JAMES L. ABBRUZZESE, MD, Professor of Medicine and Chairman, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer
Center, Houston.
ANDREW M. LOWY, MD, Associate Professor of Surgery; Chief, Division of Surgical Oncology; and Codirector, Pancreatic Disease Center, University
of Cincinnati, Cincinnati, Ohio.
DOUGLAS PLESKOW, MD, Codirector, Endoscopy, Beth Israel Deaconess Medical Center; and Assistant Professor of Medicine, Harvard Medical School,
Boston.
HENRY Q. XIONG, MD, PhD, Assistant Professor, Department of Gastrointestinal Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston,
Tex.
Acute pancreatitis (AP) is potentially life threatening and requires prompt diagnosis, effective pain management, and careful
monitoring. Recognizing chronic pancreatitis can be difficult, and a delayed diagnosis can allow the development of diabetes,
severe pain, and pseudocysts (accumulations of pancreatic secretions surrounded by a fibrous nonepithelialized shell). Pancreatic
cancer is a highly lethal malignancy that requires prompt diagnosis. For most patients, balancing the choice of treatment
with quality-of-life issues is critical, since no curative therapy exists.
ACUTE PANCREATITIS
AP is a generally self-limiting acute inflammatory process that may involve peripancreatic tissues, remote organ systems,
or both. Alcohol use and gallstone disease cause 80% of cases; 10% are idiopathic, and the remainder are caused by surgical
procedures (including endoscopic retrograde cholangiopancreatography [ERCP]), hyperlipidemia, hypercalcemia, severe hypertriglyceridemia,
hyperparathyroidism, trauma, viral infections such as hepatitis, and drug use. Toxic materials including enzymes and vasoactive
materials are liberated by the pancreas and enter retroperitoneal spaces and the peritoneal cavity, causing inflammation.
Mild episodes can resolve spontaneously, but severe disease can result in necrosis, infection, and organ failure. The clinical
course of severe disease generally comprises 3 phases: local inflammation and necrosis; a systemic inflammatory response leading
to multiple organ dysfunction syndrome during the first 2 weeks; and local complications such as necrosis, pseudocyst formation,
or infection. Because severe AP can be swiftly fatal, a rapid diagnosis and prompt treatment are essential. Infections typically
develop 8 to 20 days after disease onset.
Signs and symptoms
Consider AP in patients with an acute abdomen or severe, boring pain beginning midabdomen and radiating to the back and upper
quadrants. The pain is exacerbated by food intake and often increases in intensity over 10 to 30 minutes and then persists
at that peak level for days. Nausea, vomiting, confusion, diminished bowel sounds, and low-grade fever are sometimes present.
Findings suggestive of infection include severe epigastric tenderness, fever higher than 101F (38.3C), leukocytosis (often
greater than 20,000 cells/μL), and abdominal distention with a palpable mass. Pancreatic hemorrhage is indicated by ecchymoses
of the flank or periumbilical region.
In alcohol-induced disease, symptoms can begin after binge drinking. Suspect gallstones as the cause of AP in patients older
than 50, in nondrinkers, and when pain begins after a large meal. To distinguish alcohol-induced from gallstone-induced disease,
order an alkaline phosphatase test. A value greater than 180 U/L is suggestive of biliary disease.
Severity grading systems for both acute and chronic pancreatitis include Ranson's criteria and the Acute Physiology and Chronic
Health Evaluation (APACHE-II) scoring system. The APACHE-II can be used within hours of admission and repeated each day during
the disease course, but Ranson's criteria require a full 48 hours of measurement. In general, when the APACHE-II point score
is less than 8 during the first 24 to 48 hours, the patient is likely to survive; as points increase during that interval,
morbidity and mortality rates rise. Severe AP is also indicated by evidence of third space losses—a hematocrit value greater
than 50%, oliguria, azotemia, tachycardia, or mild hypotension due to sequestered fluid.
Diagnostic techniques
Mild AP, or interstitial disease, is defined by the absence of organ dysfunction and intact microcirculation. Severe, or necrotizing,
AP is defined by organ failure, biliary sepsis, disrupted microcirculation, or all of these. Sclerosing pancreatitis is characterized
by irregular narrowing of the main pancreatic duct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemia.
Figure 1: The marked pancreatic swelling and inflammation shown on this CT scan suggest acute pancreatitis. Although a normal
scan does not exclude the possibility of disease, contrast-enhanced CT is still the best imaging modality for assessing the
pancreas. (IMAGE: STEPHEN T. AMANN, MD)
|
No one test confirms a diagnosis of AP (see Figure 1). Elevated total bilirubin levels, ALT levels twice the upper limit of
normal, and increased alkaline phosphatase levels suggest gallstone pancreatitis and choledocholithiasis. Elevated levels
(3-5 times normal) of serum amylase and lipase are specific for AP, but negative findings do not rule out the disease. These
levels do not become elevated until 20 to 30 hours after symptom onset, after which they return to normal—amylase more quickly
than lipase.
Laboratory tests should include a CBC, WBC count (levels higher than 20,000 cells/μL suggest AP), hemoglobin, hematocrit,
electrolytes, serum urea nitrogen, creatinine, arterial blood gases, serum calcium, blood glucose (levels higher than 200
mg/dL suggest AP), and liver enzymes. Include a test of the total bilirubin level with fractionation to look for evidence
of either a stone obstructing the common duct, cholangitis, or other disordered biliary function. Measurements of serum lipid
levels, especially triglycerides, can identify hypertriglyceridemia as the cause of the acute pancreatic episode. Other prognostic
markers include C-reactive protein (CRP), phospholipase A2 catalytic activity, polymorphonuclear elastase, alpha2-macroglobulin, and trypsinogen activation peptides in the urine.
A CRP level higher than 120 mg/L is suggestive of pancreatic necrosis. Patients with sclerosing pancreatitis have high serum
IgG4 concentrations, distinguishing sclerosing pancreatitis from other diseases of the pancreas and the biliary tract.1
Ultrasonography can reveal gland enlargement, dilation of the common bile duct, pseudocyst formation, and evidence of gallstones
in the biliary tract. In the presence of allergy to either contrast material or significant renal impairment, CT should be
performed without the use of IV contrast.2 CT can best assess gland size, ductal dilation, fluid accumulation, gas in the peripancreatic retroperitoneum, and the presence
of either pseudocysts or abscesses, but normal findings do not rule out AP. Dynamic contrast-enhanced CT is needed to distinguish
interstitial from necrotizing pancreatitis and reveal the extent of necrosis. The value of MRI in AP has not been established.2
Management
The American College of Gastroenterology (ACG) guidelines for AP recommend supportive care until the episode resolves, pain
relief, elimination of inflammatory mediators, and prevention and management of systemic complications and necrosis. Stop
oral intake of all foods and liquids in order to minimize pancreatic stimulation. Prevent dehydration by providing sufficient
IV fluids. The guidelines state that a nasogastric tube is not helpful in mild AP but can play a role in treating either gastric
or intestinal ileus and preventing aspiration of gastric contents in severe AP.
In mild AP or interstitial disease, fluid resuscitation and monitoring are the most important components of treatment. Dynamic
contrast-enhanced CT may be considered after the first week in patients with severe AP. In severe, or necrotizing AP, organ
failure occurs as a result of third space losses and toxic materials from the pancreas. With severe third space losses, transfer
the patient to an intensive care unit for aggressive fluid resuscitation. Treatment should be administered by a multidisciplinary
team comprising a gastroenterologist, surgeon, and radiologist. If common bile duct stones are suspected, ERCP is recommended
within 2 to 3 days for confirmation. Sphincterotomy and extraction of duct stones should be performed, but this can result
in complications such as bleeding, cholangitis, and bacteremia.
If there is evidence of necrosis and no clinical improvement, guided percutaneous aspiration for Gram's stain and culture
should be performed to distinguish infected necrosis from severe sterile necrosis. The infected form generally requires debridement;
the sterile condition can be treated medically in the hope that systemic toxicity will eventually resolve, making surgery
unnecessary. For the infected condition, therapy with a potent antibiotic such as imipenem/cilastatin and/or percutaneous
drainage with large catheters is recommended.
Aggressive fluid resuscitation can limit necrosis, and some ongoing studies show isovolemic hemodilution to be promising.
Pancreatic infection is an important risk factor for death in patients with AP, so preventing infection is crucial in managing
necrotizing disease. Swiss investigators tried to determine the benefits of conservative versus surgical treatment in patients
with necrotizing pancreatitis.3 Their study of 204 patients with AP, of whom 86 had necrotizing disease, supported nonsurgical management including early
antibiotic treatment in patients with sterile pancreatic necrosis. Patients with infected necrosis represent a high-risk group
in severe AP, and for them surgical treatment is preferable, according to the study. The ACG guidelines recommend initiating
antibiotic treatment for patients with necrotizing pancreatitis associated with organ failure.
Monitor cardiovascular and respiratory function, and administer packed RBCs if hypotension develops and hematocrit levels
fall below normal. Prophylactic antibiotics such as imipenem/cilastatin should be administered in severe disease (30% or greater
necrosis on contrast-enhanced CT scan) to reduce complications.
Oral loxiglumide, a peripheral nonpeptide cholecystokinin receptor antagonist, may be effective for patients with AP.*,4 Investigators assessed abdominal pain and serum pancreatic enzyme levels in 207 patients randomized to receive either 300,
600, or 1200 mg/d of loxiglumide or placebo, for 4 weeks. Clinical symptoms were relieved by 36% in the placebo group, 46%
(300 mg/d), 59% (600 mg/d), and 52% (1200 mg/d) in the loxiglumide group. The optimal dosage of loxiglumide appears to be
600 mg/d because patients receiving that dosage showed significantly decreased pancreatic enzyme levels and a significantly
high rate of improvement.
Limit systemic complications, including respiratory failure, hypotension, and renal failure, by aggressive fluid resuscitation.
Laparoscopic cholecystectomy is typically performed following episode resolution in mild disease with a gallstone etiology.
For patients with severe AP with multiorgan failure and no improvement after several weeks of intensive medical therapy, surgical
debridement of the necrotic pancreas will likely be necessary.
Nutritional management
Nutritional management of patients with AP traditionally comprises total parenteral nutrition (TPN) and bowel rest. The rationale
is that enteral feeding stimulates proteolytic enzyme activity, exacerbating the disease process. But enteral feeding may
reduce gut permeability and bacterial translocation and thus limit infection in the necrotic pancreas.
Enteral feeding can be as effective as TPN, costs one tenth as much—$800 per patient admission—and results in fewer complications.5 Investigators followed 103 patients admitted for AP; alcoholism was the etiology in two thirds of cases. Some of the patients
were fed orally, some were given TPN, and some were fed enterally. No differences were noted between the outcomes of TPN and
enteral-feeding groups, but the TPN group experienced more complications. Lipids should be included in feeding unless serum
triglyceride levels are higher than 500 mg/dL.
No proven medical strategy exists for treating pseudocysts. According to the ACG guidelines, approaches to decompression that
are radiologic (percutaneous needle aspiration and catheter drainage) and endoscopic (cystogastrostomy or cystoduodenostomy)
are options.
CHRONIC PANCREATITIS
Chronic pancreatitis (CP) is not caused by AP, but the recurrent flare-ups of CP are similar to attacks of AP. The pancreas
and surrounding tissues are eroded by digestive enzymes over the disease course. Progressive inflammation, atrophy, and fibrosis
eventually mark CP, but its diagnosis may be easily missed because there are no early signs. Unrecognized symptoms may lead
to fat malabsorption, diabetes mellitus, and the formation of pseudocysts that can rupture, bleed, or form abscesses. Pancreatic
duct obstruction can also occur because of ductal strictures or pseudocysts.
Experts do not know whether CP actually predisposes to diabetes or whether it is merely an association. A group of French
researchers set out to discover under what circumstances diabetes appears in patients with CP and whether it is related to
disease progression or pancreatic surgery. The investigators followed 500 patients with CP and compared the half who underwent
surgery with the half who did not.6 The cumulative rate of diabetes in this study was approximately 83% at 25 years after disease onset and was not influenced
by prior surgery for distal pancreatectomy. Instead, the investigators attributed the risk of diabetes to disease progression.
Signs and symptoms
Severe abdominal pain radiating to the back is the symptom of CP that brings most patients to the office. In some patients,
the pain is continuous; in others, it is recurrent and mimics repeated attacks of AP. Other signs and symptoms include weight
loss, steatorrhea, and diabetes (evidence of exocrine and endocrine insufficiency). GI motility disorders, duodenal ulcer,
irritable bowel syndrome, biliary tract disease, retroperitoneal lesions, and pancreatic cancer comprise the differential
diagnosis. More men than women receive a diagnosis of CP, and the most common cause of the disease is long-term alcoholism.
Diagnostic techniques
Laboratory tests and imaging studies can detect pancreatic abnormalities and insufficiencies. Normal or moderately elevated
serum amylase and lipase levels and trypsin levels below 20 ng/mL are typical. The fecal elastase test is useful in diagnosing
pancreatitis. Fecal fat indicative of maldigestion due to exocrine insufficiency may be detected. Elevated bilirubin and alkaline
phosphatase concentrations suggest obstruction of the intrapancreatic bile duct. For analyzing pancreatic secretions, a secretin
test is less expensive and less risky than ERCP.
Recent advances in molecular and genomic technologies and progress in pancreatic imaging techniques have led to a reassessment
of current approaches to diagnosis, classification, and staging of CP.7 The diagnostic gold standard is pancreatic biopsy, which is rarely done. The most widely used diagnostic testing includes
CT, ERCP, endoscopic ultrasonography, or MRI.
Management
Options for medical treatment of CP are outlined in Table 1. Treatment involves relief from severe pain, prevention of recurrent
disease and complications, and nutritional support.
TABLE 1: Options for medical treatment of chronic pancreatitis
|
Recommend a high-carbohydrate, low-protein, low-fat diet and abstinence from alcohol. A recent study investigated whether
moderate alcohol consumption exacerbates the symptoms of CP. The researchers reported that even small amounts of alcohol can
worsen the disease, causing frequent and more severe pain, calcification, and complications such as fistulas, pseudocysts,
abscesses, and biliary obstruction.8 In patients older than 35 who participated in the study and drank less than 50 g/d of
alcohol, disease symptoms developed earlier than in those who did not drink, and those who drank more than 50 g/d of alcohol
experienced a shortened time to calcification and death. According to an accompanying editorial, the frequency of pain was
significantly associated with increasing intake of alcohol. The investigators attributed their findings to a common underlying
genetic defect.9Administration of pancreatic enzymes (protease, amylase, and lipase) before each meal may relieve pain and alleviate fat malabsorption
caused by exocrine insufficiency. Lipase replacement in particular controls steatorrhea. Patients with diabetes may require
insulin.
Surgery is sometimes an option. ERCP can gauge the caliber and morphologic features of ducts prior to surgery, and CT can
reveal inflammatory masses.
No surgical procedure is ideal for all patients with end-stage CP, but the pain of pseudocysts can be alleviated by drainage
or resection. Other surgical techniques can clear obstructions caused by chronic inflammation and fibrosis or decompress a
dilated duct.
For patients who have had total or near-total pancreatectomy, islet transplantation has been shown to be safe and may reduce
daily insulin requirements.10 Investigators recently transplanted islets into the portal vein, spleen, or both in 1 group of patients. Insulin requirements
and glycosylated hemoglobin levels were significantly lower in those patients than in a control group; only a small number
achieved lasting independence from insulin, however.
PAIN MANAGEMENT
Abdominal pain typically triggers a visit from a patient with pancreatitis or pancreatic cancer. The pain can range from mild
and intermittent to constant and disabling. It is often nocturnal or may increase after a meal. Pain is localized to the upper
abdomen, sometimes radiating to the back.
Pain control is sometimes accomplished with acetaminophen, NSAIDs, and patient-controlled opioid analgesics. Because the potential
for narcotic addiction is high in patients with pancreatitis who may be already plagued by alcoholism, alternative pain therapy
is recommended. The American Gastroenterological Association's (AGA) position statement on abdominal pain management in patients
with CP recommends a course of high-dose pancreatic enzymes (nonenteric-coated) coupled with H2-blockers before the administration of narcotics.11 The enzymes inhibit cholecystokinin activity and reduce pancreatic secretions.
Clinical studies and data on pain management are largely lacking because of a poor understanding of the pathophysiology of
pain. The mechanism of pain in CP can be due to
- Neuropathy; inflammation of nerves; entrapment and loss of perineural sheaths; fibrotic encasement of sensory nerves; and
an increase in sensory peptidergic innervation
- Main and side duct obstruction caused by strictures, calculi, or increased viscosity of pancreatic juice
- High pancreatic tissue pressure (compartment syndrome)
- Pancreatic necrosis and formation of pseudocysts
- Decreased blood flow, ischemia, and local changes in parenchymal pH.12
Surgical options
No trials compare surgical and nonsurgical therapy for pain. According to the AGA guidelines, surgical treatment should be
reserved for patients with severe pain who are not responsive to noninvasive strategies. Options include
Decompression/drainage operations
These are predicated on the presence of a widely dilated main pancreatic duct (greater than 6-7 mm). Lateral pancreatojejunostomy
is utilized for patients with dilated main pancreatic ducts, and the dilation is determined by ERCP or CT. Before those 2
exploratory techniques were available, an intraoperative pancreatogram was used to select candidates for the procedure. The
dilated ducts imply an abnormally high pressure in the duct system and pancreatic parenchyma. Drainage of pseudocysts is done
in conjunction with a lateral pancreatojejunostomy.
Resection
For patients without dilated ducts, a proximal resection of the head of the pancreas (pylorus-preserving pancreatoduodenectomy)
provides pain relief in up to 85% of patients. Distal pancreatectomy alone has poor results unless disease is confined to
the body and tail of the gland. Resection results in the loss of some exocrine and endocrine function and increases the possibility
of fat malabsorption and diabetes. Total pancreatectomy produces a total lack of insulin and glucagon, leading to brittle
diabetes.13 To lessen the adversities, islet tissue or part of the gland is sometimes autotransplanted.
Denervation procedures
These are accomplished by a transthoracic left splanchnicectomy with concomitant vagotomy. Unilateral or bilateral procedures
can result in significant decreases in pain frequency and intensity. Both pancreatoduodenectomy and duodenum-preserving resection
of the pancreatic head confer pain relief in part by denervating the area.
Transduodenal sphincteroplasty with caudal pancreaticojejunostomy
This offers relief only to patients with true recurrent AP.14
CANCER OF THE PANCREAS
Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality. Clinically, 90% of pancreatic tumors are malignant
ductal adenocarcinomas. Fewer than 5% of patients survive beyond 5 years, and experts caution physicians to avoid inappropriate
investigations and treatments that might interfere with quality of life.
Smoking and age are known risk factors, smoking accounts for approximately 30% of pancreatic cancer cases.15 Familial aggregation and genetic susceptibility may play a role in the development of PC in about 10% of patients with PC,
although the genes responsible for familial PC have not been identified. The BRCA2 gene, the familial polyposis gene, and the hereditary nonpolyposis colon cancer syndrome all predispose a person to PC.
Investigators recently evaluated whether a family history of PC increases risk in first-degree relatives and whether smoking
further increases the risk.16,17 They found that a family history and smoking doubled the risk of PC. A practical use of that finding is to target populations
for interventions. We should question patients about smoking habits and a family history of PC, then advise smoking cessation.
Signs and symptoms
Common symptoms associated with PC are nonspecific, including fatigue, weight loss, anorexia, and abdominal/back pain from
local invasion. Patients with PC in the head of pancreas frequently present with progressive obstructive jaundice (from blockage
of bile drainage into the small intestine) manifested as dark urine and pale stools. New-onset diabetes or changes in glucose
tolerance in patients with diabetes is also a frequent finding and should raise suspicion. Patients with metastatic disease
are often severely cachectic.
Diagnostic techniques
Ultrasonography is frequently used as a screening tool to evaluate patients with new onset of jaundice or abdominal pain.
Though not as sensitive as CT, it provides initial assessment of the gallbladder, bile duct, and pancreas. Helical CT remains
the test of choice for diagnosing pancreatic masses and extrapancreatic metastases and for determining resectability. MRI
can provide similar information, but it is more costly. ERCP has limited value as a diagnostic tool; it is usually indicated
as therapeutic intervention for obstructive jaundice. Brush biopsy of the bile or pancreatic duct is usually performed during
ERCP, although sensitivity of brush biopsy is low. Typically CT is ordered first for patients who present with findings suspicious
for PC. If the scan shows a mass and the tumor is resectable, the patient may either go directly to surgery or enter a clinical
trial and receive chemotherapy or radiation prior to surgery. With improvement of imaging technology, surgeons increasingly
rely on CT scans for determining resectability. The incidence of nontherapeutic exploratory surgery can be minimized.
Patients with jaundice sometimes have a tumor just large enough to obstruct the bile duct but too small to be detected by
CT. If there is a suspicion of a nonneoplastic etiology, and the CT scan demonstrates no evidence of a mass lesion, ERCP may
be ordered to rule out a duct-obstructing gallstone. When a biopsy is done, the findings may be negative. Pancreatic cancers
create much scar tissue, but tumor cells sometimes are very scant. In such cases, the tumor is small and removable.
Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) is the preferred nonsurgical method for obtaining tissue
diagnosis. Advantages of EUS-guided FNA include procuring a tissue diagnosis while obtaining additional staging information,
such as anatomic relation of the tumor with major blood vessels and surrounding lymph nodes involvement. Tissue diagnosis
is not required for patients who are scheduled to have immediate surgery. If there is radiographic evidence of metastasis
involving liver or other easily assessable organ, CT or ultrasound-guided biopsy of metastatic sites is preferred.
Management
PC is resectable in approximately 15% of patients on initial presentation. The majority of patients undergo pancreaticoduodenectomy
(Whipple resection) since most patients have cancer located in the head region of pancreas. Although patients undergoing complete
resection have a favorable long-term survival rate, recurrence or metastasis are disappointingly common. Therefore adjuvant
therapy is usually recommended. Recent clinical studies from Europe have shown that patients receiving chemotherapy have improved
survival duration when compared to those who received no treatment or radiation alone.
Patients with metastatic or locally advanced pancreatic cancer may be treated with chemotherapy. Combined chemotherapy and
radiation is indicated for patients with locally advanced disease, especially for those with severe pain.
Gemcitabine (Gemzar) is the standard chemotherapy for advanced pancreatic cancer; it is administered IV once a week for 3
weeks followed by 1 week off. The toxicity of gemcitabine is mild and tolerable to most patients. Patients frequently experience
improvement of cancer-related symptoms but limited effects in shrinkage of tumor or prolonging life.18 Many gemcitabine-containing combination regimens have been investigated in PC. Some combination regimens have shown improved
tumor response, but no significant improvement of overall survival over gemcitabine alone. A randomized phase 3 trial compared
the combination of gemcitabine plus oxaliplatin (Eloxatin) with gemcitabine administered over 30 minutes infusion or fixed-dose
rate infusion at 10 mg/m2 /minute. The trial has finished accrual, and the results are eagerly awaited.
Pancreatic carcinogenesis is driven by the accumulation of multiple genetic and epigenetic changes, including inactivation
of tumor suppression genes, coupled with activation or overexpression of proto-oncogenes. The genetic changes that can potentially
serve as targets for novel therapy include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)
and its receptor (VEGFR), and others.19 Elevated expression of EGFR is detected in more than 90% of human PC cases. A monoclonal
antibody, cetuximab (Erbitax), can inhibit EGFR. A phase 2 trial of cetuximab in combination with gemcitabine for advanced
pancreatic cancer was reported recently.20 In that trial, 41 patients whose tumor expressed EGFR were treated with cetuximab and gemcitabine. A partial response rate
of 12% and disease control (sum of partial response and stable disease) 76% were observed. The median survival duration was
7.1 months, and the 1-year survival rate was 32.5%. This encouraging activity prompted a randomized phase 3 trial comparing
gemcitabine to gemcitabine plus cetuximab sponsored by Southwest Oncology Group. The trial is actively accruing.
The National Cancer Institute of Canada conducted a randomized placebo-controlled phase 3 study of erlotinib (Tarceva), an
orally administered inhibitor of EGFR, plus gemcitabine versus gemcitabine plus placebo in patients with advanced pancreatic
cancer.21 The study demonstrated that patients receiving gemcitabine plus erlotinib had incremental improvement of median overall
survival of 2 weeks more than those who received gemcitabine plus placebo (6.4 versus 5.9 months). Although the improvement
of median survival is statistically significant, whether it is clinically meaningful is debatable.
VEGF plays a central role in regulation of angiogenesis, which supports cancer growth and metastasis. Therefore antiangiogenesis
is an attractive therapeutic target. A number of agents that target multiple points along the angiogenic pathway have been
developed. Of particular interest is the VEGF family. Several different strategies have been used to inhibit VEGF-mediated
signals, including anti-VEGF antibody, agents that inhibit the VEGF receptor tyrosine kinase, and soluble VEGFR-1 that traps
VEGF. A phase 2 trial of bevacizumab (Avastin), a humanized antibody targeting VEGF, plus gemcitabine for advanced PC was
recently reported.22 A total of 52 patients participated in the study. The tumor response rate was 19%, median survival was 8.7 months, and 1-year
survival was 29%. Based on this encouraging observation, a randomized phase 3 trial comparing gemcitabine plus bevacizumab
versus gemcitabine is being conducted by the Cancer and Leukemia Group B.
In summary, gemcitabine remains the standard care for patients with advanced PC. The combination of gemcitabine plus oxaliplatin
showed improved tumor response and progression-free survival than gemcitabine alone, but the improvement of overall survival
did not reach statistical significance in a previous phase 3 trial. The ongoing phase 3 trial of gemcitabine plus oxaliplatin
versus gemcitabine will provide a second chance to determine the usefulness of the combination. Erlotinib in combination with
gemcitabine showed incremental but statistically significant improvement of overall survival. The ongoing randomized phase
3 trials will determine the clinical usefulness of cetuximab and bevacizumab in the near future.
This article was updated by Drs Pleskow and Xiong.
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For more information
Lustgarten Foundation for Pancreatic Cancer Research
1111 Stewart Ave
Bethpage, NY 11714
(516) 803-2304; (866) 789-1000
Fax: (516) 803-2303
Web site: http://www.lustgartenfoundation.org/
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
1 Information Way
Bethesda, MD 20892-3560
(301) 654-3327
Web site: http://www.niddk.nih.gov/
National Pancreas Foundation
PO Box 935
Wexford, PA 15090-0935
Web site: http://www.pancreasfoundation.org/
"Pancreas.org"
Web site: http://www.pancreas.org/
Pancreatic Cancer Action Network
PO Box 1010
Torrance, CA 90505
(877) 2-PANCAN
Fax: (310) 791-5224
Web site: http://www.pancan.org/
Pancreatic Disease Center
University of Cincinnati
University Medical Arts Bldg Suite 6000
222 Piedmont Ave
Cincinnati, OH 45219
(513) 475-8525
Web site: http://www.ucpancreas.org/contact.htm
Drugs mentioned in this article
Acetaminophen
Allopurinol (Aloprim, Zyloprim)
Ascorbic acid
Beta carotene
Bevacizumab (Avastin)
Cetuximab (Erbitux)
Erlotinib (Tarceva)
Gemcitabine (Gemzar)
Imipenem/cilastatin (Primaxin)
Loxiglumide*
Methionine
Octreotide (Sandostatin)
Oxaliplatin (Eloxatin)
Selenium
Vitamin E
*Investigational agent.
