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Radiotherapy for Liver Metastases: a Review of Evidence

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Radiotherapy for Liver Metastases: a Review of Evidence Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 3, pp. 1047–1057, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved CME 0360-3016/$ - see front matter doi:10.1016/j.ijrobp.2011.07.020 CRITICAL REVIEW RADIOTHERAPY FOR LIVER METASTASES: A REVIEW OF EVIDENCE y z MORTEN HøYER,PH.D.,* ANAND SWAMINATH, M.D., SEAN BYDDER, B.H.B., M.B.CH.B., x k { MICHAEL LOCK, M.D., ALEJANDRA MENDEZ ROMERO,PH.D., BRIAN KAVANAGH, M.P.H., # y KARYN A. GOODMAN, M.D., PAUL OKUNIEFF, M.D.,** AND LAURA A. DAWSON, M.D. *Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; yRadiation Medicine Program, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada; zRadiation Oncology, Sir Charles Gairdner Hospital, Perth, Australia; xDepartment of Oncology, University of Western Ontario, London, Ontario, Canada; kDepartment of Radiation Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; {Department of Radiation Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO; #Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; and **Department of Radiation Oncology, University of Florida, Gainesville, FL Over the past decade, there has been an increasing use of radiotherapy (RT) for the treatment of liver metastases. Most often, ablative doses are delivered to focal liver metastases with the goal of local control and ultimately im- proving survival. In contrast, low-dose whole-liver RT may be used for the palliation of symptomatic diffuse me- tastases. This review examines the available clinical data for both approaches. The review found that RT is effective both for local ablation of focal liver metastases and for palliation of patients with symptomatic liver metastases. However, there is a lack of a high level of evidence from randomized clinical trials. Ó 2012 Elsevier Inc. Stereotactic body radiation therapy, Conformal radiotherapy, Brachytherapy, Selective internal radiotherapy, Whole liver radiotherapy, Liver metastases. INTRODUCTION Quality Committee of the American Society for Radiation On- cology (ASTRO), in coordination with the Third International The liver is a common site of metastases. In particular, Consensus Conference on Palliative Radiotherapy held at the lung, breast, and gastrointestinal cancers frequently give ASTRO 51st Annual Meeting in 2009. Members were ap- rise to liver metastases, and for some patients, the liver pointed by ASTRO, the European Society for Therapeutic may be the only site of disease. In general, systemic ther- Radiology and Oncology, the Canadian Association of Radia- apy is the preferred therapy for liver metastases. However, tion Oncology, and the Trans Tasman Radiation Oncology selected patients with limited involvement of the liver may Group. be suitable for surgical resection, minimally invasive focal The expert group was commissioned to review the current liter- ablation, or radiotherapy (RT), delivered with the goal of ature and give an overview report on the role of RT for ablation of focal liver metastases, using stereotactic body radiotherapy improving the time to progression and overall survival. (SBRT), conformal radiotherapy (CRT), brachytherapy, and se- In contrast, low-dose whole-liver radiotherapy (WLRT) lected internal radiotherapy (SIRT), and for palliation of symptom- may be delivered to patients with symptoms from diffuse atic liver metastases by WLRT. liver metastases refractory to systemic therapy, with the The review was based on a literature search of Medline with primary goal of reducing symptoms and improving quality the Medical Subject Heading term ‘‘liver metastases’’ com- of life (QL). bined with the key words ‘‘stereotactic body radiation therapy,’’ ‘‘conformal radiation therapy,’’ ‘‘brachytherapy,’’ ‘‘selected in- METHODS AND MATERIALS ternal radiation therapy,’’ ‘‘whole liver radiation therapy,’’ and so on, from January 1990 to July 2010. The Medline search This review was performed by the Liver Metastases Consen- was combined with back tracking based on published reference sus Group, a subcommittee under the Clinical Affairs and lists. Note—An online CME test for this article can be taken at http:// tional Research in Radiation Oncology (CIRRO), and the A.P. astro.org/MOC. Møller and Wife Chastine Maersk McKinney Møllers Founda- Reprint requests to: Morten Høyer, Ph.D., Department of Oncol- tion. L.A.D. has received research grants from Elekta and ogy, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Bayer. Denmark. Tel: +45 89492529; Fax: +45 89492530; E-mail: hoyer@ Received May 1, 2011, and in revised form July 12, 2011. aarhus.rm.dk Accepted for publication July 25, 2011. Conflict of interest: M.H. has received research grants from Varian Medical Systems, the Lundbeck Centre for Interven- 1047 1048 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 3, 2012 RATIONALE FOR FOCAL ABLATIVE, RADICAL- side effects (13, 14). RT is used far less often for the palliation INTENT TREATMENT OF LIVER METASTASES of liver metastases than it is for the palliation of bone, brain, or AND FOR LOW-DOSE WLRT lung metastases, possibly because of an incorrect belief that hepatic irradiation inevitably leads to radiation liver toxicity. Does surgical resection or ablative therapy improve survival in liver metastasis patients? Summary Hellman and Weichselbaum (1) suggested that cancer pro- Historical studies show long-term survival in patients with gression has a multistep nature with a state of oligometastases CRC liver metastases treated with surgical resection or abla- between the stages of purely localized and widely metastatic tion, which would otherwise not be expected, and there is disease. This is supported by retrospective studies showing growing evidence for resection or ablation of non-CRC favorable 5-year survival rates of 25% to 47% in patients metastases. Symptoms from unresectable liver metastases treated with surgical resection for colorectal (CRC) liver may be palliated by WLRT, which appears to bewell tolerated. metastases (2–6). However, there are no randomized studies comparing resection with no resection in patients with ENDPOINTS FOR TREATMENTS OF LIVER potentially resectable liver metastases. Multiple prognostic METASTASES criteria related to survival have been identified, including number of lesions, size, satellite lesions, surgical margins, Which endpoints should be considered for clinical trials of extrahepatic disease, age, preoperative carcinoembryonic RT for liver metastases? antigen (CEA), primary (CRC) tumor stage, and disease- In general, symptom control and quality of life (QL) are free interval between resection of the primary tumor and ap- considered the most valid endpoints to be used in palliative pearance of metastases (2, 4, 5, 7). RT. However, the use of these endpoints alone is not appro- Patients unsuitable for surgical resection for technical or priate for both of two very different scenarios in which RT is medical reasons may be treated by radiofrequency ablation used: (1) tumor ablation with the goal of improving survival (RFA), cryotherapy, laser-induced thermotherapy, and and (2) relief of symptoms. For the former, patients are gen- high-intensity focal ultrasound (8). The EORTC (European erally in a relatively good prognostic group with longer sur- Organisation for Research and Treatment of Cancer) 40004- vival expectancy and usually without local symptoms from CLOCC Phase II trial randomized patients with unresectable metastases. Overall survival and progression-free survival CRC liver metastases to chemotherapy folinic acid, fluoroura- are primary endpoints for these patients, with QL being a sec- cil (5-FU) and oxaliplatin [FOLFOX]) plus bevacizumab and ondary endpoint. In the latter palliative scenario, patients are RFA or to systemic therapy alone (9). Combined therapy was generally nearing the end of life. In these patients symptom associated with improved progression-free survival (17 control and short-term QL are primary endpoints. months vs. 10 months), but the statistical power was low General QL has been assessed by patient-completed ques- and did not allow comparison of survival. An American tionnaires (e.g., EORTC QL-30). Two cancer-specific ques- Society of Clinical Oncology review on RFA for CRC liver tionnaires, the QLQ-LMC21 (http://groups.eortc.be/qol/) metastases found a large variability in 5-year survival rates and the FACT-Hep (http://facit.org), have been developed (14–55%) and local tumor recurrence rates (3.6–60%) (10). for patients with liver metastases from CRC. Side effects of Tumor size of 3 cm or greater or location close to large vessels treatments should be assessed by use of the standard mea- was associated with reduced local control, whereas multiple sures with a particular focus on detecting treatment- and extrahepatic metastases were associated with poor survival. associated liver injury. Surgical resection of non-CRC liver metastases may be considered in selected indolent non-CRC cases. In a large Summary French, multi-institutional, retrospective study, long-term Primary endpoints on trials on ablation of liver metastases outcome was analyzed in 1,452 patients with non-CRC, include survival, progression-free survival, and local control non-neuroendocrine liver metastases. The most common of treated tumors. Primary endpoints for RT delivered with primary sites were breast, gastrointestinal, and urologic. the goal of symptom relief only are symptom control and The
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