Critical to the determination of the management of pancreatic adenocarcinoma involves an accurate assessment of the resectability of the primary tumor and identification of metastatic disease. The classification of resectability of a pancreatic adenocarcinoma is currently divided into three groups: (1) resectable, (2) borderline resectable, and (3) locally advanced unresectable. Definitions for what tumor characteristics qualify in each group have variability based upon the criteria produced from each of the three main publications on the management of pancreatic adenocarcinoma. Table 11.1 details the criteria for determining the resectability of each primary tumor from each of the major published guidelines.

The key component of assessing the resectability comes through proper selection of diagnostic imaging. Based upon current guidelines, the recommended study should be either a multidimensional computed tomography (MDCT) using a pancreas-specific protocol of intravenous and oral contrast, or magnetic resonance imaging (MRI) using a pancreas-specific protocol of intravenous contrast. CT pancreas protocols based upon the American Pancreatic Association guidelines should be obtained using slice thickness no larger than 3 mm (goal of 0.5–1 mm), a pancreas parenchymal arterial phase and a portal venous phase, and neutral oral contrast in order to maximize the sensitivity for pancreatic masses. Similar guidelines for MRI pancreas protocols include maximal slice thickness of 6 mm on T1-weighted in-phase and opposed-phase gradient echo (GRE), T2-weighted fat-suppressed fast-spin echo (FSE), and diffusion-weighted imaging (DWI), as well as 2–3 mm thickness for pre- and post-gadolinium contrast T1-weighted fat-suppressed echo (phases: pancreas parenchyma, portal venous, equilibrium) and T2-weighted MRCP. A benefit of MRI imaging for staging is the improved resolution for subcentimeter hepatic metastases which can be most readily seen on DWI series with proper processing software. Recent retrospective studies have demonstrated the potential improved recognition of patients with these subcentimeter metastases not appreciated on traditional pancreatic CT imaging through MRI.

In the setting of combined chronic kidney disease with hepatic insufficiency, a decision to omit intravenous contrast can have a significant impact on the reliability of staging imaging. As mentioned previously, understaging due to failed identification of metastases or locally advanced disease may lead to an unfortunate decision to proceed with surgical resection in a patient population unlikely to benefit from the effort. An effort to ameliorate renal risks using precontrast volume expansion, N-acetylcysteine, or even temporary hemodialysis in selected patients should be made to allow proper imaging with intravenous contrast in the staging phase for all patients.

Other variables which have been assessed to attempt to improve accurate preoperative stratification of patients most likely to benefit from upfront surgical resection include serum CA 19-9 and CT/PET. Serum CA 19-9 is of particular interest in many pancreatobiliary tumors due to its common production by tumors of this cell lineage. CA 19-9 is a glycopeptide which is produced in a majority of pancreatic ductal adenocarcinoma patients, with the exception of approximately 10% of patients who lack the Lewis antigen and therefore are unable to produce CA 19-9 regardless of tumor burden. Unfortunately, CA 19-9 can be elevated with a range of hepatopancreatobiliary diseases including cirrhosis and biliary obstruction. Studies which have attempted to identify a role of elevated CA 19-9 have intentionally excluded patients with cirrhosis or underlying hepatopancreatobiliary diseases to avoid the risk for false positives. The role of CA 19-9 as a decision tool in the setting of cirrhosis is therefore not currently recommended. Additionally, CT/PET has been suggested in some small retrospective series to have a potential role of identification of metastatic pancreatic disease. These studies however have been limited to a significant false-positive rate with specific false positives identified in the liver and regional lymph nodes. Furthermore, in the setting of dysplastic nodules commonly seen in cirrhosis, additional false positives in the liver would be expected due to their typically FDG-avid state on CT/PET. The decision-making ability of these adjunctive tests is therefore even more limited in the setting of cirrhosis patients and should not be used as a tool to differentiate treatment options for these patients with pancreatic adenocarcinoma.

A final consideration for pretreatment evaluation of pancreatic adenocarcinoma is the medical status of the patient. Significant experience has been gained in the surgical management of patients of greater ages and higher medical comorbidity risk within the past two decades. Current high-volume centers have demonstrated the feasibility of pancreatectomy procedures for pancreatic adenocarcinoma in these traditionally high-risk patient populations with near-equivalent morbidity and mortality. The main determinant that has been shown to be of importance in patient selection is the associated frailty assessment. Multiple methods have been described to report aspects of medical frailty across cardiovascular, pulmonary, and metabolic assessments. The ideal method to define frailty in the setting of ductal adenocarcinoma has yet to be determined. Further, in the setting of underlying cirrhosis or chronic immunosuppression for liver transplantation, the frailty of a patient may be the primary determinant for determining whether upfront surgery is appropriate. In these higher risk patients with surgically resectable tumors, a medical frailty assessment should be made to determine if neoadjuvant therapy is necessary to allow for an interval intervention to optimize frailty prior to any surgical intervention.

The use of neoadjuvant therapy implies the intention to proceed with surgical resection following completion of the intervention. Development of neoadjuvant therapies occurred in response to the lack of patients with surgically resectable disease and overall lack of increased survival despite effective surgical resection. The intent of initial neoadjuvant therapies was to make locally advanced and unresectable tumors surgical candidates, given some survival benefit seen with resection. Subsequent advances in neoadjuvant therapy for borderline resectable and locally advanced tumors have been demonstrated mostly through retrospective or prospective observational studies. A limitation of a majority of these neoadjuvant therapy studies has been the lack of an intention-to-treat analysis demonstrating survival benefit from neoadjuvant therapy versus traditional upfront surgery with adjuvant therapy. More importantly, the role of neoadjuvant in the setting of resectable disease has yet to yield a demonstrable improvement in survival and therefore remains limited to clinical trials.

Within neoadjuvant therapies, the main applied interventions are chemotherapy alone, radiation with a chemotherapy agent as a radiosensitizing agent (chemoradiation), or a combination of the two modalities. Historical evaluation of radiation alone was demonstrated to have a limited role in the subset of locally advanced and borderline resectable patients. The historical benefit seen in initial studies evaluating chemoradiation has more recently been questioned compared to the survival benefit seen with chemotherapy alone. In combined regimens of chemotherapy followed by chemoradiation, there has yet to be a demonstrated clear survival benefit by the addition of chemoradiation. Specifically, as applied to those patients with cirrhosis, the consideration for radiation field reduction and potential hepatotoxicity must be accounted for. Without a clear survival benefit and potential significant risk beyond those patients with well-compensated Child’s A cirrhosis, the use of chemoradiation should likely be avoided unless a clear benefit can be demonstrated.

A major development for neoadjuvant therapies has been seen in recent years with modified FOLFIRINOX regimens to borderline resectable and locally advanced populations. The modified FOLFIRINOX regimen relies on a 25% dose reduction of irinotecan and 5-FU to reduce the high toxicity of the initial FOLFIRINOX regimens utilized in the study of metastatic pancreatic adenocarcinoma patients. Despite this dose reduction, the associated hepatotoxicity of irinotecan and oxaliplatin generally prevents the use of this regimen to cirrhotic patients beyond those with well-compensated Child’s A class. Use of the modified FOLFIRINOX regimen in previously transplanted patients has not been evaluated to date, although the potential application would seem safe from a toxicity standpoint. Given the absence of alternative highly active chemotherapy regimens, the use of FOLFIRINOX may be warranted despite these hypothetical risks of liver injury. Another current regimen which has recently been demonstrated to yield significant survival advantages is the gemcitabine and nab-paclitaxel regimen. This regimen was demonstrated in the metastatic setting to improve overall survival from 6.6 months to 8.7 months in the MPACT trial and has also been extrapolated to the neoadjuvant setting more recently. Current evidence for this regimen in neoadjuvant setting is currently in development with ongoing studies to evaluate its efficacy. However, given the lack of underlying hepatotoxicity associated with gemcitabine and nab-paclitaxel, the use of this regimen may be preferred in the cirrhotic and liver transplantation population for neoadjuvant therapy.

Overall patients with borderline resectable or locally advanced pancreatic adenocarcinoma clearly have a survival benefit to neoadjuvant chemotherapy and possibly the addition of chemoradiation in well-selected patients. As has been shown, the implementation of neoadjuvant therapy is associated with an elevated likelihood to complete systemic and surgical therapies compared to upfront surgery. This benefit in particular is useful for those with cirrhosis who are prone to additional hepatic decompensation following a pancreatoduodenectomy, given the underlying perioperative risk for decompensation as well as progressive hepatic insufficiency from protein malabsorption associated with the reconstruction. As newer studies attempt to evaluate the benefit of patients with resectable pancreatic adenocarcinoma treated with modern neoadjuvant regimens, this pathway and its associated benefits may aid in the treatment of those cirrhosis patients who otherwise would be capable of undergoing surgical resection, but unfit to complete adjuvant therapy to yield the greatest survival benefit.

Surgical management for pancreatic adenocarcinoma should be attempted in patients with resectable tumors and those with borderline resectable or locally advanced, who are anticipated to be capable of achieving an R0 resection. Given the inability to assess for venous or arterial invasion following neoadjuvant therapies using imaging studies and the unreliability of CA19-9 in predicting resectability, beyond the presence of metastases, those who have completed neoadjuvant therapy and are medically fit for surgery should be offered resection. General considerations for surgical resection of pancreatic adenocarcinoma should be the decision to use a diagnostic laparoscopy prior to proceeding with attempted resection. Historical rates of positive liver/peritoneal findings from diagnostic laparoscopy for pancreatic adenocarcinoma were up to 21% across all patients without radiographic peritoneal metastases. More modern imaging techniques however likely have led to this rate being lower, although many consider a diagnostic laparoscopy prior to resection as an important method to prevent unnecessary open exploration and potential resection. The use of diagnostic laparoscopy therefore remains an important component of surgical exploration for cirrhotic patients, given their inherent increased perioperative morbidity and mortality.

Standard resection principles for pancreatectomy should be applied regardless of the underlying liver function, as shown in Table 11.2. The technical procedure of performing a pancreatoduodenectomy or distal pancreatectomy and splenectomy is beyond the focus of this chapter. Standard resection techniques are appropriate to apply, and attention to oncological standards should be emphasized with avoidance of atypical resections or inadequate procedures simply due to underlying liver dysfunction or prior transplantation. One challenge in reported series of cirrhotic patients undergoing pancreatectomy is the risk for a lower lymph node yield. Reasons for this traditionally lower number of nodal tissue are likely due to concern for the risk of intraoperative hemorrhage with extensive dissection. With respect to the safety of venous resection in the setting of cirrhotic patients, small series have demonstrated the safety of venous resection in the setting of cirrhosis both with and without portal hypertension. Outcomes of these patients have led to increased intraoperative blood loss and operative duration, although this is not significantly different than is seen in noncirrhotic patients.

General factors likely to be encountered in the setting of cirrhosis include both anatomical and physiological changes. Anatomical changes which may alter the operative conduct and safety of the procedure relate to portal hypertension. In the setting of cirrhosis with portal hypertension, the development of engorged portal and mesenteric veins can obscure surgical planes with an increased propensity for hemorrhage. Dissection of the portal structures and superior mesenteric vein borders, which normally have small caliber vessels, is more likely to be of significant caliber and inadequately controlled with electrodissection techniques. The underlying pressurization of these vessels may cause the caliber to be inadequate for vessel-sealing bipolar technologies, which some surgeons prefer to employ along these margins. Furthermore, in the setting of portal vein or mesenteric obstruction leading to collateralization of portal venous branches, the lesser sac can be dangerously replaced with thin-walled venous structures. Entrance into the lesser sac and attempted mobilization of the pancreatic neck can produce significant hemorrhage if these overlying vessels remain pressurized. Current recommendations for patients with portal vein obstruction or thrombosis are against surgical resection, although a report on complex venous reconstruction and decompression of collateral veins has been reported in a highly selected group of 11 patients from the Medical College of Wisconsin group following neoadjuvant therapies. The implications for portal occlusion in this setting however were related to the underlying pancreatic cancer, and therefore how these outcomes apply to those patients with chronic cavernous changes is uncertain.