Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis

INTRODUCTION — 

For patients with exocrine pancreatic cancer, a majority (85 percent) present with adenocarcinomas arising from the ductal epithelium. Surgical resection is the only potentially curative treatment. Unfortunately, because of the late presentation of the disease, only 15 to 20 percent of patients have resectable disease and are candidates for pancreatectomy. The prognosis of pancreatic cancer is poor even in those with potentially resectable disease, and despite progress in surgical techniques and adjuvant therapy, improvement in outcomes over time has lagged behind that of other common cancers.

An overview of the surgical management of cancers of the exocrine pancreas will be reviewed here. The clinical manifestations, diagnosis, staging, and medical management of exocrine pancreatic cancer are discussed separately.

●(See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer".)

●(See "Treatment for potentially resectable exocrine pancreatic cancer".)

●(See "Initial management of locally advanced unresectable or borderline resectable exocrine pancreatic cancer".)

●(See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

Specific techniques of pancreatic resection are discussed in other topics as well.

●(See "Surgical resection of lesions of the head of the pancreas".)

●(See "Surgical resection of lesions of the body and tail of the pancreas".)

●(See "Pylorus-preserving pancreaticoduodenectomy".)

●(See "Total pancreatectomy".)

WHO SHOULD UNDERGO PANCREATIC RESECTION? — 

Based on the preoperative staging evaluation that includes imaging studies and endoscopic ultrasound, exocrine pancreatic cancer can be classified along a continuum of resectability according to the involvement of adjacent structures and the presence or absence of distant metastases (figure 1).

●Metastatic diseases – Distant metastases in the liver, peritoneum, omentum, extraregional lymph nodes, or any extra-abdominal site are absolute contraindications to pancreatic resection. Patients with metastatic exocrine pancreatic cancer are typically treated with initial palliative systemic therapy. (See "Initial systemic therapy for metastatic exocrine pancreatic cancer".)

●Localized diseases – Patients without metastatic disease are classified as having either locally advanced, borderline resectable, or resectable disease, based on various resectability criteria. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Assessing resectability'.)

•Locally advanced – Local unresectability is usually (but not always) due to vascular invasion, particularly of the superior mesenteric artery. The precise criteria are presented elsewhere. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Locally advanced disease'.)

•Borderline resectable – This definition of borderline resectable disease is variable in the literature. Encasement (more than one-half of the vein circumference) or occlusion of the superior mesenteric vein (SMV) or the SMV-portal vein confluence was previously considered unresectable. However, many centers have demonstrated the feasibility of SMV reconstruction, and provided that venous reconstruction is possible, this is now considered by many to represent borderline resectable disease. Although vein resection adds a measure of complexity to pancreaticoduodenectomy, an experienced surgical team in a high-volume center can safely perform such a resection when it is required. Several groups have issued guidelines to define borderline resectable disease based upon imaging studies. The precise criteria are presented elsewhere. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Borderline resectable'.)

•Resectable – The remainder of patients have resectable disease. Because of the late presentation of pancreatic cancer, only 15 to 20 percent of patients have resectable disease and are candidates for pancreatectomy. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Resectable disease'.)

WHEN SHOULD PANCREATIC RESECTION BE PERFORMED? — 

In suitable surgical candidates, pancreatic resection can be performed upfront or after neoadjuvant therapy, depending on resectability and center/provider preferences. Multidisciplinary evaluation by medical oncology, radiation oncology, and surgical oncology is necessary to determine the sequencing of surgery with other therapies for pancreatic cancer (chemotherapy and radiation therapy).

●Borderline resectable or locally advanced disease – Patients who have borderline resectable or locally advanced pancreatic cancer and no metastatic disease are potential candidates for initial neoadjuvant therapy to reduce tumor burden, followed by re-evaluation for pancreatic resection. Some patients with locally advanced or borderline resectable disease may convert to resectable disease with neoadjuvant therapy. Further details are discussed separately. (See "Initial management of locally advanced unresectable or borderline resectable exocrine pancreatic cancer".)

●Resectable disease – For patients with potentially resectable pancreatic cancer, options for initial therapy include either immediate surgical resection followed by adjuvant therapy or neoadjuvant therapy followed by re-evaluation for surgery. Further details are discussed separately. (See "Treatment for potentially resectable exocrine pancreatic cancer".)

PREOPERATIVE CONSIDERATIONS

Role of preoperative biliary drainage — Patients with pancreatic cancer who are jaundiced at presentation are at risk for perioperative complications. The underlying biliary obstruction may be observed or stented depending on several factors:

●Delivery of neoadjuvant therapy necessitates durable biliary decompression for up to six months. (See "Initial management of locally advanced unresectable or borderline resectable exocrine pancreatic cancer", section on 'Jaundiced patients and those with a poor performance status'.)

●For those undergoing upfront surgery, some surgeons advocate an endoscopically placed stent prior to surgery, while others reserve decompression for patients with a bilirubin of >20 mg/dL, with signs of cholangitis, or in those for whom surgery will be delayed for longer than two weeks. (See "Surgical resection of lesions of the head of the pancreas", section on 'Preoperative biliary drainage'.)

●In practice, jaundiced patients may have already undergone biliary stenting before resectability or the time frame for resection has been determined, given that they are frequently initially seen by a gastroenterologist. (See "Endoscopic stenting for malignant biliary obstruction".)

●Biliary decompression in nonsurgical candidates is discussed separately. (See "Supportive care for locally advanced or metastatic exocrine pancreatic cancer", section on 'Stents'.)

Role of staging laparoscopy — Available imaging techniques are highly accurate at predicting unresectable disease, but they fall short in predicting resectable disease, mainly because of limited sensitivity for small-volume metastatic disease.

Most surgeons use a selective approach to staging laparoscopy, albeit with different selection criteria (see "Diagnostic staging laparoscopy for digestive system cancers"). A selective approach maximizes yield by limiting the procedure to those with the highest likelihood of occult metastatic disease. Diagnostic laparoscopy should be performed before the start of neoadjuvant therapy (usually coupled with Port-A-Cath placement). We consider performing diagnostic laparoscopy in patients who have potentially resectable disease, but one of the following features on imaging studies or lab tests (see "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Staging laparoscopy' and "Surgical resection of lesions of the head of the pancreas", section on 'Staging laparoscopy' and "Surgical resection of lesions of the body and tail of the pancreas", section on 'Staging laparoscopy'):

●Imaging is suggestive, but not diagnostic, of metastatic disease

●A tumor of the body or tail of the pancreas (these tumors are diagnosed at a later stage when peritoneal spread is more likely than pancreatic head tumors)

●Large (>3 cm) primary tumors

●Carbohydrate antigen 19-9 (CA 19-9) level >1000 units/mL

Some surgeons routinely perform peritoneal washing at the time of diagnostic laparoscopy, while others perform peritoneal washing selectively or not at all. Additionally, the management of patients with isolated positive peritoneal washings at the time of staging laparoscopy is also controversial. The presence of these cells is associated with a worse prognosis in patients with otherwise resectable disease [1], and the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis staging system considers positive peritoneal washings to represent distant metastatic disease (table 1). In general, most patients who have cytologically positive washings have other findings that suggest advanced disease and unresectability, such as extensive ascites and/or the presence of metastases in the liver, pelvis, or omentum. However, if these are absent, most pancreatic surgeons would not rely solely upon the results of peritoneal washings obtained at the time of laparoscopy to guide decision-making regarding resectability. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Importance of peritoneal cytology'.)

Ascites is not necessarily a contraindication to attempted resection unless peritoneal cytology is positive.

HOW SHOULD PANCREATIC RESECTION FOR CANCER BE PERFORMED? — 

Regardless of the type of resection performed, the following oncologic principles apply to pancreatic resection for cancer.

Margins — When performing pancreatic resection for exocrine pancreatic cancer, achieving clear surgical margins is critical for long-term outcomes. Overall, positive margin rates are reported to range between 15 and 85 percent, and, when present, these are regularly predictive of decreased survival [2,3]. Safe achievement of an R0 margin is the main surgical objective of pancreaticoduodenectomy for extended survival [4]. The impact of a microscopically positive (R1) resection on ultimate clinical outcome is uncertain. Multimodality therapy may improve the survival of an R1 resection to that of R0 resections. In many studies, R2 (macroscopically positive) and R1 margin results are lumped, making the determination of the individual effect on survival of each of these outcomes difficult. We routinely obtain a frozen section of the pancreatic transection margin, and if this is positive, extend the resection. We do the same for the biliary margin, which is only rarely positive. The retroperitoneal and superior mesenteric artery margins are not sent for frozen section, since there is no ability to extend them.

●A negative margin (ie, R0 resection) is defined differently in America and Europe [5].

•In the United States, the Union for International Cancer Control (UICC)/AJCC criteria are used, which define a positive resection margin when tumor cells are present at the edges of the operative specimen (tumor clearance 0 mm).

•In Europe, the criteria of the British Royal College of Pathologists (RCPath) and the Leeds Pathology Protocol (LEEPP) are adopted by leading high-volume centers. They define positive resection margins if tumor cells are ≤1 mm from the margin.

●An R1 resection is defined as a grossly negative, but microscopically positive margin.

●An R2 resection is defined as a grossly positive margin (tumor left behind, or incomplete excision).

The margin status is reported by the pathologist at seven locations on the surgical specimen:

●Anterior

●Posterior

●Medial or superior mesenteric vein (SMV) groove

●Superior mesenteric artery

●Pancreatic transection

●Bile duct

●Enteric

Of the seven margins, the status of the superior mesenteric artery margin is the most important driver of survival, because it is the most frequently involved positive margin (in up to 85 percent), and there is no fat or areolar tissue between the uncinate process and the superior mesenteric artery [2,4].

In case of mesenteric/portal vessel resections, accurate assessment of vessel invasion is mandatory. The depth of venous vessel invasion is assessed as superficial, deep, and true tumor at the intima or in contact with the vessel lumen. Deeper (eg, intima or lumen), but not superficial (eg, wall or adventitia), portal vein (PV) invasion was found to be an independent prognostic marker for poorer survival [6-8].

Vascular resection — About 30 to 40 percent of pancreatic cancers involve major visceral or mesenteric vessels at the time of diagnosis. Tumors with limited involvement of the major peripancreatic vessels, such as the SMV, PV, superior mesenteric artery, or hepatic artery, may be technically resectable. However, the impact of more aggressive resections (particularly arterial resection) on long-term prognosis is controversial [9].

Venous resection — We consider that pancreatic resection (most commonly pancreaticoduodenectomy) with PV or SMV resection and reconstruction a standard approach for pancreatic adenocarcinomas that focally involve the PV or SMV, provided that adequate inflow and outflow veins are present, the tumor does not involve the superior mesenteric artery or hepatic artery, and an R0/R1 resection can be accomplished [5].

Tumors of the pancreatic head are close to the PV and SMV, thereby placing these vessels at greater risk of involvement and need for resection and reconstruction during a pancreaticoduodenectomy. Tumors of the pancreatic body and tail also may spread to involve the SMV and PV, and in some cases, the inferior vena cava. In such instances, patients may undergo distal pancreatectomy, subtotal pancreatectomy, or total pancreatectomy. Because tumor adherence or invasion of PV or SMV cannot be reliably determined preoperatively, most surgeons make final decisions about vascular resection at the time of surgery after the pancreatic neck has been divided [10,11].

When compared with standard pancreaticoduodenectomy, adding SMV-PV resection increases the resection rate but has been associated with a greater risk of complications [12-16] and a higher mortality rate [13-15], even at very high-volume centers [12,17]. The survival benefit of SMV-PV is variably reported [13,15,16], most likely due to the heterogeneity in the completeness of resection. These findings make careful patient selection mandatory when a major venous invasion is suspected prior to surgery. Furthermore, SMV-PV resection should only be performed at high-volume centers and generally after neoadjuvant treatment, especially in cases of borderline resectable diseases [18]. (See 'When should pancreatic resection be performed?' above.)

PV thrombosis developed in 16 percent of patients who underwent pancreatectomy with PV resection at a median of 15 days [17]. Synthetic interposition graft carries the highest risk for thrombosis. SMV/PV thrombosis was associated with increased 90-day mortality (16.7 versus 4.9 percent) and overall 30-day complication rate (69.4 versus 42.9 percent), including a nearly five-times increased risk of postoperative sepsis after pancreatectomy.

Arterial resection — By contrast, we do not advocate arterial resection and reconstruction. The superior mesenteric artery courses posterior to the pancreas and is located posteromedial to the SMV, which makes involvement of the superior mesenteric artery unlikely without simultaneous involvement of the SMV. Body and tail tumors of the pancreas are commonly asymptomatic until advanced disease stages, at which time they are often deemed unresectable due to tumor involvement of the celiac axis and origin of the common hepatic artery.

These resections (mostly the superior mesenteric and hepatic arteries) are performed infrequently, and a number of systematic reviews [19-21] associated arterial resection in patients undergoing pancreatectomy with poor short- and long-term outcomes, so there is currently no evidence to support arterial resection outside of clinical trial settings.

An exception to this is tumors of the body of the pancreas that involve either the celiac axis or the common hepatic artery. Both of these vessels can be resected without reconstruction as long as there is adequate retrograde arterial flow through the gastroduodenal artery. A distal pancreatectomy and splenectomy including the celiac trunk and common hepatic artery is known as a modified Appleby procedure [22].

Lymphadenectomy — Pancreaticoduodenectomy with standard lymphadenectomy is the operation of choice. Data from four prospective, randomized controlled trials involving a total of 424 patients suggest that extended lymphadenectomy confers no survival advantage over standard lymphadenectomy and may be associated with compromised quality of life, particularly in the early postoperative period [4].

●Standard lymphadenectomy for pancreatoduodenectomy should strive to resect lymph node stations 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b (figure 2) [23].

●Extended lymphadenectomy also includes all 8, 9, all 12, all 14, 16a2, and 16b1 lymph nodes.

Some groups (mainly in Asian countries) routinely perform extensive lymph node dissection in conjunction with pancreaticoduodenectomy since periampullary malignancies frequently metastasize to lymph nodes that are beyond the confines of the conventional pancreaticoduodenectomy [24,25].

However, the evidence to support a benefit from extended lymphadenectomy is lacking in contemporary series. As summarized by a 2021 Cochrane review of seven trials, an extended lymphadenectomy increased operative time and blood loss without improving survival. In another meta-analysis of both trials and observational studies, the risk for some complications was significantly increased in the extended lymphadenectomy group (lymphatic fistula odds ratio [OR] 6.1, 95% CI 1.0-35.3; delayed gastric emptying OR 2.0, 95% CI 1.2-3.5; bile leak OR 2.6, 95% CI 1.0-6.7; pancreatic leak OR 1.7, 95% CI 1.0-2.9) [26].

The prognostic value of nodal status is discussed below. (See 'Nodal status' below.)

WHAT TYPE OF PANCREATIC RESECTION SHOULD BE PERFORMED? — 

This is usually dictated by the anatomic location of the tumor.

Tumors in the head of the pancreas — The operation for resecting pancreatic cancer of the head or uncinate process is a pancreaticoduodenectomy. The original Whipple procedure has been modified by preserving the pylorus. For patients undergoing pancreaticoduodenectomy, there is no survival benefit for either a conventional or pylorus-preserving Whipple operation, while short-term outcomes differ [27]. Thus, the preferences of the surgeon and patient should prevail.

●Conventional pancreaticoduodenectomy – The original pancreaticoduodenectomy (ie, Whipple procedure) involves removal of the pancreatic head, duodenum, first 15 cm of the jejunum, common bile duct, and gallbladder, and a partial gastrectomy (figure 3). There is good evidence that conventional pancreaticoduodenectomy reduces the rate of delayed gastric emptying compared with pylorus-preserving pancreaticoduodenectomy [27]. (See "Surgical resection of lesions of the head of the pancreas", section on 'Conventional pancreaticoduodenectomy (Whipple)'.)

●Pylorus-preserving pancreaticoduodenectomy – Pylorus-preserving pancreaticoduodenectomy preserves the gastric antrum, pylorus, and proximal 3 to 6 cm of the duodenum, which is anastomosed to the jejunum to restore gastrointestinal continuity (figure 4). The procedure may decrease the incidence of postoperative dumping, marginal ulceration, and bile reflux gastritis that can occur in some patients undergoing partial gastrectomy. There is also evidence that pylorus-preserving pancreaticoduodenectomy reduces operative time, blood loss, and transfusion requirement compared with conventional pancreaticoduodenectomy [27]. (See "Surgical resection of lesions of the head of the pancreas", section on 'Pylorus-preserving pancreaticoduodenectomy' and "Pylorus-preserving pancreaticoduodenectomy".)

Minimally invasive (laparoscopic, robotic-assisted) pancreaticoduodenectomy is technically feasible and is increasingly available. However, even with the available technology, minimally invasive pancreaticoduodenectomy is a complex operation that is only suited for select patients. (See "Minimally invasive pancreatectomy (MIP)", section on 'Pancreaticoduodenectomy'.)

Tumors in the body or tail — Because ductal adenocarcinomas involving the body or tail of the pancreas usually do not cause obstruction of the intrapancreatic portion of the common bile duct, early diagnosis is rare; the majority have locally advanced or metastatic disease at the time of presentation. In the rare patient who appears to have potentially resectable disease by computed tomography scan, laparoscopic exploration should precede attempted resection, since a significant proportion will have occult peritoneal metastases. (See 'Role of staging laparoscopy' above.)

Surgical resection of cancers located in the body or tail of the pancreas consists of a distal subtotal pancreatectomy, usually combined with splenectomy. Many of these procedures can be performed laparoscopically or robotically, which has not affected the ability to achieve a complete resection. Thus far, oncologic outcomes have not been inferior. (See "Minimally invasive pancreatectomy (MIP)", section on 'Distal pancreatectomy'.)

Tumors involving the entire gland — Total pancreatectomy is sometimes required in order to achieve a microscopically negative resection margin [28-30]. Total pancreatectomy was first advocated to remove more tissue potentially involved with the malignancy and to avoid a pancreaticojejunal anastomosis, the source of considerable morbidity and mortality. However, total pancreatectomy has been associated with a higher mortality rate than partial pancreatectomy, and the metabolic consequences of total pancreatectomy, which include permanent exocrine insufficiency and brittle diabetes, have a detrimental impact on quality of life and long-term survival. (See "Total pancreatectomy", section on 'Long-term'.)

Contemporary data on total pancreatectomy are lacking, and single-institution series are limited by small numbers [30-32]. Nevertheless, these data support the use of total pancreatectomy where oncologically appropriate (ie, under conditions where it would yield a tumor-free resection margin while a conventional Whipple procedure would not). This typically occurs when a tumor of the pancreatic head extends into the body or tail of the pancreas.

Total pancreatectomy also plays a role in the treatment of some main-duct intraductal papillary mucinous neoplasms, which may involve the entire length of the pancreatic duct, either continuously or in a multifocal fashion. When both types of pancreatic resection would provide a tumor-free margin, total pancreatectomy provides no additional benefit. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Evaluation and management".)

OUTCOMES

Perioperative morbidity and mortality

Pancreaticoduodenectomy — Although previously associated with high perioperative morbidity and mortality rates, perioperative mortality of pancreaticoduodenectomy in most modern series is less than 3 percent [33-40]. This relatively low perioperative mortality rate represents a decline from over 15 percent in the 1970s.

One of the most important reasons for this improvement is the greater experience of a more limited number of surgeons who perform the procedure on a regular basis in high-volume hepatobiliary centers [41-45]. The relationship between surgeon and hospital volume, and postoperative mortality and survival after pancreatic cancer surgery, was addressed in a meta-analysis of 14 studies [46]. There was a significant association between hospital volume and postoperative mortality (odds ratio 0.32, 95% CI 0.16-0.64) as well as overall survival (hazard ratio for death 0.79, 95% CI 0.70-0.89). (See "Surgical resection of lesions of the head of the pancreas", section on 'Perioperative morbidity and mortality'.)

Distal pancreatectomy — According to data from the National Surgery Quality Improvement Program (NSQIP), 30-day mortality occurred in 1.3 percent of patients who underwent distal pancreatectomy for cancer between 2014 and 2016 [47]. In 2135 patients who underwent distal pancreatectomy between 2001 and 2022 at a single, high-volume center, 28 percent developed one or more severe complications (postoperative pancreatic fistula 23 percent, postpancreatectomy hemorrhage 2.7 percent, delayed gastric emptying 6.3 percent, chyle leak 6.3 percent) [48]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Morbidity and mortality'.)

Total pancreatectomy — Total pancreatectomy has been associated with higher operative morbidity and mortality compared with pancreaticoduodenectomy. A review of the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database (2005 to 2009) found a mortality rate of 5.4 percent among 166 patients who underwent total pancreatectomy [39]. Perioperative mortality for pancreaticoduodenectomy (n = 4317) and distal pancreatectomy (n = 2364) was 2.9 and 1.7 percent, respectively.

Over time, the perioperative (30-day) mortality rate of total pancreatectomy has progressively declined; however, the morbidity rate remains as high as 70 percent [32]. In a meta-analysis of 45 nonrandomized comparative studies between total pancreatectomy and pancreaticoduodenectomy, there were more complications in the total pancreatectomy group [49].

Long-term survival — As noted above, even in the setting of completely resected, node-negative pancreatic cancer, the majority of patients die of their disease.

Tumors in the pancreatic head — While improvement has been observed, the prognosis for resection of adenocarcinoma of the head of the pancreas remains poor even with pancreaticoduodenectomy with surgically negative margins. Large series show five-year survival rates of only 10 to 25 percent and median survival between 10 and 20 months [35,50-55]. These series, however, include patients who did not undergo adjuvant treatment or received single-agent chemotherapy. Newer multiagent adjuvant chemotherapy regimens significantly increase both median and five-year survival after surgical resection. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Modern combination regimens (FOLFIRINOX and gem-nabpaclitaxel)'.)

The literature presents conflicting evidence on whether the prognosis of resected pancreatic cancer has improved over time [56]. One comparison of outcomes following pancreatectomy over two different time periods (1991 to 2000 and 2001 to 2010) in a single high-volume academic institution revealed significantly longer survival among patients treated during the later time period (median 27 versus 16 months, five-year survival 27 versus 15 percent) [57]. By contrast, in a large series of 1147 pancreatic resections performed over three decades at the Memorial Sloan Kettering Cancer Center, long-term survival rates were nearly identical for patients treated in the 1980s, 1990s, and 2000s (median 23.2, 25.6, and 24.5 months, respectively). The corresponding five-year survival rates were 17, 20, and 8 percent [58].

Tumors in the pancreatic body or tail — In several contemporary series of laparoscopic distal pancreatectomy for pancreatic ductal carcinoma from high-volume centers, median survival ranged between 18 to 32 months, three-year overall survival ranged from 22 to 42 percent, and five-year overall survival ranged from 20 to 38 percent [59-63].

Tumor involving the entire gland — Long-term oncologic outcomes are not necessarily better following total as compared with partial pancreatectomy [32,64]. In a meta-analysis of 45 nonrandomized comparative studies between total pancreatectomy and pancreaticoduodenectomy, there were no differences in the long-term survival rates between the two groups [49].

PROGNOSTIC FACTORS — 

Disease that is limited to the pancreas is most likely to be cured by resection, although approximately 30 percent of individuals who undergo a complete (R0) resection of a pancreatic cancer with limited nodal involvement may also be long-term survivors (figure 5) [65].

Tumor stage — Tumor stage is the most important prognostic factor. The influence of tumor stage on survival according to the newest eighth edition American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging classification (table 1) can be illustrated by a series of 8960 patients undergoing treatment for potentially resectable pancreatic adenocarcinoma and reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013 (figure 6) [66].

Nodal status — An important prognostic factor for completely resected patients is nodal status, which is technically a component of tumor stage. Five-year survival after pancreaticoduodenectomy is only approximately 10 percent for node-positive disease (even if only one node is positive [67]), while it is approximately 30 percent for node-negative disease [65]. Importantly, two-thirds of patients with newly diagnosed pancreatic cancer would be expected to have positive lymph nodes, which carry a worse prognosis. This fact has been used as a justification for neoadjuvant chemotherapy for all patients with either resectable or borderline-resectable disease. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Neoadjuvant therapy' and "Initial management of locally advanced unresectable or borderline resectable exocrine pancreatic cancer".)

The number of positive nodes is also of prognostic significance. The eighth edition AJCC TNM staging system (2017 (table 1)) subdivides node-positive disease according to the number of positive nodes to provide better prognostic stratification (figure 5) [65]. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Staging system and the staging workup'.)

Finally, as has been seen in colon and gastric cancer, the total number of nodes examined also impacts prognosis [68-70]. At least some data support the view that pathologic examination of at least 15 nodes in the pancreatectomy specimen is necessary to accurately stage a node-negative adenocarcinoma [69].

Other prognostic factors — In addition to stage, other factors that influence prognosis after resection are the status of the surgical margins (involved or uninvolved), tumor differentiation, the presence or absence of lymphatic invasion within the tumor, both preoperative and postoperative serum carbohydrate antigen 19-9 (CA 19-9) levels, and cigarette smoking [2,3,71-78]. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer".)

A model (MetroPancreas) that uses three preoperative variables (American Society of Anesthesiologists [ASA] class, CA 19-9 serum level, and tumor size) has been developed to predict futile pancreatectomy, defined as an operation resulting in patient death or disease recurrence within six months, and select patients for upfront pancreatectomy versus neoadjuvant therapy [79].

A postresection nomogram has been developed [80] and validated [68] to predict the probability that a patient will die of pancreatic cancer within three years of surgery. In addition to the T and N status (according to the seventh edition AJCC [2010] criteria), this nomogram incorporates clinical (age, sex, presence of back pain or weight loss, tumor location), pathologic (histologic differentiation, tumor size, margin status, number of positive nodes), and surgical (type of resection) variables. Other nomograms are available that incorporate adjuvant treatment [81], but few have integrated the eighth edition (2017) AJCC staging criteria [82]. (See "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Staging system and the staging workup'.)

Conditional survival — Although five-year overall survival rates remain poor overall, survival estimates for individual patients are dynamic, and they may change over time based on the time already survived (a concept referred to as "conditional survival"). This was illustrated in a retrospective analysis of 1822 patients undergoing curative-intent surgery for pancreatic cancer at Johns Hopkins between 1970 and 2008 [83]. The two-year conditional survival at three years (ie, the probability of surviving to postoperative year 5 given that the patient had already survived three years) was 66 percent, versus a five-year actuarial survival calculated from the time of surgery of 18 percent. Patients with high lymph node ratios (the number of metastatic nodes divided by the total number of resected nodes) or positive margins saw the greatest increases in two-year conditional survival as more time elapsed since treatment.

Long-term survival — Long-term survival is possible, even in the presence of positive nodes or involved margins. As an example, in the Charité Onkologie (CONKO)-001 trial examining the benefit of adjuvant gemcitabine, 15 percent of patients survived five years or more [84]. Among the 53 long-term survivors, 29 (54 percent) had node-positive disease, while seven (13 percent) had undergone R1 (microscopically positive margins) resection.

Only limited prognostic information exists for 5- to 15-year survivors. In an analysis of data from the SEER database of the National Cancer Institute (NCI), prognosis continued to improve with accrued survival beyond five years (table 2) [85]. However, deaths due to pancreatic cancer occurred as late as 20 years after diagnosis. The hazard of overall and pancreatic cancer-related death was highest at year 3 after diagnosis, declined until year 13, and then remained less than 3 percent per year. Between years 9 and 13, there was still an approximately 10 percent per-year risk of pancreatic cancer-specific death. The hazard of death due to other causes did not exceed that of pancreatic cancer-related death until 8.75 years postdiagnosis.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pancreatic cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Pancreatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Who should undergo pancreatic resection? – Surgical resection is the only potentially curative treatment for pancreatic adenocarcinoma. Unfortunately, because of the late presentation, only 15 to 20 percent of patients have resectable disease and are candidates for pancreatectomy. Pancreatic resection is contraindicated in patients with metastatic disease (such as in the liver, peritoneum, omentum, extraregional lymph nodes, or any extra-abdominal site). Some patients with locally advanced or borderline resectable disease may convert to resectable disease with neoadjuvant therapy. The precise criteria of resectability are evolving and are discussed in another topic. (See 'Who should undergo pancreatic resection?' above and "Clinical presentation, diagnosis, and staging of exocrine pancreatic cancer", section on 'Assessing resectability'.)

●When should pancreatic resection be performed? – Patients who have borderline resectable or locally advanced pancreatic cancer and no metastatic disease are potential candidates for initial neoadjuvant therapy (chemotherapy with or without radiation therapy) to reduce tumor burden before undergoing re-evaluation for pancreatic resection. (See "Initial management of locally advanced unresectable or borderline resectable exocrine pancreatic cancer".)

For patients with potentially resectable pancreatic cancer, options for initial therapy include upfront surgical resection followed by adjuvant therapy or neoadjuvant therapy followed by re-evaluation for surgery. (See "Treatment for potentially resectable exocrine pancreatic cancer".)

●How should pancreatic resection be performed? – Regardless of the type of resection performed, the following oncologic principles apply to pancreatic resection for cancer.

•Margins – When performing pancreatic resection for exocrine pancreatic cancer, surgeons should aim for clear surgical margins (R0), ideally with 1 mm or more free of tumor, which are predictive of long-term survival. The superior mesenteric artery margin is usually the closest and most often positive. (See 'Margins' above.)

•Vascular resection – For patients with exocrine pancreatic cancers that focally involve the portal vein (PV) or superior mesenteric vein (SMV), we suggest performing venous resection and reconstruction with the pancreatic resection (Grade 2C). Candidates for venous resection and reconstruction must have only focal tumor involvement with the PV or SMV, adequate inflow and outflow veins present, the tumor does not involve the superior mesenteric artery or hepatic artery, and an R0/R1 resection can be accomplished. Arterial resection for tumors involving the superior mesenteric artery does not improve outcomes based on limited evidence. (See 'Vascular resection' above.)

•Lymphadenectomy – Nodal status is an important prognostic factor for completely resected patients. For patients with exocrine pancreatic cancer, we suggest performing standard, rather than extended, lymphadenectomy (Grade 2B). The latter incurs more complications without improving survival. Pathologic examination of at least 15 nodes in the pancreatectomy specimen is necessary to accurately stage a node-negative adenocarcinoma. (See 'Lymphadenectomy' above and 'Nodal status' above.)

●What type of pancreatic resection should be performed? – This depends on the anatomic location of the tumor.

•Tumors in the head/uncinate process of the pancreas – The standard operation is pancreaticoduodenectomy. There is no evidence that either a conventional or pylorus-preserving Whipple operation is superior, and the preferences of the surgeon and patient should prevail. (See 'Tumors in the head of the pancreas' above and "Surgical resection of lesions of the head of the pancreas".)

For patients presenting with obstructive jaundice, biliary decompression is required if the patient has cholangitis or if neoadjuvant therapy is planned. In addition, we offer stenting if the bilirubin level is >20 mg/dL or if surgery will be delayed for longer than two weeks. (See 'Role of preoperative biliary drainage' above and "Surgical resection of lesions of the head of the pancreas", section on 'Preoperative biliary drainage'.)

•Tumors of the tail/body of the pancreas – The standard operation is a distal pancreatectomy, usually combined with splenectomy. (See 'Tumors in the body or tail' above and "Surgical resection of lesions of the body and tail of the pancreas".)

We perform laparoscopic exploration prior to attempted resection since a significant proportion will have occult peritoneal metastases. (See 'Role of staging laparoscopy' above and "Surgical resection of lesions of the body and tail of the pancreas", section on 'Staging laparoscopy'.)

•Tumors involving the entire gland – Total pancreatectomy is sometimes needed for tumors involving the entire gland to achieve a microscopically negative resection margin. (See 'Tumors involving the entire gland' above.)

●Prognostic factors – Tumor stage is the most important prognostic factor for long-term survival (figure 5). Other factors that influence prognosis after resection are the status of the surgical margins (involved or uninvolved), tumor differentiation, the presence or absence of lymphatic invasion within the tumor, both preoperative and postoperative serum carbohydrate antigen 19-9 (CA 19-9) levels, and cigarette smoking. Models and calculators have been developed to predict survival both prior to and after pancreatic resection. (See 'Prognostic factors' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Michael Steer, MD, who contributed to an earlier version of this topic review.