Pancreatic cancer accounts for only 3% of all cancer cases in the United States but it is the fourth leading cause of cancer death and is responsible for approximately 7% of cancer-related deaths. The American Cancer Society estimates that about 48,960 people will be diagnosed with pancreatic cancer and about 40,560 people will die from pancreatic cancer in the United States in 2015. The overall 5-year survival rate of all patients diagnosed with pancreatic adenocarcinoma is approximately 6%. For the majority of patients, the disease is either locally advanced and unresectable or metastatic at the time of diagnosis, and the median survival in these patients is 3 to 12 months. Approximately 15% of patients present with localized disease that is amenable to surgical resection; even in the most selective patient subgroups, however, median survival is only 2 years and anticipated 5-year survival rates are only 12% to 20%.

Risk factors for pancreatic cancer include age, sex, and race. The disease is more common in the elderly, with the median age at diagnosis for pancreatic cancer being 71 years of age. Men and African Americans have a higher risk than others. Cigarette smoking, obesity, diabetes, chronic pancreatitis, liver cirrhosis, Helicobacter pylori infection, and exposure to chemicals such as β-naphthylamine and benzidine are also associated with an increased risk. The link between diet and alcohol use and the development of pancreatic cancer is unclear and currently being studied. The risk of pancreatic cancer is also increased in patients with certain familial cancer syndromes, but hereditary pancreatic cancer makes up less than 10% of cases. Hereditary pancreatic cancer has been observed in hereditary breast and ovarian cancer syndrome (BRCA2 mutation), familial melanoma (p16/CDKN2A mutation), familial pancreatitis (PRSS1 mutation), Puetz-Jeghers syndrome (STK11 mutation), von Hippel-Landau syndrome (VHL mutation) and hereditary nonpolyposis colorectal cancer (most often MLH1 and MSH2 mutations). Greater than 80% of resected pancreatic cancers harbor either activating point mutations in KRAS or inactivating mutations of the tumor suppressor genes p16, p53, BRAF, and DPC4 (SMAD4).

Pancreatic cancer-associated symptoms are not specific and usually occur when the disease is already incurable. Pain is the most common presenting symptom. It occurs in three-fourths of patients with carcinoma of the head of the pancreas and in virtually all patients with carcinoma of the body or tail. Usually, the pain is a dull ache in the epigastrium that radiates to the right upper quadrant when the tumor is in the head of the pancreas or to the left upper quadrant when the tumor is in the body or tail; the pain may radiate to the lumbar region of the back. Weight loss can be significant and is associated with anorexia, steatorrhea, nausea, diarrhea, and early satiety, which are other symptoms related to cancer of the pancreas. The nonspecific, vague nature of these complaints may delay diagnosis for several months. Seventy percent of patients with carcinoma of the head of the pancreas have jaundice, whereas fewer than 15% of patients with carcinoma of the pancreatic body have jaundice. Depression and diabetes commonly precede pancreatic cancer and can be early symptoms. Of patients aged 50 years and older with recent onset of diabetes, about 1% are diagnosed with pancreatic cancer within 3 years. Physical findings are generally associated with advanced carcinomas and include weight loss, hepatomegaly, and an abdominal mass. A palpable gallbladder in the absence of cholecystitis or cholangitis suggests malignant obstruction of the common bile duct (Courvoisier sign) and it is present in about 25% of all patients with pancreatic cancer. Other physical findings, which can be indicative of distant metastases, include Trousseau syndrome (migratory superficial phlebitis), ascites, Virchow node (left supraclavicular lymph node), a periumbilical mass (Sister Mary Joseph node), or a palpable pelvic shelf on rectal examination (Blumer shelf).

Accurate diagnostic imaging is used to determine whether a patient with pancreatic cancer is a candidate for surgical resection or has an incurable disease. Computed tomography (CT) is the most commonly used study and is very effective when performed according to a standard pancreatic protocol with thin slices and triphasic cross-sectional imaging. CT scans can demonstrate masses in the pancreas or dilatation of the pancreatic duct or the common bile duct. Sensitivity and specificity of CT are about 90%, but CT can miss very small tumors. Endoscopic ultrasound may be useful for staging (i.e., nodal status), determination of major vessel invasion, and for fine needle aspiration (FNA) for the pathologic determination of tumor. To determine vascular invasion, there are three options: helical CT, magnetic resonance arteriography, or endoscopic ultrasound. Percutaneous FNA of suspicious abnormalities identified on CT scan can confirm the diagnosis of pancreatic cancer with 80% to 90% sensitivity and 100% specificity. A common histologic hallmark of pancreatic adenocarcinoma is an associated desmoplastic reaction
that, in a given tumor mass, can vastly overestimate the malignant cell mass. Furthermore, pancreatic cancer may be associated with varying degrees of acute or chronic pancreatitis or cyst formation, which may make it difficult to make a diagnosis with FNA and may lead to false-negative results.

The majority of tumor markers have not proven to be specific or sensitive enough for pancreatic cancer. Cancer antigen 19-9 is a cell surface glycoprotein that is associated with pancreatic cancer and has been shown to be elevated in 90% of patients with pancreatic cancer. A 20% or greater fall in the serum marker following treatment is a good prognostic indicator and is associated with improved survival. Rising serum levels may be a useful early indicator of recurrent or progressive disease once a diagnosis has been established, but because of low specificity it is not used as a screening method. However, there are data to support the obtaining of a CA19-9 level in all patients in whom pancreatic cancer is suspected.

The primary tumor, regional lymph nodes, and potential sites of metastatic disease must be carefully assessed. The staging system has been modified to better take into account “resectability” of disease. Resectable disease is loosely defined as disease confined to the pancreas without involvement of the celiac axis or major vessels. A surgeon experienced in pancreatic surgery should evaluate each case individually when determining resectability as there are numerous clinical caveats.

Preoperative evaluation should be performed stepwise from least invasive to most invasive as indicated by the clinical situation. Preoperative evaluation can be stopped when metastatic disease or definite evidence for unresectable locoregional spread is identified. All patients should undergo triphasic helical CT of the abdomen for detection of pancreatic masses and evaluation of vessel encasement. If there is no evidence of metastatic disease and no major blood vessel involvement is identified, then laparoscopy can be used to identify small metastases in the liver or peritoneum. The use of positron emission tomography with 2-[¹⁸F]fluoro-2-deoxy-D-glucose in the preoperative evaluation of patients with pancreatic cancer is still controversial and not routinely used.

Three-fourths of patients with pancreatic cancer are operative candidates, but only 15% to 20% have resectable tumors. Patients without evident metastatic cancer or major blood vessel involvement and whose performance status permits operative intervention are candidates for curative surgery.

1) Local and distant recurrence continues to be a common problem after complete resection of pancreatic cancer. Options for the adjuvant treatment of pancreatic cancer continue to be in evolution. One of the first prospective randomized studies to explore the role of adjuvant therapy in pancreas adenocarcinoma was the Gastrointestinal Tumor Study Group (GITSG) trial, originally published in 1985.1 This study randomized 43 patients (1974 to 1982) with surgically resected pancreas adenocarcinoma to observation versus concurrent chemoradiation with bolus fluorouracil (5-FU), followed by maintenance 5-FU for 2 years. The study showed an overall survival benefit (median survival: 20 vs. 11 months, p = 0.03) and a 2-year survival benefit (42% vs. 15%), but this study is criticized for small patient numbers, low radiation doses (40 Gy), long accrual time, and early termination. The European Organization for Research and Treatment of Cancer performed a similar trial (EORTC 40891) that randomized 218 patients with resected periampullary malignancy (1987 to 1995) to observation versus concurrent chemoradiation with bolus 5-FU but no maintenance chemotherapy.² Of these patients, 114 had a diagnosis of pancreatic adenocarcinoma. On first analysis with median follow-up of 7.3 years, results in the pancreatic cancer subgroup showed a trend toward improved outcome in the treatment group (median survival: 17.1 vs. 12.6 months, p = 0.099); however, long-term follow-up analysis at median follow-up of 11.7 years showed no significance difference in survival. This study has also been criticized for low radiation doses and underpowering of the study.

2) A complicated trial in a 2 × 2 design was completed by the European Group for Pancreatic Cancer (ESPAC-1) and randomized 289 patients (1994 to 2000) with resected pancreatic adenocarcinoma to one of four treatment arms—chemoradiation, chemotherapy, combined chemoradiation followed by chemotherapy, and observation.³ With a median follow-up time of 47 months, 5-year survival of patients treated with chemotherapy was 21% versus 8% among patients not treated with chemotherapy (median survival: 20.1 vs. 15.5 months, p = 0.009); in addition, the estimated 5-year survival was 10% for patients treated with chemoradiation compared with 20% for patients who did not receive chemoradiation (p = 0.05). However, this trial has been criticized as results are difficult to interpret given several trial design concerns including selection bias and treatment variability.

3) The Charite Onkologie (CONKO-001) trial enrolled 368 patients (1998 to 2004) with surgically resected pancreatic adenocarcinoma to either six cycles of gemcitabine or observation.⁴ This was the first trial showing that gemcitabine alone in the adjuvant setting can prolong disease-free and overall survival without significant toxicities compared with observation alone (median survival 22.8 vs. 20.2 months, p = 0.005, and 5-year survival of 21% vs. 10%).

4) At the same time as the CONKO-001 trial in Europe, the Radiation Therapy Oncology Group in North America conducted the RTOG 97-04 randomized phase III trial.⁵ This trial randomized 451 patients (1998 to 2002) with resected pancreatic adenocarcinomas to either gemcitabine or 5-FU for 3 weeks prior to chemoradiation therapy and 12 weeks following chemoradiation. This study had the benefit of modern radiation doses and the addition of gemcitabine to the chemotherapy regimen but did not evaluate the benefit of radiation to adjuvant chemotherapy. A survival benefit of gemcitabine over 5-FU (18.8 vs. 16.7 months, p = 0.047) was seen only in pancreatic head adenocarcinomas.

5) Subsequently, the ESPAC 3 trial initially randomized patients with surgically resected pancreatic adenocarcinoma to bolus 5-FU/leucovorin versus gemcitabine versus observation; however, following ESPAC 1 results, the observation arm was removed.⁶ This study accrued 1,088 patients from 2000 to 2007 and patients received 6 months of adjuvant therapy. After median follow-up time of 34 months, there was equivalency between the two regimens (median survival 23 months with 5-FU/leucovorin and 23.6 months with gemcitabine). The study also reported that 14% of patients treated with 5-FU developed serious adverse advents (>grade 3) versus 7.5% of patients treated with gemcitabine.

6) More recently, the preliminary results of the CONKO-005 trial were presented at the 2015 ASCO meeting. This study randomized 436 patients from 2008 through 2013 to 6 months of gemcitabine versus combination of gemcitabine and erlotinib following surgical resection of pancreatic adenocarcinoma. At a median follow-up of 41 months, there was no difference in disease-free survival (GemErlo 11.6 months, Gem 11.6 months; hazard ratio [HR] 0.89) or overall survival (median: GemErlo 24.6 months, Gem 26.5 months; HR 0.90). Similarly, there was no correlation between grade of rash and an improved disease-free survival in the GemErlo group. However, the overall survival curves do show a late divergence in favor of GemErlo (5-year survival, 28% vs. 19%) which will be followed further.

7) All of these trials show that in an acceptable candidate, chemotherapy improves survival and therefore adjuvant chemotherapy with 6 months of gemcitabine or 5-FU/leucovorin represents the standard of care. However, the addition of radiotherapy is still controversial. Additional retrospective data, phase II studies, and meta-analysis continue to provide evidence for and against chemoradiation in the adjuvant setting. At this time, no standardized regimen has been established for the adjuvant treatment of resected pancreatic cancer. 5-FU-based chemoradiation with additional gemcitabine chemotherapy as well as chemotherapy alone with gemcitabine, 5-FU, or capecitabine are listed in the guidelines for the adjuvant treatment of pancreatic cancer.

8) Currently, studies are underway looking at different approaches to improve outcomes in the adjuvant treatment of pancreatic cancer. These include combination of cytotoxic chemotherapeutic agents, the addition of targeted agents, and immunotherapeutic approaches. ESPAC 4 is a large randomized phase III trial comparing the addition of capecitabine plus gemcitabine with gemcitabine alone. The trial is powered for an end point of overall survival with a target of 1,080 patients and will take several more years before results are available. RTOG 0848 is enrolling 952 patients randomized to gemcitabine alone compared with erlotinib and gemcitabine for 6 months; this will be followed by restaging and if no evidence of recurrence, patients will undergo second randomization with addition of chemoradiation versus no added therapy.

9) Given the significant survival advantage seen in metastatic pancreatic cancer with both FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel compared with single-agent gemcitabine, both of these treatments are now being studied in the adjuvant setting. PRODIGE 24/ACCORD 24 is a phase III trial comparing adjuvant chemotherapy with gemcitabine versus modified FOLFIRINOX (omission of bolus 5-FU) to treat resected pancreatic adenocarcinoma. Estimated enrollment is 490 patients with primary outcome of disease-free survival at 3 years and began to accrue in January 2012. The APACT study is a phase III multicenter randomized study of nab-paclitaxel plus gemcitabine versus gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Estimated enrollment is 800 patients with primary outcome measure of disease-free survival and trial began accrual in March 2014.

10) Up to this point, no vaccine or immunotherapy has demonstrated significant improvement in overall survival in phase
III clinical trials of resected pancreatic adenocarcinoma patients. However, using the concept of hyperacute rejection, a vaccine (algenpantucel-L) was recently studied with promising results in a phase II study. Therefore, a phase III trial was recently conducted, which randomized 722 patients with surgically resected pancreatic adenocarcinoma to standard of care treatment of gemcitabine with or without 5-FU-based chemoradiation and +/- HyperAcute pancreas immunotherapy (algenpantucel-L). This study has completed enrollment and results should be available in near future.

11) Currently, alternative adjuvant chemotherapy regimens (with or without radiotherapy) include the following

a) Gemcitabine alone (1,000 mg/m² on days 1, 8, and 15 with a 1-week break) or

b) 5-FU 225 mg/m² by continuous intravenous (IV) infusion throughout radiation therapy followed by four to six courses of bolus 5-FU weekly, or gemcitabine (1,000 mg/m² on days 1, 8, and 15 with a 1-week break) or

c) 5-FU 425 mg/m² by IV push 1 hour after leucovorin 20 mg/m² by IV push daily for 4 days during the first week of radiation therapy and for 3 days during the fifth week of radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1,000 mg/m² on days 1, 8, and 15 with a 1-week break) or

d) Capecitabine 1,500 mg/m² daily in divided doses with radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1,000 mg/m² on days 1, 8, and 15 with a 1-week break). Capecitabine can be used in the chemotherapy-only part of the regimen as well, but there are no phase III data to confirm capecitabine in this setting.

On the basis of the results of the many large phase III trials above, adjuvant chemotherapy provides a proven survival benefit compared with pancreatic resection alone. However, because of the significant morbidity associated with pancreatic surgery, many patients are not able to receive adjuvant therapy within the therapeutic window provided after surgery. Therefore, a neoadjuvant sequence of therapy provides a strong theoretical rationale to increase percentage of patients who see systemic treatment. To date there are no completed phase III trials studying role of neoadjuvant chemotherapy compared with adjuvant therapy. A small phase II prospective trial, evaluating neoadjuvant gemcitabine and cisplatin for resectable pancreatic cancer, demonstrated feasibility with favorable overall survival. However, results
from meta-analysis have not shown benefit of neoadjuvant therapy over adjuvant therapy in terms of resectability or survival benefit. Recently, a multicenter U.S. phase II trial evaluating neoadjuvant and adjuvant gemcitabine and erlotinib (ACOSOG Z5041) completed recruitment of 123 patients but results are not yet available. Two phase III trials are currently underway in Europe that are studying the roles of neoadjuvant chemotherapy and neoadjuvant chemoradiation. The NEOPAC trial is a randomized multicenter phase III trial comparing adjuvant gemcitabine with neoadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in patients with resectable pancreatic cancer. This study completed enrollment of 310 patients and results should be available in near future. The NEOPA trial is a randomized multicenter phase III trial comparing neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy with upfront surgery and adjuvant chemotherapy in patients with resectable pancreatic cancer. This study is looking to enroll 410 patients and recently began recruiting patients.

Management of borderline resectable pancreatic cancer remains a challenging field without a defined approach and requires a multidisciplinary effort. This subgroup of patients with pancreatic cancer is potentially resectable if they have a good response with preoperative chemotherapy or combined chemotherapy with radiation. There are a number of phase II studies looking at gemcitabine-based chemotherapy regimens and chemoradiation regimens for the neoadjuvant treatment of borderline resectable pancreatic cancer. However, there have been no phase III studies and there is no consensus among groups as to the preferred chemotherapeutic regimen or whether radiation should be utilized in the neoadjuvant setting.

1) Over two decades ago, a series of randomized trials conducted by the GITSG demonstrated superior survival of patients with localized but unresectable pancreatic cancer when treated with combined modality therapy compared with patients treated with radiation therapy or chemotherapy alone.⁷ Around the same time, the Eastern Cooperative Oncology Group (ECOG) randomly assigned patients with locally advanced gastric and pancreas cancers to receive 5-FU alone or in combination with radiation therapy; the study showed no improvement in progression-free or overall survival. The 2000 to 2001 FFCD/SFRO French study was a 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 pancreatic cancer. This trial demonstrated worse outcome with chemoradiotherapy (8.6 vs. 13 months; p = 0.03).

2) Subsequently, an ECOG trial compared gemcitabine alone with gemcitabine and radiotherapy in patients with locally advanced pancreatic cancer. Although this trial closed prematurely because of poor accrual, it was able to randomize 71 patients and found an improved survival with the addition of radiotherapy to gemcitabine (11.1 vs. 9.2 months; p = 0.017). The therapeutic strategy used by Group Cooperateur Multidisciplinaire en Oncologie (GERCOR) was to utilize systemic chemotherapy for 3 months alone and consider chemoradiation at investigator’s discretion if no evidence of progressive disease. On retrospective analysis, the group found that chemoradiation significantly improved survival compared with chemotherapy alone (overall survival 15 vs. 11.7 months; p = 0.009). This strategy was further evaluated in the international phase III LAP-07 study, with results presented at ASCO 2013 meeting but not yet published. This study demonstrated that the addition of radiation did not improve outcomes following 4 months of systemic therapy in patients with locally advanced pancreas adenocarcinoma. This study randomized 442 patients to receive gemcitabine alone or in combination with erlotinib for 4 months. Patients with controlled disease (269 patients) were then randomized to either 2 additional months of chemotherapy or 2 months of chemoradiation with 54 Gy of radiation therapy with capecitabine. The primary end point was overall survival after second randomization and no difference was found (16.5 months for chemotherapy arm and 15.3 months for chemoradiation arm).

3) Given the discrepant data on the benefit of radiation therapy for locally advanced pancreatic cancer and benefit of FOLFIRINOX in metastatic pancreatic cancer, a phase III study of modified FOLFIRINOX with or without radiation therapy in patients with locally advanced pancreatic cancer was launched in 2013. This study will randomize 172 patients to modified FOLFIRINOX alone or modified FOLFIRINOX with stereotactic body radiation therapy (SBRT).

Patients with pancreatic cancer are often poor candidates for chemotherapy because of severe weight loss, poor performance status, severe pain, lack of measurable or evaluable disease, and presence of jaundice or hepatic involvement, which may interfere with clearance of therapeutic agents. The primary goals for advanced pancreatic cancer are palliation and improved survival. Randomized clinical
trials have demonstrated survival and quality-of-life benefits to chemotherapy in selected patients with advanced pancreatic cancer compared with best supportive care alone.

A number of single agents have demonstrated clinical activity; however, no agent has demonstrated consistent complete or partial response rates greater than 20%. Gemcitabine has been accepted as first-line therapy for metastatic pancreatic cancer in patients with adequate performance status based on a phase III trial that compared bolus 5-FU with gemcitabine, with a primary end point being the “clinical benefit score.”⁸ Clinical benefit was defined as sustained (more than 4 weeks) improvement of one of the following parameters without worsening of any of the others: performance status, composite pain measurement (average pain intensity and narcotic analgesic use), and weight. The improvement in clinical benefit score in the gemcitabine and 5-FU arms were 23.8% and 4.8%, respectively (p = 0.0022). In addition, there was a significant improvement in median survival (5.65 vs. 4.41 months, p = 0.0025) and in survival at 12 months (18% vs. 2%). Therapy was generally well tolerated with a low incidence of grade 3 or 4 toxicities. The toxicities with gemcitabine include bone marrow suppression, lethargy, flulike syndrome, nausea and vomiting, and peripheral edema.

a. For many years, despite promising phase II studies, the combination of gemcitabine with other cytotoxic drugs, including 5-FU, cisplatin, oxaliplatin, and irinotecan, had not been proven to be superior to gemcitabine alone in demonstrating a survival benefit. The first phase III trial to demonstrate a benefit with combination chemotherapy was the U.K. National Cancer Research Institute study. This study randomized 533 patients to higher doses of gemcitabine and capecitabine versus gemcitabine alone and identified a trend toward improved median overall survival (7.1 vs. 6.2 months, p = 0.077) and a statistically significant improvement in overall progression-free survival at 12 months (13.9% vs. 8.4%, p = 0.004). A second phase III trial of 319 patients similarly showed a nonstatistically significant trend in median overall survival (8.4 vs. 7.2 months, p = 0.234) and 1-year survival rates (32% vs. 30%) in combination gemcitabine/capecitabine compared with gemcitabine alone. However, subgroup analysis showed that patients with a good performance status (KPS of 90 to 100) had a statistically improved median overall survival (10.1 vs. 7.4 months, p = 0.014) and progression-free survival (HR 0.69, p = 0.022) when treated with combination gemcitabine/capecitabine compared with gemcitabine alone. In addition, a meta-analysis of these
randomized trials comparing combination gemcitabine/capecitabine with gemcitabine alone identified a significant survival benefit in favor of the gemcitabine/capecitabine combination (p = 0.02).