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 for 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 but with apparently unresectable primary disease (e.g. due to vascular involvement or encasement) are referred to as having locally advanced PDA. These patients are candidates for chemotherapy, which in some cases is followed by chemoradiation. Occasionally, and increasingly, 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 such as gemcitabine and nab-paclitaxel or FOLFIRINOX (5 fluorouracil, leucovorin, oxaliplatin, and irinotecan) have emerged as active first-line treatment options for patients with preserved functional status.

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

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 (Trousseau’s syndrome)

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

  Table I.

  Signs and Symptoms of PDA. (Adapted from The M.D. Anderson Surgical Oncology Handbook, 4th Ed, Lippincott Williams & Wilkins.)

• Sleep disturbances and anorexia

• Pain (due to celiac or mesenteric plexus invasion, subacute pancreatitis, or adjacent organ invasion)

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

• Malignant ascites

Diagnostic approach

Screening

Screening for PDA, at the present, is not cost-effective. A possible exception is high-risk families in screening registries at high-volume centers. In this subset of patients, endoscopic ultrasound (EUS), and magnetic resonance cholangiopancreatography (MRCP) show promise, although long-term, prospective, randomized trial data is lacking.

Imaging

When a pancreatic malignancy is suspected, a dynamic contrast computed tomography (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.

A pancreas protocol CT scan is the gold standard for assessing vascular involvement and for determining resectability. EUS (transgastric ultrasound) can be useful for tissue sampling both of the primary tumor and the involved lymph nodes.

Aspiration/biopsy

Benign lesions such as intraductal papillary mucinous neoplasms (IPMN) or mucinous cystic neoplasms (MCN) may be difficult to discriminate from their malignant counterparts. Main duct IPMNs carry a high risk for malignant transformation. Therefore, discriminating between these and PDA may be a largely academic point, as both lesions should be resected if locally confined and surgically feasible.

Biopsy of a mass in the pancreas is not necessarily required prior to resection. 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 of the extent of disease. Positron emission tomography (PET) is less sensitive than CT in detecting small (<1.0 cm) liver metastases and provides no anatomic guidance in surgical planning. Thus PET is not considered a standard component of staging.

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 familial disposition (Table II). The occurrence of three first-degree relatives with PDA formally defines familial pancreatic cancer; additionally, having two or more affected first-degree relatives increases risk and justifies screening.

Table II.

• The occurrence of three first-degree relatives with PDA formally defines pancreatic cancer; additionally, having two or more affected first-degree relatives increases risk and justifies screening.

• 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.

• PALB2 is a familial risk gene for PDA within the Fanconi anemia pathway.

• Lynch syndrome confers about an 8-fold risk of PDA.

• Although 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.

• ABO blood type is also emerging as a risk factor, with non-O blood type carrying an increased risk.

• Other syndromes with a very high risk of pancreatic cancer include Peutz-Jeghers syndrome (STK11 mutation) 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. Common genetic variations, such as blood group antigens, also appear to confer increased risk.

Environmental factors

A number of lifestyle and environmental factors may 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. 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 or staging 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. 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, the 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

• A triphasic multidetector CT 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. It appears to change clinical management in about 10% of potentially resectable patients, but PET-CT does not replace the “pancreas-protocol” CT scan, especially in resectable patients.

• EUS can be useful in the evaluation of PDA, particularly for characterizing potentially resectable patients’ nodal involvement more closely. EUS also has a role in assessing the status of patients suspected of harboring a PDA but without an apparent mass on CT. However, CT—and not EUS—should be used as the gold standard for assessing arterial and venous involvement of potentially resectable cases.

• A chest 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).

Figure 1.

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. Uptake of radiolabeled somatostatin analogue by scintigraphy (i.e. OctreoScan) is pathognomonic for neuroendocrine tumors of the pancreas.

Laparoscopy

Other malignancies such as lymphoma may require a diagnostic laparoscopy. Potential indications for laparoscopy in the setting of resectable 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 superior mesenteric (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 resectable patients 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 surgical procedures are deployed for PDA resection:

• Pancreatoduodenectomy

• Total pancreatectomy

• 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 it 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:

Gemcitabine (1000 mg/m²; intravenous [IV] infusion weekly for 3 of every 4 weeks).

Or

5-FU and leucovorin (folinic acid) (folinic acid, 20 mg/m²;, IV bolus injection, followed by fluorouracil, 425 mg/m²; IV bolus injection given days 1-5 every 28 days)The impact of adjuvant treatment is large, doubling the long-term survival of patients as compared to observation alone. Ideally, adjuvant therapy should be started within 8 weeks of surgery.

Adjuvant Chemoradiotherapy

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

• Gemcitabine 1000 mg/m²; weekly 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.

Neoadjuvant therapy

In medically fit, borderline resectable patients, neoadjuvant chemotherapy with or without concomitant radiotherapy, can be considered. There is no consensus on the most effective treatment regimen although maximally effective (e.g., FOLFIRINOX or Gemcitabine/Nab-paclitaxel are often used).

Treatment of unresectable, locally advanced disease

Patients with unresectable locally advanced disease are usually managed with chemotherapy, with or without chemoradiation. The role for radiation remains controversial in this disease setting. Patients who rapidly progress with metastatic disease during systemic therapy do 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:

• FOLFIRINOX: oxaliplatin 85 mg/m²;, irinotecan 180 mg/m²;, and leucovorin 400 mg/m²; on day 1 of a biweekly cycle, followed by a 5-FU bolus of 400 mg/m²; and a 46-hour continuous 5-FU infusion of 2400 mg/m²😉

• Gemcitabine 1000 mg/m²; plus nanoparticle albumin bound (nab)-paclitaxel 125 mg/m²; IV days 1, 8, 15 every 28 days

• Gemcitabine 250-600 mg/m²; IV 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/m²; IV days 1-3 first 3 days of radiation therapy and last 3 days of radiation therapy

• Starting 4 weeks after completion of radiation therapy, maintenance 5-FU 500 mg/m²; IV weekly for 2 years or until progression

• 5-FU 200-250 mg/m²;/day continuous IV infusion concurrent with radiation therapy

• Capecitabine, 830 mg/m²; orally twice daily 5 days a week concurrent with radiation therapy

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. Lung skeletal metastases are less common, but they are 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, is the mainstay of treatment for patients with metastatic PDA. Gemcitabine has been the backbone of chemotherapy for PDA for more than a decade, providing some symptomatic relief and prolonging survival. The addition of the epidermal growth factor receptor (EGFR) inhibitor erlotinib or nab-paclitaxel to gemcitabine provides additional survival benefit. Both doublets are FDA approved, but they have not been compared head to head.

As in colorectal cancer and lung cancer, development of a rash during anti-EGFR therapy is predictive of benefit of erlotinib. Despite preclinical evidence, tumor secreted protein acidic rich in cysteine (SPARC) expression is not predictive of nab-paclitaxel benefit.

FOLFIRINOX, a non-gemcitabine containing regimen, was significantly more effective than gemcitabine monotherapy, with median overall survival exceeding 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 for reserved patients with preserved performance status and few comorbidities.

The role of immunotherapy in the treatment of PDA is not currently defined. A number of clinical trials investigating the use of immune checkpoint inhibitors as well as vaccines and monoclonal antibodies directed against tumor-associated antigens are ongoing.

Selected regimens for advanced disease:

For good performance status (ECOG 0-1):

• FOLFIRINOX: oxaliplatin 85 mg/m²;, irinotecan 180 mg/m²;, and leucovorin 400 mg/m²; on day 1 of a biweekly cycle, followed by a 5-FU bolus of 400 mg/m²; and a 46-hour continuous 5-FU infusion of 2400 mg/m²😉

• Gemcitabine 1000 mg/m²; plus nab-paclitaxel 125 mg/m²; IV days 1, 8, 15 every 28 days

For compromised performance status (ECOG 2-3):

• Gemcitabine 1000 mg/m²; IV days 1, 8, 15 every 28 days

• Gemcitabine 1000 mg/m²; IV days 1, 8, 15 plus erlotinib 100 mg orally daily every 28 days

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

Progression after 1st line treatment for advanced disease:

There is no widely accepted standard regimen for use in the salvage setting. It is reasonable to consider further chemotherapy for patients with a good performance status who desire further treatment.

There is limited data to guide treatment after progression on a gemcitabine-based regimen, although oxaliplatin-based combinations (e.g., FOLFOX) have been studied and shown to increase overall survival by several months compared with best supportive care. Nanoliposomal irinotecan in combination with fluorouracil has been shown to be superior to either drug as a single agent, improving overall survival by approximately two months. Single-agent paclitaxel or nab-paclitaxel also has modest efficacy for patients not previously treated with a taxane.

There are no randomized trials to guide therapy after progression on FOLFIRINOX, although a gemcitabine-containing regimen would be typically considered in this circumstance.

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 5 years after resection. In contrast, those with metastatic disease at diagnosis have a median survival of 6 months with gemcitabine or longer with combination regimens, although survival past 2 years is uncommon. Patients with locally advanced PDA 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.

What if scenarios.

Abdominal pain

Severe abdominal pain associated with PDA can often be successfully managed with celiac plexus neurolysis, typically performed with EUS guidance.

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 occurs relatively frequently. Biliary obstruction is typically managed by ERCP-based stenting. Routine preoperative stenting prior to resection to relieve biliary occlusion does not improve outcomes and may harm long-term outcomes.

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.

Plastic stents are often used initially, while waiting for a decision on resectability. Metal stents are wider and less likely to become occluded. Thus a metal stent is preferable for more durable decompression.

Other histologies

Several post-operative scenarios occur when histology other than pancreatic ductal adenocarcinoma is encountered. Adenosquamous and acinar cancer of the pancreas are rare subtypes, and no consensus has been reached on how they should be clinically managed. Nevertheless, it is recognized that both histologies 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 these patterns can also be due to locoregional recurrence, disease) in those patients with R1 (microscopic residual disease) or R2 (macroscopic residual disease) resections. The appropriate clinical response to this development 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 regimen (for metastatic disease) should be initiated with palliative intent.

Follow-up surveillance and therapy/management of recurrences.

Surveillance for recurrence after resection of PDA, although not shown to result in improved overall survival, is generally recommended. One approach is history and physical, abdominal imaging (typically CT scan), and CA 19-9 levels every 3 to 6 months for 2 years, then annually.

Pathophysiology

PDA is characterized at the molecular level by activating mutations in the KRAS gene. Although KRAS mutations are common in many malignancies, such as non-small cell lung cancer and colorectal cancer, in PDA the prevalence of this mutation approaches 100%. Mutations in, or loss of, the CDKN2A and TP53 tumor suppressors are also very frequent (90% and 75% respectively).

Taken together, mutations in these three genes underlie the core signaling derangements in the PDA cell. Unfortunately, unlike alterations in kinase oncogenes (e.g. BCR-Abl or EGFR), inactivation of tumor suppressor genes such as TP53, SMAD4, and CDKN2A is not associated with sensitivity to any particular treatment and confers specific resistance to others. BRCA2 mutations, either germline or somatic, many engender sensitivity to platinum agents, poly-ADP ribose (PARP) inhibitors, or both.

The cell of origin that gives rise to PDA has not been fully characterized but appears to be acinar and capable of assuming a 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 scientifically controversial and biologically complex. Therapeutic agents targeting stromal components are being pursued clinically.

Figure 2.

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