2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ated with unique dose distributions that allow rapid falloff
in dose and substantial sparing of dose to tissues adjacent to
tumors. Proton or carbon RT has the best reported outcomes
postradiation in patients with HCC. 10,11 In one prospective
study, patients with Child-Pugh A liver disease and potentially
resectable single HCCs, had a 5-year survival of 56%
following proton therapy. 10 In another series, in six patients
with HCC who went on to have liver transplantation 6 to
18 months after proton therapy (63 Gy equivalent in 15
fractions), two complete pathologic responses were observed,
demonstrating proof that high-dose RT may ablate HCC. 12
Proton and photon therapy have been used to successfully
treat HCC with portal vein or inferior vena cava
thrombosis. 11
Outcomes: SBRT
More recently, SBRT has been used to treat patients with
HCC, with a summary of outcomes shown in Table 1.
Blomgren et al first reported on the use of SBRT on extracranial
sites in 1995 and 1998. 13,14 In this series that included
patients with HCC, 15 to 45 Gy was delivered over one to
five fractions. The majority of patients had objective responses.
Subsequently, Herfarth et al treated 60 liver tumors
(which included 3 primary HCCs) in 37 patients with
KEY POINTS
● Stereotactic body radiation therapy (SBRT)—highly
conformal, potent-dose radiation therapy delivered in
fewer fractions than usual (usually � 10)—is being
used more commonly in hepatocellular carcinoma
(HCC).
● SBRT is most effective in HCC smaller than 6 cm,
with local control rates from 70% to 95% at 2 years.
● SBRT can also lead to sustained control of HCCs
larger than 6 cm and the recanalization of vascular
tumor thrombi from HCC.
● Toxicity risks are increased in patients with Child-
Pugh B and C baseline liver function.
● Randomized trials of SBRT for HCC are required.
Table 1. Selected Outcomes from HCC SBRT Series
Number of Patients Dose/Fraction
Median Follow-up
(Months) Tumor Size
Overall
Response Rate Survival
Blomgren, 1998 14 9 pts HCC, 1 pt IHC 5–15 Gy/1–3 # NR NR 70% NR
Choi, 2006 23 20 pts HCC 50 Gy/5–10 # 23 3.8 cm (2–6.5 cm) 80% overall OS 1 yr: 70%
20% CR/60% PR OS 2 yr: 43.1%
Mendez Romero, 2006 17 11 pts HCC 25 Gy/5 # NR � 7 cm 1-yr LC: 82% OS 1 yr: 75%
CP A and B 30 �37.5 Gy/3 #
Tse, 2008 18 31 pts HCC 36 Gy (median)/6 # 18 Median: 173 cm 3 1-yr infield LC: 65% OS 1 yr: 48%
All CP A Range 24–54 Gy
Louis, 2010 26 25 pts HCC 45 Gy/3 # 13 Median: 150 cm 3 86% overall OS 1 yr: 79%
CP A and B OS 2 yr: 52%
Kwon, 2010 24 42 pts HCC 30–39 Gy/3# 29 15.4 cm 3 (3–82 cm 3 ) Overall: 86% OS 3 yr: 59%
CP A 90% 3-yr LC: 68%
Facciuto, 2011 22 27 pts HCC 24–36/2–4 # 22 2.0 cm � 0.8 cm Overall: 37% OS 2 yr: 82%
All CP A
Andolino, 2011 20 60 pts HCC 44 Gy (median)/3 # CP A 27 Median: 3 cm Overall: 90% OS 2 yr: 67%
CP A/B: 36/24 40 Gy (median)/5 # CP B
Abbreviations: HCC, hepatocellular carcinoma; SBRT, stereotactic body radiotherapy; Pts, patients; IHC, immunohistochemical; #, fractions; NR, not reported; OS,
overall survival; CR, complete response; PR, partial response; LC, local control; CP, Child-Pugh.
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14 to 26 Gy SBRT in one fraction. The treatment was well
tolerated. 15 Wulf et al then reported on 39 patients treated
with three-fraction SBRT to the liver, five of whom had
HCC. No more than 50% of the total functional liver tissue
could receive more than 5 Gy, and no more than 30% could
receive more than 7 Gy. The doses delivered ranged from 30
Gy to 37.5 Gy in three fractions. No local failures were seen
in two HCC patients after 15 and 48 months. Three of the
HCC patients died of disease progression in the liver outside
the RT field at 2, 7, and 17 months. No acute or late serious
toxicity was reported in any patient. 16
Mendez Romero et al treated eight patients with 11 HCCs
of Child-Pugh A or B (in addition to 17 patients with liver
metastases) with 25 Gy in five fractions, 30 Gy in three
fractions, or 37.5 Gy in three fractions over 5 to 10 days. The
maximum tumor size was 7 cm. Two of the patients with
HCC who received 25 Gy in five fractions failed locally at 4
and 7 months and were retreated with 24 Gy in three
fractions. The local control rate of the patients with HCC
was reported as 82%, and the 1- and 2-year actuarial
survival rates were 75% and 40%, respectively. One patient
in the HCC group with Child-Pugh B liver function developed
grade 5 toxicity because of liver failure and infection. 17
In Toronto, a prospective dose-escalation study of sixfraction
SBRT was conducted in 31 patients with locally
advanced HCC unsuitable for standard therapies. A typical
plan is shown in Fig. 1. The dose per fraction was determined
based on the effective volume of normal liver irradiated
(Veff). When the effective liver volume irradiated was
low (Veff � 25%), doses of 54 Gy (9 Gy � 6) were delivered
safely to HCCs, with excellent local control. For patients
requiring moderate volume liver irradiation (Veff 25% to
80%), doses from 24 to 54 Gy (4 to 9 Gy � 6) were delivered
safely. All patients had Child-Pugh liver function A, and the
majority of patients had portal vein thrombosis. No classic
RILD was seen. Five patients had a decline in their Child-
Pugh class at 3 months. These patients had extensive
tumors, and three had tumor progression that likely contributed
to the decline in liver function. The median survival
was 11.7 months (95% CI, 9.2–21.6 months). 18 One hundred
and two eligible patients were included in an update of the
Toronto phase I study and a subsequent phase II study,
using the same dose-allocation approach. Underlying liver