Carcinoma of the Pancreas
Summary of Key Points
• Pancreatic adenocarcinoma is the tenth leading cause of cancer in the United States, but the fourth leading cause of cancer-related deaths.
• The overall 5-year survival for all patients is <5%: 15% to 20% of patients present with resectable/ borderline resectable disease with median survival of 20 to 24 months; 25% to 30% present with locally advanced/unresectable with median survival of 8 to 14 months; 50% to 60% present with metastatic disease with median survival of 4 to 6 months.
• Familial atypical multiple-mole melanoma syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, and a strong family history of pancreatic cancer are the strongest risk factors and these patients should undergo screening. Risk factors also include smoking, heavy alcohol consumption, chronic pancreatitis, obesity and diabetes.
• Screening of the general population is not indicated at this time.
• Mutations in the KRAS oncogene and the CDKN2A tumor suppressor gene are found in more than 80% of pancreatic tumors and are thought to be early mutations. Inactivation of tumor suppressor genes TP53 and SMAD4 are thought to occur later in the tumorigenesis process.
• Pancreatic intraepithelial neoplasms (PanINs) are microscopic precursor lesions. PanIN-3 lesions should be fully resected when found. Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are noninflammatory cysts that can lead to pancreatic cancer. All MCNs, main duct IPMNs, and symptomatic branch duct IPMNs should be resected.
• Jaundice, abdominal pain, malabsorption, weight loss, back pain, and nausea/vomiting are common manifesting symptoms.
• Pancreatic protocol computed tomography (or magnetic resonance imaging) should be used for diagnosing and staging. Endoscopic ultrasound may offer additional staging information. It is critical to determine resectability on imaging as that will determine the course of treatment.
• All patients should be evaluated in a multidisciplinary setting when possible.
• Surgery should be considered upfront in patients with resectable disease unless treated on a neoadjuvant clinical trial.
• Patients should receive adjuvant 5-FU– or gemcitabine-based chemotherapy with 5-FU– or gemcitabine-based chemoradiation when appropriate as adjuvant therapy leads to longer survivals.
• Neoadjuvant chemotherapy followed by chemoradiation can be given in patients with borderline resectable disease to increase the likelihood of R0 resections, treat micrometastatic disease earlier, and avoid surgery in patients who demonstrate early progression.
• Locally advanced and metastatic disease patients can be treated with the same systemic chemotherapy regimens. Approved regimens include gemcitabine single-agent therapy, gemcitabine combination therapy, and 5-FU combination therapy.
• Chemoradiation or stereotactic body radiotherapy can be considered for locally advanced patients with good performance status if there is no disease progression after initial systemic chemotherapy.
• Palliative measures should be introduced early for advanced patients and focus on relieving pain, biliary obstruction, gastric outlet obstruction, and malnutrition.
• Additional studies are needed to evaluate the ability of novel biomarkers to guide pancreatic cancer management.
• Research focused on developing new therapies should take its cues from preclinical studies that are dissecting the stromal/tumor/inflammatory cascade of signals unique to pancreatic cancers.
1. With regard to the molecular biology of pancreatic cancer, which of the following is true?
A KRAS is an oncogene that is one of the earliest mutations and is mutated in greater than 80% of pancreatic cancers.
B TP53 is an oncogene that is one of the earliest mutations and is mutated in greater than 80% of pancreatic cancers.
C CDKN2A is a tumor suppressor gene that is only inactivated in a fraction of pancreatic cancers.
D Mutations in STK11 are related to hereditary pancreatitis.
2. As compared with pancreatic body/tail lesions, pancreatic head tumors:
A Present later and are more likely to be unresectable or metastatic at presentation
B Present earlier, are more likely to be resectable and are typically associated with biliary obstruction
C Less commonly involve the SMA and portal vein
D Require distal pancreatectomy/splenectomy and sometimes a total pancreatectomy to achieve negative margins
A Is not recommended as it has not been shown to prolong overall survival
B Should be started with chemoradiation as most patients will recur with local disease
C Should consist of 5-FU– or oxaliplatin-based chemotherapy and never uses chemoradiation
D Should consist of 5-FU– or gemcitabine-based chemotherapy with or without chemoradiation therapy
A Requires a larger field of radiation than adjuvant chemoradiation and therefore is not recommended
B Is indicated in patients with borderline resectable disease to allow for a higher likelihood of an R0 resection and may be considered for resectable disease on a clinical trial
C Should start with chemoradiation to treat local disease first followed by systemic chemotherapy
D Does not require restaging after the completion as all patients are able to undergo resection
5. For treatment of locally advanced or metastatic disease:
A Physicians may choose from single-agent gemcitabine, capecitabine, gemcitabine-based combinations, or 5-FU–based combination therapies.
B 5-FU– based therapies are now the standard of care and have replaced gemcitabine-based therapies in all cases.
C Chemoradiation can be used in both groups of patients as long as long as there is no progression after systemic chemotherapy.
D The addition of numerous targeted therapies (such as erlotinib, cetuximab, sorafenib, axitinib, and bevacizumab) to gemcitabine have all demonstrated significantly improved overall survivals and are used routinely.
1. Answer: A. KRAS is the most frequently mutated oncogene in pancreatic cancer and is thought to occur early in the tumorigenesis process as it is found in 30% to 45% of PanIN-1 lesions and more than 90% of PanIN-3 lesions. TP53 is a tumor suppressor gene, not an oncogene. Mutations in TP53 are found in 50% to 75% of pancreatic cancers and can be seen in PanIN-3 lesions; however, they are not found in earlier precursor lesions. CDKN2A is the most commonly inactivated tumor suppressor gene in pancreatic cancer with loss of activity in 80% to 95% of pancreatic cancers. This is one of the earlier mutations as it can be found in PanIN-2 lesions. Germline mutations of STK11 lead to Peutz-Jeghers syndrome. Hereditary pancreatitis is caused by mutations in PRSS1.
2. Answer: B. Pancreatic head tumors typically manifest earlier than body/tail lesions as they cause biliary obstruction and jaundice more frequently and earlier which prompts a more thorough workup. As they present earlier, they are more likely to be resectable. Given their location, pancreatic head tumors more commonly involve the SMA and portal vein, whereas body/tail tumors more commonly involve the splenic vein. Pancreatic head tumors are resected via the Whipple procedure, whereas body/tail tumors require a distal pancreatectomy/splenectomy. A total pancreatectomy may be required regardless of location to achieve negative margins.
3. Answer: D. Adjuvant therapy has been shown to prolong overall survival starting with the GITSG trial in 1985. This was further demonstrated in the ESPAC-1 and CONKO-001 trials that demonstrated improved overall survival as compared with observation. Adjuvant therapy is now the standard of care. It is typically recommended to start with systemic chemotherapy first and reassess after a few cycles to document lack of metastatic disease prior to initiating chemoradiation therapy as patients can recur with metastatic disease first. Adjuvant therapy should consist of 5-FU– or gemcitabine-based chemotherapy. Oxaliplatin has not been studied in the adjuvant setting, only in the locally advanced/metastatic setting in combination with gemcitabine.
4. Answer: B. Neoadjuvant chemoradiation requires a smaller volume of radiation field and therefore decreases exposure to other organs as compared to adjuvant chemoradiation. It is indicated for borderline resectable patients as it can lead to a higher likelihood of an R0 resection. At this point, it is recommended to only use neoadjuvant therapy for resectable disease patients on a clinical trial. It should start with systemic chemotherapy in order to treat micrometastatic disease earlier and avoid radiation in patients who develop metastatic disease quickly. Patients should be restaged with repeat imaging after completing neoadjuvant therapy to verify that the disease is able to be resected prior to undergoing surgery.
5. Answer: A. Numerous regimens can be used to treat locally advanced/metastatic disease, including both single-agent and combination regimens. Physicians should choose the most appropriate therapy for their patient based on performance status, comorbidities, goals of care, and ability to tolerate toxicities. Combination regimens, including GTX and FOLFIRINOX, may be preferred for patients with good performance status with an ECOG score of 0 to 1, whereas older patients with ECOG score of 2 may fair better with a single agent. The 5-FU–based combination therapy, FOLFIRINOX, was shown to be superior in a phase III trial as compared with single-agent gemcitabine and is an approved regimen for locally advanced/metastatic patients but is typically reserved for patients with good performance status and is not appropriate for all patients. Chemoradiation is indicated only for patients with locally advanced disease who have disease control after systemic chemotherapy. Radiation is only used in the metastatic setting for palliative indications like pain control. Erlotinib is the only targeted agent that has shown a statistically significant overall survival benefit when added to gemcitabine, albeit very small.
