Hepatocellular carcinoma (HCC) is a malignancy that is increasing in incidence in
the United States (4.9 per 100,000) with mortality rates that remain close to 50%
at 1 year, despite improvement in programs aimed at the prevention of cirrhosis and
early detection of liver cancer in high-risk patients. Liver cancer is now the third
cause of cancer-related death. Diagnosis at an advanced stage excludes >85% of patients
from curative surgical therapies. Medical therapy remains of limited benefit for nonsurgical
patients. Sorafenib has shown the most promising results for palliative therapy in
HCC patients, imparting a 10-week survival benefit in patients with advanced disease.
Liver-directed therapies provide alternatives to patients with HCC who are not considered
surgical candidates. Radiofrequency ablation (RFA) has survival rates comparable with
surgical resection in optimally selected patients with early disease; however, increasing
size (>3 cm), multiple lesions (more than three), and central location limits application
in patients with stage III disease and patients whose tumor location is adjacent to
vascular structures or central bile ducts. Chemoembolization with single or multiple
drugs mixed with ethiodized oil (cTACE) has the longest track record in the treatment
of nonsurgical HCC patients and has been shown to improve survival in several randomized
controlled trials compared with symptomatic treatment. Chemoembolization with drug-eluting
beads (DEB) and selective internal radiation therapy (SIRT) with yttrium are newer
therapies that appear to have similar efficacy and may be preferred in certain subpopulations.
When to use them remains controversial because direct comparative evidence to guide
choices is lacking.
This article presents several common scenarios of patients presenting with HCC to
highlight the clinical and anatomical factors that lead to a treatment decision.
Case 1
A 56-year-old man with cirrhosis secondary to hepatitis C undergoing surveillance
imaging has a new 1.8-cm lesion compatible with HCC. He continues to work and has
no physical restrictions. His serum bilirubin is 1.8 mg/dL, serum creatinine 1.0 mg/dL,
international normalized ratio (INR) 1.0, and serum albumin 3.5 g/dL. He has no encephalopathy
or ascites. He is currently undergoing liver transplant evaluation but is not yet
listed.
Case Evaluation
Three factors are important predictors of the survival of patients with HCC: overall
physical condition, liver function, and tumor burden. There are many classifications
that assess patients using these parameters. The Barcelona Clinic Liver Cancer (BCLC)
classification combines these three prognostic factors using Eastern Cooperative Oncology
Group (ECOG) performance status to evaluate physical condition, Child-Turcotte-Pugh
(CTP) classification to evaluate liver function, and the modified TNM staging classification
of malignant tumors to evaluate tumor burden. The BCLC classification is useful to
stratify the complex population of patients undergoing treatment for HCC into groups
with similar survival expectations. In addition, it prescribes treatment for each
population segment based on the currently available evidence. Although individual
and institutional biases, combined with rapidly evolving treatments, result in local
variation from this prescription, organizing treatment strategies based on the BCLC
categories permits the evaluation of therapeutic outcomes in identifiable patient
populations.
This patient is classified as BCLC A (early disease) with an ECOG performance status
of 0, CTP A (6) cirrhosis, and stage I tumor (<2 cm). If well encapsulated, this lesion
may represent in situ carcinoma, and resection or ablation might be curative. It is
not possible to make this determination until the lesion is inspected for microvascular
invasion by histology.
Patients rarely present with small HCCs without underlying liver disease. These asymptomatic
individuals who are lucky enough to be diagnosed at such an early stage are candidates
for resection or ablation therapy that can be curative with 5-year survival rates
approaching 90% for in situ tumors. Survival following resection in patients with
more advanced cancer or liver disease approximates 50% at 5 years. Unfortunately,
at 5 years, recurrence occurs in most patients.
Most patients with HCC, however, have underlying liver disease, with its separate
mortality risk that will complicate all cancer treatment decisions. The presence of
portal hypertension or bilirubin elevation has a negative impact on the otherwise
favorable outcome following resection. Surveillance of patients at risk for HCC, including
all patients with known cirrhosis, permits discovery of early cancers. Once HCC is
identified, even when the patient does not meet criteria for liver transplant based
on liver impairment alone, transplant evaluation is warranted. Liver transplant offers
patients with liver disease and HCC the best opportunity for tumor-free survival,
on the order of 70% at 4 years.
Patients are ranked for transplant according to their mortality risk score in accordance
with the Model for Endstage Liver Disease (MELD), based on bilirubin, INR, and creatinine.
The MELD score has been prospectively analyzed to predict risk of death in patients
with end-stage liver disease. Because cancer carries its own mortality risk, an automatic
MELD exception is permitted for patients with HCC based on viable tumor burden. To
qualify for an automatic upgrade, candidates must have stage II disease (one nodule
2.0 to 5.0 cm; two or three nodules, all <3.0 cm). Patients meeting this criteria
without vascular invasion or extrahepatic disease are granted extra priority on the
transplant list equivalent to the MELD score equivalent of 15% probability of death
in 3 months (MELD score of 22 points). Subsequently, every 3 months, the candidate
receives additional points. By granting exception points, these patients can move
up the list faster than they would if MELD points were assigned by the severity of
their liver disease alone. The hope is they will stay within criteria for transplant
until they reach the top of the list and are transplanted and that transplant outcomes
will approach those of a patient without cancer. Transplant evaluation prior to treatment
is important so that automatic upgrade is not compromised.
Once listed for transplant, the primary goal of treatment is to keep the patient within
criteria for transplant while waiting. There is little evidence to support the widely
applied strategy of offering adjunctive therapy to patients on the waiting list; however,
long delays between listing and transplant make this a practical solution to avoid
drop-off due to tumor progression. About 20% of patients fall off the list due to
tumor progression.
Treatment Options
This patient's elevated bilirubin suggests resection results may be diminished due
to his liver disease. Depending on the location of this tumor, he may be a candidate
for ablation therapy with favorable intermediate-term cancer survival, particularly
if microvascular invasion has not occurred in this small lesion. But transplant will
offer him the best hope of cancer-free survival. To obtain a MELD exception, the lesion
must be watched until it reaches 2 cm.
When transplant evaluation is complete, even with the upgrade of points he receives
for his HCC diagnosis, this patient will likely be on the transplant list for a long
time. At our institution the average wait time for liver transplant is >6 months.
Keeping the tumor within Milan criteria (stage II disease) with minimal impact on
his physical condition becomes the goal of therapy.
At our institution we rarely perform RFA in liver transplant candidates and typically
recommend TACE. This is because the very low tract seeding that accompanies RFA would
preclude transplant. Other transplant centers use ablation therapy as their primary
adjunctive strategy prior to transplant.
Data from the Precision V trial would suggest that cTACE and DEB with doxorubicin
result in similar tumor response in patients with BCLC B (intermediate) disease. This
study demonstrated an advantage to DEB in patients with more advanced CTP B disease
and a reduction in therapy-related liver toxicity. Once introduced 3 years ago into
our practice, we experienced a rapid preference for DEB over cTACE, for nearly all
indicating. Although initially we hoped for a less symptomatic patient (perhaps even
ready for same-day discharge), what we found anecdotally was the procedures went more
quickly, the approach was more standardized between operators, the small bead size
permitted aggressive selective embolization without more morbidity, and the postprocedure
imaging was simplified by the elimination of ethiodized oil. Rarely are patients discharged
the same day.
Recommendation
Complete transplant evaluation with MELD exception upgrade when lesion reaches 2 cm.
Single-session DEB with selective embolization utilizing a vial of 100 to 300 micron
beads loaded with 75 mg doxorubicin until near stasis is achieved. Three-month surveillance
imaging until transplant. Repeat intervention if there is significant persistent tumor
enhancement or recurrence after initial response.
Case 2
A 65-year-old asymptomatic woman with nonalcoholic steatohepatitis presents with three
lesions consistent with HCC. The largest lesion is 4.0 cm in segment 7. Two 2-cm lesions
are in segments 2 and 3. Her ECOG status is 0, CTP A (6), with a serum bilirubin of
1.8.
Case Evaluation
This patient has BCLC B (intermediate) disease, with a performance status of ECOG
0, preserved liver function but stage III tumor. She falls outside Milan criteria
and therefore is not currently a transplant candidate due to tumor burden. Survival
on average for patients with intermediate disease is 16 months. Conventional TACE
is thought to improve survival by 4 to 6 months and would be the standard of care
for this patient.
Mazzaferro initially proposed the Milan criteria to select patients with HCC for transplant
who would have survival rates following transplant that were similar to patients without
cancer. More recently, investigators have questioned whether the Milan criteria are
too stringent. Rather than using a single lesion of 5 cm or the presence of three
lesions, the largest of which must be <3 cm, the University of California, San Francisco
(UCSF) criteria propose a single lesion of 6.5 cm, three lesions with the largest
≤4.5 cm, or total tumor diameter ≤8 cm. This has introduced some variation in the
decisions of regional transplant review boards, and adjustments for candidates just
outside Milan have become more common. In addition, measurement of only enhancing
tumor diameter (modified Response Evaluation Criteria in Solid Tumors [mRECIST]) after
liver-directed therapy rather than enhancing and nonenhancing tumor diameter (RECIST)
allows patients who were initially believed to be outside of Milan criteria to be
reconsidered if downstaged to within Milan criteria.
Treatment Options
This patient is within UCSF criteria but just outside Milan criteria. At another center
she might be listed for transplant and any therapy would be considered adjunctive.
At our institution we would undertake liver-directed therapy with the goal to decrease
the size of the tumor to the point that she can be downstaged to within Milan criteria.
If that strategy fails she would have received optimum treatment to enhance survival.
Ablation of these lesions could be considered. The size of the dominant lesion and
the presence of bilobar disease would necessitate multiple probes and multiple sessions.
With current technology, it would be difficult to obtain an adequate margin surrounding
the 4.5-cm lesion.
Because response is what is required to downstage this patient, DEB may be favored
over cTACE if intra-arterial therapy is selected. A single institutional study suggests
that SIRT may be more effective at downstaging than TACE. The data are, however, sparse
at best and should be weighed against potential delays in providing the service and
cost. Both therapies should be discussed with the patient.
Recommendation
Two-session DEB therapy in a segmental distribution. Selective embolization of the
lesion in segment 7 initially with 100 to 300 micron beads. Consider partial embolization
of the surrounding segment with larger beads because this disease is multifocal and
the patient's liver function is relatively preserved. Repeat session for segments
2 and 3 in 4 to 6 weeks if no complications develop. Imaging 3 months after second
treatment to evaluate response. Re-treat persistent enhancing tumor as needed. Consider
RFA if tumor response is insufficient to downstage. Consider sorafenib once directed
therapy is considered completed, if not listed for transplantation.
Case 3
A 60-year-old Asian woman with cirrhosis and hepatitis B presents with multifocal
bilobar HCC including 15 lesions, all of which are <2 cm. She has nonenhancing intrahepatic
segmental portal vein thrombosis (PVT). She is CTP A, ECOG 1, with a bilirubin of
1.3.
Case Evaluation
This patient is asymptomatic with relatively preserved liver function. Her tumor burden,
however, is significant stage IV disease. If portal vein thrombus is due to tumor
invasion, she would be classified as having BCLC C (advanced disease) with a mean
untreated survival of 8 months. The current standard of care for patients with advanced
HCC is sorafenib, supported by the Sorafenib HCC Assessment Randomized Protocol Trial
(SHARP) trial that demonstrated a 10-week survival benefit for patients receiving
the drug compared with control (10.7 months compared with 7.9 months). There was also
an improvement in time to progression for patients in the sorafenib arm. Data to support
more aggressive therapy are lacking in the setting of either vascular invasion or
extrahepatic disease.
If portal vein thrombus is bland, her prognosis may be less severe. It is not always
possible to distinguish between the two. At our institution, liver-directed therapy
is offered to patients with extrahepatic PVT and well-developed collaterals (cavernous
transformation) and to patients with limited intrahepatic PVT when tumor enhancement
is not demonstrated. We inadvertently treat a few patients with tumor invasion with
this approach. Complications related to hepatic ischemia and progression of portal
vein thrombosis are more common.
Treatment Options
Lobar therapy is desirable in this patient to reduce treatment sessions. This approach
is poorly tolerated in patients receiving TACE when liver disease is advanced, and
it may result in progression of liver disease. TACE and SIRT have been used to treat
CTP A patients in a lobar fashion with reasonable results. The complication profile
and outpatient care following SIRT offers a significant advantage.
The safest approach for patients with nontumoral PVT is unclear. Regional therapies
may not result in substantial prolonged survival. SIRT has been promoted for the treatment
of patients with preserved liver function in this setting. An advantage in survival
is yet to be established by prospective comparison of techniques.
Recommendation
SIRT performed in a lobar fashion after planning arteriography and MAA shunt study.
Treatment of the lobe with the dominant tumor burden first; second lobe treatment
in 4 to 6 weeks.
Case 4
A 70-year-old man with alcoholic cirrhosis, stable coronary artery disease, and diabetes
mellitus has a solitary 4.5-cm lesion in segment 6. He is ECOG 1, CTP B (9) with a
total serum bilirubin of 3.2 mg/dL, INR 1.7, and albumin of 2.9 g/dL.
Case Evaluation
This patient is within Milan criteria with stage II tumor but will likely be denied
transplant because of his age and medical comorbidities. Elevation of bilirubin to
>3 mg/dL increases significantly this patient's risk of liver failure with any form
of liver-directed therapy. In addition, sorafenib is unlikely to be well tolerated.
So options are limited, and no therapy may be indicated.
Treatment Options
We have favored RFA over TACE when liver function is marginal but rarely treat patients
with bilirubin >3.5 mg/dL. RFA is more difficult in this patient because this lesion
is large and outside the range for successful ablation therapy if a margin is to be
accomplished. Although some operators ablate lesions >3 cm using multiple probes or
treatment sessions, an alternative strategy combines RFA with TACE.
Combination therapy, typically performed as RFA followed by TACE within days or weeks
of the ablation, may be possible if the initial treatment does not lead to progression
of liver failure. A follow-up scan to determine the need for TACE can be performed
as early as 1 day postablation.
Recommendation
If the lesion is in an optimal position for ablation, proceed to RFA. If significant
residual tumor enhancement persists, consider selective TACE after a delay to monitor
bilirubin.
Conclusions
Percutaneous ablation and intra-arterial therapies used in the treatment of HCC can
provide a survival benefit, afford a bridge to transplant, or be used to downstage
patients so they can undergo liver transplant. Although regional expertise plays a
role in which technique is offered to any given patient, procedures should be tailored
for each patient based on the goals of therapy, the degree of underlying liver disease,
and the tumor burden. By balancing all of these factors, treatments can be maximized
and overall outcomes improved in this otherwise challenging patient population.
