Nearly all malignancies arising from the pancreas develop from the exocrine portion of the gland. Carcinoma of the exocrine pancreas is in part a genetic disease caused by inherited and acquired mutations in specific cancer-associated genes.7
Researchers believe that pancreatic cancer is caused by an accumulation of gene mutations.8 Pancreatic adenocarcinomas are believed to originate in the ductal epithelium, but the specific cell of origin is not known. Pancreatic cancer evolves from premalignant lesions in the ductal epithelium to fully invasive cancer; this progression parallels the accumulation of gene mutations.
Multiple combinations of genetic mutations are commonly found in pancreatic adenocarcinomas. These can be divided into three broad categories:
- mutational activation of oncogenes such as K-RAS2
- inactivation of tumor suppressor genes such as TP53, p16/CDKN2A, and SMAD4
- inactivation of genome maintenance genes, such as hMLH1 and MSH2, which control the repair of DNA damage.9
Patients can have hereditary and nonhereditary risk factors for pancreatic cancer. Five percent to 10% of patients have a first-degree relative with the disease. A person with a family history of the disease has a 1.5% to 13% risk of developing pancreatic cancer. This risk is particularly high for persons in families with a case of young-onset pancreatic cancer (under age 50 years).9
Hereditary pancreatitis, an autosomal dominant disorder, accounts for a small fraction of cases of chronic pancreatitis and is associated with a markedly increased risk of pancreatic cancer.10 In patients with hereditary breast cancer, BRCA and PALB2 germ line mutations are associated with increased risk of pancreatic cancer. BRCA2 mutations are found in as many as 12% to 17% of patients with familial pancreatic cancer.11 Studies of patients with nonhereditary chronic pancreatitis suggest that these patients also are at increased risk for developing pancreatic cancer.12
Patients with non-O blood type (A, AB, or B) were significantly more likely to develop pancreatic cancer, according to the Nurses Health Study and the Health Professionals Follow-Up Study.13 Common variants of the ABO gene that determines blood type were associated with increased risk of pancreatic cancer, according to a study by the National Cancer Institute.14 The protein produced by the ABO gene determines the type of carbohydrates present on the surface of red blood cells and other cells including pancreatic cells. The proteins encoded on the A and B forms of the gene transfer different carbohydrates onto the cell surfaces to make A and B blood types. The O form encodes a protein that is unable to transfer carbohydrates. Studies have shown that ABO protein encoding in pancreatic tumor cells is different than in normal pancreatic cells.
See Table 2 for other potential risk factors for pancreatic cancer.
DIAGNOSIS AND STAGING
The choice of diagnostic tests often depends on the presenting symptoms. Initial symptoms of the disease are typically vague, so clinicians must be diligent to clinically reason and apply an evidence-based strategy to diagnostic test selection.
For patients presenting with obstructive jaundice or epigastric pain and weight loss, the initial imaging study is a transabdominal ultrasound; however, it may not detect tumors smaller than 3 cm. If an ultrasound is negative and/or if clinical suspicion is high for pancreatic cancer, a triple phase, helical multidetector row computed tomography (CT) scan with IV contrast material can be considered. Helical CT has been found to yield the highest accuracy in assessing the extent of primary tumor, local regional extension, vascular invasion, distant metastasis, tumor stage, and resectability.3 PET scan, chest CT and MRI can be useful if CT results are equivocal but are not routinely recommended.
If a transabdominal ultrasound and CT are negative, yet the clinician still suspects that the patient may have pancreatic cancer (because of jaundice, unexplained weight loss or upper abdominal pain, or unexplained episodes of pancreatitis), an endoscopic ultrasound can be ordered.
Endoscopic retrograde cholangiopancreatography (ERCP) can be used to collect tissue samples for histology as well as to visualize the biliary tree and pancreatic ducts. ERCP is superior to transabdominal ultrasound and CT for the detection of extrahepatic biliary obstruction and choledocholithiasis. Limitations of ERCP include a lower sensitivity for detection of malignancy (50% to 60% when compared to endoscopic ultrasound-guided fine needle aspiration, which has a sensitivity of 92%).15
In cases where ERCP is unsuccessful, provides limited information because of pancreatic duct obstruction, or the patient has gastric outlet or duodenal stenosis, a magnetic resonance cholangiopancreatography (MRCP) can be ordered. An MRCP creates a three-dimensional image of the pancreaticobiliary tree, liver parenchyma, and vascular structures.16
In most circumstances a histologic confirmation of pancreatic cancer is required to establish a definitive diagnosis of pancreatic cancer. The best modality for obtaining a tissue sample is an endoscopic ultrasound biopsy, which is less likely to cause intraperitoneal spread of the tumor because the biopsy is taken through the bowel wall rather than percutaneously.15
ROLE OF TUMOR MARKERS
CA 19-9, a tumor marker developed with monoclonal antibody technology, has been tested for usefulness in detecting and monitoring pancreatic cancer. Although this marker has 80% sensitivity, it is often normal in the early stages of pancreatic cancer. CA 19-9 is not specific (specificity 73%), is normally present in the cells of the biliary tract, is found in other GI cancers, and can be elevated in acute or chronic biliary disease. CA 19-9 is not recommended for screening but can be useful in differentiating chronic pancreatitis from pancreatic cancer, detecting potential metastatic disease, and in follow-up surveillance. Additionally, higher preoperative levels of CA 19-9 have been associated with more advanced disease that is not well resected (CA 19-9 level greater than 500 to 1,000 IU/mL).17 Preoperative values above 50 U/mL have been shown to be associated with higher chances of recurrence.18 Very high levels (greater than 5,000 U/mL) sometimes can lead clinicians towards the diagnosis of occult metastatic disease. Some data suggest 50% improvement in levels correlates with improved survival with systemic therapy. A falling CA 19-9 suggests a clinical response to the therapy with a rising value suggesting progressive disease.17
The goal of staging is to determine the extent of the disease and identify patients with resectable cancer with the intent of curative treatment. Research suggest two methods of staging: the TNM (tumor, node, metastasis) system, or a clinically oriented system: potentially resectable, locally advanced unresectable, and metastatic disease.
IS THE TUMOR RESECTABLE?
Unfortunately, only 15% to 20% of patients have resectable disease. Resectable pancreatic cancers are generally limited to small tumors within the head of the pancreas that can be removed by pancreaticoduodenectomy (also called a Whipple procedure). Adjuvant therapy with chemotherapy drugs may be done before or after surgery, and can improve the rate of survival and decrease the chance of relapse. Drawbacks to doing surgery first include:
- positive surgical margins are associated with poor prognosis
- patients may not recover sufficiently for adjunct therapy with up to 50% of patients being unable to tolerate adjunct therapy after surgery5
- patient morbidity and mortality are inversely related to the surgeon's experience with the procedure. Patients should go to a center that has a high volume of surgeons performing pancreaticoduodenectomies.
The goals of adjuvant therapy are to lower the risk of relapse and increase survival after surgery. Unfortunately, adjunctive therapy has not improved survival and as stated above, many patients may not be able tolerate it. Research suggests that adjunctive therapy before surgery may offer some theoretical advantages:
- Preoperative chemotherapy or chemoradiation can be delivered to a relatively well-perfused tumor bed, providing early treatment to microscopic metastases.
- Preoperative therapy may destroy the tumor, particularly at the periphery, enough to reduce the chances of positive surgical margins. Positive surgical margins are common after initial surgery without adjuvant therapy, and are associated with poor prognosis.
- Preoperative therapy lets clinicians observe the tumor's underlying biology, and may spare patients with aggressive disease from a major surgical procedure.5
TREATING LOCALLY ADVANCED DISEASE
Advanced pancreatic cancer can be difficult to treat and a referral to an experienced oncologist is recommended. Because many patients have non-resectable pancreatic cancer, the mainstay of treatment is systemic chemotherapy or chemoradiotherapy (Figure 2). For most patients a trial of chemotherapy alone is an acceptable approach. Drugs that may be used include 5-fluorouracil, a thymidylate synthase inhibitor, and gemcitabine. For 20 years, until the approval of gemcitabine, 5-fluorouracil was considered the only chemotherapeutic option.19
Gemcitabine leads to the inhibition of DNA synthesis and has demonstrated modest improvement in medial overall and 1-year survival compared to 5-fluorouracil (5.7 months versus 4.4 months and 18% versus 2% respectively).20 Gemcitabine is approved as first-line therapy for metastatic pancreatic cancer and is associated with significant clinical response and better survival.20
If the patient does not show clinical improvement, chemoradiotherapy may be an option using external beam radiation therapy (EBRT) plus concomitant 5-fluorouracil.
The latest and most common regimen is folfirinox (5-fluorouracil plus leucovorin, irinotecan, and oxaliplatin). Patients who took folfirinox demonstrated an improved overall survival rate compared to those on gemcitabine alone (11.1 vs. 6.8 months respectively). However, patients on folfirinox had greater treatment toxicity, including neutropenia, febrile neutropenia, thrombocytopenia, sensory neuropathy, vomiting, fatigue, and diarrhea. Despite greater toxicity, patients on folfirinox had improved global health status, including physical functioning along with social and cognitive functioning.21
Emerging therapies for pancreatic cancer include novel signal transduction inhibitors and cytotoxics such as nab-paclitaxel. Although clinical trials on these strategies have been promising, their use is limited.22
Patients with unresectable or recurrent pancreatic cancer should be offered palliative care. For those presenting with jaundice-associated pruritus, an expandable metal stent can be placed across the area of biliary tract obstruction. Opioids can be given for the pain of advanced cancer. If the patient cannot tolerate oral medications, transdermal patches can be used. Cachexia, anorexia, and weight loss are common in patients with advanced disease. Admin-istering pancreatic lipase with meals should help with steatorrhea and weight loss.
Pancreatic cancer is the fourth deadliest form of cancer in the United States. Diagnosis often occurs late due to its insidious onset of symptoms, making treatment futile and many times limited to approaches that are palliative. Although research continues into new treatments, the key for PAs is knowing which patients are at risk, making the right imaging choices, having a high suspicion for pancreatic cancer in patients with GI symptoms, and knowing an approach to staging that matches with treatment. By being familiar with the general treatment pathway and optimal referral to oncology, you can help and support patients through a difficult diagnosis.
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Keywords:© 2013 American Academy of Physician Assistants.
pancreatic cancer; adenocarcinoma; genetic mutation; diabetes; smoking