NcXHF

ABOU-ALFA ET AL
sess liver function is the Model for End-Stage Liver Disease
(MELD)—composed of serum total bilirubin, serum creatinine,
and international normalized ratio—and it has been
shown to be better at predicting mortality in patients with
cirrhosis when compared to the Child-Pugh score. 4 This
combined with its purely measurable parameters made the
MELD score instrumental in helping to allocate donated livers
for transplant based on the immediate need of the receiving
patient. The Child-Pugh continues to be a reference
scoring system for the assessment of liver function, and it is
included in many HCC clinical trials as a reference. There
have been an endless number of prognostic scoring systems
for HCC with a continued debate over their validity. 5 However,
a measure of hepatic function is important in the assessment
of patients with HCC.
ADVANCEMENTS IN THE TREATMENT OF
HEPATITIS C
HCV still lacks a preventative vaccine like that of HBV, which
has helped decrease the incidence of HCC in high-risk countries.
However, recent developments in direct-acting antiviral
agents for HCV infection have shown potential to alter the
natural history of the infection and, ultimately, affect the incidence
of HCC.
Certain antiviral agents act directly on HCV targets,
whereas others target host proteins that are vital for the replication
of HCV. Among the viral targets are the NS3/4A serine
protease, which cleaves the HCV polyprotein, and the
NS5B RNA-dependent RNA polymerase. However, another
target, the nonstructural protein 5A (NS5A), has claimed
success as a therapeutic target for HCV because of its importance
in the assembly of the cytoplasmic membrane-bound
KEY POINTS
Hepatocellular carcinoma (HCC) continues to have a rising
global incidence.
A 12-week course of treatement with NS5A inhibitors
ledipasvir and sofosbuvir has shown a sustained virologic
response up to 96% for patients with hepatitis C viral
infection genotype 1.
The Metro Ticket algorithm asserts that the further one
deviates from the Milan criteria with respect to tumor
burden in applying liver transplant, the higher the “price”
one pays with long-term disease recurrence.
Despite the theoretical potential synergies between
locoregional and systemic therapies with antiangiogenic
properties such as sorafenib all clinical trials completed so
far have failed to provide evidence of a clinical benefit in
that setting.
Sorafenib remains the sole standard of care for advanced
HCC with an improvement in survival to 10.7 months
compared to 7.9 months for placebo (0.69; 95% CI, 0.55
to 0.87).
replication complex and the high potency of its inhibitors
both clinically and preclinically. 6
The US Food and Drug Administration (FDA) approved
the combination of two NS5A inhibitors, ledipasvir and sofosbuvir,
a fıxed, single pill combination for the treatment of
HCV. 7 A 12-week course of treatment has shown a sustained
virologic response of 90% for genotype 1. When patients with
compensated cirrhosis were treated for 12 weeks, there had a
sustained response rate of 96%. 8 The ledipasvir and sofosbuvir
combination appears to be very well tolerated, with fatigue
and headaches as the most common side effects.
Another new agent recently approved by the FDA for the
treatment of HCV is a pack containing a combination of a
protease inhibitor ABT-450 (ritonavir, ABT-450/r), an NS5A
inhibitor (ombitasvir), and a nonnucleoside polymerase inhibitor
(dasabuvir) plus ribavirin. 9 A 12-week course showed
a sustained virologic response of 96.2% (95% CI, 94.5 to 97.9)
in genotype 1 infection. The pack was used in compensated
cirrhosis, and 12 weeks of treatment led to a sustained virologic
response of 92%. 10 This treatment has shown to be well
tolerated, with fatigue, nausea, pruritus, and insomnia as the
most common reactions.
With the advent of new curative anti-HCV therapy, it is
still unclear how this will affect HCC incidence and outcome.
No studies have evaluated the use of the new antivirals in patients
with HCC.
CURATIVE THERAPIES
Curative therapies for the treatment of HCC are evolving.
Improvements in surgical techniques and risk stratifıcation
for orthotopic liver transplantation (OLT) have expanded access
and improved the outlook for patients suffering from
HCC.
Liver Transplantation
HCC was one of the earliest recognized indications for
OLT and remains a leading indication for OLT in adults
and children today. 11 The proposal of the Milan Criteria
by Mazzaferro et al in 1996 was a sentinel event within the
transplant community as it was the fırst successful attempt
to stratify disease burden at OLT with post-OLT outcomes.
12 The limits of the Milan criteria are a single lesion
of 5 cm or less in diameter or no more than three lesions,
none of which are more than 3 cm in diameter. When the
Milan criteria are fulfılled, the post-OLT survival of recipients
transplanted because of HCC was not signifıcantly
different than OLT recipients, with no diagnosis of HCC.
This observation led to the subsequent stratifıcation of
OLT candidates into those within or outside Milan criteria.
The distinction is signifıcant, as candidates within Milan
criteria receive prioritization for OLT and are eligible
for automatic progression toward OLT that is not dependent
on a decline in their physiology. 13 All other wait list
candidates progress toward OLT based on their risk of isolated
liver failure as determined by their individual MELD
scores.
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