Resectable Disease

In general, upfront resectable disease is defined as

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  Tumor without contact with the celiac artery (CA), hepatic artery (HA), SMA, or SMV, suggesting a high likelihood that margin-negative resection can be achieved without preoperative therapy ( Fig. 1 A )

  
  

  
  

  
  

  

  
  

  
  

  ( A ) Cross-sectional imaging of a resectable pancreatic adenocarcinoma with preservation of a fat plane between the tumor and the SMV and SMA. ( B ) Resectable pancreatic adenocarcinoma with less than 180° involvement of the SMV but with a preserved fat plane between the tumor and SMA.

  
  

With improvements in surgical technique and vascular resection, some groups also include tumors with limited involvement of the SMV-PV confluence in which an R0 resection is still possible, albeit with vascular resection and reconstruction in the resectable category ( Fig. 1 B). For example, the MD Anderson Cancer Center (MDACC) definition deems tumors resectable if there is abutment of the SMV-PV with patent vessels. The National Cancer Center Network (NCCN) also allows for 180° contact or less of the SMV-PV but only in the absence of any vein contour irregularity.

Locally Advanced Disease

The definition of LA disease also varies, although in general, LA characterizes patients in whom the likelihood of attempting to resect the tumor even after treatment with systemic or locoregional therapy to allow a margin-negative resection is essentially minimal. Although several varying definitions exist, essentially tumors with extensive vascular involvement especially arterial involvement are deemed LA ( Fig. 2 , Table 1 ).

Cross-sectional imaging of an LA pancreatic cancer with greater than 180° involvement of the SMA.

Borderline Resectable Disease

The original term marginally resectable was coined to identify patients at high risk of a macroscopically positive (R2) resection with upfront surgery. The term BR pancreas cancer was subsequently adopted by the NCCN in 2006 to describe patients who might benefit from neoadjuvant therapy in order to reduce the likelihood of margin positivity. Unfortunately, what defines BR disease remains an area of significant controversy.

Over the past decade, several different classification schemes have been published to describe which patients are considered BR pancreatic cancer, including consensus statements and guidelines from the NCCN; the International Study Group of Pancreatic Surgery (ISGPS); MDACC; Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology (AHPBA/SSO); the Society for Surgery of the Alimentary Tract (SSAT); and the Moffitt Cancer Center ( Fig. 3 , Table 2 ).

Cross-sectional imaging of a BR pancreatic adenocarcinoma with encasement of the SMV, but with preservation of a fat plane between the tumor and SMA.

Despite what would seem to be rather objective criteria, all of these definitions are somewhat subjective and are continually evolving. In the recent Alliance Trial (A021101), a multi-institutional single-armed trial designed to evaluate toxicity and feasibility of neoadjuvant chemotherapy and chemoradiation for BR pancreatic cancer, for example, the investigators advocated for an easily reproducible definition based on more objective data obtained from computed tomographic (CT) imaging, avoiding subjective terms like abutment or encasement. The Alliance definition consisted of the following: (1) an interface between the tumor and SMV-PV 180° or greater of the vein wall circumference; (2) short-segment occlusion of the SMV-PV with normal vein above and below the obstruction amenable to resection and reconstruction; (3) short-segment interface of any degree between tumor and HA with normal artery proximal and distal to the interface amenable to arterial resection and reconstruction; and (4) interface between the SMA and CA measuring less than 180° of the circumference of the artery.

Imaging Modalities

Imaging modalities including CT, MRI, and endoscopic ultrasound (EUS) are the mainstay in the diagnosis and staging of pancreatic cancer, and advances in these techniques have dramatically improved the preoperative determination of resectability for pancreatic cancer. Specifically, the development of multi-detector-row CT allows for high-resolution scan as well as 3-dimensional (3D) reconstructions; this, in addition to a “pancreas protocol CT,” which includes 3 phases (arterial phase, pancreatic parenchymal phase, and venous washout phase), has given physicians the ability to analyze the relationship of the pancreatic tumor to important vascular structures discussed above. CT is also effective in detecting lymphadenopathy and peritoneal and liver metastases. Enhanced MRI (with gadolinium or pancreatic tumor, excluding mangafodipir trisodium) is also effective in detecting local extension and vascular involvement. It is often superior to CT in detecting small liver lesions. Magnetic resonance cholangiopancreatography has the added benefit of noninvasively evaluating biliary and pancreatic ducts. Finally, EUS is highly sensitive for the detection of small tumors, surpassing both CT and MRI in this regard, as well as lymph node (LN) metastases and vascular invasion. In addition, EUS provides the safest avenue for pathologic confirmation of disease, which is crucial for those patients undergoing neoadjuvant therapy.

The Role for Diagnostic Laparoscopy

Although CT and MRI are highly sensitive for detection of LA as well as distant metastatic disease, small liver metastases and peritoneal disease may be undetectable even with high-quality axial imaging. As a result, many surgeons advocate the use of diagnostic laparoscopy before attempted resection, especially among patients with findings suspicious for advanced disease on imaging, such as ascites, indeterminate liver lesions, or peritoneal or omental thickening. Staging laparoscopy is not as useful for determining resectability of LA disease because tumor involvement of the vasculature, specifically the SMA, which is not easily detected by laparoscopy.

A Cochrane database review of the use of diagnostic laparoscopy demonstrated a decreased laparotomy and aborted resection rate from 40% with CT alone to 17% with CT combined with diagnostic laparoscopy. If metastatic disease is detected, staging laparoscopy not only decreases hospital length of stay but also allows patients to initiate chemotherapy significantly earlier than those undergoing exploratory laparotomy.

An adjunct to laparoscopy includes peritoneal washings. Notably, positive peritoneal cytology occurs in 7% to 30% of potentially resectable cases, and those patients have similar outcomes to those with metastatic tumor burden; thus, they are generally not considered candidates for radical resection. By NCCN standards, positive washings are considered stage IV disease. The use of peritoneal washings for patients with pancreatic cancer, however, is not universally used.

Venous Resections

Resection of the SMV, PV, or SMV-PV confluence is not uncommon at high-volume centers. Reports indicate that an average of 30% (7%–80%) of PDs performed at major medical centers now include venous resection and reconstruction. Perioperative morbidity and mortality associated with venous resection and reconstruction are similar to PDs performed without any venous construction, with short-term mortality ranging from 4% to 12% and complications ranging from 17% to 100%.

Venous resection and reconstruction can vary in extent, including the following:

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  Partial lateral venorrhaphy with transverse closure

  
  
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  Resection with vein patch

  
  
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  Interposition graft with either autologous or prosthetic vein graft

Patch reconstruction with autologous vein is standard practice; however, both cadaveric allografts and xenografts (porcine peritoneum, bovine pericardium) have also been used. The autologous vein of choice for interposition grafts is the internal jugular vein or greater saphenous vein, but other conduits, including the superficial femoral, left renal, and inferior mesenteric veins (IMVs), have also been used. The risk of prosthetic graft in a potentially contaminated operative field with risk of pancreatic fistula is significant; thus, prosthetic grafts are not recommended but are sometimes required if suitable autologous vein is not available. Notably, up to 5- to 7-cm gaps can be primarily anastomosed with division of splenic vein (SV), mobilization of the right colon, hepatic flexure, and root of the mesentery and full mobilization of the liver, often obviating interposition graft.

Splenic Vein Ligation and Sinistral Hypertension

As noted, division of the SV to allow for additional mobilization enabling an end-to-end anastomosis and eliminating need for interposition graft is commonly practiced. In addition, when tumor involvement includes the area of confluence of SV and SMV, the SV is often ligated and divided. However, division of the SV has the theoretic risk of sinistral or left-sided portal hypertension. Some studies have demonstrated increased frequency of sinistral hypertension as defined by an increase in spleen volume or decrease in platelet count. In addition, there are case reports of hypertensive gastropathy with gastric varices and gastrointestinal (GI) bleed following SV ligation during PD. Any theoretic risk of SV thrombosis and sinistral hypertension can be avoided by preservation of not only the short gastric vessels but also the SV-IMV confluence, both of which would allow for decompression of the SV to the systemic circulation. In addition, reanastomosis in an end-to-end fashion of SV to IMV, use of an interposition graft, or even a distal splenorenal shunt, mesocaval shunt, or IMV to right gastroepiploic vein anastomosis may be performed.

The incidence and clinical significance of this theoretic complication have been called into question by several studies. In one study, only a very limited number of patients in whom the SV had been ligated actually developed clinically significant splenomegaly. The reasons for this are likely many. For one, survival following PD may not be long enough for this process to manifest itself. In addition, following ligation of the SV, venous blood can re-enter the systemic circulation via the esophageal veins or right colic tributaries. Finally, tumor involvement of the SV or confluence can cause relative stenosis, and collateral vessels may already be well developed at the time of PD.

Arterial Resections

Although venous resection is not uncommon, consensus guidelines still consider extensive tumor involvement of major arteries (SMA, celiac, and common hepatic arteries) to be unresectable. In a recent meta-analysis, patients undergoing arterial reconstruction were associated with increased operative times, higher morbidity rate, including vascular and nonvascular complications, and a higher rate of reoperation, as well as an increased mortality rate. Patients who underwent combined venous and arterial resection had worse outcomes when compared with patients undergoing venous reconstruction alone. In addition, the 1-, 3-, and 5-year survival rates of PD with arterial resection were worse than PD alone and to PD with venous reconstruction. It should be noted, however, that this meta-analysis included a heterogeneous patient population over an extended time period (1977–2010), during which significant improvements in patient outcomes as well as advancements in neoadjuvant therapy regimens took place.

At the current time, greater than 180° abutment, or encasement of the SMA, is considered a contraindication to resection. There has, however, been limited experience but acceptable outcomes achieved in young, otherwise healthy individuals who underwent extended resection for LA disease involving the CHA or celiac axes after completion of neoadjuvant chemotherapy at high-volume centers. In nearly all patients who require arterial resections, venous resections are also required, further increasing the complexity and potential morbidity of the resection.

Postoperative Anticoagulation

Although the risk of mesenteric or PV thrombosis may be increased in patients undergoing resection for malignancy, it appears to be particularly increased when vascular reconstruction is performed. It is important that the anastomoses or graft is not twisted or kinked in any way, and all venous anastomoses should allow for dilation and avoid a “waist” at the suture line once normal venous flow is re-established.

A recent review article in 2014 found a rate of thrombosis of 25% with reconstruction. Thrombosis can range from partial occlusion of the SMV or a lesser tributary to the more feared complication of early or late PV thrombosis. The area and extent of resection and reconstruction almost certainly influence venous thrombosis rates. Rates of thrombosis with polytetrafluoroethylene grafts are consistently higher than interposition grafts using autologous vein; most studies report patency rates of approximately 90% for autologous vein conduit.

Patients may be asymptomatic or, rarely, may develop severe peritonitis secondary to acute mesenteric ischemia. Early PV thrombosis is associated with a 30% to 40% mortality rate. Although early thrombosis is deadly, patients with delayed PV thrombosis following PD with vascular reconstruction have survival rates greater than those without thrombosis presumably because of interval development of collateral flow.

Intraoperative systemic anticoagulation during reconstruction is not routinely used. Some surgeons advocate its routine use, whereas others advocate its use when the SMA is formally clamped for an extended period; there are no data to support or refute its use. Data supporting the use of postoperative anticoagulation for patients undergoing vascular reconstruction during PD likewise are sparse. Most protocols are based on surgeon preference. A recent review article in 2014 summarized the available data; however, given the wide variation in practice in the primary articles (heparin and warfarin vs aspirin), no firm conclusions could be drawn. A more guided prospective multi-institutional research trial would be necessary to define best practice standards with regards to anticoagulation for venous reconstruction. Current practice at the authors’ institution involves the use of low-dose aspirin postoperatively for all PDs requiring vascular reconstruction.

Replaced Right and Common Hepatic Arteries

The most common variant overall is an RRHA, which branches from the SMA, and is seen in 11% to 20% of individuals. It typically courses behind or through the pancreatic head, predisposing it to tumor involvement especially with posteriorly located malignancies. Fortunately, an RRHA can often be preserved with careful dissection even with tumor nearby. If division is required, the primary concern is preservation of blood flow to the CBD, which could lead to failure of the bilioenteric anastomosis or delayed anastomotic stenosis. Given this, some argue that it is important to attempt to reconstruct if the replaced RHA must be sacrificed (either primarily or using an autologous vein graft), although this may be technically difficult given its small diameter. A second anatomic variant of concern to the surgeon performing PD is the rarer RCHA, in which the CHA originates from the SMA. Fortunately, this variant occurs only in 0.4% to 4.5% of population. If the replaced CHA has an intrapancreatic course, reconstruction is usually necessary.

Celiac Artery Stenosis

Celiac artery stenosis is most often secondary to intrinsic disease (plaque) or extrinsic forces secondary to either nodal disease burden, median arcuate ligament syndrome, or a tumor-associated fibroinflammatory process. Celiac stenosis is encountered in up to 5% of all pancreaticoduodenectomies. Most patients are asymptomatic due to the propensity for extensive collateralization; the CHA receives retrograde flow via the GDA or dorsal pancreatic artery coming off the SMA, or via the Arc of Buhler, which is a direct connection between SMA and CHA. Elimination of collateral flow by division of the GDA during PD in the setting of celiac stenosis has theoretic and observed implications for compromised flow to liver, stomach, and spleen.

Preoperatively, CT imaging has low sensitivity for detecting clinically significant celiac stenosis but significant collateralization or an unusually large GDA raises suspicion. Given this low sensitivity, it should be routine practice during PD to assess flow within the HA by temporarily occluding flow from the GDA before division. Significant stenosis from atherosclerosis that is identified preoperatively can be managed with angioplasty and stent, but the long-term outcome is not clear. Intraoperatively, if blood flow in the proper HA becomes significantly reduced following ligation of the GDA, it is recommended that restoration of flow be performed. In cases with eccentric compression, division of the median arcuate ligament is successful in up to 70% of cases. If that is not successful or if reduced blood flow is due to other reasons, an autologous graft from the aorta to the proper HA is recommended.

Extended Lymphadenectomy

Although the prognostic impact of overt nodal spread is rarely disputed, there was, for some time, significant debate as to whether aggressive nodal dissection at the time of PD to attain locoregional control of disease truly affected outcomes.

The need for definition of a standard nodal dissection was addressed at the 2013 ISGPS consensus meeting. The standard lymphadenectomy for PD should include the following:

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  The peripancreatic tissue to the right of SMA and proper HA—specifically nodal stations 5, 6, 8a (proper HA), 12b, 12c, 13a, 13b (posterior surface), 14a (right lateral SMA), 14b (right lateral SMA), 17a, 17b (anterior surface) as defined by the Japanese Pancreas Society

Anything beyond this is considered an extended lymphadenectomy.

Several meta-analyses have revealed no improvement in survival with extended lymphadenectomy, as extraregional LN involvement should be considered metastatic disease. In addition, more extensive dissections are associated with higher rates of postoperative complications, including delayed gastric emptying (DGE), increased weight loss, and diarrhea thought to be secondary to autonomic disruption.