Editor(s): Douglas B. Evans, M.D., Peter W. T. Pisters, M.D. Reviewers: Mark P. Callery, M.D., F.A.C.S., Steven Gallinger, M.D., MSc, FRCS, James R. Howe, MD., Steven D. Leach, M.D., Fabrizio Michelassi, M.D., Roderich E. Schwarz, M.D., Douglas Tyler, M.D., Charles J. Yeo, M.D.

General Reviews

Evans DB, Lee JE, Pisters PWT. Pancreaticoduodenectomy (Whipple Operation) and total pancreatectomy for cancer. In press: In Nyhus LM, Baker RJ, Fischer JF, eds. Mastery of Surgery, Fourth Edition. Boston: Little, Brown and Co.

Perugini RA, McDade TP, Vittimberga FJ, Callery MP. The Molecular and cellular biology of pancreatic cancer. Crit Rev Eukaryot Gene Expr 1998;8:377-393.

Wolff RA, Abbruzzese JL, Evans DB. Neoplasms of the exocrine pancreas. In Holland JF, Frei E, Bast RC, Kufe DW, Pollock RE, Weichelbaum RR, eds. Cancer Medicine, Fifth Edition. Ontario: B.C. Decker, Inc. 2000,1436-1464.

Rosenberg L. Pancreatic Cancer: A review of emerging therapies. Drugs 2000;59:1071-1089.

Yeo CJ, Cameron JL. Pancreatic Cancer. In Curr Prob Surg 1999;36:57-152.

Epidemiology and Genetics

Gates LK Jr, Ulrich CD 2nd, Whitcomb DC. Hereditary pancreatitis. Gene defects and their implications. Surg Clin North Am 1999;79(4):711-22.

Gold EB, Goldin SB. Epidemiology of and risk factors for pancreatic cancer. Surg Oncol Clin N Am 1998;7(1):67-91.

Goldstein Am, Fraser MC, Struewing JP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. NEJM 1995;333:970-974..

Hruban RH, Goggins M, Parsons J, et al. Progression model for pancreatic cancer. Clin Cancer Res 2000;6(8):2969-72.

Hruban RH, Yeo CJ, Kern SE. Pancreatic Cancer. In The Metabolic and Molecular Bases of Inherited Disease 8th Ed. Ed. By Scriver CR, et al, McGraw-Hill, New York, p. 1077-1090, 2001.

Kern SE. Advances from genetic clues in pancreatic cancer. Curr Opin Oncol 1998;10(1):74-80.

Tersmette AC, Petersen GM, Offerhaus GJA, et al. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001; 7:738-744.

Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics 1996;14:141-145.

Staging - Radiographic Imaging

Freeny PC. Pancreatic carcinoma: imaging update 2001 Dig Dis 2001;19(1):37-46.

Gloor B, Todd KE, Reber HA. Diagnostic workup of patients with suspected pancreatic carcinoma: The University of California-Los Angeles approach. Cancer 1997;79(9):1780-1786.

Loyer EM, David CL, Dubrow RA, Evans DB, Charnsangavej C. Vascular involvememnt in pancreatic adenocarcinoma: reassessment by thin-section CT. Abdom Imaging 1996;21(3):202-206.

Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15(3):928-37.

Mertz HR, Sechopoulos P, Delbeke D, et al. EUS, PET, and CT scanning for evaluation of pancreatic adenocarcinoma. Gastrointestinal Endoscopy 2000;52:367-371.

Saldinger PF, Reilly M, Reynolds K, et al. Is CT angiography sufficient for prediction of resectability of periampullary neoplasms? J Gastrointest Surg 2000;4:233-239.

The use of standardized, objective radiologic criteria for preoperative tumor staging is critical for treatment planning. The CT criteria defining a potentially resectable pancreatic cancer are: 1) the absence of extrapancreatic disease, 2) a patent superior mesenteric-portal vein (SMPV) confluence [assuming the technical ability to resect isolated involvement of the superior mesenteric vein (SMV) or SMPV confluence], and 3) no direct tumor extension to the celiac axis or superior mesenteric artery (SMA). A patient is deemed to have locally advanced, unresectable disease when there is clear evidence on CT scans of encasement of the SMA or celiac axis or occlusion of the SMPV confluence. The accuracy of CT in predicting unresectability is well established, and laparotomy is not necessary to assess local tumor resectability.

Laparoscopic staging

Callery MP, Strasberg SM, Doherty GM, et al. Staging laparoscopy with laparoscopic ultrasonography: optimizing resectability in hepatobiliary and pancreatic malignancy. J Am Coll Surg 1997;185:33-39.

Conlon KC, Dougherty E, Klimstra DS, Coit DG, Turnbull AD, Brennan MF. The value of minimal access surgery in the staging of patients with potentially resectable peripancreatic malignancy. Ann Surg 1996;223(2):134-140.

Friess H, Kleeff J, Silva JC, et al. The role of diagnostic laparoscopy in pancreatic and periampullary malignancies. J Am Coll Surg 1998;186(6):675-682.

Gress FG, Hawes RH, Savides TJ, et al. Role of EUS in the preoperative staging of pancreatic cancer: a large single-center experience. Gastrointest Endosc 1999;50:786-791.

Holzman MD, Reintgen KL, Tyler DS, Pappas TN. The role of laparoscopy in the management of suspected pancreatic and periampullary malignancies. J Gastrointest Surg 1997;1(3):236-244.

Jiminez RE, Warshaw AL, Rattner DW, et al. Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg 2000;135:409-415.

Rumstadt B, Schwab M, Schuster K, Hagmuller E, Trede M. The role of laparoscopy in the preoperative staging of pancreatic carcinoma. J Gastrointest Surg 1997;1(3):245-250.

Pisters PWT, Lee JE, Vauthey JN, et al. Laparoscopy in the staging of pancreatic cancer. Br J Surg 2001;88:325-337.

Reference 27 reviews the available literature on the use of laparoscopy in patients with localized pancreatic cancer. The authors suggest that the interpretation of the literature on staging laparoscopy is difficult because (1) there has been inconsistent use of high-quality CT with objective CT criteria for resectability as an entry requirement for prospective studies; (2) many studies have included patients with locally advanced disease; and (3) the R0/R1/R2 resection rates among patients staged by laparoscopy have not been reported making it impossible to correlate laparoscopic findings with the R0 (tumor-free margins) resection rate. Review of the aggregate data suggests that laparoscopy will prevent unnecessary laparotomy in some patients with presumably resectable pancreatic cancer based on CT findings. However, if laparoscopy is performed on patients judged to have resectable disease by high-quality CT, this fraction of patients is between 4% and 15%.

ERCP - Stents - Endoscopic Ultrasound

Martignoni ME, Wagner M, Krähenbühl L, Redaelli CA, Friess H, Buchler MW. Effect of preoperative biliary drainage on surgical outcome after pancreatoduodenectomy. Am J Surg 181:52-59, 2001.

Pisters PW, Hudec WA, Hess KR et al. Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 234:47-55, 2001.

Povoski SP, Karpeh MS, Jr., Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg 230:131-142, 1999.

Sohn TA, Yeo CJ, Cameron JL, Pitt HA, Lillemoe KD. Do preoperative biliary stents increase postpancreaticoduodenectomy complications? J Gastrointest Surg 4:258-267, 2000.

Suits J, Frazee R, Erickson RA. Endoscopic ultrasound and fine needle aspiration for the evaluation of pancreatic masses. Arch Surg 1999;134(6):639-643.

Recent reports of EUS-guided FNA of the pancreas have demonstrated its accuracy and safety. When FNA material is interpreted by an experienced cytopathologist, false-positive results should not occur; however, false-negative results may be common, resulting in negative predictive values as low as 40%. In a patient who presents with extrahepatic biliary obstruction, a malignant-appearing stricture of the intrapancreatic portion of the common bile duct, and no history of recurrent pancreatitis or alcohol abuse, the absence of a mass on CT or EUS should not rule out the possibility of a carcinoma of the pancreas or bile duct. Similarly, negative results of EUS-guided FNA should not be considered definitive proof that a malignancy does not exist. The results of EUS, with or without FNA, should be considered in the context of the clinical picture and as a complement to CT and ERCP findings.

Prognostic Factors

Conlon KC, Klimstra DS, Brennan MF. Long-term survival after curative resection for pancreatic ductal adenocarcinoma; clinicopathologic analysis of 5-year survivors. Ann Surg 1996;223(3):273-279.

Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 4:567-579, 2000.

Willett CG, Lewandrowski K, Warshaw AL, et al. Resection margins in carcinoma of the head of the pancreas: Implications for radiation therapy. Ann Surg 1993;217(2):144-8.

Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: Pathology, complications and outcomes. Ann Surg 1997;226(3):248-260

The prognostic factor of greatest significance for survival duration and which is available to the surgeon prior to the pathologic assessment of the resected specimen is the radiographic assessment of local tumor extension as it predicts eventual margin (of resection) status. The margin of greatest importance is the retroperitoneal (or mesenteric) margin along the right lateral border of the SMA. This margin can be assessed preoperatively using high-quality, contrast-enhanced CT. Incomplete resection resulting in a grossly positive margin along the proximal SMA provides no survival advantage to surgical resection. A number of investigators have examined pathologic factors of the resected tumor in an effort to establish reliable prognostic variables associated with decreased survival duration. Metastatic disease in regional lymph nodes, poorly differentiated histology, and increased size of the primary tumor have been associated with decreased survival duration. However, in an analysis of 12 five-year survivors (following complete resection) by Conlon et al. (reference 33), 4 had poorly differentiated histology, 5 had metastatic disease in regional lymph nodes, 9 had histologic evidence of extra-pancreatic soft tissue extension of tumor, and 10 patients had histologic evidence of perineural invasion. In an otherwise good-risk patient with localized, potentially resectable pancreatic cancer (by objective CT criteria) knowledge of lymph node status, degree of differentiation of the primary tumor, or other histologic (or molecular) prognostic variables is of little clinical relevance at this time; such a patient should receive multimodality therapy to include surgery and chemoradiation as part of a protocol-based treatment program. However, in an elderly patient with comorbidities which may increase the risk for pancreaticoduodenectomy, knowledge of poorly differentiated histology and the status of regional lymph nodes (now possible in major referral centers with the use of EUS-FNA) may cause one to recommend systemic therapy or chemoradiation rather than proceeding directly with major pancreatic surgery.

Outcomes Research and Pancreatectomy

Birkmeyer JD, Finlayson SR, Tosteson AN, Sharp SM, Warshaw AL, Fisher ES. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 1999;125(3):250-256.

Porter GA, Pisters PWT, Mansyur C, Bisanz A, Reyna L, Stanford P, Lee JE, Evans DB: Cost and utilization impact of a clinical pathway for patients undergoing pancreaticoduodenectomy. Ann Surg Oncol, 2000. 7:484-489.

Birkmeyer JD, Warshaw AL, Finlayson SR, Grove MR, Tosteson AN. Relationship between hospital volume and late survival after pancreaticoduodenectomy. Surgery 1999;126(2):178-183.

Simunovic M, To T, Theriault M, Langer B. Relation between hospital surgical volume and outcome for pancreatic resection for neoplasm in a publicly funded health care system. CMAJ 1999;160:643-648.

Sosa JA, Bowman HM, Gordon TA, et al. Importance of hospital volume in the overall management of pancreatic cancer. Ann Surg 1998;228:429-438.

These data are representative of a larger body of recent literature that demonstrates a linear relationship between surgical volume and outcome. Birkmeyer et al. has suggested that the referral of pancreatic cancer patients to high-volume hospitals could potentially prevent more that 100 deaths per year. Furthermore, in an analysis of survival duration, Birkmeyer et al. found that patients who underwent surgery at high-volume hospitals were less likely to experience late mortality.

Vascular resection

Bold RJ, Charnsangavej C, Cleary KR, et al. Major vascular resection as part of pancreaticoduodenectomy for cancer: Radiologic, intraoperative, and pathologic analysis. J Gastrointest Surg 1999;3(3):233-243.

Harrison LE, Klimstra DS, Brennan MF. Isolated portal vein involvement in pancreatic adenocarcinoma: A contraindication for resection? Ann Surg 1996;224(3):342-349.

Leach SD, Lee JE, Charnsangavej C, et al. Survival following pancreaticoduodenectomy with resection of the superior mesenteric-portal vein confluence for adenocarcinoma of the pancreatic head. Br J Surg 1998;85(5):611-617.

Segmental resection of the superior mesenteric-portal vein (SMPV) confluence is necessary when the tumor is inseparable from the lateral wall of the SMV or portal vein. However, such isolated venous resection should be performed only in carefully selected patients who have tumor adherence to the SMV or SMPV confluence but have no evidence of tumor extension to the SMA or celiac axis. Invasion of the SMV or portal vein is not associated with histopathologic variables (margin and lymph node positivity) that suggest a poor prognosis, and patient survival after pancreaticoduodenectomy is not affected by the need for venous resection. Because the need for venous resection is unexpected in many patients and is discovered only after gastric and pancreatic transection, when nonresectional procedures are no longer an option, surgeons who perform pancreaticoduodenectomies should be familiar with standard vascular techniques for resection and reconstruction of the SMPV confluence.

Pancreaticoduodenectomy plus "extended lymphadenectomy"

Henne-Bruns D, Vogel, I. Luttges, J. Kloppel, G. Kremer, B.: Surgery for ductal adenocarcinoma of the pancreatic head: staging, complications, and survival after regional versus extended lymphadenectomy. World J Surg 24:595-602, 2000.

Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. Ann Surg 1998(4); 228:508-517.

Yeo CJ, Cameron JL, Sohn TA, et al. Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: comparison of morbidity and mortality and short-term outcome. Ann Surg 1999;229(5):613-24.

There were slightly different definitions of "extended" lymphadenectomy as performed in these trials. The common elements of the extended portions of the procedure included a retroperitoneal lymph node dissection (removal of the lymphoareolar tissue along the great vessels from approximately the level of the inferior mesenteric artery cephalad to the origin of the SMA). In the Johns Hopkins trial, antrectomy (with resection of adjacent distal gastric and peripyloric lymph nodes) was also performed. Based on intent-to-treat analysis, the above studies did not demonstrate a significant survival benefit for patients with pancreatic adenocarcinoma treated with pancreaticoduodenectomy plus extended lymphadenectomy. The frequency of involved second echelon lymph nodes was 10%; no patients were upstaged or more accurately staged by the extended lymphadenectomy. Accrual to the Johns Hopkins trial continues with a target accrual of 242 patients. The methodologic and biostatistical issues associated with clinical trial design in this area are complex. Indeed, based on the preliminary pathology findings in the trial from Johns Hopkins, it is possible that both clinical trials may be underpowered for the primary endpoint (overall survival). The American College of Surgeons Oncology Group is considering a larger scale trial to further examine this issue.

Pisters PWT, Evans DB, Leung DHY, Brennan MF. Surgery in ductal adenocarcinoma of the pancreatic head: Staging, complications and survival after regional versus extended lymphadenectomy. World J Surg 2001; 25:533-534.

This letter to the editor examines the important biostatistical implications of the pathology data available from the existing prospective trials of extended lymphadenectomy. The model presented in this editorial suggests that clinical trials of extended lymphadenectomy may not be feasible if powered for survival as a primary endpoint.

Quality of Life

Huang JJ, Yeo CJ, Sohhn TA, et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann Surg 2000;231:890-898.

Neoptolemos JP, et al. Survival and Quality of life of patients in ESPAC-1: A European randomized study to assess the roles of adjuvant chemotherapy and chemoradiation in resectable pancreatic cancer. Gastroenterology 2001;120(suppl 1):A-24.

Postoperative chemoradiation

Demeure MJ, Doffek KM, Komorowski RA, et al. Molecular metastases in stage I pancreatic cancer: Improved survival with adjuvant chemoradiation. Surgery 1998;124:663-669.

Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006

Kalser MH, Ellenberg SS. Pancreatic cancer: Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120(8):899-903.

Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and peri-ampullary region. Phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999;230(6):776-784.

The European Organization for Research and Treatment of Cancer (EORTC) recently reported their findings for trial 40891. Between 1987 and 1995, 218 patients were randomized to receive either chemoradiation (40 Gy in a split course and 5-FU given as a continuous infusion at a dose of 25 mg/kg/day during EBRT) or no further treatment following pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region. Eleven patients were deemed ineligible for analysis due to extensive local disease with incomplete resection. Of the remaining 207 patients, 114 (55%) had pancreatic cancer. The median survival duration was 24.5 months for the group who received adjuvant therapy and 19 months for the group who received surgery alone (p=0.2); for patients with pancreatic cancer, the median survival was 17.1 months for those who received adjuvant therapy and 12.6 months for those who received surgery alone (p=0.099). Although these differences were not significant, for the subset of patients with pancreatic cancer, the wide confidence interval (relative risk, 0.7; 95% CI, 0.5-1.1) does not exclude the possibility of a clinically meaningful improvement in survival in the chemoradiation arm that was not apparent owing to the small sample size. Similar to the GITSG trial, patients were considered for enrollment in the EORTC trial after recovery from pancreaticoduodenectomy; despite this selection bias, 21 (20%) of 104 evaluable patients assigned to receive chemoradiation did not receive intended therapy because of patient refusal, medical comorbidities, or rapid tumor progression. In addition, the retroperitoneal margin of resection was not asscessed, and therefore the completeness of surgical resection could not be assessed.

Chakravarthy A, Abrams RA, Yeo CJ, et al. Intensified adjuvant combined modality therapy for resected periampullary adenocarcinoma: acceptable toxicity and suggestion of improved 1-year disease-free survival. Int J Radiation Oncology Biol. Phys 2000;48:1089-1096.

Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4:567-579, 2000.

Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997;225(3):621-36.

Despite the selection bias involved in the enrollment of patients into postoperative adjuvant therapy studies, prospective and retrospective data suggest that the addition of postoperative adjuvant chemoradiation following pancreaticoduodenectomy improves survival duration.

Nukui Y, Picozzi VJ, Traverso LW. Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2000;179:367-371.

The investigators from Virginia Mason Medical Center retrospectively reviewed their experience with 33 patients who successfully underwent pancreaticoduodenectomy and were assigned in a non-randomized fashion to receive either external-beam irradiation (EBRT; 45-54 Gy) and concomitant 5-FU, or IFN-a-based chemoradiation (45-54Gy, and concomitant continuous infusion 5-FU [200 mg/m2/day], bolus cisplatin [30 mg/m2/day], and SQ IFN-a [3 million u, qod]). While the sample size was small, the 17 patients who received the IFN-a ?regimen had a significantly greater actuarial 2-year survival when compared to those receiving EBRT and 5-FU alone (84% vs. 54%, p=0.04). The 2-year survival in the "control" arm compares favorably with other recently published series of adjuvant 5-FU and EBRT, which have generally been in the range of 40%. Note: The ACOSOG plans an adjuvant trial incorporating this treatment program.

Preoperative chemoradiation

Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123-132.

Hoffman JP, Weese JL, Solin LJ, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg 1995;169:71-8.

Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: An Eastern Cooperative Oncology Group Study. J Clin Oncol 1998;16(1):317-23.

Pisters PWT, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol 1998;16:3843-50.

Because of the risk that planned postoperative adjuvant therapy will be delayed or not delivered, many institutions initiated studies of chemoradiation given preoperatively. The results suggest that preoperative chemoradiation has certain advantages over postoperative chemoradiation: 1) because chemotherapy and radiation are given first, delayed postoperative recovery has no effect on the delivery of multimodality therapy; 2) the recently reported high frequency of positive-margin resections supports the concern that the retroperitoneal margin of excision, even when negative, may be only a few millimeters-thus, surgery alone is inadequate local therapy for most patients; and 3) patients found to have disseminated disease on restaging studies after chemoradiation will not be subjected to laparotomy.

Issues in the Management of Locally Advanced Disease

Espat NJ, Brennan MF, Conlon KC. Patients with laparoscopically staged unresectable pancreatic adenocarcinoma do not require subsequent surgical biliary or gastric bypass. J Am Coll Surg 1999;188(6):649-57.

Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 1999;230(3):322-30.

Nagorney DM, et al. The SSAT, AGA, AASLD, ASGE, AHPBA Consensus Panel. Management of unresectable pancreatic ductal cancer. J Gastrointest Surg 1999;3:331-344.

Raikar GV, Melin MM, Ress A, et al. Cost-effective analysis of surgical palliation versus endoscopic stenting in the management of unresectable pancreatic cancer. Ann Surg Oncol 1996;3(5):470-5.

Lillemoe et al. recently reported results of a prospective randomized trial of prophylactic gastrojejunostomy in patients with adenocarcinoma of the pancreatic head and periampullary region. Patients found to have unresectable disease [and not to have intraoperative evidence of impending gastric outlet obstruction (such patients were excluded from analysis)] at the time of laparotomy were randomized to receive either a prophylactic gastrojejunostomy or no further surgery. Subsequent gastric outlet obstruction developed in 8 (19%) of the 43 patients who did not receive a gastric bypass and in none of the 44 patients who received a gastrojejunostomy. Postoperative delayed gastric emptying (2% of patients) and mean hospital stay (8 days) were not different between groups. Further, there were no perioperative deaths, and the mean survival duration was 8.3 months in both groups. Lillemoe et al. concluded that a retrocolic gastrojejunostomy should be performed routinely when a patient with pancreatic or periampullary cancer is found at laparotomy to have unresectable disease. The opposite conclusion was reached by Espat et al. from Memorial Sloan-Kettering Cancer Center. They found a low incidence of gastric outlet obstruction in patients with advanced pancreatic cancer. Espat et al. reported the longitudinal follow-up of 155 patients who were found to have unsuspected locally advanced or metastatic disease at the time of staging laparoscopy for presumed localized pancreatic cancer. Only 2 patients underwent elective gastric bypass (1 was performed laparoscopically). At a median follow-up of 6 months (by which time 81% of patients had died of disease), only 3 (2%) of 155 patients had undergone a subsequent open palliative surgical procedure, including a gastrojejunostomy for symptomatic gastric outlet obstruction in 2 of these 3 patients. One additional patient required a percutaneous gastrostomy tube for poor gastric emptying during the terminal phase of his disease. The median survival was 6.2 months for those with metastatic disease and 7.8 months for those with locally advanced disease, suggesting that these patients did not have high-volume metastatic disease at the time of laparoscopy. Raikar et al. also reported a low incidence of subsequent gastric outlet obstruction in patients with unresectable pancreatic cancer who underwent endoscopic biliary decompression. In that study, only 1 (3%) of 34 patients treated with endoscopic biliary decompression required surgical bypass for gastric outlet obstruction.

Developments in the Management of Metastatic Disease

Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15(6):2403-13.

Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys 1996;34(4):867-72.

Rosenberg L. Pancreatic cancer: a review of emerging therapies. Drugs 2000;59:1071-1089.

Tempero M, Plunkett W, Ruiz van Haperen V, et al. Randomized phase II trial of dose intense gemcitabine by standard infusion vs. fixed dose rate in metastatic pancreatic adenocarcinoma [Abstract]. Proceedings of the American Society of Clinical Oncology 1999;18:273.

69. Wolff RA, Evans DB, Gravel DM, et al. Phase I trial of gemcitabine combined with radiation for treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 2001; 7:2246-2253.

Recently, gemcitabine (2'-deoxy-2'2'-difluorocytidine) has demonstrated modest reproducible activity against advanced pancreatic cancer. Following phase I evaluation, gemcitabine was used in a multicenter trial involving 44 patients with advanced pancreatic cancer. Only 5 objective responses (11%) were documented, but the investigators reported frequent subjective symptomatic benefits, often in the absence of objective responses. Based on these observations, two subsequent trials of gemcitabine for advanced pancreatic cancer were completed. In one randomized trial, gemcitabine was compared to 5-FU in previously untreated patients (Burris). Patients treated with gemcitabine achieved modest but statistically significant improvements in response rate and median survival compared to those treated with 5-FU (5.65 versus 4.41 months, p=0.0025). The 1-year survival rate for patients treated with gemcitabine was 18%, whereas the rate was only 2% for those treated with 5-FU. Importantly, more clinically meaningful effects on disease-related symptoms were recorded with gemcitabine than with 5-FU. These clinical benefits were also documented in patients treated with gemcitabine after experiencing disease progression while receiving 5-FU. These results have helped gemcitabine become accepted as the first-line therapy for patients with advanced pancreatic adenocarcinoma in the United States, although this approach is not necessarily shared worldwide. Ongoing studies of gemcitabine as a treatment for pancreatic cancer involve the combination of gemcitabine with other cytotonic agents (cisplatin) and molecular-based therapies (herceptin, C 225, etc.)

Recent Abstracts

J P Neoptolemos, J A Dunn, D D Moffitt et al. ESPAC-1 Interim Results: A European, Randomised Study to Assess the Roles of Adjuvant Chemotherapy (5FU+Folinic Acid) and Adjuvant Chemoradiation (40GY+5FU) in Resectable Pancreatic Cancer. Proc Am Soc Clin Oncol, 19:923, 2000.

The recently reported interim results of the European Study Group of Pancreatic Cancer (ESPAC)-1 study, suggest that EBRT may not be an essential treatment component. The ESPAC-1 trial is a four-arm study with a 2 x 2 factorial design which compares adjuvant chemoradiation (40 Gy in a split course and 5-FU), adjuvant chemotherapy (5-FU and folinic acid), chemoradiation followed by chemotherapy, and observation alone following pancreaticoduodenectomy for pancreatic or periampullary carcinomas. This study began accrual in 1994, and medical centers from eleven countries have randomized 530 patients. The majority of patients were entered into the randomized 2x2 factorial design. However, because of either no access to EBRT or specific institutional bias, 188 patients were randomized only to chemotherapy or no chemotherapy, and 68 patients were randomized to either chemoradiation or no chemoradiation. In these latter two non-factorial groups, patients could receive non-standardized therapy at the discretion of their treating physicians. For example, patients who were randomized in the non-factorial design to chemotherapy or no chemotherapy could receive EBRT. Importantly, non-randomized treatments were not standardized. Preliminary results suggested no benefit for the use of postoperative chemoradiation.

Current Major Clinical Trials

RTOG 97-04: In July 1998, the RTOG activated the first American phase III cooperative group study of postoperative adjuvant therapy for resected pancreatic adenocarcinoma since the GITSG trial. Patients are being randomly assigned to receive gemcitabine or 5-FU to be given before and after 5-FU-based chemoradiation.

Study Arms: Arms 1 and 2 (both receive 5-FU-based chemoradiation) Chemotherapy: Arm 1: Pre-chemoradiation 5-FU 250mg/m2/day continuous infusion x 3 weeks, then local chemoradiation, then post-chemoradiation 5-FU 250mg/m2/day continuous infusion x 2 cycles [1 cycle = 4 weeks followed by 2 weeks of rest]. Arm 2: Pre-chemoradiation gemcitabine 1000mg/m2/wk x 3 weeks, then local chemoradiation, then post-chemoradiation gemcitabine 1000mg/m2/wk x 3 cycles [1 cycle = 3 weeks followed by 1 week of rest]. Chemoradiation: 50.4 Gy (1.8 Gy/fx) with continuous infusion 5-FU (250 mg/m2/d). This is an intergroup trial that RTOG coordinates with ECOG and SWOG participating. The study opened in July of 1998. The targeted accrual is 330 patients. By September of 2000, 243 patients have been registered to the trial with accrual proceeding ahead of projections.

ESPAC-3 - The ESPAC investigators have initiated the second generation adjuvant ESPAC trial (ESPAC-3) randomizing patients following pancreatectomy to observation, 5-FU and folinic acid, or gemcitabine (based on the results of ESPAC-1, EBRT is removed from the treatment options).

ACOSOG: The American College of Surgeons Oncology Group plans a phase II (or possibly, a phase III) trial to study the Virginia Mason regimen of postoperative adjuvant chemoradiation following pancreaticoduodenectomy. This treatment involves 45 Gy of external-beam irradiation and 3-drug chemotherapy (continuous infusion 5-FU, cisplatin, and a IFN).