Borderline resectable pancreatic cancer

ARTICLE IN PRESS Cancer Letters ■■ (2016) ■■–■■

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

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Q2 Mini-review

Borderline resectable pancreatic cancer Q1 Thilo Hackert, Alexis Ulrich, Markus W. Büchler * Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany

A R T I C L E

I N F O

Article history: Received 10 January 2016 Received in revised form 20 February 2016 Accepted 23 February 2016 Keywords: Pancreatic cancer Borderline resectable Therapy

A B S T R A C T

Surgery followed by adjuvant chemotherapy remains the only treatment option for pancreatic ductal adenocarcinoma (PDAC) with the chance of long-term survival. If a radical tumor resection is possible, 5-year survival rates of 20–25% can be achieved. Pancreatic surgery has significantly changed during the past years and resection approaches have been extended beyond standard procedures, including vascular and multivisceral resections. Consequently, borderline resectable pancreatic ductal adenocarcinoma (BRPDAC), which has recently been defined by the International Study Group for Pancreatic Surgery (ISGPS), has become a controversial issue with regard to its management in terms of upfront resection vs. neoadjuvant treatment and sequential resection. Preoperative diagnostic accuracy to define resectability of PDAC is a keypoint in this context as well as the surgical and interdisciplinary expertise to perform advanced pancreatic surgery and manage complications. The present mini-review summarizes the current state of definition, management and outcome of BR-PDAC. Furthermore, the topic of ongoing and future studies on neoadjuvant treatment which is closely related to borderline resectability in PDAC is discussed. © 2016 Elsevier Ireland Ltd. All rights reserved.

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Q3 Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumor entities and the fourth leading cause for cancerassociated mortality in Western countries with – in contrast to other malignancies – still increasing rates of incidence [1]. In 15–20% of all patients, surgery is possible and offers the chance of long-term survival. When combined with adjuvant chemotherapy, 5-year survival rates of 20–25% can be achieved [2]. The importance of postoperative adjuvant chemotherapy has been demonstrated in large randomized studies during the last two decades [3–5] and represents the standard of care for all patients that are considered to be resectable by the time of diagnosis. With the ongoing development of specialization and centralization for pancreatic surgery since the late 1990s, not only postoperative mortality for these operations has been dramatically decreased [6,7]. In addition, the borders of resectability have been extended including approaches like vascular and multivisceral resections [8–10]. These developments have led to the need for a definition and standardization of local resectability with the aim to make publications on this topic comparable and to establish pathways for the diagnostic and therapeutic management of these patients. Today, the only situation that represents a clear contra-

* Corresponding author. Tel.: +49 6221 566201; fax: +49 6221 565450. E-mail address: [email protected] (M.W. Büchler).

indication for surgery is the finding of systemic spread, especially peritoneal carcinomatosis or diffuse liver metastases [11,12]. In contrast, locally advanced tumors without systemic spread – socalled borderline resectable tumors – should always be evaluated for either upfront surgery or neoadjuvant treatment and secondary resection in case of stable disease or remission during neoadjuvant therapy.

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Diagnostic workup and classification of resectability For the definition of local resectability in PDAC, the extension of the tumor toward the vascular structures, namely the superior mesenteric (SMV)/portal vein (PV) and the celiac axis (CA) as well as the superior mesenteric artery (SMA) is of utmost importance. A valid evaluation can be done by contrast-enhanced computed tomography (CE-CT) [13]. This diagnostic modality is available in nearly all institutions which has become a quick and relatively cheap diagnostic tool achieves sensitivity and specificity rates of 63–82% and 92–100%, respectively, with regard to PDAC diagnosis [14]. The use of a pancreas-specific CE-CT examination protocol with a 30° rightsided position of the patient and oral water intake to enhance the contrast in the gastro-duodenal region is the basis to maximize accuracy in the preoperative diagnostics [15]. In case of contraindications for a CE-CT, magnet-resonance imaging (MRI) can be used instead of CE-CT as the accuracy of MRI is comparable to CE-CT regarding diagnosis of PDAC and evaluation of the local tumor

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Fig. 2. BR-PDAC: axial CE-CT scan showing a hypodense tumor extension to the AMS <180° (white arrow).

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Fig. 1. BR-PDAC: axial CE-CT scan showing a hypodense PDAC (white circle) with involvement of the PV/SMV (white arrow).

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extension [14]. With regard to possible vascular involvement, the use of endoscopic ultrasound (EUS) has gained widespread acceptance today. This diagnostic tool shows best rates of sensitivity and specificity compared to CE-CT and MRI as it offers a very high resolution local imaging along the vessels [14]. The possible disadvantages of EUS include that – besides the invasive character of EUS from the patients’ perspective – the region of interest is limited, the accuracy of EUS is depending on the examiner’s experience and the results of this dynamic examination can be reproduced only during the procedure itself. Therefore, EUS has to be regarded as a complementary tool CE-CT or MRI and is not available as a standard procedure in all institutions. A prerequisite for the planning of a resection is the exclusion of distant metastases which is done with regard to the liver by the above-mentioned cross-sectional imaging modalities. Furthermore, pulmonary spread should be excluded by conventional chest X-ray and thoracic CT scan in case of any doubts. Local resectability is defined as primary resectable PDAC, borderline resectable (BR-PDAC) or irresectable PDAC according to the criteria published by the ISGPS in 2014 [16] which are mainly based on the recommendations of the National Comprehensive Cancer Network [11]. Resectable PDAC is characterized by the absence of any vascular attachment (no distortion of SMV or PV and clearly preserved fat planes toward CA and AMS, BR-PDAC comprises findings with a distortion/narrowing or occlusion of the respective veins but a technical possibility of reconstruction on the proximal and distal margin of the veins (Fig. 1). With regard to the arterial structures, a semicircumferential abutment (≤180°) of the SMA (Fig. 2) or an attachment at the hepatic artery (HA) without contact toward the CA is regarded as a borderline resectable finding. Finally, irresectable PDAC is defined as a more extended involvement of the SMA, CA, aorta or inferior vena cava as well as a SMV/PV venous involvement without a possibility for surgical reconstruction of the venous tract due to the lack of a suitable luminal diameter of the feeding and/or draining vein. This situation is most likely to be found in tumor-associated portal cavernous transformation. Besides these definitions, two other classifications are in clinical use, namely the definition of the AHPBA/SSO/SSAT published in 2009 [17] and the M.D. Anderson criteria, that were published in 2006 [18]. Both definitions are similar to the above mentioned

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in terms of resectable PDAC. Regarding arterial involvement, there are no relevant differences between all definitions either, however, with regard to PV involvement, the M.D. Anderson definition does not include contact or narrowing of the vein, but gives occlusion as the criterion for BR-PDAC. Furthermore, in this publication, irresectability is termed “locally advanced”. An additional aspect with regard to patient management is the recommendation of the AHPBA/ SSO/SSAT consensus that diagnostic laparoscopy should be performed in resectable tumors of the pancreatic head >3 cm, in all tumors of the body and tail and in patients who display CA 19-9 levels >100 U/ ml. This aspect is not mentioned in any other definition or consensus and is based on the observation that a considerable proportion of patients fulfilling these criteria show unexpected peritoneal or liver metastases despite local resectability. For the consecutive therapeutic decision, the recommendations for resectable and irresectable PDAC are clearly defined. While patients with resectable PDAC should undergo surgical exploration and radical resection, for irresectable PDAC patients the option of neoadjuvant treatment should be considered as the therapy of choice with the chance of a re-evaluation and eventually surgical exploration (see below). In BR-PDAC, therapeutic decisions have to differentiate between venous and arterial vessel involvement. In venous BR-PDAC, upfront surgery should be performed and – if the intraoperative finding matches the presumed borderline situation as defined above – completed as an en bloc tumor removal with venous replacement [19,20]. In contrast, when suspected arterial BR-PDAC is intraoperatively found to be a true arterial involvement, no general recommendation for resection is given, neoadjuvant treatment with a consecutive re-exploration and the option for a secondary resection is possible as well as direct arterial resection in exceptional cases or under study conditions. Beyond the topic of vascular tumor involvement, the involvement of any adjacent organ, i.e. mesocolon, colon, stomach, adrenal gland or kidney may be regarded as BR-PDAC as well. Although this is not covered by the ISGPS definition for BR-PDAC, surgery for respective findings is defined as an extended approach by the ISGPS [21]. There is international consensus that these extended approaches are feasible in terms of surgical and oncological outcome and organ involvement should not be considered an obstacle for resection as long as a radical tumor removal is possible. Consequently, these patients should undergo upfront surgery and should not be treated in a neoadjuvant setting [21].

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The feasibility of SMV/PV resection has been demonstrated in large series that showed surgical morbidity and mortality rates comparable to pancreatic head resections without vascular involvement [9,25,26] as well as in a recent systematic review including data on the outcome of more than 1.600 patients from 52 publications [20]. With a median operation time of 8.5 hours and a median blood loss of 1750 ml SMV/PV resections resulted in an average perioperative mortality of 5.9% and overall morbidity of 42%. Even if preoperative diagnostics show a tumor-related complete obstruction of the portal vein, this must not be regarded as a contraindication for surgery. Although intraoperatively, the preparation may be more difficult due to the collateral vessels, the restoration of the portal venous flow after resection and anastomosis offers an adequate drainage of the bowel despite the removal of most of the collateral vessels that may be necessary during the preparation. Oncological outcome in patients with venous resections is similar to patients undergoing standard resections for PDAC without increased rates of local or systemic failure [20]. The rate of histologically proven SMV/PV invasion is app. 65% and, in addition, a positive lymph node stage is found in two thirds of the patients, too. These findings result in a 1-, 3-, and 5-year overall survival of app. 50%, 18%, and 8% [9,20] which is clearly superior to any type of palliative treatment. To address the high percentage of positive nodal findings in patients who undergo portal or superior mesenteric vein resection, the importance of adjuvant therapy has to be underlined. Since adjuvant treatment has strongly improved survival and been introduced as the standard of care for patients with pancreatic cancer, future survival rates of patients with venous resection should be even better than those reported so far. SMV/PV resections during PDAC surgery can therefore be regarded as a standard procedure to achieve a complete removal of the tumor and can also be performed during multivisceral resections with the same intent of complete tumor clearance [27]. 177 178 179

Fig. 3. BR-PDAC: intraoperative situs after partial pancreato-duodenectomy with en bloc resection of tumor and. End-to-end anastomosis (type 3) of the SMV (black circle), hepatic artery taped (black arrow), cut pancreatic remnant (broken black arrow).

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Surgical approaches Vascular resections Venous resections Vascular resections during pancreato-duodenectomy to achieve tumor clearance and improved survival instead of declaring irresectability in case of SMV/PV involvement have been advocated for the last three decades [22]. Today, these approaches have gained wide acceptance and been included in national and international guidelines around the world [11,12,16]. As described before, the technical possibility to restore vessel continuity must be intraoperatively confirmed by evaluation of the diameter of the proximal and distal vein before resection. There are mainly four types of PV/ SMV resection [23]. As the easiest possibility, resection can be performed as a tangential resection of the vein with a direct suture (type 1). This is possible for pancreato-duodenectomy as well as for distal pancreatectomy if the direct closure does not lead to a hemodynamically relevant stenosis. The second possibility is the closure of a short tangential defect by a patch insertion (type 2). If this is not possible due to the length of the resected segment, the mesenteric root can be mobilized completely by resolving the attachment of the right hemicolon to the retroperitoneal adhesions (Cattell– Braasch maneuver [24]) and a direct anastomosis in an end-toend fashion (type 3, Fig. 3) or the interposition of a graft (type 4) can be performed.

Arterial resections In contrast to venous tumor adhesion, arterial infiltration of CA or SMA can be regarded as a symptom of an very aggressive tumor biology and the decision to perform a surgical resection in this situation is highly individual and still regarded as an extraordinary approach in PDAC surgery [28–32]. Both major arterial structures have to be evaluated differently with regard to the performance of a pancreatico-duodenectomy or a distal pancreatectomy and the extent of tumor abutment. If the SMA is involved in the tumor process exceeding 180° of the circumference or CA abutment, this is rather a general exclusion criterion for resection and has only been reported in few patients [31]. In contrast, situations with an arterial tumor abutment <180° along the SMA or short segment abutment of the HA as the only vitally important structure of the CA must not be considered as irresectable but fulfill the criteria of BR-PDAC [16]. There is consensus that all patients with suspected BR-PDAC due to an arterial involvement should undergo surgical exploration to confirm this situation and decide on the consecutive therapy. To evaluate arterial infiltration along the SMA and/or CA, “artery-first” approaches can be useful [33–35]. These techniques describe the preparation of the SMA or CA as an initial step before reaching any “point-of-no-return” situation during surgery. In the meantime, more than six different techniques have been described as “artery-first” techniques and are used according to the respective surgeons’ or centers’ preferences [34]. In case of confirmed tumor infiltration of the CA or the SMA, palliative treatment is recommended as the standard of care. However, the possibility of arterial resections as an individual approach or within clinical trials and the consideration of a neoadjuvant treatment with a consecutive re-exploration have to be mentioned. On

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Table 1 Series of distal pancreatectomies with CA resection including >10 patients.

275

Author, year

n

POPF

Overall morbidity

Mortality

Median survival

276 277 278 279 280 281 282 283 284

Wang, 2015 [40] Miura, 2014 [41] Jing, 2013 [37] Okada, 2013 [42] Yamamoto, 2012 [44] Takahashi, 2011 [43] Wu, 2010 [45] Hirano, 2007 [39] Shimada, 2006 [46]

15 50 24 16 13 16 11 23 12

40% nm nm 19% 62% 31% 14% 17% nm

66.7% 54% 54% nm 92% 56% nm 48% nm

7% 4% 0% 0% 0% 6% 0% 0% 0%

19.0 months 24.7 months 9.3 months 25.0 months 18.0 months 9.7 months 14 months 21.0 months 17.0 months

285 POPF: postoperative pancreatic fistula, nm: not mentioned. 286 287 one hand these approaches have been reported especially during 288 distal pancreatectomy, on the other hand the topic of neoadjuvant 289 therapy of BR-PDAC is currently one of the most important fields 290 in PDAC treatment. 291 Regarding distal pancreatectomy, CA resection without re292 vascularization (modified Appleby procedure) is an option for tumor 293 removal as long as the proper hepatic artery is preserved and a suf294 ficient arterial inflow via the gastroduodenal artery is present. 295 Numerous case series have described this procedure with reason296 able results in terms of surgical and oncological outcome which 297 seems to be nearly equal to the standard approaches [36–43]. Ac298 cording to the larger series in the literature, that include more than 299 10 patients, these procedures can be carries out with mortality rates 300 of 0–7% and an average overall morbidity of app. 50%. Median sur301 vival in these reports ranges between 10 and 25 months, in the 302 majority of publications app. 20 months can be achieved. Accord303 ing to these retrospective studies, CA resection during distal 304 pancreatectomy seem to be a considerable option in terms of post305 operative and long-term outcome, however, no high-level evidence 306 is available to support these findings. Table 1 summarizes the re307 spective studies. 308 In case of resection of the HA or SMA during pancreato309 duodenectomy or total pancreatectomy, restoration of the arterial 310 perfusion has to be performed either with a direct anastomosis or 311 graft insertion to replace the resected vessel. This reconstruction 312 can be done with an interposition of any arterial vessel of the celiac 313 axis or a venous interposition graft. In a recent review, the role of 314 arterial resection has been critically evaluated including all cur315 rently available studies [32]. Regarding resection of the SMA, five 316 studies were identified, including a total number of less than 30 pa317 tients. All authors showed that the resection is technically possible, 318 grafting with the saphenous vein was the most commonly used 319 method for reconstruction. However, morbidity of this approach is 320 high and the oncological outcome is not yet convincing from the 321 limited evidence. 322 CA or HA resection is performed more often. The available lit323 erature on this topic includes approximately 200 patients [36–43]. Surgical morbidity is up to 40%, mortality in pancreaticoduo324 denectomy with arterial resection ranges from 0 to 35%, showing 325 the inconsistent data basis of this approach. The major risk follow326 ing HA reconstruction is the occurrence of arterial hepatic perfusion 327 failure that may cause acute problems postoperatively in terms of 328 liver ischemia, necrosis and infection with a high associated mor329 330 Q4 tality [47,48]. The most comprehensive meta-analysis on arterial resection during PDAC surgery by Mollberg et al. [32] confirmed the 331 high risk of surgery-associated morbidity and mortality. Even more 332 importantly, it showed a poor oncological outcome with signifi333 cantly impaired survival in comparison to standard PDAC resections. 334 Consequently, resection of arterial vessels during PDAC surgery does 335 not represent a standard procedure. It may be a feasible option with 336 regard to distal pancreatectomy and en-bloc CA resection under pres337 ervation of the proper HA without reconstruction of a major arterial 338 vessel. All other arterial resections are highly-individual ap339

proaches for selected patients and need to be carried out by experienced pancreatic surgeons to minimize postoperative complications. Multivisceral resections Beyond infiltration of vascular structures, also adjacent organs can be affected by locally advanced PDAC. Mainly, the colon, stomach, left adrenal gland, small bowel or left kidney are affected. A complete tumor removal therefore requires partial or total resection of these organs during partial, distal or total pancreatectomy. These multivisceral resections fulfill the criteria of “extended resections” defined by the ISGPS in 2014 [21]. A neoadjuvant treatment is not indicated if technically a complete resection seems to be possible on the basis of the preoperative cross-sectional imaging. In larger series reporting on multivisceral resections, between 20 and more than 270 patients are included [8,27,49–51]. The most commonly resected organs are the colon and stomach in case of partial or total pancreatectomy and the adrenal gland during distal pancreatectomy. Remarkably, also PV/SMV resections are often performed synchronously reflecting the local extension of the tumor and the close anatomic relationship of these venous structures. The currently largest single-center series from Heidelberg included 101 patients and showed that multivisceral resections were associated with an increased postoperative morbidity but not mortality [27]. Postoperative morbidity was predicted by a long operation time and a resection of two or more additional organs as independent risk factors for intraabdominal complications or need for relaparotomy. Regarding oncological outcome, survival was similar to standard resections. In a study on 55 patients with multivisceral resections for PDAC [51], median survival was 16 months vs. 18 months for standard resections, which was significantly better than palliative bypass surgery. Multivariate risk factors for postoperative morbidity during multivisceral resections in this study included intraoperative blood transfusion and nephrectomy whereas survival was determined by T status, kidney resection, resection of four or more organs, any postoperative transfusion, and intensive care unit stay of >2 days in the univariate analysis and T status alone was confirmed as a predictor of survival in the multivariate analysis. A present update of the first study analyzing 600 PDAC patients who underwent extended resections for BR-PDAC compared to 1200 standard resections confirms the mentioned findings [52]. The performance of extended resections is associated with increased postoperative morbidity and mortality for patients with relevant co-morbidities and operation times of more than five hours. Apart from these two risk factors, multivisceral and vascular resections were not identified as parameters for poor postoperative outcomes and extended PDAC resections resulted in 16 months median and 11% five-year survival, which is clearly superior to any palliative treatment option. On one hand, these results underline that extended surgery is a feasible approach; on the other hand they raise the unsolved question of an accurate patient selection as certain subgroups seem to have a much greater benefit from surgery than

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Table 2 Series of neoadjuvant treatment with FOLFIRINOX schemes in BR-PDAC and unresectable PDAC.

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Khushman, 2015 [60] Blazer, 2015 [63] Nitsche, 2015 [61] Nanda, 2015 [76] Paniccia, 2014 [62] Christians, 2014 [77] James, 2014 [78] Faris, 2013 [65] Vasile, 2013 [79] Mahaseth, 2013 [80] Boone, 2013 [64] Gunturu, 2013 [81] Tinchon, 2013 [82] Hazariwala, 2013 [83] Peddi, 2012 [84] Hosein, 2012 [85] Kharofa, 2012 [86] Lowery, 2012 [87]

n

BR-PDAC

Unresectable

Resection rate

Survival [months]

51 43 14 29 20 18 22 22 32 24 25 16 12 14 23 18 12 19

11 18 – 14 20 18 – – nm 4 12 – 12 6 4 4 – –

40 25 14 15 – – 22 22 nm 20 13 16 – 8 19 14 12 19

20% 51% 29% 41% 85% 67% 46% 23% 41% 43% 43% 13% 83% 50% 35% 55% 58% 5%

35 overall 18 PFS 31 median 19 median na na na na na 18 median na na na na na na na 14 median

PFS: progression-free survival, nm: not mentioned, na: not achieved.

415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460

others and valid preoperative markers for this stratification are not defined yet. Neoadjuvant treatment Today, there is no sufficient evidence to support neoadjuvant treatment – neither by chemoradiation nor by chemotherapy alone – for patients that are considered to be resectable [53]. Comparably, in case of BR-PDAC no neoadjuvant treatment is recommended for venous tumor adherence or involvement of adjacent organs if a resection is technically possible and complete tumor removal can be achieved. According to the consensus recommendation of the ISGPS, both groups of patients should undergo upfront resection [16]. However, there are a number of ongoing studies on this issue that evaluate the effect of neoadjuvant therapy in the above-mentioned situations [54–65].The possible advantages of neoadjuvant therapy could include a stratification of patients with regard to tumor biology indicating those subgroups of patients with a very aggressive tumor that would not benefit from a resection despite the absence of systemic spread at the time of diagnosis. Furthermore, neoadjuvant treatment could improve R0 resection rates and decrease the incidence of local recurrence. Therefore, the results of these studies are highly warranted and may change clinical practice within the next years, comparable to studies investigating esophageal-gastric cancer outcome during the early 2000s and establishing the recommendation and international agreement on neoadjuvant treatment for the majority of these patients, today [66]. In case of BR-PDAC or clearly unresectable PDAC due to arterial involvement, neoadjuvant treatment should always be considered instead of immediate surgery [16]. This consideration is based on the fact that arterial resections – although technically often possible – are associated with a significant increase in postoperative morbidity as well as mortality and the observation that even patients that have successfully undergone arterial resections often have a very limited oncological benefit and suffer from early recurrence or metastatic spread [32]. These limitations can be overcome by neoadjuvant therapy as on one hand a patient selection is possible excluding patient with a tumor progression from surgery. On the other hand, an arterial resection can be avoided during surgery in a considerable number of patients as there is only fibrosis found along the arterial structures instead of former vital tumor formations and dissection of the arteries instead of resection can be performed. This clinical observation raises the question of diagnostic accuracy of the re-staging after completion of neoadjuvant treatment. Many patients do not show an explicit downstaging of

the local findings in CT scans after chemotherapy or chemoradiation [67]. As perineural spread has been shown to be an important prognostic factor [68], this has been investigated in several studies with regard to preoperative imaging prediction [69–71]. Although in primary diagnosis, high-resolution CT scan can predict perineural invasion along larger vessels with an accuracy of 95% [71], this does not seem to be reliable in a post-neoadjuvant setting and diagnostic sensitivity and specificity is highly limited [67]. An additional particular challenge of restaging is as the differentiation of vital tumor and fibrosis by conventional cross-sectional imaging is limited and even PET-CT scans do not offer 100% accuracy [72,73]. Patients with a clear tumor progression under neoadjuvant treatment should be excluded from secondary exploration. As to date, no valid diagnostic modality or marker is available that differentiates between vital tumor and residual fibrotic tissue with a sufficient sensitivity and specificity, all other patients should undergo surgical exploration to definitely evaluate this and perform a resection whenever possible. Intraoperatively, after confirming the absence of vital tumor by frozen section, a resection is often possible and eventually an ypT0 situation may be found. Due to the three scenarios described, neoadjuvant treatment is helpful to stratify patients and recognize those with BR-PDAC who do not benefit from extended resections. The debate on the most effective neoadjuvant treatment scheme is a currently unsolved issue. Traditionally, chemoradiation for locally advanced PDAC using gemcitabine- or 5FU-based protocols along with 50–54 Gy of radiation have been used [74] and shown secondary resection rates of app. 30% [75]. With the introduction of highly-effective chemotherapy regimens such as FOLFIRINOX or nabpaclitaxel, this approach has been challenged [44–46,76–87]. Preliminary study results have shown that these schemes may be equally or even more efficient and resection rates of up to 60% can be achieved. As there are no randomized studies comparing these approaches, evidence-based recommendations on the best treatment option cannot be given but a FOLFIRINOX-based regimen seems to be the most promising approach. Table 2 summarizes the available studies on this therapy option. To facilitate patient selection with BR-PDAC for the most promising therapy (upfront resection vs. neoadjuvant treatment), various prognostic scores and parameters have been examined. Imaging criteria (i.e. suspicion of lymph node metastases) and clinical performance status were used in a publication by Katz et al. [88] but did not reliably predict prognosis. Currently, the modified Glasgow Prognostic Score (mGPS) and CA 19-9 levels are the most reliable

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506 prognostic parameters [89–92]. Especially a decrease or even nor507 malization of elevated CA19-9 during neoadjuvant treatment is 508 associated with a good prognosis [90,91]. The mGPS – although not as commonly used as CA 19-9 – seems to be an additional valid pre509 dictor as a score value of 2 can be regarded as a poor prognostic 510 outcome parameter in the neoadjuvant setting [92]. Other 511 biomarkers or genetic specifications cannot yet be recommended 512 for prognostic stratification or therapy decisions [16]. 513 In conclusion, BR-PDAC remains an interdisciplinary treatment 514 challenge. Current developments focus on neoadjuvant therapy con515 cepts in BR-PDAC. Advanced surgical approaches including vascular 516 and multivisceral resections can be performed with good postop517 erative outcome and offer a chance of long-term survival. Recent 518 definitions of borderline resectability and extended resections by 519 the NCCN and the ISGPS definitions will help to standardize these 520 procedures in the scientific reporting in the future and make studies 521 on this topic more comparable. All surgical approaches must be part 522 of interdisciplinary multimodal concepts as radical resection alone 523 cannot achieve optimal patient outcome and always needs to be fol524 lowed by adjuvant treatment. 525 526 Conflict of interest 527 528 The authors declare no conflict of interest. 529 Q5 530 References 531 532 [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2015, CA Cancer J. Clin. 65 533 (1) (2015) 5–29. 534 [2] T. Hackert, M.W. Büchler, Pancreatic cancer: advances in treatment, results and 535 limitations, Dig. Dis. 31 (1) (2013) 51–56. 536 [3] J.W. Valle, D. Palmer, R. Jackson, T. Cox, J.P. Neoptolemos, P. Ghaneh, et al., 537 Optimal duration and timing of adjuvant chemotherapy after definitive surgery 538 for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 539 study, J. Clin. Oncol. 32 (6) (2014) 504–512. 540 [4] H. Oettle, P. Neuhaus, A. Hochhaus, J.T. Hartmann, K. Gellert, K. Ridwelski, et al., 541 Adjuvant chemotherapy with gemcitabine and long-term outcomes among 542 patients with resected pancreatic cancer: the CONKO-001 randomized trial, 543 JAMA 310 (14) (2013) 1473–1481. 544 [5] D.P. Ryan, T.S. Hong, N. Bardeesy, Pancreatic adenocarcinoma, N. Engl. J. Med. 545 371 (11) (2014) 1039–1049. 546 [6] M.W. Büchler, M. Wagner, B.M. Schmied, et al., Changes in morbidity after 547 pancreatic resection: toward the end of completion pancreatectomy, Arch. Surg. 548 138 (12) (2003) 1310–1314. 549 [7] B.N. Reames, A.A. Ghaferi, J.D. Birkmeyer, J.B. Dimick, Hospital volume and 550 operative mortality in the modern era, Ann. Surg. 260 (2) (2014) 244–251. 551 [8] M. Nikfarjam, M. Sehmbey, E.T. Kimchi, N.J. Gusani, S. Shereef, D.M. Avella, et al., 552 Additional organ resection combined with pancreaticoduodenectomy does not 553 increase postoperative morbidity and mortality, J. Gastrointest. Surg. 13 (5) 554 (2009) 915–921. 555 [9] V. Beltrame, M. Gruppo, S. Pedrazzoli, S. Merigliano, D. Pastorelli, C. Sperti, 556 Mesenteric-portal vein resection during pancreatectomy for pancreatic cancer, 557 Gastroenterol. Res. Pract. 2015 (2015) 659730. 558 [10] J. Weitz, P. Kienle, J. Schmidt, H. Friess, M.W. Büchler, Portal vein resection for 559 advanced pancreatic head cancer, J. Am. Coll. Surg. 204 (2007) 712–716. 560 [11] M.A. Tempero, M.P. Malafa, S.W. Behrman, A.B. Benson 3rd, E.S. Casper, E.G. 561 Chiorean, et al., Pancreatic adenocarcinoma, version 2.2014: featured updates 562 to the NCCN guidelines, J. Natl Compr. Canc. Netw. 12 (8) (2014) 1083–1093. 563 [12] T. Seufferlein, J.B. Bachet, E. Van Cutsem, P. Rougier, ESMO Guidelines Working 564 Group, Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines 565 for diagnosis, treatment and follow-up, Ann. Oncol. 23 (Suppl. 7) (2012) 566 vii33–vii40. 567 [13] M. Klauss, A. Mohr, H. von Tengg-Kobligk, H. Friess, R. Singer, P. Seidensticker, 568 et al., A new invasion score for determining the resectability of pancreatic 569 carcinomas with contrast-enhanced multidetector computed tomography, 570 Pancreatology 8 (2) (2008) 204–210. 571 [14] S.V. Shrikhande, S.G. Barreto, M. Goel, S. Arya, Multimodality imaging of 572 pancreatic ductal adenocarcinoma: a review of the literature, HPB (Oxford) 14 573 (10) (2012) 658–668. 574 [15] L. Grenacher, M. Klauss, Computed tomography of pancreatic tumors, Radiologe 575 49 (2) (2009) 107–123. 576 [16] M. Bockhorn, F.G. Uzunoglu, M. Adham, C. Imrie, M. Milicevic, A.A. Sandberg, 577 et al., Borderline resectable pancreatic cancer: a consensus statement by the 578 International Study Group of Pancreatic Surgery (ISGPS), Surgery 155 (6) (2014) 579 977–988. 580 [17] M.P. Callery, K.J. Chang, E.K. Fishman, M.S. Talamonti, L. William Traverso, D.C. 581 Linehan, Pretreatment assessment of resectable and borderline resectable 582

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