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Spieler et al. Hepatoma Res 2019;5:4 I http://dx.doi.org/10.20517/2394-5079.2018.77 Page 5 of 13

[22]
when photon therapy cannot meet dose constraint objectives . Such advantages have yet to be validated
clinically. A national cancer institute-sponsored phase 3 prospective randomized trial (NRG GI-003) is
underway, comparing proton vs. photon SABR for unresectable HCC using either 5 or 15 fractions. While
few radiation oncology centers in the world currently have the ability to treat patients with proton therapy,
80 proton facilities are in development in US. As the number of proton centers equipped with respiratory
gating continues to increase, proton SABR will become more widely available.

The safety of SABR allows the radiation oncologist to prescribe a very high dose per fraction. Prescriptions
in the range of 50 Gy in five fractions can be delivered safely to the target. A high radiation dose delivered
in few fractions produces much greater biological effect than the same dose delivered over a protracted
regimen. For this reason, 50 Gy delivered in 5 fractions has an ablative, tumoricidal effect while 50 Gy in 25
fractions is associated with low tumor control probability for HCC [23,24] .

Compared to other liver directed therapies, SABR has the additional advantage of being minimally-invasive.
It can be delivered to lesions regardless of adjacent vascular structures, vascularity of the tumor, associated
venous thrombus, or location within the liver. In contrast to more invasive liver-directed therapies, SABR
can be used to treat patients at high risk of bleeding, a clinical situation frequently encountered in the
cirrhotic patient population. It can also be used to simultaneously target enlarged portal nodes or portal
vein tumor thrombus. An example of SABR target and dose distribution, as well as tumor response on post-
treatment imaging, is shown in Figure 1.

SABR CLINICAL INDICATIONS
SABR is often used to treat liver lesions beyond the capabilities of other local, ablative techniques: large
volume tumors; lesions near the liver capsule, major vessels, or diaphragm; and disease complicated by
portal vein tumor thrombus (PVTT).

HCC tends to invade the portal vein causing PVTT, especially in patients with advanced disease at
[25]
presentation. If untreated, overall survival (OS) after PVTT diagnosis is 2.7-4 months . SABR can re-
cannulate the portal vein, facilitating subsequent embolic therapies for which the presence of PVTT is a relative
[26]
contraindication. In this setting, SABR used in combination with embolic therapies increases patient OS .

Although SABR is a liver directed therapy most frequently used for patients who are not candidates for
surgery or OLT, it can also be used as a bridge procedure to downstage lesions that do not meet the Milan
criteria or to prevent disease progression while patients are on a waiting list for OLT.

Published clinical series demonstrate that SABR is a safe and well-tolerated procedure when used as a
[27]
bridge to transplant. In 2011 O’Connor et al. evaluated a clinical series of 10 patients with 11 HCC lesions
treated with SABR while on the OLT waiting list. Local control over this period was 100% and all patients
underwent OLT without increased surgical complications. In another phase I study, a 27-patient subgroup
[28]
treated with SABR as a bridge to transplant had a 100% local control rate .

Alternatives techniques used as bridge procedures to transplant include RFA and transarterial
chemoembolization (TACE). RFA, a commonly employed percutaneous technique in HCC treatment,
involves the insertion of a monopolar or bipolar probe into targeted liver tissue, using frictional heat
[29]
generated by alternating current to destroy tumor via coagulative necrosis . With RFA, best outcomes
occur when the lesion is less than 3 cm in diameter, distant from large hepatic vessels that divert heat from
the intended target, and with at least a 1 cm margin from adjacent organs such as bowel to avoid injury to
[30]
critical structures . RFA is an invasive procedure often requiring general anesthesia.