Monotherapie (Gem) 1000 mg/m2 Infusion 1x pro Woche über 3 Wochen 1 Woche Pause Zyklus: 4 Wochen 6 Zyklen	Primary: Gesamtüberleben Secondary: 1-Jahres-Überleben 2-Jahres-Überleben 5-Jahres-Überleben Rezidivfreies Überleben Toxizitäten Lebensqualität Results: Follow-Up: Median 43,2 Monate (95% CI 39,7-45,5) Gesamtüberleben GemCap vs. Gem statistisch signifikant länger bei GemCap GemCap: 28,0 Monate (95% CI 23,5-31,5) Gem: 25,5 Monate (95% CI 22,7-27,9) HR 0,82 (95% CI 0,68-0,98) p=0,032 1-Jahres-Überleben GemCap vs. Gem GemCap: 84,1% (95% CI 79,9-87,5) Gem: 80,5% (95% CI 76,0-84,3) 2-Jahres-Überleben GemCap vs. Gem GemCap: 53,8% (95% CI 48,8-58,8) Gem: 52,1% (95% CI 46,7-57,2) 5-Jahres-Überleben GemCap vs. Gem GemCap: 28,8% (95% CI 22,9-35,2) Gem: 16,3% (95% CI 10,2-23,7) Rezidivfreies Überleben GemCap vs. Gem kein statistisch signifikanter Unterschied GemCap: 13,9 Monate (95% CI 12,1-16,6) Gem: 13,1 Monate (95% CI 11,6-15,3) HR 0,86 (95% CI 0,73-1,02) p=0,082 Toxizitäten Schwere Toxizitäten GemCap vs. Gem Kein statistisch signifikanter Unterschied GemCap: 24% Gem: 26% p>0,05 Lebensqualität GemCap vs. Gem kein statistisch signifikanter Unterschied HR -0,10 (95% CI -0,29-0,09) p=0,3 Author's Conclusion: Added value of this study In ESPAC-4, estimated 5 year survival confirmed the ESPAC-3(v2) estimates for gemcitabine. Survival favoured adjuvant gemcitabine plus capecitabine in most clinical subgroups, including patients with R1 resection margins. This was a pragmatic trial including all patients who had undergone resection for pancreatic ductal adenocarcinoma including WHO performance status 0, 1 and 2, R1 resection margins, and all patients irrespective of postoperative CA19-9 concentration. The improved survival results were achieved without any significant increase in overall toxicity and was manageable with protocol driven capecitabine dose reduction when required. Implications of all the available evidence The ESPAC-4 trial establishes the combination of gemcitabine and capecitabine as the treatment of choice in the adjuvant setting after resection for pancreatic ductal adenocarcinoma.
Methodical Notes
Funding Sources: This study was funded by Cancer Research UK (grant number C245/A8968/A15957) and sponsored by the Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. DC is funded by the National Institute for Health Research Biomedical Research Centre at the Royal Marsden. TM is funded by the National Institute for Health Research Biomedical Research Centre at University College London Hospital. COI: JPN reports grants from Cancer Research UK, Taiho Pharma (Japan), KAEL GemVax (Korea), AstraZeneca, Clovis Oncology and Ventana, and Pharma Nord; payment for lectures from Amgen, and Mylan; paid consultancy from Boehringer Ingelheim Pharma GmbH & Co KG, Novartis Pharma AG, KAEL GemVax, and Astellas; and educational travel grants from NUCANA, all outside the submitted work. JPN is a National Institute for Health Research (NIHR) senior investigator and is part funded by the NIHR Biomedical Research Centre at the Royal Liverpool University, Liverpool. DC reports grants from Amgen, AstraZeneca, Bayer, Celgene, Merrimack, Medimmune, Merck Serono, and Sanofi, outside the submitted work. JW reports grants and personal fees from AstraZeneca; personal fees and non-financial support from Celgene and Novartis; personal fees from Baxalta, Ipsen, Eisai, Lilly, and Bayer; and non-financial support from Sobi, outside the submitted work. JWV reports personal fees from Abbott, AstraZeneca, Baxalta, Ipsen, Lilly, Merck, Pfizer; personal fees and non-financial support from Celgene; and grant and personal fees from Novartis, outside the submitted work. PJR reports grants and personal fees from Sanofi Aventis; personal fees and non-financial support from Roche, Merck Serono, Celgene, Bayer, and Sirtex; non-financial support from Amgen; and personal fees from Baxalta, outside the submitted work. PH reports a patent issued by Roche. All other authors declare no competing interests. Randomization: Eligible patients were randomly assigned (1:1) to receive gemcitabine or gemcitabine plus capecitabine within 12 weeks of surgery by trained authorised staff within the Liverpool Clinical and Cancer Trials Unit. Randomisation was based on a minimisation routine with a random element of 20% including the resection margin (negative or positive) and country was used as a stratification factor. Blinding: keine Verblindung (open-label) Dropout Rate/ITT-Analysis: All efficacy analyses were done in the intention-to-treat population retaining all patients in their initially randomised groups irrespective of any protocol deviations with the exception of patients who withdrew consent between randomisation and the start of therapy. Toxicity was analysed in all patients who received trial treatment according to the treatment they received. Notes: Gesamtqualität: ausreichend Studiendesign: RCT PICO Frage: ja Randomisiert: ja Gruppen vergleichbar: unklar Gruppen gleichbehandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Agalianos, C. et al. Positive para-aortic lymph nodes following pancreatectomy for pancreatic cancer. Systematic review and meta-analysis of impact on short term survival and association with clinicopathologic features. HPB. 18. 633-641. 2016
Evidence level/Study Types	P - I - C	Outcomes/Results	Literature References
Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: Medline, Embase, Ovid, Cochrane Search period: bis 07/2015 (keine Angabe zum Suchzeitraum) Inclusion Criteria: 1. Bericht über den Zustand der paraaortalen Lymphknoten 2. Anzahl eingeschlossener Patienten (mind. 10 Patienten), 3. mindestens ein Outcome berichtet Exclusion Criteria: 1. Unklarer Status paraaortaler Lymphknoten 2. gemischte Ergebnisse bei periampullären Tumoren, 3. erhebliche Überschneidungen zwischen Autoren/Zentren oder Patientenkohorten 4. erforderliche Daten aus den veröffentlichten Ergebnissen nicht berechenbar	Population: Patienten mit Pankreasgang-Adenokarzinom nach Pankreatektomie Intervention: positive para-aortale Lymphknoten (PALN+) Comparison: negative para-aortale Lymphknoten (PALN-)	Primary: 1-Jahres-Überleben 2-Jahres-Überleben Zusammenhang PALN+ und T-Status Zusammenhang PALN+ und R1-Resektion Zusammenhang pos. Lymphknoten Stationen 13, 14, 17 und 12 mit PALN+ Secondary: Results: n=12 Studien (10 retrospektive, 2 prospektive Studien) n=2467 Patienten, 1-Jahres-Überleben PALN- vs. PALN+ (6 Studien) Statistisch signifikant höher bei PALN- OR 0,36, (95%CI: 0,25-0,53) p<0,00001 2-Jahres-Überleben PALN- vs. PALN+ (7 Studien) Statistisch signifikant höher bei PALN- OR 0,36, (95%CI: 0,25-0,51) p<0,00001 SUBGRUPPENANALYSE N1 Patienten mit PALN-: 1-Jahres-Überleben N1-PALN- vs. PALN+ (4 Studien) Statistisch signifikant höher bei N1-PALN- OR 0,34 (95%CI: 0,17-0,68) p=0,002 2-Jahres-Überleben N1-PALN- vs. PALN+ (4 Studien) Statistisch signifikant höher bei N1-PALN- OR 0,60 (95%CI: 0,38-0,95) p=0,03 Zusammenhang zwischen PALN+/- und T-Stadium (6 Studien): kein statistisch signifikanter Unterschied p=0,78 Zusammenhang zwischen R1-Status und PALN+ (4 Studien): Statistisch signifikant mehr R1 bei PALN+ OR 3.99 (95%CI: 2.79-5.69) p<0,00001 Zusammenhang zwischen pos. Lymphknotenstatus der Stationen 13, 14, 17 und 12 und PALN+: statistisch signifikant mehr PALN+ bei positiven Lymphknoten der Stationen 14, 17 und 12 kein statistisch signifikanter Zusammenhang bei Station 13 Station 14: OR 5,98 (95%CI: 3,77-9,48) p<0,00001 (4 Studien) Station 17: OR 5,64 (95%CI: 3,37-9,44) p<0,00001 (3 Studien) Station 12 OR 4,94 (95%CI: 3,06-7,98) p<0,00001 (4 Studien) Author's Conclusion: Infiltration of para-aortic lymph nodes is associated with decreased survival in pancreatic cancer patients. Station 16 involvement is associated with positive resection margins but is independent of the tumour size, whereas lymph node stations 12,14 and 17 can be regarded as junctional to station 16. Although, PALN+ patients have a worse prognosis, recognition of the factors affecting their survival and identification of the characteristics of the long term survivors should be the tool which will guide the selection of the optimal treatment modality for these pancreatic cancer patients	Doi R, Kami K, Ito D, Fujimoto K, Kawaguchi Y, Wada Met al. (2007)Prognostic implication of para-aortic lymph node metastasis inresectable pancreatic cancer.World J Surg31:147–154 Kayahara M, Nagakawa T, Ohta T, Kitagawa H, Ueno K, Tajima Het al.(1999) Analysis of paraaortic lymph node involvement in pancreaticcarcinoma: a significant indication for surgery?Cancer85:583–590 Choi SH, Kim SH, Choi JJ, Kang CM, Hwang HK, Lee WJ. (2013)Clinical necessity of the immunohistochemical reassessment of para-aortic lymph nodes in resected pancreatic ductal adenocarcinoma.Oncol Lett6:1189–1194. Kanda M, Fujii T, Nagai S, Kodera Y, Kanzaki A, Sahin TTet al. (2011)Pattern of lymph node metastasis spread in pancreatic cancer.Pancreas40:951–955 Paiella S, Malleo G, Maggino L, Bassi C, Salvia R, Butturini G. (2015)Pancreatectomy with para-aortic lymph node dissection for pancreatichead adenocarcinoma: pattern of nodal metastasis spread and analysisof prognostic factors.J Gastrointest Surg–Off J Soc Surg AlimentTract19:1610–1620. Sakai M, Nakao A, Kaneko T, Takeda S, Inoue S, Kodera Yet al. (2005)Para-aortic lymph node metastasis in carcinoma of the head of thepancreas.Surgery137:606–611. Shimada K, Sakamoto Y, Sano T, Kosuge T. (2006) The role of para-aortic lymph node involvement on early recurrence and survival aftermacroscopic curative resection with extended lymphadenectomy forpancreatic carcinoma.J Am Coll Surg203:345–352. Sho M, Murakami Y, Motoi F, Satoi S, Matsumoto I, Kawai Met al.(2015) Postoperative prognosis of pancreatic cancer with para-aorticlymph node metastasis: a multicenter study on 822 patients.J Gastroenterol50:694–702. Yamada S, Nakao A, Fujii T, Sugimoto H, Kanazumi N, Nomoto Set al.(2009) Pancreatic cancer with paraaortic lymph node metastasis: acontraindication for radical surgery?Pancreas38:e13–e17. Yoshida T, Matsumoto T, Sasaki A, Shibata K, Aramaki M, Kitano S.(2004) Outcome of paraaortic node-positive pancreatic head and bileduct adenocarcinoma.Am J Surg187:736–740. Kurosaki I, Kawachi Y, Nihei K, Tsuchiya Y, Aono T, Yokoyama Net al.(2009) Liver perfusion chemotherapy with 5-Fluorouracil followed by sys-temic gemcitabine administration for resected pancreatic cancer: pre-liminary results of a prospective phase 2 study.Pancreas38:161–167. Schwarz L, Lupinacci RM, Svrcek M, Lesurtel M, Bubenheim M,Vuarnesson Het al. (2014) Para-aortic lymph node sampling inpancreatic head adenocarcinoma.Br J Surg101:530–538
Methodical Notes
Funding Sources: None. COI: Authors declare there are no conflicts of interest. Study Quality: nicht angegeben Heterogeneity: Überleben Pat. PALN- im Vergleich zu Pat. mit PALN+ (6 Studien) 1-Jahres Überleben (Chi²=2,51, df=5 (p=0,77);I²=0%) 2-Jahres Überleben (Chi²=3,16, df=6 (p=0,79);I²=0%) Überleben N1 Pat. mit PALN- im Vergleich zu N1 Pat. mit PALN+ (4 Studien) 1-Jahres Überleben (Chi²=3,86, df=3 (p=0,28);I²=22%) 2-Jahres Überleben (Chi²=0,60, df=3 (p=0,90);I²=0%) Zusammenhang zwischen R1-Status und PALN+: Chi²=5,64, df=3 (p=0,13);I²=47% (4 Studien) Zusammenhang zwischen pos. Lymphknotenstatus Stationen 13, 14, 17 und 12 und PALN+ Station 3 (Chi²=10,25, df=2 (p=0,0006); I²=80%) (3 Studien) (hohe Heterogenität) Station 14 (Chi²=5,10, df=3 (p=0,16); I²=41%) (4 Studien) Station 17 (Chi²=0,16, df=2 (p=0,92); I²=0%) (3 Studien) Station 12 (Chi²=2,72, df=3 (p=0,44);I²=0%) (4 Studien) Publication Bias: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel PICO Frage klar formuliert: ja Ausreichende Suchstrategie: ja Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metanalyse erfolgt: ja Prüfung der Heterogenität: Daten sind homogen

Cao, F. et al. Prognostic significance of positive peritoneal cytology in resectable pancreatic cancer: A systemic review and metaanalysis. Oncotarget. 8. 15004-15013. 2017

Cao, F. et al. Prognostic significance of positive peritoneal cytology in resectable pancreatic cancer: A systemic review and metaanalysis. Oncotarget. 8. 15004-15013. 2017
Evidence level/Study Types	P - I - C	Outcomes/Results	Literature References
Evidence level: 1 Study type: Systematisches Review + Metaanalyse Databases: PubMed, Web of Science, China National Knowledge Infrastructure Search period: bis 06/2016 (keine Angabe zum Suchzeitraum) Inclusion Criteria: 1. potenziell resektable Pankreaskarzinome 2. Peritoneale Zytologie durchgeführt 3. Mindestens ein Outcome berichtet 4. Hazard Ratio (HR) oder Odds Ratio (OR) mit Konfidenzintervall (CI) oder ausreichende Datenzur Berechnung angegeben Exclusion Criteria: 1. Briefe, Fallberichte, Reviews und Konferenzzusammenfassungen ohne Originaldaten; 2. Duplikate früherer Veröffentlichungen 3. Artikel ohne Schlüsselinformationen wie Kaplan-Meier-Kurven, HRs mit 95% CIs oder klinisch-pathologischen Merkmalen	Population: Patienten mit resektablem Pankreaskarzinom Intervention: positive Peritonealzytologie (CY+) Comparison: negative Peritonealzytologie (CY-)	Primary: Gesamüberleben Krankheitsfreies Überleben Rezidiv Klinisch pathologische Merkmale (Tumorgröße, Tumorlokalisation, Serosainvasion, Invasion der Vena Porta, Lymphbahninvasion, T-Status, N-Status, Alter, Geschlecht, Grading, retroperitoneale Invasion, Invasion der Arterien, Perineuralinvasion, Invasion der Venen) Secondary: Results: n=10 retrospektive Studien n=2522 Patienten Gesamtüberleben: CY+ vs. CY- (10 Studien) Statistisch signifikant niedriger bei CY+ HR 3,18 (95%CI: 1,88-5,39) p=0,000 Krankheitsfreies Überleben CY+ vs. CY- (5 Studien) Statistisch signifikant niedriger bei CY+ HR 2,88 (95%CI: 2,39-3,49) p=0,000 Rezidiv CY+ vs. CY- statistisch signifikant höhere Wahrscheinlichkeit bei CY+ für: Rezidive insgesamt (4 Studien) OR 5,21 (95%CI: 2,45-11,00) p=0,000 Peritonealrezidive (4 Studien) OR 4,57 (95%CI: 3,08-6,78) p<0,000 kein statistisch signifikanter Unterschied für: Lokalrezidive (4 Studien) OR 1,01 (95%CI: 0,60–1,70) p=0,973 Lebermetastasen (4 Studien) OR 0,75 (95%CI: 0,47–1,19) p=0,214 Klinisch-pathologische Merkmale statistisch signifikanter Zusammenhang zwischen CY+ und: 1. Tumorgröße (größter vs kleinster Tumor) (4 Studien) OR 11,65 (95%CI: 2,62-51,86) p=0,001 2. Tumorlokalisation (Pankreaskopf vs -Körper/-Schwanz) (6 Studien) OR 0,37 (95%CI: 0,27-0,52) p<0,000 3. Serosainvasion (4 Studien) OR 3,89 (95%CI: 2,26-6,71) p<0,000 4. Invasion der Portalvene (3 Studien) OR 1,82 (95%CI: 1,12-2,95) p=0,016 5. Lymphgefäßinvasion (3 Studien) OR 2,71 (95%CI: 1,13-6,50) p=0,026 6. T-Stadium (T3+4 vs T1+2) (5 Studien) OR 2,65 (95%CI: 1,06-6,63) p=0,037 7. N-Stadium (N1 vs N0) (5 Studien) OR 2,34 (95%CI: 1,44-3,82) p=0,001 kein statistisch signifikanter Zusammenhang zwischen CY+ und: 1. Alter (3 Studien) 2. Geschlecht (7 Studien) 3. Grading (schlecht vs gut/moderat) (4 Studien) 4. retroperitoneale Invasion (4 Studien) 5. Invasion der Arterien (3 Studien) 6. Perineuralinvasion (4 Studien) 7. Invasion der Venen (3 Studien) Author's Conclusion: In conclusion, CY+ status was associated with advanced tumor and poor prognosis, radical resection should not be performed on such pancreatic cancer patients.	Iwagami Y, Eguchi H, Wada H, Tomimaru Y, Hama N, Kawamoto K, Kobayashi S, Mori M, Doki Y, Nagano H. Implications of peritoneal lavage cytology in resectable leftsided pancreatic cancer. Surg Today. 2015; 45:444–450. Satoi S, Murakami Y, Motoi F, Uemura K, Kawai M, Kurata M, Sho M, Matsumoto I, Yanagimoto H, Yamamoto T, Mizuma M, Unno M, Hashimoto Y, et al. Reappraisal of peritoneal washing cytology in 984 patients with pancreatic ductal adenocarcinoma who underwent margin-negative resection. J Gastrointest Surg. 2015; 19:6–14, 14. Hirabayashi K, Imoto A, Yamada M, Hadano A, Kato N, Miyajima Y, Ito H, Kawaguchi Y, Nakagohri T, Mine T, Nakamura N. Positive Intraoperative Peritoneal Lavage Cytology is a Negative Prognostic Factor in Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Center Study. Front Oncol. 2015; 5:182. Aoyama T, Katayama Y, Murakawa M, Shiozawa M, Morimoto M, Yamamoto N, Yoshikawa T, Rino Y, Masuda M, Morinaga S. Clinical implication of peritoneal cytology in the pancreatic cancer patients who underwent curative resection followed by adjuvant gemcitabine or S-1 chemotherapy. Hepatogastroenterology. 2015; 62:200–206. Yamada S, Fujii T, Kanda M, Sugimoto H, Nomoto S, Takeda S, Nakao A, Kodera Y. Value of peritoneal cytology in potentially resectable pancreatic cancer. Br J Surg. 2013; 100:1791–1796. Yoshioka R, Saiura A, Koga R, Arita J, Takemura N, Ono Y, Yamamoto J, Yamaguchi T. The implications of positive peritoneal lavage cytology in potentially resectable pancreatic cancer. World J Surg. 2012; 36:2187–2191. Ferrone CR, Haas B, Tang L, Coit DG, Fong Y, Brennan MF, Allen PJ. The influence of positive peritoneal cytology on survival in patients with pancreatic adenocarcinoma. J Gastrointest Surg. 2006; 10:1347–1353. Meszoely IM, Lee JS, Watson JC, Meyers M, Wang H, Hoffman JP. Peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreas. Am Surg. 2004; 70:208–213, 213–214. Konishi M, Kinoshita T, Nakagohri T, Inoue K, Oda T, Takahashi S. Prognostic value of cytologic examination of peritoneal washings in pancreatic cancer. Arch Surg. 2002; 137:475–480. Yachida S, Fukushima N, Sakamoto M, Matsuno Y, Kosuge T, Hirohashi S. Implications of peritoneal washing cytology in patients with potentially resectable pancreatic cancer. Br J Surg. 2002; 89:573–578.
Methodical Notes
Funding Sources: nicht angegeben COI: The authors declare no conflicts of interest. Study Quality: Bewertungsinstrument: Newcastle-Ottawa-Skala (NOS) ((maximale Punktzahl 9 Punkte, NOS > von 7 = hohe Qualität NOS-Wert < 3 = niedrige Qualität) Ergebnisse der eingeschlossenen Studien: Iwagami Y, 8; Satoi S, 6; Hirabayashi K, 6; Aoyama T, 7; Yamada S, 6; Yoshioka R, 8; Ferrone CR, 6; Meszoely IM, 6; Konishi M, 6; Yachida S, 6 Heterogeneity: CY + und klinisch-pathologische Merkmale CY + korreliert mit: 1. Tumorgröße Chi²=9,79; p=0,020; I²=69,4% (hohe Heterogenität) 2. Tumorlokalisation Chi²=6,60; p=0,169; I²=39,4% 3. Serosainvasion Chi²=4,27; p=0,234; I²=29,7% 4. Invasion der Portalvene Chi²=2,45; p=0,294; I²=18,2% 5. Lymphgefäßinvasion Chi²=0,34; p=0,842; I²=0% 6. T-Stadium (T3+4 vs T1+2) Chi²=0,62; p=0,961; I²=0% 7. N-Stadium (N1 vs N0) Chi²=6,33; p=0,176; I²=36,8% CY + korreliert nicht mit: 1. Alter Chi²=7,83; p=0,020; I²=74,5% (hohe Heterogenität) 2. Geschlecht Chi²=10,14; p=0,119; I²=40,8% 3. Grading Chi²=1,71; p=0,635; I²=0% 4. retroperitoneale Invasion Chi²=2,64; p=0,450; I²=0% 5. Invasion der Arterien Chi²=1,83; p=0,401; I²=0% 6. Perineuralinvasion Chi²=1,11; p=0,776; I²=0% 7. Invasion der Venen Chi²=2,51; p=0,285; I²=20,3% CY + und Rezidiv total recurrence p=0,205; I²=36,4% Peritonealrezidiv p=0,662; I²=0% local recurrence p=0,983; I²=0% liver metastasis p=0,556; I²=0% CY + und Gesamtüberleben Chi²=85,08; p=0,000; I²=89,4% (hohe Heterogenität) CY + und krankheitsfreies Überleben Chi²=4,86; p=0,302; I²=17,7% Publication Bias: Bewertungsverfahren: Beggs Test Ergebnis: kein Publikationsbias der Studien für die Metaanalyse zum Gesamtüberleben (P=0,142) und krankheitsfreiem Überleben (P=0,129) Notes: Gesamtqualität: keine methodischen Mängel PICO Frage klar formuliert: ja Ausreichende Suchstrategie: ja Ein- und Ausschlusskriterien klar definiert: ja Qualitätsbewertung der eingeschlossenen Studien erfolgt: ja Metaanalyse erfolgt: ja Prüfung der Heterogenität: Gesamtüberleben: heterogen, krankheitsfreies Überleben: homogen, peritoneales Rezidív: homogen

Crippa, S. et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy?. European Journal of Surgical Oncology. 42. 1533-1539. 2016

Crippa, S. et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy?. European Journal of Surgical Oncology. 42. 1533-1539. 2016
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, multizentrisch (2 Kliniken), Italien Number of Patient: n=127 n=116 ohne Resektion (R-) n=56 radiologisches Ansprechen nach primärer Chemotherapie davon n=11 Resektion (R+) Recruitung Phase: 01/2003 - 12/2013 Inclusion Criteria: 1. pathologisch nachgewiesenes PDAC Exclusion Criteria: 1. Vorliegen von extrahepatischen Metastasen 2. ECOG PS ≥3 3. alleinige Supportive Therapie	Intervention: Resektion des Primärtumors und der Metastasen nach Ansprechen auf primäre Chemotherapie (R+) Comparison: Keine Resektion nach primärer Chemotherapie (R-)	Primary: Gesamtüberleben Postoperative Mortalität Morbidität Rezidiv Secondary: Results: Follow-up nicht angegeben Gesamtüberleben: R+ vs. Gesamtkohorte Statistisch signifikant längeres Gesamtüberleben bei R+ R+: 39 Monate Gesamtkohorte: 11 Monate p < 0.0001 R+ vs. Patienten mit Ansprechen nach primärer Chemotherapie (mit und ohne Resektion) (n=56) Statistisch signifikant längeres Gesamtüberleben bei R+ R+: 39 Monate Patienten mit Ansprechen: 12 Monate p < 0.0001 unabhängige Faktoren für das Gesamtüberleben: primäre Chemotherapie mit multiplen Agentien HR 0,512 (95%CI 0.310-0.844) p=0.009 chirurgische Resektion HR 0,360 (95%CI 0.152-0.856) p=0.006 >5 Metastasen bei Diagnosestellung HR 3,515 (95%CI 1.304-9.479) p=0.013 CA 19-9 Reduktion <50% zur Baseline HR 2,708 (95%CI 1.417-5.175) p=0.003 Postoperative Mortalität: keine Morbidität (R+): 27% Rezidiv (R+): 10/11 Patienten Author's Conclusion: In summary, to our knowledge, this is the first study that describes the results of surgical resection of patients with metastatic pancreatic cancer limited to the liver after primary chemotherapy. This study demonstrates that multiagent chemotherapy can be effective in treating patients with good performance status, achieving complete/partial radiological response in 4/10 cases and major biochemical response in 3/10. Surgical resection was carried out in a limited number of highly-selected patients and was associated with improved survival. Further prospective studies are needed to confirm the possible benefit of surgery and to define the possible indications of surgical resection.
Methodical Notes
Funding Sources: All authors declare that this paper has no sources of funding. COI: All authors declare no conflict of interest. Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: ausreichend Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): nein Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Gebauer, F. et al. [Oligometastasis in pancreatic cancer : Current state of knowledge and spectrum of local therapy]. Oligometastasierung beim Pankreaskarzinom : Aktueller Kenntnisstand und Spektrum der Lokaltherapie. 89. 510-515. 2018

Gebauer, F. et al. [Oligometastasis in pancreatic cancer : Current state of knowledge and spectrum of local therapy]. Oligometastasierung beim Pankreaskarzinom : Aktueller Kenntnisstand und Spektrum der Lokaltherapie. 89. 510-515. 2018
Evidence level/Study Types	P - I - C	Outcomes/Results	Literature References
Evidence level: 1 Study type: systematische Recherche Databases: Medline, PubMed Search period: nicht angegeben Inclusion Criteria: nicht angegeben Exclusion Criteria: nicht angegeben	Population: Patienten mit duktalem Adenokarzinom des Pankreas (PDAC) mit Oligometastasierung Intervention: Lokaltherapie (Resektion, RFA, MWA) bei Hepatischen Metastasen, Pulmonalen Metastasen (LT+) Comparison: keine Lokaltherapie (LT-)	Primary: Gesamtüberleben Perioperative Mortalität Secondary: Results: Fallserien Keine quantitative Zusammenfassung der Ergebnisse Gesamtüberleben: Hepatische Metastasierung: Resektion Möglicherweise verlängertes Gesamtüberleben RFA/MWA keine Ergebnisse für PDAC Pulmonale Metastasen Resektion Möglicherweise verlängertes Gesamtüberleben Perioperative Mortalität Hepatische Metastasierung: in den meisten Studien <5% Fazit für die Praxis Das Evidenzniveau für eine synchrone hepatische Metastasen- und Primärtumorresektion ist schwach, auch wenn einige Fallserien ein vergleichbares Gesamtüberleben berichten konnten, wie es mit modernen Chemotherapieregimen erreicht werden kann. Eine Empfehlung für dieses Vorgehen kann anhand der vorliegenden Daten nicht gegeben werden, die Ergebnisse der vorhandenen Studien zeigen allerdings die Notwendigkeit für prospektive Untersuchungen zu diesem Thema. Patienten mit pulmonalen Metastasen scheinen sich in ihrem biologischen Verlauf grundlegend von Patienten mit intraabdominellen Metastasen zu unterscheiden, hier scheint eine metachrone pulmonale Metastasenresektion bei ausgewählten Patienten gerechtfertigt zu sein. Author's Conclusion: Die Ergebnisse der vorliegenden Studie erlauben keine generelle Aussage darüber, ob resezierende Eingriffe im metastasierten Stadium gerechtfertigt sind. Dennoch zeigen die Ergebnisse einen möglichen Vorteil für gewisse Patientensubpopulationen. Prospektive Studien sind zwingend notwendig, um einen möglichen Stellenwert chirurgischer Eingriffe im metastasierten Stadium belegen zu können.	1. Arnaoutakis GJ, Rangachari D, Laheru DA et al (2011)Pulmonary resectionfor isolatedpancreatic adenocarcinoma metastasis: an analysis of outcomes and survival. J Gastrointest Surg 15:1611–1617 2. Broomfield JA, Greenspoon JN, Swaminath A (2014) Utilization of stereotactic ablative radiotherapy in the management of oligometastatic disease.CurrOncol21:115–117 3. Chiapponi C, Berlth F, Plum PS et al (2017) Oligometastatic disease in upper gastrointestinal cancer–howtoproceed?ViscMed33:31–34 4. Conroy T, Desseigne F, Ychou M et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.NEngl JMed364:1817–1825 5. De Jong MC, Tsai S, Cameron JL et al (2010) Safety and efficacy of curative intent surgery for peri-ampullary liver metastasis. J Surg Oncol 102:256–263 6. DisibioG, French SW(2008)Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol LabMed132:931–939 7. Fidler IJ, Hart IR (1982) Biological diversity in metastatic neoplasms: origins and implications. Science217:998–1003 8. Frigerio I, Regi P, Giardino A et al (2017) Downstaging in stage IV pancreatic cancer: a new population eligible for surgery? Ann Surg Oncol 24:2397–2403 9. Gebauer F, Kloth K, TachezyMet al (2012) Options andlimitations inapplying thefistula classification by the Study Group for Pancreatic Fistula (ISGPF). Ann Surg 256(1):130–138. https://doi.org/10. 1097/SLA.0b013e31824f24e4 10. Gleisner AL, Assumpcao L, Cameron JL et al (2007) Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified?Cancer110:2484–2492 11. Hackert T, NiesenW, Hinz U et al (2017) Radical surgery of oligometastatic pancreatic cancer. Eur J SurgOncol 43:358–363 12. Hellman S, Weichselbaum RR (1995) Oligometastases. JClinOncol13:8–10 13. HuaYQ,WangP,ZhuXYetal (2017)Radiofrequency ablation for hepatic oligometastatic pancreatic cancer: an analysis of safety and efficacy. Pancreatology17:967–973 14. Huang L, Jansen L, Balavarca Y et al (2017) Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations. Gut. https://doi.org/10.1136/ gutjnl-2017-314828 15. Klein F, Puhl G, Guckelberger O et al (2012) The impact of simultaneous liver resection for occult liver metastases of pancreatic adenocarcinoma. Gastroenterol Res Pract. https://doi.org/10.1155/ 2012/939350 16. Klempnauer J, Ridder GJ, Bektas H et al (1996) Extended resections of ductal pancreatic cancer— impact on operative risk and prognosis. Oncology53:47–53 17. Kneuertz PJ, Cunningham SC, Cameron JL et al (2011) Palliative surgical management of patients with unresectable pancreatic adenocarcinoma: trends and lessons learned from a large, single institution experience. J Gastrointest Surg 15:1917–1927 18. KrugerS,HaasM,BurgerPJetal(2016)Isolatedpulmonary metastases define a favorable subgroup in metastatic pancreatic cancer. Pancreatology 16:593–598 19. Louvet C, Philip PA (2008) Accomplishments in 2007 in the treatment of metastatic pancreatic cancer.GastrointestCancerRes 2:S37–S41 20. Martin RC 2nd, Augenstein V, Reuter NP et al (2009) Simultaneous versus staged resection for synchronous colorectal cancer liver metastases. JAmCollSurg208:842–850(discussion850–842) 21. Mayo SC, Nathan H, Cameron JL et al (2012) Conditional survival in patients with pancreatic ductal adenocarcinoma resected with curative intent.Cancer118:2674–2681 22. Michalski CW, Erkan M, Huser N et al (2008) Resection of primary pancreatic cancer and liver metastasis: a systematic review. Dig Surg 25:473–480 23. Rahib L, Smith BD, Aizenberg R et al (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921 24. Seufferlein T, Porzner M, Becker T et al (2013) S3- guideline exocrine pancreatic cancer. Z Gastroenterol 51:1395–1440 25. Shrikhande SV, Kleeff J, Reiser C et al (2007) Pancreatic resection for M1 pancreatic ductal adenocarcinoma.AnnSurgOncol14:118–127 26. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics,2017.CaCancer JClin 67:7–30 27. Singh A, Singh T, Chaudhary A (2010) Synchronous resection of solitary liver metastases with pancreaticoduodenectomy. JOP11:434–438 28. Tachezy M, Gebauer F, Janot M et al (2016) Synchronous resectionsofhepaticoligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenteranalysis. Surgery160:136–144 29. TemperoMA,MalafaMP, Behrman SWet al (2014) Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl ComprCancNetw12:1083–1093 30. VonHoffDD, ErvinT,ArenaFPet al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plusgemcitabine.NEngl JMed369:1691–1703 31. Wangjam T, Zhang Z, Zhou XC et al (2015) Resectedpancreaticductal adenocarcinomaswith recurrence limited in lung have a significantly better prognosis than thosewith other recurrence patterns.Oncotarget6:36903–36910
Methodical Notes
Funding Sources: nicht angegeben COI: F. Gebauer, A. I. Damanakis und C. Bruns geben an, dass kein Interessenkonflikt besteht. Study Quality: nicht angegeben Heterogeneity: nicht angegeben Publication Bias: nicht angegeben Notes: Gesamtqualität: abgewertet (-) PICO Frage klar formuliert: nein Ausreichende Suchstrategie unklar Ein- und Ausschlusskriterien klar definiert: unklar Qualitätsbewertung der eingeschlossenen Studien erfolgt: unklar Metanalyse erfolgt: nein Prüfung der Heterogenität: keine Prüfung erfolgt

Hempel, S. et al. Para-aortic lymph node metastases in pancreatic cancer should not be considered a watershed for curative resection. Scientific reports. 7. 7688. 2017

Hempel, S. et al. Para-aortic lymph node metastases in pancreatic cancer should not be considered a watershed for curative resection. Scientific reports. 7. 7688. 2017
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, Deutschland Number of Patient: n=95 Resektion n=14 PALN+ n=81 PALN- Subgruppe PALN- n=37 pN0 n=44 pN1 n=194 palliative Operation Recruitung Phase: 01/2005 - 03/2015 Inclusion Criteria: 1. duktale Adenokarzinome des Pankreas (PDAC) 2. partielle pyloruskonservierende Pankreatoduodenektomie (PD), klassische PD (cPD) oder totale Pankreatektomie (TP) des Pankreaskopfs oder -halses 3. eindeutig markierte PALN (PALN+/-) 4. palliative Operation bei nicht-resektablem oder metastasiertem duktalem Adenokarzinom des Pankreas Exclusion Criteria: nicht angegeben	Intervention: Resektion bei Patienten mit metastatischen paraaortalen Lymphknoten (PALN+) Comparison: Resektion bei Patienten mit nicht-metastatischen paraaortalen Lymphknoten (PALN-) ODER palliativer Operation bei nicht-resektablem oder metastasiertem PDAC	Primary: Gesamtüberleben Krankheitsfreies Überleben Postoperative Morbidität 30-Tage Mortalität Secondary: Results: Follow-up Median 17,9 Monate Medianes Gesamtüberleben PALN+ vs. PALN-: Kein statistisch signifikanter Unterschied PALN+ 14,1 Monate PALN- 20,2 Monate (95%CI 17.0-24.8) p=0,093) PALN- N0 vs. PALN- N1 Statistisch signifikant länger bei PALN- N0 PALN- N0 23,9 Monate (95%CI 18,8-48,0) PALN- N1 19,3 Monate (95%CI 10,9-22,9) p=0,047 PALN+ vs. PALN- N1 Kein statistisch signifikanter Unterschied PALN+ 14,1 Monate PALN- N1 19,3 Monate (95%CI 10,9-22,9) p=0,743 PALN+ vs. Palliative OP Kein statistisch signifikanter Unterschied PALN+ 14,1 Monate Palliative OP 8,8 Monate (95%CI 7,3-10,1) p=0,158 Medianes Krankheitsfreies Überleben PALN+ vs. PALN- Statistisch signifikant länger bei PALN- PALN+ 7,4 Monate PALN- 12,3 Monate (95%CI 10,0-16,0) p=0,003 Postoperative Morbidität PALN+ vs. PALN- Signifikant höhere Rate an postoperativer Diarrhoe bei PALN+ 30-Tage Mortalität Gesamt: 2,1 % (2/95 Patienten) Author's Conclusion: In conclusion, the present study confrms that patients with PALN metastases (pM1 LYM) have a relative poor prognosis, resulting in a median survival of approximately 14 months. However, one-third of these patients demonstrated a longer survival. Compared with other studies on PALN resection, the present study explicitly analysed the lymph node status and demonstrated that the survival of patients with positive PALN was comparable to patients with pN1pM0 disease, and even more to pN2pM0 patients according to the 8th edition of TNM staging (UICC). Because preoperative imaging studies fail to reliably predict PALN metastases, PALN status prior to tumour resection can only be assessed by intraoperative frozen section analysis. However, abandoning tumour resection in the case of Ln16b1 metastases should not be routinely recommended; we would rather recommend a tailored approach taking into account the individual risk profle of the patient.
Methodical Notes
Funding Sources: The present work was not supported by any third party funding or research grant. COI: The authors declare that they have no competing interests. Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Klaiber, U. et al. Prognostic Factors of Survival After Neoadjuvant Treatment and Resection for Initially Unresectable Pancreatic Cancer. Annals of surgery. . . 2019

Klaiber, U. et al. Prognostic Factors of Survival After Neoadjuvant Treatment and Resection for Initially Unresectable Pancreatic Cancer. Annals of surgery. . . 2019
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, Deutschland Number of Patient: n=280 n=82 R0 n=99 R1 < 1 mm n=99 R1 direct n=45 Oligometastasen (13 Peritoneum, 27 Leber, 4 entfernte Lymphknoten, 1 Lunge, 1 Milz, 1 Nebenniere, 1 Schambein) (gleichmäßig über die 3 Resektionsgruppen verteilt) Recruitung Phase: 01/2006 – 02/2017 Inclusion Criteria: 1. primär irresektable PDAC 2. borderline resektabel, lokal fortgeschritten nach neoadjuvanter Therapie und Resektion 3. Oligometatastasierung die komplett reseziert werden konnte Exclusion Criteria: 1. periampulläre Karzinome, neuroendokrine Tumore, anaplastische Karzinome, Carcinoma in situ 2. andere synchron metastasierte Tumore 3. mittlere bis große Metastasen, die nicht reseziert werden konnten 4. makroskopische (R2) oder unbestimmbare (Rx) Residualtumore 5. resektable Tumoren	Intervention: R0-Resektion nach neoadjuvanter Therapie (R0) (R0 = tumorfreier Resektionsrand von >1mm) Comparison: R1-Resektion nach neoadjuvanter Therapie: 1. R1≤1mm = tumorfreier Resektionsrand ≤1mm (R1-1 mm) 2. R1 direct = mikroskopische Tumorinfiltration am Resektionsrand (R1-direct)	Primary: Gesamtüberleben 3-Jahres-Gesamtüberlebensrate krankheitsfreies Überleben 3-Jahres krankheitsfreies Überlebensrate 30-Tage-Mortalität 90-Tage Mortalität Prognosefaktoren Secondary: Results: Follow-up Median 18 Monate (11-36) Gesamtüberleben Medianes Gesamtüberleben Gesamtkohorte (n=280) 19,0 (14,6–22,3) Monate R0 vs. R1-1-mm vs. R1-direct statistisch signifikant länger nach R0 R0 (n=82): 25,1 Monate (95% CI 16,2–30,0) R1-1-mm (n=99): 15,3 Monate (95% CI 11,0–23,5) R1-direct (n=99): 16,1 Monate (95% CI 9,8–22,3) p=0,0076 3-Jahres-Gesamtüberlebensrate Gesamtkohorte (n=280):24,7% (19,1–30,6) R0 vs. R1-1-mm vs. R1-direct statistisch signifikant höher nach R0 R0 (n=82): 35,0% (95% CI 24,3–45,8) R1-1-mm (n=99): 20,7% (95% CI 12,0–31,0) R1-direct (n=99): 18,5% (95% CI 10,5–28,4) P=0,0076) Medianes Gesamtüberleben mit/ohne adjuvante Chemotherapie Statistisch signifikant länger mit adjuvanter Chemotherapie ohne adjuvante Chemotherapie: 12,8 Monate (95% CI: 8,8–20,6) mit adjuvanter Chemotherapie: 24,1 Monate (95% CI 19,8–29,6) p=0,0225 3-Jahres-Gesamtüberlebensraten mit/ohne adjuvante Chemotherapie: statistisch signifikant höher mit adjuvanter Chemotherapie ohne adjuvante Chemotherapie: 20,0% (95% CI 11,4–30,3) mit adjuvanter Chemotherapie: 31,9% (95% CI 23,7–40,3) p=0,0225 Medianes krankheitsfreies Überleben Gesamtkohorte (n=252) 9,0 Monate (95% CI 7,9–10,3) R0 vs. R1-1-mm vs. R1-direct statistisch signifikant länger nach R0 R0: 9,8 Monate (95% CI 7,6–16,9) R1-1-mm: 8,9 Monate (95% CI 7,4–10,5) R1-direct: 8,3 Monate (95% CI 6,2–10,4) p=0,0250 Medianes krankheitsfreies Überleben mit/ohne adjuvante Chemotherapie: statistisch signifikant länger mit adjuvanter Chemotherapie ohne adjuvante Chemotherapie: 6,2 Monate (95% CI 4,6–7,6) mit adjuvanter Chemotherapie: 11,5 Monate (95% CI 9,7–13,6) p=0,0071 3-Jahres-kranheitsfreies Überlebensrate: Gesamtkohorte (n=252) 11,6% (7,7–16,4) R0 vs. R1-1-mm vs. R1-direct statistisch signifikant höher nach R0 R0: 19,6% (95% CI 11,3–29,6) R1-1-mm: 9,8% (95% CI 4,1–18,6) R1-direct: 5,9% (95% CI 2,0–13,0) p=0,0250 3-Jahres-krankheitsfreies Überlebensrate mit/ohne adjuvante Chemotherapie: statistisch signifikant höher bei adjuvanter Chemotherapie ohne adjuvante Chemotherapie: 12,0% (95% CI: 7,0–18,5) mit adjuvanter Chemotherapie: 13,0% (95% CI 6,4–21,9) p 0,0071 30-Tage-Mortalität R0 vs. R1-1-mm vs. R1-direct kein statistisch signifikanter Unterschied 90-Tage Mortalität R0 vs. R1-1-mm vs. R1-direct kein statistisch signifikanter Unterschied Prognosefaktoren Unabhängige prognostische Faktoren für kürzeres Gesamtüberleben (multivariate Analyse): 1. präoperativer CA 19–9-Serumspiegel von 100 U / ml: ≥100 vs <100 HR 1.58 (95% CI 1.15–2.17) p=0.0046 2. Lymphknotenbefall: ypN1 vs ypN0 HR 1.72 (95% CI 1.23–2.40) p=0.0013 ypN2 vs ypN0 HR 2.25 (95% CI 1.51–3.36) p<0.0001 3. ypM1-Stadium: ypM1 vs ypM0 HR 2.04 (95% CI 1.39–3.01) p=0.0003 4. arterielle/venöse Infiltration: ja vs nein HR 1.87 (95% CI 1.39–2.52) p<0.0001 Unabhängige prognostische Faktoren für kürzeres krankheitsfreies Überleben (mulitvariate Analyse): 1. präoperative CA 19–9-Werte im Serum ≥100 vs <37 HR 1.80 (95% CI 1.26–2.56) p=0.0011 2. präoperative CEA-Werte im Serum ≥2.5 vs <2.5 HR 1.45 (95% CI 1.06–1.98) p=0.0213 3. ypT4-Stadium ypT4 vs ypT0/1/2/3 HR 1.79 (95% CI 1.06–3.02) p=0.0290 4. Lymphknotenbefall ypN1 vs ypN0 HR 1.43 (95% CI 1.02–2.01) p=0.0377 ypN2 vs ypN0 HR 2.02 (95% CI 1.36–3.01) p=0.0005 5. Fernmetastasen bei Erstdiagnose M1 vs lokale Ausbreitung HR 1.85 (95% CI 1.35–2.54) p=0.0002 6. multiple Tumorlokalisationen im Pankreas multiple vs single HR 1.70 (95% CI 1.26–2.31) p=0.0006 Author's Conclusion: In patients undergoing resection after neoadjuvant therapy for initially unresectable PDAC, preoperative CA 19–9 levels, lymph node involvement, metastasis category, and vascular involvement, but not the R status, were independent prognostic factors of overall survival.
Methodical Notes
Funding Sources: The resources and the facilities available at the Department of Surgery, University of Heidelberg, were used to conduct this study. No additional funding source was used. COI: All authors declare no financial interests and no conflicts of interest. Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: 11 Patienten (innerhalb von 90 Tagen nach Operation nachuntersucht: 5 Patienten mit R1 1 mm und 6 mit R1 direkt) und 17 Patienten (innerhalb von 90 Tagen nach Operation verstorben (4 Patienten mit R0, 5 mit R1 1 mm), und 8 mit R1 direct) wurden aus krankheitsfreien Überlebensanalysen ausgeschlossen Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Liu, X. et al. Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. BMC Gastroenterology. 18. 168. 2018

Liu, X. et al. Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer. BMC Gastroenterology. 18. 168. 2018
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, China Number of Patient: n=235 n=62 WM n=173 NM Recruitung Phase: 01/2014 – 12/2015 Inclusion Criteria: 1. Exploration bei potenziell resezierbarem PDAC Exclusion Criteria: 1. palliative Operation 2. keine präoperative interne Multidetektor-Computertomographie (MDCT)-Untersuchung 3. Fernmetastasen in präoperativer MDCT nachgewiesen	Intervention: Fernmetastasen (z.B. Leber, Peritoneum) bei Exploration (WM) Comparison: keine Fernmetastasen bei Exploration (NM)	Primary: Risikofaktoren für Fernmetastasen Secondary: Scoring-Systems zur Vorhersage von Fernmetastasen bei einer Exploration Results: Follow-up nicht angegeben unabhängige Risikofaktoren für okkulte Fernmetastasen (multivariate Analyse) Alter < 62 Jahre: >62 Jahre vs. ≤62 Jahre OR 3.97 (95% CI 1.87-8.42) p<0,001 männl. Geschlecht: weibl. vs männl. OR 2.79 (95% CI 1.26-6.19) p=0,011 Tumorgröße > 4 cm <4 vs ≥4,0cm OR 16.02 (95% CI 5.31-48.30) p<0,001 ALT Level < 125 U/L: ≥125 vs <125 U/L OR 6.19 (95% CI 2.26-16.92) p<0,001 CA19-9 Level > 385 U/ml <385 vs ≥385 U/ml OR 2.49 (95% CI 1.19-5.21) P=0,015 Scoring System: Alter >62 Jahre = 0 Punkte <62 Jahre = 1 Punkt Geschlecht Weiblich = 0 Punkte Männlich = 1 Punkt Tumorgröße <4,0 cm = 0 Punkte >4,0 cm = 3 Punkte ALT >125 U/L = 0 Punkte <125 U/L = 2 Punkte CA 19-9 <385 U/mL = 0 Punkte >385 U/mL = 1 Punkte ein Score von 6 wird als cut-off-Wert zur Risikostratifizierung vorgeschlagen (Sensitivität 85%, Spezifität 69%) Author's Conclusion: In conclusion, we showed that for patients with potentially resectable PDAC based on MDCT, distant metastasis is still frequently encountered during surgery. Younger age, male sex, large tumor size, lower ALT and higher CA19–9 are independent predictive factors for finding distant metastasis during exploration.
Methodical Notes
Funding Sources: This work was supported by the Natural Science Foundation of China (81672449); Natural Science Foundation of Jiangsu Province (BK20161590); and the International Exchange and Cooperation Projects of Nanjing Medical University (C046). The founding resources had no role in study design, data collection and analysis, preparation of the manuscript, or decision to publish. COI: The authors declare that they have no competing interests. Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Lowder, C. Y. et al. Clinical Implications of Extensive Lymph Node Metastases for Resected Pancreatic Cancer. Annals of Surgical Oncology. 25. 4004-4011. 2018

Lowder, C. Y. et al. Clinical Implications of Extensive Lymph Node Metastases for Resected Pancreatic Cancer. Annals of Surgical Oncology. 25. 4004-4011. 2018
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, USA Number of Patient: n=610 n=185 extensive LN+ (LNC > 4 LN+, LNR > 0,4) n=430 Daten zu Rezidiven Historische Vergleichskohorten Patienten aus 3 Studien zu medikamentösen Therapien n=223 Gemcitabin (Hammel et al., JAMA 2016) n=171 FOLFIRINOX (Conroy et al., NEJM 2011) n=431 nab-Paclitaxel Gemcitabine (von Hoff et al., NEJM 2011) Recruitung Phase: 2002-2014 Inclusion Criteria: 1. PDAC 2. invasive intraduktale papilläre muzinöse Neoplasien (IPMN-assoziierte Karzinome) Exclusion Criteria: 1. Intra-/Postoperative Mortalität unabhängig vom PDAC	Intervention: Resektion bei Patienten mit extensiven LN+ (LNC > 4 LN+, LNR > 0,4) (R) Comparison: Medikamentöse Therapien (historische Vergleichskohorten) (MT)	Primary: Gesamtüberleben Rezidiv Secondary: Results: Follow-up Median Gesamtkohorte: 17,4 Monate Median lebende Patienten: 24,0 Monate Gesamtüberleben Medianes Gesamtüberleben R vs. MT Statistisch signifikant länger bei R R 14,6 Monate MT Gemcitabine: 13,6 Monate FOLFIRINOX: 11,1 Monate nab-Paclitaxel Gemcitabine: 8,5 Monate p<0,001 18-Monate Überlebensraten R vs. MT Statistisch signifikant höher bei R R: 38,5% MT: Gemcitabine: 29,5% FOLFIRINOX: 18,8% nab-Paclitaxel Gemcitabine: 16,4% p<0,001 24-Monate Überlebensraten R vs. MT Statistisch signifikant höher bei R R: 24,6% MT: Gemcitabine: 14,8% FOLFIRINOX: 15,6% nab-Paclitaxel Gemcitabine: 10,0% p<0,001 36-Monate Überlebensraten R vs. MT Statistisch signifikant höher bei R R: 12,0% MT: Gemcitabine (33 Monate): 5,4% FOLFIRINOX: 6,3% nab-Paclitaxel Gemcitabine: 5,0% p<0,001 Rezidive Mediane Zeit bis zum Rezidiv: LN+ vs. LN- Statistisch signifikant länger bei LN- LN+ 9,7 Monate LN- 11,7 Monate, p<0,004 Extensive LN+ vs. LN- Statistisch signifikant länger bei LN- Extensive LN+: 7,2 Monate LN-: 11,7 Monate p<0,001 Rezidivlokalisationen: n=146 Leber n=152 Retroperitoneum n=112 Peritoneum n=66 Lunge LN+ mit häufigerem Auftreten distanter Metastasen im Vergleich zu lokalen Rezidiven assoziiert, insbesondere bei extensivem LN+ Author's Conclusion: This study provides evidence that N2 disease is appropriately defined by the AJCC 8th edition staging system. Moreover, a finding of very extensive lymph node burden should not be dismissed as comparable to macroscopic metastatic PDA. In fact, the prognosis is better. The finding of extensive lymph node metastases likely reflects residual, occult, and microscopic metastatic disease. Along these lines, a high lymph node burden seems to be associated with a systemic pattern of failure. Thus, the absence of regional lymph node metastases may be the most suitable subgroup of patients for adjuvant radiotherapy, because nearly one-third of patients experience recurrence locally.
Methodical Notes
Funding Sources: nicht angegeben COI: None Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: ausreichend Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: unklar Gruppen gleich behandelt (abgesehen von untersuchter Intervention): nein Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Philips, Prejesh et al. The role of hepatic artery lymph node in pancreatic adenocarcinoma: prognostic factor or a selection criterion for surgery. HPB : the official journal of the International Hepato Pancreato Biliary Association. 16. 1051-1055. 2014

Philips, Prejesh et al. The role of hepatic artery lymph node in pancreatic adenocarcinoma: prognostic factor or a selection criterion for surgery. HPB : the official journal of the International Hepato Pancreato Biliary Association. 16. 1051-1055. 2014
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, USA Number of Patient: n=247 n=50 HALN-/PPLN- n=197 LN+ davon: n=3 HALN+/PPLN- n=38 HALN+/PPLN+ n=156 HALN-/PPLN+ Recruitung Phase: 2002-2012 Inclusion Criteria: 1. Pankreatoduodenektomie 2. Adenokarzinome des Pankreas 3. Lymphknoten an der Arteria Hepatica (HALN) beurteilbar 4. Lymphknotenmetastasen Exclusion Criteria: 1. andere Pathologie 2. Alter < 18 Jahre 3. unvollständige Daten	Intervention: Lymphknoten-negative Patienten (Lymphknoten an der A. hepatica (HALN) und peripankreatische Lymphknoten (PPLN)) (HALN-/PPLN-) Comparison: Lymphknoten-positive Patienten (LN+): 1. positive Lymphknoten an der A. hepatica (HALN+), negative peripankreatische Lymphknoten (PPLN-) (HALN+/PPLN-) 2. positive Lymphknoten an der A. hepatica (HALN+), positive peripankreatische Lymphknoten (PPLN+) (HALN+/PPLN+) 3. negative Lymphknoten an der A. hepatica (HALN-), positive peripankreatische Lymphknoten (PPLN+) (HALN-/PPLN+)	Primary: Gesamtüberleben Krankheitsfreies Überleben Secondary: Results: Follow-up Median: 18,5 Monate (4,1-28,2) Medianes Gesamtüberleben Gesamtkohorte: 22,7 Monate (4,1-28,2 Monate) HALN-/PPLN- vs. LN+ Statistisch signifikant länger bei HALN-/PPLN- HALN-/PPLN- (n=50) 40,2 Monate (26,1-63,0 95% CI: 29,2-76,2) LN+ (n=197) 19,5 Monate (11,0-33,0 95% CI: 15,4-23,6) p<0,001 HALN+/PPLN+ vs. HALN-/PPLN+ Kein statistisch signifikanter Unterschied HALN+/PPLN+16,9 Monate (10,0–26,0 95% CI: 11,7–25,9) HALN-/PPLN+20,5 Monate (11,8–33,0 95% CI: 16,0–24,0) p=0,659 Medianes krankheitsfreies Überleben Gesamtkohorte vs. LN+ Statistisch signifikant länger in Gesamtkohorte Gesamtkohorte 12,6 Monate (7,4-33,8 95% CI: 10,2-15,2) LN+ 10,8 Monate (8,4-13,3 95% CI: 6,9-15,3) p<0,001 HALN+/PPLN+ vs. HALN-/PPLN+ Kein statistisch signifikanter Unterschied HALN+/PPLN+ 10,6 Monate (8,3-12,7 95% CI: 8,4-12,6) HALN-/PPLN+ 11,6 Monate (6,3-16,8 95% CI: 7,9-15,0) p=0,219 unabhängige Prognosefaktoren für kürzeres Gesamtüberleben (multivariater Analyse): Lymphknoten ratio > 0.2 HR 1.129 (95% CI 1.0–1.2) p=0.012 schlechte Differenzierung HR 1.090 (95% CI 1.02–1.33) p=0.029 Keinen Effekt auf das Überleben (uni-/multivariate Analysen) Resektionsstatus perineurale oder lymphovaskuläre Invasion Tumorstadium adjuvante Chemotherapie vaskuläre Invasion Author's Conclusion: The HALN is almost never the isolated site of disease. Metastasis in the HALN is associated with a higher burden of LN metastasis. However, among patients with node-positive pancreatic head adenocarcinoma, the presence of HALN-positive disease is not an independent adverse prognostic marker for OS and therefore metastasis to the HALN should not be considered as a criterion for exclusion from PD.
Methodical Notes
Funding Sources: nicht angegeben COI: None declared Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: 32 Patienten lost from follow-up Notes: Gesamtqualität: ausreichend Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: unklar Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Shi, H. J. et al. Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability. World Journal of Gastroenterology. 22. 10024-10037. 2016

Shi, H. J. et al. Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability. World Journal of Gastroenterology. 22. 10024-10037. 2016
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, China Number of Patient: n=69 mit resektablem Pankreaskarzinom und synchronen Lebermetasen davon n=30 simultane kurative Resektion (Gruppe A) n=39 palliativer Bypass (Gruppe B) Zur Untersuchung von Prädiktoren für Lebermetasten n=138 mit kurativer Resektion, ohne Metastasen als gematchte Kontrollgruppe (1:2) (Gruppe C) Recruitung Phase: 03/2007-12/2015 Inclusion Criteria: 1. histologisch bestätigtes PDAC 2. Lebermetastasen 3. Operation Exclusion Criteria: 1. unresektables PDAC 2. neuroendokrine Tumore 3. Zystadenokarzinome 4. Ampulläre Karzinome 5. Karzinome im distalen Gallengang 6. Karzinome im Duodenum 7. extrahepatischen Metastasen 8. peritoneale Metastasen 9. serosale Implantate	Intervention: Intervention I: kurative simultane Resektion von Karzinom und Lebermetastasen (Gruppe A) Intervention II: kurative simultane Resektion oder palliativer Bypass Karzinom mit synchronen Lebermetastasen (Gruppe A + Gruppe B) Comparison: Comparison I: palliative Bypass-Operation Karzinom mit synchronen Lebermetastasen (Gruppe B) Comparison II: kurative Resektion Karzinom ohne Metastasen (Gruppe C)	Primary: Gesamtüberleben Resektabilitätskriterien für Patienten mit PDAC und Lebermetastasen Prädiktoren für synchrone Lebermetastasen Peri- und postoperativer Verlauf Secondary: Results: Follow-up nicht angegeben Medianes Gesamtüberleben Gruppe A+B vs. Gruppe C Statistisch signifikant längeres Überleben Gruppe C Gruppe A+B: 7,0 Monate Gruppe C: 16,9 Monate p<0,001 Gruppe A vs. Gruppe C Kein statistisch signifikanter Unterschied Gruppe A: 15,7 Monate Gruppe C: 16,9 Monate p<0,085 Gruppe B: 4,4 Monate Prognostische Faktoren für ein verkürztes Langzeitüberleben (multivariate Analyse) Alter (>62) HR 2,191; 95% CI: 1,182-4,060 p=0,013 CA125 (>62 U/mL) HR 2,601 95% CI: 1,403-4,832 p=0,002; Resektabilitätskriterien: Parameter für Irresektabilität (multivariate Analyse) Gruppe A vs. Gruppe B Alter (>62) OR 3,921; 95% CI: 1,271-12,632 p=0,022 CA125 (>62 U/mL) OR 5,181 95% CI: 1,612-16,665 p=0,006 Sensitivität 71,79% Spezifität 70,00% Keine Parameter für Irresektabilität: CA19-9 (>400 U/mL) OR 1.760 95% CI: 0,517-5992 p=0,366 Albumin (≤35 g/L) OR 1,796 95% CI: 0,516-6,253 p=0,357 Prädiktoren für synchrone Lebermetastasen Gruppe A+B vs. Gruppe C CA125 >38 U/mL OR 12,397 95% CI: 5,468-28,105 p<0,001 Sensitivität 71,01% Spezifizität 87,61% diabetes mellitus OR 3,343 95% CI: 1,539-7,262, p=0,002 Keine Prädiktoren für synchrone Lebermetastasen CA19-9 (>400 U/mL) OR 2,398 95% CI: 0,909-6,327 p=0,077 CEA (≤5 U/mL) OR 0,672 95% CI: 0,249-1,817 p=0,434 Neutrophile-Lymphozyten-Ratio (NLR; >5) OR 0,934 95% CI: 0,283-3,083 p=0,911 Intra- und postoperativer Verlauf Gruppe A vs. Gruppe C Keine statistisch signifikanten Unterschiede bei: Durchschnittlicher Operationszeit Medianem Blutverlust Häufigkeit von Transfusionen roter Blutkörperchen postoperativen Komplikationen Dauer des Krankenhausaufenthaltes in-Hospital Mortalität keine Author's Conclusion: In conclusion, diagnosis and treatment of liver metastasis from PDAC must be individualized in the era of precision medicine because of its highly malignant biological behavior. Serum CA125 level over 38 U/mL predicts synchronous liver metastasis from PDAC, and serum CA125 level over 62 U/mL is associated with unresectability of metastatic disease burden. The criterion set up by serum CA125 levels facilitates the careful diagnosis of synchronous liver metastases from PDAC pre-operatively and the prudent selection of appropriate patients for simultaneous resections for primary PDAC and synchronous liver metastasis for the sake of prolonged survival and substantially reduced morbidity or mortality. Therefore, simultaneous resections for primary PDAC and synchronous liver metastasis are justified by prolonged survival in patients selected by serum CA125. It is foreseeable that the indication for the simultaneous resections for precisely diagnosed liver-metastasized PDAC will be extended with the evelopment of surgical techniques and thus more PDAC patients will have a clear survival benefit.
Methodical Notes
Funding Sources: Supported by the National Natural Science Foundation of China, No. 81472221; Clinical key projects of the National Health and Family Planning-Oncology 2013-2015. COI: The authors declare no conflict of interest Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: ausreichend Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: unklar Gruppen gleich behandelt (abgesehen von untersuchter Intervention): unklar Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Tachezy, Michael et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery (United States). 160. 136-144. 2016

Tachezy, Michael et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery (United States). 160. 136-144. 2016
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, multizentrisch (6 Pankreas-Zentren), Europa Number of Patient: n=138 n=69 kurative Resektion (R) n=69 abdominale Exploration (E) Recruitung Phase: 06/1994 - 07/2014 Inclusion Criteria: 1. histologisch bestätigtes PDAC und Lebermetastasen 2. Lebermetastasen sicher resezierbar 3. vollständige makroskopische Tumorresektion 4. simultane Resektion der Lebermetastasen Exclusion Criteria: 1. Ampulläre Karzinome 2. Karzinome im distalen Gallengang 3. Karzinome im Duodenum 3. Metastasen in anderen Regionen als der Leber 4. regionaler Lymphknotenbefall, (Fernmetastasen, nicht-regionale Lymphknotenstationen)	Intervention: kurative simultane Resektion von Karzinom und Lebermetastasen (R) Comparison: abdominale Exploration ohne Tumorresektion (E)	Primary: Gesamtüberleben Morbidität und Mortalität Secondary: Results: Follow-up Median 8,7 Monate. Medianes Gesamtüberleben R vs. E statistisch signifikant längeres Überleben bei R R: 14.5 Monate, 95% CI 10.8–18.2 E: 7.5 Monate, 95% CI 4.9–10.2 p<0.001 5-Jahres Überlebensrate R vs. E R: 5,8% (4/69) E 0% Subgruppenanalyse medianes Gesamtüberleben nach Tumorlokalisation linksseitige Tumoren (n=36): R vs. E Kein statistisch signifikanter Unterschied R: 14.0 Monaten (95% CI 6,7-21,3) E: 12.0 Monaten (95% CI 4,4-19,6) p=0,198 rechtsseitige Tumoren (n=102) R vs. E statistisch signifikant längeres Überleben bei R R: 14.5 Monate (95% CI 10.4–18.5) E: 7.0 Monate (95% CI 5.5–8.5) p<0.001 Morbidität und Mortalität Mediane Dauer des Krankenhausaufenthaltes R vs. E Statistisch signifikant länger bei R R: 16 Tage (6-99) E: 12 Tage (2-34) p<0,02 Medianer Aufenthalt auf der Intensivstation R vs. E Statistisch signifikant länger bei R R: 0 Tage (0-20) E: 0 Tage (0-5) p<0,02 Gesamtmorbidität R vs. E Statistisch signifikant höher bei R R: 68% E: 48% , p=0.025 Reoperationsraten R vs. E Kein statistisch signifikanter Unterschied 30-Tage-Mortalität: R vs. E Kein statistisch signifikanter Unterschied gleich (1/1) p=1,000 Prognosefaktoren für Gesamtüberleben (multivariate Analyse) Resektion prognostisch für mediane Gesamtüberleben E vs. R HR 2.224 (95% CI 1.448-3.415) p<0,001 Author's Conclusion: In conclusion, this study has added some reasonable information to the discussion about combined pancreatic and liver resection for selected patients with PDAC complicated by a limited burden of liver metastases. Despite the multiple limitations of our study and the caution required in the interpretation of the data, the apparent improved survival due to synchronous resections, in our opinion, merits a prospective study to address the potential survival benefits of such a procedure in highly selected patients.
Methodical Notes
Funding Sources: No funding was received to conduct the study. COI: The authors declare no conflicts of interest. Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

Kim, Y. et al. Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma. HPB. 18. 325-331. 2016

Kim, Y. et al. Improved survival after palliative resection of unsuspected stage IV pancreatic ductal adenocarcinoma. HPB. 18. 325-331. 2016
Population	Intervention - Comparison	Outcomes/Results
Evidence level: 4 Study type: retrospektive Kohorte, unizentrisch, Südkorea Number of Patient: n=70 n=35 mit Resektion (R) n=35 ohne Resektion, gematcht (NR) Recruitung Phase: 2000-2009 Inclusion Criteria: 1. PDAC mit intraoperativ gefundenen Metastasen Exclusion Criteria: 1. intraduktale papilläre, muzinöse Neoplasie 2. neuroendokrinem Tumor 3. Metastasen im Pankreas, die von einem anderen Primärtumor ausgehen	Intervention: Resektion bei intraoperativ gefundenen Metastasen (R) Comparison: keine Resektion bei intraoperativ gefundenen Metastasen (Bypass oder Biopsie) (NR)	Primary: Gesamtüberleben Operationszeit Bluttransfusionen Dauer des Krankenhausaufenthaltes 30-Tage Mortalität Postoperative Morbidität Postoperative Chemotherapie Secondary: Results: Follow-up Median 5,9 Monate (0,7-81,5) Gesamtüberleben R vs. NR statistisch signifikant höhere Überlebensrate bei R p<0,001 R + Chemotherapie vs. NR + Chemotherapie statistisch signifikant höhere Überlebensrate bei R + Chemotherapie p=0,017 Operationszeit R vs. NR statistisch signifikant länger bei R R: 491,9 min NR: 174,9 min p<0,001 Bluttransfusionen R vs. NR statistisch signifikant mehr bei R R: 2,40 units NR: 0,26 units p<0,001 Dauer des Krankenhausaufenthaltes R vs. NR statistisch signifikant länger bei R R: 23,5 Tage NR: 16,3 Tage p=0,009 30-Tage Mortalität Keine Postoperative Morbidität R vs. NR statistisch signifikant häufiger bei R R: 42,9% NR: 17,1% p=0,023 kein statistisch signifikanter Unterschied bei schweren Komplikationen Postoperative Chemotherapie R vs. NR statistisch signifikant häufiger nach R R: 82,9% NR: 57,1% p=0,019 Author's Conclusion: In summary, our data couldn’t suggest any recommendation but may implicate some possibility of stage IV PDAC operation. The basic premise for this aggressive approach is acceptable perioperative morbidity and mortality. In highly selected patients of stage IV PDAC, pancreatic resection and chemotherapy might have some role in survival gain.
Methodical Notes
Funding Sources: nicht angegeben COI: None declared Randomization: keine Randomisierung (retrospektiv) Blinding: keine Verblindung (retrospektiv) Dropout Rate/ITT-Analysis: nicht angegeben Notes: Gesamtqualität: keine methodischen Mängel Studiendesign: retrospektive Kohorte PICO Frage: ja Randomisiert: nein Gruppen vergleichbar: ja Gruppen gleich behandelt (abgesehen von untersuchter Intervention): ja Patienten nachverfolgbar (Loss of Follow-Up dokumentiert etc.): ja objektive Messung: ja Verblindung: nein

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