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Pancreaticoduodenectomy with vascular resection for pancreatic head adenocarcinoma Expert Rev. Anticancer Ther. 14(8), 919–929 (2014)

Joe Spencer Liles and Matthew HG Katz* Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT17.6000, Houston, TX 77030, USA *Author for correspondence: [email protected]

Traditionally, pancreatic ductal adenocarcinoma with regional vascular involvement was thought to represent unresectable disease and was associated with disease progression and death within 1 year of diagnosis. Recent evidence demonstrates that pancreaticoduodenectomy with vascular resection and reconstruction can be safely performed in select patients with 5-year survival rates as high as 20%. In order to safely treat and to optimize survival in these complex patients, it is essential to accurately identify vascular involvement preoperatively, to utilize a multidisciplinary treatment approach, and to emphasize meticulous surgical technique with awareness of the critical margins of resection. KEYWORDS: celiac axis • hepatic artery • multimodality therapy • pancreatic adenocarcinoma • portal vein • superior mesenteric artery • superior mesenteric vein • vascular involvement • vascular resection

Pancreatic ductal adenocarcinoma is a lethal disease associated with a 5-year overall survival of only 6% [1]. This dismal outcome is largely due to the fact that nearly 80% of patients present with advanced disease characterized by an overall survival duration of only 6–12 months [2,3]. Results are not as poor for the 20% of patients who present with potentially or borderline resectable disease and are able to undergo radical resection of their primary tumor and regional lymph nodes. Modern multimodality treatment regimens that include surgical resection may yield rates of actual 5-year survival as high as 27% among this select group [4,5]. These results represent a significant improvement in survival relative to historical controls and bring some optimism to a historically dismal field. The pancreas lies deep within the retroperitoneum and is anatomically associated with several critical vascular structures: the celiac axis, hepatic artery, the superior mesentery artery, the portal vein and the superior mesenteric vein. As resection is currently the only possible means of cancer cure and systemic chemotherapy alone has done little to provide more than several months of survival for

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10.1586/14737140.2014.919860

patients with locally advanced disease, motivation exists to attempt more extensive resections when tumor involves these vital structures. Individual case reports and small series describing portal vein and superior mesenteric vein confluence resection concomitant with pancreaticoduodenectomy for the treatment of pancreatic adenocarcinoma date to the 1950s and 1960s [6–8]. In 1983, Fortner published the first large series of vascular resection with pancreaticoduodenectomy [9]. It must be pointed out that this publication was not intended to highlight vascular resection as a means of achieving a margin-negative resection but rather to introduce the concept of a ‘regional pancreatectomy’ performed in an attempt provide a more oncologically sound operation through wide anatomic clearance of all regional soft tissues [10]. Although Fortner’s initial description did demonstrate the feasibility of vascular resection and reconstruction in the setting of pancreatic cancer surgery, the ‘regional pancreatectomy’ he advocated did not improve oncological outcomes [9]. Vascular resection in the setting of operations for pancreatic cancer therefore lost favor over the next 20 years.

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Today, vascular resection in the surgical management of pancreatic cancer remains controversial. Standard pancreaticoduodenectomy is a complex operation associated with significant perioperative morbidity; concomitant vascular resection by those inexperienced with the techniques may increase the potential for additional morbidity or mortality. Furthermore, the oncologically aggressive nature of pancreatic adenocarcinoma, the low frequency with which cure is achieved even in the setting of a complete surgical resection and the unfamiliarity with the indications for and the technical aspects of vascular resection have all dissuaded many surgeons from attempting these radical operations [11,12]. Here, we review the current data regarding vascular resection, discuss treatment guidelines and resectability classifications and explain the critical principles of management regarding pancreatic cancer with vascular involvement. Vascular resection

Among patients who have tumors that involve major vascular structures, poor long-term prognosis after complete resection and high-operative risk are frequently cited as reasons to avoid aggressive resection. A plethora of single and multi-institution, prospective studies over the last 20 years have investigated these outcome measures in the setting of tumors with venous and arterial involvement, and their findings are worthy of further discussion. Due to the differences in outcomes for each of these topics, venous resection and arterial resection are discussed separately. Venous involvement

Pancreaticoduodenectomy with venous resection for tumors that appear to involve the superior mesenteric vein, portal vein or the confluence of these two veins has been critically investigated over the past two decades. Although the frequency of vascular involvement and resection varies widely between different treatment centers and countries, many recent studies have demonstrated that aggressive resection of pancreatic tumors with venous involvement can be performed with similar morbidity and mortality to standard pancreaticoduodenectomy, and more significantly, that resection of these complex tumors may yield reasonably favorable long-term survival. In order to appreciate the impact of venous resection on the long-term prognosis of locally aggressive pancreatic adenocarcinoma with limited vascular involvement, one must measure survival after resection relative to other available treatment options. Lygidakis et al. randomized patients with limited vascular involvement to either complete resection or palliative gastro-biliary bypass followed by loco-regional chemoimmunotherapy in both groups and found a striking 2-year survival of 81.8% in the resection group compared with 0% in the palliative bypass group [13]. In a multi-institutional, prospective study comparing pancreatectomy with vascular resection to chemoradiation alone, Doi et al. found that surgical resection was associated with a more favorable mean survival duration by 11.8 months (p < 0.03) [14]. From these studies, it can be concluded that 920

pancreaticoduodenectomy with venous resection offers a chance at prolonged overall survival relative to palliative therapies in well-selected patients. However, the potential morbidity and mortality associated with surgery must be carefully considered. In this regard, the findings of Fuhrman et al., who published a prospective series of 59 consecutive patients who underwent pancreaticoduodenectomy for treatment of adenocarcinoma of the duodenum or pancreas, are noteworthy. Twenty-three of these patients required concomitant venous resection. Morbidity included intra-abdominal hemorrhage, abscess formation, pancreatic fistula and delayed gastrointestinal motility, but there was no significant difference in morbidity rates between patients who required venous resection (n = 7, 30%) and those who did not (n = 10, 28%; p = NS). Furthermore, there was no difference in perioperative mortality between the groups [15]. A subsequent study from the same group published in 2004 further demonstrated the operative safety of venous resection but also addressed the question of prognosis. In the largest singleinstitution experience at its time of publication, Tseng et al. showed that the need for vascular resection did not significantly impact survival duration [16]. From 1990 to 2002, 291 patients underwent pancreaticoduodenectomy for pancreatic adenocarcinoma and 110 of these patients required vascular resection (venous resection = 100, arterial resection = 10) to achieve complete gross tumor removal. Median survival was 23.4 months in the group that required vascular resection and 26.5 months in the group that underwent standard pancreaticoduodenectomy (p = 0.177). Several recent large-volume, multi-institutional studies have analyzed perioperative morbidity and mortality following vascular resection. An analysis of the American College of Surgeons National Surgical Quality Improvement Program database identified 281 patients receiving vascular resection during pancreaticoduodenectomy and found a significantly higher rate of operative morbidity (39.9 vs 33.3%) and 30-day mortality (5.7 vs 2.9%) in these patients compared with the 3201 patients who underwent standard pancreaticoduodenectomy [17]. It should be pointed out that due to National Surgical Quality Improvement Program data collection entry, operations with inadvertent venous or arterial injury and subsequent repair are included, and these operations carry significantly higher rates of perioperative morbidity and mortality than those in which planned and controlled vascular resection is utilized [18]. Indeed, in a multicenter retrospective cohort study, Ravikumar et al. found no significant difference in perioperative morbidity or mortality between 230 portal vein resection patients and 840 standard pancreaticoduodenectomy patients [19]. A recently published meta-analysis further clarifies the role of venous resection for treatment of pancreatic adenocarcinoma with limited venous involvement. Zhou et al. identified 19 studies comprising 2247 patients from the USA, Europe and Asia, among which 661 patients underwent superior mesenteric vein or portal vein resection at the time of pancreatectomy. Pooled analysis of the 13 studies that reported morbidity data failed to show significantly higher morbidity in patients requiring Expert Rev. Anticancer Ther. 14(8), (2014)

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Pancreaticoduodenectomy with vascular resection for pancreatic head adenocarcinoma

venous resection [20], and these findings are further corroborated by another meta-analysis of vascular resection [21]. Furthermore, a meta-analysis of survival estimated a 1, 3 and 5-year overall survival of 61.3, 19.4 and 12.3% in the venous resection group compared with 61.8, 26.6 and 17.0% in the standard pancreaticoduodenectomy group, respectively [20]. These studies suggest that concomitant venous resection can be performed safely in select centers and by select surgical groups, and that highly selected patients that have locally invasive cancers may be treated with pancreatectomy and survive as long as patients with less invasive tumors who undergo less complex procedures. Although no data exist to support the practice, some major pancreatectomy groups have even suggested routine resection and reconstruction of the portal vein for all patients who undergo pancreaticoduodenectomy, whether or not the vein is involved [22]. While there are no prospective randomized studies that evaluate the value of preoperative therapy, increasing evidence suggests that preoperative chemoradiation followed by surgical resection with venous resection may provide an even more impressive survival benefit for at least a subset of these complex patients relative to surgery as primary therapy. Nakao et al. retrospectively reviewed 463 patients that received pancreaticoduodenectomy for treatment of pancreatic head cancer without neoadjuvant therapy. Portal vein resection was required in 297 patients and an increasing degree of vein involvement on preoperative imaging correlated with significantly poorer overall survival [23]. This study provides a rationale for preoperative therapy to both select patients and to attempt to sterilize margins of resection. In a study from Fox Chase Cancer Center, Chun et al. identified 109 patients with pancreatic cancers that involved the superior mesenteric-portal vein confluence that underwent attempted surgical resection. Seventy-four patients received preoperative chemoradiation and these patients had a significantly longer median overall survival than those not treated prior to surgery (23 vs 15 months, p = 0.001). Preoperative chemoradiation was associated with a higher complete microscopic resection rate and a lower rate of lymph node involvement (p < 0.0001) [24]. Arterial involvement

The issue of pancreaticoduodenectomy with arterial resection for tumors with local involvement of the celiac artery, the common hepatic artery or the superior mesenteric artery (SMA) is more complex. While it has long been believed that tumor involvement of these arteries was a contraindication to aggressive resection [25], several single-institutional, retrospective studies have revisited this question, and consequentially, review of these results is warranted. In the largest study to date, Bockhorn et al. identified 29 patients that underwent arterial resection with reconstruction over a 13-year period. Analysis of short-term outcomes between this group and 478 patients that underwent standard pancreaticoduodenectomy revealed significantly higher morbidity and mortality among the arterial resection group [26]. informahealthcare.com

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A recent meta-analysis of 26 studies including 2609 patients (366 with arterial resection and 2243 without arterial resection) found a similar increase in morbidity and mortality in patients requiring arterial resection. Data from select studies providing comparative data between the two groups revealed arterial resection as a risk factor for morbidity (7 studies; OR: 2.17; p = 0.006) and reoperation (15 studies; OR: 3.28; p < 0.001). Studies that reported bleeding, thrombosis and ischemic complications included 141 arterial resection patients and identified 24 events among these patients (17.0%). Furthermore, analysis of studies including 291 arterial resection patients found a postoperative median mortality rate of 11.8% and comparative data demonstrated a postoperative mortality risk five times greater in patients with arterial resection relative to those patients without arterial resection [27]. From an oncological standpoint, Mollberg et al. reported a 1, 3 and 5 year median survival rate of 49.1, 8.3 and 0%, respectively, in patients undergoing arterial resection. When compared with patients who underwent pancreatectomy without arterial resection, there was a significantly reduced chance of survival at 1 year (OR: 0.49; p = 0.002). While it is interesting to evaluate oncological outcomes relative to patients undergoing pancreaticoduodenectomy without concomitant arterial resection, evaluating benefit in the context of palliative alternatives is also important. The same authors identified five studies with 1 and 2 year overall survival data in patients with arterial involvement that did not undergo resection. Meta-analysis of these studies with comparative data from the studies including arterial resection identified a significant benefit in survival at 1 year (OR: 4.28; p < 0.0001) and 2 years (OR: 19.65; p < 0.0001) for patients undergoing arterial resection versus patients who did not undergo resection [27]. It must be emphasized, however, that in this meta-analysis, even after an aggressive complete resection, less than one-half of these patients were alive at 1 year. A recent multi-institutional study by the Japanese Society of Pancreatic Surgery identified 624 patients that underwent pancreaticoduodenectomy and median overall survival among the 84 patients with concomitant arterial resection was just 13.4 months [28]. While there are small volume single-center studies that report a longer median overall survival of 18 months after arterial resection, a majority of these highly selected patients completed extensive neoadjuvant and adjuvant therapy [29,30]. Thus, for a vast majority of pancreatic adenocarcinoma patients with local arterial involvement, the significant increase in perioperative morbidity and mortality associated with arterial resection does not justified the minimal, yet significant, benefit seen in overall survival. Tumor biology

Overall survival after arterial resection is significantly worse than that seen in patients that undergo pancreaticoduodenectomy with venous resection or standard PD, suggesting an underlying more aggressive tumor biology [27,28]. It is hypothesized that the rich network of autonomic nerve fibers found surrounding the celiac, superior mesenteric and hepatic arteries 921

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allow for diffuse tumor extension and more frequent locoregional and distant failure [11]. Although this has not been demonstrated at a microscopic level, the question as to whether vascular involvement is secondary to aggressive tumor biology or simply unfortunate tumor location has been investigated by several studies. In Fuhrman’s evaluation, patients that had a venous resection (n = 23) were more likely to have perineural invasion [15]. However, no significant difference in median tumor size, nodal positivity, retroperitoneal margin positivity or DNA proliferative fraction was observed, suggesting that involvement of the superior mesenteric-portal vein confluence is not associated with other histopathological variables associated with poor prognosis [15]. Subsequently, this question has been investigated further by several groups that microscopically evaluated the resected vein for tumor involvement. Wang et al. evaluated the impact of histological involvement of the superior mesenteric or portal vein in 225 patients with stage II pancreatic adenocarcinoma that underwent resection after neoadjuvant therapy. Of the 85 patients that received venous resection, 57 patients had histological tumor involvement of the resected vein, and these patients not only had significantly larger tumors, but also higher frequency of resection with microscopically positive margins, locoregional recurrence and distant metastasis. On multivariant analysis, histological involvement of the resected vein was an independent predictor of shorter disease-free survival and shorter overall survival suggesting that venous tumor involvement has negative prognostic value [31]. Yekebas et al. identified 585 patients that underwent potentially curative pancreatic resection and evaluated the impact of histological vessel involvement with different findings. Vascular resection was performed in 100 patients with pancreatic adenocarcinoma, of which 77 patients had histopathologically proven vessel invasion. Median survival in these patients (15 months) was no different than in those without histological vessel involvement (16 months) [32]. Similarly, the prognostic importance of histological involvement of the resected vein was not seen in other studies [33,34]. Recently, Rehders et al. analyzed peripheral blood for circulating pancreatic tumor cells and the presence of peripheral tumor cells did not correlate with the need for vascular resection or vessel invasion [35]. Early in the disease process, pancreatic adenocarcinoma has access to the systemic circulation through a network of small pancreatic vessels, thus dissemination of tumor cells would occur prior to major vessel invasion. Additionally, the biology of metastasis involves multiple genetic and molecular changes within the tumor cell and is less reliant on tumor location [11]. Resectability

The likelihood of attaining negative surgical margins is the critical measure when determining whether a patient is a candidate for surgical resection [36]. Traditionally, based on preoperative imaging and staging by the American Joint Committee on Cancer (AJCC), patients with pancreatic adenocarcinoma were described as having either resectable (stages I and II) or locally 922

advanced, unresectable (stages III and IV) disease. The ability to safely resect pancreatic tumors with vascular involvement in part supported the characterization of a new category of tumors along the continuum from localized to widely metastatic pancreatic cancer. This category is referred to as borderline resectable pancreatic cancer and includes patients that are at high risk of undergoing surgery with incomplete tumor resection. The resection status (R-status) is a system that involves the pathological and clinical description of the surgical margins. An R1 resection occurs when a margin is grossly negative but microscopic disease is identified on pathological evaluation, while a grossly negative specimen with pathologically negative margins is referred to as an R0 resection. The presence of gross residual tumor after attempted resection is described as an R2 resection. An R2 resection is a clinical observation that can only be made by the surgeon at the time of surgery [11,12]. An R2 resection can be predicted by preoperative imaging and preventing this occurrence is essential because patients undergoing an R2 resection have overall survival equal to those receiving only palliative therapies. While the goal of surgery is to safely achieve an R0 resection, R1 resections are frequently encountered despite adequate preoperative evaluation and surgical technique. The true impact of an R1 resection on patient outcome is unknown due to a lack of standardization of pathological examination, but evidence suggests that these patients clearly do better than those with gross residual disease (R2) but may have slightly decreased survival relative to R0 patients [37,38]. A recent publication with meticulous evaluation of the resection margin found that R0 resections had an improved overall survival relative to R1 resections, but this survival advantage is lost when the R0 tumor is within 1 mm of the resected margin [39]. In patients receiving preoperative chemoradiation, a SMA margin of > 1 mm correlated with the longest progression-free survival [40]. These findings and the poor standardization of pathologic margin evaluation have pushed some groups to reconsider the current definition of an R1 resection [38]. Over the last several years, the University of Texas MD Anderson Cancer Center (MDACC) Group and the American Hepatopancreatobiliary Association (AHPBA)/Society of Surgical Oncology (SSO)/Society for Surgery of the Alimentary Tract (SSAT) Group have provided detailed imaging criteria that define borderline resectability. These definitions have been used by the National Comprehensive Cancer Network (NCCN) to help develop standardized treatment regiments and appropriately categorize patients for enrollment in clinical trials [41]. The MDACC and the AHPBA/SSO/SSAT groups agree that limited interface between the tumor and the superior mesenteric or hepatic artery denotes borderline resectable disease (defined as tumor–arterial interface 180˚ of the portal or superior mesenteric vein required venous resection at the time of surgery [50]. A similar study by Nakao et al. demonstrated that the degree of portal vein involvement seen on CT can predict pathologic vein wall invasion and long-term patient survival after resection [23]. Furthermore, Yamada et al. identified similar prognostic relevance of different levels of portal vein involvement and demonstrated radiographic SMA involvement as a predictor of worst overall survival after resection [51]. Cross-sectional imaging, either CT or MRI, should be obtained prior to endoscopy, biliary stenting or invasive tissue sampling to prevent peri-pancreatic inflammation that can obscure the tumor–tissue interface and diminish imaging sensitivity [47]. To optimize CT visualization, the protocol should include oral contrast administered 90–120 min prior to dualphase imaging, which is obtained following injection of 120150 ml of iodinated contrast at a rate of 4–5 ml/s. The first phase is captured approximately 40 s after injection, at which time arterial contrast optimally enhances the pancreatic parenchyma. Twenty to thirty seconds later, a second phase captures contrast within the portal venous system and allows for evaluation of venous involvement and liver metastases [42,48]. Due to the wide variety in reporting of radiographic findings and the significant implications of these findings in designing 923

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Box 1. MD Anderson Cancer Center definition of potentially resectable, borderline resectable, and unresectable pancreatic head adenocarcinoma. Potentially resectable • Absence of extrapancreatic disease • No evidence of tumor extension to the SMA, celiac axis, or

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• Patent SMV-PV confluence with interface between the pri-

mary tumor and SMV-PV measuring less than 180˚ of the circumference of the vein wall Borderline resectable (one or more of the following) • An interface between the primary tumor and SMV-PV mea-

suring 180˚ or greater of the circumference of the vein wall • Short-segment occlusion of the SMV-PV with normal vein

above and below the level of obstruction that is amenable to resection and venous reconstruction • Short-segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and arterial reconstruction • An interface between the tumor and SMA or celiac trunk measuring less than 180˚ of the circumference of the artery wall Unresectable (locally advanced) • Distant metastases • Metastases to lymph nodes beyond the field of resection • Encasement (>180˚) of SMA of celiac axis or IVC abutment • Unreconstructible SMV or portal vein occlusion • Aortic invasion or encasement IVC: Inferior vena cava; PV: Portal vein; SMA: Superior mesenteric artery; SMV: Superior mesenteric vein.

multimodality treatment plans, a radiology reporting template was recently published by the Society of Abdominal Radiology and the American Pancreatic Association [47]. The role of EUS in tumor staging and assessing resectability is unknown. While multiple studies have demonstrated that EUS is equivalent or possibly better than CT at determining local tumor staging [52], CT appears superior in predicting vascular invasion [53]. In cases of uncertainty, EUS can be used as an adjunct imaging modality. Furthermore, EUS allows for tissue sampling through fine-needle aspiration, and is safer and has a potentially lower risk of peritoneal seeding than CTguided percutaneous biopsy [54]. In patients requiring a tissue diagnosis prior to initiating preoperative therapy, EUS with fine-needle aspiration is an excellent resource. A complete review of all imaging is essential to evaluate for local and distant disease and to determine potential tumor resectability. In addition to assessing major vascular involvement, regional arterial and venous anatomy should be thoroughly examined. This anatomic review should include inspection of the first-order jejunal and ileal venous branches, as well as the celiac trunk anatomy, as hepatic artery variants 924

are commonly encountered and can drastically affect the operative strategy [55,56]. Furthermore, severe stenosis of the celiac trunk can become relevant after ligation of collateral flow through the gastroduodenal artery [57]. Arterial variants should be identified on preoperative imaging and management of these variants are discussed at length in other reviews [49,58]. Only after thorough review of all imaging can there be a discussion of resectability with the patient. Multimodality treatment

Multiple studies have shown that staging, time to treatment initiation, efficacy of care and overall survival is maximized at high-volume, specialized pancreatic cancer treatment centers that deliver coordinated multimodality care involving medical, radiation and surgical oncologists with specialized radiologists and pathologists [59,60]. As a result, a multimodality treatment approach has become the standard of care [61,62]. Any patient diagnosed with pancreatic adenocarcinoma, especially patients with borderline resectable tumors, should be evaluated by a multidisciplinary team and should be considered for preoperative therapy. Patients with borderline resectable pancreatic cancer are at higher risk of undergoing a margin-positive resection and are likely at higher risk for systemic disease due to the advanced nature of their primary tumor, and as a result, neoadjuvant therapy including chemotherapy, chemoradiation or both, has been strongly advocated [43,63,64]. The administration of preoperative therapy is associated with several potential advantages. First, postoperative morbidity is common after pancreaticoduodenectomy and frequently delays or excludes patients from receiving systemic therapy. A recently published series of 2047 patients with stage I–III pancreatic adenocarcinoma that underwent surgical resection found that only 57.7% of these patients received adjuvant chemotherapy and the development of a postoperative complication was a significant risk factor for the omission of adjuvant therapy [65]. Other groups have demonstrated similar low rates of adjuvant therapy and delays in delivery of adjuvant therapy due to operative complications [66–69]. Delivery of systemic therapy is critical because a large number of patients with borderline resectable pancreatic cancer will have undetectable micro-metastatic disease at the time of presentation. This is evidenced by the fact that a significant majority, despite a complete resection with negative margins, succumbs to distant disease within 2 years. Preoperative delivery of chemotherapy ensures that these patients fully receive this critical systemic treatment. A recently published study found that patients who receive preoperative systemic therapy are significantly more likely to complete their entire multimodality treatment regimen (surgery and chemoradiation) than are patients that undergo pancreatectomy first. While the sequence of treatment did not impact overall survival in those completing all therapy (surgery first, 42.3 months; preoperative therapy, 35.2 months; p = 0.86), patients that received preoperative systemic therapy were more likely to complete all therapy and this was the strongest predictor of survival identified [68]. Expert Rev. Anticancer Ther. 14(8), (2014)

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Pancreaticoduodenectomy with vascular resection for pancreatic head adenocarcinoma

Secondly, despite frequent distant failure, complete resection with negative margins has been consistently shown to be a strong prognostic factor for overall survival. Despite the fact that neoadjuvant chemoradiation rarely results in obvious radiographic tumor regression [70,71], it does appear to increase the rate of margin negativity, and thereby increase the likelihood of complete resection [24,72–74]. It has been suggested that chemoradiation causes margin sterilization. Lastly, preoperative therapy provides a time interval before surgery in which local disease or indeterminate metastatic lesions can progress. Patients who have worsening disease or develop metastases during systemic therapy are presumed to have aggressive tumor biology and would have done poorly after primary tumor resection [75,76]. Currently, there are very few ongoing prospective trials involving neoadjuvant therapy for borderline resectable pancreatic cancer, none of which directly compare neoadjuvant therapy to the ‘surgery-first’ approach, and thus, the optimal treatment sequence remains unknown. There are significant singleinstitution data supporting neoadjuvant chemotherapy or chemoradiation. Chun et al. identified 107 patients with pancreatic cancer and local venous involvement. Seventy-four patients received preoperative chemoradiation and these patients had significantly longer median overall survival relative to patients that did not receive preoperative therapy (23 vs 15 months; p < 0.001). This survival advantage was limited to patients that had pretreatment imaging that revealed a smooth shift or unilateral narrowing of the associated vein, but was not observed in patients with bilateral vein involvement. Furthermore, these patients had significantly less nodal disease and a higher rate of complete resection [24]. Similar studies evaluating preoperative therapy in borderline resectable patients demonstrate that roughly 50% of patients complete therapy and undergo resection with curative intent and demonstrate a median overall survival of 23 months [77,78]. In 2008, the senior author published a series of 160 patients with borderline disease treated at MDACC. Onehundred and twenty-five (78%) of these patients completed neoadjuvant therapy and 66 (41%) underwent subsequent pancreatectomy with a median overall survival of 40 months. In patients with borderline resectable pancreatic cancer, multimodality therapy with preoperative systemic therapy has been shown to directly impact overall survival, and in select patients, results in survival rates significantly longer than patients that undergo surgical resection without preoperative therapy [24]. Surgical technique & margin status

Although frequently performed, the specifications of pancreaticoduodenectomy and pathological evaluation of the specimen vary widely from institution to institution. This fact was highlighted in a recent review of patients enrolled in a nationwide trial, which found that surgeons marked the critical SMA margin 25% of the time and 34% of the pathology reports met the College of American Pathologists criteria [79]. While neoadjuvant therapy is emphasized for the treatment of patients with borderline resectable pancreatic cancer, the importance of a well-performed informahealthcare.com

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surgical resection with meticulous evaluation of the resection margins is critical to long-term survival. Upon completion of preoperative therapy, all patients with borderline resectable pancreatic cancer should be reimaged and those without evidence of tumor progression, either local or distant, should undergo surgical exploration. Radiographic evidence of down-staging or tumor regression is not required prior to laparotomy [70,80]. While improvements in cross-sectional imaging have enabled more accurate prediction of the need for vascular resection and reconstruction, this decision is made based on intraoperative findings and is not performed routinely in borderline resectable patients. If dissection of the associated artery or vein does not allow separation of the tumor from the vessel, then resection and reconstruction is performed with the goal of obtaining a margin-negative resection. As a result, any surgeon willing to care for these patients must be comfortable with techniques of vascular resection and reconstruction with pancreaticoduodenectomy [44]. In the surgical approach to pancreatic head tumors, the superior mesenteric vein and the portal vein should be completely mobilized off of the uncinate process to expose the superior mesenteric artery. At this point, dissection of the uncinate process from the retroperitoneum directly along the peri-adventitial plane of the SMA is critical [40]. Meticulous removal of all the tissue on the anterior, right lateral and posterior aspect of the SMA is crucial to maximizing tissue yield and minimizing the likelihood of leaving tumor cells behind. This dissection should not be performed using surgical staplers or the ‘clamp and cut’ technique as these methods result in a gross residual margin of tissue along the artery [81,82]. In patients that received neoadjuvant chemoradiation, meticulous dissection of this tissue plane demonstrated significantly longer progression-free survival [40]. Further surgical techniques of tumor mobilization, vascular resection and subsequent reconstruction have been described in detail previously and are beyond the scope of this review article [83–85]. Completeness of resection is determined by pathological evaluation of the margin status of the specimen. Surgical margins occur at planes where the specimen is separated from surrounding tissue or where the pancreas, biliary system or gastrointestinal tract is divided. The reported surgical margins for pancreatic head resection include the superior mesenteric artery, pancreatic, common bile duct, gastric/duodenal, proximal jejunal and other soft tissue margins such as the anterior and posterior pancreatic margins [74,86]. The SMA margin is also referred to as the retroperitoneal, mesenteric or uncinate margin, and describes the space where the uncinate process abuts the proximal 3–4 cm of the SMA and its associated neural and lymphatic tissue [74,83]. Appropriate dissection of this margin is of utmost importance because, whereas the pancreatic or bile duct margin can be re-excised to negative tissue, the SMA margin cannot be. Furthermore, the SMA margin is the most frequent positive margin, and this finding may impact local failure [40]. Some advocate the ‘artery-first’ surgical approach that is hypothesized to facilitate complete tumor resection, especially at the SMA margin, by identifying the SMA at its origin on the aorta and using the anatomic course of the artery to guide additional resection and 925

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maximize margin distance on the right side and the posterior aspect of the SMA [87]. Currently, there is a lack of uniformity in pancreaticoduodenectomy margin analysis and surgical technique that limits further advancements in treatment of pancreatic adenocarcinoma [62,79]. Further standardization of pathological reporting and surgical technique would lead to better understanding of individual patients’ disease as well as a better understanding of disease burden for more accurate patient grouping and comparison in clinical trials that assess new therapeutic regimens [44,62].

achieve significant disease-free and long-term survival. Patients with vascular involvement must be treated in a multidisciplinary, multimodality setting that often involves administration of preoperative systemic therapy and emphasizes aggressive surgical resection of all disease and reconstruction of any involved vessels. Just as medical oncologist have an increased role in delivering preoperative therapy, surgeons must be prepared for vascular resection and reconstruction and must be diligent in technique to maximize the probability of complete tumor removal. Five-year view

Conclusion

The understanding and treatment of pancreatic head adenocarcinoma with involvement of local vascular structures has progressed extensively over the last few years. A plethora of reports have demonstrated morbidity and long-term survival similar to that seen in patients with tumors that do not involve vascular structures. Select patients with limited involvement of the portal vein, superior mesenteric vein or hepatic artery who complete multimodality therapy have median survival in excess of 24 months. The key to achieving these results is accurately identifying this complex subgroup of patients and approaching their treatment in a multimodality fashion often consisting of preoperative therapy and subsequent operative resection with critical attention to surgical technique and margin analysis. Expert commentary

Understanding of the treatment of pancreatic cancer with vascular involvement has increased drastically in the last 10 years. These complex patients can undergo multimodality treatment and

Evidence clearly supports vascular resection with pancreaticoduodenectomy for tumors with limited vessel involvement. Despite these findings, less than 40% of patients with pancreatic cancer are treated following the NCCN treatment guidelines [88], and among those that are treated, there is wide variability in surgical and pathologic technique that compromises long-term outcome [79]. Over the next 5 years, we anticipate increased standardization of preoperative therapy, operative technique and pathological evaluation, in order to decrease heterogeneity among patients enrolled in clinical trials of multimodality and adjuvant therapy and to more accurately understand the true results of these trials. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Pancreatic ductal adenocarcinoma is a lethal disease associated with a dismal 5-year overall survival, but results are not as poor in the 20% of patients that present with potentially or borderline resectable disease and are able to undergo radical resection of their primary tumor and regional lymph nodes. • Pancreaticoduodenectomy with venous resection for tumors that appear to involve the superior mesenteric vein, portal vein or the confluence of these two veins can be performed with similar morbidity and mortality to standard pancreaticoduodenectomy in select centers. Resection of these complex tumors may yield reasonably favorable long-term survival. • For a vast majority of pancreatic adenocarcinoma patients with local arterial involvement, the significant increase in perioperative morbidity and mortality associated with arterial resection does not justified the minimal, yet significant, benefit seen in overall survival relative to nonoperative, palliative therapies. • In order to safely and optimally treat patients with pancreatic adenocarcinoma with vascular involvement, it is essential to accurately identify these patients, to utilize a multidisciplinary treatment approach to therapy and to emphasize meticulous surgical technique and awareness of the critical margins of resection. • The interface between tumor and SMV-portal vein on CT images has been found to be highly predictive of the need for venous resection, pathologic venous involvement and overall survival. Nearly 90% of tumors that have an interface with >180˚ of the circumference of the portal or superior mesenteric vein will require venous resection at the time of surgery. • In patients with borderline resectable pancreatic cancer, multimodality therapy with preoperative systemic therapy and chemoradiation is believed to directly impact overall survival, and in select patients, results in survival rates significantly longer than that of patients that undergo surgical resection without preoperative therapy. • Further standardization of pathological reporting and surgical technique would lead to better understanding of individual patients’ disease as well as a better understanding of disease burden for more accurate patient grouping and comparison in clinical trials that assess new therapeutic regimens.

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Pancreaticoduodenectomy with vascular resection for pancreatic head adenocarcinoma

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