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医療専門家向け Pancreatic Cancer Treatment (Adult) (PDQ®)

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult 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.

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).

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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:

Incidence and Mortality

Estimated new cases and deaths from pancreatic cancer in the United States in 2020:[ 1 ]

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 ]

Anatomy

Pancreas

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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:

Diagnostic and Staging Evaluation

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

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 ]

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:

Exocrine pancreatic cancer is rarely curable and has an overall survival (OS) rate of less than 6%.[ 10 ] As pancreatic cancer is associated with significant morbidity and mortality, and treatment decisions are complex, management with a comprehensive multidisciplinary team should be considered.

The highest cure rate occurs when 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, but should be considered only alongside systemic therapy. Patients with unresectable, metastatic, or recurrent disease are unlikely to benefit from surgical resection.

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 (systematic chemotherapy).

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

参考文献
  1. American Cancer Society: Cancer Facts and Figures 2020. Atlanta, Ga: American Cancer Society, 2020. Available online. Last accessed May 12, 2020.[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. 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.[PUBMED Abstract]
  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.[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. 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]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  10. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63 (1): 11-30, 2013.[PUBMED Abstract]
  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.[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

Pancreatic cancer includes the following carcinomas:

参考文献
  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

The staging system for pancreatic exocrine cancer continues to evolve. Clinical staging is guided by resectability, which is strongly influenced by surgical judgment. Consensus guidelines for surgical resectability (e.g., National Comprehensive Cancer Network, MD Anderson Cancer Center, American Hepato-Pancreato-Biliary Association, and International Hepato-Pancreato-Biliary Association) continue to be refined, but are traditionally stratified by the following:

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

AJCC Stage Groupings and TNM Definitions

Table 1. Definitions for Exocrine Pancreas TNM Stage 0a
Stage TNM Description Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
0 Tis, N0, M0 Tis = Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.  
Stage 0 pancreatic cancer; drawing shows abnormal cells in the pancreas.

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N0 = No regional lymph node metastases.
M0 = No distant metastasis.
Table 2. Definitions for Exocrine Pancreas TNM Stages IA and IBa
Stage TNM Description Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
IA T1, N0, M0 T1 = Tumor ≤2 cm in greatest dimension.  
Stage I pancreatic cancer; drawing on the left shows stage IA pancreatic cancer. The cancer is in the pancreas and the tumor is 2 centimeters or smaller. An inset shows 2 centimeters is about the size of a peanut. The drawing on the right shows stage IB pancreatic cancer. The cancer is in the pancreas and the tumor is larger than 2 centimeters but not larger than 4 centimeters. An inset shows 2 centimeters is about the size of a peanut and 4 centimeters is about the size of a walnut.

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–T1a = Tumor ≤0.5 cm in greatest dimension.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
IB T2, N0, M0 T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N0 = No regional lymph node metastases.
M0 = No distant metastasis.
Table 3. Definitions for Exocrine Pancreas TNM Stages IIA and IIBa
Stage TNM Description Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
IIA T3, N0, M0 T3 = Tumor >4 cm in greatest dimension.  
Stage IIA pancreatic cancer; drawing shows cancer in the pancreas and the tumor is larger than 4 centimeters. An inset shows 4 centimeters is about the size of a walnut.

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N0 = No regional lymph node metastases.
M0 = No distant metastasis.
IIB T1, N1, M0 T1 = Tumor ≤2 cm in greatest dimension.  
Stage IIB pancreatic cancer; drawing shows cancer in the pancreas and in 1 to 3 nearby lymph nodes.

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–T1a = Tumor ≤0.5 cm in greatest dimension.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T2, N1, M0 T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T3, N1, M0 T3 = Tumor >4 cm in greatest dimension.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
Table 4. Definitions for Exocrine Pancreas TNM Stage IIIa
Stage TNM Description Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
III T1, N2, M0 T1 = Tumor ≤2 cm in greatest dimension.  
Stage III pancreatic cancer; drawing shows cancer in the pancreas and in (a) 4 or more nearby lymph nodes and (b) the common hepatic artery. Also shown are the portal vein, celiac axis (trunk), and superior mesenteric artery.

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–T1a = Tumor ≤0.5 cm in greatest dimension.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T2, N2, M0 T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T3, N2, M0 T3 = Tumor >4 cm in greatest dimension.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T4, Any N, M0 T4 = Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastasis in one to three regional lymph nodes.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
Table 5. Definitions for Exocrine Pancreas TNM Stage IVa
Stage TNM Description Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.
IV Any T, Any N, M1 TX = Primary tumor cannot be assessed.  
Stage IV pancreatic cancer; drawing shows other parts of the body where pancreatic cancer may spread, including the lung, liver, and peritoneal cavity. An inset shows cancer cells spreading from the pancreas, through the blood and lymph system, to another part of the body where metastatic cancer has formed.

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T0 = No evidence of primary tumor.
Tis = Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.
T1 = Tumor ≤2 cm in greatest dimension.
–T1a = Tumor ≤0.5 cm in greatest dimension.
–T1b = Tumor >0.5 cm and <1 cm in greatest dimension.
–T1c = Tumor 1–2 cm in greatest dimension.
T2 = Tumor >2 cm and ≤4 cm in greatest dimension.
T3 = Tumor >4 cm in greatest dimension.
T4 = Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastases.
N1 = Metastasis in one to three regional lymph nodes.
N2 = Metastasis in four or more regional lymph nodes.
M1 = Distant metastasis.
参考文献
  1. Kakar S, Pawlik TM, Allen PJ: Exocrine Pancreas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 337–47.[PUBMED Abstract]
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] Treatment is often guided by resectability, but this may vary depending on surgical judgment and experience. Referral to a high-volume center should be considered.[ 4 ]

The addition of postoperative chemotherapy improves overall survival, but the role of chemoradiation remains controversial.

Complications of pancreatic cancer include the following:

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.

Table 6. Treatment Options for Pancreatic Cancer
Treatment Options
Resectable or borderline resectable pancreatic cancer Neoadjuvant therapy
Surgery
Postoperative chemotherapy
Postoperative chemoradiation therapy
Locally advanced pancreatic cancer Chemotherapy with or without targeted therapy
Chemoradiation therapy
Surgery
Palliative surgery
Metastatic or recurrent pancreatic cancer Chemotherapy with or without targeted therapy

Palliative therapies can be considered in patients with any stage of disease. Refer to the Palliative Therapy section of this summary for more information.

参考文献
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  4. Lidsky ME, Sun Z, Nussbaum DP, et al.: Going the Extra Mile: Improved Survival for Pancreatic Cancer Patients Traveling to High-volume Centers. Ann Surg 266 (2): 333-338, 2017.[PUBMED Abstract]
Resectable or Borderline Resectable Pancreatic Cancer Treatment

Treatment Options for Resectable or Borderline Resectable Pancreatic Cancer

Treatment options for resectable or borderline resectable pancreatic cancer include the following:

  1. Neoadjuvant therapy: chemotherapy with or without radiation therapy before radical pancreatic resection.
  2. Surgery: radical pancreatic resection including:
  3. Postoperative chemotherapy: radical pancreatic resection followed by chemotherapy.[ 3 ]
  4. Postoperative chemoradiation therapy: radical pancreatic resection followed by fluorouracil (5-FU) chemotherapy and radiation therapy.[ 4 ][ 5 ][ 6 ][ 7 ][ 8 ]

Palliative therapies can be considered in patients with any stage of disease. Refer to the Palliative Therapy section of this summary for more information.

Neoadjuvant therapy

Neoadjuvant therapy is chemotherapy with or without chemoradiation therapy given before surgery. The role of neoadjuvant therapy has been evaluated in retrospective studies (Surveillance, Epidemiology, and End Results [SEER] database and National Cancer Database) and is recommended by multiple consensus guidelines for the management of patients with borderline resectable pancreatic cancer. It is being evaluated in resectable pancreatic cancer, however, large randomized clinical trials have not yet been completed.[ 9 ][ 10 ][ 11 ]

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. Thus, systemic therapy is also recommended for treatment.[ 12 ][ 13 ][ 14 ][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%.[ 15 ][ 16 ][ 17 ][ 18 ][ 19 ] 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).[ 15 ]

Postoperative chemotherapy

Historically, multiple randomized trials have established that adjuvant gemcitabine monotherapy [ 20 ] or adjuvant 5-FU monotherapy [ 3 ] improve overall survival (OS) for 6 months after surgical resection compared with surgery alone. More recent studies have looked at newer combination regimens that might further improve outcomes after surgical resection.

For patients with good performance status, adjuvant FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-FU) chemotherapy or the combination of gemcitabine and capecitabine should be considered. However, for older patients or patients with marginal performance status, adjuvant gemcitabine or 5-FU monotherapy can be considered. In Asia, S-1 (tegafur, gimeracil, and oteracil potassium) is an appropriate alternative to gemcitabine-based therapies.

Evidence (postoperative chemotherapy):

  1. FOLFIRINOX: The PRODIGE-24 trial (NCT01526135) was a randomized, open-label, phase III trial in which 493 patients with R0/R1 resections were randomly assigned 1:1 to receive six cycles of gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) or 12 cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and 5-FU 2,400 mg/m2 over 46 hours every 2 weeks).[ 21 ][Level of evidence: 1iiA]
  2. Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 [NCT00058201]) trial randomly assigned 732 patients with resected pancreatic cancer to receive either six cycles of gemcitabine alone (1,000 mg/m2 administered weekly for 3 weeks of every 4 weeks) or oral capecitabine (1,660 mg/m2 administered for 21 days followed by 7 days of rest [one cycle]).[ 22 ][Level of evidence: 1iiA]
  3. S-1: The Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01) study was a phase III, multicenter, noninferiority trial conducted in Japan that randomly assigned 385 patients to receive either gemcitabine (1,000 mg/m2 administered weekly for 3 weeks of every 4 weeks) for six cycles or S-1 (tegafur, gimeracil, and oteracil potassium) (administered orally twice a day for 4 weeks then followed by a 2-week break).[ 23 ][Level of evidence: 1iiA]
  4. Gemcitabine: Charité Onkologie (CONKO)-001 was 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.[ 20 ][Level of evidence: 1iiDii] In contrast to the previous trials, the primary endpoint was DFS.
  5. Gemcitabine or 5-FU: 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.[ 3 ][Level of evidence: 1iiA]

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.[ 4 ][ 5 ][ 6 ][ 7 ][ 8 ]

Evidence (postoperative chemoradiation therapy):

Several phase III trials examined the potential 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.[ 4 ][Level of evidence: 1iiA];[ 5 ][Level of evidence: 2A]
  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;[ 6 ][Level of evidence: 1iiA] however, this trial treated patients with pancreatic and periampullary cancers (with a potentially better prognosis).
  3. An updated analysis of a subsequent 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).[ 7 ][ 8 ][ 25 ][Level of evidence: 1iiA]
  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.[ 26 ][Level of evidence: 1iiA] The primary endpoints were OS for all patients and OS for patients with pancreatic head tumors.

The EORTC/U.S. Gastrointestinal Intergroup RTOG-0848 phase III adjuvant trial evaluating the impact of chemoradiation therapy after completion of a full course of gemcitabine with or without erlotinib has closed and results are pending.

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

Treatment Options Under Clinical Evaluation for Resectable or Borderline Resectable Pancreatic Cancer

Treatment options under clinical evaluation include the following:

  1. Preoperative chemotherapy and/or radiation therapy.
  2. Alternative radiation techniques.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  3. 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]
  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.[PUBMED Abstract]
  5. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120 (8): 899-903, 1985.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  9. Stessin AM, Meyer JE, Sherr DL: Neoadjuvant radiation is associated with improved survival in patients with resectable pancreatic cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry. Int J Radiat Oncol Biol Phys 72 (4): 1128-33, 2008.[PUBMED Abstract]
  10. Versteijne E, Vogel JA, Besselink MG, et al.: Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 105 (8): 946-958, 2018.[PUBMED Abstract]
  11. Mokdad AA, Minter RM, Zhu H, et al.: Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis. J Clin Oncol 35 (5): 515-522, 2017.[PUBMED Abstract]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. Spanknebel K, Conlon KC: Advances in the surgical management of pancreatic cancer. Cancer J 7 (4): 312-23, 2001 Jul-Aug.[PUBMED Abstract]
  18. Balcom JH, 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]
  19. 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]
  20. 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]
  21. Conroy T, Hammel P, Hebbar M, et al.: FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 379 (25): 2395-2406, 2018.[PUBMED Abstract]
  22. Neoptolemos JP, Palmer DH, Ghaneh P, et al.: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 389 (10073): 1011-1024, 2017.[PUBMED Abstract]
  23. Uesaka K, Boku N, Fukutomi A, et al.: Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 388 (10041): 248-57, 2016.[PUBMED Abstract]
  24. 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.[PUBMED Abstract]
  25. Choti MA: Adjuvant therapy for pancreatic cancer--the debate continues. N Engl J Med 350 (12): 1249-51, 2004.[PUBMED Abstract]
  26. 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]
  27. 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.[PUBMED Abstract]
Locally Advanced Pancreatic Cancer Treatment

Treatment Options for Locally Advanced Pancreatic Cancer

While locally advanced and metastatic pancreatic cancer are both incurable, the natural history of locally advanced disease may be different than it is for metastatic disease. An autopsy series demonstrated that 30% of patients presenting with locally advanced disease died without evidence of distant metastases.[ 1 ][Level of evidence: 1iiA] Therefore, investigators have struggled with the question of whether chemoradiation therapy for patients presenting with locally advanced disease is warranted.

Treatment options for locally advanced pancreatic cancer include the following:

  1. Chemotherapy with or without targeted therapy.
  2. Chemoradiation therapy: chemotherapy followed by chemoradiation, for patients without metastatic disease.
  3. Surgery: radical pancreatic resection.
  4. Palliative surgery: palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.[ 2 ][ 3 ]

Palliative therapies can be considered in patients with any stage of disease. Refer to the Palliative Therapy section of this summary for more information.

Chemotherapy with or without targeted therapy

Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers and uses the same regimens as those used to treat patients with metastatic disease.

Evidence (chemotherapy):

  1. FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.[ 4 ][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 fluorouracil [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).
  2. 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.[ 5 ][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).
  3. Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[ 6 ][ 7 ][ 8 ] 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 (the 1-year survival rate was 18% with gemcitabine compared with 2% with 5-FU; P = .003).[ 7 ][Level of evidence: 1iiA]
  4. 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 with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[ 9 ][Level of evidence: 1iiA]
  5. 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.[ 10 ][ 11 ]
  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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients in the second line of chemotherapy to either the OFF regimen or BSC.[ 12 ][ 13 ][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.

Chemoradiation therapy

The role of chemoradiation in locally advanced pancreatic cancer remains controversial. Table 7 summarizes phase III randomized studies of chemoradiation for locally advanced pancreatic cancer.

Table 7. Randomized Studies in Locally Advanced Pancreatic Cancer: Median Survival
Trial Regimen Chemoradiation Radiation Alone Chemotherapy Alone Value
5-FU = 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); P value = probability value; XRT = x-ray or radiation therapy.
Pre-2000
GITSG [ 14 ] Radiation alone vs. 5-FU/60 Gy XRT 40 wk 20 wk   <.01
ECOG [ 15 ] Radiation vs. 5-FU, mitomycin C/59 Gy XRT 8.4 mo 7.1 mo   .16
Post-2000
FFCD [ 16 ] GEM vs. GEM, cisplatin, 60 Gy XRT 8.6 mo   13 mo .03
ECOG [ 17 ] GEM vs. GEM/50.4 Gy XRT 11.1 mo   9.2 mo .017

Evidence (chemoradiation therapy):

Three trials attempted to look at combined modality therapy versus radiation therapy alone.[ 14 ][ 15 ][ 16 ] 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. LAP07 (NCT00634725): The LAP07 study was an international, randomized phase III study based on the results of the Groupe Coopérateur Multidiciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[ 18 ][Level of evidence: 1iiA]

    The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

  2. Gastrointestinal Tumor Study Group (GITSG) GITSG-9273 trial: Before 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.[ 14 ][Level of evidence: 1iiA]
  3. 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/d on days 2–5 and 28–31) plus mitomycin (10 mg/m2 on day 2).[ 15 ]
  4. 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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[ 20 ][Level of evidence: 1iiA]
  5. 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.[ 17 ] Of note, the study was closed early as the result of poor accrual.
  6. GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with locally advanced 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.[ 21 ][Level of evidence: 3iiiA]

Surgery

Patients with locally advanced pancreatic cancer have tumors that are technically unresectable because of local vessel impingement or invasion by tumor. However, with the combination of chemotherapy and chemoradiation therapy, some patients may become candidates for radical pancreatic resection.

Palliative surgery

A significant proportion (approximately one-third) of patients with pancreatic cancer will present with locally advanced disease. Patients may benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological means.[ 22 ]

Treatment Options Under Clinical Evaluation for Locally Advanced 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.[ 23 ][ 24 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  4. Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011.[PUBMED Abstract]
  5. 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.[PUBMED Abstract]
  6. 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.[PUBMED Abstract]
  7. Burris HA, 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.[PUBMED Abstract]
  8. 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.[PUBMED Abstract]
  9. 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.[PUBMED Abstract]
  10. 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.[PUBMED Abstract]
  11. 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.[PUBMED Abstract]
  12. 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.[PUBMED Abstract]
  13. 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.[PUBMED Abstract]
  14. 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]
  15. Cohen SJ, Dobelbower R, 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.[PUBMED Abstract]
  16. 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.[PUBMED Abstract]
  17. Loehrer PJ, 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.[PUBMED Abstract]
  18. Hammel P, Huguet F, van Laethem JL, et al.: Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 315 (17): 1844-53, 2016.[PUBMED Abstract]
  19. 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.[PUBMED Abstract]
  20. 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.[PUBMED Abstract]
  21. 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.[PUBMED Abstract]
  22. 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]
  23. Tepper JE, Noyes D, Krall JM, et al.: Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21 (5): 1145-9, 1991.[PUBMED Abstract]
  24. 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.[PUBMED Abstract]
Metastatic or Recurrent Pancreatic Cancer Treatment

Treatment Options for Metastatic or Recurrent Pancreatic Cancer

Treatment options for metastatic or recurrent pancreatic cancer include the following:

  1. Chemotherapy with or without targeted therapy.

Palliative therapies can be considered in patients with any stage of disease. Refer to the Palliative Therapy section of this summary for more information.

Chemotherapy with or without targeted therapy

Because of the low objective response rate and limited efficacy of palliative chemotherapy regimens, enrollment into clinical trials should be considered for all newly diagnosed patients. Multiagent chemotherapy combinations have been shown to prolong outcomes compared with single-agent gemcitabine.[ 1 ][ 2 ][ 3 ]

Evidence (single-agent chemotherapy):

  1. Gemcitabine versus fluorouracil (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 (the 1-year survival rate was 18% with gemcitabine vs. 2% with 5-FU; P = .003).[ 1 ][Level of evidence: 1iiA]

Evidence (multiagent chemotherapy):

  1. FOLFIRINOX (leucovorin calcium, 5-FU, irinotecan hydrochloride, and oxaliplatin) 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.[ 4 ][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).
  2. 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.[ 5 ][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).
  3. 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 with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.[ 6 ][Level of evidence: 1iiA]

Evidence (second-line chemotherapy):

  1. Nanoliposomal irinotecan with or without 5-FU and folinic acid: The NAPOLI-1 trial (NCT01494506) evaluated the role of nanoliposomal irinotecan in patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapies.[ 7 ] Nanoliposomal irinotecan is an encapsulated formulation of irinotecan designed to increase intratumoral levels of irinotecan and its active metabolite. In this study, a total of 417 patients were randomly assigned to either nonliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks; n = 151), 5-FU and folinic acid (n = 149), or nanoliposomal irinotecan (80 mg/m2 every 2 weeks plus 5-FU) and folinic acid (n = 117).[ 7 ][Level of evidence: 1iiD]
  2. 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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients in the second line of chemotherapy to either an OFF regimen or BSC.[ 2 ]; [ 3 ][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.
  3. FOLFOX (leucovorin calcium [folinic acid]), 5-FU, and oxaliplatin) versus 5-FU/leucovorin after gemcitabine chemotherapy: The PANCREOX study, a prospective multicenter trial, randomly assigned 108 patients with advanced pancreatic cancer who had previously received first-line gemcitabine-based chemotherapy to receive 5-FU/leucovorin without oxaliplatin (n = 54) or with oxaliplatin (n = 54), administered as modified FOLFOX-6 (mFOLFOX-6).[ 8 ][Level of evidence: 3iA] With a target accrual of 128 patients, the study closed prematurely because of slow accrual.

Special considerations for patients with germline BRCA1/BRCA2 mutations

In patients with pancreatic adenocarcinoma, 4% to 8% have germline mutations in BRCA1 or BRCA2.[ 9 ][ 10 ] BRCA1/BRCA2 encode for proteins in the homologous repair pathway and DNA double-stranded break repair, and thus may be more sensitive to further DNA damage. Pancreatic tumors with BRCA1/BRCA2 mutations demonstrate improved responses to platinum-based therapies.[ 11 ] Poly (ADP-ribose) polymerase (PARP) inhibition has been posited to act synergistically with BRCA1/BRCA2 mutations by inhibiting single-stranded break repair. Several PARP inhibitors have been approved for treatment of patients with BRCA1/BRCA2 mutated advanced ovarian and breast cancers, and are actively being studied for the management of patients with BRCA1/BRCA2 mutated pancreatic adenocarcinoma.

Olaparib

Olaparib (a PARP inhibitor) maintenance therapy can be considered for patients with germline BRCA1/BRCA2 mutations and metastatic pancreatic adenocarcinoma who have responded to first-line platinum-based therapy for more than 4 months.

Evidence (olaparib):

  1. POLO Trial [NCT02184195]: A multicenter, phase III, randomized, double-blind, placebo-controlled trial that included 154 patients with metastatic pancreatic adenocarcinoma with germline BRCA1 or BRCA2 mutations whose disease had not progressed after 16 weeks of first-line platinum-based chemotherapy.[ 12 ][Level of evidence: 1iDiii] The patients were assigned 3:2 to receive olaparib (300 mg twice daily) or placebo and were assessed for PFS.

Treatment Options Under Clinical Evaluation for Metastatic or Recurrent Pancreatic Cancer

Treatment options under clinical evaluation include the following:

  1. Clinical trials evaluating new anticancer agents alone or in combination with chemotherapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

参考文献
  1. Burris HA, 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.[PUBMED Abstract]
  2. 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.[PUBMED Abstract]
  3. 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.[PUBMED Abstract]
  4. Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011.[PUBMED Abstract]
  5. 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.[PUBMED Abstract]
  6. 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.[PUBMED Abstract]
  7. Wang-Gillam A, Li CP, Bodoky G, et al.: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 387 (10018): 545-57, 2016.[PUBMED Abstract]
  8. Gill S, Ko YJ, Cripps C, et al.: PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol 34 (32): 3914-3920, 2016.[PUBMED Abstract]
  9. Holter S, Borgida A, Dodd A, et al.: Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. J Clin Oncol 33 (28): 3124-9, 2015.[PUBMED Abstract]
  10. Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard.edu, Cancer Genome Atlas Research Network: Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 32 (2): 185-203.e13, 2017.[PUBMED Abstract]
  11. Golan T, Kanji ZS, Epelbaum R, et al.: Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 111 (6): 1132-8, 2014.[PUBMED Abstract]
  12. Golan T, Hammel P, Reni M, et al.: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 381 (4): 317-327, 2019.[PUBMED Abstract]
Palliative Therapy

Palliative therapy options for patients with pancreatic cancer include the following:

  1. Palliative surgical bypass procedures such as endoscopic or radiologically placed stents.[ 1 ][ 2 ]
  2. Palliative radiation procedures.
  3. Pain relief by celiac axis nerve or intrapleural block (percutaneous).[ 3 ]
  4. Other palliative medical care alone.
参考文献
  1. Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999.[PUBMED Abstract]
  2. 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]
  3. 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.[PUBMED Abstract]
Changes to This Summary (05/15/2020)

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.

Editorial changes were made to this summary.

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 adult 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:

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.

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 (Adult). 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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