Current Concepts in the Surgical Management of Pancreatic Cancer

Current Conceptsin the SurgicalManagement ofPancreatic Cancer

Ryan M. Thomas, MDa, Syed A. Ahmad, MDa,b,*

KEYWORDS

� Pancreatic ductal adenocarcinoma � Surgical resection� Perioperative care � Surgical techniques

Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic malignancy,comprising approximately 85% of cases. In 2009, it is estimated that more than 34,000patients will die of PDA and the incidence closely matches this mortality rate, illus-trating the aggressive nature of the disease, which is worsened by an often delayeddiagnosis. Despite minor improvements in chemotherapeutic regimens, the mediansurvival for patients diagnosed with PDA is 4 to 6 months. However, for the 10% to20% of patients who are operative candidates at the time of diagnosis, the mediansurvival, as reported in phase 3 trials, is 11 to 22 months. Many aspects of surgicalresection of pancreatic cancer have been evaluated as to their effects on morbidityand mortality, including evaluation of anastomotic techniques, the role of extendedlymphadenectomies, and the use of vascular reconstruction. In addition, progress inthe perioperative care of those undergoing pancreatic resection for PDA has resultedin improved outcomes. This review discusses the preoperative evaluation of a patientwith pancreatic cancer and addresses the surgical management of these patients,with special attention to recent areas of progress and controversy.

CLINICAL PRESENTATION

The retroperitoneal location of the pancreas creates a diagnostic challenge for theclinician regarding PDA. Because of this anatomic location, patients do not typically

a Department of Surgery, Division of Surgical Oncology, University of Cincinnati College ofMedicine, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH45267–0558, USAb Department of Surgery, Division of Surgical Oncology, University of Cincinnati, The BarrettCancer Center, 234 Goodman Street, ML 0772, Cincinnati, OH 45219-0772, USA* Corresponding author. Department of Surgery, Division of Surgical Oncology, University ofCincinnati, The Barrett Cancer Center, 234 Goodman Street, ML 0772, Cincinnati, OH45219-0772.E-mail address: [email protected]

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Thomas & Ahmad336

present with symptoms until their disease has progressed, often past the point wheresurgical therapy can offer a cure. Lesions in the tail of the pancreas are particularlydifficult because any symptoms are usually due to invasion of contiguous structuresor metastatic disease. Most patients with PDA present with lesions in the pancreatichead or neck (65%), with 15% present in the body/tail, and the remaining 20%being diffuse in nature. Symptoms of pancreatic cancer are often nonspecificones such as weight loss and anorexia/malnutrition. Painless jaundice is a commonpresenting symptom, but occasionally symptoms are more ominous: abdominalpain, gastric outlet obstruction, and pruritus indicate potentially extensive tumorgrowth with biliary obstruction.1,2 In addition, new-onset diabetes is often diagnosedin 40% of patients concomitantly with their diagnosis of PDA or can be detectedupward of 2 years before the diagnosis of PDA.3,4 The clinical manifestations ofpancreatic cancer are therefore variable and often delayed in their presentation,creating a hazard for patients with the disease to receive timely treatment anda challenge to the clinician (Table 1).

PANCREATIC ADENOCARCINOMA STAGING

The staging of pancreatic cancer has undergone an evolution in the past 10 years thatreflects a better understanding of the pathophysiology of the disease as well as betterpreoperative imaging and surgical techniques. At present, the tumor-node-metastasis(TNM) staging of the American Joint Commission on Cancer (AJCC) is employed(Table 2). The current system, in its sixth version, emphasizes preoperative imagingto stratify patients who have invasion of the celiac axis or superior mesenteric arteryand are therefore unable to undergo potentially curative resection. Invasion of thesuperior mesenteric vein or portal vein was once considered a locally advanced andunresectable disease according to earlier AJCC guidelines. However, as discussedlater, this T3 disease no longer precludes patients from resection, as venous recon-struction in these patients can achieve survival rates similar to those without venousinvasion. In addition, regional lymph node disease is categorized as being presentor absent, without designation based on number of nodes involved as the fifth versionof the AJCC staging system previously outlined. Finally, although there has been nochange in the distinction between the absence or presence of distant metastaticdisease (M0 vs M1), the overall staging has changed and incorporates a better under-standing of prognosis for patients with pancreatic cancer. The current system there-fore attempts to identify patients with metastatic disease (Stage IV) versus those whoare potentially resectable (Stage I–III) based on high-resolution imaging.

Table 1Incidence of presenting symptoms in newly diagnosed pancreatic cancer

Sign/Symptom Incidence (%)

Weight loss 50–90

Pain 75–80

Malnutrition 50–75

Jaundice 70

Anorexia 60

Diabetes 15–40

Ascites 5

Gastric outlet obstruction 5

Table 2TNM classification of pancreatic ductal adenocarcinoma and AJCC staging classification

Primary Tumor (T)Regional LymphNodes (N)

DistantMetastasis (M) AJCC Stage

T0: No evidenceof primary

N0: No nodalmetastasis

Mx: Distant metastasiscannot be assessed

0: Tis, N0, M0

Tis: in situ N1: Regional lymphnode metastasis

M0: No distantmetastasis

IA: T1, N0, M0IB: T2, N0, M0

T1: Limited topancreas (%2 cm)

M1: Distant metastasis IIA: T3, N0, M0IIB: T1-3, N1, M0

T2: Limited topancreas (>2 cm)

III: T4, N0-1, M0

T3: Extends beyondpancreas without CAor SMA involvement

IV: T1-4, N0-1, M1

T4: Involves CA or SMA

Surgical Management of Pancreatic Cancer 337

ASSESSMENT FOR SURGICAL RESECTION AND PREOPERATIVE BILIARY DRAINAGEImaging Modalities

The use of preoperative imaging is a critical factor in the workup of patients with PDA.This imaging begins the staging process for the disease and influences the possibilityof undergoing a surgical resection. The sensitivity of detecting PDA on a computedtomography (CT) scan has been reported to be 89% to 97% but decreases, as ex-pected, with smaller pancreatic tumors.5,6 For tumors greater than 15 mm, Legmannand colleagues7 determined a sensitivity of 100% for CT scan compared with only67% for tumors less than 15 mm. To acquire the most optimal images for the diagnosisof PDA, a dual-phase or ‘‘pancreatic protocol’’ CT should be used. With this protocol,images are acquired at 2 phases of peak contrast enhancement. The first is immedi-ately after the arterial phase but before the hepatic phase of enhancement, referred toas the pancreatic phase, with the second phase correlating to the venous enhance-ment of the liver. The pancreatic phase allows optimal distinction between normalpancreatic parenchyma and a pancreatic mass while enabling evaluation of peri-pancreatic vessels to determine the extent of tumor involvement. The ability of CTto detect lymph node involvement is very poor based on size criteria alone, becauseenlarged lymph nodes may merely be reactive or normal-sized nodes may harbor mi-crometastasis. Enlarged peripancreatic lymph nodes should therefore not precludea patient from surgery, as the ability of CT to determine vascular invasion is the singlebest predictor of resectability. The goal of the hepatic phase is to differentiate betweennormal hepatic parenchyma and hypovascular metastasis. Reports have indicatedthat up to 11% of pancreatic cancers are isoattenuating on the pancreatic and hepaticphases, making it potentially difficult to distinguish tumor from surrounding normalparenchyma unless other signs such as ductal dilatation or mass effect are present.8

Although magnetic resonance imaging (MRI) has not been demonstrated to be supe-rior to CT scanning based on a meta-analysis showing a sensitivity of 84% for MRIcompared with 91% for CT, selected cases such as evaluation of an isoattenuatingtumor may show benefit in using MRI as an adjunct to a CT scan.9 Where MRI isperhaps most efficacious is in the evaluation of suspicious hepatic lesions that areless than 1 cm as seen on CT. CT is often unable to discriminate between benignand malignant lesions at this size but MRI has been shown to more accurately

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differentiate between the two.10 Although other technologies such as positron emis-sion tomography, ultrasound, and endoscopic ultrasound are available and havebeen used in the evaluation of a patient with PDA or suspected PDA, their utility islimited to circumstances of diagnostic uncertainty or preparation for potential neoad-juvant therapy. In addition, newer MRI techniques may prove beneficial in the evalua-tion of pancreatic masses; however, in the absence of a contraindication for CT scan,such as contrast dye allergy, MRI is more costly and time consuming. Therefore, noneof these alternative modalities have proved to be superior to pancreatic protocol CT inthe determination of patients who are candidates for surgical resection.

Diagnostic Laparoscopy

As previously described, the ability of CT to accurately stage patients is limited by itsinability to detect hepatic metastasis smaller than 1 cm or peritoneal metastasis. Withlaparoscopy continuously becoming more mainstream, surgeons responsible fortreating patients with pancreatic cancer have adopted the technology to assist in clin-ically staging patients. The main source of debate relates to which patients shouldundergo laparoscopy, selective patients with advanced disease or all patients, todetect occult metastatic or advanced pancreatic cancer. However, with imaging tech-nology constantly improving, the ability to pick up metastasis has also improved. Thisadvance places the utility of preoperative laparoscopy into question. The morbidityassociated with a diagnostic laparoscopy for staging of PDA is very low and rangesfrom 0% to 4%, with most literature reporting a mortality rate of 0%.11 Severalprospective trials have not only reaffirmed the ability of laparoscopy to preventa certain subset of patients from undergoing an unnecessary laparotomy but havealso demonstrated it to be fiscally sound. In one of the earlier trials, Warshaw andcolleagues12 evaluated 40 patients with histologically confirmed PDA who wereappropriate surgical candidates based on preoperative evaluation. All 40 patientsunderwent laparoscopy and 14 demonstrated metastatic disease at the time of lapa-roscopy (35%). The remaining 26 patients had a negative laparoscopy but on subse-quent laparotomy, the negative finding was confirmed in 23 (82% positive predictivevalue). Two of the false-negative cases were due to inadequate exposure during lapa-roscopy, while the third case resulted from the metastatic lesion located within theliver parenchyma discovered only during manual palpation. Therefore, 43% of thepatients had metastatic disease not detected by CT scan, of which laparoscopy de-tected 82%. Unfortunately, this study was performed in an era before high-resolutionhelical CT scans. It is argued, therefore, that such numbers would not be duplicated ifmore modern CT scanners were used. In a more recent study by Maithel andcolleagues13 a prospectively gathered database was retrospectively analyzed, and491 patients were identified with PDA that was amenable to surgical resection bydual-phase CT scan or MRI. Patients with borderline resectable disease as identifiedby tumor extension to the celiac axis, abutments of the superior mesenteric artery, orshort segment involvement of the portal or superior mesenteric veins were excluded,as were any patients with suspicion for distant metastasis. These 491 patients thenunderwent diagnostic laparoscopy with detailed examination of the liver, peritonealsurfaces, and transverse colon mesentery. Ninety-six patients were unresectable atthe time of laparoscopy because of metastasis to the liver (62%), peritoneum(17%), or locoregional spread (22%). Seventy-two percent of patients were spareda nontherapeutic laparotomy based on the results of laparoscopy alone. Excludingpatients who had locoregional spread, 92% of those with hepatic or peritoneal metas-tasis were spared a nontherapeutic laparotomy. Maithel and colleagues went on todetermine if carbohydrate antigen (CA) 19-9 levels correlated with unresectability in


this patient population. The median preoperative CA 19-9 level for those patients whowere resected was 131 U/mL compared with 379 U/mL in those who had unresectabledisease (P<.003). Using multivariate regression analysis, a CA 19-9 value greater than130 U/mL preoperatively was a predictor of tumor unresectability (hazard ratio 2.7).Some groups have sought to increase the sensitivity of laparoscopy for detecting un-resectable PDA by performing a more extensive peripancreatic and periportal dissec-tion or through the use of intraoperative ultrasound to detect occult hepaticmetastasis.14–16 Finally, there are few studies to address the question of cost benefitfrom the use of staging laparoscopy. In general, use of staging laparoscopy has beenfound to be cost effective in selected cases and only when it will detect occult metas-tasis, thus avoiding an unnecessary laparotomy.11,17 To optimize the utility of staginglaparoscopy for pancreatic cancer, it should follow a pancreatic protocol CT scan andbe used only in selected cases of patients who are at high risk for metastatic disease,such as those with primary tumors greater than 4 cm, markedly elevated CA 19-9levels, or equivocal findings of locally advanced or metastatic disease on CT scan.

Preoperative Biliary Drainage

Because the vast majority of pancreatic cancers are located in the pancreatic head,obstructive jaundice is a common presenting symptom. Therefore, preoperative biliarydrainage is often employed to alleviate the symptoms of pruritus or in the setting ofneoadjuvant therapy in which surgical treatment will be delayed. The use of preoper-ative biliary diversion was previously routinely performed following concerns aboutperioperative morbidity in a jaundiced individual undergoing a pancreaticoduodenec-tomy (PD).18,19 However, these studies are faulted by their retrospective nature andheterogeneous patient population. Modern literature does not corroborate thesestudies, and recent randomized trials have proven these concerns unfounded.

To ascertain whether preoperative biliary drainage or the process of preoperativebiliary instrumentation alone is responsible for increased postoperative morbidity afterPD, Povoski and colleagues20 evaluated their experience of 240 consecutive patientsat Memorial Sloan-Kettering Cancer Center from 1994 to 1997 who underwent PD.Eighty percent of the PDs were performed for adenocarcinoma of the pancreas orperiampullary region. Of the 240 patients, 175 (73%) underwent preoperative biliaryinstrumentation defined as cannulation of the biliary tract by surgical or nonsurgicaltechniques (percutaneous transhepatic cholangiography, endoscopic retrogradecholangiopancreatography, or common bile duct exploration). A cohort of 126patients subsequently underwent biliary drainage preoperatively (endoscopic stents,percutaneous drains/stents, or surgical drainage procedure). The overall morbidityfollowing PD was 48% (114/240) with a postoperative mortality of 5% (12/240). Overallinfectious complications were seen in 34% (81/240) of patients while 14% (33/240)suffered from intra-abdominal abscess post-PD. Preoperative biliary stenting, butnot instrumentation, was determined to be the only statistically significant factor asso-ciated with overall complications (P 5 .025), infectious complications (P 5 .014), intra-abdominal abscess (P 5 .022), and postoperative death (P 5 .037). Despite theheterogeneity of the patient population, an evaluation of patients who underwentPD for PDA or periampullary adenocarcinoma still determined that biliary drainagewas the only statistically significant predictor of postoperative infectious complica-tions (P 5 .038), intra-abdominal abscess (P 5 .001), and death (P 5 .01).

In contrast, a study performed by Sohn and colleagues21 at the Johns HopkinsMedical Institutions evaluating preoperative biliary stenting in their population ofpatients who underwent PD did not reveal an overall increase in complication ratesor in the rate of mortality in patients who underwent preoperative biliary drainage

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compared with patients who did not undergo preoperative stenting. This group retro-spectively analyzed the data from 567 patients who underwent PD but had no previoushistory of biliary bypass. Of these people, 408 (72%) underwent preoperative biliarystenting, with 146 patients from this cohort (36%) having undergone an endoscopicapproach. PD was performed for periampullary adenocarcinoma in 74% of thestented group and 57% of the unstented group (P 5 .0001) with 47% and 38% ofthe pancreatic resections performed specifically for PDA, respectively. In comparingpostoperative morbidity and mortality in the stented versus unstented groups, theonly statistically significant difference was in the rates of wound infection and pancre-atic fistula formation between the 2 groups (Table 3). The overall complication rate(35% vs 30%, respectively) and mortality rate (1.7% vs 2.5%, respectively) betweenstented and unstented was not statistically significant. However, the rate of woundinfection in the stented group was 10% compared with a 4% incidence in the un-stented group (P 5 .02), corroborating the findings of Povoski and colleagues. Oneadditional finding of interest was the increased incidence of pancreatic fistula forma-tion in the stented group (10%) versus the unstented group (4%), which was likewisestatistically significant (P 5 .02). However, this particular difference was not significantwhen evaluating patients who had periampullary adenocarcinoma (9% vs 3% in

Table 3Preoperative biliary stenting in pancreatic cancer

Author NMorbidity(%)

Mortality(%)

InfectiousComplications(%)

WoundInfection(%)

Intra-abdominalAbscess(%)

PancreaticLeak/Fistula(%)

Povoski20

Total 240 48 5 34 16 14 10

Stented 126 55* 8* 41* n/a 19* n/a

Unstented 114 39 3 25 n/a 8 n/a

Sohn21

Total 567 34 1.9 29 8 4 8

Stented 408 35 1.7 32 10* 4 10*

Unstented 159 30 2.5 22 4 6 4

Pisters22

Total 265 87 1 35 10 8 8

Stented 172 88 1 37 13* 6 8

Unstented 93 86 1 31 4 11 10

Hodul23

Total 212 64 2 26 5.7 6 11

Stented 154 33 2 29 8* 7 10

Unstented 58 43 2 21 0 5 14

Sewnath24

Total 290 51 1 35.5 7.6 15.5 12.4

Stented 232 50 1.3 37 7.3 15.5 13.8

Unstented 58 55 0 31 8.6 15.5 6.9

Abbreviation: n/a, not available.* Statistically significant difference noted for indicated parameter when comparing the

‘‘stented’’ versus ‘‘unstented’’ group in each particular trial (P<.05).


stented vs unstented, P 5 .07) perhaps reflecting an increased risk for individuals whounderwent resection for chronic pancreatitis rather than adenocarcinoma, as thisgroup of patients represented 11% and 15% of the stented and unstented groups,respectively.

Pisters and colleagues22 from the MD Anderson Cancer Center similarly evaluatedtheir experience of 300 patients who underwent PD for malignancy or suspectedmalignancy, with 60% of patients having PDA on final histology. A total of 93 patients(31%) did not undergo any preoperative biliary decompression compared with 172patients (57%) who did. Of this cohort, the drainage procedure consisted of 81% en-dobiliary stents, 16% percutaneous transhepatic catheter, and 2% undergoing otherforms of biliary drainage (T-tube, Wallstent, or cholecystostomy tube). Despite a differ-ence in wound infection rates between patients undergoing preoperative biliary stent-ing and those who did not (13% vs 4%, respectively, P 5 .028), there was nostatistically significant difference between the groups when compared with overallcomplications, major complications, anastomotic leak, or perioperative death. Despitethe increase in wound infection seen in these 3 studies, several prospective random-ized trials of preoperative biliary stenting have not shown such a difference.25–28 Aprospective randomized multicenter trial is currently accruing patients and will hope-fully offer better insight into the controversial topic of preoperative biliary stenting.29

Until that time, preoperative biliary diversion should likely be reserved for patientswho will undergo neoadjuvant therapy for pancreatic cancer and thus have a delayedsurgical intervention, or for those with severe symptoms who also will have a delay insurgical treatment, being cognizant that a slightly increased risk of postoperativewound infections may be present.

Metallic versus Plastic Biliary Stents

Additional debate exists over the type of material used for a biliary stent, as metalstents have a longer patency rate that is ideal in patients who are not surgical candi-dates, and therefore offer a more definitive option for biliary decompression duringchemotherapy treatment.30,31 In addition, the longer patency of metal stents wouldbenefit those undergoing neoadjuvant therapy for PDA to avoid the complications ofstent occlusion and the necessity of having a plastic stent frequently changed.However, earlier practices favored plastic stents in those who would undergo defini-tive surgery, as it was thought that metal stents created an inflammatory reactionthat made the dissection during PD difficult. These claims have proved unfounded,as the preoperative use of expandable metal stents before PD has not been shownto significantly increase operative time, operative blood loss, or perioperativemortality.32,33 For these reasons expandable metallic stents may be an appropriatemeans of preoperative biliary decompression in the appropriate patient who willundergo PD. Otherwise, the clinician must understand the risk of biliary stent compli-cations in those patients who have a plastic stent in place, most often related to stentocclusion and cholangitis.32

SURGICAL TECHNIQUESHistory and Overview of Surgery for Pancreatic Cancer

PD was first described in 1912 by Walter Kausch and later reformed by Allen O. Whip-ple in 1935 to consist of a 2-stage PD whereby biliary diversion and a gastrojejunos-tomy were performed during the first stage, followed 3 to 4 weeks later by pancreatichead and duodenal resection.34 Whipple eventually modified the PD into a 1-stageprocedure that now bears his name. Despite years of technical advancements as

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well as advancements in pre- and postoperative management, the surgical goalsremain the same. Surgical treatment of pancreatic cancer aims to resect all grossand microscopic evidence of disease and subsequently reestablish enteric continuity.

The approach used to resect pancreatic cancer depends on the location of thetumor. For example, a lesion in the tail of the pancreas necessitates a distal pancre-atectomy. Because approximately 60% to 70% of pancreatic cancers arise fromthe head of the pancreas, the most common operation performed to resect thesetumors is a PD. Pancreatic cancers that arise in the body of the pancreas often arelocally advanced at the time of diagnosis and are unable to be resected. However,if resection is possible, the anatomic position of the tumor dictates the extent of resec-tion, with lesions nearer to the pancreatic tail being treated with a distal pancreatec-tomy and those closer to the head with an extended pancreatiocoduodenectomy.With this measure as much pancreatic parenchyma as possible can be preservedto limit postoperative diabetes. Central pancreatectomies have been performed forpremalignant or low-grade (T1) tumors, but is rarely employed for patients with PDAdue to concerns regarding lymph node clearance.35,36

Technique of Pancreaticoduodenectomy

After appropriate preoperative workup as described previously, a PD is performed inseveral discrete steps. After entry into the abdomen is established with either a midlinelaparotomy or bilateral subcostal incision (Chevron incision), the liver and peritonealsurfaces are inspected to assess for metastatic disease that may not have beendetected on preoperative imaging. A diagnostic laparoscopy, if performed, would like-wise satisfy this criterion to rule out previously undetected Stage IV disease beforelaparotomy as described previously. The dissection begins by incising the posteriorperitoneum of the duodenal C-loop and mobilizing the hepatic flexure such that theduodenum and transverse mesocolon are separated. A Kocher maneuver is then per-formed to mobilize the duodenum and pancreatic head to the level of the superiormesenteric vein (SMV) anteriorly and left renal vein posteriorly. Finally, the ligamentof Treitz can be incised behind the superior mesenteric vessels, which facilitates theexposure of the distal duodenum and uncinate process of the pancreas. Attention isnext directed to the portal dissection, which begins with a cholecystectomy. Thecommon bile duct is circumferentially isolated and the common hepatic duct is dividedjust above the junction with the cystic duct, and the distal common bile duct isdissected to the pancreatic head. The gastroduodenal artery is then identified andligated, and the avascular plane between the anterior portal vein (PV) and posteriorpancreas is initiated above the level of the duodenum. Next, the SMV is identifiedby entering the lesser sac via separation of the greater omentum from the transversemesocolon. The middle colic vein is then followed to the inferior border of thepancreas where the posterior peritoneum is divided and the SMV is encountered.Dissection is performed anterior to the SMV and posterior to the pancreas, eventuallyconnecting with the previous anterior PV/posterior pancreas dissection. Once thisstage is completed, the stomach is divided (or duodenum if pylorus preservation isdesired) as well as the jejunum approximately 8 to 10 cm distal to the ligament ofTreitz. This action is followed by division of the pancreas, which proceeds along thepreviously created dissection plane traveling from the SMV to the SMV/PV confluence.Most critical for oncologic purposes is the separation of the divided pancreatic headfrom the SMV and superior mesenteric artery (SMA), which is performed next. TheSMA is mobilized to its origin and the pancreatic head is separated from the rightlateral wall of the SMA by serial ligation and division of the tissue, attaching the unci-nate to the SMA. Once completed, the specimen is removed and the retroperitoneal


margin is marked for the pathologist. Frozen sections of the transected pancreatic andcommon bile duct margins are performed to ensure an R0 resection. If this is notconfirmed, then additional excision is needed. At this time, reconstruction is per-formed by creating the pancreaticojejunostomy/pancreaticogastrostomy, choledo-chojejunostomy, and gastrojejunostomy/duodenojejunostomy. Some surgeonsplace a feeding jejunostomy, as some patients may develop delayed gastric emptyingor may need their caloric intake augmented postoperatively.

Traditional versus Pylorus-Preserving Pancreaticoduodenectomy

Much debate has existed regarding the optimal strategy for gastrointestinal recon-struction after PD since Watson first reported the preservation of the entire stomachand duodenum with reconstruction via a duodenojejunostomy in 1944, and themodern popularization of the procedure by Traverso and Longmire.37–39 Proponentsof the pylorus-preserving PD argue that it offers better digestion, with prevention ofmarginal ulceration at the anastomosis. Opponents of the procedure raise concernsthat nodal clearance of the suprapyloric and infrapyloric perigastric nodes may belimited. Several randomized trials have been conducted comparing such outcomesas delayed gastric emptying, resection margins, and overall survival (Table 4).

Tran and colleagues40 performed a multicenter, randomized controlled trial to eval-uate standard PD (SP) versus pylorus-preserving PD (PPP) in 170 patients for pancre-atic and periampullary adenocarcinoma. Eighty-three patients underwent SP and 87underwent PPP with 52% and 54% of cases operated on for pancreatic adenocarci-noma, respectively. The patients were well matched for age, gender, preoperativeweight, and tumor location. The investigators found no difference between the 2procedures for operative time, blood loss or replacement, or hospital stay. In addition,there was no statistically significant difference in postoperative complications,morbidity, or mortality between the 2 groups (pancreatic fistula, bile leak, postopera-tive bleeding, intra-abdominal abscess, or relaparotomy). Although there was nota difference between the 2 groups regarding delayed gastric emptying (23% vs22% in the SP vs PPP, respectively; P 5 .80), there was a correlation betweenintra-abdominal complication (postoperative bleeding, abscess, anastomotic leak)and delayed gastric emptying (P<.05). Because debate exists regarding adequacyof resection, the investigators reported 73.6% of patients in the PPP group havingachieved an R0 resection versus 82.6% R0 resection in the SP group (P 5 .23). Inaddition, median disease-free survival was similar between the 2 groups who under-went treatment of pancreatic cancer, with a 7-month median disease-free survival inthe SP versus 6 months in the PPP group (P 5 .9). Tran and colleagues likewise did notdetermine a significant difference in median overall survival. The investigators there-fore concluded that both operations are adequate for the treatment of periampullarycarcinomas, including pancreatic adenocarcinoma.

Seiler and colleagues41 likewise performed a prospective randomized trial of SPversus PPP in 130 patients, of whom 80 were for pancreatic cancer (43 underwentSP and 37 underwent PPP). Seventy-two percent of those who underwent SP forpancreatic cancer had an R0 resection compared with 86% in those who had PPP(P 5 .117). These investigators reported an 18.2-month median survival in pancreaticcancer patients who underwent SP versus 19.2 months in those who underwent PPP(P 5 .217). Although they did not separately analyze patients with pancreatic cancerversus periampullary cancer (ampullary, distal bile duct, and duodenal), comparingSP versus PPP in this combined patient population they found no statistical differencein terms of lymph node positivity, tumor recurrence, or postoperative morbidity suchas delayed gastric emptying, bleeding, infection, or fistula formation.

Table 4Comparison of outcomes from selected trials involving standard pancreaticoduodenectomy(SP) versus pylorus-preserving pancreaticoduodenectomy (PPP)


OperativeMortality(%)

R0Resection(%)

MedianSurvival(Months)

DGE(%)

PancreaticLeak/Fistula(%)

Tran40

Totala 170 58 5 78 n/a 22 13.5

SP 83 61 7 83 11 23 14

PPP 87 54 3 74 12 22 13

Seiler41

Total 130 62 2.3 79 19.3 38.5 2.3

SP 66 68 3 72 18.2 45 2

PPP 64 55 2 86 19.2 31 3

Lin42

Total 36 n/a 8 n/a 16 17 5.5

SP 22 n/a 9 n/a 12 0 4.5

PPP 14 n/a 7 n/a 33 43* 7

Paquet43

Total 40 52 2.5 100 n/a 17.5 7.5

SP 23 48 4 100 n/a 4 9

PPP 17 59 0 100 n/a 35* 6

Roder44

Totalb 110 51 1.8 47 12 8 24.5

SP 62 40 1.6 45 n/a 0 21

PPP 48 65 2.1 50 n/a 19* 29

Median survival for patients with PDA only.* Statistically significant difference noted for indicated parameter when comparing the ‘‘SP’’

versus ‘‘PPP’’ group in each particular trial (P<.05).a R0 resection recorded in all patients with either PDA, periampullary adenocarcinoma, or other

malignancy.b R0 resection recorded in patients with PDA only.

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In 2005 Lin and colleagues42 reported their randomized prospective comparison of19 patients who underwent SP versus 14 who underwent PPP for pancreatic adeno-carcinoma. Like Tran and colleagues they found no difference between the 2 proce-dures in terms of operative time, blood loss or replacement, and overall mortality.The group did report that 6 of 14 patients (42.8%) experienced DGE in the PPP groupversus none in the SP group (P 5 .05). Although smaller studies such as that per-formed by Lin and colleagues may demonstrate a difference in DGE, most largerstudies and meta-analyses do not bear this out.41,45,46 Studies have sought to eval-uate the use of octreotide or alternative enteric feeding regimens to decrease the inci-dence of DGE, but results are mixed.47–49 The use of erythromycin may possess moreof a benefit in reducing the length or incidence of DGE. In a prospective, randomized,placebo-controlled trial conducted by Yeo and colleagues,50 118 patients wererandomized to either 200 mg erythromycin intravenously every 6 hours (n 5 58) orto saline control (n 5 60). A radionuclide gastric emptying study was performed onpostoperative day 10 to determine the presence of delayed gastric emptying to


both liquids and solids. Although the study was not designed to compare patients whounderwent SP versus PPP in terms of response to erythromycin because 100 patientsunderwent PPP and only 18 underwent SP, the investigators found that erythromycinaccelerates gastric emptying of both liquids and solids after PD and reduces the inci-dence of DGE by 37% when administered postoperatively. A study by Ohwada andcolleagues51 likewise showed similar utility of using erythromycin post-PPP but hada small cohort of patients, of whom only 4 had pancreatic cancer.

Neither retrospective nor prospective trials of SP versus PPP have demonstrateda difference in terms of morbidity, mortality, recurrence, survival, or DGE for the treat-ment of pancreatic cancer.52 Therefore, surgeon experience should dictate the type ofprocedure performed as the data suggest that patients receive similar oncologicbenefit with similar morbidity between the 2 reconstructions.

Extended Lymphadenectomy

With the known metastatic pattern of pancreatic cancer being to the lymph nodes,interest has been generated in achieving a greater overall clearance of the nodal basinthat drains the pancreatic head. Because the presence of nodal metastasis influencesthe prognosis of patients with pancreatic cancer, achieving a greater lymphadenec-tomy should hypothetically influence recurrence and survival rates. Clinical trials,unfortunately, have not been able to prove this hypothesis (Table 5). The first prospec-tive randomized trial to evaluate the utility of performing an extended lymphadenec-tomy at the time of PD for pancreatic cancer was by Pedrazzoli and colleagues53 in1998, with their experience of 81 patients who did not receive adjuvant chemoradia-tion. Performing an extended lymphadenectomy that included routine clearance of theperipancreatic and subpyloric nodes as removed during a standard PD, the dissectionalso included removal of nodes from the hepatic hilum, along the aorta from the dia-phragmatic hiatus to the inferior mesenteric artery and laterally to both renal hila, aswell as circumferential clearance of the celiac trunk and SMA origins. With this dissec-tion, there was no statistically significant increase in operative time, length of hospitalstay, perioperative morbidity, or mortality. As expected, extended lymphadenectomyyielded a significant increase in nodes harvested but there was no difference insurvival, with an actuarial survival of 12% versus 6% for standard versus extendedlymphadenectomy, respectively. Of note, using an a posteriori analysis the groupfound that node positive patients who had an extended lymphadenectomy had a bettersurvival than those who underwent standard lymphadenectomy (P<.05). The flaw withthis analysis is that it was not originally planned in the study design. Additionalprospective randomized trials from the Johns Hopkins Medical Institutions and theMayo Clinic corroborate these results.54,55 Riall and colleagues55 demonstrateda 13% and 29% 5-year actuarial survival rate in standard versus extended lymphade-nectomy for patients undergoing PD for pancreatic cancer, respectively (P 5 .13).Despite no difference in overall mortality, this group demonstrated an increase in over-all complication rates, DGE, and pancreatic fistulas in the extended lymphadenectomygroup. Despite the perioperative morbidity differences seen in the Johns Hopkinsstudy, in 2005 Farnell and colleagues54 showed no difference in perioperativemorbidity or mortality between the 2 groups. In addition, the 1-, 3-, and 5-year survivalrates for their standard lymphadenectomy cohort (n 5 38) was 82%, 41%, and 16%,respectively. In comparison, the 1-, 3-, and 5-year survival rate for those patientsundergoing extended lymphadenectomy (n 5 34) was 71%, 25%, and 17%, respec-tively. These data were not statistically significant. In general, the number of patientsthat could potentially benefit from extended lymphadenectomy is likely to be small.Pawlik and colleagues58 performed a retrospective analysis of 158 patients who

Table 5Comparison of outcomes from selected trials involving standard pancreaticoduodenectomy(SP) versus standard pancreaticoduodenectomy with extended lymphadenectomy (ExSP)



MedianSurvival(mo)

MedianSurvivalin LND

R0Resection(%)

TotalNodesResected(Mean)

LND

(%)

Pedrazzoli53

Total 81 48 5 n/a n/a 75 n/a 59

SP 40 50 5 11 n/a 72.5 13.3 60

ExSP 41 46 5 17 n/a 78 19.8* 58.5

Farnell54

Total 79 n/a 1 n/a n/a 79 n/a 61

SP 40 35 0 26 19 76 15 55

ExSP 39 45 2.5 18.8 17 82 34* 68

Riall55

Total 294 36 3 n/a n/a 87 n/a 80

SP 146 29 4 20 19 76 17 82

ExSP 148 43* 2 22 18 94* 28.5* 77

Iacono56

Total 31 47 3 n/a n/a 83 n/a 73

SP 14 46 7 n/a n/a 77 12.8 61.5

ExSP 17 47 0 n/a n/a 88 34.2* 82.4

Capussotti57

Total 149 38 5 15 n/a n/a n/a 59

SP 112 38 6.3 n/a n/a n/a 10.8 54

ExSP 37 35 5.4 n/a n/a n/a 32.4* 68

Morbidity and perioperative mortality reported for all patients undergoing procedure, regardlessof final pathology. All other parameters reported are for those patients with confirmed pancreaticadenocarcinoma on final pathology.

* Statistically significant difference noted for indicated parameter when comparing the ‘‘SP’’versus ‘‘ExSP’’ group in each particular trial (P<.05).

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underwent PD with separate pathologic analysis of second-echelon lymph nodes, toascertain the sample size required in a randomized trial to detect a survival benefit forpatients undergoing an extended lymphadenectomy during PD. Assuming that theonly patients who would benefit from extended lymphadenectomy are those withR0 resection margins, M0 disease, and who would actually have disease removedfrom second-echelon lymph nodes during extended lymphadenectomy, they foundthat only 0.3% of patients may achieve a survival benefit from extended lymphadenec-tomy. In addition, 202,000 patients would need to be accrued into each study arm todetect this small difference in survival benefit. Numerous prospective and retrospec-tive trials have not demonstrated a survival benefit, and some have even shownincreased morbidity with extended lymphadenectomy.59 Therefore it is likely thatextending the lymphatic dissection will offer no benefit, and energy should be directedtoward earlier diagnosis and systemic therapies instead. This proposal is based on thebiologic principle that, for most patients, pancreatic cancer is already a systemicdisease at diagnosis.


Vascular Resection and Reconstruction

Once considered a contraindication to surgery, vascular invasion of the SMV/PV bypancreatic cancer does not necessarily preclude surgery. Invasion of the celiac trunkor SMA, however, is considered a contraindication as there is a rich neural plexus thatsurrounds these vessels, which when invaded will result in positive margins andprovide no additional benefit to the patient. The prior thought that SMA/SMV/PV inva-sion was a contraindication to surgery was first challenged by Fortner andcolleagues60 in 1977. This study is notable in that it demonstrated vascular resectionand reconstruction can be performed during surgical treatment of pancreatic cancer.However, this study was limited by the number of patients treated for their pancreaticcancer (n 5 11) and by the fact that of the 11 patients, 9 had perineural invasion as wellas positive lymph nodes. This result demonstrates that aggressive tumor biology andpositive margins portend a poor prognosis and not merely inadequate surgical resec-tion. This study encouraged other groups to perform prospective and retrospectivetrials involving the ability to perform vascular resections and reconstructions at thetime of PD (Table 6).

Table 6Comparison of selected trials involving pancreatic resection with or without SMV/PVresection and reconstruction



MedianOperativeBlood Loss(ml)

R1Resection(%)

MedianSurvival(mo)

Tseng61

Total 291 n/a n/a n/a n/a 24.9

SR 181 22 1 800 12 26.5

VR 110 18 1 1600* 22* 23.4

Leach62

Total 75 n/a 0 n/a n/a 21

SR 44 n/a 0 900 16 20

VR 31 n/a 0 1700* 13 22

Fuhrman63

Total 59 29 1.7 n/a 15 n/a

SR 36 28 0 1100 14 n/a

VR 23 30 4 1700* 17 n/a

Nakagohri64

Total 81 n/a 0 n/a 22 n/a

SR 48 n/a 0 n/a 21 10

VR 33 n/a 0 n/a 24 15

Howard65

Total 36 47 5.5 n/a n/a n/a

SR 23 43 4 848 17 12

VR 13 54 8 1567* 25 13

Abbreviations: SR, standard resection; VR, standard pancreatic resection with vascular resection.* Statistically significant difference noted for indicated parameter when comparing the ‘‘SR’’

versus ‘‘VR’’ group in each particular trial (P<.05).

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In 2004 the group from MD Anderson Cancer Center performed a retrospectiveanalysis of 291 patients who underwent either standard PD for pancreatic cancer(n 5 181) or PD combined with vascular resection (n 5 110).61 A higher incidence ofpositive retroperitoneal margin was demonstrated in the vascular resection group(P 5 .02), but there was no difference in median survival between this group (23.4months) versus the standard PD group (26.5 months, P 5 .18), demonstrating thata subset of patients who would otherwise have poor survival can achieve survivalsimilar to patient with resectable disease. Yekebas and colleagues66 likewise evalu-ated their experience of 77 patients with pancreatic cancer and confirmed vascularinvasion on final pathology who underwent PD with vascular resection with 405patients who underwent standard PD and did not have histopathologic evidence ofvessel invasion. There was a higher rate of R0 resection in the vascular resectiongroup than in the standard PD group (90% vs 82%, respectively), but this was notstatistically significant (P 5 .1). Similar to the MD Anderson series, there was no differ-ence in survival between those patients with histologically confirmed vessel invasionwho underwent vascular resection compared with those who did not have vessel inva-sion and did not undergo vascular resection as part of their pancreatic cancer resec-tion (median survival 15 months vs 16 months, respectively; P 5 .856). Therefore, inthe appropriate patient population that has venous involvement but in whom an R0margin can be achieved, SMV/PV reconstruction can be performed with limitedmorbidity and similar survival rates to those who do not have vessel involvement.

Use of Surgical Drains

The use of drains placed in the intra-abdominal cavity has become commonplace bymany surgeons to prevent or detect anastomotic leakage after PD. However, the useof drains in other major abdominal surgeries has been shown in some studies to beunwarranted and to perhaps even increase complication rates. In the first randomizedprospective trial to evaluate morbidity associated with drains placed after pancreaticresection, a group from the Memorial Sloan-Kettering Cancer Center evaluated theirexperience.67 One hundred and seventy-nine patients underwent pancreatic resectionwith 139 cases being PD. Of those patients who underwent PD, 73 had surgical drainsplaced and 66 did not (P 5 .11). These drains were removed between postoperativedays 5 to 7 as long as there was no increase in the drain amylase. Although the inves-tigators did not separately analyze drain outcome data from patients having specifi-cally undergone PD, they evaluated their overall drain versus no-drain experiencefor any pancreatic resection (PD, distal pancreatectomy). There was no difference inthe complication rate or the number of complications between the 2 groups. However,there was a statistically significant increase in the incidence of pancreatic fistula andintra-abdominal abscess/collection in the drain group versus no-drain group (19 vs 8,respectively; P<.02). There was also a trend for increased readmissions to the hospitalwithin 3 months of discharge in the drain group, although this was not significant (P 5.07). The median duration stay for these readmissions was also longer in the drainedgroup and was statistically significant (10 days vs 5 days, P<.05). Because manysurgeons still used intra-abdominal drainage after their pancreatic resections, othertrials were set up to provide guidelines regarding the ideal time to remove drains orwhat dictates a pancreatic leak. Kawai and colleagues68 performed a prospectiveanalysis of 52 patients from January 2000 to 2002 who underwent PD for pancreaticcancer and had their intra-abdominal drain removed on postoperative day 8 versus 52patients from February 2002 to December 2004 who had it removed on day 4. Patientswho had their drain removed on postoperative day 8, compared with day 4, had anincreased incidence of rate of pancreatic fistula (23% vs 3.6%, respectively;


P<.004) and intra-abdominal infections/abscesses (38% vs 7.7, respectively;P<.0003). By multivariate analysis, the period of drain insertion (years 2000–2002 vs2002–2004) was the only independent risk factor for intra-abdominal infections. Basedon these results, Kawai and colleagues recommended removing drains by postoper-ative day 4 to decrease the risk of fistula and intra-abdominal infections.

Pancreatic Anastomotic Leak and the Use of Octreotide or Fibrin Glue

There are instances when elevated amylase levels from a drain may signify a pancre-atic leak and therefore necessitate a drain. The difficulty is to determine when elevatedamylase levels or volume signify a leak and subsequently require intervention. Twodefinitions of pancreatic leak exist. (1) The Sarr definition classifies a pancreatic leakif greater than 30 mL/day of drain output and if that drain amylase is greater than 5times the serum amylase on or after postoperative day 5. (2) The International StudyGroup on Pancreatic Fistula Definition (ISGPF) definition describes a pancreatic leakas any volume of drainage that has a drain amylase greater than 3 times the serumamylase on or after postoperative day 3.69,70 Shinchi and colleagues71 used theSarr criteria to group a total of 207 patients who underwent PD into no leak, chemicalleak (but asymptomatic), or clinical leak (requiring intervention, readmission, or pro-longed hospital stay). A total of 29 patients had a chemical leak only (n 5 12) or clinicalleak (n 5 17). Although the daily drain amylase values did not differ between the 2 leakgroups, the drain volume was significantly greater in the clinical leak group such thata volume greater than 200 mL/day with a drain amylase 5 times the serum amylaseresulted in a positive predictive value (PPV) of 84% and negative predictive value(NPV) of 99% for clinically relevant leak. By increasing the volume criteria from 30mL/day to 200 mL/day, the PPV increased from 59% to 84% while keeping theNPV at 99%. In 2007 the Pancreatic Anastomotic Leak Study Group compared theISGPF and Sarr definitions on pancreatic leaks.72 PD was performed in 76.2% ofpatients and drain placement occurred in 98% of these individuals. Pancreatic leakwas detected in 26.7% of patients using the ISGPF definition and 14.3% utilizingthe Sarr definition. Both criteria were equal in detecting leaks that required reoperationor resulted in death (9%). Neither criterion is perfect for detecting clinically relevantleaks, and the use of drains, at least in some studies, may increase the risk of pancre-atic leaks and fistula formation.

Many surgical methods have been described in an attempt to decrease the rate ofpancreatic leak and fistula formation. Despite the wealth of literature available, 2factors seem to increase the risk of pancreatic leak: pancreatic duct size and thetexture of the pancreas. The reason for this is likely because anastomosis of a smallerduct is technically more challenging and a soft, normal pancreas does not hold suturewell and presumably has a higher output of pancreatic enzymes. There have beenmany trials on the use of octreotide, a somatostatin analogue, to reduce the risk ofpancreatic leaks and fistulas. Most of the trials based in Europe have demonstratedmixed results and those that have shown a decrease in leak rates have been in thesetting of surgical treatment of chronic pancreatitis or for those undergoing distalpancreatectomies.73–75 Subset analysis has indicated that there is no benefit of oc-treotide use in patients who undergo PD. Lowy and colleagues76 examined thisdiscrepancy with a prospective, randomized trial of 180 patients undergoing PDspecifically for malignancy (58% PDA) in which they were randomized to octreotidetreatment for the first 5 postoperative days or no additional treatment. These investi-gators found no statistically significant difference in either the type or number ofcomplications between the 2 treatment arms. Yeo and colleagues77 conducteda similar study in which PD was the only surgical procedure to treat periampullary

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disease (39% for PDA) and even attempted to control for pancreatic texture (soft,intermediate, or hard). There was no difference in complication rate or pancreaticfistula with the use of octreotide, yet there was an increase in pancreatic fistula ratewith soft-textured pancreas versus hard-textured pancreas, irrespective of octreotideuse (25% vs 0%, respectively; P<.001). Other groups have found similar results withthe use of octreotide.70,78 In similar fashion, groups have attempted to use fibringlue either within the pancreatic duct or over the pancreatic anastomosis to decreasepancreatic leak, fistula formation, or intra-abdominal complications. These studieshave not shown any benefit with the use of such products and incur considerablecost to institutions.79–81 Therefore, the use of octreotide or fibrin glue to reducepancreatic leak and fistula formation in patients undergoing PD for PDA cannot berecommended.

STANDARDIZED PATHOLOGIC REVIEW AND MARGIN STATUS

Margin status and lymph node involvement have been shown to play an important rolein terms of treatment and survival. It is therefore imperative that these parameters bescrutinized carefully. The European Study Group for Pancreatic Cancer (ESPAC)reported their experience of 541 patients with histologic confirmed PDA who under-went resection to determine the effect of resection margin status in patients with orwithout chemoradiation, and with or without chemotherapy.82 One hundred and onepatients had an R1 resection, and were matched for demographic and tumor charac-teristics to the R0 resection group except for a greater proportion of node positivity(67% vs 50%, P<.01) and local invasion (35% vs 15% P<.001), respectively. Themedian survival for the 101 patients with an R1 resection was 10.9 months (46.8%1-year survival) compared with 16.9 months (65.5% 1-year survival) for patientswho had an R0 resection. Based on Cox regression modeling, however, resectionmargin status was an independent factor only in the absence of tumor grade andlymph node status. Stratifying for adjuvant treatment, the magnitude of chemotherapybenefit was reduced for patients with R1 margins versus those with R0 margins.Chemotherapy increased the median survival from 15.3 months to 20.7 months inpatients with R0 margins who received adjuvant chemotherapy compared with thosewho did not. Although the difference was less apparent in patients with R1 margins,adjuvant chemotherapy increased the median survival from 10.3 months to 11 monthscompared with those with R1 margins who did not receive adjuvant chemotherapy.However, chemoradiation showed no survival benefit irrespective of margin status.This study demonstrated the importance of margin status and how it can affectsurvival based on adjuvant treatment.

A multi-institutional study performed to determine the utility of adjuvant chemora-diation after surgery versus surgery alone for PDA was performed, with an analysisof survival based on margin and lymph node status. The majority of cases were per-formed for pancreatic head disease (92%) with most patients receiving 5-fluorouracilbased therapy.83 Irrespective of lymph node status, the overall survival for those indi-viduals who underwent surgery alone was 15.9 months versus 8.9 months in the R0versus R1 cohorts, respectively. The addition of adjuvant chemoradiation increasedoverall survival to 23.4 months and 15 months for R0 versus R1, respectively. Theaddition of adjuvant chemotherapy had a statistically significant increase in overallsurvival for these cohorts but not in disease-free survival. More stringent evaluationof the data by stratifying based on lymph node status as well as resection statusdemonstrated an overall survival in patients who were lymph node negative but withR0 resection versus R1 resection of 24.4 months versus 15.4 months, respectively.


With the addition of adjuvant chemoradiation, the overall survival was 29.6 monthsversus 15.6 months, respectively. In those individuals who underwent surgery alonebut were lymph node positive, the overall survival for R0 versus R1 resection was10.8 months versus 8.5 months, respectively. In this cohort the addition of adjuvant che-moradiation to surgical resection increased the overall survival to 23.3 months for thosewith an R0 resection and 14.4 months for those with R1 resection. Using multivariateanalysis, resection margin was an independent predictor of overall survival as well asdisease-free survival. This study demonstrates that not only does a difference in survivalexist between patients undergoing an R0 versus R1 resection, but a survival benefit canalso be seen in patients who undergo such resections followed by adjuvant chemora-diation. Centers have sought to standardize their pathologic evaluation of margin statusin an effort to more accurately stage patients, guide treatment, and predict survival. Thegroup at MD Anderson Cancer Center has adopted a standardized approach for eval-uating both the retroperitoneal margin and lymph node involvement since 1990.84 Usingtheir standardized pathologic examination (SPE), this group has been able to showa statistically significant increase in the median number of lymph nodes harvested inthe SPE group compared with the non-SPE group (12 vs 3, respectively) demonstratingthat increased lymph node numbers can be evaluated using a simplified standardizedapproach. Their experience of 360 patients who underwent PD for PDA demonstratedthat 60 patients (16.7%) had an R1 resection with a median survival of 21.5 monthscompared with 83.7% with an R0 resection and 27.8-month median survival (P 5.026).85 In contrast to the ESPAC-1 trial, multivariate analysis did not detect a survivaldifference in patients based on margin status. Only lymph node status, major perioper-ative complications, and blood loss adversely affected survival. In addition, the datafrom this group differs from the ESPAC-1 trial as patients in the MD Anderson serieswere treated with neoadjuvant chemoradiation. The significance of margin status inthis situation is less clear.

OPERATIVE MORTALITY

Up until the 1980s, the operative mortality for PD exceeded 20% even at majoracademic institutions. With improved surgical techniques, as well as pre- and postop-erative care, these rates are much improved. However, surgeons and medical institu-tions with limited experience in PD still have mortality rates that are inferior tohigh-volume centers. An analysis of the Medicare claims database by Birkmeyerand colleagues86 found that 3-year survival rates were higher for patients treated athigh-volume centers (>5 PD/year) versus medium-volume (2–5 PD/year) and low-volume centers (1–2 PD/year). The 3-year survival rate was 37%, 29%, and 26% forthe 3 stratifications, respectively. This finding has been demonstrated by otherstudies, which have also shown that improvements in survival based on high-volumecenters is most striking when evaluating specifically pancreatic resection for cancer,with an improvement in operative mortality from 12.9% to 5.8%.87 Some institutionshave implemented clinical pathways as well as specialized units to care for patientsafter PD, thus demonstrating the feasibility of such a system, with improvement innot only perioperative morbidity and mortality but also decreased hospital costswhen patients are referred to high-volume centers that specialize in the treatment ofpancreatic cancer.88–90

PALLIATIVE SURGERY

A major tenet of pancreatic cancer surgery is to perform resection only if there is a highlikelihood of cure, because performing bypass procedures or R2 resections offers little

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benefit to the patient and results in unwarranted hospitalization. For those patientswho undergo a laparotomy with the goal of palliation, the median hospital stay isgreater than 10 days in most series.91 In patients who present with Stage IV pancreaticcancer and biliary/gastric obstructive symptoms, the utility of operative bypass proce-dures is debatable, as these patients typically have a prolonged hospitalization andtake months to recover to their baseline quality of life.92 However, in the appropriateindividual with a good performance status and a predicted life expectancy of over 1year, palliative surgery is often beneficial. Endoscopic or biliary decompression maybe performed, with its inherent risks and benefits (see Preoperative Biliary Drainagesection). Two randomized controlled trials have attempted to address the issue ofpalliative gastrojejunostomy alone or combined with hepaticojejunostomy. Lillemoeand colleagues93 showed a similar length of stay and postoperative morbiditybetween 44 patients who underwent palliative gastrojejunostomy and 43 patientswho did not. The mean survival between the 2 groups was similar (8.3 months), but19% of patients who did not undergo bypass developed gastric outlet obstruction,all requiring therapeutic intervention (gastrojejunostomy in 7 and endoscopicduodenal stent in 1, P<.01). Van Heek and colleagues92 found similar results whencomparing patients who underwent either single palliative bypass procedure (hepati-cojejunostomy alone) or double palliative bypass (gastrojejunostomy combined withhepaticojejunostomy). Operative morbidity, mortality, and hospital stay were similarbetween the 2 groups, with similar median survival (8.4 months vs 7.2 months, respec-tively; P 5 .15). After palliation, symptoms of gastric outlet obstruction were present in5.5% of the double bypass group and 41.4% of the single bypass group (P 5 .0001).One patient in the double bypass group (2.8%) and 6 patients in the single bypassgroup (20.7%) required (re)gastrojejunostomy (P 5 .04). The absolute risk reductionfor reoperation in the double bypass group was 18%, with a number needed to treatof 6. These trials demonstrate that in the appropriate individual, enteric bypass canalleviate symptoms of gastric outlet obstruction and limit hospitalization.

SUMMARY

The surgical treatment of PDA has improved survival in patients afflicted with thisdisease, and remains the only hope for a ‘‘cure,’’ but further work is needed. Advance-ments in imaging have enabled more accurate staging and prevented nontherapeuticlaparotomies in patients with advanced disease. In addition, patients with diseaseonce considered unresectable because of SMV/PV involvement can now be treatedsafely, and with survival and recurrence results that mimic those without invasivedisease. Although adjuvant chemoradiation is the standard in the United States, neo-adjuvant trials are challenging these algorithms and may prove to be superior to suchtreatments. Multi-institutional, well-controlled trials are therefore necessary to developmore beneficial treatment regimens that likely will take advantage of targeted biologicagents and unique, personalized tumor genomics.

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Current Concepts in the Surgical Management of Pancreatic Cancer

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