LIVER AND PANCREATIC CANCERS
| NEW THERAPEUTIC APPROACHES TO HEPATOCELLULAR CARCINOMA —Donald J. Hillebrand, MD, Medical
Director of Liver Transplantation, Scripps Clinic, La Jolla, CA
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| Hepatocellular carcinoma (HCC): increasing incidence over time; high case fatality rate (0.9); little difference in outcome
among racial groups (although Asians may do better, reflecting lower rate of underlying cirrhosis); in United
States, 90% to 95% of HCC seen in hepatitis C in setting of cirrhosis
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| Prognosis: roughly 50% die of tumor and other 50% die due to progression of liver disease; more aggressive therapy (particularly
if not candidate for transplantation) may hasten ultimate demise, even though locoregional tumor control
achieved; individuals with adverse factors (eg, impaired performance status, constitutional symptoms) have poor 3-yr
survival; risk factors of portal vein thrombosis and extrahepatic spread allow stratification of patients into risk groups;
better 3-yr survival (28%) if patient has early small HCC and no adverse risk factors; factors determining prognosis—
include tumor stage (number, size, and location of tumor, presence of macrovascular invasion, and extrahepatic spread),
underlying liver function (Child’s class A patient with cirrhosis has better prognosis than class B or C, regardless of
amount of tumor), performance status, and intervention-specific outcome; groups with best prognosis—those with performance
status 0 (no constitutional symptoms; most commonly detected by screening program along with individuals
with cirrhosis and hepatitis B), Child’s class A cirrhosis (no significant ascites or encephalopathy, and normal albumin,
bilirubin, prothrombin time [PT]), no vascular invasion, no extrahepatic spread, and relatively normal alpha fetoprotein
(AFP)
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| Key concepts in management of HCC: liver transplantation achieves best outcome in patients with decompensated cirrhosis
who meet criteria; transplantation part of long-term survival (but tremendous shortage of organ donors); surgical
resection effective for patients without cirrhosis, particularly those without vascular involvement, or those with cirrhosis
who meet specific criteria (preserved liver function and relatively early stage HCC); those with single lesion, particularly
if located peripherally, and Child’s class A cirrhotic without significant portal hypertension do well (60% long-term survival);
patients with small tumors stratified based on ability to survive or withstand resection; presence of clinically significant
portal hypertension and increased serum bilirubin hallmarks for inability to tolerate resection; local ablative
methods option for individuals with small nodules who are not candidates for definitive resection; transarterial chemoembolization
improves 2-yr survival in subset of patients with early-stage cirrhosis and intermediate-stage HCC
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| Staging system for HCC: modified tumor, node, metastasis (TNM) staging system by American Liver Tumor Study
Group (also used for transplantation by United Network for Organ Sharing [UNOS]); T1 (early tumors)—1 nodule <1.9
cm; T2—1 nodule 2.0 to 5.0 cm; 2 or 3 nodules, all <3.0 cm (without extrahepatic or major vascular involvement)
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| Management of HCC: early HCC—perform curative therapies (resection if patient not cirrhotic or cirrhotic with certain
criteria); intermediate to advanced HCC—curative intent may not be possible; combination therapies, chemoembolization,
or yttrium90 microspheres (TheraSphere) treatment for palliation; advanced or terminal HCC—only palliative options;
new development of systemic therapy specifically approved for advanced HCC
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| Surgical resection: indications—in patients with no cirrhosis, tumors of any size with no macrovascular or extrahepatic
metastases and if technically feasible; patients with cirrhosis must have well-preserved liver function (Child’s class A)
with no clinically significant portal hypertension (whether defined by varices, variceal bleeding, ascites, and wedge hepatic
venous pressure gradient [HVPG] >10 mm Hg debatable) and fairly normal bilirubin; 5% of HCC in Western world
eligible for resection; portal vein embolization—performed before resection on same side as tumor to promote hypertrophy
of remaining liver after resection (improves resectability of large tumors); outcome of patients able to undergo
resection—choose patients with early cirrhosis and good prognostic signs, ie, normal portal pressure, no significant varices
or ascites, wedge HVPG <10 mm Hg, normal bilirubin; achieve good long-term survival but not disease-free survival;
50% to 75% have recurrent tumor; risk for local recurrence or development of second primary tumor (still have
underlying cirrhosis as premalignant condition); if patients not chosen carefully, results of resection dismal; Mt Sinai
study—>600 patients with hepatoma; 70% unresectable; of 30% resected, only 36% considered transplant-eligible; 5-yr
survival 60%, but many developed recurrent tumor; treatment not curative but can provide significant palliation
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| Liver transplantation: only treatment that offers reasonable likelihood of cure; Milan criteria for transplantation—
based on hallmark study of 40 participants with cirrhosis and HCC; single tumor ≤5 cm or ≤3 tumors ≤3 cm with no vascular
invasion and no extrahepatic spread (stage T2); outcome of transplantation, 75% 4-yr survival; 83% recurrence-free
survival; 10% overall recurrence; on pathologic review, 27% had more advanced disease (decreasing with improved imaging
studies); overall 70% to 75% 5-yr survival; patients who did not meet criteria had <50% 5-yr survival; UNOS
criteria—automatic model for end-stage liver disease (MELD) exception request; not necessary to send to regional review
board; presence of imaging studies confirming T2 lesion (single lesion 2-5 cm in size or 3 nodules, all <3 cm) results
in automatic addition of points and advancement on waiting list (MELD score of 22); increase of 2 to 3 points, as
long as criteria met, every 3 mo in waiting time (corresponds to estimated increase in mortality); since adoption of Milan
criteria, survival improved significantly (>60% at 5 yr); survival maintained at 10 yr; median survival with transplantation
15 to 18 yr; University of California San Francisco (UCSF) criteria—expanded Milan criteria; single nodule must
be <6.5 cm; if multiple nodules present, must have ≤3, largest must be ≤4.5 cm, and total tumor diameter ≤8 cm; good
long-term survival (≈70% at 5 yr) if transplantation restricted to patients who meet pathologic criteria; before deciding
whether to resect or transplant, consider availability of organs and what is best for patient; resection—readily available;
good long-term survival in compensated cirrhosis without significant portal hypertension; better early survival under certain
criteria; disadvantage high rate of recurrence; transplantation—curative; only option for long-term survival in advanced
cirrhosis; disadvantages include dropout while awaiting transplantation due to tumor progression and higher
immediate mortality and morbidity because of procedure and immunosuppression; recurrence rates—with Milan criteria,
≈10% after transplantation; with more liberal criteria, >20%; clear survival advantage of transplantation over resection
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| Ablation therapies: performed if unable to resect tumor, if patient not candidate for transplantation, or if necessary to
maintain patient as candidate; make sense because liver accessible to needle-based therapies and no injury to cirrhotic
liver involved; performed laparoscopically or by laparotomy if unable to obtain direct access percutaneously; local ablation
therapy—serves as “bridge” to transplant; minimally invasive; avoids upper abdominal scar; provides effective
control of tumor for 1 to 2 yr while awaiting transplantation; may offer same 5-yr survival results as resection; question
of whether additional benefit from tumor reduction before transplantation (downstaging)
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 | Percutaneous ethanol injection (PEI): preferred method for accessible tumors <2 cm; advantages— inexpensive; performed
with ultrasonography [US]; can be repeated; low morbidity and mortality; small needle size; lower risk for
bleeding and needle-track seeding; disadvantages—unequal distribution of ethanol; may need repeat treatments; needle-track
seeding possible
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| Cryosurgical ablation: seldom done; disadvantages—requires open surgical approach; higher perioperative morbidity and
mortality; advantages—treats relatively large tumors
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| Radiofrequency ablation (RFA): most common treatment; uses energy to cause necrosis of tumor; effective for treatment
of focal liver tumors; good 5-yr survival if patients have good liver function; excellent for tumors <3 cm; rate of complete
tumor necrosis lower in tumors 4 to 5 cm (still done as part of multimodality approach)
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| RFA compared to PEI: RFA—more cost-effective than ethanol injection if only single session performed; several studies
suggest that RFA leads to higher rate of needle-track seeding, particularly in superficial tumors; limitations as to
which tumors treatable; if tumor next to large vessels, can lead to heat sink, causing incomplete treatment; large probe
increases risk for bleeding; if performed laparoscopically, involves exposure to anesthesia and procedure itself; PEI—
inexpensive; produces better ablation of tumors close to vessels; little risk for bleeding and needle-track seeding; requires
3 to 4 sessions; not as effective as RFA
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| Chemoembolization: selective catheterization of hepatic artery and branch that feeds vascular tumors; mixture of embolization
agent and chemotherapy drugs infused; data suggest that if appropriate patients chosen (those with well preserved
liver function and intermediate-stage tumors), 2-yr survival benefit achieved; if patients not chosen correctly
(eg, class B or C cirrhotics, those with large tumors or portal vein thrombosis), survival decreased
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| Yttrium90 microspheres (TheraSphere): transarterial administration of local emission of radiation therapy; microspheres
instilled into branch of hepatic artery that goes to tumor; must ensure relatively selective perfusion of liver tumor
(rather than extrahepatic shunting); if microspheres go to gastroduodenal artery, can lead to necrosis of gastrointestinal
tract; radiation-induced lung disease if microspheres get to lung; recent data show that antitumor effect of yttrium better
than chemoembolization (but liver more affected; ascites increased); not as selective; directed delivery of radiation
into tumor not as clear-cut as chemoembolization; limitations for bilirubin more restrictive than with chemoembolization
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| Radiation therapies: substantial dose of radiation to kill tumor also kills liver; conformational 3-dimensional radiation
therapy or more directed proton beam therapy; proton beam therapy—protons have characteristics that allow creation
of straight laser beam that penetrates certain depth into solid organ before releasing energy and causing necrosis; tumor
sensitive to 50 rad (underlying liver to 35 rad)
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| Systemic therapies: to date, no effective chemotherapy regimens; tamoxifen, antiandrogens, and somatostatin and analogues
ineffective; no clear benefit fron interferon alone or combined with other agents; nolatrexed (Thymitaq)—
multicenter international trial showed only one partial response held for 7 mo; mean overall survival 32 wk; sorafenib
(Nexavar)—Food and Drug Administration (FDA)-approved for renal cell carcinoma; multikinase inhibitor; blocks angiogenesis
and tumor cell proliferation on multiple levels; phase 2 study of 137 participants, of whom 75% Child’s class
A; participants had inoperable HCC and no previous systemic therapy; given oral sorafenib 400 mg bid in 4-wk cycles;
found partial response in 2%, minor response in 5.8%, and stable disease in 33%; delayed time to progression to 4 mo,
and overall survival increased to median of 9 mo; well tolerated; Sorafenib HCC Assessment Randomized Protocol
(SHARP) trial—terminated early due to improvement in overall survival
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| Summary of treatment: transplantation—has best long-term survival outlook but most restrictive (patient eligibility, and
availability of organs); resection—second-best; requires absence of cirrhosis and macrovascular involvement; cirrhotic patient
must be in early stage with no clinically relevant portal hypertension; ablative therapies—available to more patients
but have limited tumor control; chemoembolization option for patients with well-preserved liver function and multifocal disease
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| PANCREATIC CYSTIC NEOPLASMS —R. Matthew Walsh, MD, Department of General Surgery, Cleveland Clinic,
Cleveland, OH
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| Introduction: pancreatic cystic neoplasms uncommon, occurring in <1% of population; most postinflammatory; since
found incidentally, tend to be smaller in size; treatable; good outcome, even when malignant
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| World Health Organization (WHO) classification: mucinous cystadenoma now specific diagnosis of mucinous cystic
neoplasm (MCN; presence of ovarian stroma required for diagnosis); MCN and intraductal papillary mucinous neoplasm
(IPMN), whether invasive or noninvasive, still considered cancer or malignant; MCNs—have thick-walled “rind” (ovarian
stroma); tend not to communicate with duct; have papillary projections; tend to be located in tail (in main duct
IPMN, usually involves head); usually in younger women (in IPMN, equal sex distribution and usually older; increasing
in relative frequency); risk for carcinoma 50%; invasive ductal adenocarcinoma much worse disease
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| Diagnosis: cross-sectional imaging typically used; serous cystadenoma—benign; tends to have central scar and honeycomb
appearance; calcifications on MCNs usually occur on rim of lesion (not necessarily benign; usually septated); diagnosed
as IPMN when main duct >50 mm without obstructing cancer; magnetic resonance cholangiopancreatography
(MRCP) valuable; radiologist often not helpful; study—compared histology from resected specimen to computed tomography
(CT); all 3 radiologists agreed on diagnosis and diagnosis correct only 8% of time; small lesions ( ≈2.5 cm) more
difficult for radiologist; can also perform endoscopic US, endoscopic retrograde cholangiopancreatography (ERCP;
rarely done), pancreatoscopy (not done), and sometimes MRCP
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| Decision making: symptoms direct course of action; complete resection indicated in symptomatic patients; asymptomatic
lesions difficult because goal of surgery not clear; symptomatic patients tend to have mucinous lesions (true
for most series); biopsy of wall should not be performed (usually inconclusive); any surgery for removal acceptable
(typically distal pancreatectomy); Whipple procedure not uncommon; argument for resection—retrospective study
of 9 patients; in mucinous lesions ≤2 cm, ≈50% still potentially malignant; data on serous neoplasms (cystadenomas)
show that if >4 cm, growth rate high and resection indicated
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| Protocol used by speaker: for pancreatic cyst found by CT, if symptomatic or strongly suggestive of mucinous-type lesion
by imaging, perform resection; if not, base management on cyst aspiration (looking at mucin and carcinoembryonic antigen
[CEA]); if negative, follow yearly; if size increases, repeat and put on CT surveillance; if mucin becomes positive or
patient develops symptoms, perform resection
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| Data on natural history of cysts: 333 patients (104 resected); majority asymptomatic; most aspirated and most did not
have positive mucin; of those with positive mucin, 50% had surgery; of those followed >1 yr, only 4 required surgery
(one mucinous); overall increase in size, 19%; as many likely to decrease in size as increase in size; looked at presence of
acid mucin in cyst and CEA; cytology specific but not sensitive; CEA >200 µg/mL considered positive
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| Summary: location of incidental lesion does not matter but size does; resection not indicated if lesion <1.5 cm; symptoms
overriding factor that guides management; aspiration of lesions valuable in determining management; resect any mucinous
lesion, regardless of size
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Suggested Reading
Amersi FF et al: Long-term survival after radiofrequency ablation of complex unresectable liver tumors. Arch Surg
141:581, 2006; Badruddoja M: Ablative therapy of malignant liver neoplasm. Arch Surg 141:947; author reply 947, 2006;
Bush DA et al: High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial.
Gastroenterology 127:S189, 2004; Davila JA et al: Diabetes increases the risk of hepatocellular carcinoma in the United
States: a population based case control study. Gut 54:533, 2005; Davila JA et al: Hepatitis C infection and the increasing
incidence of hepatocellular carcinoma: a population-based study. Gastroenterology 127:1372, 2004; El-Serag HB et al:
The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med
139:817, 2003; Erratum in: Ann Intern Med 140:151, 2004; Summary for patients in: Ann Intern Med 139:I28, 2003; Goh
BK: Intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms of the pancreas differentiated by ovarian-
type stroma. Surgery 141:545, 2007; Gondolesi GE et al: Adult living donor liver transplantation for patients with hepatocellular
carcinoma: extending UNOS priority criteria. Ann Surg 239:142, 2004; Hardacre JM et al: An aggressive surgical
approach is warranted in the management of cystic pancreatic neoplasms. Am J Surg 193:374, 2007; Hawkins MA et al:
Radiation therapy for hepatocellular carcinoma: from palliation to cure. Cancer 106:1653, 2006; Lim HS et al: Imaging
features of hepatocellular carcinoma after transcatheter arterial chemoembolization and radiofrequency ablation. AJR Am J
Roentgenol 187:W341, 2006; Madoff DC et al: Portal vein embolization with polyvinyl alcohol particles and coils in preparation
for major liver resection for hepatobiliary malignancy: safety and effectiveness--study in 26 patients. Radiology
227:251, 2003; Mazzaferro V et al: Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting
liver transplantation: a prospective study. Ann Surg 240:900, 2004; Michaels PJ et al: Intraductal papillary mucinous
neoplasm of the pancreas: cytologic features predict histologic grade. Cancer 108:163, 2006; Pelaez-Luna M et al: Cyst
fluid analysis to diagnose pancreatic cystic lesions: an as yet unfulfilled promise. Gastroenterology 130:1007, 2006; Vauthey
JN et al: Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform
staging after surgical treatment. J Am Coll Surg 204:1016, 2007.
Educational Objectives
| The goal of this program is to improve the management of hepatocellular carcinoma (HCC) and pancreatic cystic
neoplasms. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Determine the prognosis of HCC based on specific factors.
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| 2. Choose the appropriate treatment modality, based on the indications present.
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| 3. Review the criteria for liver transplantation.
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| 4. Distinguish mucinous cystic neoplasms from intraductal papillary mucinous neoplasms.
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| 5. Review the indications for resection of pancreatic cysts.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Hillebrand was recorded at New Treatments in Chronic Liver Disease, held March 31 to April 1, 2007, in San Diego,
CA, and sponsored by the Scripps Clinic. Dr. Walsh was recorded at the 42nd Annual Gastroenterology Update, held November
16-17, 2007, in Cleveland, OH, and sponsored by the Cleveland Clinic, Department of Gastroenterology and Hepatology.
The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this
program.
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