Pancreatic Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Pancreatic Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Pancreatic Cancer Treatment

General Information About Pancreatic Cancer

Related Summary

Note: Another PDQ summary containing information related to pancreatic cancer includes:

  • Unusual Cancers of Childhood (pancreatic cancer in children)

Statistics

Note: Estimated new cases and deaths from pancreatic cancer in the United States in 2010:[1]

  • New cases: 43,140.
  • Deaths: 36,800.

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.)

Carcinoma of the pancreas has had a markedly increased incidence during the past several decades and ranks as the fourth leading cause of cancer death in the United States. Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood.[2] Cancer of the exocrine pancreas is rarely curable and has an overall survival (OS) rate of less than 4%.[3] The highest cure rate occurs if the tumor is truly localized to the pancreas; however, this stage of the disease accounts for fewer than 20% of cases. For those patients with localized disease and small cancers (<2 cm) with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection can yield actuarial 5-year survival rates of 18% to 24%.[4][Level of evidence: 3iA] Improvements in imaging technology, including spiral computed tomographic scans, magnetic resonance imaging scans, positron emission tomographic scans, endoscopic ultrasound examination, and laparoscopic staging can aid in the diagnosis and the identification of patients with disease that is not amenable to resection.[5] In a case series of 228 patients, positive peritoneal cytology had a positive predictive value of 94%, specificity of 98%, and sensitivity of 25% for determining unresectability.[6] For patients with advanced cancers, the OS rate of all stages is less than 1% at 5 years with most patients dying within 1 year.[7,8,9,10]

No tumor-specific markers exist for pancreatic cancer; markers such as serum CA 19-9 have low specificity. Most patients with pancreatic cancer will have an elevated CA 19-9 at diagnosis. Following or during definitive therapy, the increase of CA 19-9 levels may identify patients with progressive tumor growth.[11][Level of evidence: 3iDiii] The presence of a normal CA 19-9, however, does not preclude recurrence.

Patients with any stage of pancreatic cancer can appropriately be considered candidates for clinical trials because of the poor response to chemotherapy, radiation therapy, and surgery as conventionally used. Palliation of symptoms, however, may be achieved with conventional treatment. Symptoms caused by pancreatic cancer may depend on the site of the tumor within the pancreas and the degree of involvement. Palliative surgical or radiologic biliary decompression, relief of gastric outlet obstruction, and pain control may improve the quality of life while not affecting OS.[12,13] Palliative efforts may also be directed to the potentially disabling psychological events associated with the diagnosis and treatment of pancreatic cancer.[14] (Refer to the PDQ summary on Pain for more information.)

Information about ongoing clinical trials is available from the NCI Web site.

References:

1. American Cancer Society.: Cancer Facts and Figures 2010. Atlanta, Ga: American Cancer Society, 2010. Also available online. Last accessed June 16, 2011.
2. Silverman DT, Schiffman M, Everhart J, et al.: Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Br J Cancer 80 (11): 1830-7, 1999.
3. Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. CA Cancer J Clin 50 (1): 7-33, 2000 Jan-Feb.
4. 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.
5. Riker A, Libutti SK, Bartlett DL: Advances in the early detection, diagnosis, and staging of pancreatic cancer. Surg Oncol 6 (3): 157-69, 1997.
6. Merchant NB, Conlon KC, Saigo P, et al.: Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma. J Am Coll Surg 188 (4): 421-6, 1999.
7. Lillemoe KD: Current management of pancreatic carcinoma. Ann Surg 221 (2): 133-48, 1995.
8. Yeo CJ: Pancreatic cancer: 1998 update. J Am Coll Surg 187 (4): 429-42, 1998.
9. Nitecki SS, Sarr MG, Colby TV, et al.: Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221 (1): 59-66, 1995.
10. Conlon KC, Klimstra DS, Brennan MF: Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg 223 (3): 273-9, 1996.
11. Willett CG, Daly WJ, Warshaw AL: CA 19-9 is an index of response to neoadjunctive chemoradiation therapy in pancreatic cancer. Am J Surg 172 (4): 350-2, 1996.
12. Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999.
13. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
14. Passik SD, Breitbart WS: Depression in patients with pancreatic carcinoma. Diagnostic and treatment issues. Cancer 78 (3 Suppl): 615-26, 1996.

Cellular Classification of Pancreatic Cancer

Pancreatic cancer includes the following carcinomas:

Malignant

  • Duct cell carcinoma (90% of all cases).
  • Acinar cell carcinoma.
  • Papillary mucinous carcinoma.
  • Signet ring carcinoma.
  • Adenosquamous carcinoma.
  • Undifferentiated carcinoma.
  • Mucinous carcinoma.
  • Giant cell carcinoma.
  • Mixed type (ductal-endocrine or acinar-endocrine).
  • Small cell carcinoma.
  • Cystadenocarcinoma (serous and mucinous types).
  • Unclassified.
  • Pancreatoblastoma.
  • Papillary-cystic neoplasm (Frantz tumor). (This tumor has lower malignant potential and may be cured with surgery alone.)[1,2]
  • Invasive adenocarcinoma associated with cystic mucinous neoplasm or intraductal papillary mucinous neoplasm.

Borderline Malignancies

  • Mucinous cystic tumor with dysplasia.
  • Intraductal papillary mucinous tumor with dysplasia.[3]
  • Pseudopapillary solid tumor.

References:

1. Sanchez JA, Newman KD, Eichelberger MR, et al.: The papillary-cystic neoplasm of the pancreas. An increasingly recognized clinicopathologic entity. Arch Surg 125 (11): 1502-5, 1990.
2. Warshaw AL, Compton CC, Lewandrowski K, et al.: Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 212 (4): 432-43; discussion 444-5, 1990.
3. Sohn TA, Yeo CJ, Cameron JL, et al.: Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 234 (3): 313-21; discussion 321-2, 2001.

Stage Information for Pancreatic Cancer

The staging system for pancreatic exocrine cancer continues to evolve. The importance of staging beyond that of resectable and unresectable is uncertain since state-of-the-art treatment has demonstrated little impact on survival. To communicate a uniform definition of disease, however, knowledge of the extent of the disease is necessary. Cancers of the pancreas are commonly identified by the site of involvement within the pancreas. Surgical approaches differ for masses in the head, body, tail, or uncinate process of the pancreas.

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define pancreatic cancer.[1]

Table 1. Primary Tumor (T)a

a Reprinted with permission from AJCC: Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241–9.
b This also includes the "PanInIII" classification.
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis Carcinoma in situ. b
T1 Tumor limited to the pancreas, ≤2 cm in greatest dimension.
T2 Tumor limited to the pancreas, >2 cm in greatest dimension.
T3 Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery.
T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor).

Table 2. Regional Lymph Nodes (N)a

a Reprinted with permission from AJCC: Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241–9.
NX Regional lymph nodes cannot be assessed.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis.

Table 3. Distant Metastasis (M)a

a Reprinted with permission from AJCC: Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241–9.
M0 No distant metastasis.
M1 Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groupsa

a Reprinted with permission from AJCC: Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241–9.
Stage T N M
0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1 N1 M0
T2 N1 M0
T3 N1 M0
III T4 Any N M0
IV Any T Any N M1

References:

1. Exocrine and endocrine pancreas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 241-9.

Treatment Option Overview

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.)

The survival rate of patients with any stage of pancreatic exocrine cancer is poor. Clinical trials are appropriate alternatives for treatment of patients with any stage of disease and should be considered prior to selecting palliative approaches. To provide optimal palliation, determination of resectability must be made. Staging studies for resectability include helical computed tomographic scan, magnetic resonance imaging scan, and endoscopic ultrasound. The introduction of minimally invasive techniques, such as laparoscopy and laparoscopic ultrasound, may decrease the use of laparotomy.[1,2] Surgical resection remains the primary modality when feasible since, on occasion, resection can lead to long-term survival and provides effective palliation.[3,4,5][Level of evidence: 3iA] The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of this disease remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[6,7,8,9,10] Frequently, malabsorption caused by exocrine insufficiency contributes to malnutrition. Attention to pancreatic enzyme replacement can help alleviate this problem. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.) Celiac axis (and intrapleural) nerve blocks can provide highly effective and long-lasting control of pain for some patients. (Refer to the PDQ summary on Pain for more information.)

Information about ongoing clinical trials is available from the NCI Web site.

References:

1. John TG, Greig JD, Carter DC, et al.: Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography. Ann Surg 221 (2): 156-64, 1995.
2. Minnard EA, Conlon KC, Hoos A, et al.: Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg 228 (2): 182-7, 1998.
3. 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.
4. Conlon KC, Klimstra DS, Brennan MF: Long-term survival after curative resection for pancreatic ductal adenocarcinoma. Clinicopathologic analysis of 5-year survivors. Ann Surg 223 (3): 273-9, 1996.
5. 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.
6. 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.
7. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.
8. 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.
9. 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.
10. 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.

Stage I and II Pancreatic Cancer

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%.[1,2,3,4,5] Using information from the Medicare claims database, a national cohort study of more than 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 because of the high incidence of both local and distant tumor recurrence.[6,7,8][Level of evidence: 3iA] The role of postoperative therapy (chemotherapy with or without chemoradiation therapy [CRT]) in the management of this disease remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[9,10,11,12,13]

Three phase III trials examined the potential overall survival (OS) benefit of postoperative adjuvant 5-fluorouracil (5-FU)–based CRT. 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-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 CRT 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 towards improved median, 2-year, and 5-year OS with adjuvant therapy compared with surgery alone (17.1 months, 37% and 20% vs. 12.6 months, 23% and 10%, P = .09 for median survival). An updated analysis of a subsequent European Study for Pancreatic Cancer (ESPAC 1) trial examined only patients who underwent strict randomization following pancreatic resection. The patients were assigned to one of four groups (observation, bolus 5-FU chemotherapy, bolus 5-FU CRT, or CRT followed by additional chemotherapy). With a 2 × 2 factorial design reported, at a median follow-up of 47 months, a median survival benefit was observed for only the patients who received postoperative 5-FU chemotherapy. These results were difficult to interpret, however, because of a high rate of protocol nonadherence and the lack of a separate analysis for each of the four groups in the 2 x 2 design.[12,13,14][Level of evidence: 1iiA]

The United States Gastrointestinal Intergroup has reported the results of a randomized phase III trial (RTOG-9704) that included 451 patients with resected pancreatic cancers who were assigned to receive either postoperative infusional 5-FU plus infusional 5-FU and concurrent radiation or adjuvant gemcitabine plus infusional 5-FU and concurrent radiation.[15] The primary endpoints were OS for all patients and OS for patients with pancreatic head cancers. The median OS for the 388 patients with pancreatic head tumors was 20.5 months in the gemcitabine arm versus 16.9 months in the 5-FU arm; 3-year survival was 31% versus 22%, respectively (P = .09; hazard ratio = 0.82; confidence interval [CI], 0.65–1.03). OS for all patients was not reported in the publication; however, median survival estimates extrapolated from the presented survival curve were approximately 19 months for the gemcitabine group and 17 months for the 5-FU group.[15][Level of evidence: 1iiA]

Results have also been reported from CONKO-001, a multicenter phase III trial of 368 patients with resected pancreatic cancer who were randomly assigned to six cycles of adjuvant gemcitabine versus observation.[16] In contrast to the previous trials, the primary endpoint was disease-free survival (DFS). Median DFS was 13.4 months in the gemcitabine arm (95% CI, 11.4–15.3) and 6.9 months in the observation group (95% CI, 6.1–7.8; P < .001). However, there was no significant difference in OS between the gemcitabine arm (median 22.1 months, 95% CI, 18.4–25.8) and the control group (median 20.2 months, 95% CI, 17–23.4).[16][Level of evidence: 1iiDii]

Although the available data do not resolve the controversy of the optimal adjuvant therapy strategy for patients with resected pancreatic cancer, the results of CONKO-001 and RTOG-9704 suggest that a gemcitabine-containing platform represents an appropriate choice for current management and may be considered as a building block for future clinical trials.

Additional trials are still warranted to determine more effective adjuvant therapy for this disease.

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.[17,18]
2. Radical pancreatic resection with or without postoperative 5-FU chemotherapy and radiation therapy.[9,10,11,12,13]

Treatment options under clinical evaluation:

1.For patients with resected tumors, postoperative radiation therapy with other chemotherapeutic agents.
2.For patients with resected tumors, postoperative chemotherapy alone. The RLUH-NCRI-ESPAC-3V2 trial evaluated postoperative chemotherapy with either 5-FU/leucovorin or gemcitabine versus no additional treatment.[19] Results are pending.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I pancreatic cancer and stage II pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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.
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.
3. Spanknebel K, Conlon KC: Advances in the surgical management of pancreatic cancer. Cancer J 7 (4): 312-23, 2001 Jul-Aug.
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.
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.
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.
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.
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.
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.
10. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.
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.
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.
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.
14. Choti MA: Adjuvant therapy for pancreatic cancer--the debate continues. N Engl J Med 350 (12): 1249-51, 2004.
15. Regine WF, Winter KA, Abrams RA, et al.: Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 299 (9): 1019-26, 2008.
16. Oettle H, Post S, Neuhaus P, et al.: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297 (3): 267-77, 2007.
17. 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.
18. 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.
19. 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 March 30, 2010.

Stage III Pancreatic Cancer

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.)

Patients with stage III pancreatic cancer have tumors that are technically unresectable because of local vessel impingement or invasion by tumor. These patients may benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological means.[1]

Three trials attempted to look at issues of combined modality therapy versus radiation therapy alone (the Gastrointestinal Tumor Study Group's GITSG-9173 trial, the Eastern Cooperative Oncology Group's EST-8282 trial, and the Federation Francophone de Cancerologie Digestive-Société Française de Radiothérapie Oncologie group's FFCD-2000-01 trial).[2,3,4] The three trials had substantial deficiencies in design or analysis. Until recently, the standard of practice has been to give chemoradiation therapy, and that was based on the first two studies; however, with the preliminary publication of the third study, standard practice has changed.

Prior to the use of gemcitabine for patients with locally advanced or metastatic pancreatic cancer, investigators from the GITSG randomly assigned 106 patients with locally advanced pancreatic adenocarcinoma to receive external beam radiation therapy (EBRT) (60 Gy) alone or to receive concurrent EBRT (either 40 Gy or 60 Gy) plus bolus fluorouracil (5-FU).[2][Level of evidence: 1iiA] The study was stopped early when the chemoradiation therapy arms were found to have better efficacy. The 1-year survival was 11% for patients who received EBRT alone compared with 38% for patients who received chemoradiation with 40 Gy and 36% for patients who received chemoradiation with 60 Gy. After an additional 88 patients were enrolled in the combined modality arms, there was a trend toward improved survival with 60 Gy EBRT plus 5-FU, but the difference in time-to-progression and overall survival (OS) was not statistically significant when compared to the 40 Gy arm.[5]

In contrast, investigators from the ECOG randomly assigned 114 patients to radiation therapy (59.4 Gy) alone or with concurrent infusional 5-FU (1,000 mg/m2 daily on days 2 through 5 and days 28 through 31) plus mitomycin (10 mg/m2 on day 2) and found no difference in OS between the two groups.[3]

Whether chemoradiation therapy should be considered for patients with stage III pancreatic cancer is controversial. Preliminary results from a study of the FFCD-SFRO were presented in abstract form at the 2006 American Society of Clinical Oncology meeting.[4] Patients with locally advanced pancreatic cancer were randomly assigned to receive either concurrent chemoradiation therapy followed by gemcitabine or gemcitabine alone. The trial was halted because of poor accrual after 109 of the planned 176 patients were enrolled. In a preliminary report with a median 16-month follow-up, patients who received chemoradiation followed by gemcitabine had a median survival of 8.4 months versus 14.3 months for the group who received gemcitabine alone (stratified log-rank, P = .014).

Standard treatment options:

1.Palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.[6,7]
2.Chemotherapy with gemcitabine.

Treatment options under clinical evaluation:

1.For patients with technically unresectable tumors, clinical trials evaluating novel agents in combination with chemotherapy or chemoradiation therapy (RTOG-PA-0020 is one example).
2.Intraoperative radiation therapy and/or implantation of radioactive sources.[8,9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999.
2. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg 189 (2): 205-8, 1979.
3. Cohen SJ, Dobelbower R Jr, Lipsitz S, et al.: A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys 62 (5): 1345-50, 2005.
4. Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: a FFCD-SFRO study. [Abstract] J Clin Oncol 24 (Suppl 18): A-4008, 180s, 2006.
5. Moertel CG, Frytak S, Hahn RG, et al.: Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48 (8): 1705-10, 1981.
6. van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al.: Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg 219 (1): 18-24, 1994.
7. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
8. 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.
9. Reni M, Panucci MG, Ferreri AJ, et al.: Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 50 (3): 651-8, 2001.

Stage IV Pancreatic Cancer

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.)

The low objective response rate and lack of survival benefit with current chemotherapy indicates clinical trials as appropriate treatment of all newly diagnosed patients. Occasional patients have palliation of symptoms when treated by chemotherapy with well-tested older drugs such as fluorouracil (5-FU). Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[1,2,3] A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (1-year survival was 18% with gemcitabine as compared with 2% with 5-FU, P = .003).[2][Level of evidence: 1iiA] A preliminary report, in abstract form, of a phase III trial (CAN-NCIC-PA3) comparing gemcitabine alone versus the combination of gemcitabine and erlotinib (100 mg/day) in patients with advanced or metastatic pancreatic carcinomas showed that erlotinib modestly prolonged survival when combined with gemcitabine alone.[4] Differences in overall survival (OS) favored the erlotinib arm (hazard ratio = 0.81; 95% confidence interval, 0.67–0.97; P = .025). The corresponding median and 1-year survival rates for patients receiving erlotinib versus placebo were 6.37 months and 5.91 months, and 24% versus 17%, respectively.[4][Level of evidence: 1iiA] When 5-FU was added to gemcitabine and compared with gemcitabine alone, the median survival of patients with advanced or metastatic disease (6.7 months vs. 5.7 months, respectively, P = .09) was not significantly improved.[5][Level of evidence: 1iiA]

Standard treatment options:

1.Chemotherapy with gemcitabine or gemcitabine and erlotinib.[1,6,7,8,9,10,11,12,13,14]
2. Pain-relieving procedures (e.g., celiac or intrapleural block) and supportive care.[15]
3.Palliative surgical biliary bypass, percutaneous radiologic biliary stent placement, or endoscopically placed biliary stents.[16,17,18]

Treatment options under clinical evaluation:

  • Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy.[6,7,8,9,10,11,13,19,20,21,22,23,24]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Rothenberg ML, Moore MJ, Cripps MC, et al.: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7 (4): 347-53, 1996.
2. Burris HA 3rd, 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 15 (6): 2403-13, 1997.
3. Storniolo AM, Enas NH, Brown CA, et al.: An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 85 (6): 1261-8, 1999.
4. Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. [Abstract] J Clin Oncol 23 (Suppl 16): A-1, 1s, 2005.
5. Berlin JD, Catalano P, Thomas JP, et al.: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 20 (15): 3270-5, 2002.
6. MacDonald JS, Widerlite L, Schein PS: Biology, diagnosis, and chemotherapeutic management of pancreatic malignancy. Adv Pharmacol Chemother 14: 107-42, 1977.
7. Bukowski RM, Balcerzak SP, O'Bryan RM, et al.: Randomized trial of 5-fluorouracil and mitomycin C with or without streptozotocin for advanced pancreatic cancer. A Southwest Oncology Group study. Cancer 52 (9): 1577-82, 1983.
8. DeCaprio JA, Mayer RJ, Gonin R, et al.: Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. J Clin Oncol 9 (12): 2128-33, 1991.
9. Kelsen D, Hudis C, Niedzwiecki D, et al.: A phase III comparison trial of streptozotocin, mitomycin, and 5-fluorouracil with cisplatin, cytosine arabinoside, and caffeine in patients with advanced pancreatic carcinoma. Cancer 68 (5): 965-9, 1991.
10. O'Connell MJ: Current status of chemotherapy for advanced pancreatic and gastric cancer. J Clin Oncol 3 (7): 1032-9, 1985.
11. Crown J, Casper ES, Botet J, et al.: Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. J Clin Oncol 9 (9): 1682-6, 1991.
12. Carmichael J, Fink U, Russell RC, et al.: Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 73 (1): 101-5, 1996.
13. Haller DG: Chemotherapy for advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 56 (4 Suppl): 16-23, 2003.
14. Kulke MH, Blaszkowsky LS, Ryan DP, et al.: Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 25 (30): 4787-92, 2007.
15. Polati E, Finco G, Gottin L, et al.: Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer. Br J Surg 85 (2): 199-201, 1998.
16. van den Bosch RP, van der Schelling GP, Klinkenbijl JH, et al.: Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg 219 (1): 18-24, 1994.
17. Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999.
18. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
19. Rougier P, Adenis A, Ducreux M, et al.: A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma. Eur J Cancer 36 (8): 1016-25, 2000.
20. Bramhall SR, Rosemurgy A, Brown PD, et al.: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19 (15): 3447-55, 2001.
21. Stathopoulos GP, Mavroudis D, Tsavaris N, et al.: Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: a phase II study of the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 12 (1): 101-3, 2001.
22. Feliu J, López Alvarez MP, Jaraiz MA, et al.: Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group. Cancer 89 (8): 1706-13, 2000.
23. Rocha Lima CM, Savarese D, Bruckner H, et al.: Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20 (5): 1182-91, 2002.
24. Smith D, Gallagher N: A phase II/III study comparing intravenous ZD9331 with gemcitabine in patients with pancreatic cancer. Eur J Cancer 39 (10): 1377-83, 2003.

Recurrent Pancreatic Cancer

Chemotherapy occasionally produces objective antitumor response, but the low percentage of significant responses and lack of survival advantage warrant use of therapies under evaluation.[1]

Standard treatment options:

1.Chemotherapy with fluorouracil [2] or gemcitabine.[3,4,5]
2.Palliative surgical bypass procedures, such as endoscopic or radiologically placed stents.[6,7]
3.Palliative radiation procedures.
4.Pain relief by celiac axis nerve or intrapleural block (percutaneous).[8]
5.Other palliative medical care alone.

Treatment options under clinical evaluation:

  • Clinical trials evaluating pharmacologic modulation of fluorinated pyrimidines, new anticancer agents, or biologicals (phase I and II).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Yeo CJ, Yeo TP, Hruban RH: Cancer of the pancreas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 945-82.
2. Cullinan SA, Moertel CG, Fleming TR, et al.: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253 (14): 2061-7, 1985.
3. Rothenberg ML, Moore MJ, Cripps MC, et al.: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7 (4): 347-53, 1996.
4. Burris HA 3rd, 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 15 (6): 2403-13, 1997.
5. Storniolo AM, Enas NH, Brown CA, et al.: An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 85 (6): 1261-8, 1999.
6. Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999.
7. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
8. Polati E, Finco G, Gottin L, et al.: Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer. Br J Surg 85 (2): 199-201, 1998.

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Changes to This Summary (08 / 13 / 2010)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage Information For Pancreatic Cancer

Editorial changes were made to this section.

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pancreatic cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pancreatic Cancer Treatment are:

  • David P. Ryan, MD (Massachusetts General Hospital)
  • Raymond C. Wadlow, MD (Virginia Cancer Specialists)

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Pancreatic Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/pancreatic/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2010-08-13

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