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 .
 pancreatic ductal adenocarcinoma is a highly aggressive disease , and medical as well as surgical therapeutic options are limited . 
 this article reviews stage dependent treatment options , with a special focus on the current controversy of perioperative treatment regimens in initially borderline resectable or locally advanced patients . 
 neoadjuvant treatment can potentially increase the rate of complete tumor resection and may be more effective than adjuvant systemic therapy . 
 further , in the case of disease progression during or after neoadjuvant therapy , patients can be spared extensive surgery . today , common therapeutic regimens include gemcitabine / nab - paclitaxel and folfirinox , as well as chemoradiation . 
 however , because of the paucity of evidence from randomized trials , most guidelines do not recommend neoadjuvant therapy in resectable tumors , and for borderline or locally advanced tumors only within clinical trials . 
 importantly , every patient should be discussed in multidisciplinary tumor boards . 
INTRODUCTION
TREATMENT RESPONSE AND SURGICAL RESECTABILITY
FROM ADJUVANT TO NEOADJUVANT TREATMENT IN PANCREATIC DUCTAL ADENOCARCINOMA
RATIONALE OF NEOADJUVANT TREATMENT
TREATMENT ALGORITHM FOR PANCREATIC DUCTAL ADENOCARCINOMA
SUMMARY
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