Hospital Medicine

Pancreatic Cancer

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I. What every physician needs to know.

Pancreatic cancer is one of the most fatal forms of cancer as it typically presents at an advanced stage and can be challenging to treat. It is the fourth leading cause of cancer death in the United States for both men and women, and the overall 5-year survival rate is <5%. Because of the high mortality rate associated with this disease, the incidence and prevalence are nearly the same. The incidence of pancreatic cancer ranges from 1 to 10 per 100,000 people, and has been noted to be higher in developed countries and among men. In 2014, there were an estimated 46,420 new cases of pancreatic cancer, with 39,590 estimated deaths that same year. Eighty percent of patients present with advanced and unresectable disease and the majority of patients die with one year of diagnosis.

II. Diagnostic Confirmation: Are you sure your patient has Pancreatic Cancer?

Tissue biopsy is needed to confirm the presence of pancreatic cancer. Laboratory data and imaging can be useful in raising suspicion for the disease but tissue diagnosis is needed to proceed with treatment. Other diagnoses that can mimic pancreatic cancer include other malignancies, benign tumors, chronic pancreatitis and autoimmune pancreatitis.

A. History Part I: Pattern Recognition:

The symptoms of pancreatic cancer can be fairly non-specific. Patients may complain of malaise, vomiting, constipation, flatulence or bloating, unintentional weight loss or painless jaundice. In fact, 70% of patients will present with these complaints.

Symptoms are dependent on the size and location of the tumor within the pancreas. Lesions in the head of the pancreas often cause biliary obstruction and these patients often present with painless jaundice and other symptoms associated with hyperbilirubinemia such as clay colored stools and dark urine. Patients with lesions in the tail of the pancreas often present with more progressive disease because they do not typically develop biliary obstruction and instead usually present with abdominal pain, which is typically a late symptom. Abdominal pain usually occurs because of invasion of the tumor into or near the celiac or mesenteric plexus. Additionally, patients can develop back pain if they are having retro-peritoneal invasion.

Patients can also develop diabetes as the tumor size begins to interfere with beta cell function. In fact, sudden onset of diabetes in an older adult can be a finding that should raise suspicion for pancreatic cancer. Other symptoms of pancreatic dysfunction such as steatorrhea can also develop. Additionally, patients can have other non-specific complaints related to fever of unknown origin or migratory thrombophlebitis.

B. History Part 2: Prevalence:

Pancreatic cancer most commonly affects older adults. The median age of diagnosis is 71 years old with the peak incidence between 60 and 80 years old. It is unusual to find disease in patients under the age of 40.

Risk factors associated with pancreatic cancer includes smoking, with a 2 to 3 times increased risk relative to the general population. Other risk factors include nonhereditary chronic pancreatitis (2 to 6 times), long standing diabetes (2 times), obesity/inactivity or both (2 times), and non-O blood group (1 to 2 times).

Genetic syndromes are also associated with an increased risk of developing pancreatic cancer. Hereditary pancreatitis (associated with genes PRSS1, SPINK1), a rare autosomal dominant disorder that can lead to chronic pancreatitis confers a 50 fold increased risk. Other associated genetic syndromes include Peutz-Jeghers syndrome with a 30 to 40 times increased risk, familial atypical multiple mole and melanoma syndrome with a 10 to 20 times increased risk, and hereditary nonpolyposis colon cancer (Lynch syndrome) with a 4 times increased risk. Also of note, hereditary breast and ovarian cancer syndromes (BRCA1, BRCA2, PALB2) are associated with pancreatic cancer, with a 1-2 times increased risk. Other syndromes that have been associated but their relative risk has not been quantified includes ataxis-telangiectasia (ATM) and Li-Fraumeno syndrome (P53).

Also, tropical pancreatitis, seen predominantly in South India and Africa, can lead to early onset diabetes and pancreatic calcifications and is associated with a probable increased risk.

C. History Part 3: Competing diagnoses that can mimic Pancreatic Cancer.

Other diagnoses that can mimic pancreatic cancer include other malignancies, benign tumors, chronic pancreatitis and autoimmune pancreatitis. Chronic pancreatitis can cause the abdominal pain, pancreatic dysfunction and strictures seen in pancreatic cancer. Imaging typically helps to further evaluate this possibility. Autoimmune pancreatitis is rare but can cause many of the symptoms and findings associated with pancreatic cancer. Patients can have pancreatic masses and strictures which can cause painless jaundice and many of the other symptoms associated with pancreatic cancer.

There are several clues that can help to differentiate autoimmune pancreatitis from pancreatic cancer. For instance, autoimmune pancreatitis is often associated with diseases outside the pancreas such as retroperitoneal fibrosis, sclerosing cholangitis and sclerosing sialedenitis. Also, patients will have brushings and biopsies taken that are negative for malignancy. Additionally, further lab work-up can reveal an elevated gamma globulin, total IgG and IgG4.

Elevated IgG4 is the most sensitive and specific test for autoimmune pancreatitis. Imaging in patients with autoimmune pancreatitis can also differ from pancreatic cancer in that it often reveals diffuse enlargement of the pancreas and there can be an encasing capsule. Autoimmune pancreatitis also generally has an excellent response to steroid therapy, which can, in some cases, also help to differentiate it from pancreatic cancer.

D. Physical Examination Findings.

Because of the location of the pancreas deep in the abdominal cavity, signs of pancreatic cancer typically develop with more advanced disease. The most common sign will be painless jaundice and icterus which occurs if there is an obstructing mass in the head of the pancreas. Another sign associated with pancreatic head tumors is a palpable gallbladder, also known as Courvoisier's sign. Also, depending on body habitus and location of the tumor, a palpable mass may be felt in the upper abdomen or epigastric region.

Other signs can be observed when the disease is complicated by thrombosis. For instance, patients can have splenomegaly or ascites associated with compression or thrombosis of the splenic or portal veins or can develop lower extremity edema associated with obstruction of the vena cava. The presentation of a thrombus in the setting of malignancy is referred to as Trousseau's Syndrome, and this can be a common presenting symptom of pancreatic cancer. A rare finding is a palpable supra-clavicular lymph node, also known as Virchow's node.

E. What diagnostic tests should be performed?

There are no specific physical examination findings that confirm the diagnosis. Labs can be helpful in guiding diagnosis but imaging and biopsy are needed to confirm the presence of malignancy.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are several abnormalities that will be noted on the basic labs of a patient with pancreatic cancer. Lab abnormalities that are associated with chronic disease such as anemia and hypoalbuminemia will generally be seen. Additionally, if the patient has a tumor causing biliary obstruction, elevated alkaline phosphatase and bilirubin levels will be seen on the hepatic panel. Patients can also have evidence of impaired glucose tolerance as the tumor becomes large enough to affect beta cell function.

There is no serum marker that is useful in screening for pancreatic cancer. The most utilized tumor marker is carbohydrate antigen 19-9 (CA 19-9) but this is not specific for pancreatic cancer. CA 19-9 levels can be elevated in malignancies of the colon, stomach and biliary tree, as well as more benign medical conditions such as hepatitis, pancreatitis, cholangitis, cirrhosis and biliary obstruction. If a patient initially presents with obstructive jaundice, the CA 19-9 level should not be checked until this issue has been addressed with decompression as an elevated bilirubin can falsely elevate the CA 19-9 level. The sensitivity and specificity of the CA 19-9 level in pancreatic cancer are 70-90% and 43-91% respectively. It is most useful to measure CA 19-9 levels once the diagnosis has been made and then use it to monitor response to treatment or to aid in prognosis. In addition, an estimated 10% of patients with pancreatic cancer will not be able to synthesize CA 19-9 (due to being negative for Lewis antigen a or b) and will have undetectable levels.

Pathology studies

A tissue biopsy is the only way to confirm the diagnosis of pancreatic cancer. Biopsies of pancreatic lesions are typically done using fine needle aspiration (FNA) in conjunction with endoscopic ultrasound (EUS). Also, metastatic lesions can be biopsied if they are more readily accessible. A negative FNA biopsy does not rule out cancer. In this case, a core biopsy or excisional biopsy may be needed.

The most common type of pancreatic cancer is ductal infiltrating adenocarcinoma (DIA). This originates from ductal epithelial cells and accounts for greater than 80% of pancreatic cancers. There are multiple other less clinically common types of pancreatic cancer. The tissue type will generally not change the management of the patient but can in some cases, change the prognosis.

Pancreatic cancer is staged by a TNM system produced by the American Joint Committee on Cancer (AJCC). Stage I disease is limited to the pancreas with no lymph node involvement. Stage IIa disease is tumor that extends outside the pancreas but does not involve the celiac axis or SMA or any lymph nodes. Stage IIb disease occurs when a lymph node is involved. Stage III disease is tumor that involves the celiac axis or SMA but has no metastasis. Stage IV disease is metastatic.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Ultrasound is often the first imaging modality used to investigate the most common presenting complaint of obstructive jaundice. It provides good accuracy in terms of evaluating for biliary obstruction but is operator dependent and can be limited by large body habitus or by bowel gas. It is able to identify the cancer 57-81% of the time. The sensitivity of ultrasound improves as the tumor enlarges and it is best at identifying tumors greater than 3 centimeters.

Computed Tomography (CT) scan is the most often used imaging modality for both diagnosis and staging. The CT pancreas protocol is triphasic, with an arterial, late arterial and venous phase. Pancreatic cancers are not generally very vascular and are easiest to see in the parenchymal phase of the image. The enhancement between the parenchyma and the tumor is generally greatest during the late arterial phase, while hepatic metastases are generally best seen on the venous phase.

CT scanning can also help to determine if the tumor is resectable because resectability depends, in part, on vascular involvement and good views of the celiac axis, superior mesenteric artery (SMA), superior mesenteric veins (SMV), portal and splenic veins can generally be obtained. Additionally, common metastases such as peritoneal or hepatic lesions are generally well visualized. The sensitivity of CT scanning for pancreatic cancer is 86%. Once the diagnosis of pancreatic cancer is made, CT scan is also used to stage the disease. Non-contrast imaging of the chest in concert with contrast examination of the abdomen and pelvis is generally performed.

Magnetic Resonance Imaging (MRI) is an acceptable alternative to CT scanning but has not been found to be superior. It can be a good option if there is a contraindication to CT scanning such as a contrast allergy. It does give excellent views of the pancreatic duct and biliary tree and can be used to determine the effect of the tumor on these structures.

Endoscopic ultrasound (EUS) is also frequently used, especially to biopsy lesions. While it is more invasive, operator dependent and expensive than CT scanning, it is also more sensitive, especially when there is a small or peri-ampullary tumor. The sensitivity of EUS is 93-100%. Additionally, real time FNA of the lesion can be performed with EUS and this has been found to be safer than CT-guided biopsy. EUS is superior to CT scanning for staging of the actual pancreatic tumor but is not superior for staging structures outside of the pancreas such as lymph nodes.

Endoscopic Retrograde Cholangiopancreatography (ERCP) can be helpful to evaluate the effect of the tumor on the pancreatic duct and to identify and potentially relieve the source of obstruction by stenting. Additionally, it offers the opportunity to obtain brushings for cytology. If resection of the tumor is planned, stenting is generally not performed prior to surgery as it can lead to intra-operative and post-operative complications. However, it is sometimes performed pre-operatively if a long lag time prior to surgery is anticipated.

Positron Emission Tomography (PET) can be used for evaluating small tumors and metastases. There will likely be an emerging role for PET-CT scanning but there is currently no data to suggest that this imaging modality is superior to other available methods.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Obtaining CA 19-9 levels before the diagnosis of pancreatic cancer is made and before hyperbilirubinemia is corrected is generally not helpful. CA 19-9 levels can be elevated in other malignancies and in more benign medical conditions such as hepatitis and biliary obstruction. The CA 19-9 level can also be falsely elevated if the serum bilirubin level is high.

III. Default Management.

After the initial basic work-up is complete, consultation will be needed to aid in diagnosis and treatment. The diagnosis can only be confirmed by tissue biopsy. Which site to biopsy will likely depend on which lesions are present on imaging. Metastatic lesions may be more accessible and biopsy can be performed by radiology or surgery. More commonly, consultation with gastroenterology is performed for EUS and biopsy. While awaiting diagnosis, supportive care should be offered for treatment of symptoms.

Once the diagnosis is made, consultation with a multi-disciplinary team should be initiated. These teams generally consist of surgery, medical oncology, gastroenterology and possibly radiation oncology. Additionally, palliative care consultation is often needed.

A. Immediate management.

While awaiting diagnostic confirmation and staging, supportive care should be offered for symptoms such as pain and nausea. Additionally, a discussion should be initiated with the patient about goals of care and the level of invasive care that they might desire.

B. Physical Examination Tips to Guide Management.

Physical exam findings will vary depending on the burden of disease and location of metastases. In general, patients are at risk for and should be monitored for signs of:

- worsening jaundice

- cholangitis

- ascites

- hepatic encephalopathy

- coagulopathy and bleeding

- duodenal obstruction

- thromboembolic disease

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Patients with signs of worsening hepatic dysfunction may need to have hepatic function tests monitored intermittently as it may influence the timing or urgency of surgery or biliary decompression. Patients with significant intolerance to oral intake from nausea or pain may need intermittent monitoring of electrolytes and renal function. Patients with glucose intolerance secondary to a high burden of pancreatic disease may need monitoring of blood glucose finger sticks three to four times per day.

D. Long-term management.

Long term management of the disease will be determined by the stage of the disease. The stages of pancreatic cancer are generally divided into four categories. Stage I disease is resectable, stage IIa or IIb is borderline resectable, stage III is locally advanced and unresectable and stage IV is metastatic. The only opportunity for cure is with surgically resectable disease and the vast majority of patients will present with unresectable disease. There are multiple therapeutic interventions:

Surgery

Surgical candidacy is generally determined by imaging and staging. Generally, patients will not have evidence of metastases and will not have too much invasion of local vascular structures. Important nearby arterial structures are the SMA and the celiac, hepatic arteries. Patients generally need to have clear fat planes around these structures and tumor that does not surround more than 180 degrees of the arteries. Additionally, patients with significant involvement of the SMV or portal vein or with substantial venous thrombosis may not be candidates.

Surgical strategy will depend on the location of the tumor. The majority of tumors occur in the head of the pancreas and a Whipple procedure (pancreaticoduodenectomy) will be performed. The gallbladder, gastric antrum or duodenum, proximal jejunum and pancreatic head will be removed. If the tumor is located in the pancreatic body or tail, a distal pancreatectomy will be performed, frequently in conjunction with splenectomy. Extended lymphadenectomy has been studied and has thus far not been shown to improve survival and is thus not generally performed.

In the past, these pancreatic surgeries were associated with higher mortality rates but with improved techniques, the mortality rate in high volume centers is less than 5%. However, surgical morbidity can still exist in the form of abscess, leaks and fistula formation. When surgery is performed and yields microscopically negative margins, the 5-year survival improves significantly to 20-25%. However, despite efforts at standardization, there can be microscopically positive margins in 16-85% of cases. After surgery, recurrence of ductal adenocarcinoma does occur in approximately 80% of patients within 2 years.

Adjuvant therapies

Adjuvant therapy is therapy given after surgical resection. Several studies in the last several years have established that when compared to observation, adjuvant chemotherapy after surgery is recommended for 6 months of either gemcitabine or fluorouracil and improves overall survival. Radiation therapy remains controversial. There are conflicting data about the benefits of radiation and the majority of European centers do not offer radiation. There are a number of clinical trials underway to further elucidate the optimal treatment for pancreatic cancer and patients should be encouraged to enroll in these.

Neoadjuvant therapy

This is chemotherapy or radiation given before surgical intervention. There is not enough data to support a standard protocol. Most centers will consider neoadjuvant therapy for patients with borderline resectable disease, with the hope that the disease may become resectable after treatment. It may also be considered for patients with medical co-morbidities that might delay surgery or for patients with findings on imaging that might suggest the presence of metastases.

Some centers may also give neoadjuvant therapy to patients with resectable disease. The rationale for this strategy is that it may improve the chances of achieving a margin negative resection or that patients may be able to tolerate chemotherapy or radiation better before surgery. Clinical trials continue in order to clarify this issue. If patients do receive neoadjuvant therapy, they should be restaged prior to surgery.

Therapy for unresectable or metastatic disease

There have been strides in the last several years regarding chemotherapy for patients with metastatic disease, in particular those with good performance status. A study that analyzed treatment with gemcitabine alone vs combination chemo with FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin, and leucovorin) showed significant improvement in median survival, global health status and quality of life. Another trial studying gemcitabine alone vs gemcitabine + nab-paclitaxel also showed improved survival. These treatments are primarily for patients with good functional status (Eastern Cooperative Oncology Group [ECOG] Performance Status 0 or 1) and with limited comorbid conditions. Treatment strategies will vary based on the specific disease and the patient's functional status. For patients with metastatic disease and poor functional status, chemotherapy with gemcitabine either alone or with other agents is the most common therapy and is offered in conjunction with other palliative measures.

Long-term palliative and supportive management

The median survival for patients with unresectable cancer is approximately 7 months. As the disease becomes more progressive, symptoms associated with biliary obstruction, duodenal obstruction, pain and pancreatic insufficiency can become significant. However, there are multiple treatment modalities available to palliate these symptoms.

Biliary obstruction can cause worsening jaundice, coagulopathy and liver failure. The least invasive and preferred method for addressing this is endoscopic placement of a stent at the site of the obstruction. Plastic stents are generally less durable and are generally used for patients with a shorter life expectancy while self-expanding metal stents are preferred for patients with a longer prognosis. Stents can become obstructed resulting in cholangitis and the need for further intervention.

Surgery can also be used to address biliary obstruction and can be performed during an attempted resection if full resection is not found to be possible. An anastomosis is made from the biliary tree to the intestine. The site of anastomosis will depend on which area is obstructed. Percutaneous biliary drainage is another available option if endoscopy or surgery cannot be performed.

Duodenal obstruction occurs in 11-20% of patients with pancreatic head tumors and can cause significant symptoms. Endoscopic placement of a stent is generally safe and effective but is less helpful in patients with multiple sites of obstruction or with more distal obstruction. Surgical intervention with gastric bypass (gastroenterostomy) is another option and can also be performed during an attempt at resection. Another option for patients unable to tolerate either procedure is placement of a percutaneous endoscopic gastrostomy (PEG) tube.

Pain is another significant symptom for patients with pancreatic cancer. Celiac plexus ablation can help to significantly reduce the need for narcotic pain control and has been found to be underutilized. Celiac plexus neurolysis (CPN) can be performed surgically or percutaneously. Generally, a 50% alcohol solution is injected into the celiac plexus. The procedure can be performed percutaneously guided by ultrasound, endoscopy, CT or fluoroscopy.

Another supportive care measure is treatment of pancreatic insufficiency with supplemental pancreatic enzymes. This can lead to decreased steatorrhea and can aid with weight gain.

E. Common Pitfalls and Side-Effects of Management.

Treatment of pancreatic cancer is developing and there are new studies that are shaping the way that it is approached. Patients with the most favorable outcomes are treated at centers that manage at least 5-20 cases per year and have a multi-disciplinary team for treatment planning.

A. Renal Insufficiency.

Gemcitabine must be used with caution in patients with renal insufficiency. No standard dose adjustments exist but dose reduction is usually indicated. Additionally, gemcitabine has been associated with hemolytic uremic syndrome so monitoring of renal function during administration is indicated.

B. Liver Insufficiency.

Gemcitabine and Fluorouracil (5-FU) must be used with caution in patients with liver insufficiency. There are no standard dose adjustments but patients will usually need a dose reduction. Additionally, gemcitabine can cause a temporary rise in liver enzymes. Close monitoring of hepatic function may be indicated if this occurs.

C. Systolic and Diastolic Heart Failure.

5-FU is the second most common cause of chemotherapy induced cardiotoxicity after anthracyclines. It may cause coronary vasospasm which can result in various cardiac issues such as pulmonary edema, chest pain, myocardial infarction or arrhythmia. Patients with ischemic heart failure are likely at higher risk for these events.

D. Coronary Artery Disease or Peripheral Vascular Disease.

5-FU can cause cardiotoxicity, likely by inducing vasospasm. This can result in chest pain, myocardial infarction, pulmonary edema or arrhythmia. If these problems occur, the agent will likely need to be stopped indefinitely. Patients with pre-existing coronary artery disease are likely at higher risk for this complication.

E. Diabetes or other Endocrine issues.

Many patients with large or progressive tumors may have or develop beta cell dysfunction. If this occurs, these patients may need to be initiated on insulin therapy.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients on chronic steroids who are going to undergo surgery for definitive resection or palliation will require stress dose steroids in the peri-operative period.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

Patients will commonly have symptoms of pancreatic dysfunction and weight loss. Support with pancreatic enzyme supplements can improve symptoms such as steatorrhea and can also help with weight gain.

J. Hematologic or Coagulation Issues.

Patients are at high risk for thromboembolic disease. For patients who develop thromboembolic disease, treatment with low molecular weight heparin is preferred over warfarin therapy.

K. Dementia or Psychiatric Illness/Treatment.

Patients will have a variety of complex medical and end of life decisions to make. This can be significantly complicated by psychiatric disease or dementia. Identification of proxy decision makers should be a priority. Consultation with psychiatry may be indicated if the patient's capacity for decision making is in question.

A. Sign-out considerations While Hospitalized.

One of the most important elements of information that should be passed along during sign out is goals of care. Patients with pancreatic cancer can have abrupt decompensations and knowing the level of invasive care desired by the patient is necessary. Patients are at risk for acutely developing:

- cholangitis

- hepatic encephalopathy

- coagulopathy and bleeding

- duodenal obstruction

- thromboembolic disease

B. Anticipated Length of Stay.

There is no typical length of stay. Length of stay will depend on disease burden and treatment planning. Some patients may need a short stay for symptomatic supportive care and can be discharged once they are feeling improved and have an appropriate follow up plan. Patients with significant biliary obstruction may require an intervention such as surgery and may require a longer stay.

C. When is the Patient Ready for Discharge.

Readiness for discharge will typically depend on the patient's symptom management. Most patients will need symptomatic treatment for issues such as pain, jaundice and decreased oral intake. Once these symptoms have been adequately controlled, the patient will likely be ready for discharge as long as an appropriate follow up plan has been made.

D. Arranging for Clinic Follow-up.

Follow up care will be dependent on the patient's disease burden and desire for continued treatment.

1. When should clinic follow up be arranged and with whom.

For patients with potentially surgically resectable disease, a multi-disciplinary team should be involved in order to ensure the best prognosis. The patient may need close follow up with surgery, medical oncology, radiation oncology or gastroenterology. Patients with more advanced disease that is not amenable to surgery may still need oncology follow up if they choose to proceed with chemotherapy or radiation therapy. Coordination with consultants will be needed as follow up is being arranged.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

No specific tests are needed prior to discharge but coordination with consultants regarding this issue will help to expedite treatment planning.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

No specific tests.

E. Placement Considerations.

Depending on the functional status of the patient and disease burden, nursing home placement or hospice care may be indicated. If the functional status of the patient is poor enough to warrant nursing home placement, the likelihood that the patient will be able to tolerate therapy is low. Discussion with the patient about prognosis and goals of care will help guide the need for placement or hospice.

F. Prognosis and Patient Counseling.

Despite developments in surgical techniques and improving data to guide adjuvant therapy, pancreatic cancer remains a very fatal disease. Approximately 80% of patients present with non-resectable disease and the overall 5-year survival rate is less than 4%. Patients who are able to undergo resection have an improvement in 5-year survival up to 15-25%. Poor functional status caused by medical co-morbidities or weight loss often worsens the patient's ability to tolerate therapy and worsens prognosis.

A. Core Indicator Standards and Documentation.

There are currently no core indicator standards for pancreatic cancer.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with pancreatic cancer are at high risk for thromboembolic disease and should be maintained on DVT prophylaxis during hospitalization unless there is a strong contraindication. Counseling regarding prognosis and close follow-up planning with a multi-disciplinary team is likely the best way to prevent un-necessary readmissions.

VII. What's the evidence?

Takhar, A,, Palaniappan, P,, Dhingsa, R,, Lobo, D.. "Recent developments in diagnosis of pancreatic cancer.". BMJ. vol. 329. 2004. pp. 668-673.

Kleeff, J,, Michalski, CW,, Friess, H,, Buchler, MW.. "Surgical treatment of pancreatic cancer: The role of adjuvant and multimodal therapies.". EJSO. vol. 33. 2007. pp. 817-823.

Lowenfels, A,, Maisonneuve, P.. "Epidemiologic and etiologic factors of pancreatic cancer.". Hematol Oncol Clin N Am. vol. 16. 2002. pp. 1-16.

Sharma, C,, Eltawil, K,, Renfrew, P,, Walsh, M,, Molinari, M.. "Advances in diagnosis, treatment and palliation of pancreatic carcinoma: 1990-2010.". World J Gastroenterol. vol. 17. 2011. pp. 867-897.

Law, R,, Bronner, M,, Vogt, D,, Stevens, T.. "Autoimmune pancreatitis: A mimic of pancreatic cancer.". Cleveland Clinic Journal of Medicine. vol. 76. 2009. pp. 607-615.

Tamm, E,, Silverman, P,, Charnsangave, C,, Evans, D.. "Diagnosis, Staging and Surveillance of Pancreatic Cancer.". AJR. vol. 180. 2003. pp. 1311-1323.

Tempero, M,, Arnoletti, J,, Behrman, S,, Ben-Josef, E,, Benson, AB,, Casper, E. "Pancreatic Adenocarcinoma.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.". 2011.

Howard, T,, Krug, J,, Yu, J,, Zyromski, N,, Schmidt, C,, Jacobson, L. "A Margin-Negative R0 Resection Accomplished With Minimal Postoperative Complications Is the Surgeon's Contribution to Long-Term Survival in Pancreatic Cancer.". J Gastrointest Surg. vol. 10. 2006. pp. 1338-1346.

Katz, M,, Merchant, N,, Brower, S,, Branda, M,, Posner, M,, Traverso, W. "Standardization of Surgical and Pathologic Variables is Needed in Multicenter Trials of Adjuvant Therapy for Pancreatic Cancer: Results from the ACOSOG Z5031 Trial.". Ann Surg Oncol. vol. 18. 2011. pp. 337-344.

Mayo, S,, Austin, D,, Sheppard, B,, Mori, M,, Shipley, D. "Billingsley K. Adjuvant Therapy and Survival After Resection of Pancreatic Adenocarcinoma.". Cancer. vol. 116. 2010. pp. 2932-40.

Katz, M,, Wang, H,, Fleming, J,, Sun, C,, Hwang, R,, Wolff, R. "Long-Term Survival After Multidisciplinary Management of Resected Pancreatic Adenocarcinoma.". Ann Surg Oncol. vol. 16. 2009. pp. 836-847.

Kruse, EJ.. "Palliation in Pancreatic Cancer.". Surg Clin N Am. vol. 90. 2010. pp. 355-364.

Dalzell, J,, Samuel, L.. "Spectrum of 5-fluorouracil cardiotoxicity.". Anti-Cancer Drugs. vol. 20. 2009. pp. 79-80.

Conroy, T,, Desseigne, F,, Ychou, M. "FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.". N Engl J Med. vol. 364. 2011. pp. 1817-25.

(The study that showed the improved survival in patients using FOLFIRINOX for metastatic pancreatic cancer.)

Hidalgo,, MM.. "Pancreatic Cancer.". N Engl J Med.. vol. 362. 2010. pp. 1605-17.

(Helpful for describing presenting signs, symptoms, work-up and staging.)

Ryan, DP,, Hong, TS, and, Bardessy, N.. "Pancreatic Adenocarcinoma.". N Engl J Med.. vol. 371. 2014. pp. 1039-49.

(Provided information regarding the risk factors for pancreatic cancer [modifiable and genetic].)

Siegel,, R.,, Ma,, J.,, Zou,, Z. and, Jemal,, A.. "Cancer statistics, 2014.". CA: A Cancer Journal for Clinicians,. vol. 64. pp. 9-29.

(Helpful for including most up to date information about prevalence.)

Von Hoff, DD,, Ervin, T,, Arena, FP. "Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.". N Engl J Med.. vol. 369:. 2013;. pp. 1691-703.

(The study that showed improved survival for metastatic pancreatic cancer using nab-paclitaxel and gemcitabine.)

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