Page 643 - Read Online

Page 2 of 9 John et al. Hepatoma Res 2020;6:56 I http://dx.doi.org/10.20517/2394-5079.2020.37

While systemic therapy is still the mainstay of treatment, most tumour responses are short-lived. Moreover,
the response to systemic therapy can be mixed, with some tumours regressing and others remaining
stable or progressing. Aggressive local therapy (such as surgical resection) can be considered for patients
with oligometastatic disease. For example, surgical resection is recommended for patients with isolated
[1]
liver metastases from colorectal primaries, with the potential of long-term disease control . Early studies
demonstrated a 30% 5-year survival in patients who underwent “metastectomy” for one to three liver
[2]
metastases . Factors that determine patient eligibility for resection include the size, number, and location
of lesions, and hepatic reserve. While surgical techniques have improved, not all patients are good surgical
candidates because of surgical factors and patient co-morbidities. Thus, such patients may be considered for
non-surgical liver-directed therapies. These include invasive techniques such as radio-frequency ablation
(RFA) and non-invasive techniques such as stereotactic body radiotherapy (SBRT).

Traditionally, the role of radiation therapy in liver metastases has been purely for palliation, as the
[3]
tolerance of whole liver to radiation is limited to 30 Gy (in 2 Gy fractions) , and sustained tumor control
is very unlikely at such doses. Technological advances with improvements in target localization, patient
immobilization, motion management, and delivery of conformal radiation have allowed the use of high
doses of radiation to ablate liver metastases. Moreover, mounting evidence shows that high doses of
[3]
radiation can be delivered to small targets within the liver without causing toxicity . In the context of
SBRT, doses ranging from 45 to 60 Gy, over three to five fractions (given over 1-2 weeks), is delivered
conformally to the target while sparing normal liver parenchyma.

The purpose of this narrative review is to describe the role of radiotherapy in liver metastases - both in the
setting of ablative treatment (including SBRT and brachytherapy) for patients with oligometastatic disease,
and in the setting of symptom palliation in patients with uncontrolled liver metastases. We will elaborate
on the treatment technique, patient selection, expected outcomes and treatment-related toxicities.

USE OF RADIOTHERAPY IN PATIENTS WITH OLIGOMETASTATIC LIVER DISEASE
Hellman and Weichselbaum were the first to introduce the concept of oligometastatic disease, which
represented an intermediate state in the spectrum between locally confined and widely metastatic cancer .
[4]
They proposed that the process of metastatic disease occurs in a step-wise manner, and patients with
limited disease should be managed aggressively. In more recent years, advances in systemic and targeted
therapy have rendered a greater number of patients with upfront widely metastatic disease to a state of
limited volume metastatic disease. In these patients, aggressive management of drug-resistant clones may
improve cancer outcomes. However, to date, there is no universally accepted definition of oligometastasis
with regards to the number of lesions involved. The most accepted number of metastatic lesions is
considered to be 5 or less (with up to 3 metastases in any one organ).

Although surgery and RFA have a longer history of being used in management of oligometastatic disease
involving the liver, there are no trials directly comparing these to SBRT. However, the use of SBRT has been
reinvigorated by a recently published randomized phase II trial (SABR-COMET) which investigated the
use of SBRT in patients with oligometastatic disease (including liver metastases). They compared SBRT to
[5]
standard of care palliative treatment, and showed an overall survival benefit with SBRT .

The role of SBRT in oligometastatic liver disease
Technique
Stereotactic radiosurgery was first applied for intracranial targets, and similar concepts have been adapted
to treat extracranial targets. SBRT involves the use of high doses of radiation delivered to a well-defined
target whilst minimizing radiation to surrounding healthy tissue. The American College of Radiology and
American Society for Radiation Oncology defines SBRT as the use of very large doses of radiation, defined