Carcinomas of the Pancreas, Liver, Gallbladder, and Bile Ducts
Timothy J. Kennedy
Steven K. Libutti
I. ADENOCARCINOMA OF THE PANCREAS
A. Epidemiology
Pancreatic cancer is the eighth most common cancer for both genders combined but is the fourth leading cause of cancer death and is responsible for approximately 5% of cancer-related deaths. Recent estimates are that 42,000 individuals were diagnosed with pancreatic adenocarcinoma in the United States in 2009. The overall 5-year survival rate of all patients diagnosed with pancreatic adenocarcinoma remains less than 5%. For the majority of patients, the disease is either locally advanced and unresectable or metastatic at the time of diagnosis, and the median survival in these patients is 3 to 18 months. Approximately 15% of patients present with localized disease that is amenable to surgical resection; even in the most selective patient subgroups, however, median survival is only 2 years and anticipated 5-year survival rates are only 12% to 20%.
B. Etiology
Risk factors for pancreatic cancer include age, sex, and race. The disease is more common in the elderly, with the median age at diagnosis for pancreatic cancer being 72 years of age. Men and African-Americans have a higher risk than others. Cigarette smoking, alcohol consumption, obesity, Helicobacter pylori infection, and exposure to chemicals such as beta-naphthylamine and benzidine
are also associated with an increased risk. Chronic pancreatitis and diabetes have been commonly associated with carcinoma of the pancreas but whether this association is causal is uncertain. The risk of pancreatic cancer is also increased in patients with certain familial cancer syndromes, but hereditary pancreatic cancer makes up less than 5% of cases. Hereditary pancreatic cancer has been observed in rare families with an autosomal site-specific pattern, in families with BRCA2 mutations, and in families with hereditary nonpolyposis colorectal cancer. Likewise, families with p16 germline mutations may be at higher risk of developing pancreatic cancer. Greater than 80% of resected pancreatic cancers harbor either activating point mutations in KRAS or inactivating mutations of the tumor suppressor genes p16, p53, and DPC4.
C. Presenting signs and symptoms
Pancreatic cancer-associated symptoms are not specific and usually occur when the disease is already incurable. Pain is the most common presenting symptom. It occurs in three-fourths of patients with carcinoma of the head of the pancreas and in virtually all patients with carcinoma of the body or tail. Usually, the pain is a dull ache in the epigastrium that radiates to the right upper quadrant when the tumor is in the head of the pancreas or to the left upper quadrant when the tumor is in the body or tail; the pain may radiate to the lumbar region of the back. Weight loss can be significant and is associated with anorexia, steatorrhea, nausea, diarrhea, and early satiety, which are other symptoms related to cancer of the pancreas. The nonspecific, vague nature of these complaints may delay diagnosis for several months. Seventy percent of patients with carcinoma of the head of the pancreas have jaundice, whereas fewer than 15% of patients with carcinoma of the pancreatic body have jaundice. Depression and diabetes commonly precede pancreatic cancer and can be early symptoms. Of patients aged 50 years and older with recent onset of diabetes, about 1% are diagnosed with pancreatic cancer within 3 years. Physical findings are generally associated with advanced carcinomas and include weight loss, hepatomegaly, and an abdominal mass. A palpable gallbladder in the absence of cholecystitis or cholangitis suggests malignant obstruction of the common bile duct (Courvoisier sign), and it is present in about 25% of all patients with pancreatic cancer. Other physical findings, which can be indicative of distant metastases, include Trousseau syndrome (migratory superficial phlebitis), ascites, Virchow node (left supraclavicular lymph node), a periumbilical mass (Sister Mary Joseph node), or a palpable pelvic shelf on rectal examination (Blumer shelf).
D. Diagnostic evaluation
Accurate diagnostic imaging is used to determine whether a patient with pancreatic cancer is a candidate for surgical resection or has an incurable disease. Computed tomography (CT) is the
most commonly used study and is very effective when performed according to a standard pancreatic protocol with thin slices and triphasic cross-sectional imaging. CT scans can demonstrate masses in the pancreas or dilatation of the pancreatic duct or the common bile duct. Sensitivity and specificity of CT are about 90%, but CT can miss tumors less than 2 cm in size. Endoscopic retrograde cholangiopancreatography demonstrates subtle ductal abnormalities; sensitivity and specificity are in excess of 90% with biopsies detecting tumors smaller than 1 to 2 cm in diameter. Endoscopic ultrasound (EUS) may be useful for staging (i.e., nodal status), determination of major vessel invasion, and at times for fine needle aspiration (FNA) for pathologic determination of tumor. To determine vascular invasion, there are three options: helical CT, magnetic resonance arteriography, or EUS. Percutaneous FNA of suspicious abnormalities identified on CT scan can confirm the diagnosis of pancreatic cancer with 80% to 90% sensitivity and 100% specificity. A common histologic hallmark of pancreatic adenocarcinoma is an associated desmoplastic reaction that, in a given tumor mass, can vastly overestimate the malignant cell mass. Furthermore, pancreatic cancer may be associated with varying degrees of acute or chronic pancreatitis or cyst formation, which may make it difficult to make a diagnosis with FNA and may lead to false-negative results.
E. Laboratory tests
The majority of tumor markers have not proven to be specific or sensitive enough for pancreatic cancer. Cancer antigen (CA) 19-9 is a cell surface glycoprotein that is associated with pancreatic cancer and has been shown to be elevated in 90% of patients with pancreatic cancer. A 20% or greater fall in the serum marker following treatment is a good prognostic indicator and is associated with improved survival. Rising serum levels may be a useful early indicator of recurrent or progressive disease once a diagnosis has been established, but because of low specificity it is not used as a screening method. However, there are data to support the obtaining of a CA19-9 level in all patients in whom pancreatic cancer is suspected.
F. Staging and preoperative evaluation
1. Staging. The primary tumor, regional lymph nodes, and potential sites of metastatic disease must be carefully assessed (Table 8.1). The staging system has been modified to better take into account “resectability” of disease. Resectable disease is loosely defined as disease confined to the pancreas without involvement of the celiac axis or major vessels. A surgeon experienced in pancreatic surgery should evaluate each case individually when determining resectability as there are numerous clinical caveats.
TABLE 8.1 TNM Staging for Pancreatic Cancer
Stage
Definition
0
Tis, N0, M0
Ia
T1 (tumor ≤2 cm, confined to pancreas), N0, M0
Ib
T2 (tumor >2 cm, confined to pancreas), N0, M0
IIa
T3 (extrapancreatic extension but no celiac axis or mesenteric artery involvement), N0, M0
IIb
T1-3, N1, M0
III
T4 (involvement of celiac axis or superior mesenteric artery; unresectable primary tumor), any N, M0
IV
Any T, any N, M1
N1, any nodal metastases; M1, any distant metastases.
From American Joint Committee on Cancer. AJCC cancer staging manual (7th ed.). New York: Springer; 2010.
2. Preoperative evaluation. Preoperative evaluation should be performed stepwise from least invasive to most invasive as indicated by the clinical situation. Preoperative evaluation can be stopped when metastatic disease or definite evidence for unresectable locoregional spread is identified. All patients should undergo triphasic helical CT of the abdomen for detection of pancreatic masses and evaluation of vessel encasement. If there is no evidence of metastatic disease and no major blood vessel involvement is identified, then laparoscopy can be used to identify small metastases in the liver or peritoneum. The use of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose in the preoperative evaluation of patients with pancreatic cancer is still controversial and not routinely used.
G. Primary therapy
1. Surgery. Three-fourths of patients with pancreatic cancer are operative candidates, but only 15% to 20% have resectable tumors. Patients without evident metastatic cancer or major blood vessel involvement and whose performance status permits operative intervention are candidates for curative surgery.
2. Radiation therapy. External-beam radiation therapy can palliate locally advanced unresectable carcinomas. It may also be used as a surgical adjuvant in combination with chemotherapy. Great care and expertise must be exercised to plan the radiation fields. These fields must encompass known disease without excessive involvement of adjacent normal tissue. Surgical clips placed during laparotomy or laparoscopy can guide treatment. Intraoperative external-beam radiotherapy has been successful in placing a high dose on the local tumor while protecting the surrounding normal tissues but has not increased the cure rate of pancreatic cancer.
3. Combined-modality therapy
a. Resected carcinomas. Local and distant recurrence continues to be a common problem after complete resection of pancreatic cancer. Options for the adjuvant treatment for pancreatic cancer continue to be in evolution. A prospective randomized study by the Gastrointestinal Tumor Study Group (GITSG) compared observation to postoperative chemoradiation with bolus fluorouracil (5-FU). The study showed an overall survival benefit (median survival: 20 months versus 11 months, p = 0.03) and a 2-year survival benefit (42% versus 15%), but this study is criticized for small patient numbers, low radiation doses, long accrual time, and early termination. The European Organization for Research and Treatment of Cancer performed a similar trial that showed a trend toward improved outcome in the treatment group (median survival: 17.1 months versus 12.6 months, p = 0.099). This study is also criticized for low radiation doses and underpowering of the study. A complicated trial in a 2×2 design was completed by the European Group for Pancreatic Cancer (ESPAC-1); it is difficult to interpret and has some trial design concerns including selection bias and treatment variability. An intriguing outcome of the analysis is that the chemotherapy group seemed to have a survival benefit over observation (median survival: 20.1 months versus 15.5 months, p = 0.009); however, the chemoradiotherapy group seemed to do worse than the controls. The Radiation Therapy Oncology Group trial 97-04 had the benefit of modern radiation doses and the addition of gemcitabine to the chemotherapy regimen. However, a survival benefit of gemcitabine over 5-FU (18.8 months versus 16.7 months, p = 0.047) was seen only in pancreatic head adenocarcinomas. Most recently, the Charite Onkologie (CONKO-001) was the first trial showing that gemcitabine alone in the adjuvant setting can prolong disease-free and overall survival without significant toxicities compared to observation alone (median survival 22.8 months versus 20.2 months, p = 0.005, and 5-year survival of 21% versus 9%). All of these trials show that in an acceptable candidate, chemotherapy improves survival; however, the addition of radiotherapy is still controversial. A prospective randomized trial of bolus 5-FU/leucovorin versus gemcitabine versus observation following surgery (ESPAC-3) is currently in progress and should provide more definitive results on the use of chemotherapy without chemoradiation in the adjuvant setting. At this time, no standardized regimen has been established for the adjuvant treatment of resected pancreatic cancer. 5-FU-based chemoradiation with additional gemcitabine
chemotherapy as well as chemotherapy alone with gemcitabine, 5-FU, or capecitabine are listed in the guidelines for the adjuvant treatment of pancreatic cancer. Alternative adjuvant chemotherapy regimens (with or without radiotherapy) include the following:
1. Gemcitabine alone (1000 mg/m2 on days 1, 8, and 15 with a 1-week break) or
2. 5-FU 225 mg/m2 by continuous intravenous (IV) infusion throughout radiation therapy followed by four to six courses of bolus 5-FU weekly, or gemcitabine (1000 mg/m2 on days 1, 8, and 15 with a 1-week break) or
3. 5-FU 425 mg/m2 by IV push 1 hour after leucovorin 20 mg/m2 by IV push daily for 4 days during the first week of radiation therapy and for 3 days during the fifth week of radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1000 mg/m2 on days 1, 8, and 15 with a 1-week break) or
4. Capecitabine 1500 mg/m2 daily in divided doses with radiation therapy followed by four to six courses of bolus 5-FU weekly or gemcitabine (1000 mg/m2 on days 1, 8, and 15 with a 1-week break). Capecitabine can be used in the chemotherapy only part of the regimen as well, but there is no phase III data to confirm capecitabine in this setting.
b. Borderline resectable pancreatic cancer. Management of borderline resectable pancreatic cancer remains a challenging field without a defined approach and requires a multidisciplinary effort. This subgroup of patients with pancreatic cancer is potentially resectable if they have a good response with preoperative chemotherapy or combined chemotherapy with radiation. There are a number of phase II studies looking at gemcitabine-based chemotherapy regimens and chemoradiation regimens for the neoadjuvant treatment of borderline resectable or resectable pancreatic cancer. However, there have been no phase III studies and there is no consensus among groups as to the preferred chemotherapeutic regimen or whether radiation should be utilized in the neoadjuvant setting.
c. Localized unresectable carcinoma. A series of randomized trials conducted by the GITSG demonstrated superior survival of patients with localized but unresectable pancreatic cancer when treated with combined-modality therapy compared with patients treated with radiation therapy or chemotherapy alone. These clinical trials utilized split-course radiation therapy, which most contemporary studies no longer use. Current clinical trials do not support a specific combined-modality treatment program; however, most studies utilize doses of 50 to 60 Gy with concomitant 5-FU. Other radiation
sensitizers being utilized in studies are gemcitabine, paclitaxel, and cisplatin. There is evidence to suggest that concurrent gemcitabine and radiation can yield similar results to 5-FU-based chemoradiation, although this has not been assessed in any randomized trials. Most recommend that an additional course of gemcitabine-based chemotherapy be considered for patients with locally advanced pancreatic cancer who are receiving chemoradiation therapy. Other options for locally advanced disease are systemic chemotherapy without radiotherapy or chemotherapy followed by consolidated chemoradiation.
H. Chemotherapy of metastatic disease
Patients with pancreatic cancer are often poor candidates for chemotherapy because of severe weight loss, poor performance status, severe pain, lack of measurable or evaluable disease, and presence of jaundice or hepatic involvement, which may interfere with clearance of therapeutic agents. The primary goals for advanced pancreatic cancer are palliation and improved survival. Randomized clinical trials have demonstrated survival and quality-of-life benefits to chemotherapy in selected patients with advanced pancreatic cancer compared to best supportive care alone.
1. Single agents. A number of single agents have demonstrated clinical activity; however, no agent has demonstrated consistent complete or partial response rates greater than 20%. Gemcitabine has been accepted as first-line therapy for metastatic pancreatic cancer in patients with adequate performance status based on a phase III trial that compared bolus 5-FU and gemcitabine with a primary endpoint being the “clinical benefit score.” Clinical benefit was defined as sustained (more than 4 weeks) improvement of one of the following parameters without worsening of any of the others: performance status, composite pain measurement (average pain intensity and narcotic analgesic use), and weight. The improvement in clinical benefit score in the gemcitabine and 5-FU arms were 23.8% and 4.8%, respectively (p = 0.0022). In addition, there was a significant improvement in median survival (5.65 months versus 4.41 months, p = 0.0025) and in survival at 12 months (18% versus 2%). Therapy was generally well tolerated with a low incidence of grade 3 or 4 toxicities. The toxicities with gemcitabine include bone marrow suppression, lethargy, flulike syndrome, nausea and vomiting, and peripheral edema.
2. Combination chemotherapy. Despite promising phase II studies, the combination of gemcitabine with other cytotoxic drugs, including 5-FU, cisplatin, oxaliplatin, and irinotecan, has not been proven to be superior to gemcitabine alone in demonstrating a survival benefit. A recently reported U.K. Phase III trial (U.K. National
Cancer Research Institute study) utilizing higher doses of gemcitabine and capecitabine identified a trend toward improved median overall survival (7.1 months versus 6.2 months, p = 0.077). When this group performed a meta-analysis of their study with two additional studies, they identified a significant survival benefit in favor of the gemcitabine combination (p = 0.02). Furthermore, a meta-analysis of five platinum-based randomized trials did reveal a significant improvement in median overall survival (p = 0.01) for the combination over gemcitabine alone. The results of a randomized phase II trial of three different regimens in patients with advanced pancreatic cancer suggested that capecitabine plus oxaliplatin is comparable to gemcitabine combined with either capecitabine or oxaliplatin. Gemcitabine has also been investigated in multidrug combination chemotherapy regimens. Two regimens, which have shown promising activity but are associated with higher rates of toxicity, are a combination of cisplatin, epirubicin, 5-FU, and gemcitabine and a combination of gemcitabine, docetaxel, and capecitabine.
3. Novel targeted agents.Related posts:
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