pancreatic ductal adenocarcinoma ( pdac ) is associated with the worst prognosis of all gastrointestinal malignancies , mainly due to late and unspecific symptoms , an aggressive tumor biology , and resistance to most therapies . , these patients were subjected to primary resection ; however , new data suggest that this group of patients may benefit from perioperative / neoadjuvant systemic chemotherapy . another 3040% of patients present with borderline resectable or locally advanced / unresectable tumors . here , the risk of occult distant metastasis is higher than in patients with smaller resectable tumors , and perioperative / neoadjuvant treatment is generally recommended to downsize the primary tumor and estimate tumor biology . depending on the patient 's performance status and preferences , more or less aggressive regimens can be chosen . the further course is determined to be neoadjuvant / curative or palliative depending on the radiological and tumor marker response . however , radiological response prediction is difficult , and tumor markers are informative only in a subgroup of patients . the largest group of patients ( 50% ) with pdac has metastases at the time of diagnosis which is associated with a very limited prognosis of < 1 year . for these patients , this review discusses the current controversy whether patients with pdac should consistently be treated in a perioperative / neoadjuvant setting . further , different treatment approaches for patients with pdac who are resectable or can likely be converted to resectability are briefly addressed . accurate staging and discussion in multidisciplinary tumor boards are necessary to classify the extent of tumor growth / tumor stage and to be able to make treatment decisions . classification of resectability into borderline resectable and locally advanced , unresectable disease should follow the most widely used radiological guidelines of the national comprehensive cancer network , which have also been adopted by the international study group for pancreatic surgery . however , re - classification during or after ( neoadjuvant ) treatment has turned out to be difficult as radiological findings are often not able to discriminate between vital tumor cells and fibrotic nonmalignant stroma , which may result from effective neoadjuvant treatment . thus , if in doubt , liberal indication for surgical exploration can be beneficial for those patients with radiological unclear response . indeed , some centers advocate exploration in all patients whose tumors do not progress during therapy . depending on the tumor localization and the grade of vessel infiltration , surgical resections are highly complex . first approaches to pdacs that were resectable or borderline resectable ( at least not clearly unresectable ) consisted of exploration with primary tumor removal if possible . however , over three - quarter of patients with any extent of the primary pdac , who undergo macroscopic complete surgical resection will develop distant metastases as the first evidence of recurrence . thus , clinically occult metastases may be present already at the time of diagnosis , which limits postoperative prognosis . this is one reason why adjuvant chemotherapy is effective and recommended for all patients after resection of pdac . however , due to the extent of surgery and delayed recovery and rehabilitation , in approximately 50% of all cases , adjuvant chemotherapy is not given as planned preoperatively . due to this fact , recent recommendations advocate neoadjuvant treatment not only for patients with locally advanced / borderline resectable pdac . rather , neoadjuvant schemes are also preferred over adjuvant schemes for patients with primary resectable tumors . since there has been a lack of effective single or combination chemotherapies for pdac , traditionally , preoperative therapy consisted of chemoradiation . this resulted in an increased median postoperative survival of nearly 2 years for initial resectable patients who underwent neoadjuvant therapy . within the last two decades , many neoadjuvant treatment protocols have been developed since a higher chance of local control was shown in retrospective analyses of pdac patients who underwent preoperative therapy . however , till date , no completed randomized controlled clinical trial on the effectiveness of neoadjuvant therapy has been published . preoperative treatment , such as neoadjuvant chemotherapy or chemoradiation , may be an effective strategy for all patients with pdac regardless the local tumor extent . more patients are able to complete therapy in a preoperative setting since approximately 50% of patients do not complete adjuvant therapy as planned preoperatively due to delayed recovery and rehabilitation . furthermore , neoadjuvant treatment can induce tumor regression , which may increase the likelihood of complete tumor resection ( r0 resection ) in both , borderline and primary resectable tumors . however , at the moment , evidence - based guidelines for neoadjuvant therapy in primary resectable pancreatic cancer are still missing due to lack of randomized studies . at least , up to 50% of initially borderline / unresectable patients become eligible for surgical resection after neoadjuvant therapy . further rationale for a neoadjuvant approach for all patients with pdac regardless of the tumor extent is that during an induction therapy of 23 months , unfavorable tumor biology can be anticipated if progression occurs during therapy . in the subset of 2030% of patients who develop local progression or distant metastasis under induction chemotherapy , an operation with its associated morbidity can therefore be avoided . initial concerns that the time point of resectability is missed by neoadjuvant therapy and postoperative complications are elevated have neither been proven nor ruled out . in fact , disease progression during or after neoadjuvant therapy , if it occurs , is usually seen at distant sites such as the liver , peritoneum , and lung , and < 1% of patients develop isolated local disease progression at the time of restaging after neoadjuvant therapy . furthermore , the texture of a preoperative treated pancreas usually becomes more firm and has reduced enzyme production , which would be more likely to reduce the rates of pancreatic fistula and anastomotic leakage , the most frequent serious postoperative complications , rather than to increase it . even if a tumor is radiologically staged resectable from the beginning , there seems to be a higher rate of r0 resections after neoadjuvant - combined chemoradiation . for all that , no differences in the postoperative mortality and morbidity could be shown . however , potential disadvantages of neoadjuvant therapy are complications from pretreatment endoscopic or endosonographic interventions ( i.e. , fine needle aspiration or true cut biopsy ) for histological proof of pdac before therapy , as well as the challenge of collaboration between different disciplines ( oncologists , pathologists , radiation oncologists , and surgeons ) . further , even if the primary tumor shrinks , the relationship of the tumor to the adjacent vessels may stay unchanged , and only in a small percentage , a change in the clinical tumor stage has been reported . finally , tumor progression can not be excluded in the setting of a tumor that does not respond to neoadjuvant treatment . chemotherapeutic regimens have evolved from gemcitabine alone to 5-fu , leucovorin , irinotecan , oxaliplatin ( folfirinox ) , gemcitabine , docetaxel , capecitabine ( gtx ) , gemcitabine / nab - paclitaxel , and other less established combination therapies . because recommendations differ , individualized concepts should be discussed for every patient in multidisciplinary tumor boards . a recently suggested approach is to administer 2 months of neoadjuvant chemotherapy , followed by restaging . in the case of no significant tumor regression by radiological and cancer antigen 19 - 9 findings , rather transition to chemoradiation to reach resectability is recommended than the second - line systemic chemotherapy . figure 1 depicts a flowchart with all currently justifiable treatment options depending on the stage and extent of pdac . in contrast to many other solid tumors , the treatment algorithm for patients with localized pdac , especially borderline resectable and locally advanced tumors , remains controversial and multimodal therapies are increasing . due to shrinkage of the primary tumor as well as putative destruction of distant micrometastases , preliminary clinical data are pointing less toward primary resection , rather suggesting improved outcome for neoadjuvant - intended treatment for every patient with localized pdac . if chemotherapy alone is applied , gemcitabine / nab - paclitaxel and folfirinox over 2 months are the most common regimens , under consideration of both , the patient 's physical status and personal preferences , respectively . chemoradiation can be used as well ; however , compared to chemotherapy alone , it is more controversial and less effective in the palliative setting . in the case of chemoradiation , gemcitabine combined with external - beam radiation therapy is favored . finally , since there is no high - quality evidence available , it is still reasonable not to treat every patient with pdac before surgery , and indeed , most guidelines do not suggest neoadjuvant therapy in resectable tumors yet . finally , as radiological findings do not always represent the true extent of vital tumor , every patient who underwent neoadjuvant therapy and whose tumor did not progress may benefit from surgical exploration .