This summary provides information about the treatment of exocrine pancreatic cancer.

Incidence and Mortality

Estimated new cases and deaths from pancreatic cancer in the United States in 2024:

• New cases: 66,440.
• Deaths: 51,750.

The incidence of pancreatic cancer has markedly increased over the past several decades. In the United States, it ranks as the fourth leading cause of cancer death in men and the third leading cause of cancer death in women. Despite the high mortality rate associated with pancreatic cancer, its etiology is poorly understood.

Risk Factors

Risk factors for development of pancreatic cancer include the following:

• A family history of pancreatic cancer.
• Cigarette smoking.
• Obesity.
• Chronic pancreatitis.
• Certain genetic disorders (such as those associated with the BRCA1, BRCA2, PALB2, and ATM genes).

Anatomy

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 may include the following:

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

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.

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 have an elevated CA 19-9 level at diagnosis. An increase of CA 19-9 levels during or after definitive therapy may identify patients with progressive tumor growth. However, the presence of a normal CA 19-9 level 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%. 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%.

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 be candidates for clinical trials because of the poor response to chemotherapy, radiation therapy, and surgery as conventionally used.

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

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:

• Surgical or radiological 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.

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.
• Papillary mucinous carcinoma.
• Signet ring carcinoma.
• Small cell carcinoma.
• Unclassified.
• Undifferentiated carcinoma.

Borderline Malignancies

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

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:

• Resectable: tumors without vascular involvement.
• Borderline resectable: tumors with involvement of vasculature, involvement of local structures, or other evidence of a high risk of R1 resection.
• Locally advanced: tumors with local invasion (primarily vascular involvement) that preclude surgical intervention.
• Metastatic: cancer that has spread beyond the primary pancreatic tumor to other organs.

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

AJCC Stage Groupings and TNM Definitions

Table 1. Definitions for Exocrine Pancreas TNM Stage 0a

Table 2. Definitions for Exocrine Pancreas TNM Stages IA and IBa

Table 3. Definitions for Exocrine Pancreas TNM Stages IIA and IIBa

Table 4. Definitions for Exocrine Pancreas TNM Stage IIIa

Table 5. Definitions for Exocrine Pancreas TNM Stage IVa

Surgical resection remains the primary treatment modality for patients with pancreatic cancer when feasible. On occasion, resection can lead to long-term survival and provides effective palliation. 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.

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

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.
• Pain: Celiac axis and intrapleural nerve blocks can provide highly effective and long-lasting control of pain for some patients. For more information, see Cancer Pain.

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

Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body. Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects. Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles. DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines. In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.

Treatment Options for Resectable or Borderline Resectable Pancreatic Cancer

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

1. Neoadjuvant therapy: Neoadjuvant chemotherapy with or without chemoradiation therapy.
2. 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.
3. Postoperative chemotherapy: Radical pancreatic resection followed by chemotherapy.
4. Postoperative chemoradiation therapy: Radical pancreatic resection followed by fluorouracil (5-FU) chemotherapy and radiation therapy.
5. Preoperative chemotherapy and/or radiation therapy (under clinical evaluation).
6. Alternative radiation techniques (under clinical evaluation).

Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.

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 Program 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 patients with resectable or borderline resectable pancreatic cancer in several ongoing trials.

Evidence (neoadjuvant chemotherapy with or without chemoradiation therapy):

1. The phase II, multicenter, randomized A021501 trial (NCT02839343) enrolled 126 patients with borderline resectable pancreatic cancer from institutions in the National Clinical Trials Network cooperative groups between February 2017 and January 2019. Patients were assigned to receive either eight 2-week cycles of modified FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-FU) (n = 65) or seven 2-week cycles of modified FOLFIRINOX followed by stereotactic body radiotherapy (33 Gy–40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions) (n = 55). Patients without disease progression then underwent surgery followed by four 2-week cycles of adjuvant FOLFOX6 (oxaliplatin, leucovorin, and 5-FU).
   • In the neoadjuvant chemotherapy-alone arm, the median overall survival (OS) was 29.8 months (95% confidence interval , 21.1–36.6) with a 43% microscopically margin-negative (R0) resection rate. This was compared with estimated historical controls of median OS at 18 months.
   • Grade 3 or greater treatment-related adverse events occurred in 57% of patients who received neoadjuvant chemotherapy alone.
   • The neoadjuvant chemotherapy with radiation arm was closed at interim futility analysis because of low R0 resection rates (33%) in the first 30 patients enrolled.
2. The multicenter phase III PREOPANC trial included 246 patients diagnosed with resectable or borderline resectable pancreatic cancer between April 2013 and July 2017. Patients at 16 Dutch centers were randomly assigned to receive either diagnostic laparoscopy, neoadjuvant chemoradiation therapy, surgical resection, and four cycles of adjuvant gemcitabine or up-front surgery and six cycles of adjuvant gemcitabine. Neoadjuvant chemoradiation therapy included the following: cycle 1 (21 days) with gemcitabine 1,000 mg/m2 on days 1 and 8; cycle 2 (28 days) with gemcitabine on days 1, 8, and 15 with 15 concurrent fractions of hypofractionated radiation (36 Gy) to the tumor and suspected associated lymph nodes; and cycle 3 (21 days) with gemcitabine on days 1 and 8.
   • The 5-year OS rate was 20.5% (95% CI, 14.2%–29.8%) for patients who received neoadjuvant chemoradiation therapy and 6.5% (95% CI, 3.1%–13.7%) for patients who received up-front surgery (hazard ratio , 0.73; 95% CI, 0.56–0.96; P = .025).
   • The median OS was 15.7 months in the neoadjuvant chemoradiation therapy group and 14.3 months in the up-front surgery group.
   • In the intention-to-treat arm, 61% of patients who received neoadjuvant chemoradiation therapy underwent resection, resulting in R0 resection for 41% of patients and node-negative disease for 65% of patients. The resection rate was 72% in the up-front surgery arm, resulting in R0 resection in 28% of patients and node-negative disease in 18% of patients.

   The optimal neoadjuvant therapy regimen is unknown, and additional chemotherapy regimens are being evaluated in the following trials: ALLIANCE (NCT04340141), PREOPANC-3 (NCT04927780), PANACHE-01-PRODIGE (NCT02959879), and NorPACT-01 (NCT02919787).

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.

Approximately 20% of patients present with pancreatic cancer amenable to local surgical resection, with operative mortality rates of approximately 1% to 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).

Postoperative chemotherapy

Historically, multiple randomized trials have established that adjuvant gemcitabine monotherapy or adjuvant 5-FU monotherapy improve 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 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).
   • With a median follow up of 33.6 months, median disease-free survival (DFS) was 21.6 months with FOLFIRINOX and 12.8 months with gemcitabine (HR, 0.58; 95% CI, 0.46–0.73, P = .001).
   • Median OS was 54.4 months with FOLFIRINOX and 35.0 months with gemcitabine (HR, 0.64; 95% CI, 0.48–0.86, P = .003).
   • Toxicity was higher with combination therapy; 75.9% of patients treated with FOLFIRINOX had grade 3/4 toxicities (compared with 52.9% of those who received gemcitabine), with similar rates of neutropenia (although 62.2% of patients on FOLFIRINOX received granulocyte colony-stimulating factor). Thirty-three percent of patients who received FOLFIRINOX stopped treatment prematurely, compared with 21% of patients who received gemcitabine alone.
2. Gemcitabine and capecitabine: The European Study for Pancreatic Cancer (ESPAC-4 ) 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 ).
   • With a median follow-up of 43.2 months, the median OS for patients in the gemcitabine/capecitabine group was 28.0 months (95% CI, 23.5–31.5) compared with 25.5 months for the gemcitabine-alone group (95% CI, 22.7–27.9; HR, 0.82; P = .032). Treatment with gemcitabine/capecitabine yielded an improvement in the estimated 5-year OS rate from 16.3% with gemcitabine alone to 28.8% with gemcitabine/capecitabine.
   • There was no significant difference in overall rates of grade 3/4 toxicities between treatment arms. Compared with gemcitabine alone, capecitabine was associated with higher rates of grade 3/4 diarrhea (5% vs. 2%), neutropenia (38% vs. 24%), and hand-foot syndrome (7% vs. 0%).
   • There was no significant effect on the quality of life in the treatment groups.
   • On the basis of these findings, the adjuvant combination of gemcitabine and capecitabine should be the new standard of care after a resection for pancreatic cancer.
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).
   • The prespecified criteria for early discontinuation was met at interim analysis for efficacy with all of the protocol treatments completed. On early interim analysis, the HRmortality was 0.57 (95% CI, 0.44–0.72; P for noninferiority .001; P for superiority .001). These results were associated with a 5-year OS rate of 24.4% in the gemcitabine group and 44.1% in the S-1 group.
   • Grade 3 or 4 leukopenia, neutropenia, and liver transaminitis were observed more frequently in the gemcitabine group, and stomatitis and diarrhea were experienced more frequently in the S-1 group.
   • Among Japanese patients, adjuvant chemotherapy with S-1 can be a new standard of care for resected pancreatic patients. Additional studies are needed to validate these results in patients of other races and ethnicities.
   • The pharmacokinetics and pharmacodynamics of S-1 may be different between Eastern and Western patient populations because grade 3/4 gastrointestinal toxicities, especially diarrhea, have been reported more commonly in the Western patient population. S-1 is not currently approved by the U.S. Food and Drug Administration for use in the United States.
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. In contrast to the previous trials, the primary end point was DFS.
   • With a median follow-up of 136 months, long-term follow-up of the CONKO-001 study demonstrated 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 the survival rates at 10 years were 12.2% for the gemcitabine arm versus 7.7% for the observation-alone arm.
5. Gemcitabine or 5-FU: The ESPAC-3 trial (NCT00058201) 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.
   • 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).

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.

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.;
   • 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 Organisation 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; 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 (17.1 months, 37%, and 20%, respectively) compared with surgery alone (12.6 months, 23%, and 10%, respectively); P = .09 for median survival).
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).
   • 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 -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. The primary end points were OS for all patients and OS for patients with pancreatic head tumors.
   • A 5-year update of RTOG-9704 reported that patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 5-year OS rate of 22% with gemcitabine, versus a median survival of 17.1 months and a 5-year OS rate of 18% with 5-FU (HR, 0.84; 95% CI, 0.67–1.05; P = .12).
   • 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%).

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 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. Therefore, investigators have struggled to determine 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.
5. Clinical trials evaluating novel agents in combination with chemotherapy or chemoradiation therapy for patients with unresectable tumors.
6. Intraoperative radiation therapy and/or implantation of radioactive sources (under clinical evaluation).

Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.

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. The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin , irinotecan , leucovorin , and fluorouracil 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 (hazard ratio death, 0.57; 95% confidence interval , 0.45–0.73; P .001).
   • Median progression-free survival (PFS) 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.
2. Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international, phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease. 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 (HRdeath, 0.72; 95% CI, 0.62–0.83; P .001).
   • Median PFS was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease 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 in the nab-paclitaxel/gemcitabine group were neutropenia (38%), fatigue (17%), and neuropathy (17%); febrile neutropenia occurred in 3% of patients. In the gemcitabine-alone group, the most common grade 3 toxicities were neutropenia (27%), fatigue (1%), and neuropathy (1%); febrile neutropenia occurred in 1% of patients.
   • 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/gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
   • Quality-of-life data were not measured for this regimen, and this study did not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
3. Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent. 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).
4. Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 ) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.
   • The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (HR, 0.81; 95% CI, 0.69–0.99; P = .038).
   • The median and 1-year survival rates for patients who received erlotinib were 6.2 months and 23%. The median and 1-year survival rates for patients who received placebo were 5.9 months and 17%.
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.
   • None of these phase III trials have demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic 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 Charité Onkologie (CONKO)-003 investigators randomly assigned patients in the second line of chemotherapy to either the OFF regimen or BSC. The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 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/OFF and 7.90 months for gemcitabine/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.

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

Evidence (chemoradiation therapy):

Three trials evaluated combined modality therapy versus radiation therapy alone. 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 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 Multidisciplinaire 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.
   • The primary end point was OS. After interim analysis, the study was stopped early because of futility.
   • With a median follow-up of 36.7 months, the median OS from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5–18.5) and chemoradiation therapy at 15.2 months (95% CI, 13.9–17.3; P = .83).
   • Median OS after the first randomization was 13.6 months (95% CI, 12.3–15.3) for the patients who received gemcitabine and was 11.9 months (95% CI, 10.4–13.5; P = .09) for the patients who received gemcitabine plus erlotinib.

   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.
   • The study was stopped early when the chemoradiation therapy groups were found to have better efficacy. The 1-year survival rate 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 OS was not statistically significant when compared with the 40 Gy arm.
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).
   • The trial reported no difference in OS between the two groups.
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.Level of evidence A1
   • Median survival was superior in the gemcitabine group (13 vs. 8.6 months; P = .03).
   • Nonhematological grade 3 to 4 toxicities (primarily gastrointestinal) were significantly more common in the chemoradiation therapy group (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 group because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).
   • As a result of this study, giving induction chemoradiation therapy has lost support.
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. Of note, the study was closed early as the result of poor accrual.
   • The primary end point was survival, which was 9.2 months (95% CI, 7.9–11.4) for chemotherapy and 11.1 months (95% CI, 7.6–15.5) for combined modality therapy (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%).
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.
   • 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).

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.

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

Palliative therapies can be considered in patients with any stage of disease. For more information, see the Palliative Therapy section.

Chemotherapy with or without targeted therapy

Because of the low objective response rate and limited efficacy of palliative chemotherapy regimens, all newly diagnosed patients should consider enrolling in clinical trials. Multiagent chemotherapy combinations have been shown to prolong outcomes compared with single-agent gemcitabine.

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).

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. The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin , irinotecan , leucovorin , and 5-FU 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 (hazard ratio death, 0.57; 95% confidence interval , 0.45–0.73; P .001).
   • Median progression-free survival (PFS) 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.
2. Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma. Patients had a Karnofsky Performance Status of at least 70 and had not previously received chemotherapy for metastatic disease. 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 (HRdeath, 0.72; 95% CI, 0.62–0.83; P .001).
   • Median PFS was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease 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 in the nab-paclitaxel/gemcitabine group were neutropenia (38%), fatigue (17%), and neuropathy (17%); febrile neutropenia occurred in 3% of patients. In the gemcitabine-alone group, the most common grade 3 toxicities were neutropenia (27%), fatigue (1%), and neuropathy (1%); febrile neutropenia occurred in 1% of patients.
   • In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 neuropathy 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 did not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
3. Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 ) that compared gemcitabine alone with the combination of gemcitabine and erlotinib (100 mg/d) in patients with advanced or metastatic pancreatic carcinomas.
   • The addition of erlotinib modestly prolonged survival when combined with gemcitabine alone (HR, 0.81; 95% CI, 0.69–0.99; 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.

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. 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 nanoliposomal 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).
   • Median OS was 6.1 months (95% CI, 4.8–8.9) in patients assigned to nanoliposomal irinotecan with 5-FU and 4.2 months (95% CI, 3.6–4.9) in those assigned to receive 5-FU and folinic acid (P = .012). Median OS was 4.9 months (95% CI, 4.2–5.6) for patients who received nanoliposomal irinotecan monotherapy, compared with 4.2 months (95% CI, 3.6–4.9) for those who received 5-FU and folinic acid (unstratified HR, 0.99; P = .94). On multivariate analysis, nanoliposomal irinotecan plus 5-FU and folinic acid was associated with improved OS (HR, 0.58; 95% CI, 0.42–0.81).
   • Grade 3 or 4 adverse events occurred most frequently in the patients who received nanoliposomal irinotecan plus 5-FU and folinic acid and included neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%).
   • Despite differences in survival and toxicity between regimens, quality of life was not significantly different between treatment groups.
   • The benefit of using nanoliposomal irinotecan rather than unencapsulated irinotecan has not been established because the regimen for the control arm of this study was 5-FU/folinic acid. Additionally, the value of using nanoliposomal irinotecan after FOLFIRINOX in the first-line setting is not clear.
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.; The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 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/OFF and 7.90 months for gemcitabine/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.
3. FOLFOX (leucovorin calcium ), 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). With a target accrual of 128 patients, the study closed prematurely because of slow accrual.
   • After a median follow-up of 8.8 months, the median PFS was 3.1 months in the mFOLFOX-6 arm and 2.9 months in the infusional 5-FU arm (HR, 1.00; 95% CI, 0.66–1.53, P = .989).
   • Overall response rate and quality of life was not significantly different in the two arms.
   • The overall incidence of grade 3 or 4 adverse events was 63% in the mFOLFOX-6 arm and 11% in the 5-FU/leucovorin arm. However, more patients in the mFOLFOX-6 arm withdrew from the study because of adverse events than did patients in the 5-FU/leucovorin arm (20% vs. 2%).
   • On the basis of this study, no benefit was seen with the addition of oxaliplatin, administered in the mFOLFOX-6 regimen, versus infusional 5-FU/leucovorin among patients with advanced pancreatic cancer after first-line gemcitabine-based chemotherapy. These results may suggest that oxaliplatin-based regimens for metastatic pancreatic cancer may yield the greatest benefit in the first-line setting.

Special considerations for patients with germline BRCA1/BRCA2 mutations

Germline mutations in BRCA1 or BRCA2 are present in 4% to 8% of patients with pancreatic adenocarcinoma. 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. 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. The patients were assigned 3:2 to receive olaparib (300 mg twice daily) or placebo and were assessed for PFS.
   • Of 3,315 patients screened, 247 patients were identified with germline BRCA mutations.
   • The median PFS was 7.4 months in the olaparib arm and 3.8 months in the placebo arm (HR, 0.53; 95% CI, 0.35‒0.82; P = .004)
   • Median OS was 18.9 months in the olaparib group and 18.1 months in the placebo arm (HR, 0.91; 95% CI, 0.56‒1.46; P = .68).
   • There were more grade 3 or 4 treatment related adverse events with olaparib (40%) compared with placebo (23%).

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

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