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NCI/PDQ^® Health professionals: Pancreatic Cancer Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 17 de julio del 2012

TABLE OF CONTENTS

• General Information About Pancreatic Cancer
  • Incidence and Mortality
  • Related Summary

• Cellular Classification of Pancreatic Cancer

• Stage Information for Pancreatic Cancer
  • Definitions of TNM

• Treatment Option Overview

• Stage I and II Pancreatic Cancer
  • Current Clinical Trials

• Stage III Pancreatic Cancer
  • Current Clinical Trials

• Stage IV Pancreatic Cancer
  • Current Clinical Trials

• Recurrent Pancreatic Cancer
  • Current Clinical Trials

• Changes to This Summary (07/17/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Pancreatic Cancer

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Incidence and Mortality

Estimated new cases and deaths from pancreatic cancer in the United States in 2012: 1

• New cases: 43,920.
• Deaths: 37,390.

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.

Related Summary

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

• Unusual Cancers of Childhood (pancreatic cancer in children)

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
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. [PUBMED Abstract]
3. Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. CA Cancer J Clin 50 (1): 7-33, 2000 Jan-Feb. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
7. Lillemoe KD: Current management of pancreatic carcinoma. Ann Surg 221 (2): 133-48, 1995. [PUBMED Abstract]
8. Yeo CJ: Pancreatic cancer: 1998 update. J Am Coll Surg 187 (4): 429-42, 1998. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
14. Passik SD, Breitbart WS: Depression in patients with pancreatic carcinoma. Diagnostic and treatment issues. Cancer 78 (3 Suppl): 615-26, 1996. [PUBMED Abstract]

Cellular Classification of Pancreatic Cancer

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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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

Stage Information for Pancreatic Cancer

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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

^aReprinted 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.^bThis 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

^aReprinted 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

^aReprinted 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 Groups^a

^aReprinted 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. [PUBMED Abstract]

Treatment Option Overview

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

Stage I and II Pancreatic Cancer

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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 prior to 2000 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 í 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 í 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 [HR], 0.82; 95% confidence interval [CI], 0.651.03). 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, 11.415.3) and 6.9 months in the observation group (95% CI, 6.17.8; P < .001). However, there was no significant difference in OS between the gemcitabine arm (median 22.1 months, 95% CI, 18.425.8) and the control group (median 20.2 months, 95% CI, 1723.4). 16[Level of evidence: 1iiDii] At the American Society of Clinical Oncology annual meeting in 2008, the investigators, with longer follow-up, reported a significant improvement in OS that favored gemcitabine (median survival 22.8 months vs. 20.2 months, P = .005; 5-year survival 21% vs. 9%). 17

The ESPAC-3 (NCT00058201) trial randomly assigned 1,088 patients who had undergone complete macroscopic resection to either 6 months of 5-FU (425 mg/m²) and folinic acid (20 mg/m²) on days 1 to 5 every 28 days or 6 months of gemcitabine (1,000 mg/m²) on days 1, 8, and 15 every 28 days. 18 Median OS was 23.0 months (95% CI, 21.1 25.0) for patients treated with 5-FU plus folinic acid and 23.6 months (95% CI, 21.426.4) for those treated with gemcitabine (HR, 0.94, 95% CI, 0.811.08, P = .39). 18[Level of evidence: 1iiA]

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. 19 20

2. Radical pancreatic resection with postoperative chemotherapy (gemcitabine or 5-FU/folinic acid). 18
3. Radical pancreatic resection with postoperative 5-FU chemotherapy and radiation therapy. 9 10 11 12 13

Treatment options under clinical evaluation:

1. Gemcitabine and capecitabine (ESPAC-4).
2. Gemcitabine and erlotinib (CONKO-005).
3. Gemcitabine and erlotinib with or without 5-FU/capecitabine-based chemoradiation (RTOG-0848).
4. Preoperative chemotherapy and/or radiation therapy.

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. [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. 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. [PUBMED Abstract]
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. [PUBMED Abstract]
17. Neuhaus P, Riess H, Post S, et al.: CONKO-001: final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC). [Abstract] J Clin Oncol 26 (Suppl 15): A-LBA4504, 2008. [PUBMED Abstract]
18. Neoptolemos JP, Stocken DD, Bassi C, et al.: Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304 (10): 1073-81, 2010. [PUBMED Abstract]
19. 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]
20. 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]

Stage III Pancreatic Cancer

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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 A significant proportion of patients approaching one-third of all patients with pancreatic cancer will present with stage III or locally advanced disease. While stage III and stage IV pancreatic cancer are both incurable, the natural history of stage III (locally advanced) disease may be different than it is for stage IV disease. An autopsy series demonstrated that 30% of patients presenting with stage III disease died without evidence of distant metastases. 2[Level of evidence: 1iiA] Therefore, investigators have struggled with the question of whether chemoradiation for patients presenting with stage III disease is worthwhile.

Table 5. Randomized Studies in Stage III Pancreatic Cancer: Median Survival

P value = probability value; XRT = x-ray or radiation therapy.

Trial	Regimen	Chemoradiation	Radiation Alone	Chemotherapy Alone	P Value
Pre-2000
GITSG	Radiation alone vs. 5-FU/60 Gy XRT	40 weeks	20 weeks		<.01
ECOG	Radiation vs. 5-FU, mitomycin C/59 Gy XRT	8.4 months	7.1 months		.16
Post-2000
FFCD	GEM vs. GEM, cisplatin, 60 Gy XRT	8.6 months		13 months	.03
ECOG	GEM vs. GEM/50.4 Gy XRT	11.1 months		9.2 months	.017
5 FU = 5-fluorouracil; ECOG = Eastern Cooperative Oncology Group; FFCD = Fédération Francophone de Cancérologie Digestive; GEM = gemcitabine; GITSG = Gastrointestinal Tumor Study Group; Gy = gray (unit of absorbed radiation of ionizing radiation);

Prior to 2000, several phase III trials evaluated combined modality therapy versus radiation therapy alone. 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). 3[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. 7 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. 4

As it became clear that radiation therapy alone was an inadequate treatment, investigators evaluated combined modality approaches versus chemotherapy alone. Investigators from the FFCD-SFRO randomly assigned 119 patients to induction chemoradiation therapy (60 Gy in 2 Gy fractions with 300 mg/m²/day of continuous infusion 5-FU on days 1 through 5 for 6 weeks and 20 mg/m²/day of cisplatin on days 1 through 5 during weeks 1 and 5) or induction gemcitabine (1,000 mg/m² weekly for 7 weeks). 8[Level of evidence: 1iiA] Maintenance gemcitabine was administered to both groups until stopped by disease progression or treatment discontinuation as a result of toxicity. Median survival was superior in the gemcitabine arm (13 vs. 8.6 months, P = .03).

Nonhematological grade 3 to 4 toxicities (primarily gastrointestinal) were significantly more common in the chemoradiation arm (44% vs. 18%, P = .004), and fewer patients completed at least 75% of induction therapy (42% vs. 73%). Nonetheless, the survival benefit persisted in a per-protocol analysis of patients receiving at least 75% of planned therapy. Notably, the dose intensity of maintenance gemcitabine was significantly less in the chemoradiation arm because of a greater incidence of grade 3 to 4 hematological toxicities (71% vs. 27%, P = .0001). As a result of this study, induction chemoradiation has fallen out of favor.

The results of the FFCD study stand in contrast to the results of a study from ECOG where investigators randomly assigned 74 patients to either gemcitabine alone or gemcitabine with radiation followed by gemcitabine. 6 Of note, the study was closed early as the result of poor accrual. The primary endpoint was survival, which was 9.2 months (95% CI, 7.911.4 months) and 11.1 months (95% CI, 7.615.5 months) for chemotherapy and combined modality therapy, respectively (one-sided P = .017 by stratied log-rank test). Grade 4 and 5 toxicity was greater in the chemoradiation arm than in the chemotherapy arm (41% vs. 9%).

Given the increased toxicity of chemoradiation and the early development of metastatic disease in a large percentage of patients with stage III pancreatic cancer, investigators are pursuing a strategy of selecting patients with localized disease for chemoradiation. With this strategy, the selected patients have an absence of progressive disease locally or systemically after several months of chemotherapy. A retrospective analysis of 181 patients enrolled in prospective phase II and III GERCOR studies revealed that 29% had metastatic disease after three months of gemcitabine-based chemotherapy. For the remaining 71%, median OS was significantly longer among patients treated with chemoradiation compared to additional chemotherapy (15.0 months vs. 11.7 months, P = .0009). 9[Level of evidence: 3iiiA] Taken together, the FFCD and GERCOR studies provide support for gemcitabine-based chemotherapy for at least 3 months, followed by chemoradiation in the absence of metastatic disease. This approach has yet to be validated in a prospective phase III trial.

Chemotherapy options:

Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent. 10 11 12 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). 11[Level of evidence: 1iiA]

The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone versus the combination of gemcitabine and erlotinib (100 mg/day) in patients with advanced or metastatic pancreatic carcinomas. They showed that the addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (hazard ratio [HR], 0.81; 95% CI, P = .038). 13 The corresponding median and 1-year survival rates for patients who received erlotinib versus placebo were 6.2 months and 5.9 months, and 23% versus 17%, respectively. 13[Level of evidence: 1iiA]

Many phase III studies have evaluated a combination regimen with either a platinum analogue (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine. 14 15 Not one of these phase III trials has demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.

A multicenter phase IIIII trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1. 16 The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m²], irinotecan [180 mg/m²], leucovorin [400 mg/m²], and fluorouracil [400 mg/m²] given as a bolus followed by 2400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks). The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HR for death, 0.57; 95% CI, 0.450.73; P < .001). 16[Level of evidence: 1iiA] Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression, 0.47; 95% CI, 0.370.59; P < .001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P < .001). FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (HR, 0.47; 95% CI, 0.300.70; P < .001). Therefore, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.

Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The CONKO-003 investigators randomly assigned patients in the second line of chemotherapy to either a regimen of 5-FU, leucovorin, and oxaliplatin (OFF regimen) or best supportive care (BSC). 17 18 The OFF regimen consisted of folinic acid (200 mg/m²) followed by 5-FU (2 g/m² [24 hours] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m² on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC. Median second-line survival was 4.82 months (95% CI, 4.295.35) for the OFF-regimen treatment and 2.30 months (95% CI; 1.762.83) with BSC alone (HR, 0.45; 95% CI, 0.240.83). 18[Level of evidence: 3iA] Median OS was 9.09 months for the sequence of gemcitabine/5-FU, leucovorin, and oxaliplatin or GEM-OFF and 7.90 months for gemcitabine/best supportive care or GEM-BSC. The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be associated with improved survival.

Standard treatment options:

1. Palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement. 19 20
2. Chemotherapy with gemcitabine, gemcitabine and erlotinib, or FOLFIRINOX.
3. Chemoradiation followed by chemotherapy.
4. Chemotherapy followed by chemoradiation for patients without metastatic disease.

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. 21 22

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:

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3. 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. [PUBMED Abstract]
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