Hepatocellular carcinoma (HCC) is the third leading
cause of global cancer mortality, with a 5-year
survival rate of 5% and an increasing incidence in
North America. Cure is possible in patients who are
treated with liver transplantation, resection, or
ablative therapies (e.g., radiofrequency ablation
for tumors <3 cm). Unfortunately, in most patients,
these local therapies are not options, and hepatic
progression is inevitable. One may expect that
radiation therapy would have an established role in
HCC; yet radiation therapy is not a universally
accepted treatment, and many radiation oncologists
have never treated a patient with HCC.
It is time to establish the role of radiation
therapy in HCC.
Progress
has been slow in HCC for many reasons. Underlying
liver disease and impaired liver function are almost
universally present. Any insult to the liver
(including treatment) can trigger liver failure and
hasten death. The
whole liver
tolerance to radiation therapy is low and is reduced
further in patients with HCC compared with those
with liver metastases . As the liver volume
irradiated increases, the risk of radiation induced
liver disease rises. Reactivation of hepatitis B and
a general decline in liver function are also
possible, and both are poorly correlated with
radiation dose and volume irradiated. Furthermore,
the tolerance of other normal tissues around the
liver (e.g., the stomach, duodenum, bowels, and
kidneys) needs to be respected. In addition to
potential toxicities, organ motion in the upper
abdomen makes delivery of conformal HCC radiation
therapy particularly challenging.
Can
tumorcidal doses of radiation be delivered safely to
focal HCCs? Yes, this is possible because of
technological advances that have occurred over the
past few decades, including improved HCC
imaging, conformal 3D planning, automated
optimization and IMRT, better understanding of
normal tissue complication risks, breathing motion
management strategies and soft tissue targeting
(e.g., image guided radiation therapy [IGRT]). There
is a growing body of literature on the use of
conformal radiation therapy in HCC ; however most
papers are retrospective and/or single-institution
studies. One exception is the French multi-center
phase II study that reported
sustained
local control in 78% of patients with early HCC (one
≤5 cm or three ≤3 cm) treated with 66 Gy in 2 Gy per
fraction using conformal radiation therapy. A
decline in liver function was seen in some patients
with impaired liver function (Child-Pugh class B) at
baseline. Radiation therapy has also been used
safely in patients with more advanced HCC (e.g.,
with portal vein thrombosis) who are not ideal
candidates for other local or regional therapies.
The
article by Fukumitsu from Tsukuba, Japan is
provocative, as the outcomes are outstanding. In
this prospective study of 51 patients, proton
therapy was used to deliver 66 GyE in 10 fractions
to patients with one to three HCCs (≤10 cm),
diagnosed using standard HCC criteria. Of the
patients, 20% were in Child Pugh class B.
The 5-year
local control and survival were 88% and 39%,
respectively. In Child-Pugh class A patients with
solitary tumors, 5-year survival was 46%, similar to
results obtained after surgery. Liver
function remained stable or improved in 84% of
patients, and no radiation-induced liver disease was
observed. Late rib fractures were seen in 3
patients, adding ribs tissue to the list of normal
tissues to be avoided. No other serious late
toxicities were observed. Patients with tumors near
the gastrointestinal tract or porta hepatis were
ineligible for this hypofractionated protocol, to
reduce the risk of luminal gastrointestinal and
biliary toxicities that may occur after high doses
per fraction.
Did the
use of protons have an impact on these excellent
results? Possibly. Particle therapy is another
example of a technologic advance that should benefit
HCC patients by reducing the integral dose to the
liver, facilitating treatment of larger tumors, and
allowing more patients to be treated safely with
high doses. However, the use of protons comes at a
cost (in addition to the financial costs). Protons
are more susceptible to dosimetric and geometric
uncertainties because of the increased sensitivity
to tissue heterogeneity and the range uncertainty.
Although the HCC target tissues are relatively
homogeneous, the proton beams often pass through
tissues with variable heterogeneities (e.g., ribs
and lung). Thus, changes in path length (e.g.,
because of breathing motion or change in the mean
liver position from fraction to fraction) can lead
to differences in the delivered doses from the
planned doses. These adverse effects can be reduced
with the use of breathing motion management and
IGRT, both which were used in the Fukumitsu et al.
study.
Are there
other explanations for these excellent outcomes? The
majority of tumors treated on this study were less
than 5 cm (with a median maximal tumor diameter of
2.8 cm), suggesting that some patients may have been
suitable for other local therapies, which could have
led to similar outcomes. Approximately two thirds of
all patients treated with proton therapy during the
same time period were not treated in this study,
emphasizing that patients were well selected. In
all, 65% of patients received prior (predominantly
hepatic arterial–based) therapy, which may have
contributed to the excellent outcomes. The latter
point is not a criticism, as there is rationale to
combine local and regional/systemic therapies in HCC
because hepatic cancer recurrences and/or new
primary cancers commonly occur. Finally, HCC is a
highly heterogeneous cancer. The great variability
in etiology of liver disease, liver function, and
performance status affects survival and limits
interpretation of single-institution series.
Nonetheless, a 5-year survival rate of approximately
40% after radiation therapy is evidence of a strong
treatment effect, regardless of potential selection
bias. Some individuals may argue that these results
are too good to be true, but these results are
consistent with prior proton and carbon ion
experience For example, in a Phase I/II study of 50
to 80 GyE in 15 fractions delivered to HCC patients
using carbon ions, was associated with 5-year local
control and survival rates were 81% and 25%
respectively. We should not ignore these results.
Could the
same outcomes be obtained with quality high-dose
conformal photon irradiation in similar HCC
patients? There is no reason to think that this
should not be possible in selected patients.
The most appropriate patients for conformal photon
therapy are those with Child-Pugh A liver function
who can be irradiated with enough sparing of the
liver (e.g., mean liver dose <28 Gy in 2-Gy per
fraction). Patients with smaller tumors (<6
cm) and tumors at the dome of the diaphragm are
those most likely to be able to be treated with
biologically potent photon therapy safely. Patients
with Child-Pugh B class liver function or large (>8
cm) central tumors, associated with higher liver
doses after conformal photon therapy, have an
increased risk of liver toxicity; these are the
patients in whom protons should have the greatest
benefits. Patients with diffuse multi-focal HCC and
those with Child-Pugh C liver function are not well
suited for high-dose photon or proton therapy.
In HCC,
multi-center, randomized studies of the clinical
application of conformal radiation therapy are a
priority, rather than studies that compare specific
technologies. Although radiation therapy is an
accepted HCC treatment in some specialized centers,
randomized trials will be required for widespread
acceptance, for both early and advanced HCC.
Randomized trials will control for heterogeneity in
prognostic factors and will allow us to learn about
how outcomes from specialized centers translate to
the broader community. The studies need not be
technology specific, as long as safety can be
ensured through quality assurance (QA) strategies.
There is a strong need for collaboration with the
HCC multi-disciplinary team, educational workshops,
normal tissue dosimetric guidelines, and real-time
radiation plan review, as many radiation oncologists
have limited experience in HCC. Protons and photons
should both be included in such studies. Motion
management and IGRT should be strongly encouraged to
increase the likelihood that the delivered doses
match the planned doses, so that dose-outcomes
relationships can be better understood. The relative
benefits of a specific technical advance (e.g.,
protons, IGRT) are challenging to prove but could be
built in as secondary study endpoints.
There are
several hurdles to overcome before randomized trials
of radiation therapy can be conducted in HCC. The
technical issues described above have been adopted
with substantial variability, and they are not
widely available in developing countries where HCC
is endemic. Radiation therapy has been used in early
disease with curative intent (as in the Fukumitsu,
in locally advanced disease to improve survival and
quality of life, and in the palliative setting to
improve symptoms. Each of these settings is
important to study. There are many competing local
and regional HCC therapies, with wide variability in
specific techniques, which make studies of
combination therapy more challenging. Recently,
Sorafenib, an oral agent targeting kinases involved
in tumor growth and angiogenesis, was shown to
improve median survival in advanced HCC from 7.9
months to 10.7 months compared with supportive care
(hazard ratio, 0.69; p < 0.001). Although the time
to radiologic progression was improved, there was no
significant difference in the time to symptomatic
progression (4.1 months vs. 4.9 months, p = 0.77).
This study of 602 patients from 21 countries
demonstrates that randomized trials are feasible in
HCC. Given the radiation-sensitizing properties of
Sorafenib and other biologic targeted agents, the
combination of radiation therapy and targeted agents
should be studied. Hopefully these combinations will
lead to more dramatic improvements in HCC outcomes.
In
summary, the well-conducted prospective study by
Fukumitsu is a substantial contribution to the
growing literature on HCC radiation therapy. This
study demonstrates that cure of early-stage HCC is
possible with high-quality radiation therapy.
Several questions remain, including what the ideal
radiation dose and fractionation are, and whether
the excellent outcomes seen with protons can be
obtained with conformal photons. It is time that we
work together to develop multi-institutional and
randomized trials to increase the level of evidence
demonstrating radiation therapy as an effective
treatment in the armamentarium against HCC.