Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 16%.[1-5] Using information from the Medicare claims database, a national cohort study of over 7,000 patients undergoing pancreaticoduodenectomy between 1992 and 1995 revealed higher in-hospital mortality rates at low-volume hospitals (<1 pancreaticoduodenectomy per year) versus high-volume hospitals (>5 per year)(16% vs 4% respectively, P<.01).[1] Complete resection can yield 5-year survival rates of 18% to 24%, but ultimate control remains poor due to the high incidence of both local and distant tumor recurrence.[6-8] [Level of evidence: 3iA] The role of postoperative therapy in the management of this disease is inadequately defined as there are limited randomized clinical trial data to support the use of postoperative therapy in patients with resected pancreatic cancer.[9-13] These trials are all statistically underpowered and provide conflicting results.

A small randomized trial conducted by the Gastrointestinal Study Group (GITSG) in 1985 demonstrated a significant but modest improvement in median-term and long-term survival over resection alone with postoperative bolus 5-fluorouracil (5-FU) and regional split course radiation given at a dose of 40 Gy.[9] [Level of evidence: 1iiA];[10] [Level of evidence: 2A] An attempt by the European Organization for the Research and Treatment of Cancer to reproduce the results of the GITSG trial failed to confirm a significant benefit for adjuvant chemoradiation over resection alone;[11] [Level of evidence: 1iiA] however, this trial treated patients with pancreatic as well as periampullary cancers (with a potential better prognosis). A subset analysis of the patients with primary pancreatic tumors indicated a trend toward improved median, 2-year, and 5-year overall survival with adjuvant therapy compared with surgery alone (12.6 months, 23%, 10% vs 17.1 months, 37% and 20%, P=.09 for median survival). An updated analysis of a subsequent European Study for Pancreatic Cancer (ESPAC 1) trial that examined only patients who underwent strict randomization following pancreatic resection to 1 of 4 groups (i.e., observation, chemotherapy, chemoradiation or chemoradiation followed by additional chemotherapy), with a 2 X 2 factorial design, reported, at a median follow-up of 47 months, a survival benefit for only the patients who received postoperative chemotherapy. These results were difficult to interpret, however, because there was a high rate of protocol nonadherence.[12-14] [Level of evidence: 1iiA] Additional trials are still warranted, therefore, to determine effective adjuvant therapy for this disease.

Further phase I and phase II clinical trials exploring other local and systemic combination adjuvant therapies such as preoperative chemoradiation (CRT), CRT with protracted infusion 5-FU or the addition of mitomycin-C, CRT with elective hepatic irradiation, intra-arterial CRT, and CRT with intraoperative radiation or high-dose standard radiation therapy have failed to produce significant improvements in survival over historical controls with postoperative 5-FU and 50.4 Gy radiation therapy.[15-19]

Standard treatment options:

1. Radical pancreatic resection:
   • Whipple procedure (pancreaticoduodenal resection).
   • Total pancreatectomy when necessary for adequate margins.
   • Distal pancreatectomy for tumors of the body and tail of the pancreas.[20,21]
2. Radical pancreatic resection with or without postoperative 5-FU chemotherapy and irradiation.[9-13]

Treatment options under clinical evaluation:

1. Postoperative radiation therapy with other chemotherapeutic agents. In 2002, the Radiation Therapy Oncology Group completed a prospective, multicenter randomized trial to evaluate whether gemcitabine chemotherapy administered before and following radiation with concurrent 5-FU is superior to adjuvant 5-FU for patients with completely resected tumors; preliminary analysis is pending.[22] Information about ongoing clinical trials is available from the NCI Cancer.gov Web site.
2. Postoperative chemotherapy alone. The ESPAC-3 trial is ongoing to evaluate postoperative chemotherapy with either 5-FU/leucovorin or gemcitabine versus no additional treatment.[23]
3. Postoperative biologic agents including farnesyl transferase inhibitors and avastin in combination with radiation therapy and/or chemotherapy.

References

1. Birkmeyer JD, Finlayson SR, Tosteson AN, et al.: Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 125 (3): 250-6, 1999.  [PUBMED Abstract]
   
   
2. Cameron JL, Pitt HA, Yeo CJ, et al.: One hundred and forty-five consecutive pancreaticoduodenectomies without mortality. Ann Surg 217 (5): 430-5; discussion 435-8, 1993.  [PUBMED Abstract]
   
   
3. Spanknebel K, Conlon KC: Advances in the surgical management of pancreatic cancer. Cancer J 7 (4): 312-23, 2001 Jul-Aug.  [PUBMED Abstract]
   
   
4. Balcom JH 4th, Rattner DW, Warshaw AL, et al.: Ten-year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 136 (4): 391-8, 2001.  [PUBMED Abstract]
   
   
5. Sohn TA, Yeo CJ, Cameron JL, et al.: Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4 (6): 567-79, 2000 Nov-Dec.  [PUBMED Abstract]
   
   
6. Cameron JL, Crist DW, Sitzmann JV, et al.: Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am J Surg 161 (1): 120-4; discussion 124-5, 1991.  [PUBMED Abstract]
   
   
7. Yeo CJ, Cameron JL, Lillemoe KD, et al.: Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg 221 (6): 721-31; discussion 731-3, 1995.  [PUBMED Abstract]
   
   
8. Yeo CJ, Abrams RA, Grochow LB, et al.: Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 225 (5): 621-33; discussion 633-6, 1997.  [PUBMED Abstract]
   
   
9. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer 59 (12): 2006-10, 1987.  [PUBMED Abstract]
   
   
10. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.  [PUBMED Abstract]
    
    
11. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230 (6): 776-82; discussion 782-4, 1999.  [PUBMED Abstract]
    
    
12. Neoptolemos JP, Dunn JA, Stocken DD, et al.: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 358 (9293): 1576-85, 2001.  [PUBMED Abstract]
    
    
13. Neoptolemos JP, Stocken DD, Friess H, et al.: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350 (12): 1200-10, 2004.  [PUBMED Abstract]
    
    
14. Choti MA: Adjuvant therapy for pancreatic cancer--the debate continues. N Engl J Med 350 (12): 1249-51, 2004.  [PUBMED Abstract]
    
    
15. Tepper JE, Noyes D, Krall JM, et al.: Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21 (5): 1145-9, 1991.  [PUBMED Abstract]
    
    
16. Whittington R, Neuberg D, Tester WJ, et al.: Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. J Clin Oncol 13 (1): 227-32, 1995.  [PUBMED Abstract]
    
    
17. 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 16 (1): 317-23, 1998.  [PUBMED Abstract]
    
    
18. Evans DB, Abbruzzese JL, Cleary KR, et al.: Preoperative chemoradiation for adenocarcinoma of the pancreas: excessive toxicity of prophylactic hepatic irradiation. Int J Radiat Oncol Biol Phys 33 (4): 913-8, 1995.  [PUBMED Abstract]
    
    
19. Thomas CR Jr, Weiden PL, Traverso LW, et al.: Concomitant intraarterial cisplatin, intravenous 5-flourouracil, and split-course radiation therapy for locally advanced unresectable pancreatic adenocarcinoma: a phase II study of the Puget Sound Oncology Consortium (PSOC-703). Am J Clin Oncol 20 (2): 161-5, 1997.  [PUBMED Abstract]
    
    
20. Dalton RR, Sarr MG, van Heerden JA, et al.: Carcinoma of the body and tail of the pancreas: is curative resection justified? Surgery 111 (5): 489-94, 1992.  [PUBMED Abstract]
    
    
21. Brennan MF, Moccia RD, Klimstra D: Management of adenocarcinoma of the body and tail of the pancreas. Ann Surg 223 (5): 506-11; discussion 511-2, 1996.  [PUBMED Abstract]
    
    
22. Regine WF, Radiation Therapy Oncology Group: Phase III Randomized Study of Adjuvant Fluorouracil-Based Chemoradiotherapy Preceded and Followed By Fluorouracil Versus Gemcitabine in Patients With Resected Adenocarcinoma of the Pancreas, RTOG-9704, Clinical trial, Closed.  [PDQ Clinical Trial]
    
    
23. ESPAC-3(v2) Phase III Adjuvant Trial in Pancreatic Cancer Comparing 5FU and D-L-Folinic Acid vs. Gemcitabine. Leeds, UK: National Cancer Research Network Trials Portfolio, 2004. Available online. Last accessed June 7, 2004. 
    
    

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