GASTROINTESTINAL CANCER UPDATE
Highlights from Liver Disease: Therapeutic Challenges, sponsored by Washington University School of Medicine, St.
Louis
| SCREENING FOR HEPATOBILIARY MALIGNANCY —Paul Martin, MD, Professor of Medicine, Mount Sinai School
of Medicine, New York City
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| Hepatocellular carcinoma (HCC): incidence has increased in United States over last 30 yr; largest increases seen in
black men; improved diagnostic techniques have led to increased rates of detection; risk factors—liver disease, primarily
caused by infection with hepatitis C virus (HCV); other causes include chronic infection with hepatitis B virus
(HBV), alcohol abuse, and fatty liver disease; all forms of cirrhosis increase risk; patients with chronic HBV infection at
risk, even in absence of cirrhosis (but patients with HCV infection at risk only after cirrhosis develops); other forms of
liver disease (eg, genetic hemochromatosis) also increase risk; 3% to 4% of patients with cirrhosis develop HCC each
year; screening important in cirrhotic patients (standard of practice for gastroenterologists to screen cirrhotic patients for
HCC)
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| Detection and survival: effectiveness of interventions depends on stage of disease; therapeutic options limited in patients
with end-stage disease; outcomes better if disease detected by screening or surveillance; studies show screening cost-effective,
and early detection increases long-term survival; liver transplantation (in appropriate patients) cost-effective and
increases survival
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| Screening tools: most protocols include test for α-fetoprotein (AFP) and ultrasonography; frequency—European study
showed benefit of shorter screening intervals; 70% of tumors found in patients screened every 6 mo measured <3 cm,
but only 29% of tumors found in patients screened every 12 mo measured <3 cm; in many patients in study, AF
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 | AFP: often elevated in patients with benign liver disease, especially if liver enzymes elevated; levels persistently >100
ng/mL associated with increased risk for HCC; follow-up—repeated imaging necessary; multiple imaging techniques
(eg, ultrasonography followed by spiral computed tomography [CT]) helpful in high-risk patients; note—although patients
with high levels of AFP more likely to have HCC, some patients have only moderately elevated levels at time of
diagnosis
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| Ultrasonography: high sensitivity but relatively low specificity (ie, often detects benign lesions); if ultrasonography does
not detect mass and patient has normal level of AFP, HCC unlikely
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| Screening recommendations: patients with cirrhosis should undergo screening (AFP and ultrasonography) every 6 mo;
evidence of liver nodule necessitates additional tests (eg, biopsy or advanced imaging studies); patients without evidence
of liver mass but who have elevated AFP should receive additional radiologic studies (eg, spiral CT); indicated in—
patients eligible for curative therapy who have cirrhosis or chronic infection with HBV; age—screening often begun at
40 yr of age in patients with HBV, but fatal ruptures recorded in younger patients (speaker recommends screening these
patients at time of diagnosis of chronic HBV infection); in all other patients, begin screening after diagnosis of cirrhosis
made (clinically or histologically)
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| Cholangiocarcinoma: peripheral—tumors rarely associated with cirrhosis or primary sclerosing cholangitis (PSC); patients
typically present with abdominal pain and weight loss; central—tumors arise in major bile duct, often in association
with chronic inflammatory conditions; patients often present with obstructive jaundice; incidence—absolute
increases have occurred, but detection rates have also improved; risk factors—major factors include PSC and inflammatory
bowel disease (IBD), typically ulcerative colitis; cholangiocarcinoma can arise in IBD patients without PSC; patients
with cirrhosis may have increased risk
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| Screening: focus on patients with PSC or other disorders, eg, Caroli disease (congenital abnormality of bile duct), associated
with high risk; cancer antigen (CA) 19-9—in patients with PSC, level of CA 19-9 >100 U/mL associated with cholangiocarcinoma
(sensitivity 89%; specificity 86%); knowing level of carcinoembryonic antigen (CEA) may increase
accuracy; detection—presence of fibrosis in bile ducts complicates early detection of tumors; recent survey found no
correlation of duration of PSC, severity of liver disease, IBD activity, or endoscopic intervention with presence of cholangiocarcinoma
(ie, clinical history does not aid in stratifying patients with PSC into risk groups); study identified alcohol
abuse as risk factor for development of cholangiocarcinoma in patients with PSC
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| HEPATOCELLULAR CANCER: RESECTION VS TRANSPLANT —Jeffrey A. Lowell, MD, Professor of Surgery and
Pediatrics, Washington University, School of Medicine, St. Louis
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| Hepatocellular carcinoma: cirrhosis greatly increases risk; most common primary hepatic neoplasm worldwide;
prognosis—survival rates not favorable among patients who undergo resection or chemotherapy
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| Surgical resection: patients with cirrhosis, advanced liver disease, or end-stage cancer unable to undergo resection; 50%
to 80% of patients who undergo resection develop recurrence (second primary lesions or intrahepatic spread); field effects
of chronic injury to liver cells increase risk for recurrence; only 25% of patients qualify for resection; patients with
advanced cirrhosis (Child-Pugh class B or C) may require sophisticated techniques (eg, embolization of portal vein);
multidisciplinary centers with capability to perform transplantations offer best options for treatment; 5-yr survival—
50% overall; 20% disease-free survival; “essentially zero” in patients with multiple nodules; vascular invasion decreases
survival time by 50%
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| Chemoembolization: good technique for down-staging lesions, but limited role as curative therapy; temporizing measure;
requirements for selection—patent portal vein; cirrhosis classified as Child-Pugh A or B (preferred); treatment
strategy—best done as bridge to transplantation or as part of resection strategy; procedure generally repeated several
times
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| Transplantation: best option for cirrhotic patients with HCC; 4-yr survival >80%; patient selection—patients with single
tumor 5 cm or up to 3 tumors, with largest measuring 3 cm; patients with cirrhosis; allocation system — weighted
toward medical urgency; model for end-stage liver disease (MELD) score based on levels of creatinine, bilirubin, and
international normalized ratio (INR); pediatric end-stage liver disease (PELD) score also incorporates growth factor,
age, and albumin level; organs allocated based on blood group and MELD or PELD score; because of success of transplantation
in patients with less advanced disease, patients with stage-I or stage-II HCC given “bonus points” to increase
priority for allocation (now restricted to stage II); staging—stage I, single nodule measuring <2 cm; stage II,
single nodule measuring 2 to 5 cm, or up to 3 nodules, each <3 cm; stage III, single nodule >5 cm, or up to 3 nodules,
with 1 nodule >3 cm; prognosis—recent study suggested patients with larger tumors (1 nodule 6.5 cm or 3 nodules
with total diameter 8 cm) also have very good prognosis after transplantation; presence of HCC (stages II-III) does not
adversely affect 5-yr survival rate (≤65%; as good as transplant patients without HCC))
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| Protocol: transplantation offered to acceptable candidates with stage-I or stage-II lesions; local ablation considered if
waiting time long ( clinical value unproven); currently, patients with stage-III lesions do not qualify for “bonus points”;
advanced techniques for resection (eg, embolization of portal vein in attempt to stimulate growth in healthy lobes) or
techniques to downsize tumor may be appropriate in these patients; surveillance with serial imaging recommended for
cirrhotic patients with normal levels of AFP and lesions <1 cm (qualify for transplantation if lesion expands)
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| CHOLANGIOCARCINOMA: RESECTION VS TRANSPLANT —William C. Chapman, MD, Professor and Chief, Section
of Transplantation, Washington University School of Medicine, St. Louis
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| Cholangiocarcinoma: relatively uncommon, difficult to manage primary malignancy; 30% of malignancies arise in mid
or distal bile duct (managed like pancreatic cancer); 60% of malignancies arise in hilar region; these present many challenges
for diagnosis and management; 6% to 10% of malignancies present as intrahepatic tumors (managed as primary
liver tumors); because few patients can undergo isolated resection of mid-duct, most tumors that occur here managed as
lower-duct or upper-duct tumors
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| Hilar tumors: growth usually slow (exceptions occur); hematogenous metastasis uncommon, but regional metastasis (ie,
local nodal or perineural invasion) occurs in 40% to 50% of patients; direct invasion of liver and perihepatic structures
common; resection of liver and bile duct required to ensure negative margins; morphologic subtypes—sclerosing variant
most common, presents as firm annular thickening of bile duct; nodular variant presents as firm irregular nodule that
projects into lumen of bile duct; papillary tumors less common and larger (may cause expansion of bile duct), but associated
with less invasion into hepatic parenchyma and better prognosis, compared to nodular or sclerosing types
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| Diagnosis of hilar cholangiocarcinoma: clinical features critical for diagnosis; biliary stricture in patient without explanatory
history (eg, surgery in right upper quadrant, trauma) indicates cholangiocarcinoma until proven otherwise; verification
of diagnosis difficult without excision of bile duct; diagnosis sometimes achieved using endoscopic retrograde cholangiography
(ERC), brush cytology, endoscopic ultrasonography (EUS)-guided biopsy, or fine needle aspiration (FNA); CA 19-9
>100 ng/mL associated with positive diagnosis, but many false positives occur; histologic diagnosis plays larger role in patients
unable to undergo resection, especially if liver transplantation considered; imaging—CT and magnetic resonance imaging
(MRI) useful; fluorescence in situ hybridization (FISH) demonstrates aneuploidy (commercially available, and results
strongly correlate with histology and cytology
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| Standard surgical resection: gold standard for treatment of patients with hilar cholangiocarcinoma; tumors in distal bile
duct typically necessitate pancreaticoduodenectomy (Whipple resection); tumors in proximal bile duct warrant portal
lymphadenectomy and liver resection
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| Tumor staging: Bismuth-Corlette classification for hilar cholangiocarcinoma commonly used; type 1—tumor occurs in
mid bile duct and does not involve confluence; type 2—tumor involves confluence, but does not extend into either side
of liver; type 3a—extension into right hepatic duct; type 3b—extension into left hepatic duct; type 4—involves both
sides of liver; considered unresectable; note—distinguishing between type 3 and type 4 tumors often difficult with available
imaging techniques
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| Candidates for resection: according to recent report, 33% of patients referred for cholangiocarcinoma not eligible for resection;
of those initially identified as candidates, 50% determined unsuitable for resection at time of exploratory surgery
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| Prognosis after resection: report showed patients with nodular-sclerosing tumors had 5-yr survival rate of 25% and 10-yr
survival rate of 10%; patients with papillary tumors had 10-yr survival rate of 25% (aggressive surgical resection recommended
in this group); patients able to undergo resection have better long-term survival than patients unable to undergo
resection; among those undergoing resection, patients with negative margins had 5-yr survival rate of 45%; no patients
with microscopically positive margins survived 5 yr
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| Primary sclerosing cholangitis: chronic cholestatic liver disease with fibrosing inflammation in biliary tree; disease typically
occurs in men <50 yr of age; most frequently seen in patients with IBD; IBD patients with and without PSC at increased
risk of developing cholangiocarcinoma
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| Liver transplantation for PSC: patients with PSC, but without cholangiocarcinoma, account for 10% of liver transplantations
in United States; because of risk for cholangiocarcinoma, patients with compensated PSC often push for transplantation
as preventive strategy; patients with PSC and no evidence of cholangiocarcinoma have long-term survival rate of ≈90%
and graft survival rate of ≈70%; if unsuspected cholangiocarcinoma discovered in explant and bile duct margins negative,
patients did extremely well; however, if cholangiocarcinoma found during transplantation or bile duct margins positive, patients
did poorly (series of 200 patients found no long-term survivors in this subset); most transplant centers exclude patients
with clinically detectable cholangiocarcinoma or positive margins
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| PSC and risk for cholangiocarcinoma: study—161 patients; median follow-up >11 yr; 33% underwent transplantation
for progression of liver disease; 33% of patients died (causes of death included progression of liver disease); only 6.8% of
patients developed cholangiocarcinoma (0.6% per yr); variceal bleeding only factor associated with development of cholangiocarcinoma;
conclusion—because of low overall risk for cholangiocarcinoma and lack of predictive factors to
identify patients with elevated risk, early transplantation in patients with PSC not justified as preventive strategy;
prognosis—patients with PSC and cholangiocarcinoma have low rate of long-term survival, regardless of treatment
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| Cholangiocarcinoma and liver transplantation: early results not favorable; many centers abandoned transplantation as
treatment option in these patients; but, recent report showed 5-yr survival rate >80%; conclusion—properly selected patients
may benefit from transplantation, but more data needed
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| Suggested protocol: obtain positive histologic diagnosis, if possible (diagnosis using FISH or CA 19-9 acceptable when
clinical history highly suggestive of cholangiocarinoma); selection criteria—hilar tumor above cystic duct; candidates
meet general requirements for transplantation, have reasonable performance status, and no evidence of metastasis;
exclusion criteria—previous attempt at surgical resection; regional nodal involvement; strategy—early
diagnostic laparoscopy; induction gemcitabine; external beam conformal chemoradiation; limited laparotomy (to sample
nodes); patients with no evidence of local nodal involvement listed for transplantation
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Educational Objectives
| The goal of this activity is to improve the care of patients with hepatobiliary malignancies by providing information about
screening, diagnosis, and treatment. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Identify patients at risk for hepatocellular carcinoma (HCC) or cholangiocarcinoma and implement screening programs.
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| 2. Discuss limitations of current diagnostic tests and imaging for identifying patients with hepatobiliary malignancies.
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| 3. Discuss treatment options for patients with HCC.
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| 4. Identify candidates for liver transplantation.
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| 5. Discuss factors that affect prognosis after liver transplantation for hepatobiliary malignancies.
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Suggested Reading
Burns JM, Greene FL: Controversies in staging of hepatocellular carcinoma. J Hepatobiliary Pancreat Surg 12:456, 2005;
El-Serag HB, et al: Treatment and outcomes of treating of hepatocellular carcinoma among Medicare recipients in the
United States: a population-based study. J Hepatol 44:158, 2006; Geller DA, et al: Outcome of 1000 liver cancer patients
evaluated at the UPMC liver cancer center. J Gastrointest Surg 10:63, 2006; Jonas S, et al: Extended indications in living-
donor liver transplantation: bile duct cancer. Transplantation 80:S101, 2005; Kaneko H: Laparoscopic hepatectomy: indications
and outcomes. J Hepatobiliary Pancreat Surg 12:438, 2005; Lau WY, et al: Transarterial chemoembolization for
hepatocellular carcinoma. J Am Coll Surg 202:155, 2006; Lim LY, Kowdley KV: Chemoprevention of hepatocellular carcinoma
in chronic hepatitis B with lamivudine. Gastroenterology 129:2120, 2005; Lubienski A: Hepatocellular carcinoma:
interventional bridging to liver transplantation. Transplantation 80:S113, 2005; Salmon JS, et al: Anti-angiogenic treatment
of gastrointestinal malignancies. Cancer Invest 23:712, 2005; Sauer P, et al: Liver transplantation for hepatocellular
carcinoma: is there evidence for expanding the selection criteria? Transplantation 80:S105, 2005; Silverman PM, Szklaruk
J: Controversies in imaging of hepatocellular carcinoma: multidetector CT (MDCT). Cancer Imaging 5:178, 2005; Sutcliffe
R, et al: Selection of patients with hepatocellular carcinoma for liver transplantation. Br J Surg 93:11, 2006; Wiesner
RH: Patient selection in an era of donor liver shortage: current US policy. Nat Clin Pract Gastroenterol Hepatol 2:24,
2005; Yao FY, et al: A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver
Transpl 11:1505, 2005; Yu J, et al: Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo.
Hepatology 43:134, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Drs. Martin, Lowell, and Chapman were recorded in St. Louis at Liver Disease: Therapeutic Challenges, sponsored
by Washington University School of Medicine and held April 23, 2005. The Audio-Digest Foundation thanks the
speakers and Washington University School of Medicine for their cooperation in the production of this program.
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