Oncology

Pancreatic Cancer

Pancreatic Cancer (Pancreatic Ductal Adenocarcinoma)

What every physician needs to know:

Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the pancreas. It is currently the fourth leading cause of cancer death in the United States. Unfortunately, the disease comes to clinical attention late in its course and, as a result, the vast majority of patients with this disease are not candidates for surgical resection.

Patients in whom a resection is feasible will undergo either a partial or total pancreatectomy with curative intent, followed by adjuvant therapy. A subset of patients without distant metastases in whom resection does not appear feasible (e.g. due to vascular involvement or encasement) are referred to as locally advanced PDA. These patients are candidates for chemoradiation or chemotherapy followed by chemoradiation. Occasionally, this approach can be followed by successful resection.

For the majority of patients with distant metastases, chemotherapy for symptom management and extension of life is standard. In addition, close medical attention to disease symptoms and complications such as bile duct obstruction or deep venous thrombosis is paramount . After years of gemcitabine monotherapy defining the standard of care, multi-drug regimens that are gemcitabine based (with capecitabine, nab-paclitaxel or erlotinib) or flouropyrimide based (5FU and oxaliplatin with or without irinotecan) are emerging as active first or second-line therapies for patients with preserved functional status.

Future clinical horizons in this disease include better early detection strategies, optimizing perisurgical care and adjuvant therapy in the resectable patient, and identifying more active drug regimens for use across all stages of presentation.

Clinical presentations

PDA often presents with vague symptoms that are very common in the general population, such as poorly localizing abdominal discomfort and dyspepsia.

Signs of PDA include:

  • Jaundice with or without a palpable gallbladder (Courvoisier's sign) in pancreatic head tumors.

  • Migratory superficial thrombophlebitis (Troussou's syndrome).

  • Unexplained weight loss and/or hyperglycemia (Table I).

  • Sleep disturbances and anorexia are also common.

  • Pain is a common presentation and can be due to celiac or mesenteric plexus invasion as well as subacute pancreatitis or adjacent organ invasion.

  • Gastrointestinal bleeding (from local invasion of the small bowel).

  • Malignant ascites.

Table I.

Diagnostic approach

Screening

Screening for PDA, at the present, is not cost effective except in settings of high-risk such as familial PDA.

Imaging

When a pancreatic malignancy is suspected, a dynamic contrast CT scan should be obtained with consultation from an abdominal imaging specialist. Appropriately done, this can identify a lesion in the pancreas with 95% accuracy and can often discriminate between ductal adenocarcinoma and neuroendocrine tumors.

Endoscopic ultrasound (EUS) (transgastric ultrasound) can be useful in further determining extent of vascular and peri-pancreatic nodal involvement.

Aspiration/biopsy

Benign lesions such as intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms may be different to discriminate from their malignant counterparts. Aspiration of cystic lesions for CEA measurements can be helpful since lesions with high cyst CEA levels (greater than192 ng/mL)are usually mucinous cysts rather than non mucinous cysts or pseudocysts. Most main duct IPMNs have a high-risk for malignant transformation. Thus, discriminating between these and PDA may be a largely academic point since as should be resected if locally confined.

Biopsy of a mass in the pancreas is not required prior to resection since false negative biopsies are common and should not delay surgical resection in most cases.

Decisions about resectability should be made by a multidisciplinary team guided by CT assessment on the extent of disease.

Which individuals are most at risk for pancreatic cancer:

Heritable factors

Risk for PDA can be inherited and occurs in known syndromes as well as in isolated families; up to 10% of PDA is attributable, at least in part, to familialdisposition (Table II).

Table II.

  • The occurrence of three first-degree relatives with PDA defines familial pancreatic cancer but increasingly two or more affected first degree relatives appear to confer similar risk.

  • Hereditary forms of PDA tendto present in younger patients than dosporadic cases (those without a first degree relative with the disease).

  • Having a first degree relative with PDA diagnosed before the sixth decade of life can increase risk for PDA 2.74 to 9.31 fold.

  • PDA is the third most common cancer in BRCA1/2 mutation carriers.

  • Individuals with heritable mutations in CDKN2a are also at increased risk.

  • PALB2 is a newly discovered familial risk gene.

  • Lynch syndrome confers about an eight-fold risk of PDA.

  • While very rare, hereditary pancreatitis also confers extraordinary risk for PDA in affected individuals, with one in two patients with this condition being diagnosed with PDA by age 75.

  • Other syndromes with a very high risk of pancreatic cancer include Peutz-Jeghers syndrome and familial atypical mole and malignant melanoma (FAMMM) syndrome (CDKN2a mutation).

Despite what we now know about the contribution of predisposing genes to familial PDA, these genes in the aggregate appear to explain only about two in ten patients' risk for PDA occurring in families. There is still much to be learned. Common genetic variation, such as blood group antigens, also confer increased risk.

Environmental factors

Lifestyle and environmental factors contribute to PDA risk:

  • Tobacco use is reproducibly identified as imparting a 1.5 to 5-fold risk of PDA.

  • High-fat diet, obesity, diabetes or exposure to wood pulp or petroleum products have also been associated with PDA risk.

  • The association with diabetes is complex, as diabetes can also be caused by PDA.

Staging, radiographic and laboratory evaluation

Diagnosing patients with PDA can be difficult and clinicians must be mindful of the early subtle manifestations of this disease. History (including family history) and physical exam are the beginning of any diagnostic orstaging evaluation.

Laboratory studies:

  • A complete blood count, chemistries and liver function tests are appropriate. Mild, normocytic anemia is not infrequent, seen in about 25% of patients,and fasting glucose tolerance is often impaired.

  • CA-19-9, a sialylated Lewis antigen associated with circulating mucins, is a useful tumor marker in metastatic disease, and in assessing response to therapy. At the most commonly used cut-off level of 37 U/mL, its sensitivity and specificity for diagnosis of PDA exceed 80%; CA-19-9 levels higher than 1,000 U/mL are highly associated with unresectable disease. CA-19-9 is neither a screening nor a diagnostic test, but should be evaluated preoperatively in resectable patients. Post-operative CA19-9 levels in the normal range are a favorable prognostic feature. Deep declines in high CA19-9 levels during treatment predict for improved survival. Up to 10% of Caucasians lack Lewis antigen (which is found on red blood cells), and these individuals do not express CA 19-9.

Imaging studies

  • Atriphasic multidetector computed tomography scan with thin cuts through the pancreas is the cornerstone of establishing diagnosis and assessing resectability. The difference in contrast enhancement between the parenchyma and adenocarcinoma is highest during the late arterial phase, thereby providing a clear distinction between a hypodense lesion in the pancreas and the rest of the organ.

  • PET/CT scanning is investigational at present and appears to change clinical management in about 10% of potentially resectable patients, but cannot replace the "pancreas-protocol" CT scan.

  • Endoscopic ultrasound (EUS) can be useful in PDA as well, especially in characterizing potentially resectable patients' vascular or nodal involvement more closely, and in better assessing the status of patients suspected of harboring a PDA but without an apparent mass on CT.

  • Achest X-ray or CT scan of the chest is recommended in patients prior to surgery to complete staging.

Unlike many other malignancies where diagnostic biopsy is required prior to definitive management, a resectable mass in the pancreas that is radiographically consistent with PDA (e.g. hypoattenuation presenting with an abnormal main pancreatic duct) can be resected with both diagnostic and therapeutic intent (Figure 1).

Alternatively, in cases where alternative histologies (e.g. pancreatic neuroendocrine tumor or lymphoma) are suggested by imaging, or where radiographically occult (e.g. peritoneal) metastases are suspected, other approaches are indicated. Scintigraphy with radiolabeled somatostatin analogue is pathognomonic for neuroendocrine tumors of the pancreas.

Figure 1.

Laparoscopy

Other malignancies such as lymphoma may require a diagnostic laparoscopy. Potential indications for laparoscopy in the setting of PDA include:

  • Markedly elevated CA19-9.

  • A large primary tumor.

  • Borderline resectable disease.

Borderline resectable disease is based on radiographic findings and is defined as:

1. Venous involvement of the SMV/portal vein demonstrating tumor abutment with impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction.

2. Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis.

3. Tumor abutment of the SMA not to exceed greater than 180 degrees of the circumference of the vessel wall.

Staging

Table III. TNM staging for pancreatic cancer.

Table III.

What should the initial definitive therapy for the cancer be?

Surgery

In cases that appear surgically resectable, surgery is the initial treatment of choice for all patients with PDA, keeping in mind that about 10-20% of potentially resectablepatients will be found to be unresectable at laparotomy.

Metastases to lymph nodes beyond the field of resection should be considered unresectable, as should distant metastases, SMA or celiac encasement greater than 180 degrees, aortic invasion, or an unreconstructible SMV/portal occlusion.

Four operations are used in PDA resection:

  • Pancreatoduodenectomy.

  • Totalpancreatectomy.

  • Regional or extended pancreatectomy.

  • Distal pancreatectomy with or without splenectomy (for tail of pancreas cancers).

Perioperative mortality has dropped to below 5% at most centers, but remains inversely proportional to surgical volume, likely reflecting the importance of both surgical skill in the operating room as well as specialized nursing support for these complicated surgical patients.

Biliary drainage/stenting

Routine pre-operative biliary drainage in patients with obstructive jaundice caused by tumors in the pancreatic head can have complications and does not appear to improve surgical outcome. Pre-operative stenting is recommended for biliary obstruction and cholangitis, or if surgery is delayed. If surgery is planned and a stent is required, an easily removable plastic stent is preferred.

Adjuvant (post-operative) therapy

Adjuvant Chemotherapy

Adjuvant treatment for 6 months should be considered for all resected patients suitable for therapy. Commonly used regimens include:

  • 5-FU and leucovorin (folinic acid) (folinic acid, 20 mg/m2, intravenous bolus injection, followed by fluorouracil, 425 mg/m2 intravenous bolus injection given days 1-5 every 28 days),

or

  • Gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks).

The impact of adjuvant treatment is large, and doubles the long term survival of patients as compared to observation alone. Ideally, adjuvant therapy should be started within 8 weeks of therapy.

Adjuvant Chemoradiotherapy

The impact of chemoradiotherapy (CRT) is uncertain and is variably used. A popular regimen is:

  • Gemcitabine at 1000 mg/m2weekly for 3 weeks before and 12 weeks after CRT. CRT is provided at 50.4 Gy over 28 fractions, concurrent with 5-FU 250 mg/m2/day continuous IV infusion.

Neodjuvant therapy

In medically fit, borderline resectable patients, neoadjuvant chemotherapy with or without concomitant radiotherapy, can be considered although there is no consensus on the most effective treatment regimen.

Treatment of unresectable, locally advanced disease

Patients with unresectable locally advanced disease are often managed with chemoradiation with or without additional chemotherapy. Increasingly, systemic chemotherapy is given before chemoradiation. Patients who rapidly progress with metastatic disease during systemic therapy may not benefit from further local therapy with chemoradiation. Occasionally, when a patient has an excellent response to treatment, surgery can be reconsidered.

Selected regimens for locally advanced, unresectable disease:

  • Gemcitabine 250-600 mg/m2IV weekly for 7 weeks (or duration of radiation therapy) concurrent with radiation therapy (Variable doses of gemcitabine have been studied. It is recommended to start at a lower dose and titrate upward based on toxicities and hematologic parameters.).

  • 5-FU 500 mg/m2IV days 1-3 first three days of radiation therapy and last three days of radiation therapy.

  • Starting 4 weeks after completion of radiation therapy, maintenance 5-FU 500 mg/m2IV weekly for 2 years or until progression.

  • 5-FU200-250 mg/m2/day continuous IVinfusionconcurrent with radiationtherapy.

Treatment of metastatic disease

About 50% of patients present to medical attention with metastatic disease. The liver and peritoneum are the most common sites of metastasis with lung and bone lesions being somewhat less common, but by no means rare. All cases of PDA should be confirmed with a tissue diagnosis, either from the primary or metastatic site.

Systemic chemotherapy, coupled with symptom management, are the mainstays of treatment for patients with metastatic PDA. Gemcitabine has been the backbone of chemotherapy for PDA for over a decade, providing some symptomatic relief and prolonged survival. The addition of erlotinib to gemcitabine provides additional survival benefit and is FDA approved.

As in colorectal cancer, development of a rash during anti-EGFR therapy is predictive of benefit. Newer chemotherapy regimens also hold promise. Gemcitabine combined with nab-paclitaxel at maximum tolerated doses resulted in a median survival of greater than 12 months in patients with metastatic disease and appeared especially efficacious in tumors with expression of SPARC protein. This regimen is being compared to gemcitabine montherapy in a phase III trial.

FOLFIRINOX, a non-gemcitabine containing regimen, wassignificantly more effective than gemcitabine monotherapy, with half of treated patients surviving more than 11 months as compared to less than 7 months in the gemcitabine arm of a randomized phase III trial. Because of toxicity, particularly myelosuppression, combination regimens are best reserved for younger patients with an excellent performance status.

Selected regimens for advanced disease:

  • Gemcitabine 1000 mg/m2IV days 1, 8, 15 every 28 days.

  • Gemcitabine 1000 mg/m2IV days 1, 8, 15 plus erlotinib 100 mg orallydaily every 28 days

  • Gemcitabine 1000 mg/m2IV days 1, 8, 15 plus capecitabine 1660 mg/m2/day (divided into twice daily doses of 830 mg/m2/day) orally days 1-21 every 28 days.

  • FOLFIRINOX: oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2on day 1 of a biweekly cycle, followed by a 5-FU bolus of 400 mg/m2and a 46-hour continuous 5-FU infusion of 2,400 mg/m2).

What should you tell the patient and the family about prognosis?

The prognosis of PDA is determined to a large extent by the stage at which the disease is diagnosed. Resectable patients who receive adjuvant therapy have a median survival of about 20 months and up to one in four will be alive five years after resection. In contrast, those with metastatic disease at diagnosis willsurvive a median of six months with gemcitabine or longer with combination regimens, although survival past two years is uncommon. Patients with locally advanced PDA (as defined above) have a median survival of 10-12 months.

In the metastatic setting, relatively favorable outcomes are seen in patients with a high performance status or those with lung only metastases. Decline of Ca19-9 in response to therapy is an encouraging prognostic sign.

From a molecular standpoint, mutations in the SMAD4 gene may confera poor prognosis, as may overexpression of S100A2 protein. However, neither test is used clinically at present.

What if scenarios.

Severe abdominal pain associated with PDA can often be successfully managed with celiac plexus neurolysis, typically administered by endoscopic ultrasound.

Biliary obstruction

Due to the intimate association of the pancreas to the hepatobiliary tree, and the cancer's propensity to metastasize to the liver, biliary obstruction is not uncommon. Biliary obstruction is typically managed by ERCP based stenting.

It should be kept in mind that indwelling stents increase the risk of infection, particularly cholangitis, although prophylactic antibiotics are not routinely recommended. Internal stenting is preferred, but when an endoscope cannot be passed external stenting is an option.

Metal stents are wider and less likely to become occluded. Plastic stents can be changed more easily than metal stents. The optimal decompression procedure is a patient specific decision.

Other histologies

Several post-operative scenarios occur when histology other than pancreatic ductal adenocarcinoma is encountered. Adenosquamous and acinar cancer of the pancreas are both rare and no consensus has been reached on how they should be clinically managed, but both are aggressive and probably warrant some form of adjuvant therapy in fit individuals.

On the other hand, patients with neuroendocrine histology, irrespective of differentiation should not be treated with adjuvant therapy outside the setting of a clinical trial.

Recurrent disease

Recurrence during adjuvant therapy is also not uncommon. Patterns of recurrence during this interval are typically systemic (e.g. liver metastases), but can also be due to locoregional recurrence, especially in those patients with R1 or R2 resections. The appropriate clinical response to this therapy is realigning treatment goals with the patient, stressing the palliative rather than curative intent of ongoing treatment. After clarifying these goals, a non-cross resistant metastatic regimen (e.g. FOLFIRINOX, FOLFOX e.t.c.) should be initiated with palliative intent.

Follow-up surveillance and therapy/management of recurrences.

Surveillance for recurrence after resection of PDA, while not shown to result in improved overall survival, is generally recommended. One approach is history and physical, abdominal imaging (typically CTscan), and CA 19-9 levels every 3-6 months for two years, then annually.

Pathophysiology

PDA is characterized at the molecular level by activating mutations in the KRAS gene. While KRAS mutations are common in many malignancies, such as non-small cell lung and colorectal carcinomas, in PDA the prevalence of this mutation approaches 100% when examined properly. Mutations in, or loss of, the CDKN2a and TP53 tumor suppressor genes are also very frequent (90% and 75% respectively).

Taken together, mutations in these three genes underlie the very core signaling derangements in the PDA cell. Unfortunately, unlike mutations in kinase oncogenes (BCR-Abl, or EGFR) or inactivation of tumor suppressor genes like BRCA2, mutations in KRAS, TP53 and CDKN2a are not associated with sensitivity to any particular treatment and confer specific resistance to others.

The cell of origin that gives rise to PDA has not been fully characterized but appears to be capable of populating the ductal lineage in the pancreas. The finding of a dense, desmoplastic stromal reaction accompanies virtually every diagnosis of PDA (Figure 2). The role this stroma plays is increasingly understood to promote growth and invasion and may be a barrier to effective drug delivery.

Figure 2.

What’s the evidence?

Epidemiology and risk factors

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