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

General Information About Pancreatic Cancer

This summary provides information about the treatment of exocrine pancreatic cancer. Other PDQ summaries containing information related to cancer in the pancreas include the following:

• Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment.
• Unusual Cancers of Childhood Treatment (pancreatic cancer during childhood).

Incidence and Mortality

Estimated new cases and deaths from pancreatic cancer in the United States in 2017:[1]

• New cases: 53,670.
• Deaths: 43,090.

The incidence of carcinoma of the pancreas has markedly increased over 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]

Risk Factors

Risk factors for development of pancreatic cancer include the following:[3,4]

• A family history of pancreatic cancer.
• Cigarette smoking.
• Obesity.
• Chronic pancreatitis.

Anatomy

Anatomy of the pancreas.

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.

Clinical Features

Pancreatic cancer symptoms depend on the site of the tumor within the pancreas and the degree of tumor involvement.

In the early stages of pancreatic cancer there are not many noticeable symptoms. As the cancer grows, symptoms may include the following:

• Jaundice.
• Light-colored stools or dark urine.
• Pain in the upper or middle abdomen and back.
• Weight loss for no known reason.
• Loss of appetite.
• Fatigue.

Diagnostic and Staging Evaluation

Pancreatic cancer is difficult to detect and diagnose for the following reasons:

• There are no noticeable signs or symptoms in the early stages of pancreatic cancer.
• The signs of pancreatic cancer, when present, are like the signs of many other illnesses, such as pancreatitis or an ulcer.
• The pancreas is obscured by other organs in the abdomen and is difficult to visualize clearly on imaging tests.

To appropriately treat pancreatic cancer, it is crucial to evaluate whether the cancer can be resected.

Imaging

The use of imaging technology may aid in the diagnosis of pancreatic cancer and in the identification of patients with disease that is not amenable to resection. Imaging tests that may be used include the following:[5]

• Helical computed tomographic scan.
• Magnetic resonance imaging scan.
• Endoscopic ultrasound.
• Minimally invasive techniques, such as laparoscopy and laparoscopic ultrasound may be used to decrease the use of laparotomy.[6,7]

Peritoneal cytology

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.[8]

Tumor markers

No tumor-specific markers exist for pancreatic cancer; markers such as serum cancer antigen (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.[9][Level of evidence: 3iDiii] The presence of a normal CA 19-9, however, does not preclude recurrence.

Prognosis and Survival

The primary factors that influence prognosis are:

• Whether the tumor is localized and can be completely resected.
• Whether the tumor has spread to lymph nodes or elsewhere.

Exocrine pancreatic cancer is rarely curable and has an overall survival (OS) rate of less than 6%.[10]

The highest cure rate occurs if the tumor is truly localized to the pancreas; however, this stage of disease accounts for less than 20% of cases. For 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 is associated with an actuarial 5-year survival rate of 18% to 24%.[11][Level of evidence: 3iA]

Surgical resection is the mainstay of curative treatment and provides a survival benefit in patients with small, localized pancreatic tumors. Patients with unresectable, metastatic, or recurrent disease are unlikely to benefit from surgical resection.

Pancreatic tumors are resistant to treatment with chemotherapy and radiation.

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.

Palliative Therapy

Palliation of symptoms may be achieved with conventional treatment.

Palliative measures that may improve quality of life while not affecting OS include the following:[12,13]

• Surgical or radiologic biliary decompression.
• Relief of gastric outlet obstruction.
• Pain control.
• Psychological care to address the potentially disabling psychological events associated with the diagnosis and treatment of pancreatic cancer.[14]

References:

1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online. Last accessed May 25, 2017.
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. Tersmette AC, Petersen GM, Offerhaus GJ, et al.: Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 7 (3): 738-44, 2001.
4. Nöthlings U, Wilkens LR, Murphy SP, et al.: Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst 97 (19): 1458-65, 2005.
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. 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.
7. 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.
8. 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.
9. 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.
10. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63 (1): 11-30, 2013.
11. 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.
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.
• Adenosquamous carcinoma.
• Cystadenocarcinoma (serous and mucinous types).
• Giant cell carcinoma.
• Invasive adenocarcinoma associated with cystic mucinous neoplasm or intraductal papillary mucinous neoplasm.
• Mixed type (ductal-endocrine or acinar-endocrine).
• Mucinous carcinoma.
• Pancreatoblastoma.
• Papillary-cystic neoplasm (Frantz tumor). This tumor has lower malignant potential and may be cured with surgery alone.[1,2]
• Papillary mucinous carcinoma.
• Signet ring carcinoma.
• Small cell carcinoma.
• Unclassified.
• Undifferentiated carcinoma.

Borderline Malignancies

• Intraductal papillary mucinous tumor with dysplasia.[3]
• Mucinous cystic tumor with dysplasia.
• 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 establishing whether a tumor is resectable is uncertain since state-of-the-art treatment has demonstrated little impact on survival. However, knowledge of the extent of the disease is necessary to communicate a uniform definition of disease.

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

Table 2. Definitions of TNM Stages IA and IB^a

Stage	TNM	Description	Illustration
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.
IA	T1, N0, M0	T1 = Tumor limited to the pancreas, ≤2 cm in greatest dimension.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.
IB	T2, N0, M0	T2 = Tumor limited to the pancreas, >2 cm in greatest dimension.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 3. Definitions of TNM Stage IIA^a

Stage	TNM	Description	Illustration
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.
IIA	T3, N0, M0	T3 = Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery.
		N0 = No regional lymph node metastasis.
		M0 = No distant metastasis.

Table 4. Definitions of TNM Stage IIB^a

Stage	TNM	Description	Illustration
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.
IIB	T1, N1, M0	T1 = Tumor limited to the pancreas, ≤2 cm in greatest dimension.
		N1 = Regional lymph node metastasis.
		M0 = No distant metastasis.
	T2, N1, M0	T2 = Tumor limited to the pancreas, >2 cm in greatest dimension.
		N1 = Regional lymph node metastasis.
		M0 = No distant metastasis.
	T3, N1, M0	T3 = Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery.
		N1 = Regional lymph node metastasis.
		M0 = No distant metastasis.

Table 5. Definitions of TNM Stage III^a

Stage	TNM	Description	Illustration
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.
III	T4, Any N, M0	T4 = Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor).
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastasis.
		N1 = Regional lymph node metastasis.
		M0 = No distant metastasis.

Table 6. Definitions of TNM Stage IV^a

Stage	TNM	Description	Illustration
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 pancreatic intraepithelial neoplasia (PanIN)-3 classification.
IV	Any T, Any N, M1	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).
		NX = Regional lymph nodes cannot be assessed.
		N0 = No regional lymph node metastasis.
		N1 = Regional lymph node metastasis.
		M1 = Distant metastasis.

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 for Pancreatic Cancer

Surgical resection remains the primary modality when feasible; on occasion, resection can lead to long-term survival and provides effective palliation.[1,2,3][Level of evidence: 3iA]

The role of postoperative therapy (chemotherapy with or without chemoradiation therapy) in the management of pancreatic cancer remains controversial because much of the randomized clinical trial data available are statistically underpowered and provide conflicting results.[4,5,6,7,8]

Complications of pancreatic cancer include the following:

• Malabsorption: 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.)
• Pain: 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 Cancer Pain 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 before palliative approaches are selected.

Information about ongoing clinical trials for pancreatic cancer is available from the NCI website.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.
6. 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.
7. 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.
8. 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 Stage II Pancreatic Cancer Treatment

Treatment Options for Stages I and II Pancreatic Cancer

Treatment options for stages I and II pancreatic cancer include the following:

1. Surgery: radical pancreatic resection including:
   • Whipple procedure (pancreaticoduodenal resection).
   • Total pancreatectomy when necessary for adequate margins.
   • Distal pancreatectomy for tumors of the body and tail of the pancreas.[1,2]
2. Postoperative chemoradiation therapy: radical pancreatic resection followed by 5-fluorouracil (5-FU) chemotherapy and radiation therapy.[3,4,5,6,7]
3. Postoperative chemotherapy: radical pancreatic resection followed by chemotherapy (gemcitabine or 5-FU/leucovorin).[8]

Surgery

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.[9,10,11][Level of evidence: 3iA]

Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 16%.[12,13,14,15,16] 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).[12]

Postoperative chemoradiation therapy

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.[3,4,5,6,7]

Evidence (postoperative chemoradiation therapy):

Several phase III trials examined the potential overall survival (OS) benefit of postoperative adjuvant 5-FU-based chemoradiation therapy:

1. Gastrointestinal Study Group (GITSG): A small randomized trial conducted by the GITSG in 1985 compared surgery alone with surgery followed by chemoradiation.[3][Level of evidence: 1iiA];[4][Level of evidence: 2A]
   • The investigators reported 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.
2. European Organization for the Research and Treatment of Cancer (EORTC): An attempt by the EORTC to reproduce the results of the GITSG trial failed to confirm a significant benefit for adjuvant chemoradiation therapy over resection alone;[5][Level of evidence: 1iiA] however, this trial treated patients with pancreatic and periampullary cancers (with a potentially better prognosis).
   • A subset analysis of the patients with primary pancreatic tumors indicated a trend toward improved median, 2-year, and 5-year OS with adjuvant therapy compared with surgery alone (17.1 months, 37%, and 20%, respectively, vs. 12.6 months, 23%, and 10%, respectively; P = .09 for median survival).
3. An updated analysis of a subsequent European Study for Pancreatic Cancer (ESPAC 1) trial examined only patients who underwent strict randomization after pancreatic resection. The patients were assigned to one of four groups (observation, bolus 5-FU chemotherapy, bolus 5-FU chemoradiation therapy, or chemoradiation therapy followed by additional chemotherapy).[6,7,17][Level of evidence: 1iiA]
   • 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. However, these results were difficult to interpret because of a high rate of protocol nonadherence and the lack of a separate analysis for each of the four groups in the 2 × 2 design.
4. U.S. Gastrointestinal Intergroup: The U.S. Gastrointestinal Intergroup has reported the results of a randomized phase III trial (Radiation Therapy Oncology Group (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.[18][Level of evidence: 1iiA] The primary endpoints were OS for all patients and OS for patients with pancreatic head tumors.
5. A 5-year update of RTOG-9704 reported that patients with pancreatic head tumors (n = 388) had a median survival and 5-year OS of 20.5 months and 22% survival rate with gemcitabine, versus 17.1 months and 18% with 5-FU (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.67-1.05; P = .12).[19]
   • Univariate analysis showed no difference in OS; however, on multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = .08). Distant relapse remained the predominant site of first failure (78%).
6. A secondary analysis of RTOG-9704 explored the correlation of adherence to protocol-specified radiation with patient outcomes.[20][Level of evidence: 1iiA]
   • Radiation therapy adherence was scored as per protocol (n = 216) and less than per protocol (n = 200). The major deviation seen was deviation in field size and field placement.
   • For all pancreatic sites, median survival for patients per protocol was significantly longer than patients treated less than per protocol (1.74 years vs. 1.46 years; P = .008).
   • On multivariate analysis, treatment per protocol correlated more strongly with median survival than assigned treatment arm (P = .014). However, this is an exploratory analysis that cannot control for potential unknown confounders.

The EORTC/U.S. Gastrointestinal Intergroup RTOG-0848 phase III adjuvant trial evaluating the impact of chemoradiation after completion of a full course of gemcitabine with or without erlotinib is currently enrolling patients.

Postoperative chemotherapy

Evidence (postoperative chemotherapy):

1. Charité Onkologie (CONKO)-001: 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 receive six cycles of adjuvant gemcitabine versus observation.[21][Level of evidence: 1iiDii] 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, 11.6-15.3) and 6.7 months in the observation arm (95% CI, 6.0-7.5; P < .001). In this initial publication of results, there was no significant difference in OS between the gemcitabine arm (median 22.1 months; 95% CI, 18.4-25.8) and the control arm (median 20.2 months; 95% CI, 17-23.4).
   • With a median follow-up of 136 months, long-term follow-up of the CONKO-001 study demonstrates a significant improvement in OS that favors gemcitabine (median survival 22.8 months vs. 20.2 months; HR, 0.76; 95% CI, 0.61-0.95, P = .01). Gemcitabine compared with observation alone yielded improved survival rates at 5 years of 20.7% for the gemcitabine arm versus 10.4% for the observation-alone arm and at 10 years the survival rates were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm.[22][Level of evidence: 1iiA]
2. ESPAC-3: 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 leucovorin (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.[8][Level of evidence: 1iiA]
   • Median OS was 23.0 months (95% CI, 21.1- 25.0) for patients treated with 5-FU plus leucovorin and 23.6 months (95% CI, 21.4-26.4) for those treated with gemcitabine (HR = 0.94; 95% CI, 0.81-1.08; P = .39).

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

Treatment Options Under Clinical Evaluation for Stages I and II Pancreatic Cancer

Treatment options under clinical evaluation include the following:

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 the list of NCI-supported 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 website.

References:

1. 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.
2. 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.
3. 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.
4. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Birkmeyer JD, Finlayson SR, Tosteson AN, et al.: Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery 125 (3): 250-6, 1999.
13. 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.
14. Spanknebel K, Conlon KC: Advances in the surgical management of pancreatic cancer. Cancer J 7 (4): 312-23, 2001 Jul-Aug.
15. 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.
16. 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.
17. Choti MA: Adjuvant therapy for pancreatic cancer--the debate continues. N Engl J Med 350 (12): 1249-51, 2004.
18. 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.
19. Regine WF, Winter KA, Abrams R, et al.: Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol 18 (5): 1319-26, 2011.
20. Abrams RA, Winter KA, Regine WF, et al.: Failure to adhere to protocol specified radiation therapy guidelines was associated with decreased survival in RTOG 9704--a phase III trial of adjuvant chemotherapy and chemoradiotherapy for patients with resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 82 (2): 809-16, 2012.
21. 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.
22. Oettle H, Neuhaus P, Hochhaus A, et al.: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310 (14): 1473-81, 2013.

Stage III Pancreatic Cancer Treatment

Treatment Options for Stage III Pancreatic Cancer

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.[1][Level of evidence: 1iiA] Therefore, investigators have struggled with the question of whether chemoradiation for patients presenting with stage III disease is warranted.

Treatment options for stage III pancreatic cancer include the following:

1. Palliative surgery: palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.[2,3]
2. Chemoradiation therapy:
   • Chemoradiation followed by chemotherapy.
   • Chemotherapy followed by chemoradiation, for patients without metastatic disease.
3. Chemotherapy: gemcitabine; gemcitabine and erlotinib; gemcitabine and nab-paclitaxel; or 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).

Palliative surgery

A significant proportion (approximately one-third) of patients with pancreatic cancer will present with stage III or locally advanced disease. 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.[4]

Chemoradiation therapy

The role of chemoradiation in locally advanced pancreatic cancer remains controversial. Table 8 summarizes phase III randomized studies of chemoradiation for stage III pancreatic cancer.

Evidence (chemoradiation therapy):

Three trials attempted to look at combined modality therapy versus radiation therapy alone.[5,6,7] The trials had substantial deficiencies in design or analysis. Initially, the standard of practice was to give chemoradiation therapy based on data from the first two studies; however, with the publication of the third study, standard practice has changed to chemotherapy followed by chemoradiation in the absence of metastases.

1. Gastrointestinal Tumor Study Group (GITSG)-9273 trial: Prior to 2000, several phase III trials evaluated combined modality therapy versus radiation therapy alone. Before 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 concurrent EBRT (either 40 Gy or 60 Gy) plus bolus 5-FU.[5][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 therapy with 40 Gy and 36% for patients who received chemoradiation therapy 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 with the 40 Gy arm.[9]
2. Eastern Cooperative Oncology Group (ECOG) E-8282 trial: Investigators from the ECOG randomly assigned 114 patients to receive radiation therapy (59.4 Gy) alone or with concurrent infusional 5-FU (1,000 mg/m² daily on days 2-5 and 28-31) plus mitomycin (10 mg/m² on day 2).[6]
   • The trial reported no difference in OS between the two groups.
3. Fédération Francophone de Cancérologie Digestive-Société Française de Radiothérapie Oncologie (FFCD-SFRO) trial: 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 1-5 for 6 weeks and 20 mg/m² /day of cisplatin on days 1-5 during weeks 1 and 5) or induction gemcitabine (1,000 mg/m² weekly for 7 weeks). Maintenance gemcitabine was administered to both groups until stopped by disease progression or treatment discontinuation as a result of toxicity.[10][Level of evidence: 1iiA]
   • 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 therapy 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 therapy arm because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).
   • As a result of this study, induction chemoradiation therapy has fallen out of favor.
4. ECOG: The results of the FFCD-SFRO study stand in contrast to the results of a study from ECOG in which investigators randomly assigned 74 patients to either gemcitabine alone or gemcitabine with radiation followed by gemcitabine.[8] Of note, the study was closed early as the result of poor accrual.
   • The primary endpoint was survival, which was 9.2 months (95% confidence interval [CI], 7.9-11.4 months) and 11.1 months (95% CI, 7.6-15.5 months) for chemotherapy and combined modality therapy, respectively (one-sided P = .017 by stratified log-rank test).
   • Grades 4 and 5 toxicity were greater in the chemoradiation therapy arm than in the chemotherapy arm (41% vs. 9%).
5. Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR): Given the increased toxicity of chemoradiation therapy 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 therapy. With this strategy, the selected patients have an absence of progressive disease locally or systemically after several months of chemotherapy.[11][Level of evidence: 3iiiA]
   • A retrospective analysis of 181 patients enrolled in prospective phase II and III GERCOR studies revealed that 29% had metastatic disease after 3 months of gemcitabine-based chemotherapy.
   • For the remaining 71%, median OS was significantly longer among patients treated with chemoradiation therapy than among patients treated with additional chemotherapy (15.0 months vs. 11.7 months; P = .0009).

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

Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers. Although gemcitabine has long been considered the standard regimen, newer chemotherapy regimens have recently emerged.

Evidence: (chemotherapy):

1. Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[12,13,14] 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 compared with 2% with 5-FU; P = .003).[13][Level of evidence: 1iiA]
2. Gemcitabine alone versus gemcitabine and erlotinib: 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.[15][Level of evidence: 1iiA]
   • The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (hazard ratio [HR] = 0.81; 95% CI, 0.69-0.99; P = .038).
   • 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.
3. Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[16,17]
   • 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.
4. Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[18][Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m² of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
   • The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HR_death, 0.72; 95% CI, 0.62-0.83; P < .001).
   • Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HR_{disease progression}, 0.69; 95% CI, 0.58-0.82; P < .001).
   • Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel/gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel/gemcitabine group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
   • On the basis of this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
   • Quality of life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
5. FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an ECOG performance status score of 0 or 1.[19][Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m²], irinotecan [180 mg/m²], leucovorin [400 mg/m²], and 5-FU [400 mg/m²] given as a bolus followed by 2,400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 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_death = 0.57; 95% CI, 0.45-0.73; P < .001).
   • 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, 0.37-0.59; 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 quality of life, versus 66% in the gemcitabine group (HR = 0.47; 95% CI, 0.30-0.70; P < .001).
   • On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
6. 5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): 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 the OFF regimen or BSC.[20]; [21][Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m²) followed by 5-FU (2,000 mg/m²[24-hour continuous infusion] 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 survival on second-line chemotherapy was 4.82 months (95% CI, 4.29-5.35) with the OFF treatment regimen and 2.30 months (95% CI, 1.76-2.83) with BSC alone (HR = 0.45; 95% CI, 0.24-0.83).
   • Median OS was 9.09 months for the sequence of gemcitabine (GEM)-OFF and 7.90 months for 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 falsely associated with improved survival.

Treatment Options Under Clinical Evaluation for Stage III Pancreatic Cancer

Treatment options under clinical evaluation include the following:

1. For patients with 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.[22,23]

Current Clinical Trials

Check the list of NCI-supported 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 website.

References:

1. Iacobuzio-Donahue CA, Fu B, Yachida S, et al.: DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27 (11): 1806-13, 2009.
2. 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.
3. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
4. 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.
5. 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.
6. 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.
7. 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.
8. Loehrer PJ Sr, Feng Y, Cardenes H, et al.: Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 29 (31): 4105-12, 2011.
9. 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.
10. Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 19 (9): 1592-9, 2008.
11. Huguet F, André T, Hammel P, et al.: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25 (3): 326-31, 2007.
12. 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.
13. 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.
14. 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.
15. Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25 (15): 1960-6, 2007.
16. Poplin E, Feng Y, Berlin J, et al.: Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27 (23): 3778-85, 2009.
17. Colucci G, Labianca R, Di Costanzo F, et al.: Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28 (10): 1645-51, 2010.
18. Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18): 1691-703, 2013.
19. Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011.
20. Pelzer U, Kubica K, Stieler J, et al.: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. [Abstract] J Clin Oncol 26 (Suppl 15): A-4508, 2008.
21. Pelzer U, Schwaner I, Stieler J, et al.: Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47 (11): 1676-81, 2011.
22. 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.
23. 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 Treatment

Treatment Options for Stage IV Pancreatic Cancer

Treatment options for stage IV pancreatic cancer include the following:

1. Palliative therapy.
2. Chemotherapy: gemcitabine; gemcitabine and erlotinib; or oxaliplatin, irinotecan, leucovorin, and fluorouracil (5-FU) (FOLFIRINOX).[1,2,3,4,5,6,7,8,9,10]

Palliative therapy

Palliative therapy for advanced pancreatic cancer includes the following:

1. Pain-relieving procedures (e.g., celiac or intrapleural block) and supportive care.[11]
2. Palliative surgical biliary bypass, percutaneous radiologic biliary stent placement, or endoscopically placed biliary stents.[12,13,14]

Chemotherapy

The low objective response rate and lack of survival benefit with current chemotherapy indicates that clinical trials are appropriate treatment of all newly diagnosed patients. Occasionally, patients have palliation of symptoms when treated with chemotherapy with well-tested older drugs, such as 5-FU. Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[1,15,16]

Evidence (chemotherapy):

1. Gemcitabine versus 5-FU: 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 compared with 2% with 5-FU; P = .003).[15][Level of evidence: 1iiA]
2. Gemcitabine alone versus gemcitabine and erlotinib: 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.[17][Level of evidence: 1iiA]
   • The addition of erlotinib modestly prolonged survival when combined with gemcitabine alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI]; P = .038).
   • The corresponding median survival rate for patients receiving erlotinib was 6.2 months, versus 5.9 months for patients receiving placebo. The 1-year survival rate for patients receiving erlotinib was 23%, versus 17% for patients receiving placebo.
3. Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[18,19]
   • 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.
4. Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[20][Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1,000 mg/m²) and nab-paclitaxel (125 mg/m² of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1,000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
   • The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HR_death, 0.72; 95% CI, 0.62-0.83; P < .001).
   • Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HR_{disease progression}, 0.69; 95% CI, 0.58-0.82, P < .001).
   • Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
   • On the basis of this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
   • Quality of life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel-gemcitabine versus FOLFIRINOX.
5. FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group performance status score of 0 or 1.[21][Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m²], irinotecan [180 mg/m²], leucovorin [400 mg/m²], and 5-FU [400 mg/m²] given as a bolus followed by 2,400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
   • The median overall survival (OS) was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HR_death = 0.57; 95% CI, 0.45-0.73; P < .001).
   • 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, 0.37-0.59; 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 quality of life, versus 66% in the gemcitabine group (HR = 0.47; 95% CI, 0.30-0.70; P < .001).
   • On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
6. 5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): 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 an OFF regimen or BSC.[22]; [23][Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m²) followed by 5-FU (2,000 mg/m²[24 hours continuous infusion] 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 survival on second-line chemotherapy was 4.82 months (95% CI, 4.29-5.35) for the OFF-regimen treatment and 2.30 months (95% CI, 1.76-2.83) with BSC alone (HR = 0.45; 95% CI, 0.24-0.83).
   • Median OS was 9.09 months for the sequence of gemcitabine (GEM)-OFF and 7.90 months for 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 erroneously associated with improved survival.

Treatment Options Under Clinical Evaluation for Stage IV Pancreatic Cancer

Treatment options under clinical evaluation include the following:

1. Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy.[2,3,4,5,6,7,9,24,25,26,27,28,29]

Current Clinical Trials

Check the list of NCI-supported 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 website.

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. MacDonald JS, Widerlite L, Schein PS: Biology, diagnosis, and chemotherapeutic management of pancreatic malignancy. Adv Pharmacol Chemother 14: 107-42, 1977.
3. 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.
4. 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.
5. 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.
6. O'Connell MJ: Current status of chemotherapy for advanced pancreatic and gastric cancer. J Clin Oncol 3 (7): 1032-9, 1985.
7. 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.
8. 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.
9. Haller DG: Chemotherapy for advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 56 (4 Suppl): 16-23, 2003.
10. 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.
11. 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.
12. 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.
13. 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.
14. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
15. 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.
16. 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.
17. Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25 (15): 1960-6, 2007.
18. Poplin E, Feng Y, Berlin J, et al.: Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27 (23): 3778-85, 2009.
19. Colucci G, Labianca R, Di Costanzo F, et al.: Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28 (10): 1645-51, 2010.
20. Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18): 1691-703, 2013.
21. Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011.
22. Pelzer U, Kubica K, Stieler J, et al.: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. [Abstract] J Clin Oncol 26 (Suppl 15): A-4508, 2008.
23. Pelzer U, Schwaner I, Stieler J, et al.: Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47 (11): 1676-81, 2011.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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 Treatment

Treatment Options for Recurrent Pancreatic Cancer

Treatment options for recurrent pancreatic cancer include the following:

1. Palliative therapy.
2. Chemotherapy: fluorouracil [1] or gemcitabine.[2,3,4]

Palliative therapy

Palliative therapy for recurrent pancreatic cancer includes the following:

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

Chemotherapy

Chemotherapy occasionally produces objective antitumor response, but the low percentage of significant responses and lack of survival advantage warrant use of therapies under evaluation.[8]

Treatment Options Under Clinical Evaluation for Recurrent Pancreatic Cancer

Treatment options under clinical evaluation include the following:

1. Phase I and II clinical trials evaluating pharmacologic modulation of fluorinated pyrimidines, new anticancer agents, or biological agents.

Current Clinical Trials

Check the list of NCI-supported 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 website.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001.
7. 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.
8. Royal RE, Wolfe RA, Crane CH: Cancer of the pancreas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 961-89.

Changes to This Summary (01 / 26 / 2017)

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.

General Information About Pancreatic Cancer

Updated statistics with estimated new cases and deaths for 2017 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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 reviewer for Pancreatic Cancer Treatment is:

• Jennifer Wo, MD (Massachusetts General Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Pancreatic Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389394]

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Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2017-01-26