Timothy J. Kennedy and Steven K. Libutti
I. ADENOCARCINOMA OF THE PANCREAS
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 adeno-carcinoma 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 se-lective patient subgroups, however, median survival is only 2 years and anticipated 5-year survival rates are only 12% to 20%.
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. Helicobacterpylorimfection, 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 sati-ety, 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 ad-vanced 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 indica-tive 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 duc-tal 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.
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 20.1 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 gemcit-abine, 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, pacli-taxel, 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 op-tions 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). Further-more, a meta-analysis of five platinum-based randomized trials did reveal a significant improvement in median overall surviva (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. A better understanding of the biology of cancer has led to the development of novel agents targeting pathways of cancer cell survival. Clinical trials have explored the combination of gemcitabine with a variety of biologica “targeted” agents such as bevacizumab, cetuximab, and erlo-tinib over the past decade. Despite their promise in preclini-cal studies, most of these studies have not shown a surviva advantage over standard monotherapy gemcitabine. Results of the Cancer and Leukemia Group B phase III trial, which evaluated gemcitabine plus bevacizumab (antivascular endothelia growth factor [VEGF] antibody) compared with gemcitabine plus placebo, and the Southwest Oncology Group phase III trial which assessed gemcitabine plus cetuximab (targets epiderma growth factor receptor [EGFR]) versus gemcitabine alone, did not reveal any improvement in survival with the addition o the biologic agent. However, in a phase III trial of patients with advanced or metastatic pancreatic cancer randomly assigned to receive either erlotinib (inhibitor of EGFR tyrosine kinase) plus gemcitabine or gemcitabine alone, patients in the erlotinib arm showed statistically significant improvement in median and 1-year survival (6.24 months versus 5.91 months, p = 0.038 and 23% versus 17%, respectively). There was a slight increase in incidence of grade 3 to 4 skin rash and diarrhea in the group receiving erlotinib, although there was no overall difference in quality of life between the two groups. The U.S. Food and Drug Administration has approved erlotinib in combination with gemcitabine for first-line treatment of patients with locally advanced or metastatic pancreatic cancer.
4. Current recommendations
a. Erlotinib 100 mg by mouth daily plus gemcitabine 1000 mg/m2 weekly for 3 weeks with a 1-week break.
b. Single-agent therapy with gemcitabine 1000 mg/m2 IV of 4-week cycles of three weekly doses followed by a 1-week rest is recommended for patients with metastatic pancreatic cancer and with an Eastern Cooperative Oncology Group performance status of 0 to 2, who are not eligible for clinical trials.
c. Patients with a very good performance status can use a doublet such as gemcitabine and oxaliplatin (GemOx) with gemcitabine 1000 mg/m2 on days 1 and 8 plus oxaliplatin 130 mg/m2 over 2 hours on day 8 every 3 weeks or
d. Capecitabine and gemcitabine. Capecitabine at 1500 mg/m2 daily in twice-daily divided doses on days 1 to 14 and gemcit-abine 1000 mg/m2 on days 1 and 8 every 3 weeks or
e. Capecitabine and oxaliplatin. Capecitabine at 1500 mg/m2 daily in twice daily divided doses on days 1 to 14 plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks.
5. Second-line chemotherapy. There is no standard second-line regimen for advanced pancreatic cancer after gemcitabine failure, and there is a paucity of trials in this setting. Current recommendations encourage treatment in a clinical trial but when an investigational therapy is not available there are other alternatives. Gemcitabine may offer palliative benefits in the second-line setting in patients who have not been treated with gemcitabine previously. Results from a phase II study suggest that fixed-dose–rate GemOx may have activity in patients who become resistant to standard gemcitabine therapy. Other treatment options include 5-FU or capecitabine with or without oxaliplatin. The CONKO-3 study randomized 168 gemcitabine refractory patients with pancreatic cancer to 5-FU and leuco-vorin or 5-FU, leucovorin, and oxaliplatin. This study revealed an improved overall survival of 2 months in the arm containing oxaliplatin (4.8 months versus 2.3 months, p = 0.0077).
II. PANCREATIC NEUROENDOCRINE TUMORS (PNETs)
PNETs are rare malignancies with an overall incidence of 1 to 2 cases/100,000 people per year. They account for less than 2% of all digestive malignant tumors and 1% of all endocrine tumors. These tumors cover a spectrum of neoplasms, many, but not all, of which originate from the pancreatic islets of Langerhans and are therefore known as “islet cell tumors.” Although the peak incidence of occurrence is between 40 and 60 years of age, a significant number of patients diagnosed are under 35 years of age. PNETs are broadly categorized into those with and those without a clinical syndrome and therefore have been termed “functional” or “nonfunctional.” Approximately 50% of these tumors secrete one or more hormones excessively, which may cause clinical symptoms of excessive hormone release: most commonly insulin or gastrin; less commonly glucagon, serotonin, or adrenocorticotropic hormone; and rarely vasoactive intestinal peptides (VIPs), growth hormone–releasing hormone, or somatostatin. The other 50% are nonfunctional and are generally discovered through symptoms related to tumor burden itself or as incidental findings. Most neuroendocrine tumors (with the exception of insulinomas, of which 90% are benign) are malignant and have the ability to metastasize, most commonly to lymph nodes or the liver and less commonly to bone, lung, brain, or other organs. However, these tumors are usually slow growing with low mitotic activity and often have an insidious presentation. Management of PNETs depends on the pathologic differentiation, stage at diagnosis, and presence of symptoms related to hormone secretion.
Islet cell tumors may occur with the multiple endocrine neoplasia type I (MEN-I) syndrome. In families with this autosomal dominant syndrome, 80% of affected members develop islet cell tumors, most commonly gastrinoma (54%), insulinoma (21%), glucagonoma (3%), or VIPoma (1%). Gastrinoma is often suspected in patients with recurrent peptic ulcers and associated diarrhea and steatorrhea. Evaluation includes measuring gastrin levels (basal and stimulated) and gastric acidity. The frequent use of proton pump inhibitors (PPIs) can be responsible for false positive tests and therefore PPIs must be discontinued 1 week prior. About one-fourth of gastrinomas are associated with MEN-I and tend to be multicentric. Eighty percent to ninety percent of gastrinomas occur in the duodenum and head of the pancreas and the majority of gastrinomas (60% to 90%) are malignant. Insulinomas are typically single, small, benign lesions equally distributed in the head, body, and tail of the pancreas that present with symptoms of fasting hypoglycemia. The diagnosis of insulinoma may be established by a supervised 48- to 72-hour fasting of the patient followed by insulin and glucose testing. Patients with insulinoma have elevated C-peptide. An insulin level greater than 3 jxU/mL when blood glucose is less than 40 mg/dL with an insulin to glucose ratio of 0.3 or less reflects an inappropriate secretion of insulin at the time of hypoglycemia and is used to document these tumors. Classically, glucagonomas are associated with necrolytic migratory erythema, mild diabetes, diarrhea, severe muscle wasting, and marked hyperaminoaciduria. VIPomas are associated with episodic severe secretory diarrhea with hypokalemia, hypochlorhydria, and metabolic acidosis.
C. Primary treatment
Surgical resection is the optimal treatment for pancreatic endocrine tumors. Before resection, the first goal of treatment must be to control endocrine syndromes.
1. Gastric acid suppression. The H+/K+-adenosine triphosphatase inhibitors omeprazole and lansoprazole successfully control gastric acid secretion in patients with gastrinoma. Optimal doses must be individualized and periodically re-evaluated. Gastric acid secretion in the hour preceding the next dose of omeprazole or lansoprazole should be less than 10 mEq in patients who have had no previous gastric surgery and less than 5 mEq in those who have had an acid-reducing procedure. The starting dose is 60 mg/day with both agents. Doses greater than 80 mg/day should be divided. Similar, newer agents in the same class of PPIs are equally as efficacious.
2. Insulin suppression. Diazoxide, an insulin release inhibitor, when given at 3 to 8 mg/kg/day by mouth divided in three doses (e.g., 50 to 150 mg by mouth three times a day), is the therapy of choice for hypoglycemia associated with insulinoma when dietary measures fail. A diuretic should be given with diazoxide to prevent water retention.
3. Octreotide acetate is a somatostatin analog that inhibits gut hormone secretion. It is generally useful for carcinoid and VIPoma syndromes and is possibly useful for controlling symptoms in patients with glucagonomas, gonadotrophic hormone-releasing tumors, and gastrinomas. In patients with unresectable insulinoma, it can reduce insulin secretion by 50% and return blood glucose levels to normal. However, it must be initiated cautiously in patients in the hospital because profound hypoglycemia may occur. The usual starting dose of octreotide is 50 μg subcutaneously twice a day; thereafter, the dose and frequency of injections can be increased to 100 μg three times a day. More recently, a long-acting preparation (octreotide LAR) has become available. The dose should be 20 to 30 mg intramuscularly monthly, depending on doses that the patient was requiring of the short-acting preparation. It is designed to provide the convenience of once-a-month or twice-a-month injections once a stable dose of the shorter-acting preparation is established.
D. Management of locally advanced or metastatic islet cell tumors
Surgical resection is recommended for resectable locoregional recurrence. For patients with unresectable locoregional recurrence, radiation therapy for symptom control or participation in a clinical trial is recommended. Patients with metastatic disease to the liver should be considered for surgical resection as well. However, for patients who are found to be unresectable and have symptomatic or clinically significant tumor burden, somatostatin analogs can be helpful in the management of symptomatic disease related to hormonal secretion. The most commonly utilized somatostatin analogs in clinical studies for PNETs are octreotide, lanreotide, and pasireotide. A recent phase III placebo–controlled randomized study comparing long-acting octreotide to placebo for the treatment of midgut neuroendocrine tumors demonstrated a 66% reduction in risk of disease progression. The PROMID study showed antitumor benefit in patients with functioning and nonfunctioning tumors treated with octreotide LAR. In an analysis of patients with nonfunctioning tumors, time to tumor progression for patients receiving octreotide LAR was 28.8 months versus 5.9 months for those on placebo (hazard ratio [HR] = 0.25). For patients with functioning tumors, time to tumor progression for patients receiving octreotide LAR was 14.3 months and 5.5 months for those on placebo (HR = 0.23). Current studies are being conducted to compare pasireotide to placebo for the management of symptoms and lanreotide to placebo for evaluation of impact on progression-free survival.
The systemic chemotherapeutic agents that have shown most benefit in PNETs are streptozocin, doxorubicin, 5-FU, and temozolomide. Streptozocin is the most active single agent, with a 50% response rate. The addition of other agents such as 5-FU and doxorubicin was associated with even higher response rates. The combination of streptozocin and doxorubicin was demonstrated to have a superior response rate (69%), median survival (26.5 months), and time to tumor progression (20 months) than the combination of streptozocin and 5-FU or single agent chlo-rozotocin in a North Central Cancer Treatment Group study. The dosing of this regimen was streptozocin 500 mg/m2 IV on days 1 to 5 and doxorubicin 50 mg/m2 IV on days 1 and 22; this regimen was repeated every 6 weeks. Toxicity from this regimen was common, with renal impairment occurring in about 30% of patients receiving a streptozocin-based regimen; nausea and vomiting in about 60% of patients; and leukopenia in about 75%, but only 10% with a white blood cell count of less than 1000 μL. A more recent phase III study comparing streptozotocin and 5-FU to doxorubicin and 5-FU demonstrated improved median survival in the streptozotocin/5-FU arm (24.3 months versus 15.7 months, p = 0.03). Another agent that has demonstrated some efficacy against PNETs in phase II trials is temozolomide, which has been used in combination with other agents such as thalidomide and bevacizumab.
Recent investigations in PNETs have identified attractive po-tential molecular targets such as EGFR, VEGF and its receptor (VEGFR), and insulinlike growth factor receptor (IGFR). Multiple studies have demonstrated overexpression of VEGF and VEGFR in PNETs and that this overexpression correlates with decreased progression-free survival. Phase II studies of bevacizumab, sorafenib, and sunitinib have been promising and have demonstrated response rates of 10% to 20% and improvements in progression-free survival. Recently, an international phase III trial comparing suni-tinib (37.5 mg once a day) to placebo in the treatment of PNETs was closed prematurely after accruing 171 patients. Interim analysis revealed a significant difference in progression-free survival (11.4 months versus 5.5 months).
Another potentially promising target in PNETs is the mTOR pathway. mTOR is a conserved serine/threonine kinase that regulates cell growth and metabolism in response to environmental factors and signaling downstream of receptor tyrosine kinases, such as IGFR, VEGFR, and EGFR. Two mTOR inhibitors that have been studied in PNETs are temsirolimus and everoli-mus. Temsirolimus was found to have modest clinical activity, with a response rate of 5.6% and median time to progression of 6 months. Everolimus in combination with octreotide LAR demonstrated a response rate of 27% and a progression-free survival of 63 weeks. Based on these encouraging results, RADIANT 3, a randomized double-blind, placebo-controlled, multicenter phase III study of everolimus or best supportive care in patients with advanced islet cell carcinoma, was developed and is currently accruing.
Locoregional therapies are also available and include ablative therapies such as radiofrequency ablation (RFA), microwave ablation, cryoablation, or embolization therapies such as bland embolization, chemoembolization, drug-eluting beads, and radio-embolization. Newer experimental techniques such as percutaneous hepatic perfusion (PHP) may also have a role in this setting.
III. CARCINOMA OF THE BILE DUCTS (CHOLANGIOCARCINOMA) AND GALLBLADDER CARCINOMA
Biliary tract cancers are invasive adenocarcinomas that arise from the epithelial lining of the gallbladder and intrahepatic (peripheral) and extrahepatic (hilar and distal biliary tree) bile ducts. Biliary tract cancers affect approximately 12,000 people in the United States annually. In 2009, there were an estimated 9760 new cases and 3370 deaths in the United States. However, this figure does not include cases of intrahepatic biliary cancers, which are included with primary liver cancers in national databases. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, the incidence of intrahepatic cholangiocarcinoma has increased markedly over the past two decades.
B. Epidemiology and presentation
The development of biliary tract cancers appears to be related to chronic inflammatory conditions, autoimmune disease, biliary calculi, several infectious agents, and certain carcinogens. Risk factors for gallbladder cancer, of which cholelithiasis is the most prevalent, are associated with the presence of chronic inflammation. Calcification of the gallbladder (porcelain gallbladder), a result of chronic inflammation, has also been associated with gallbladder cancer. No predisposing factors have been found in most patients diagnosed with cholangiocarcinoma, although there is evidence that particular risk factors may be associated with the disease in some patients. These risk factors are associated with chronic inflammation and include cholelithiasis, ulcerative colitis, liver flukes, exposure to thorium oxide (Thorotrast), primary scle-rosing cholangitis, and congenital anomalies such as choledochal cysts. Recently, intrahepatic cholangiocarcinoma has been associated with hepatitis C viral infection and may be partly responsible for an increased incidence of intrahepatic cholangiocarcinoma. Biliary tract cancers are usually diagnosed at a late stage due to the aggressive nature and rapid spreading of these tumors. Patients with gallbladder cancer can present with a clinical presentation that mimics biliary colic or chronic cholecystitis. Primary gallbladder malignancy is incidentally found in 0.4% to 2% of laparoscopic cholecystectomy specimens. Carcinoma of the gallbladder most commonly presents with pain, nausea and vomiting, and weight loss. Other possible clinical presentations of gallbladder cancer include a suspicious mass detected on ultrasound or jaundice. About one-third of patients present with jaundice, which is typically associated with advanced disease not amenable to surgical resection. Patients with intrahepatic cholangiocarcinoma are likely to present with nonspecific symptoms such as fever, weight loss, or abdominal pain; symptoms of biliary obstruction are uncommon. Alternatively, intrahepatic cholangiocarcinoma may be detected incidentally as an isolated intrahepatic mass on imaging. In contrast, patients with extrahepatic cholangiocarcinoma are more likely to present with jaundice with evidence of biliary obstruction on subsequent imaging.
C. Natural history and pathogenesis
Biliary tract malignancies are related anatomically and are characterized by local invasion, regional lymph node metastasis, vascular encasement, and distant metastasis. The only chance for cure of biliary tract cancers is complete surgical resection; however, only 10% of patients present with early stage disease and are considered surgical candidates. The key prognostic factors are completeness of resection, lymph node status, and tumor differentiation. However, recurrence rates even in this group of resectable patients remains quite high and thus systemic chemotherapy in either the adjuvant or palliative setting is the mainstay of the treatment plan for almost all patients. Median overall survival in patients with unresectable or metastatic biliary tract cancer is less than 1 year. Gallbladder cancer appears to be the most aggressive of biliary tract cancers and has the shortest median survival. Although biliary tract cancers are similar in their aggressive course and resistance to chemotherapy, gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma have different molecular profiles and ideally should be studied independently. However, due to a relatively small number of patients, these diseases have been combined in most clinical trials analyzing systemic chemotherapy. Despite a paucity of randomized phase III studies, consensus first-line systemic therapy is emerging from the results of smaller phase II trials.
The advantage of systemic chemotherapy over supportive care alone in improving survival and quality of life was first suggested in an evaluation of 5-FU plus leucovorin and etoposide therapy versus best supportive care among a group ofpatients with pancreatic and biliary tract cancer. The overall survival in the chemotherapy group was 6 months versus 2.5 months for the supportive care group but only 37/90 patients had biliary tract cancers. Despite limitations of this study, because of ethical considerations, this will likely represent the only trial comparing benefits of chemotherapy to best supportive care in advanced biliary tract cancer.
5-FU–based regimens have been the most tested regimens in a randomized fashion in biliary tract cancer. 5-FU plus leucovorin has demonstrated response rates of 32% and overall survival of 6 months. Combination therapy with cisplatin consistently yields response rates of 10% to 40% and median survival times somewhat better than 5-FU alone. 5-FU combinations with taxanes, etoposide, streptozotocin, and irinotecan have not shown superiority over 5-FU alone. Similar to the experience with 5-FU plus cisplatin combinations, capecitabine plus cisplatin demonstrated somewhat higher response rates and overall survival. The fluoro-pyrimidines uracil-tegafur and S-1 (a fluoropyrimidine mixture) have also been evaluated in biliary tract cancers and results have been similar to the experiences with 5-FU and capecitabine, and slightly better with the addition of cisplatin.
Gemcitabine, a nucleotide analogue determined to be active against advanced pancreatic cancer, has been extensively studied in patients with advanced or metastatic biliary tract cancer. Response rates with single-agent gemcitabine are in the range of 0% to 30% with median overall survival of 5 to 14 months. Gemcitabine and cisplatin or oxaliplatin combinations have been extensively studied in biliary tract cancers. Studies have demonstrated response rates of 21% to 53% and median overall survival of 5 to 15 months; these results are somewhat better than the results from single-agent gemcitabine. Gemcitabine in combination with capecitabine demonstrated response rates of 30% and median overall survival of 14 months, suggesting a benefit similar to the gemcitabine-based platinum combinations. A recent pooled analysis of 104 chemotherapy trials involving 1368 biliary tract cancer patients from 1999 to 2006 pointed toward gemcitabine as the most active agent and that gemcitabine-based platinum regimens offer a slight advantage over other regimens. Among gemcitabine-cisplatin or GemOx combinations, which have similar response rates and median overall survival rates, the toxicity and tolerability data tend to favor GemOx combinations.
Recent studies utilizing molecular features of biliary tract cancers and targeted therapies have been published. The most promising of these appears to be a multicenter phase II trial looking at bevacizumab, a humanized monoclonal antibody against VEGF, being tested in combination with gemcitabine and oxaliplatin.
E. Current recommendations
1. 5-FU 500 mg/m2 IV push on days 1 to 5 every 4 weeks or 500 mg/m2 IV weekly.
2. 5-FU 400 mg/m2 IV on days 1 to 5 and streptozocin 500 mg/m2 IV on days 1 to 5.
3. Patients with a very good performance status can use a doublet such as GemOx with gemcitabine 1000 mg/m2 on day 1 and 8 plus oxaliplatin 130 mg/m2 over 2 hours on day 8 every 3 weeks or
4. Gemcitabine 1000 mg/m2, 5-FU 600 mg/m2, and leucovorin 20 mg/m2 IV on days 1, 8, and 15 every 4 weeks.
5. Capecitabine 1500 mg/m2 daily in twice-daily divided doses on days 1 to 14 and gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks or
6. Capecitabine 1500 mg/m2 daily in twice-daily divided doses on days 1 to 14 plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks.
IV. PRIMARY CARCINOMA OF THE LIVER
Hepatocellular carcinoma (HCC) accounts for 80% to 90% of primary liver cancer. HCC is a major health problem worldwide with well over 500,000 cases diagnosed each year. It is the fifth most common cancer worldwide and the third most common cause of cancer-related death, with most cases occurring in Asia. Although less common in the United States, the incidence is rising with ap-proximately 20,000 cases diagnosed in 2009. The latest statistics for 2009 estimated 22,620 cases, but this number also includes intrahepatic bile duct cancer as well. Ninety percent of primary cancers of the liver are HCC or hepatoma; the remaining cancers include cholangiocarcinomas (about 7%), hepatoblastomas, angiosarcomas, and other sarcomas. In the United States, the peak incidence is in the sixth decade of life, whereas in Asia and Africa it occurs much earlier in life.
B. Etiology and risk factors
The rates of HCC are two to four times higher in males than females. Eighty to ninety percent of cases of HCC develop in a cirrhotic liver, and cirrhosis is the strongest predisposing factor for HCC. Overall, 80% of cases of HCC are attributable to chronic infections with either hepatitis B or hepatitis C virus. Chronic hepatitis B viral infection is common in Asian and African countries and accounts for most cases of HCC. Chronic carriers of hepatitis B have a 100-fold relative risk for developing HCC with an annual incidence rate of 2% to 6% in cirrhotic patients. In contrast, chronic hepatitis C viral infection is more common in Western countries. Other causes of HCC include alcoholic liver cirrhosis, aflatoxin (a natural product of the Aspergillus fungus found in various grains), hereditary hemochromatosis, autoimmune hepatitis, α1-antitrypsin deficiency, and Wilson disease.
The incidence of HCC is increasing in the United States, par-ticularly among the population infected with the hepatitis C virus. Approximately 4 million people in the United States are chronically infected with hepatitis C virus, and the annual incidence among hepatitis C patients with hepatitis C–related cirrhosis is estimated to be between 2% and 8%. Approximately 1.5 million people are chronically infected with hepatitis B in the United States; the annual incidence of HCC in patients with hepatitis B–induced cirrhosis is 2.5%. In those carriers without cirrhosis, the annual incidence is 0.5%.
C. Presenting signs and symptoms
Patients with primary carcinoma of the liver commonly complain of right upper quadrant pain, abdominal distention, or weight loss. The pain is usually dull or aching but may be acute and radiate to the right shoulder. Fatigue, loss of appetite, and unexplained fever may occur. Patients with underlying cirrhosis may present with hepatic decompensation: new ascites, variceal bleeding, jaundice, or encephalopathy. Rarely, patients present with paraneoplastic syndromes. Erythrocytosis is the most common; hypercalcemia, hyperthyroidism, and carcinoid syndrome have also been described. Physical findings include nodular hepatomegaly with an arterial bruit and hepatic rub. Extrahepatic spread occurs in about 50% of patients during the course of the illness. Twenty percent of patients have lung metastases.
D. Diagnostic evaluation and screening
There are several published studies that have demonstrated reduc-tion in HCC mortality with the utilization of screening programs for high-risk individuals such as those with cirrhosis or chronic hepatitis viral infections. Serum α-fetoprotein (AFP) and liver ultrasound are the most widely used methods for screening for HCC. Most groups recommend periodic testing with AFP and ultrasonog-raphy every 6 to 12 months. Additional imaging is recommended in the setting of a rising serum AFP or following identification of a liver nodule on liver ultrasound. HCC lesions are characterized by arterial hypervascularity, deriving most of their blood supply from the hepatic artery. This is in contrast to surrounding liver, which receives most of its blood supply from the portal venous system. Therefore, the most commonly utilized tests for diagnostic imaging of HCC are triphasic helical CT or triphasic dynamic contrast-enhanced magnetic resonance imaging (MRI). CT or MRI for lesions greater than 2 cm demonstrating classic arterial enhancement is diagnostic for HCC. For lesions 1 to 2 cm in size, a classic arterial enhancement pattern on both CT and MRI is considered diagnostic for HCC. Liver lesions less than 1 cm should be followed closely with periodic repeat imaging. Liver lesions greater than 1 cm that do not demonstrate classic arterial enhancement should undergo tissue biopsy to confirm the diagnosis.
E. Laboratory tests
AFP is a tumor marker that is elevated in 60% to 70% of patients with HCC. Serum AFP is not a sensitive or specific test for HCC. However, results of AFP testing can be used in conjunction with imaging to guide management of patients with suspected AFP. An AFP greater than 200 in a patient with a liver lesion greater than 2 cm has a high predictive value for HCC and can be considered diagnostic even without the classic enhancement pattern on imaging.
F. Staging and preoperative evaluation
1. Staging. Patients diagnosed with HCC should undergo an extensive work-up that includes determination of the etiology of underlying liver disease including hepatitis panel, assessment of other comorbidities, imaging studies to evaluate for metastatic disease (chest imaging and bone scan as most common sites for metastases are lung, bone, and abdominal lymph nodes), and evaluation of underlying hepatic function, including a de-termination of any evidence of portal hypertension. An effective staging system should incorporate tumor characteristics (AJCC TNM classification, Table 8.2) and underlying liver disease (Child-Pugh classification), as both of these factors impact choice of treatment and patient survival. A number of staging systems for patients with HCC have been devised. Some of the most commonly utilized include the Okuda staging system, Cancer of the Liver Italian Program score, Japanese Integrated Staging score, Chinese University Prognostic Index, simplified (Vauthey) staging for HCC, Izumi TNM modification, French classification system, and the Barcelona Clinic Liver Cancer staging classification. Each of these scoring systems has limitations, and therefore no one staging system has been universally accepted. Following work-up, patients are stratified into one of the following groups: metastatic disease, locally advanced unresectable disease not amenable to transplantation, resectable or transplantable but performance status precludes operation, and resectable or transplantable with appropriate performance status.
2. Preoperative evaluation. The selection of patients with HCC for surgical resection incorporates information regarding tumor extent, severity of underlying liver disease, assessment of liver functional reserve, and general medical condition of the patient. The general criteria for unresectability of HCC includes large size of tumor with insufficient hepatic remnant after liver resection, multifocal bilobar lesions, extrahepatic tumor metastases, and tumor with main portal vein or hepatic vein/inferior vena cava involvement. In addition, resection is generally recommended only in the presence of preserved liver function with no evidence of portal hypertension.
G. Primary therapy
At presentation, only 25% of patients with HCC have potentially resectable lesions. Results of large retrospective studies have dem-onstrated 5-year survival of 50% to 70% in select patients undergoing liver resection for HCC in the setting of preserved liver function. However, the number of patients with HCC considered good can-didates for resection in the United States is quite low because the majority of patients have underling Child grade B or C cirrhosis. In addition, recurrence rates at 5 years following liver resection for HCC are quite high and approach 70%. Liver transplantation may permit resection of small tumors in patients with advanced cirrhosis, and survival is similar to or better than that seen after resection without transplantation. Patients with HCC who meet the Milan criteria for transplantation are those patients with one nodule less than 5 cm or two to three nodules that are less than 3 cm and no evidence of macrovascular involvement or extrahepatic disease. These select patients treated with liver transplantation have low recurrence rates with 5-year survival rates of greater than 75%. The main problem with transplantation is timely organ availability. Patients with localized disease who are not candidates for either resection or transplantation should be considered for ablative therapies or embolization. In addition, for patients awaiting liver transplantation, a number of studies have investigated the role of locoregional therapies in controlling disease as a bridge to transplantation. The locoregional therapies available include ablative therapies such as RFA, microwave ablation, cryoablation, or percutaneous ethanol injection and embolization therapies such as bland embolization, chemoembolization, drug-eluting beads, and radioembolization. Newer experimental techniques such as PHP may also have a role in this setting.
H. Therapy of advanced HCC
The majority of patients diagnosed with HCC have advanced disease at presentation and are not candidates for surgery or locoregional therapies. Unfortunately, HCC is a relatively chemoresistant tumor and is highly resistant to cytotoxic chemotherapy. Clinical studies evaluating the use of chemotherapy such as doxorubicin have reported low response rates to therapy and evidence for a fa-vorable impact on survival is lacking. However, two recent phase III studies have found sorafenib to be beneficial in the treatment of patients with metastatic or locally advanced HCC. Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis. In a large multicenter, randomized, placebo-controlled phase III trial (SHARP), the efficacy of sorafenib versus placebo in patients with advanced HCC was evaluated. In this study, 602 patients with advanced measurable HCC, no prior systemic therapy, good performance status, and preserved liver function were randomized to either sorafenib 400 mg twice a day or placebo with best supportive care. Median survival was significantly longer in the sorafenib arm (10.7 months versus 7.9 months, HR = 0.69,p 0.001). Another phase III trial with similar design, the Asia-Pacific study, randomized 226 patients in a 2:1 fashion to either sorafenib or placebo. Patients in this study were Asian and tended to be younger with underlying hepatitis B and a higher number of tumor sites compared to the SHARP trial. This study also demonstrated improved median survival in the sorafenib arm (6.5 months versus 4.2 months, HR = 0.68, p = 0.014). Overall, sorafenib is well tolerated with limited side effects, the most common being diarrhea, weight loss, and hand-foot skin reaction. As a result of these studies, sorafenib is now considered the standard of care for patients with advanced and metastatic HCC who are not candidates for curative or locoregional therapies, but at present only patients with good liver function have been rigorously studied.
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