Advances in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma☆
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer death.1 Following liver transplant or resection of early-stage HCC, 5-year survival is approximately 50%-70%.2 Unfortunately, only 30% of patients with HCC are suitable for resection or transplant because of poor liver function, poor general condition, or the locally advanced nature of HCC.3 In patients unsuitable for transplant or resection of smaller tumors, ablative therapies such as radiofrequency ablation (RFA) may result in long-term control, with 5-year survival rates of more than 60% for tumors <3 cm, in selected patients.4 Larger HCC and lesions adjacent to major vessels are less well suited for RFA. For patients inappropriate for curative options, some may be candidates for hepatic arterial transarterial chemoembolization (TACE) or drug-eluting beads. Conventional TACE improves survival from 11%-27% to 24%-63% at 2 years,5 and drug-eluting beads may provide additional benefit.6 Sorafenib is another treatment that improves survival from 33% to 44% at 1 year compared to placebo in patients with intact liver function.7
Traditionally, radiotherapy was not considered appropriate for HCC as the whole liver radiation tolerance is lower than the doses required for HCC ablation.8 In addition, HCC most often occurs on a background of liver disease, and there is a fine balance between adequate treatment of the HCC and avoidance of liver toxicity. Modern radiotherapy and imaging, however, permit ablative doses to be delivered to HCC without excessive dose to normal liver. HCC Stereotactic Body Radiation Therapy (SBRT) was first described in 1995 by Blomgren et al.9 Robust target delineation, highly conformal planning, online image guidance, and methods to minimize respiratory motion are required for optimal delivery. Despite often being reserved for patients unsuitable for other treatments, and in whom poor outcomes are expected, studies of SBRT in HCC have demonstrated excellent long-term control. SBRT may be used as a stand-alone treatment for patients unsuitable for standard treatments, and there is interest in its use as an alternative or adjunct to other HCC therapies. Partly owing to a lack of level 1 evidence, SBRT is currently not considered as a standard treatment in most HCC management guidelines.10, 11, 12 This review examines clinical advancements in SBRT for HCC.
Section snippets
Clinical Evidence: Prospective Data
A number of early-phase trials specifically examining SBRT for HCC have been reported, amounting to more than 250 patients and in excess of 350 HCC lesions.13, 14, 15, 16, 17 Key prospective studies are summarized in Table 1 and discussed below.
Mendez Romero et al13 published the first prospective trial in 2006. Eight patients with HCC, with 11 liver lesions measuring up to 7 cm, ineligible for other local treatments, were included. The prescription dose was based on lesion size and presence of
Clinical Evidence: Retrospective Data
Several retrospective series have been published. Those including more than 60 patients are summarized in Table 2. The 2 largest studies are reviewed below.
Sanuki et al,19 in 2013, reported on 185 patients with 185 HCC lesions, all ≤5 cm. Patients were unsuitable for surgery or percutaneous ablative therapies. Planned prescription doses were 40 and 35 Gy for patients with CP A and CP B disease, respectively, in 5 fractions, reduced as necessary to meet constraints. Local control and overall
Summary: Efficacy and Safety of SBRT for HCC
SBRT is effective in HCC, resulting in local control rates of 75%-100% at 1 year, with responses achieved in the majority (Fig.), and long-term survival reported.21 Most patients have CP A disease, and between 1 and 3 lesions,13, 16, 17, 19, 22, 23, 24 often measuring up to 5-7 cm.13, 16, 17, 19, 20, 22, 23, 24 There is more limited experience of SBRT in patients with CP B disease. SBRT has frequently been employed in patients who have failed or are unsuitable for more established therapies. A
Current Questions: The Place of SBRT for HCC
Given the encouraging results in patients with traditionally poor prognosis unsuitable for surgery or other local therapies, questions arise as to the role of SBRT as an alternative or adjunct to standard liver therapies. To date, no randomized evidence exists comparing SBRT to other HCC therapies, and selection bias hampers nonrandomized comparisons. Small retrospective studies have nonetheless attempted to address these questions and are discussed later.
Patient Selection
The most suitable patients with HCC for SBRT have CP A disease. CP B patients have also been successfully treated although toxicity is more frequent, and lower doses should be considered for these patients. Preservation of adequate liver function and avoidance of excessive dose to luminal structures are needed: a threshold volume of uninvolved liver15, 16, 17, 20 (often 700 mL) may be specified, and a minimum distance (eg, 5 mm) between tumors and luminal structures may be mandated.16, 23, 50
Conclusions
SBRT for HCC is effective in early-phase trials and retrospective series, with acceptable toxicity, with long-term survival achieved in a proportion. Caution is required when treating patients with CP B disease. SBRT has been shown to complement existing HCC therapies, but comparative trials are required to better determine the place of SBRT among more recognized HCC treatments.
References (59)
- et al.
Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis
HPB (Oxford)
(2012) - et al.
Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival
Hepatology
(2003) - et al.
Tolerance of normal tissue to therapeutic irradiation
Int J Radiat Oncol Biol Phys
(1991) - et al.
Treatment variables related to liver toxicity in patients with hepatocellular carcinoma, Child-Pugh class A and B enrolled in a phase 1-2 trial of stereotactic body radiation therapy
Pract Radiat Oncol
(2015) - et al.
Outcomes following definitive stereotactic body radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma
Radiother Oncol
(2014) - et al.
Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma
Radiother Oncol
(2015) - et al.
Stereotactic body radiotherapy for patients with unresectable primary hepatocellular carcinoma: Dose-volumetric parameters predicting the hepatic complication
Int J Radiat Oncol Biol Phys
(2010) - et al.
Adjuvant stereotactic body radiotherapy following transarterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of ≥ 3 cm
HPB (Oxford)
(2015) - et al.
Liver transplantation for hepatocellular carcinoma: Analysis of survival according to the intention-to-treat principle and dropout from the waiting list
Liver Transpl
(2002) - et al.
Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: Clinical outcome and pathologic correlation
Int J Radiat Oncol Biol Phys
(2012)
Sorafenib potentiates irradiation effect in hepatocellular carcinoma in vitro and in vivo
Cancer Lett
Phase 1 trial of sorafenib and stereotactic body radiation therapy for hepatocellular carcinoma
Int J Radiat Oncol Biol Phys
Stereotactic body radiation therapy in recurrent hepatocellular carcinoma
Int J Radiat Oncol Biol Phys
Reproducibility of liver position using active breathing coordinator for liver cancer radiotherapy
Int J Radiat Oncol Biol Phys
Potentials and limitations of guiding liver stereotactic body radiation therapy set-up on liver-implanted fiducial markers
Int J Radiat Oncol Biol Phys
Analysis of radiation-induced liver disease using the Lyman NTCP model
Int J Radiat Oncol Biol Phys
Stereotactic body radiation therapy for liver tumors: Impact of daily setup corrections and day-to-day anatomic variations on dose in target and organs at risk
Int J Radiat Oncol Biol Phys
Assessment of residual error in liver position using kV cone-beam computed tomography for liver cancer high-precision radiation therapy
Int J Radiat Oncol Biol Phys
Surgical placement of biologic mesh spacers to displace bowel away from unresectable liver tumors followed by delivery of dose-intense radiation therapy
Pract Radiat Oncol
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int J Cancer
Selection criteria for liver resection in patients with hepatocellular carcinoma and chronic liver disease
World J Gastroenterol
Comparison of hepatic resection and radiofrequency ablation for small hepatocellular carcinoma: a meta-analysis of 16,103 patients
Sci Rep
Doxorubicin-eluting beads versus conventional transarterialchemoembolization for the treatment of hepatocellular carcinoma: A meta-analysis
Int J Clin Exp Med
Sorafenib in advanced hepatocellular carcinoma
N Engl J Med
Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients
Acta Oncol
A report from the Canadian Association for the Study of the Liver Hepatocellular Carcinoma Meeting
Can J Gastroenterol Hepatol
EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma
J Hepatol
Management of hepatocellular carcinoma: An update
Hepatology
Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase I-II study
Acta Oncol
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Conflict of interest: Louise J. Murray reports no conflicts of interest. Laura A. Dawson is on the advisory board for Merc and SIRTEX and has a licensing agreement with Raysearch.