2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

EVOLVING TREATMENT OF HCC
Endpoint
Table 2. Phase III Studies of Sorafenib in Hepatocellular
Carcinoma
SHARP Sorafenib
versus Placebo 3
Hazard Ratio
(95% CI) P value
TACE had improved OS compared with those who received
BSC (p � 0.009). 17 Survival probabilities at 1 year and 2
years were 82% and 63% for chemoembolization and 63%
and 27% for control. In another single-center study conducted
in Hong Kong where the majority of patients had
underlying HBV infection, Lo and colleagues showed that
patients with unresectable HCC who received cisplatinbased
TACE had improved survival (1 year, 57%; 2 years,
31%; 3 years, 26%) compared with those who received only
symptomatic control (1 year, 32%; 2 years, 11%; 3 years,
3%; p � 0.002). 18 A meta-analysis of randomized, controlled
trials assessing the use of arterial embolization, chemoembolization,
or both as primary palliative treatment for
HCC showed that these procedures were associated with an
improved 2-year survival rate as compared with conservative
treatment. 19
In addition to conventional TACE, several novel regional
therapies, including drug-eluting beads TACE, radioembolization,
and external beam radiation, are under active investigation
in HCC. Whether certain techniques will perform
better than others and how to incorporate regional therapy
for patients with portal vein invasion requires additional
studies. Current clinical studies are also assessing the role
of sorafenib given concurrently or following TACE or other
regional treatment modalities. Despite the early studies
demonstrating the tolerability of combining sorafenib with
TACE, 20,21 this approach has not definitively shown clinical
benefits of sorafenib either following TACE or concurrently
with TACE. 22,23
Management of Advanced-Stage HCC
Asia-Pacific Sorafenib
versus Placebo 4
Hazard Ratio
(95% CI) P value
OS 10.7 vs. 7.9 mo �0.001 6.5 vs. 4.2 mo 0.014
0.69 (0.55–0.87) 0.68 (0.50–0.93)
TTSP 1.08 (0.88–1.31) 0.768 0.90 (0.67–1.22) 0.50
TTP 5.5 vs. 2.8 mo �0.001 2.8 vs. 1.4 mo �0.001
0.58 (0.45–0.74) 0.57 (0.42–0.79)
RR 2% vs. 1% 3.3% vs. 1.3%
Abbreviations: OS, overall survival; TTSP, time to symptomatic progression;
TTP, time to tumor progression; RR, response rate.
Following the initial experience in a phase II study, 24 two
randomized phase III trials definitively demonstrated the
improved OS benefit of sorafenib in advanced HCC (Table 2).
The approval and wide application of sorafenib has changed
the treatment paradigm for HCC. However, as sorafenib is
gaining more clinical experience, several important findings
and related questions have emerged. First, the clinical
benefits are modest and only seen in certain patients. This
highlights the importance of understanding the mechanism
of action of sorafenib and identifying potential predictive
markers. Second, as sorafenib-related toxicities, including
hand and foot skin reaction, diarrhea, and fatigue can be
challenging to manage and affect the quality of life of
patients, many clinicians and investigators have asked the
relevant question: what is the optimal dose of sorafenib?
Although the targeted dose of sorafenib should be 400 mg
twice daily based on phase III data, many clinicians have
adopted a dose titration step-up approach, starting at 400
mg daily and increase the dosage by 200 mg every 1–2 weeks
to the targeted 800 mg daily as tolerated. Experience form
the observational GIDEON study showed that 34% of patients
in the United States started sorafenib at 400 mg daily.
Third, because the agent was tested only in patients with
underlying Child A cirrhosis in the phase III trials, the
benefits of sorafenib in patients with worsening hepatic
dysfunction remains uncertain. Several institutional-based
retrospective studies have examined the use of sorafenib
in patients with Child B cirrhosis. Although these studies
have their inherent limitation, these findings suggest that
sorafenib can be safely given to most patients with underlying
Child B cirrhosis. However, increased hyperbilirubinemia
and other side effects can be encountered at higher
frequency. The pharmacokinetic (PK) parameters are similar
or modestly different in patients with Child B in comparison
with those with Child A. The treatment duration
and OS are generally shorter in Child B than those with
underlying Child A cirrhosis. Based on the available data,
the starting dose for patients with good performance status
and compensated hepatic function should be 800 mg daily.
However, in patients with borderline performance status
and compromised hepatic function, a reduced dose of
sorafenib at 200–400 mg can be started with the goal of
escalating to full dosage if tolerated. The PK study of
sorafenib in patients with hepatic and renal dysfunction also
provides some guideline for dosing for these patients.
New Targets and Regimens under Development for
Advanced HCC
The approval of sorafenib has greatly stimulated research
in drug development in HCC. Many molecularly targeted
agents that inhibit different pathways of hepatocarcinogenesis
are under various phases of clinical development, and
novel targets are being assessed in HCC. There are three
main strategies in this area: (1) identifying and testing
targeted agents with novel mechanisms of action; (2) combining
various targeted agents that blocks specific targets in
different or same pathways; (3) combining targeted agents
with chemotherapy. Despite the excitement for these extensive
efforts in the past few years, we have observed a few
worrisome trends. First, all ongoing phase III studies with
targeted agents are conducted in unselected populations.
Second, most agents that are in phase III testing are not
based on robust data from randomized phase II studies.
Third, there is a high rate of failure of phase III trials in
HCC. Table 3 lists some of the key studies in various phases
of clinical development.
Antiangiogenic Agents
HCCs are vascular tumors, and increased levels of vascular
endothelial growth factor (VEGF) and microvessel density
(MVD) have been observed. 25 VEGF is one of the main
inducers of liver tumor angiogenesis. High VEGF expression
has been associated with lower survival. Inhibition of angiogenesis
represents a potential therapeutic strategy and has
been extensively tested in HCC.
Several VEGF-R inhibitors have moved to phase III development
based on the initial phase II data. 25 Sunitinib is
an oral multikinase inhibitor that targets receptor tyrosine
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