Pancreatic adenocarcinoma: ESMO–ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: T. Seufferlein, J.B. Bachet, E. Van Cutsem, P. Rougier
Journal: Annals of Oncology (2012)

epidemiology and risk factorsIn Europe, cancer of the pancreas is the seventh most frequent cancer, accounting for some 2.8% of cancer in men and 3.2% in women. It is the fifth leading cause of cancer-related death with ∼70 000 estimated deaths each year and predicted to become the fourth cause of cancer death in both sexes in due course in the European Union [1.Ferlay J. Parkin D.M. Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008.Eur J Cancer. 2010; 46: 765-781doi:10.1016/j.ejca.2009.12.014Abstract Full Text Full Text PDF PubMed Scopus (1877) Google Scholar, 2.Jemal A. Bray F. Center M.M. et al.Global cancer statistics.CA Cancer J Clin. 2011; 61: 69-90doi:10.3322/caac.20107Crossref PubMed Scopus (30015) Google Scholar]. In men, the estimated annual average incidence rate is 11.6 per 100 000 ranging from 4.7 (Cyprus) to 17.2 (Hungary). Mortality in men is ∼35 000 cases per year. The estimated average incidence rate in women is 8.1 per 100 000 ranging from 2.1 (Cyprus) to 11.4 (Finland). Mortality in women is also ∼35 000 cases per year [3.Malvezzi M. Bertuccio P. Levi F. et al.European cancer mortality predictions for the year 2012.Ann Oncol. 2012; 23: 1044-1052doi:10.1093/annonc/mds024Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Incidence increases with age and the majority of cases are diagnosed above the age of 65. Smoking, obesity and dietary factors such as high consumption of processed meat increase the risk for pancreatic cancer [4.Li D. Morris J.S. Liu J. et al.Body mass index and risk, age of onset, and survival in patients with pancreatic cancer.Jama. 2009; 301: 2553-2562doi:10.1001/jama.2009.886Crossref PubMed Scopus (321) Google Scholar, 5.Larsson S.C. Wolk A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies.Br J Cancer. 2012; 106: 603-607doi:10.1038/bjc.2011.585Crossref PubMed Scopus (177) Google Scholar] (II).Pancreatic cancer still has a dismal prognosis. According to the EUROCARE 4 study, the overall 1-year survival rate in Europe ranges from ∼11% in Malta to 28.3% in Belgium; >95% of those affected die of the disease. The high mortality rate is due to late diagnosis, early metastasis and poor response to chemo- and radiotherapy in most cases. Moderate improvement in survival in resectable pancreatic cancer has been achieved by adjuvant chemotherapy. Recently, some improvement in survival in the metastatic setting could be achieved by novel combination chemotherapy (see below).histology and geneticsThe major histological type of pancreatic cancer is ductal pancreatic adenocarcinoma accounting for >80% of pancreatic neoplasms. Other types are acinar cell carcinoma or neuroendocrine tumors. Most ductal pancreatic cancers (90%) are considered sporadic. There are some genetic conditions that are associated with an increased risk of pancreatic cancer, e.g. hereditary pancreatitis, Peutz–Jeghers syndrome, familial malignant melanoma, hereditary breast and ovarian cancer syndrome and Lynch syndrome. Hereditary conditions account for ∼5%–10% of pancreatic cancers.About 75% of all ductal pancreatic carcinomas occur within the head or neck of the pancreas, 15%–20% in the body and 5%–10% in the tail of the pancreas.More than 80% of ductal pancreatic cancers exhibit KRAS mutations, predominantly a G12V or G12D mutation. Furthermore, ∼90% of the tumors exhibit deletions, mutations or epigenetic alterations in the CDKN2 gene. Nearly 50% have mutations in the tumor suppressor p53 and also ∼50% exhibit mutations or homozygous deletions in the DPC4/Smad4 gene.symptoms and diagnosisLate diagnosis of pancreatic cancer results from a lack of early symptoms of the disease and the fact that even late symptoms are often not characteristic (abdominal or back pain). Currently there are no efficient screening tools available that can be recommended outside a high risk population, e.g. those suffering from the hereditary conditions outlined above. For those, regular endoscopic ultrasound (EUS) that allows the detection of small lesions and magnetic resonance imaging (MRI) is recommended [6.Verna E.C. Hwang C. Stevens P.D. et al.Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics.Clin Cancer Res. 2010; 16: 5028-5037doi:10.1158/1078-0432.CCR-09-3209Crossref PubMed Scopus (175) Google Scholar, 7.Zubarik R. Gordon S.R. Lidofsky S.D. et al.Screening for pancreatic cancer in a high-risk population with serum CA 19–9 and targeted EUS: a feasibility study.Gastrointest Endosc. 2011; 74: 87-95Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. (III; B)In case of a tumor of the pancreatic head that compresses the bile duct patients present with painless jaundice. Abdominal pain, back pain or weight loss are usually signs of late-stage disease. Sometimes patients also present with newly diagnosed diabetes or pancreatitis.For the diagnosis of suspected pancreatic cancer abdominal ultrasound is useful for the initial examination. For further evaluation, EUS, contrast-enhanced multi-detector computed tomography (MD-CT) and MRI combined with magnetic resonance cholangiopancreatography (MRCP) are more appropriate (level of evidence: good clinical practice). EUS, MD-CT and MRI together with MRCP have the highest sensitivity for the detection of pancreatic cancer and provide additional information on the pancreatic and the bile duct. Furthermore, EUS allows biopsy and/or fine needle aspiration cytology. MD-CT and MRI allow evaluation of invasion of vessels and metastasis (e.g. lymph nodes, liver, peritoneal cavity). Endoscopic retrograde cholangiopancreatography (ERCP) has a role only to relieve bile duct obstruction. However, in the preoperative setting ERCP and biliary stenting should only be performed if surgery cannot be done expeditiously (I; B). A recent trial demonstrated a substantial increase in serious complications in the group undergoing biliary stenting prior to surgery for cancer of the head of the pancreas [8.van der Gaag N.A. Rauws E.A. van Eijck C.H. et al.Preoperative biliary drainage for cancer of the head of the pancreas.N Engl J Med. 2010; 362: 129-137doi:10.1056/NEJMoa0903230Crossref PubMed Scopus (745) Google Scholar]. Positron emission tomography scanning (PET scan) has no role in the diagnosis of pancreatic cancer since it does not allow a reliable differentiation between chronic pancreatitis and pancreatic cancer [9.Murakami K. FDG-PET for hepatobiliary and pancreatic cancer: advances and current limitations.World J Clin Oncol. 2011; 2: 229-236Crossref PubMed Google Scholar].Tumor markers such as CA19.9 are of limited diagnostic value since CA19.9 is not specific for pancreatic cancer and persons lacking the Lewis antigen are unable to synthesize CA19.9. Furthermore, high levels of CA19.9 are also found if a patient is jaundiced with cholestasis. CA19.9 levels are therefore insufficient to make a diagnosis at this time. Baseline CA19.9 can be used to guide treatment and follow-up and may have a prognostic value in absence of cholestasis.Histological proof of malignancy is only mandatory in unresectable cases or when a neoadjuvant strategy is planned. For patients who will undergo surgery with radical intent, a previous biopsy is not obligatory. Biopsy should be restricted to cases, e.g. in which imaging results of a pancreatic lesion are ambiguous. Here, EUS-guided biopsy is preferred and percutaneous sampling should be avoided due to a lower risk of tumor seeding using EUS guided biopsy [10.Micames C. Jowell P.S. White R. et al.Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA.Gastrointest Endosc. 2003; 58: 690-695doi:10.1016/S0016-5107(03)02009-1Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar]. Metastatic lesions can be biopsied percutaneously under ultrasound or CT guidance or during EUS.staging and risk assessmentThe established staging system for pancreatic cancer is the one developed by the TNM committee of the AJCC-UICC (see Table 1). Stage grouping of pancreatic cancer is presented in Table 2. MD-CT or MRI plus MRCP should be used for staging. EUS can complement the staging by providing information on vessel invasion and potential involvement of lymph nodes and is the preferred means to obtain a biopsy of the pancreatic lesion.Table 1TNM classification for pancreatic cancerPrimary tumor TXPrimary tumor cannot be assessed T0No evidence of primary tumor TisCarcinoma in situb T1Tumor limited to the pancreas, ≤2 cm in greatest dimension T2Tumor limited to the pancreas, >2 cm in greatest dimension T3Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)Regional lymph nodes NXRegional lymph nodes cannot be assessed N0No regional lymph node metastasis N1Regional lymph node metastasisDistant metastases M0No distant metastasis M1Distant metastasis Open table in a new tab Table 2Stage grouping of pancreatic cancerStageTNM0TisN0M0IAT1N0M0IBT2N0M0IIAT3N0M0IIBT1N1M0T2N1M0T3N1M0IIIT4Any NM0IVAny TAny NM1 Open table in a new tab MD-CT of the chest is recommended to evaluate potential lung metastases. In the absence of typical symptoms, a bone scan is not useful since only a few patients with pancreatic cancer present with bone involvement at diagnosis. PET scan is currently not routinely recommended for the staging of ductal pancreatic cancer.The National Comprehensive Cancer Network (NCCN) guidelines provide imaging criteria of borderline resectable and definitely irresectable pancreatic cancers depending upon the extent of vein invasion as well as artery invasion [11.National Comprehensive Cancer NetworkPractice Guidelines in Oncology for Pancreatic Adenocarcinoma-v.1. 2011; (last accessed April 2012)http://www.nccn.orgGoogle Scholar].Laparoscopy may detect small peritoneal and liver metastases changing the therapeutic strategy in <15% of patients. It can be performed before resection in left-sided large tumors and/or in case of high CA19.9 levels or when neoadjuvant treatment is considered. However, the extent of cancer spread in cancer of the pancreas can often be determined accurately only during surgery.Recent data have shown that upon thorough reevaluation of a resected specimen in many cases a previous R0 resection had to be regarded as R1 [12.Verbeke C.S. Leitch D. Menon K.V. et al.Redefining the R1 resection in pancreatic cancer.Br J Surg. 2006; 93: 1232-1237doi:10.1002/bjs.5397Crossref PubMed Scopus (431) Google Scholar]. The concept of the circumferential resection margin (CRM) has been established for the analysis of rectal cancer but can also be adapted to the situation in pancreatic cancer. The definition of the CRM requires a specific pathological procedure to be correctly assessed [13.Verbeke C.S. Menon K.V. Redefining resection margin status in pancreatic cancer.HPB (Oxford). 2009; 11: 282-289doi:10.1111/j.1477-2574.2009.00055.xAbstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar]. Therefore, specific recommendations for the histopathological reporting of carcinomas of the pancreas have been published, e.g. by the British Royal College of Pathologists (http://www.rcpath.org/NR/rdonlyres/954273A2-3F01-4B97-B0F6-C136231DF65F/0/datasethistopathologicalreportingcarcinomasmay10.pdf). Here, painting of the CRM of the pancreas with an agreed color code is recommended and the recommended techniques to dissect the surgical specimen are described (Table 3). The CRM status is as a key prognostic factor. However, the rates of margin involvement and local tumor recurrence are often incongruous. Nevertheless, using a standardized, detailed pathology examination protocol, microscopic margin involvement is a common finding in pancreatic carcinoma (>75%) and correlates with survival. There is a controversy over the adequate minimum clearance for pancreatic, common bile duct and ampullary carcinoma. The British guidelines currently recommend that a carcinoma <1 mm from a resection margin is considered to be incompletely excised. Another established prognostic factor is the post-resection CA19.9 level.Table 3Summary of recommendationsScreening•Currently there are no efficient screening tools available that can be recommended outside a high risk population, e.g. those suffering from hereditary conditions. For those, regular EUS that allows the detection of small lesions and MRI is recommendedDiagnosis•Abdominal ultrasound is useful for the initial examination•For further evaluation, EUS, contrast-enhanced MD-CT and MRI combined with MRCP are more appropriate•ERCP has a role only to relieve bile duct obstruction•In the preoperative setting ERCP and biliary stenting should only be performed if surgery cannot be done expeditiously•PET scan has no role in the diagnosis of pancreatic cancer•Baseline CA19.9 can be used to guide treatment and follow-up and may have a prognostic value in absence of cholestasis•For patients who will undergo surgery with radical intent, a previous biopsy is not obligatory. Biopsy should be restricted to cases, e.g. in which imaging results of a pancreatic lesion are ambiguous. Here, EUS guided biopsy is preferred and percutaneous sampling should be avoided•Metastatic lesions can be biopsied percutaneously under ultrasound or CT guidance or during EUSStaging•The established staging system for pancreatic cancer is the one developed by the TNM committee of the AJCC-UICC•MD-CT or MRI plus MRCP should be used for staging. EUS can complement the staging by providing information on vessel invasion and potential involvement of lymph nodes and is the preferred means to obtain a biopsy of the pancreatic lesion•MD-CT of the chest is recommended to evaluate potential lung metastases•In the absence of typical symptoms, a bone scan is not useful since only a few patients with pancreatic cancer present with bone involvement at diagnosis. PET scan is currently not routinely recommended for the staging of ductal pancreatic cancer•Laparoscopy may detect small peritoneal and liver metastases changing the therapeutic strategy in <15% of patients. It can be performed before resection in left-sided large tumors and/or in case of high CA19.9 levels or when neoadjuvant treatment is considered•Using a standardized, detailed pathology examination protocol, microscopic margin involvement is a common finding in pancreatic carcinoma (>75%) and correlates with survivalTreatment•The only curative treatment of pancreatic cancer is radical surgery. This approach is mainly suitable for patients with early stage of disease mainly stage I and some stage II•Elderly patients do benefit from radical surgery. However, comorbidity can be a reason to abstain from an otherwise possible resection especially in patients older than 75–80 years•In case of tumors of the pancreatic head, partial pancreatico-duodenectomy is the treatment of choice•Cancer of the pancreatic body or tail is usually treated by distal resection of the pancreas. In some cases total pancreatectomy is required•It is recommended to refer to the National Comprehensive Cancer Network criteria for resectability/irresectability [11.National Comprehensive Cancer NetworkPractice Guidelines in Oncology for Pancreatic Adenocarcinoma-v.1. 2011; (last accessed April 2012)http://www.nccn.orgGoogle Scholar]•In pancreatic cancer there is no evidence that extended lymphadenectomy is beneficial. Standard lymphadenectomy comprises dissection of the lymph nodes of the hepatoduodenal ligament, the common hepatic artery, the portal vein, the right sided celiac artery lymph node and lymph nodes at the right half of the superior mesenteric artery. The LNR (number of involved LN/number of examined LN) should be indicated since an LNR ≥0.2 is a negative prognostic factor•Postoperatively, 6 months of GEM or 5-FU chemotherapy are recommended•Patients do also benefit from adjuvant/additive chemotherapy after R1 resection•Chemoradiation in the adjuvant or additive setting should only be performed within randomized controlled clinical trials•In case of resectable pancreatic cancer neoadjuvant chemotherapy, radiotherapy or chemoradiation should only be performed within clinical trials•Neoadjuvant strategies could be useful in patients with resectable tumors and patients should be encouraged to join clinical trials in this setting•In case of larger tumors and/or tumors with vessel encasement that are borderline resectable or technically non resectable, patients may benefit from neoadjuvant chemotherapy or chemoradiotherapy to achieve downsizing of the tumor and may convert the tumor to become resectable•Patients who develop metastases during neoadjuvant chemotherapy or who progress locally are not candidates for secondary surgery•Intraoperative radiotherapy is still experimental and cannot be recommended for routine use•In patients with unresectable tumors, GEM treatment in conventional dosing (1000 mg/m2 over 30 min) is recommended•For patients with metastatic disease, GEM is a reasonable choice and was the standard chemotherapy until recently•Combinations of GEM and other cytotoxic agents, such as 5-FU or capecitabine, irinotecan, cis- or oxaliplatin, do not confer a significant advantage in survival even in large randomized phase III trials and should not be used as standard first line treatment of locally advanced or metastatic pancreatic cancer•The FOLFIRINOX protocol confers a significant improvement in the OS of patients with stage IV pancreatic cancer and can be considered as a novel therapeutic option for patients ≤75 years of age with a good PS (0 or 1) and a level of bilirubin ≤1.5 ULN•Patients with metastatic pancreatic cancer can be treated with a combination of GEM and erlotinib, but treatment with erlotinib is only continued if patients develop skin rash within the first 8 weeks of treatment•The combination of 5-FU and oxaliplatin can be considered as a treatment option in the second line setting after first-line GEM•In patients treated with first-line FOLFIRINOX who can receive second-line chemotherapy after progression, GEM can be considered as an optionPalliative therapy•Endoscopic stenting is the preferred procedure in unresectable patients•Metal prostheses should be preferred for patients with a life expectancy of >3 months. In case plastic stents are used they should be replaced at least every 6 months to avoid stent occlusion and ascending cholangitis•When endoscopic treatment is not possible, percutaneous transhepatic biliary drainage is recommended•Pro-kinetics such as metoclopramide can be useful to speed gastric emptying•Duodenal obstruction may be overcome by the use of an expandable metal stent•Patients who present with severe pain must receive opioids. Morphine is generally the drug of choice. Usually, the oral route is preferred in routine practice. Parenteral or transdermal routes of administration should be considered for patients who have impaired swallowing or gastrointestinal obstruction•In some cases, hypofractionated radiotherapy may be delivered to these patients in order to improve pain control and reduce analgesic consumption•Percutaneous or per-EUS celiacoplexus blockade can be considered, especially for patients who experience poor tolerance of opiate analgesicsResponse evaluation in the palliative setting•Patients should be followed at each cycle of chemotherapy for toxicity and evaluated for response to chemotherapy every 8 weeks•Clinical benefit and ultrasound may be useful tools to assess the course of disease in the metastatic setting•When performing abdominal ultrasound patients should be monitored for the presence of ascites that can indicate peritoneal diseaseFollow-up after surgical treatment•A follow-up schedule should be discussed with the patient and designed to avoid emotional stress and economic burden for the patient•In the case of elevated preoperative serum CA19.9 levels the assessment of this marker could be performed every 3 months for 2 years and an abdominal CT scan every 6 monthsEUS, endoscopic ultrasound; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; FOLFIRINOX, 5-FU, irinotecan and oxaliplatin; 5-FU, 5-fluorouracil; GEM, gemcitabine; LNR, lymph node ratio; MD-CT, multi-detector computed tomography; PET scan, positron emission tomography scanning. Open table in a new tab treatment optionsThe only curative treatment of pancreatic cancer is radical surgery. This approach is mainly suitable for patients with early stage of disease mainly stage I and some stage II.Age is no criterion to select patients for a surgical approach. Elderly patients do benefit from radical surgery. However, comorbidity can be a reason to abstain from an otherwise possible resection especially in patients older than 75–80 years.The major goal of surgery is the R0 resection (I; A). In case of tumors of the pancreatic head, partial pancreatico-duodenectomy is the treatment of choice. Preservation of the pylorus does not confer a survival advantage for the patients [14.Diener M.K. Fitzmaurice C. Schwarzer G. et al.Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma.Cochrane Database Syst Rev. 2011; 11: CD006053Google Scholar]. Cancer of the pancreatic body or tail is usually treated by distal resection of the pancreas. In some cases total pancreatectomy is required.A critical issue is to define resectability in pancreatic cancer. It is recommended to refer to the NCCN criteria for resectability/irresectability [11.National Comprehensive Cancer NetworkPractice Guidelines in Oncology for Pancreatic Adenocarcinoma-v.1. 2011; (last accessed April 2012)http://www.nccn.orgGoogle Scholar]. If the tumor is deemed not resectable, the aim of treatment is prolongation of survival and palliation of symptoms related to the disease by optimal local control and control of metastatic growth.R0 resection can be possible despite infiltration of the tumor into neighboring organs (e.g. the duodenum). Infiltration of the portal or superior mesenteric vein can still allow an R0 resection, but confers a worse prognosis. Infiltration of the celiac artery or the superior mesenteric artery by the tumor rarely allows a R0 resection of the tumor and should therefore be regarded as non-curative surgery. There is no proven indication and no clear recommendation for such operations.In pancreatic cancer there is no evidence that extended lymphadenectomy is beneficial. Standard lymphadenectomy comprises dissection of the lymph nodes of the hepatoduodenal ligament, the common hepatic artery, the portal vein, the right sided celiac artery lymph node and lymph nodes at the right half of the superior mesenteric artery. The lymph node ratio (LNR, number of involved LN/number of examined LN) should be indicated since an LNR ≥ 0.2 is a negative prognostic factor [15.Riediger H. Keck T. Wellner U. et al.The lymph node ratio is the strongest prognostic factor after resection of pancreatic cancer.J Gastrointest Surg. 2009; 13: 1337-1344doi:10.1007/s11605-009-0919-2Crossref PubMed Scopus (286) Google Scholar] (III; B).adjuvant treatmentPostoperatively, 6 months of gemcitabine (GEM) or 5-fluorouracil (5-FU) chemotherapy are recommended on the basis of three randomized trials [16.Neoptolemos J.P. Stocken D.D. Friess H. et al.A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med. 2004; 350: 1200-1210doi:10.1056/NEJMoa032295Crossref PubMed Scopus (2171) Google Scholar, 17.Neoptolemos J.P. Stocken D.D. Bassi C. et al.Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.Jama. 2010; 304: 1073-1081doi:10.1001/jama.2010.1275Crossref PubMed Scopus (1048) Google Scholar, 18.Oettle H. Post S. Neuhaus P. et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.Jama. 2007; 297: 267-277doi:10.1001/jama.297.3.267Crossref PubMed Scopus (1974) Google Scholar] (I; A). There is no substantial difference in terms of disease-free survival or overall survival (OS) in a formal comparison between adjuvant 5-FU and GEM. Adjuvant chemotherapy either with GEM or with 5-FU using the Mayo Clinic bolus 5-FU schedule improves the 5-year survival rate from ∼9% to 20% in R0/R1 resected patients. However, GEM treatment is associated with less toxic side-effects compared to bolus 5-FU [17.Neoptolemos J.P. Stocken D.D. Bassi C. et al.Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.Jama. 2010; 304: 1073-1081doi:10.1001/jama.2010.1275Crossref PubMed Scopus (1048) Google Scholar]. Patients do also benefit from adjuvant/additive chemotherapy after R1 resection [18.Oettle H. Post S. Neuhaus P. et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.Jama. 2007; 297: 267-277doi:10.1001/jama.297.3.267Crossref PubMed Scopus (1974) Google Scholar].The role of adjuvant chemoradiation is controversial as reported in a few randomized phase III trials, particularly in the negative ESPAC-1 trial [16.Neoptolemos J.P. Stocken D.D. Friess H. et al.A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.N Engl J Med. 2004; 350: 1200-1210doi:10.1056/NEJMoa032295Crossref PubMed Scopus (2171) Google Scholar]. Since there is no proof of any advantage of adjuvant or additive chemoradiation as compared to adjuvant/additive chemotherapy alone, chemoradiation in the adjuvant or additive setting should only be performed within randomized controlled clinical trials (I; B).neoadjuvant chemotherapy or chemoradiotherapyIn case of resectable pancreatic cancer neoadjuvant chemotherapy, radiotherapy or chemoradiation should only be performed within clinical trials (III; B). However, the majority of patients relapse after resection of pancreatic cancer with metastases and it is increasingly recognized that many pancreatic cancers metastasize rather early during carcinogenesis. Thus, neoadjuvant strategies could be useful in patients with resectable tumors and patients should be encouraged to join clinical trials in this setting.In case of larger tumors and/or tumors with vessel encasement that are borderline resectable or technically non resectable, patients may benefit from neoadjuvant chemotherapy or chemoradiotherapy to achieve downsizing of the tumor and may convert the tumor to become resectable. However, the optimal neoadjuvant strategy is still under investigation and there is so far no standard protocol for neoadjuvant chemoradiotherapy in Europe. In the case of borderline resectable patients, a neoadjuvant chemotherapy approach may be able to identify a subgroup of patients unlikely to benefit from surgical resection. Patients who develop metastases during neoadjuvant chemotherapy or who progress locally are not candidates for secondary surgery [19.Arvold N.D. Ryan D.P. Niemierko A. et al.Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer.Cancer. 2010; 118: 3026-3035doi:10.1002/cncr.26633Crossref Scopus (52) Google Scholar] (IV; B)Intraoperative radiotherapy (IORT) is still experimental and cannot be recommended for routine use.In patients with unresectable tumors, GEM treatment in conventional dosing (1000 mg/m2 over 30 min) is recommended [20.Burris 3rd, H.A. Moore M.J. Andersen J. et al.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.J Clin Oncol. 1997; 15: 2403-2413Crossref PubMed Scopus (5110) Google Scholar, 21.Poplin E. Feng Y. Berlin J. et al.Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group.J Clin Oncol. 2009; 27: 3778-3785doi:10.1200/JCO.2008.20.9007Crossref PubMed Scopus (381) Google Scholar] (I; A). Trials comparing chemoradiation with chemotherapy alone reported contradictory results [22.Loehrer Sr., P.J. Feng Y. Cardenes H. et al.Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial.J Clin Oncol. 2011; 29: 4105-4112doi:10.1200/JCO.2011.34.8904Crossref PubMed Scopus (615) Google Scholar] and one phase III trial was in favor of using chemotherapy as first line treatment [23.Barhoumi M. Mornex F. Bonnetain F. et al.Locally advanced unresectable pancreatic cancer: induction chemoradiotherapy followed by maintenance gemcitabine versus gemcitabine alone: definitive results of the 2000–2001 FFCD/SFRO phase III trial.Cancer Radiother. 2011; 15: 182-191Crossref PubMed Scopus (20) Google Scholar]. A suggestion for the treatment of patients with locally advanced pancreatic cancer arose from a retrospective analysis of patients enrolled in the GERCOR studies and from a systematic review of trials of chemoradiation in locally advanced pancreatic cancer. Patients treated with GEM not progressing after 3 months of treatment and with a good perf