Pancreatic cancer usually refers to ductal adenocarcinomas of the pancreas, because more than 90% of pancreatic tumours arise from the ductal epithelium. Other major tumours of the pancreas include endocrine malignancies, carcinoid tumours, lymphomas, and a variety of rare sarcomas.
Pancreatic ductal adenocarcinoma (PDAC) has one of the highest incidence-to-mortality ratios of any disease. Although it represents the tenth leading cause of cancer in the United States, it is the fourth leading cause of cancer-related deaths, because the vast majority of patients will die from their disease. Annually, approximately 40,000 individuals will die in the United States from PDAC or its complications. The incidence of pancreatic cancer is slowly increasing based on the changing demographics of the U.S. population. The risk of developing PDAC increases with age, with a mean age at onset of 71 years; the risk in men and women is equivalent. The average lifetime risk for developing PDAC is about 1 in 78 for both men and women. Globally, 70% of all pancreatic cancer cases occur in people living in advanced economies, with over 270,000 deaths per year worldwide. Some PDACs occur in association with other cancers or diseases, but most do not occur in association with a defined syndrome. The overwhelming majority of PDAC cases are sporadic—that is, occurring without a history of the disease in first-degree relatives. Smoking tobacco, as well as passive exposure to tobacco smoke in the environment, contributes significantly to the development of PDAC. Occupational hazards that have been associated with an enhanced risk of developing PDAC include exposure to chlorinated hydrocarbon solvents and heavy metals.
Approximately 10% of PDACs occur in families with a history of PDAC; in these patients, the risk of developing PDAC is increased seven-fold compared with the general population. Premalignant cystic lesions of the pancreas also occur in pancreatic cancer families. In addition to the recent discovery of the PALB2 gene in 3% of these families, mutations in ATM or BRCA2, critical partners in the DNA damage repair pathway, as well as p16 , have also been discovered.
Chronic pancreatic inflammation from alcohol misuse or genetic anomalies significantly enhances the risk of being diagnosed with PDAC. Although the association between chronic pancreatitis and the development of PDAC has been well known for decades, only recently have studies clarified how pro-inflammatory cytokines contribute to the progression from premalignant lesion to advanced tumour. In addition to chronic pancreatitis, the role of diabetes mellitus and obesity in the development of PDAC has been emphasized. Long-standing type 1 and type 2 diabetes mellitus may represent increased risk of PDAC, but the cause-and-effect relationship between pancreatic cancer and diabetes is complex. Recently, epidemiologic studies have focused on the development of PDAC in patients with type 3c diabetes (diabetes related to pancreatic disease, or pancreatogenic diabetes), a major subset of diabetes characterized by a severe deficiency of all glucoregulatory hormones. Patients with type 3c diabetes appear to have the highest associated risk of developing PDAC, especially in the setting of coexisting chronic pancreatitis. Type 3c diabetes is also a consequence of PDAC in approximately 30% of patients. The increase in obesity in the U.S. population and the concomitant increase in associated diabetes mellitus are strongly associated with an enhanced lifetime risk of developing PDAC.
Understanding the molecular characteristics of cancers of the exocrine pancreas is critical for the development of targeted therapies. Pancreatic cancer is caused by inherited (germline) and acquired (somatic) mutations in cancer-causing genes. Several oncogenes and tumour suppressor genes have been demonstrated to be involved in the development of pancreatic cancer, both by contributing to the growth of the tumour itself as well as to the surrounding microenvironment. Oncogenes, typically inactive in normal cells, cause uncontrolled cell proliferation by inhibiting apoptosis and activating the cell cycle when mutations render them constitutively active. The KRAS oncogene, located on chromosome 12, is the most frequently mutated oncogene in pancreatic cancer in (>90% of tumours). It encodes a membrane-bound protein that has GTP-ase activity and is involved in signal transduction. When activated by mutation, typically a point mutation in codon 12, the functions of KRAS are independent of growth factor control, leading to chronic activation of its downstream signaling partners, PI3K , MAPK , and RAF , causing inhibition of apoptosis and activation of the cell cycle, migration, angiogenesis, cytoskeletal remodeling, and unchecked proliferation. Tumour suppressor genes, when functioning normally, act in the opposite manner by enhancing apoptosis and inhibiting cell proliferation. The tumour suppressor CDKN2A/TP16, a cell cycle control gene, is commonly inactivated in pancreatic cancer, with 80 to 95% loss of activity leading to increased cell cycle progression. TP53 is activated by DNA damage to stop cell cycle progression and repair damaged DNA or initiate apoptosis. Mutations in this tumour suppressor gene are commonly found in 50 to 75% of pancreatic tumours. Inactivation of SMAD4 (DPC4), involved in regulating cell cycle progression through the transforming growth factor (TGF)-β pathway, is observed in over 50% of pancreatic cancers and is associated with worse prognosis and the development of metastases. Inactivation of RB1 (in < 10% of pancreatic cancers) and STK11 (responsible for Peutz-Jeghers syndrome) is also observed.
There are several major signaling pathways involved in pancreatic tumourigenesis. Hedgehog (Hh) signaling, critical in embryogenesis, regulates the cell cycle and apoptosis, aids in the formation of tumour stroma, and is often upregulated and abnormal in pancreatic cancers. The NOTCH pathway, also important in normal embryogenesis to prevent terminal differentiation of cells until appropriate, can be abnormally activated in pancreatic cancer, allowing cells to remain in an undifferentiated state that contributes to tumour growth. When the Wnt pathway is activated, β-catenin is stabilized and migrates into the nucleus, where it activates its target genes. The epidermal growth factor receptor (EGFR), TGF-β, and JAK/STAT pathways have also been found to be abnormal in pancreatic cancer cells, leading to the promotion of cell growth, proliferation, differentiation, and cell survival. Epigenetic modification, the process by which gene expression is altered by mechanisms other than changes in actual DNA sequence, also has a role in pancreatic cancer tumourigenesis. Telomere shortening and overexpression of microRNAs lead to chromosomal instability and dysregulation of gene expression, respectively, and are also observed.
In addition to cancer cells themselves, the tumour microenvironment is composed of stromal cells, inflammatory cells, and endothelial cells that all play a particularly important role in pancreatic cancer growth. Cancer cells secrete growth factors, including insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF), TGF-β, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), that stimulate pancreatic stellate cells (also called myofibroblasts) to secrete excess amounts of extracellular matrix. The matrix and its stromal cells, in turn, secrete cytokines and growth factors that promote cancer cell growth, invasion, and dissemination and protect pancreatic cancer cells from apoptosis, as well as generating a desmoplastic reaction that interferes with the delivery of chemotherapy to the tumour site. The local presence of TGF-β also leads to decreased helper T-cell activity, which suppresses the body’s immune reaction against pancreatic cancer cells.
A major advance in understanding the development of pancreatic cancer has been the appreciation that the majority of pancreatic adenocarcinomas progress sequentially from histologically normal ductal epithelium to low-grade pancreatic intraepithelial neoplasia (PanIN), to high-grade PanIN, to invasive carcinoma. This process is associated with the accumulation of specific gene alterations.
Symptoms of early PDAC are often subtle and include nonspecific gastrointestinal complaints (nausea, vague abdominal pain), fatigue, and weight loss of undetermined etiology. Epigastric pain and obstructive jaundice often prompt the initial diagnostic work-up of the biliary tree, but are frequently late symptoms that are associated with advanced local or regionally disseminated disease. Because approximately 75% of pancreatic carcinomas are located in the head of the pancreas, it is not unexpected that clinical presentations are often related to compression or invasion of the biliary tree or pancreatic ducts. Deep or superficial venous thrombosis (Trousseau syndrome) is not infrequent, either early or late in the presentation of PDAC. Observation of a palpably distended gallbladder (from obstruction of the distal common bile duct), or Courvoisier’s sign, is uncommon.
The laboratory abnormalities that accompany PDAC at presentation include anemia and elevations of serum bilirubin, alkaline phosphatase, and aminotransferases. A majority of patients eventually develop signs of obstructive jaundice as well as hyperglycemia, reflective of associated diabetes mellitus. Unfortunately, pre-neoplastic cystic lesions of the pancreas often remain asymptomatic until discovered following acute symptoms (due to ductal obstruction) that precipitate an abdominal computed tomography (CT) scan. Early PanIN lesions are asymptomatic.
The differential diagnosis of PDAC includes conditions that can present as a solid pancreatic mass, including acute (or an exacerbation of chronic) pancreatitis, ampullary or distal cholangiocarcinomas with associated biliary obstruction and jaundice, and non-neoplastic cystic pancreatic neoplasms.
Cystic neoplasms of the pancreas are frequent, detectable in 2% of abdominal magnetic resonance imaging (MRI) examinations. Whereas serous cystadenomas are benign abnormalities that do not connect to pancreatic ducts and warrant surgery only if symptomatic, mucinous cystadenomas (MCN) are precursors of PDAC that often occur in the tail of the pancreas, more frequently in women in their 40s; they are overtly malignant in 15% of patients and require surgical resection. Intraductal papillary mucinous neoplasms (IPMN) of the pancreas occur in the head of the organ, are often polycystic, and contain malignant elements in 40% of patients; all patients with this lesion require surgery.
CT scan with dynamic contrast and thin cuts through the pancreas is the imaging procedure of choice when PDAC is suspected. CT scans can provide information regarding the presence of metastatic disease, vascular invasion, and potential for resection. Endoscopic ultrasound (EUS) may provide additional information useful for preoperative assessment, including fine-needle aspiration biopsy under endoscopic guidance. It is important to point out that the typical desmoplastic reaction that can encase PDACs increases the possibility of false-negative biopsy findings. Patients with locally advanced or metastatic disease should have their diagnosis confirmed pathologically by fine-needle biopsy of the primary site or of a metastasis.
A recent preliminary study identified two diagnostic panels based on microRNA expression in whole blood, with the potential to distinguish patients with pancreatic cancer from healthy controls. However, so far, no serum- or tumour-based biomarkers or biomarker panels have been established that are both sensitive and specific enough for accurate early detection in clinical practice. CA19.9 is the most commonly used tumour biomarker for monitoring therapeutic progress in PDAC, but the lack of specificity of the assay is a concern, and CA19.9 therefore cannot be used for early detection. EUS is useful for the evaluation of cystic lesions and permits sampling of cystic fluid for genetic markers associated with the development of PDAC in cancer-prone families, as well as for cytologic studies.
Surgery offers the only chance to cure pancreatic cancer. Tumours are considered resectable if a clear fat plane is present around the celiac and superior mesenteric arteries, and if the mesenteric and portal veins are patent. Unfortunately, tumour will recur in the majority of patients who undergo resection. Adjuvant therapy is indicated to decrease the risk and delay the timing of locoregional and metastatic recurrence. It is typically started 1 to 2 months after surgery to allow the patient to recover from the complications associated with the underlying cancer as well as from surgery itself. Although no regimen has been proven substantially more effective than others, 6 months of adjuvant therapy with 5-fluorouracil (5-FU) or gemcitabine-based chemotherapy is an appropriate standard. A meta-analysis has shown that chemotherapy with 5-FU or gemcitabine is the optimum adjuvant treatment for pancreatic adenocarcinoma and reduces mortality after surgery by about a third. Chemoradiation plus chemotherapy is less effective in prolonging survival and is more toxic than chemotherapy.
SELECTED ADJUVANT STUDIES
|STUDY||TREATMENT||1-YEAR SURVIVAL (%)||2-YEAR SURVIVAL (%)||5-YEAR SURVIVAL (%)||DISEASE-FREE SURVIVAL (MO)||MEDIAN SURVIVAL (MO)|
N = 289
|2 × 2 design:|
|v. Chemorad||v. 7||v. no chemorad, 15.2||v. 13.9|
|v. Chemo||v. 29||Chemo, 15.3||v. 21.6|
|v. Chemorad plus chemo||v. 13||v. no chemo, 9.4||v. 19.9|
N = 451
|Gem/XRT v. 5-FU/XRT||69 v. 65||35 v. 39||20 v. 20||NR||20.5 v. 16.9|
N = 1088
|Gem v. 5-FU||70 v. 70||40 v. 40||NR||14.3 v. 14.1||23.6 v. 23|
|Johns Hopkins and Mayo Clinic Retrospective (2010)
N = 1272
|Observation v. chemorad||58. v. 80||34.6 v. 44.7||16.1 v. 22.3||15.5 v. 21.1 ( P < .001)|
N = 89
|IFN-cisplatin-5-FU plus XRT||80||60||NR||14.1||25.4|
N = 354
|Observe v. gem||72 v. 72||42 v. 47||11 v. 22||6.7 v. 13.4 ( P < .001)||10.4 v. 21.7 ( P = .06)|
5-FU = 5-flourouracil; chemo = chemotherapy; chemorad = chemoradiation therapy; gem = gemcitabine; IFN = interferon; NR = not reported; XRT = radiation therapy.
Neoadjuvant (presurgical) therapy remains an option in the treatment of pancreatic cancer. It has the potential to downstage patients of borderline resectability who achieve a partial response with therapy, allowing them to undergo surgery with a higher likelihood of complete resection. In fact, 15 to 40% of patients who initially present with borderline or unresectable tumours may eventually be deemed appropriate to undergo surgery. In addition, neoadjuvant therapy spares some patients the risks and stress of a complex surgical procedure, because rapidly developing metastatic disease may be detected by routine restaging following the completion of neoadjuvant treatment. Unfortunately, chemotherapy-resistant cancer can be demonstrated in 15 to 35% of patients initially considered for surgery in this setting. The use of neoadjuvant treatment also guarantees that almost all patients will receive some form of chemotherapy and/or chemoradiation because they do not have any postoperative complications from which to recover. Studies show that 73 to 100% of patients are able to complete the majority of their neoadjuvant regimens. The chemoradiation component of neoadjuvant therapy also decreases local recurrence rates in patients who undergo surgery.
However, surgery is required for cure, and neoadjuvant therapy does delay potentially curable surgery. Although the same percentage of patients ultimately undergo surgery, there are no randomized trials favoring neoadjuvant over adjuvant treatment. Therefore, at this time neoadjuvant therapy is usually reserved for borderline resectable patients, whereas resectable patients are taken to surgery immediately, with adjuvant therapy administered following recovery. Patients treated with either adjuvant or neoadjuvant therapy have similar survival rates when resection can be completed successfully. Decisions regarding initial treatment should, if possible, be made in a multidisciplinary manner to achieve the most timely and coordinated therapy.
For many years, 5-FU was the standard of care to treat advanced PDAC. In 1997, a phase III trial demonstrated a survival benefit for gemcitabine over bolus 5-FU, with a median survival of 5.65 months compared to 4.41 months, and 1-year survival of 18% versus 2%, favoring treatment with gemcitabine. Gemcitabine also had a superior clinical benefit response, described as improvement in pain, performance status, or weight in 24% of patients versus 5% in the 5-FU group; it is therefore appropriate treatment for patients with moderate performance status.
Gemcitabine has also been combined with targeted therapies; however, addition of the EGFR inhibitor erlotinib has been the only molecularly targeted agent shown to improve overall survival, albeit modestly. Newer combination regimens, both with improved efficacy based on phase III clinical trials for metastatic PDAC patients, include FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) and the nab-paclitaxel and gemcitabine doublet.
SELECTED METASTATIC PANCREATIC CANCER STUDIES
|STUDY||CHEMOTHERAPY||RESPONSE RATE (% PARTIAL RESPONSE)||MEDIAN SURVIVAL (MO)||1-YEAR SURVIVAL (%)|
N = 126
|5-FU v. gem||NR||4.4 v. 5.6 (P = .0025)||2 v. 18|
N = 533
|Gem ± capecitabine||14 v. 7 ( P = .008)||7.4 v. 6 ( P< .05)||26 v. 19|
N = 343
|Gem v. FOLFIRINOX||9 v. 32||6.8 v. 11.1 ( P < .0001)||17 v. 36|
|Van Hoff (2013)
N = 861
|Gem ± nab-paclitaxel||23 % v. 7%||8.5 v. 6.7 (P < .001)||35 v. 22 (P < .001)|
5-FU = 5-fluorocil; FOLFIRINOX = combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin; gem = gemcitabine; NR = rot reported.
The overall 5-year survival for all patients with pancreatic cancer is less than 5%. This is in part because there is no appropriate screening test for the general population, and presenting symptoms are vague. Once patients are diagnosed, only 15 to 20% present with resectable, and thus potentially curable, disease. In these patients, the somatostatin analogue pasireotide (900 mg subcutaneously twice daily for 7 days beginning in the morning of surgery) can reduce the risk of fistula leak with abscess by 50%. However, even in patients with early-stage disease, median survival is 20 to 24 months, with a 5-year survival of only 15 to 20% because the majority will eventually recur despite surgery and adjuvant or neoadjuvant therapy. Patients with locally advanced (≈25 to 30% at presentation) and metastatic disease (≈50 to 60% at presentation) have median survivals of 8 to 14 months and 4 to 6 months, respectively. Because many patients suffer from biliary obstruction, diarrhea, pain, and malnutrition, palliative care can provide great benefit. Surgery can also play an important palliative role; patients found to be unresectable may be improved symptomatically by a biliary or gastric bypass procedure, depending on the site of obstruction. Placement of both biliary and duodenal stents in the absence of a surgical approach may also improve pruritus, pain, or other complications of biliary tract obstruction. Palliative care for patients with PDAC necessitates scrupulous attention to pain management that often requires a multidisciplinary approach, as well as maintenance of hydration and adequate nutritional status.