How can I be sure that the patient has pancreatic adenocarcinoma?

Common signs and symptoms of pancreatic cancer include fatigue, abdominal pain often radiating to the back, jaundice, nausea with or without vomiting, anorexia, early satiety, and weight loss. Additionally, up to 80% of individuals with pancreatic cancer will be shown to have glucose intolerance or overt diabetes mellitus at diagnosis.

The usual constellation of clinical features includes abdominal pain, weight loss, anorexia, jaundice and, often, depression. Jaundice is a common, early sign in patients with pancreatic head tumors (constituting about 65% of all cases), while it is less likely to be present in patients with pancreatic body (15 %) and tail (10%) tumors. Jaundice may also be observed in the approximately 10% of cases in which the adenocarcinoma is multifocal.

A tabular or chart listing of features and signs and symptoms

Some of the characteristic features of later stage disease, in addition to pain, include migratory thrombophlebitis due to coagulation abnormalities, abdominal distention due to ascites, a palpable and enlarged liver, and a normochromic, normocytic anemia. Pathognomonic signs of pancreatic cancer include Courvoisier’s gallbladder (a palpable gallbladder in the presence of obstructive jaundice) and rectal shelf on physical exam, due to the presence of pelvic masses. Depression is often observed, even before the diagnosis has been made.

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Less common presentations include acute pancreatitis (presenting symptom in only about 1% of patients) and steatorrhea. Migratory thrombophlebitis is observed in about 10% of individuals with pancreatic cancer.

Signs and symptoms of pancreatic cancer are heterogeneous and are common to a number of benign or more serious conditions.

  • – For instance, the differential diagnosis of abdominal pain includes acute or chronic pancreatitis, intestinal obstruction, peptic ulcer, intestinal ischemia, and other forms of neoplasia (gastric, colon, endometrial, ovarian, gallbladder, ampullary).

  • – The differential diagnosis of jaundice includes gallstones (cholelithiasis) and other forms of gallbladder disease, such as cholecystitis, benign obstructive jaundice, hemolytic anemia, primary sclerosing cholangitis, gallbladder cancer, primary biliary cirrhosis, viral hepatitis, chronic hepatitis B or C, infiltrative hepatic diseases (Wilson’s disease).

  • – Malabsorption and/or steatorrhea can be caused by chronic pancreatitis, lactose intolerance, celiac disease, and sometimes inflammatory bowel disease.

  • – Anorexia/ early satiety may be the result of gastric outlet obstruction, diabetic or other form of autonomic neuropathy, gastritis, gastroesophageal reflux disease (GERD), duodenal or gastric ulcer, as well as other forms of neoplasia (ovarian, gallbladder, intrahepatic bile duct, ampulla of Vater, duodenal mucosal carcinoma).

  • – Weight loss can be a consequence of diabetes mellitus, infection (HIV, tuberculosis), collagen vascular disorder, other forms of neoplasia (ovarian, gallbladder, intrahepatic bile duct, ampulla of Vater, duodenal mucosal carcinoma). (See Table I.)

  • – Migratory thrombophlebitis (i.e., Trousseau sign, thrombophlebitis migrans) is a hypercoagulable state that is common in other forms of malignancies, such as gastric and lung cancer.

Table I.
Disease Characteristics Notes
Chronic pancreatitis Classic triad of pancreatic calcification, steatorrhea, and diabetes mellitus is observed in one-third of patients. Abdominal pain and weight loss are frequently present. Obstructive jaundice may also be present. Symptoms may be recurring and associated with features of intestinal malabsorption. Chronic pancreatitis is a recognized risk factor for pancreatic cancer. EUS, ERCP, or MRCP may be used to diagnose chronic pancreatitis and differentiate from pancreatic cancer, but differentiation may be difficult. Additional testing to exclude pancreatic cancer must be undertaken when the index of suspicion is high because chronic pancreatitis often co-exists with pancreatic cancer or dysplastic (pre-cancerous) lesions.
Pancreatic pseudocysts Pseudocysts should be suspected in patients with a recent history of pancreatitis and an elevated serum amylase level, especially when the cyst contains enzyme-rich watery fluid. Pseudocysts of the pancreas develop because of pancreatic inflammation and necrosis. They may be of any size, single or multiple, located within or outside the pancreas. The walls of the pseudocysts are formed by the pancreas and adjacent structures; they do not contain their own epithelium. Radiographic features and analysis of the cyst differentiate pseudocysts from cystic neoplasms of the pancreas.
Intraductal papillary mucinous neoplasm (IPMN) Same demographics as pancreatic cancer – typically affecting men more than women, and people ages 60-80 yrs. Symptoms include nausea, vomiting, pain, weight loss, and jaundice; occasionally presents as acute pancreatitis. Dilatation of the main pancreatic duct is associated with mucin overproduction, which is evident emerging from the ampulla of Vater at endoscopy. Main duct IPMN carries a higher risk of neoplastic transformation than side branch IPMN. Imaging studies with EUS, MRCP, or ERCP usually distinguish IPMN from pancreatic cancer. On imaging, IPMN is observed as multiple separate cysts with papillary projections located in the pancreatic head and uncinate process. Although CT and MRI cannot differentiate mucin content from pancreatic juice, communication between the cystic lesion and a dilated main pancreatic duct and a bulging papilla with a patent orifice are characteristics of IPMN. Correlation of the results of biopsy procedures with the endoscopic and radiographic appearances of the lesion by expert pathologist and radiologist is important for accurate diagnosis.
Mucinous cystadenoma Usually presents in young to middle-aged women as a single multilocular cyst located in the tail of the pancreas. Symptoms can be similar to pancreatic cancer: recurrent bouts of pancreatitis, chronic abdominal pain, and/or or jaundice are common. Mucinous cystadenomas are much less common than ductal pancreatic cancers. Up to 10% of pancreatic cystic lesions are neoplastic, which may be incorrectly diagnosed pseudocysts. These tumors are less aggressive than the common variety pancreatic cancers.
Carcinoma of the ampulla of Vater Usually presents with obstructive jaundice. ERCP is the best means to diagnose ampullary cancers.
Pancreatic endocrine (islet cell) tumors Patients frequently experience abdominal pain and rarely have jaundice; diarrhea and peptic ulceration are common and are related to hormone production. Rare tumors of the pancreas that may have an indolent clinical course. Histology is essential for the diagnosis. Specific histologic appearance and immunostaining will differentiate from pancreatic adenocarcinoma. Abnormal endocrine function may be detected through blood levels of various hormones.
Pancreatic lymphoma Commonly presents with abdominal pain and obstructive jaundice. Patients must be managed according to the stage of the disease. An atypical presentation of non-Hodgkin’s lymphoma that is highly responsive to chemotherapy and does not require surgery. Histology shows malignant lymphoid cell infiltration, which differentiates it from adenocarcinoma cells
Acute cholangitis Jaundice, abdominal pain, RUQ pain, tenderness, and fever are common symptoms. Cholangitis may rarely complicate biliary obstruction due to newly diagnosed pancreatic cancer. However, cholangitis as a presenting condition is unlikely for patients with pancreatic cancer.
Benign obstructive lesions of the bile duct (gallstones, strictures, etc.) Characterized by icterus, itching, anorexia, dark color urine, steatorrhea, abdominal discomfort, elevated serum bilirubin (direct) and serum alkaline phosphatase, dilated extrahepatic, and intrahepatic bile ducts. Diagnosis may be established by MRCP or an ERCP.
Distal cholangiocarcinoma Usually presents with obstructive jaundice, bile duct dilation. May be difficult to differentiate between a primary adenocarcinoma of the pancreas since the distal bile duct courses through the head of the pancreas. Surgery and, at times, imaging may assist in the differentiation from pancreatic cancer (surgery is the most reliable).
Gastric cancer Abdominal pain, anorexia, early satiety, dysphagia, and weight loss. Additional findings may include anemia and vomiting. Endoscopic examination will demonstrate a gastric mass.

How can I confirm the diagnosis?

Contrast-enhanced multidetector CT scan (using pancreas protocol CT with 1-mm sliced images) can achieve diagnosis at a rate of about 97%. This modality has a diagnostic accuracy for predicting that a tumor is not resectable of around 90% but is less accurate at predicting that a lesion is resectable (80-85%). Small hepatic metastases (<1 cm diameter) and small peritoneal deposits are difficult to see on CT. Lymph node staging can only be performed with accuracy in the setting of systematic biopsy. MRI is an appropriate alternative to CT in patients with obstructive jaundice. Initial serum tests should include a CBC with differential.

Patients who do not have conclusive results by multidetector CT or those for whom a preoperative diagnosis is desired should undergo endoscopic ultrasound (EUS). EUS is a great modality for detecting small pancreatic cancer mass lesions that cannot be visualized on CT and it is superior at visualizing biliary and pancreatic ductal abnormalities. While CT scan is better at evaluating for metastatic disease, EUS offers advantages for local staging (T, N). EUS is superior to CT in staging pancreatic cancer but similar for nodal staging and resectability of preoperatively suspected pancreatic cancer. Additionally, fine needle aspiration (FNA) at the time of EUS can reliably make a tissue diagnosis via histological verification.

When CT and EUS cannot confirm a diagnosis and a high degree of suspicion remains, MRCP or ERCP (magnetic resonance cholangiopancreatography; endoscopic retrograde cholangiopancreatography, respectiively) are the next logical tests, especially when the pancreaticobiliary system may be the location of the tumor or it is very small in size. ERCP is the best means of demonstrating ampullary tumors and also allows for simultaneous biliary stent placement.

Suspicion of pancreatic cancer → take a detailed history and perform physical exam, evaluating especially for abdominal distention (ascites), a palpable gallbladder, hepatomegaly, and enlarged supraclavicular lymph node(s) → draw serum lab work → proceed to multidetector, multislice detector CT with biopsy of a metastatic lesion, if present. EUS +/- FNA should be the next study if diagnosis is still in question or if preoperative tissue confirmation is necessary; rule out chronic pancreatitis and ampullary tumors. ERCP if biliary drainage is required, ideally following EUS. → If pancreatic cancer confirmed, determine resectability. If not confirmed, consider other diagnoses.

What other diseases, conditions, or complications should I look for in patients with pancreatic adenocarcinoma?

Pancreatic cancer is more common in African Americans than other racial and ethnic groups, increases in likelihood with advancing age, and has a higher incidence in men than in women. The most elevated risks are for individuals with a family predisposition to pancreatic cancer (risk increases multiplicatively with the greater number of affected first-degree relatives), hereditary pancreatitis patients, and those with a recognized cancer syndrome, such as Peutz-Jeghers syndrome or hereditary breast and ovarian cancer due to BRCA2 mutations.

Environmental and behavioral/host risks include cigarette smoking, obesity, diabetes mellitus, chronic pancreatitis, ABO blood group, and combinations of lifestyle factors, such as not maintaining a healthy weight, heavy alcohol consumption, lack of physical activity, and an unhealthful diet. Heavy alcohol consumption may be a risk factor on its own.

Chronic pancreatitis, diabetes mellitus, exocrine pancreatic insufficiency, thromboembolic disease (DVT, PE), acute cholangitis, malnutrition; COPD may be seen in heavy smokers; liver disease may be observed in heavy drinkers, especially those with chronic pancreatitis.

Complications related to resective surgery include delayed gastric emptying, pancreatic duct fistula development, malnutrition, infection and thromboembolism – the last three are common even in nonsurgical patients. Other complications of disease progression include biliary obstruction, gastric outlet (duodenal) obstruction, severe/intractable disease-related pain, acute cholangitis, diabetes, exocrine pancreatic insufficiency, thromboembolic disease, and depression. Side effects of chemotherapy for patients who receive it include neutropenia and fever. (See Table II.)

Table II.
Complication Comments and magnitude of risk
Postoperative complications include early delayed gastric emptying, pancreatic fistula, malnutrition, infection, and thromboembolism. Incidence of postoperative complications is about 30%; factors include preoperative comorbidities and operative factors; fewer complications typically encountered for surgeons with higher case volume.
Biliary obstruction Biliary obstruction is common and develops in about 65-75% of all pancreatic cancer patients.Surgical decompression at the time of surgery is recommended for patients with resectable disease.Endoscopic placement of an expandable metallic biliary stent is recommended for patients with unresectable disease.Percutaneous transhepatic drainage of bile and insertion of a stent is recommended for patients who are unable to undergo ERCP or for whom endoscopic stenting of the bile duct has been unsuccessful.Palliative choledochojejunostomy or hepaticojejunostomy during laparotomy is recommended when pancreatic resection is attempted but found to be impossible.In patients who are surgical candidates, carefully consider the need for preoperative biliary drainage due to its potentially increased rate of complications.
Duodenal obstruction About 15-20% of patients with pancreatic cancer will develop a duodenal blockage; in one study of 39 patients, 9 patients presented with and 3 patients very quickly developed duodenal obstruction. Endoscopic duodenal metallic stent placement may be the best short-term method of relieving this complication in patients with poor performance status and gastrojejunostomy – laparoscopic or open – should be undertaken for unresectable pancreatic cancer patients with better performance status.
Pain Pain is very likely in pancreatic cancer patients – about 80% or more of all patients will experience significant pain and it is a common presenting symptom. Pain may be difficult to control in the ambulatory setting. A tiered approach to medication is warranted and hospitalization for intractable pain may be warranted. EUS-guided celiac plexus neurolysis and palliative chemoradiation may provide relief for intractable pain.
Acute cholangitis Acute cholangitis is a common complication of biliary obstruction, especially in the presence of biliary stents. Infections can be very serious and require close clinical monitoring, obtaining blood cultures, starting broad spectrum IV antibiotics.
Neutropenia and fever Induced by chemotherapy, patients should be admitted to the hospital for management of symptoms and potentially life-threatening infections.
Endocrine and exocrine failure Late stage complication that may be presenting symptom for some patients; more often develops months after diagnosis; exocrine should be treated with enteric-coated pancreatic enzymes, whereas endocrine insufficiency necessitates insulin.
Thromboembolic disease Develops in about 10% of all patients; low molecular weight heparin is preferable to warfarin for treatment of pulmonary embolism.

What is the right therapy for the patient with pancreatic adenocarcinoma?

The first step in deciding on treatment is to determine whether the patient’s tumor is resectable or nonresectable.

Resectable pancreatic tumors would be described as a tumor that has not metastasized to nearby organs (liver, peritoneum), that does not involve the superior mesenteric or portal venous system, and that does not encase the superior mesenteric, celiac, or hepatic artery.

Borderline resectable/locally advanced tumors are those that may involve the superior mesenteric or portal vein but hold the possibility of reconstruction, that abut the celiac or superior mesenteric artery, and that may invade the colon, mesocolon, or stomach.

Unresectable tumors are those that demonstrate distant metastases (liver, peritoneal, etc.) and encase the superior mesenteric, celiac, or hepatic artery; portal or superior mesenteric venous invasion, in which the degree of obstruction does not allow for reconstruction; lymph node metastases, which are outside of the field of dissection; and severe concomitant disease.

Resection should be attempted when imaging indicates that it is possible; adjuvant chemotherapy or chemoradiation has been shown to prolong survival post resection and is recommended for all patients who are healthy enough to be treated. For borderline tumors, neoadjuvant chemoradiation is currently recommended for potential downstaging and is commonly being given at many treatment centers. Unresectable, metastatic disease should be treated with one of the therapeutic regimens described below. Clinical trials are recommended for all pancreatic cancer patients, especially those whose cancer is not resectable. Palliative treatments include pain management, alleviation of biliary or gastric outlet obstruction, treatment of infections or thrombophlebitis, and monitoring of nutrition and depressive symptoms. Radiotherapy directed toward the primary tumor bed with a margin is an effective form of palliative treatment for pain and obstruction in nonsurgical candidates.

Surgical resection (pancreaticoduodenectomy for tumors of the pancreatic head, neck, or uncinate body and distal pancreatectomy for tumors of the body and tail of the pancreas), chemotherapy, combined treatment with chemotherapy and chemoradiation, radiation to the tumor bed (for palliation), biliary stenting or equivalent measure for biliary obstruction such as choledochojejunostomy, gastrojejunostomy or endoscopic duodenal stenting for duodenal obstruction, opiate pain medications or celiac plexus block for severe pain, pancrelipase enteric-coated enzymes for pancreatic exocrine insufficiency and malnutrition, insulin for endocrine insufficiency, antidepressants for severe depression, clinical trials of novel agents and therapies for all stages of pancreatic cancer, and a palliative medicine team for end-of-life care.

What is the most effective initial therapy?

Initially, the status of the cancer must be determined in order to proceed with proper treatment. If the cancer is believed to be resectable, proceed to Whipple procedure or distal pancreatectomy, depending on the location of the primary tumor. At laparascopy, true resectability will be recognized and tissue sampling for diagnostic verification should be undertaken; for those deemed unresectable at laparoscopy, stent placement should be performed if biliary obstruction exists. For unresectable tumors, determine whether cancer is of borderline resectability (see following section), locally advanced, or metastatic, Determine patient performance status and the best treatment regimen for appropriate patients.

Patients with locally advanced or metastatic disease should be informed of relevant clinical trials or should be treated if they are felt to be of appropriate performance status to tolerate the side effects of cytotoxic therapy. The regimen of therapy depends mainly on the performance status of patient. Evaluation for chemotoxicity should take place prior to giving chemoradiation. If/when metastatic disease occurs, patients are not candidates for additional chemoradiation unless it is used exclusively for palliation.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Early stage cancer. Resection and adjuvant treatment for patients with good performance status. Controversy remains about whether chemotherapy alone or chemoradiation is the most effective treatment. At this time, accepted adjuvant regimens in the United States include chemotherapy with 5-FU/leucovorin or gemcitabine OR gemcitabine chemotherapy combined, sequentially, with 5-FU-based chemoradiation. Survival at 5-years following surgery and adjuvant therapy is about 10% to 20% and has been shown to be significantly lower among patients not treated adjuvantly. Unfortunately, about 25% of all post-resection patients are not healthy enough to receive additional treatment following their surgery.

Locally advanced disease. Mono or combination chemotherapy can be given prior to chemoradiation for unresectable, locally advanced pancreatic cancer in hopes that the patient’s tumor will be converted to resectable. The majority of patients progress during this time period, however, and are no longer surgical candidates after their combined therapy has been completed. These patients can be treated with a chemotherapy type that they have not previously received, and they are excellent candidates for clinical trials. The expected result of therapy is disease stability and improvement in quality of life.

Metastatic disease. Gemcitabine alone, gemcitabine in combination with capecitabine, gemcitabine combined with erlotinib, or the combination of gemcitabine, docetaxel, and capecitabine. Alternatively, combination treatment with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) has recently been shown to be an effective treatment in younger individuals with better performance status. The anticipated result of therapy is lack of disease progression and improvement, or lack of degradation, in patient quality of life.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Second-line therapy includes gemcitabine for patients who have not received it previously, or capecitabine, or 5-FU/leucovorin/oxaliplatin, or CapeOx. For evidence of metastatic disease following adjuvant treatment of resected pancreatic cancer, if the metastases are noted prior to 6 months after completing adjuvant treatment, a different form of chemotherapy should be chosen. For evidence of metastatic disease that is noted 6 months or more following adjuvant treatment, the same type of chemotherapy can be used as was initially used. Chemoradiotherapy should be considered only for those who have not received it previously and is only appropriate for local disease recurrence.

Salvage chemotherapy consists of gemcitabine monotherapy or combination therapy for patients previously treated with fluoropyrimidine-based therapy and fluoropyrimidine-based therapy for those previously treated with gemcitabine. Adding oxaliplatin to 5-FU/leucovorin may provide a survival advantage, based on the results of the CONKO 003 trial.

There are numerous potential side effects of chemotherapeutic treatment, radiotherapy, and opiate pain medications, which are listed below. Complications from surgery are described above.

Listing of these, including any guidelines for monitoring side effects.

Side effects of chemotherapy vary by the agent used but generally include myelosuppression, neutropenia, anemia, increased risk of infection, mucositis, diarrhea, hand-foot syndrome (5-FU), fatigue, anorexia, nausea, vomiting, skin rash, edema, lung toxicity, hypercoaguability, fever, headache, mouth sores (stomatitis), dizziness, cholinergic syndrome, asthenia, alopecia, dyspnea, arthralgia, and myalgia. Side effects are monitored during and after treatment; severe side effects requiring hospitalization, such as neutropenia and fever, necessitate at least temporary, if not permanent, cessation of chemotherapy to allow for patient recovery and return to baseline performance status. Significant side effects may result in permanent discontinuation of treatment.

Side effects of radiotherapy include fatigue, which may be extreme; redness and itching of skin in the area of treatment; bronzing of skin and hair loss in the area of treatment; nausea; vomiting; diarrhea; anorexia constipation; and other gastrointestinal effects. Side effects are very common during radiotherapy treatment and are monitored consistently by the treatment team.

Side effects of morphine and fentanyl include nausea, vomiting, constipation, pruritus, sedation, confusion, lethargy, respiratory depression, miosis, hypotension, biliary spasm, and bradycardia. Excessive systemic side effects to the opiates may be ameliorated by switching drug classes or by the intrathecal administration of drugs.

How should I monitor the patient with pancreatic adenocarcinoma?

Pancreatic cancer patients who have undergone resective surgery should be monitored at regular intervals, although data regarding surveillance remain limited. Recommendations are that a history and physical be performed every 3 to 6 months for symptoms of recurrence and then annually thereafter. CT scan and serum CA 19-9 are also used to assess for recurrence at 3- to 6-month intervals for 2 years and annually thereafter, although this regimen is not followed unanimously by all treating physicians. PET/CT, abdominal ultrasound and chest X-ray are also used by many physicians to assess for recurrence.

There are no standard guidelines for disease monitoring in patients who have not undergone pancreatic resection, although abdominal, thin-slice CT, and PET/CT are surveillance modalities, following treatment for locally advanced and metastatic disease, which are used every 2 to 3 months to monitor disease progression for the duration that they are in treatment. If a patient decides against treatment, he or she will typically not be monitored. However, every time a new form of treatment is initiated, monitoring will be re-instituted.

Patients should be hospitalized and treated for biliary or duodenal obstruction, acute cholangitis, severe pain, neutropenia and fever, and malnutrition. A multidisciplinary palliative care center is a good setting in which to address symptoms of potentially fatal disease progression in a coordinated and holistic manner.

Patients are monitored as described above, at regular intervals during treatment to assess for signs of disease progression, such as increase in tumor burden, local invasion, or new metastases. Response to treatment for pancreatic cancer patients is characteristically poor. Nonresponse to treatment or disease progression may present the opportunity to give a novel form of therapy, a form of therapy not previously used, or for the patient to enter into a clinical trial. Palliative measures are recommended to maintain patient quality of life as needed in conjunction with treatment and when treatment failures occur.

What's the evidence?

Jiao, L, Mitrou, PN, Reedy, J. “A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study”. Arch Intern Medi. vol. 169. 2009. pp. 764-70. (Study observes strong evidence that preventive measures, such as physical activity, may be able to help decrease pancreatic cancer risk.)

Conroy, T, Desseigne, F, Ychou, M. “for the Groupe Tumeurs Digestives of Unicancer; FOLFIRINOX versus gemcitabine for metastatic cancer”. N Engl J Med. vol. 364. 2011. pp. 1817-25. (Work shows how a combination chemotherapy may prolong survival time for patients with incurable disease.)

Brand, RE, Lerch, MM, Rubinstein, WS. “Advances in counseling and surveillance of patients at risk for pancreatic cancer”. Gut. vol. 56. 2007. pp. 1460-9. (This article is the first comprehensive review on pancreatic cancer surveillance in high-risk cohorts.)

Neoptolemos, JP, Stocken, DD, Friess, H. “A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer”. N Engl J Med. vol. 12;351. 2004. pp. 726-10. (This work demonstrated a survival advantage in individuals who received chemotherapy only vs. those who received chemoradiotherapy or had no postsurgical treatment.)

van der Gaag, NA, Rauws, EA, van Eijck, CH. “Preoperative biliary drainage for cancer of the head of the pancreas”. New Engl J Med . vol. 362. 2010. pp. 129-37. (This study observed a greater likelihood of postsurgical complications for individuals who had undergone preoperative biliary drainage.)

Yeo, CJ, Cameron, JL, Lillemoe, KD. “Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients”. Annals of Surgery. vol. 221. 1995. pp. 721-31; discussion 31-3. (A sizeable series of patients treated surgically for cancer of the pancreatic head are described in this article; results demonstrated tumor size, lymph nodes, and margins were most significant survival effectors.)

Egawa, S, Takeda, K, Fukuyama, S. “Clinicopathological aspects of small pancreatic cancer”. Pancreas. vol. 28. 2004. pp. 235-40. (This frequently cited article demonstrates considerable advantage to the limited number of individuals with true stage I disease at diagnosis.)

Burris, HA, Moore, MJ, Andersen, J. “Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial”. J Clin Oncol. vol. 15. 1997. pp. 2403-13. (This study established gemcitabine as the standard treatment for unresectable, locally advanced or metastatic pancreatic cancer.)

Wong, GY, Schroeder, DR, Carns, PE. “Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial”. JAMA. vol. 291. 2004. pp. 1092-9. (Study demonstrates how optimal pain control may significantly improved quality of life and that celiac plexus block may improve pain control more than opioid-only analgesics.)

Greer, JB, Brand, RE. “New developments in pancreatic cancer”. Curr Gastroenterol Rep . vol. 13. 2011. pp. 131-9. (Work describes the most recent updates in prevention, diagnostics, and treatment of pancreatic adenocarcinoma.)