Pancreatic cancer

CHAPTER 62  Pancreatic cancer: clinical aspects, assessment, and management Michael J. Pucci, Eugene P. Kennedy, and Charles J. Yeo CLINICAL PRESENTATION The diagnosis of pancreatic cancer (namely, the entity of pancreatic ductal adenocarcinoma) is typically a devastating experience for patients. Currently the fourth leading cause of cancer death in the United States, it is projected to become the second leading cause by the year 2020, because of both a rise in incidence and the death rate (Yeo, 2012). These tumors often arise insidiously, invade locally, and spread distantly before any clinical signs or symptoms. The symptoms that bring these malignancies to clinical attention vary based upon the location of the tumor within the pancreas and the stage at presentation. The majority of resectable pancreas cancers occur in the right side of the pancreas, in the head, or uncinate process of the gland. Classic symptoms from these right-sided tumors include jaundice from biliary obstruction, often accompanied by pruritus, and epigastric pain radiating to the back from tumor involvement of the celiac plexus. Less commonly, persistent nausea or vomiting, as a result of gastric outlet obstruction (GOO) from tumor narrowing at the duodenal C-loop, is the initial symptom. Additionally, pancreatitis in the absence of cholelithiasis or ethanol abuse should arouse suspicion for cancer in patients age 60 years or older. Tumors arising in the left side of the pancreas typically cause few symptoms until they are locally advanced or metastatic. For such left-sided tumors, pain is the most common presenting symptom, occasionally steatorrhea may be seen, and jaundice is rare. Other nonspecific symptoms often occur in association with pancreatic cancer. Nausea, anorexia, weight loss, and fatigue are commonly reported and often are present for some time before diagnosis. Because of the generalized and common nature of these symptoms, they rarely lead directly to a diagnosis unless they become profound. Significant weight loss without GOO is often indicative of advanced disease. Typically, jaundice is the only physical finding in “early”stage pancreatic cancer. The classic physical findings of left supraclavicular adenopathy (Virchow node), periumbilical adenopathy (Sister Mary Joseph node), or a firm circumferential rim of tumor at the top of the rectum on digital rectal examination (Blumer shelf from drop metastases) are found only with advanced, disseminated disease. Less specific findings that also typically indicate advanced disease include temporal wasting, ascites, hepatomegaly from metastatic disease, or a palpable abdominal mass. Laboratory analysis is of limited benefit in the diagnosis of pancreatic cancer. Elevated liver function tests are nonspecific and require both further serologic testing and imaging to investigate their etiology. It is not uncommon to have hyperbilirubinemia with marked increases in alkaline phosphatase and γ-glutamyl transpeptidase, with mild elevations of alanine aminotransferase and aspartate aminotransferase. New-onset dia-

betes mellitus is often associated with pancreatic cancer. However, such new-onset diabetes has a low sensitivity and specificity for the diagnosis of pancreatic cancer, and significant overlap is found between the typical age of onset of diabetes mellitus and pancreatic cancer. The incidence of diabetes mellitus is also much greater than that of pancreatic cancer, further limiting its utility as a diagnostic sign. Ongoing research has produced many potential diagnostic biomarkers for pancreatic cancer (Harsha et al, 2009; Winter et al, 2013). Currently, the only biomarker that has recognized clinical utility is carbohydrate antigen 19-9 (CA 19-9); however, its usefulness has two significant limitations. First, it is not specific for pancreatic cancer because it can be elevated in benign conditions, particularly those that cause obstructive jaundice. Second, its sensitivity is reduced by the fact that patients who test negative for Lewis blood group antigens A and B are unable to synthesize CA 19-9 and therefore do not express it in their serum. The percentage of pancreatic cancer patients who fall into this group has been reported to range from 10% to 34% (Berger et al, 2008; Tempero et al, 1987). Thus, CA 19-9 serves best as a marker of treatment response and recurrence in patients who have a pathologic diagnosis of pancreatic cancer. However, promising research to discover other diagnostic, prognostic, and predictive biomarkers is ongoing (Winter et al, 2013).

DIAGNOSIS Once suspicion for pancreatic cancer is sufficient, high-quality imaging is critical for diagnosis and treatment planning. Many patients initially undergo an abdominal ultrasound (US) or a limited computed tomography (CT) scan of the abdomen. These modalities will suggest processes in the pancreas that require appropriate additional evaluation. Currently, the best diagnostic modality for imaging the pancreas is a “pancreas protocol” multidetector CT (MDCT) scan with dedicated arterial and venous phases and three-dimensional (3D) reconstruction (Buchs et al, 2010; Horton & Fishman, 2002; Raman et al, 2012) (see Chapter 18). Water is given orally, because oral contrast in the stomach or duodenum can cause a streak artifact that limits visualization of the pancreas and subsequent 3D image rendering. Such scans typically demonstrate the tumor as a low-density (hypodense) lesion within the pancreas, best seen during the arterial phase of contrast enhancement. The venous phase of contrast enhancement is useful to evaluate distant (mainly liver) metastases, and regional lymphadenopathy (Raman et al, 2012). Most important, however, these highquality imaging studies show the relationship between the tumor and the surrounding visceral vessels, including the superior mesenteric vein (SMV), portal vein, splenic vein, superior mesenteric artery (SMA), and the branches of the celiac axis. 979

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Such high-quality CT imaging can reliably predict visceral vessel involvement and thereby surgical resectability approximately 80% to 90% of the time (House et al, 2004; Karmazanovsky et al, 2005). Additionally, the arterial phase with 3D reconstruction can assist in surgical planning by identifying variations in hepatic arterial anatomy and other vascular anomalies preoperatively, most notably a “replaced” right hepatic artery originating from the SMA, which is seen in one of six patients (see Chapter 2). Continuing improvement in the technology that produces magnetic resonance imaging (MRI) has resulted in image quality and resultant diagnostic sensitivities that approach those of CT (see Chapter 19). No advantage has been demonstrated by obtaining both CT and MRI for uncomplicated patients who display classic symptoms of pancreatic cancer, and this practice should be discouraged. We typically reserve the use of MRI for patients with renal impairment or sensitivity to the intravenous contrast used for CT. However, in select instances, such as diagnosing small (<2 cm) pancreatic tumors and small (<1 cm) hepatic metastasis, MRI may be superior to CT imaging (Raman et al, 2012). The use of MR cholangiopancreatography (MRCP) is valuable in evaluating and following small cystic lesions of the pancreas, but a detailed discussion of these lesions is outside the scope of this chapter (see Chapters 19 and 60). Endoscopic evaluation of patients with classic symptoms of pancreatic cancer is not always necessary, but is appropriate in specific situations. Esophagogastroduodenoscopy (EGD) may be useful in cases of GOO to visualize any anatomic distortion and the presence of other diagnoses. In the setting of metastatic or unresectable disease, or when a patient with GOO is not physiologically appropriate for immediate surgical intervention, a therapeutic EGD combined with duodenal stenting can be of some benefit, allowing the patient to return to oral intake (see Chapter 29). Endoscopic retrograde cholangiopancreatography (ERCP) was once commonly used as a diagnostic modality for patients with a suspected periampullary pancreatic cancer. With the improvement of cross-sectional imaging, the use of strictly diagnostic ERCP is currently unsupported. Therapeutic ERCP with stenting of biliary strictures can be of benefit in the same patient population (metastatic, unresectable, or physiologically unfit) as therapeutic EGD (see Chapters 20 and 29). However, the routine placement of a biliary endoprosthesis for all jaundiced patients without cholangitis should be discouraged. Multiple studies have shown a doubling of the wound infection risk and a slight increase in overall complication risk with preoperative biliary stenting (Pisters et al, 2001a; Sohn et al, 2000). For most patients seen initially with a pancreatic mass and jaundice, early attempt at operative resection is preferable to endoscopic biliary stenting and delayed surgical resection (Kennedy et al, 2010). Endoscopic ultrasound (EUS) is a newer imaging and diagnostic technology compared with those previously discussed (see Chapter 16). Already well established at specialty referral centers, it is rapidly becoming more widely available. Interpretation of EUS imaging is operator dependent, a factor that may account for the wide range of diagnostic sensitivities reported in the literature and encountered in real-world clinical settings (Hunt & Faigel, 2002; Lewis & Kowalski, 2012; Varadarajulu & Eloubeidi, 2010). Reported sensitivities for the diagnosis of pancreatic neoplasia have ranged from 69% to 94%. Several studies have found EUS to be superior to CT

for the detection of lesions smaller than 2 cm. EUS is of particular utility when a patient has a presentation consistent with pancreatic cancer (biliary or pancreatic duct obstruction) but no evidence of mass on cross-sectional imaging. However, for larger lesions, the ability of EUS to accurately estimate the T stage is decreased when compared with CT imaging. Additionally, EUS has shown some superiority versus CT for the detection of venous invasion, but it is less useful for the determination of arterial involvement (Varadarajulu & Eloubeidi, 2010). An important additional advantage of EUS is the ability to obtain tissue via fine needle aspiration (FNA) for diagnostic purposes at the time of evaluation. This can be of great benefit to unresectable or borderline resectable patients who need a confirmed tissue diagnosis before the initiation of chemotherapy. However, for the vast majority of patients with a symptomatic pancreatic mass that appears completely resectable by CT or MR imaging, EUS with FNA is not needed because, in most cases, the mass will require resection regardless of the EUS and FNA results. 18 F-Fluorodeoxyglucose–positron-emission tomography (18FDGPET) is a functional imaging modality based on the observation that neoplastic cells exhibit accelerated glucose uptake and metabolism (see Chapter 17). Once transported into the cell and phosphorylated by hexokinase, the first step in glycolysis, 18FDG remains trapped within the cell. Although studies suggest 18FDG-PET is sensitive for the detection of pancreatic cancer, the precise role of this technique in the diagnosis and staging of patients with localized pancreatic cancer is limited. Its use is confounded by the difficulty of using 18FDG-PET to distinguish benign from malignant masses as a result of localization, both to sites of inflammation and infection as well as neoplasms. 18FDG-PET is of greater utility in evaluating indeterminate masses in the liver that are not amenable to biopsy. A confirmed tissue diagnosis of a primary pancreatic cancer made by EUS, when combined with a PET-positive liver lesion, is adequate to initiate palliative chemotherapy at many centers.

DIAGNOSTIC BIOPSY As mentioned previously, in low-risk patients with resectable lesions suspicious for periampullary pancreatic cancer, a tissue diagnosis is not required before surgical resection because a negative or inconclusive biopsy result should not alter the decision to operate (Asbun et al, 2014). Pancreatic biopsy should be reserved for patients with locally unresectable or metastatic disease or for those clinical situations in which a true diagnostic or management dilemma is present or when neoadjuvant therapy is considered. Such situations would include patients with a history of other cancers with a realistic chance of a metastasis to the periampullary region (renal cell cancer, melanoma), patients with a suspicion for autoimmune pancreatitis, or patients with marginal physiologic reserves at prohibitive risk for surgical intervention. When preoperative imaging suggests that autoimmune pancreatitis (see Chapters 18, 57, and 59) may be present, IgG4 levels should also be obtained, because elevated IgG4 is highly specific for this process. Whenever possible, biopsy of a pancreatic lesion should be performed endoscopically with EUS-FNA (see Chapter 16). Percutaneous US- or CT-guided pancreatic biopsy should be discouraged, and patients should be referred to centers where EUS-FNA is available. Percutaneous biopsy should be reserved

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TABLE 62.1  AJCC Staging of Pancreatic Cancer Stage

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastases (M)

0 IA

Tis T1

N0 N0

M0 M0

Carcinoma in situ, includes PanIN3

IB

T2

N0

M0

IIA

T3

N0

M0

IIB III

T1, T2, T3 T4

N1 Any N

M0 M0

IV

Any T

Any N

M1

Tumor limited to the pancreas, >2 cm in greatest dimension Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery Regional lymph node metastasis Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor) Distant metastasis

Description Tumor limited to the pancreas, ≤2 cm in greatest dimension

AJCC, American Joint Commission on Cancer; PanIN3, pancreatic intraepithelial neoplasia. From Edge SB: American Joint Committee on Cancer. AJCC cancer staging manual, ed 7, New York, 2010, Springer.

for evaluation of suspected metastatic lesions, typically liver metastases. In the presence of suspected metastatic disease, biopsy of the distant lesion, if accessible, is preferred versus biopsy of the primary pancreatic lesion.

STAGING Pancreatic cancer is staged by the seventh edition (2010) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual according to clinical parameters that are available from high-quality CT imaging (Edge, 2010). Classic T, N, and M parameters are used for tumor size, nodal involvement, and distant metastases, but stage grouping is performed according to surgical resectability. Patients are classified with localized resectable disease (stages I and II), locally advanced unresectable disease (stage III), or distant metastatic disease (stage IV; Table 62.1). Although there are multiple guideline consensus statements to define surgical resectability, we have chosen to include the 2016 version of National Comprehensive Cancer Network guidelines (National Comprehensive Cancer Network , 2016). These define a resectable tumor as characterized on a high-quality “pancreas protocol” CT by no evidence of metastatic disease, a clear tissue (fat) plane between the tumor and the visceral arteries (celiac axis and SMA), and 180 degree or less circumferential involvement of the SMV–portal vein confluence (Fig. 62.1). In contrast, patients with unresectable disease exhibit distant metastases, ascites, involvement of greater than 180 degrees of the celiac axis or SMA (Fig. 62.2), unreconstructable SMV/portal occlusion, or aortic involvement. The term “borderline resectable” is now used more commonly and refers to lesions that have more than 180 degree involvement of the SMV/portal system or with contour irregularity or thrombosis (as long as there is a reconstruction option), tumor contact with less than 180 degrees of the SMA or celiac axis, or tumor contact with the common hepatic artery that is reconstructable (Table 62.2). Venous vascular involvement is considered potentially resectable in the AJCC system and is therefore categorized as stage II disease, and arterial involvement is considered unresectable and is categorized as stage III disease. A small subset of patients with complete occlusion of the SMV–portal vein confluence and significant collateralization that precludes safe venous resection and reconstruction are typically deemed unresectable but are still classified as stage II in the current AJCC system. This system has been validated by

T

A

FIGURE 62.1.  Resectable pancreatic adenocarcinoma in the head and uncinate process, showing well-preserved fat plane (arrow) between tumor (T) and superior mesenteric artery (A).

correlation to overall survival (OS) using the National Cancer Database (Table 62.3; Bilimoria et al, 2007a).

LAPAROSCOPY Staging laparoscopy for suspected or confirmed pancreatic cancer has the potential to detect small liver surface or peritoneal metastases often not seen on CT or MR imaging (see Chapter 23). However, it is limited in its ability to evaluate locally advanced disease without extensive laparoscopic exploration and mobilization of the adjacent structures (Schnelldorfer et al, 2014). Before the development of current imaging techniques, namely the 3D MDCT scan, unresectability rates at laparotomy exceeded 30%. Modern cross-sectional imaging has reduced that rate considerably, as discussed earlier. Disagreement exists in the literature about the role of staging laparoscopy in the evaluation of patients with radiographically resectable pancreatic cancer. The rate at which this intervention alters subsequent management is reported at between 4% and

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TABLE 62.2  National Comprehensive Cancer Network® (NCCN®) Criteria Defining Resectability Status Resectability Status

Arterial

Venous

Resectable

No arterial tumor contact with CA, SMA, or CHA

Borderline resectable

Head/uncinate process • Solid tumor contact with the SMA of ≤180 degree • Solid tumor contact with the CHA without extension to CA or bifurcation of the hepatic artery to allow safe and complete resection and reconstruction • Presence of variant arterial anatomy (ex: accessory right hepatic artery, replaced right hepatic artery, replaced CHA and the origin of replaced or accessory artery) and the presence and degree of tumor contact should be noted if present as it may affect surgical planning. Body/tail • Solid tumor contact with the CA ≤180 degrees • Solid tumor contact with the CA of >180 degrees without involvement of the aorta and with intact and uninvolved gastroduodenal artery Distant metastasis (including non-regional lymph node metastasis) Head/uncinate process • Solid tumor contact with SMA >180 degrees • Solid tumor contact with CA >180 degrees • Solid tumor contact with first jejunal SMA branch Body/tail • Solid tumor contact of >180 degrees with the SMA or CA • Solid tumor contact with the CA and aortic involvement

No tumor contact with SMV or PV or ≤180-degree contact without vein contour irregularity Solid tumor contact with the SMV or PV of >180 degrees, contact of ≤180 degrees with contour irregularity of the vein, or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing safe and complete resection with reconstruction Solid tumor contact with the IVC

Unresectable

Head/uncinate process • Unreconstructible SMV/PV due to tumor involvement or occlusion • Contact with the most proximal draining jejunal branch into SMV Body/tail • Unreconstructible SMV/PV due to tumor involvement or occlusion

CA, Celiac axis; CHA, common hepatic artery; IVC, inferior vena cava; PHA, proper hepatic artery; PV, portal vein; RHA, right hepatic artery; SMA, superior mesenteric artery; SMV, superior mesenteric vein. Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Carcinoma V.2.2016. © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

TABLE 62.3  Median Survival by Surgical Treatment and AJCC Stage in Months

T A

Stage

Nonresected Patients

Resected Patients

All Patients

Ia 1b IIa IIb III IV Total

6.8 6.1 6.2 6.7 7.2 2.5 3.5

24.1 20.6 15.4 12.7 10.6 4.5 12.6

10.0 9.1 8.1 9.7 7.7 2.5 4.4

AJCC, American Joint Commission on Cancer. Data from Bilimoria KY, et al, 2007: Validation of the 6th edition AJCC pancreatic cancer staging system: report from the National Cancer Database. Cancer 110(4):738-744.

FIGURE 62.2.  Unresectable pancreatic adenocarcinoma in the head and uncinate process, showing loss of fat plane (arrow) between tumor (T) and superior mesenteric artery (A). A metallic endoprosthesis is seen as a circular structure in the distal common bile duct.

use staging laparoscopy for right-sided lesions, and our use of staging laparoscopy for left-sided tumors (where laparoscopic resection is not feasible) has declined in recent years as CT staging has become more accurate.

40% (Pisters et al, 2001b; Schnelldorfer et al, 2014; Shah et al, 2008; Stefanidis et al, 2006). Taking the data as a whole, staging laparoscopy seems best reserved for select patients in whom an increased likelihood of intraabdominal dissemination exists. Such cases include tumors greater than 4 cm, particularly those on the left side of the pancreas; ascites; markedly elevated CA 19-9 (>1000 U/mL); and small, indeterminate liver or peritoneal lesions seen on CT, which are too small to investigate with percutaneous biopsy or PET imaging. We rarely

TREATMENT The goal of the initial evaluation process for patients with pancreatic cancer is to enable classification into one of three broad categories: resectable, locally advanced/borderline resectable, or unresectable. This determination should be made in consultation with an expert in pancreatic surgery. Surgical resection of pancreatic cancer remains the only potentially curative therapy. Unfortunately, only a minority of patients (approximately 20%



C.  Malignant Tumors  Chapter 62  Pancreatic cancer: clinical aspects, assessment, and management

to 30%) diagnosed with pancreatic cancer are candidates for curative resection at the time of diagnosis. Hopefully, while our ability to identify high-risk patient populations improves and early detection schemes evolve and gain widespread use, the percentage of patients who are candidates for resection with curative intent will increase. A 2007 study by Bilimoria and colleagues revealed that of the more than 9500 U.S. patients identified in the National Cancer Database with clinical stage 1 pancreatic cancer, more than 70% did not undergo surgical intervention (Bilimoria et al, 2007b). The reason these patients deferred an operation could not be identified in more than 50% of patients, and a notable minority were deemed too old or unfit for pancreatectomy. It should be noted, however, that in the group of stage 1 patients who did not undergo resection, the median survival was less than 1 year. The reason for this extremely low survival in patients who presented with localized cancer is unclear, as even patients with locally unresectable tumors experience better median disease specific outcomes. More recently, Raigani and colleagues (2014) confirmed the still alarmingly low surgical resection rates, 36% to 63%, for stage 1 and 2 pancreatic cancers, respectively. This represents a gross underutilization of surgical intervention for potentially curable pancreatic cancer in the United States, which the authors postulate may be due to a nihilistic attitude toward pancreatic cancer care.

SURGICAL TREATMENT Resectable Disease Standards as to what constitutes resectable disease have broadened while more experience is gained with pancreatic resection (see Chapters 66 and 67). High-volume pancreatic surgery centers assess resectability based on local expertise and experience, as well as accessibility of neoadjuvant trial protocols. Resectional approaches are based on tumor location and extent. Resection of right-sided tumors typically requires pancreaticoduodenectomy, most often performed with pylorus preservation. Distal pancreatectomy (and at times, more extensive variants such as radical antergrade modular pancreatosplenectomy or distal pancreatecomy with celiac axis resection) is used to resect left-sided tumors (Strasberg & Fields, 2012). In a small group of patients with extensive parenchymal involvement of the pancreas, total pancreatectomy may be required. “Extended” pancreatectomy may be considered in select instances; however, in general, this is limited to patients with small invasive intraductal papillary mucinous neoplasms with diffuse pancreatic involvement (Hartwig et al, 2014). Some groups apply neoadjuvant chemotherapy or chemoradiation regimens to all patients with resectable tumors to help maximize exposure to chemotherapy, allow latent metastatic disease to be discovered, identify patients who progress quickly and would not have seen a benefit from a complex pancreatic resection, and maximize R0 surgical resection rates (Winner et al, 2015). The specific techniques of such resectional procedures can be found in Chapters 66 and 67. It is clear that high-volume centers have more favorable perioperative outcomes for complex pancreatic resections. Although surgical experience is paramount, it is hypothesized that “institutional experience” is what ultimately affects patient outcomes. Experienced interventional and diagnostic radiologists, advanced gastrointestinal endoscopists, medical and radiation oncologists, pathologists, operating room staff, nursing

983

units, and house staff all contribute to the care of these complex patients. At our institution, the use of an advanced recovery pathway, fluid restriction protocols, discharge planning, and postoperative exercise regimens have improved the perioperative outcomes and recovery of our patients (Kennedy et al, 2007; Lavu et al, 2014; Yeo et al, 2012). Additionally, highvolume centers have experience with advanced technologies (i.e., intraoperative pancreatoscopy or intraoperative ultrasonography) that may assist in complex decision making during operations (Pucci et al, 2014).

Results Recurrent controversies have persisted over the effectiveness of surgical resection for pancreatic cancer (Crile, 1970; Gudjonsson, 1995). The preponderance of recent data that have emerged from large specialized centers refute past claims of futility and lack of long-term survival. A publication in 2006 by Riall and colleagues examined the actual 5 year survival rates after pancreaticoduodenectomy, all stages combined, for pancreatic and periampullary cancer and reported actuarial 10 year survival. The actual 5 year survival for resected pancreatic cancer (all stages combined) was 17%, but the estimated 10 year survival was 9% (Fig. 62.3). This analysis included a positive lymph node rate of 48% and a positive margin rate of 8% in the overall periampullary cohort. A similar study by Ferrone and colleagues (2008) revealed an actual 5-year survival rate of 23% for resected stage Ia disease, and all-stage actual 5 year and 10 year survival rates of 12% and 5%, respectively, were reported. This group recently updated these data with an actual 5 year survival rate of 19% and a 10 year survival rate of 10%. They found that the significant clinicopathologic factors predicting 5 and 10 year survival were negative surgical margins and negative nodal status; however, interestingly, 41% of long-term survivors had positive lymph nodes, and 24% had a positive surgical margin (Ferrone et al, 2012).

ADJUVANT THERAPY Although surgical resection currently is the only opportunity to cure patients with pancreatic cancer, postresection survival outcomes unfortunately remain suboptimal. Intense efforts to improve these outcomes with the addition of postoperative adjuvant chemotherapy with or without radiotherapy have allowed for some progress (see Chapter 68). Distinction between “standard” postoperative adjuvant regimens in the United States and Europe are presented and will follow. Interestingly, the divergence in the use of adjuvant chemoradiotherapy evolves from different interpretation of data from the same trials (Smaglo & Pishvaian, 2012). A list of select randomized trials addressing adjuvant chemotherapy and chemoradiotherapy are reviewed in Table 62.4 (see Chapter 68). Beginning in 1985, a prospective, randomized trial from the Gastrointestinal Tumor Study Group (GITSG) using splitcourse irradiation (40 Gy) with concurrent bolus 5-fluorouracil (5-FU), followed by maintenance 5-FU for a duration of up to 2 years, was performed (Kalser & Ellenberg, 1985). Patients were randomly assigned to either the treatment arm or a no-treatment control arm. The trial demonstrated a survival advantage for adjuvant chemoradiotherapy (median survival, 20 months) compared with surgery alone (median survival, 11 months; P = .01). Although criticized for its small numbers (43 total patients), slow accrual, and failure to meet accrual

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PART 6  PANCREATIC DISEASE  Section II  Neoplastic 1.0 0.9

P < .0001

0.8

Proportion surviving

0.7 0.6 Duodenum 0.5 0.4 Ampulla 0.3 Bile duct

0.2 0.1

Pancreas

0.0 0

12

24

36

48

60

72

84

96

108

120

Months FIGURE 62.3.  Kaplan-Meier actuarial 10 year survival by site of tumor origin after right-sided pancreatectomy for pancreatic and periampullary adenocarcinoma. Results from a cohort of 890 patients treated by pancreaticoduodenectomy (pancreas, n = 564; ampulla, n = 144; bile duct, n = 135; duodenum, n = 47). The first 5 years of the curve represent the actual 5 year survival because no patients were censored during that time. Five year actual survival rates were 17% for pancreas, 37% for ampulla, 23% for bile duct, and 51% for duodenum. Ten year actuarial survival rates were 9% for pancreas, 25% for ampulla, 17% for bile duct, and 44% for duodenum. All patients were censored after 5 years, so all 890 were at risk for recurrence. Censoring points are shown with horizontal lines. (Modified from Riall, et al: Resected periampullary adenocarcinoma: 5-year survivors and their 6- to 10-year follow-up. Surgery 140[5]:764-772, 2006.)

targets, the GITSG trial was the first trial to document a survival advantage for general adjuvant therapy (including chemoradiotherapy) in pancreatic adenocarcinoma and helped to define expected outcomes. A follow-up randomized, controlled study conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed a trend toward improved survival with adjuvant 5-FU–based chemoradiotherapy compared with surgery alone in patients with periampullary and pancreatic cancer (without maintenance chemotherapy); however, this difference did not reach statistical significance (Klinkenbijl et al, 1999). Criticisms of this trial included its underpowered sample size, splitting the course of radiation, suboptimal dosing of radiation, and deletion of maintenance chemotherapy (Smaglo & Pishvaian, 2012). In an effort to address the differences between the GITSG and EORTC trials, the European Study Group for Pancreatic Cancer (ESPAC) created a three-track (due to fear of poor patient accrual) randomized, controlled trial. Track 1 assigned patients to one of four treatment arms using a 2 × 2 factorial design. These four arms included concurrent chemotherapy and radiation therapy, concurrent chemotherapy and radiation therapy followed by additional chemotherapy, chemotherapy alone, and observation. Track 2 compared chemotherapy alone versus observation. Track 3 compared chemotherapy plus radiation therapy alone versus observation. The results of this trial were reported at a median follow-up time of 10 months and also at 47 months (Neoptolemos et al, 2001, 2004). In the initial report with median 10 month follow-up, a survival benefit was demonstrated with the addition of chemotherapy,

but no benefit was seen with the addition of chemotherapy plus radiation therapy (Neoptolemos et al, 2001). This was criticized due to physician selection bias, the ability of physicians to administer background chemotherapy and radiation therapy at their discretion, and the split dosing of radiation adminis­tration (Smaglo & Pishvaian, 2012). Subsequently, the group reported an updated analysis on only the track 1 group (with the 2 × 2 factorial design), with a median follow-up of 47 months. This analysis revealed a significant improvement in survival in the patients who received adjuvant chemotherapy (either alone or after chemoradiotherapy) and a nonsignificant deleterious effect of chemoradiotherapy on survival (Neoptolemos et al, 2004). Again, these conclusions were met with controversy and often criticized for methodologic problems, such as a high rate of nonadherence for the patients assigned to receive chemotherapy, and for radiation therapy quality-control issues (Choti, 2004). Because of the study design, statistical power was insufficient to compare each of the four treatment groups individually. However, when compared with the observation group, patients who received chemoradiotherapy alone appeared to have a worse median survival, suggesting a possible role for treatment-related toxic radiation effects. This landmark ESPAC study tends to be the basis for European centers omitting adjuvant chemoradiotherapy in favor of adjuvant chemotherapy alone (in contrast to US centers where adjuvant chemotherapy plus chemoradiotherapy is generally the standard of care). The EORTC-40013-22012/FFCD-9203/GERCOR trial is the other large-scale trial that evaluated adjuvant chemotherapy (gemcitabine) with concurrent chemotherapy and radiation

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TABLE 62.4  Randomized Adjuvant Chemotherapy and Chemoradiotherapy Trials in Pancreas Cancer SURVIVAL Study (Reference, Year)

No. Patients

EBRT Dose (Gy)

Chemotherapy

Median

1 yr

2 yr

GITSG (Kalser & Ellenberg, 1985)

22: Surgery alone 21: Adjuvant tx 54: Surgeryalone 60: Adjuvant tx 69: Surgery alone 75: Chemo tx 73: Chemorad tx 72: Chemorad plus additional chemo 221: 5-FU arm 221: Gemarm

None 40 Split course None 40 None None 40 Split course 40 Split course

None 5-FU bolus None 5-FU CI None 5-FU bolus 5-FU bolus 5-FU bolus

11 mo 20 mo 12.6 mo 17.1 mo 16.9 mo 21.6 mo 13.9 mo 19.9 mo

49% 63% 40% 65%

15% 42% 23% 37%

50.4 50.4

5-FU CI

NR NR

68% 69%

33% 39%

194: 5-FU arm 187: Gem arm

50.4 50.4

175: Surgery alone 179: Gem arm

None None

Gem + 5FU CI None Gem

551: 5-FU/LV arm 537: Gem arm

None None

5-FU/LV Gem

23.0 mo 23.6 mo

60: 58: 45: 45:

None None None 50.4

None Gem Gem Gem

18.4 mo 22.3 mo 24.4 24.3

EORTC (Klinkenbijl et al, 1999) ESPAC-1 (Neoptolemos et al, 2004), includes the 2001 data RTOG (Regine et al, 2008), pancreatic head subset

CONKO-001 (Neuhaus et al, 2008) ESPAC-3 (Neoptolemos et al, 2009) JSAP-02 (Ueno et al, 2009) EORTC-4001322012/FFCD9203/GERCOR (Van Laethem et al, 2010)

Surgery alone Gem arm Gem arm Chemorad tx

Gem + 5FU CI 5-FU CI

16.9 mo 20.6 mo 20.2 mo 22.8 mo

3 yr

5 yr NR NR 10% 20% 11% 29% 7% 13%

32% 21% 72.5% 72.5%

42% 47.5%

75% 78%

40% 48% 50.2% 50.6%

20.5% 34%

11.5% 22.5%

11% 24%

CI, Continuous infusion; Chemo, chemotherapy; Chemorad, chemoradiotherapy; Gem, gemcitabine; EBRT, external-beam radiation therapy; 5-FU, 5-fluorouracil; LV, leucovorin; tx, treatment; NR, not reported.

therapy versus adjuvant chemotherapy (gemcitabine) alone. The median survival between the two groups was essentially the same (24.3 months in the adjuvant chemotherapy plus chemoradiotherapy group vs. 24.4 in the adjuvant chemo­ therapy alone group). Although no survival advantage was demonstrated, the authors concluded that concurrent chemoradiotherapy was well tolerated and not deleterious (Van Laethem et al, 2010). The Radiation Therapy Oncology Group (RTOG) protocol R97-04 was designed to determine whether the addition of gemcitabine to postoperative adjuvant 5-FU chemoradiotherapy improved survival for patients with resected pancreatic adenocarcinoma (Regine et al, 2008). This Phase III multiinstitution trial randomly assigned patients with resected pancreatic adenocarcinoma to either one cycle of continuous infusion 5-FU, followed by continuous infusion 5-FU during radiotherapy (50.4 Gy), followed by two additional cycles of continuous 5-FU, or one cycle of gemcitabine, followed by continuous infusion 5-FU during radiotherapy (50.4 Gy), followed by three additional cycles of gemcitabine. Patients with pancreatic head tumors had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group versus 16.9 months and 22% in the 5-FU group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.65 to 1.03; P = .09). After adjusting for the protocol-specified stratification variables of nodal status, which strongly affected survival (P = .001), tumor diameter, and surgical margin status, the multi-

variate analysis for patients with pancreatic head tumors treated with gemcitabine yielded an HR of 0.80 (95% CI, 0.63 to 1.00; P = .05), reflecting significantly improved survival for the gemcitabine group. The Charité Onkologie study (CONKO-001) compared adjuvant gemcitabine therapy with no postoperative anticancer therapy in patients following surgical resection of pancreatic cancer (Neuhaus et al, 2008). Patients in the treatment arm received six cycles of gemcitabine therapy during 6 months, with acceptable toxicity. Overall, 368 patients were randomly assigned, and 354 were included in the intention-to-treat analysis. Patients in the gemcitabine treatment arm had a statistically significant increase in OS on final analysis, with a median OS of 22.8 months and a 5 year survival of 21% compared with a 20.2-month median survival and a 5 year survival of only 9.0% for the control arm (P = .005). ESPAC-3 is the largest reported randomized trial of adjuvant postresection treatment of pancreas cancer to date (Neoptolemos et al, 2009). The trial randomly assigned patients who had undergone either an R0 or R1 resection to either adjuvant 5-FU plus leucovorin versus adjuvant gemcitabine. Radiation therapy was not used. During a 6.5 year period, 1088 patients from 16 countries were randomly assigned. Median survival for the 5-FU/leucovorin arm was 23.0 months, and median survival for the gemcitabine arm was 23.6 months. The authors concluded that no significant difference in survival was evident between the two treatment arms.

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PART 6  PANCREATIC DISEASE  Section II  Neoplastic

A study published by the Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer ran concurrent with the CONKO-001 trial and was of similar design (Ueno et al, 2009). It also randomly assigned patients with resected pancreas cancer to either observation or adjuvant gemcitabine therapy. OS was extended in the gemcitabine group (22.3 months vs. 18.4 months in the control arm), but the difference did not reach statistical significance. The authors reported their belief that their study was underpowered to detect a difference, given its smaller enrollment than the CONKO-001 trial. Taken together, the preponderance of evidence indicates that adjuvant therapy for pancreatic cancer has a survival benefit (see Table 62.3). Controversy remains, however, as to the optimal chemotherapeutic regimen and the role of radiotherapy. RTOG-0848 has been designed to address these questions. Opened in November 2009, it has a target enrollment of 950 patients. This Phase III trial was initiated as a doublerandomization design, assigning patients randomly first to either adjuvant gemcitabine or adjuvant gemcitabine plus erlotinib, followed by a second randomization involving radiotherapy. After 385 patients were accrued, the trial closed the first randomization. Now all patients will receive five cycles of adjuvant gemcitabine chemotherapy (erlotinib was abandoned), and will then be assessed by cross-sectional imaging for evidence of disease progression. Patients without progression then undergo the now sole randomization to continue chemotherapy alone or to proceed to chemoradiotherapy. All patients receive one additional cycle of the gemcitabine chemotherapy, totaling six cycles. Patients randomly assigned to receive chemoradiotherapy then receive external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions. This radiotherapy is given in combination with either oral capecitabine or infusional 5-FU. As of March 2015, the organizers have accrued close to 500 patients. Because there is no clear “standard” adjuvant treatment protocol currently, successfully surgically resected patients with pancreatic cancer should be encouraged to enroll in ongoing clinical trials.

NEOADJUVANT THERAPY, BORDERLINE RESECTABLE, AND LOCALLY ADVANCED DISEASE All new nonmetastatic cases of pancreatic cancer should be carefully evaluated by an experienced pancreatic surgeon for hopes of resection. Currently, up front surgical resection, when possible, remains “standard” therapy. Tumors that encroach with significant compromise of the mesenteric venous structures that are not amenable to reconstruction or encroachment on the SMA, celiac axis, or common hepatic artery are classified as “borderline” resectable (see Table 62.2). A skilled pancreatic surgeon can often remove such tumors safely; however, it is statistically unlikely that a R0 resection can be accomplished in all cases in such settings. Neoadjuvant chemotherapy or chemoradiotherapy is usually initiated with the goal of improving the R0 surgical resection rate (i.e., downstaging tumors). Beyond improving complete surgical extirpation rates (and perhaps reducing the complexity required for resection), neoadjuvant therapy offers a few theoretical advantages. These include eliminating the risk of delayed or incomplete treatment postoperatively, because full therapy is given up front; avoiding an operation that is unlikely to be benefical by exposing latent metastatic disease or local progression of disease (aggressive tumor biology); and because radiation efficacy is dependent on

oxygenation, it may be more effective if given before tissues are devascularized by surgery. The potential negative effects of up front chemotherapy or chemoradiation in borderline resectable patients are toxic complications of the regimens that exclude patients from major abdominal surgery or tumors becoming “upstaged” during the treatment time. It is difficult to accurately assess the literature due to variations in terminology between “borderline” resectable and “locally unresectable,” because many patients earlier classified as locally unresectable may actually be now classified as “borderline” (Winner et al, 2015). However, taken together, the data seem to support consideration of neoadjuvant treatment in borderline resectable patients and to support its standard use in locally unresectable tumors. Recently, the Massachusetts General Hospital group published the largest series of surgically resected cases of borderline and locally unresectable tumors treated with a neoadjuvant regimen—FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan)—reporting a 92% R0 resection rate (Ferrone, et al, 2015). Interestingly, after patients were restaged with imaging, a blinded senior pancreatic surgeon still designated the imaging studies on 28 of the 40 resected patients as borderline or locally advanced. This clearly calls into question whether standard imaging guidelines should apply to patients treated up front with chemotherapy. The authors suggest an aggressive attempt at resection when metastatic disease and progression of disease are not present after neoadjuvant treatment, even in the setting of perceived vascular involvement on imaging because it is not possible to distinguish between fibrosis and viable cancer. The MD Anderson group has published reports of two Phase II trials of either gemcitabine-based neoadjuvant chemoradiotherapy or preoperative gemcitabine and cisplatin chemotherapy in addition to chemoradiation (Evans et al, 2008; Varadhachary et al, 2008). They reported resection rates of 74% and 58%, respectively, for patients entered into each protocol. Median survival for the subset of patients who actually underwent resection is promising at 34 months and 31 months, respectively. Another report from the same group described three different types of borderline patients: type A is borderline resectable by objective anatomic criteria; type B is borderline resectable, because of findings suggestive but not diagnostic of metastatic disease; and type C is borderline operable, because of marginal performance status or extensive comorbidity (Katz et al, 2008). The 160-patient group was composed of 84 type A, 44 type B, and 32 type C patients classified as borderline resectable. After neoadjuvant treatment and restaging, only 66 patients (41%) underwent pancreatectomy. The median survival was 40 months for the 66 borderline patients who completed all therapy but only 13 months for the 94 patients who did not undergo pancreatectomy (P < .001). Multiple random assignment trials are underway to look more closely at the neoadjuvant approach. The NEOPAC study comparing adjuvant gemcitabine versus neoadjuvant gemcitabine and oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer is enrolling currently. The American College of Surgeons Oncology Group (ACOSOG) 5041 study (NCT00733746) is looking at preoperative and postoperative gemcitabine and erlotinib in patients with potentially resectable pancreatic cancer. Moreover, a three-arm study in Italy is investigating a combination of cisplatin, gemcitabine, epirubicin,



C.  Malignant Tumors  Chapter 62  Pancreatic cancer: clinical aspects, assessment, and management

and capecitabine in the adjuvant and neoadjuvant setting (Winner et al, 2015).

PALLIATIVE THERAPY Unresectable Disease The first goal in treating patients with unresectable and/or metastatic disease is to provide adequate palliation for symptoms related to their diagnosis, particularly obstructive jaundice, gastroduodenal obstruction, and abdominal pain. A more detailed discussion of these topics is provided in Chapter 69. Modern endoscopic therapy and interventional radiology procedures can often provide substantial palliation of biliary obstruction and GOO. When patients cannot be palliated in this fashion, surgical palliation through gastrojejunostomy and Roux-en-Y hepaticojejunostomy (see Chapter 31) is indicated to relieve symptoms of duodenal and biliary obstruction, respectively, and to allow physiologic improvement such that patients can subsequently receive palliative chemotherapy or chemoradiotherapy. Additionally, when patients are determined to be unresectable at the time of exploration with curative intent, the opportunity exists to provide surgical palliation of duodenal obstruction or tumor-associated pain, two symptom complexes that can cause suffering and interrupt other cancerdirected therapies. Prophylactic gastrojejunostomy at the time of initial exploration in the setting of duodenal encroachment by tumor has been shown to avoid subsequent symptomatic duodenal obstruction in this population of patients (Lillemoe et al, 1999). Another beneficial intervention that can be provided at the time of exploration is celiac plexus nerve block (see Chapter 16). This simple intervention has been shown to decrease pain and postoperative narcotic use, and, in a small subset of unresectable patients who present with pain, to prolong survival in one study (Lillemoe et al, 1993). Additional studies using endoscopic means to perform the celiac block have failed to demonstrate a survival benefit (Wong et al, 2004). Moreover, a recent single-institution randomized trial from Thomas Jefferson University Hospital failed to demonstrate a convincing benefit of an intraoperative celiac block in the palliative setting (Lavu et al, 2015). Yet, the procedure is simple and carries minimal risk and expense when done during surgical exploration. It can also be done endoscopically or percutaneously, with pain relief that is often superior to that suggested by the stepwise analgesic ladder provided by the World Health Organization (Wong et al, 2004).

Palliative Chemotherapy Chemotherapy is provided in the unresectable and metastatic setting with the intention of prolonging life while preserving or improving quality of life (see Chapter 68). The traditional standard of care for advanced pancreatic cancer was set in 1997 by Burris and colleagues in their landmark study, which showed a significant prolongation in OS, as well as a concurrent clinical

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benefit response, in patients with advanced pancreatic cancer treated with gemcitabine compared with the previous standard chemotherapy (5-FU) (Burris et al, 1997). The efficacy measure was “clinical benefit response,” which was a composite of measurements of pain, specifically, analgesic consumption and pain intensity; Karnofsky performance status; and weight. Clinical benefit required a sustained (≥4 weeks) improvement in at least one parameter without worsening in any others. Since that time, erlotinib was granted a Food and Drug Administration therapeutic indication for use against pancreatic cancer (Moore et al, 2007). However, the inclusion of erlotinib as standard of care has been controversial, given the minimal improvement in OS (only 0.33 months) when evaluated in the context of the drug’s expense and side effects. Multiple groups have continued to study combination therapies involving currently available chemotherapeutics and investigational agents (Stathis & Moore, 2010). Most have failed to show any evidence of benefit to patients with advanced pancreatic cancer, until recently. Conroy and colleagues (2011) presented the results of a randomized Phase III trial comparing FOLFIRINOX versus gemcitabine as first-line therapy for advanced pancreas cancer. At a median duration of follow-up of 26.6 months, the median OS for the FOLFIRINOX group was 11.1 months compared with 6.8 months for the gemcitabine group (P < .001). OS rates at 6, 12, and 18 months were 75.9%, 48.4%, and 18.6%, respectively, in the FOLFIRINOX arm, compared with 57.6%, 20.6%, and 6.0%, respectively, in the gemcitabine group. FOLFIRINOX is the first therapy not containing gemcitabine that has shown a significantly longer OS, progression-free survival, and higher response rate than gemcitabine alone. This has caused rapid adoption of FOLFIRINOX for metastatic pancreatic cancer; however, the regimen can be toxic and is perhaps best restricted to patients with excellent functional performance status (Sullivan & Kozuch, 2012). As the understanding of the molecular pathogenesis of pancreatic cancer improves, more potential targets for drug development are identified. Some of these targets may include epidermal growth factor receptor, vascular endothelial growth factor, cell membrane proteins (mesothelin and death receptors), type I insulin-like growth factor receptor, RAS, Src kinase, mitogen-activated protein kinase, Hedgehog pathway, c-Kit, platelet-derived growth factor receptor, fibroblast growth factor receptor, prostate stem cell antigen, and others (Cinar & Tempero, 2012). However, currently, with the exception of erlotinib, these targets have not been translated to clinical benefit. The rational use of these powerful and potentially beneficial agents awaits the development of appropriate predictive biomarkers that can guide therapy. Then, the treatment of pancreatic cancer can evolve into a future of individualized patient care (also termed “precision medicine”) based on the combined efforts of the hundreds of investigators working worldwide. References are available at expertconsult.com.



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