cancers Review Contralateral Liver Hypertrophy and Oncological Outcome Following Radioembolization with 90Y-Microspheres: A Systematic Review 1, 1, 1 2 2 Emrullah Birgin y, Erik Rasbach y, Steffen Seyfried , Nils Rathmann , Steffen J. Diehl , Stefan O. Schoenberg 2, Christoph Reissfelder 1 and Nuh N. Rahbari 1,* 1 Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; [email protected] (E.B.); [email protected] (E.R.); steff[email protected] (S.S.); [email protected] (C.R.) 2 Institute of Clinical Radiology and Nuclear Medicine, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; [email protected] (N.R.); steff[email protected] (S.J.D.); [email protected] (S.O.S.) * Correspondence: [email protected]; Tel.: +49-621-383-3591 The authors E.B. and E.R. contributed equally to the work. y Received: 5 January 2020; Accepted: 23 January 2020; Published: 27 January 2020 Abstract: Radioembolization with 90Y-microspheres has been reported to induce contralateral liver hypertrophy with simultaneous ipsilateral control of tumor growth. The aim of the present systematic review was to summarize the evidence of contralateral liver hypertrophy and oncological outcome following unilateral treatment with radioembolization. A systematic literature search using the MEDLINE, EMBASE, and Cochrane libraries for studies published between 2008 and 2020 was performed. A total of 16 studies, comprising 602 patients, were included. The median kinetic growth rate per week of the contralateral liver lobe was 0.7% and declined slightly over time. The local tumor control was 84%. Surgical resection after radioembolization was carried out in 109 out of 362 patients (30%). Although the available data suggest that radioembolization prior to major hepatectomy is safe with a promising oncological outcome, the definitive role of radioembolization requires assessment within controlled clinical trials. Keywords: SIRT; selective internal radiation therapy; preconditioning; hepatectomy; neoadjuvant; liver resections 1. Introduction Extended liver resection for primary and secondary hepatic malignancies is dependent on an adequate future liver remnant (FLR) volume [1,2]. Preoperative measures to increase the volume of the FLR are effective in preventing posthepatectomy liver failure in marginally resectable disease, underlying liver cirrhosis, or heavily pretreated patients [3,4]. These interventions include selective occlusion of the contralateral portal venous supply via portal vein ligation or portal vein embolization (PVE) [5]. Portal vein ligation requires a laparoscopy or laparotomy with manipulation of the hepatic hilum that can render a subsequent resection more challenging, whereas PVE can be performed percutaneously with comparable hypertrophy rates [5]. Therefore, PVE has been used at most hepatobiliary units as the primary intervention to increase the FLR. However, tumor progression during the hypertrophy period after PVE has remained an unsolved issue and prevents subsequent hepatectomy in up to 40% of patients [6,7]. An alternative approach to portal vein ligation and PVE is associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Unfortunately, the Cancers 2020, 12, 294; doi:10.3390/cancers12020294 www.mdpi.com/journal/cancers Cancers 2020, 12, 294 2 of 14 results for ALPPS in patients with primary liver malignancies have been disappointing due to high perioperativeCancers 2020 morbidity, 12, x FOR PEER and REVIEW mortality rates [8]. 2 of 15 Recently, there has been increasing interest in radioembolization with 90Y-microspheres (also knownthe asresults selective for ALPPS internal in patients radiation with therapy), primary liver as thismalignancies treatment have off ersbeen local disappointing tumor control due to with simultaneoushigh perioperative hypertrophy morbidity of the and contralateral mortality rates lobe [8]. [9,10]. Radioembolization (RE) is a minimally 90 invasive procedureRecently, there with has transarterial been increasing delivery interest of 90inY-loaded radioembolization microspheres with madeY-microspheres of glass (diameter:(also known as selective internal radiation therapy), as this treatment offers local tumor control with 25 10 µm; activity per particle: 2500 Bq) or resin (diameter: 35 10 µm; activity per particle: ± simultaneous hypertrophy of the contralateral lobe [9,10]. Radioembolization± (RE) is a minimally 50 Bq) [11,12]. The first reports of treatment with 90Y-microspheres dates back to 1965 for patients invasive procedure with transarterial delivery of 90Y-loaded microspheres made of glass (diameter: with25 unresectable ± 10 µm; activity pancreatic per particle: and liver2500 Bq) cancer or resin [13]. (diameter: The concept 35 ± 10 of µm; radioembolization-induced activity per particle: 50 Bq) liver hypertrophy,[11,12]. The also first termed reports as radiationof treatment lobectomy, with 90Y-microspheres was first described dates back in 2008 to 1965 in patients for patients with colorectalwith liverunresectable metastasis, andpancreatic in 2009 and in patients liver cancer with [13]. hepatocellular The concept carcinoma of radioembolization-induced (HCC) [14,15]. liver Sincehypertrophy, then, several also termed cohort as studies radiation have lobectomy, reported the was eff firstectiveness described of RE-induced in 2008 in patients contralateral with liver hypertrophycolorectal in liver predominantly metastasis, and primary in 2009 liver in patients cancer with [16, 17hepatocellular]. Moreover, carcinoma a recent secondary(HCC) [14,15]. analysis of a randomizedSince trial then, revealed several acohort higher studies resectability have reported rate for the patients effectiveness with initiallyof RE-induced unresectable contralateral colorectal liverliver metastasis hypertrophy (CRLM) in whopredominantly received REprimary and chemotherapyliver cancer [16,17]. compared Moreover, to chemotherapy a recent secondary only [18]. analysis of a randomized trial revealed a higher resectability rate for patients with initially Hence, RE seems to be a promising approach for multimodal treatment of primary and secondary liver unresectable colorectal liver metastasis (CRLM) who received RE and chemotherapy compared to malignancies. However, the effective hypertrophy rate and its simultaneous impact on local tumor chemotherapy only [18]. Hence, RE seems to be a promising approach for multimodal treatment of 90 controlprimary remains and unclear. secondary Although liver malignancies. several reviews Howe aboutver, theY-microspheres effective hypertrophy have been rate reported and its in the 90 literaturesimultaneous before, theimpact effectiveness on local tumor of Y-microspherescontrol remains unclear. in liver Although preconditioning several reviews and its about simultaneous 90Y- oncologicalmicrospheres outcome have for been the reported treatment in the of literature primary before, and/or the secondary effectiveness liver of malignancies90Y-microspheres have in liver not been thoroughlypreconditioning assessed and [10, 12its, 16simultaneous,17,19,20]. oncological outcome for the treatment of primary and/or Therefore,secondary liver the malignancies aim of this analysis have not wasbeen to thoroughly summarize assessed the evidence [10,12,16,17,19,20]. of RE as a method to induce contralateralTherefore, liver hypertrophy the aim of this with analysis simultaneous was to summar ipsilateralize the evidence control of of tumor RE as a growth. method to induce contralateral liver hypertrophy with simultaneous ipsilateral control of tumor growth. 2. Results 2. Results A total of 189 studies were identified by the search criteria. Following abstract and full-text A total of 189 studies were identified by the search criteria. Following abstract and full-text screening for eligibility, 173 studies were excluded according to our inclusion criteria. Finally, 16 studies screening for eligibility, 173 studies were excluded according to our inclusion criteria. Finally, 16 remainedstudies eligible remained for eligible inclusion for ininclusion this review in this (Figure review 1().Figure 1). Records identified through Additional records identified database searching through other sources n = 179 n = 10 Identification Records after duplicates removed n = 188 Records excluded n = 56 reviews Screening n = 46 no volumetric analysis Records screened n = 19 case reports n= 188 n = 14 comments/letters n = 1 no abstract Full-text articles excluded Eligibility Full-text articles assessed for n = 34 missing data on eligibility volumetric analysis n = 52 n = 2 less than 5 patients Studies included in quantitative and qualitative Included synthesis n = 16 FigureFigure 1. 1.The The PRISMA flow flow chart. chart. Cancers 2020, 12, 294 3 of 14 2.1. Baseline Characteristics The 16 included studies comprised a total of 602 patients who underwent RE for primary and/or secondary liver malignancies [14,15,21–34]. Patient characteristics and outcomes are summarized in Table1. Table 1. Baseline characteristics of patients in included papers. Sex Underlying Prior MINORS Author Year Pts Age Pathology y (M/F) Liver Disease Therapy Score Cirrhosis: 34 Edeline [21] 2013 34 n/a 29:5 HCC: 34 PHTN: 19 None 10 PVT: 14 HCC: 52 CCC: 4 Cirrhosis: 44 Fernandez-Ros 2014 83 66 61:22 CRLM: 13 PHTN: none CTx: 29 7 [22] NCRLM: PVT: 8 14 Cirrhosis: 17 CTx: 16 HCC: 17 Gaba [15] 2009 20 67 § 16:4