Y90 Radiation Segmentectomy versus Microwave Ablation for Hepatocellular Carcinoma in Locations Suboptimal for Percutaneous Ablation

Purpose The purpose of our study was to evaluate outcomes following percutaneous microwave ablation (MWA) versus yttrium-90 (Y90) radiation segmentectomy (RS) for tumors in suboptimal locations for ablation. Materials and Methods Retrospective review (January 2014 – July 2019) was performed on patients who underwent Y90-RS or MWA (with or without prior transarterial chemo-embolization [TACE]) with curative intent for early-stage hepatocellular carcinoma (HCC) lesions in suboptimal locations for percutaneous ablation, de ﬁ ned as locations in which needleplacementiswithin5 mmofcriticalstructures(liverdome,livercapsule,gallbladder, and hilum). The primary endpoints were treatment response as per the modi ﬁ ed Response Evaluation Criteria in Solid Tumors criteria and complications.


Introduction
2][3] Surgical resection and transplant remain the gold standard for HCC given the high curative potential; for unresectable HCC, locoregional therapies (ablation, transarterial chemoembolization [TACE], radioembolization) can be performed for curative intent, palliation, or bridge to transplant. 2,4Specifically, for patients with Barcelona Classification of Liver Cancer (BCLC) 0 or A, surgical resection or percutaneous ablation are preferred, depending on transplant candidacy and lesion size. 2 Percutaneous ablation offers comparable overall survival to resection for lesions 3 cm while minimizing invasiveness and cost, with microwave ablation (MWA) favored over radiofrequency ablation (RFA) for lesions 4 cm given its ability to achieve better tumor necrosis. 2,5,64][15] Furthermore, recent studies indicate Y90 radiation segmentectomy (Y90-RS) may have comparable outcomes to MWA for early-stage HCC. 6,7,16Herein, we compare the safety and efficacy of Y90-RS and MWA when performed with curative intent for HCC lesions in locations otherwise suboptimal for MWA.

Patient Selection and Inclusion Criteria
Institutional Board Review approval was obtained for this single-center retrospective study of patients who underwent Y90-RS or MWA (AEprior TACE) for HCC with curative intent between January 2014 and July 2019.Treatment decisions for HCC patients at our institution were made with multidisciplinary consensus at a weekly tumor board involving interventional radiology, hepatology, oncology, and transplant surgery.Patients in both groups had lesions in suboptimal locations for percutaneous ablation, defined as lesions within 5 mm of the liver dome, capsule, hilum, or gallbladder; locations where needle placement or achieving sufficient margins may be difficult. 17,18Those with lesions > 3 cm, vascular invasion of the tumor, extrahepatic metastases, portal venous thrombosis, prior resection, or orthotopic liver transplant were excluded.Y90 radioembolization was performed by two interventional radiologists with institutional authorized user status.All other procedures were conducted by one of five interventional radiologists with 1 to 15 years of experience.Y90-RS dosimetry and treatment protocol using glass microspheres TheraSphere (Boston Scientific Corp., Marlborough, Massachusetts, United States) have been previously detailed. 9,16,19,20Dose was calculated using the Medical Internal Radiation Dosimetry dosing model for perused volume.Whole lobar volume was used for dose calculation with a target of 120 Gy and subsequently delivered selectively into the segment. 9Dose to perfused volume was sufficiently higher (> 400 Gy).MWA probes (MicroThermX Varian Medical Systems, Austin, Texas, United States) were placed percutaneously under computed tomography (CT) guidance (AEultrasound [US]) to obtain a 5-to 10-mm circumferential margin.Examples for treatment and follow-up imaging are provided for Y90-RS (►Fig. 1) and MWA (►Fig. 2).
Neither temperature monitoring nor hydrodissection were performed prior to MWA.The tract was coagulated while removing the thermal probe, followed by CT to rule out complications.

Treatment Response and Toxicity Assessment
Follow-up visits and imaging were performed 6 weeks postprocedure and at 3-month intervals thereafter.Tumor response and progression was assessed by independent alanine aminotransferase (ALT) 48.0 AE 32.4, and total bilirubin 2.4 AE 2.7.Of the Y90-RS cohort, 15 were Child-Pugh class A, 4 were B, and 1 was C and pretreatment laboratory values were as follows: MELD-Na 10.5 AE 3.3 (Y90-RS), AFP 762.2 AE 1793.8 (Y90), AST 50.3 AE 30.5 (Y90), ALT 30.1 AE 16.9 (Y90), and total bilirubin 1.6 AE 1.1 (Y90).Complete response rate following Y90 was 96 versus 76% for MWA, with no disease progression after Y90-RS within the follow-up period.Three (13%) lesions demonstrated progression of disease (time to progression 6.3 months) after MWA.No grade > 2 toxicities or procedure-related complications were noted following Y90-RS.There were 7 major (arterioportal fistula with hemoperitoneum, pneumothorax, liver infarction, and capsular burn) and 3 minor complications following MWA.Conclusion Y90-RS is a valuable alternative to percutaneous MWA as a first-line therapy for early-stage HCC for tumors in suboptimal locations for ablation, offering a favorable treatment response and safety profile.
subspecialty trained abdominal radiologists with > 10 years of experience on 3-month follow-up imaging per the modified Response Evaluation Criteria in Solid Tumors algorithm. 21Time to progression (TTP) was recorded for all patients during the study period.Liver function tests and treatment complications were assessed at 1-month postprocedure.Complications were characterized per the Common Terminology Criteria for Adverse Events (CTCAE). 22The threshold for minor laboratory events was grade 3.

Statistical Analysis
Fischer's exact test was performed for categorical variables, and Student's t-tests for nominal variables.The threshold of significance was p < 0.05.All statistical analyses were conducted using SPSS version 25 (IBM, Armonk, New York, United States).

Patient Demographics and Characteristics
Fifty patients with 53 lesions were included; 23 lesions in 20 patients received Y90-RS and 30 lesions in 30 patients received MWA.Baseline demographics and disease characteristics are displayed in ►Table 1.There were no significant differences in demographics between groups (p > 0.05).All patients were Eastern Cooperative Oncology Group performance status 0 to 1.Of the MWA cohort, 19   ).The MWA group had significantly higher pretreatment transaminases (p < 0.05) and the Y90-RS group had significantly larger tumor diameter; mean tumor diameter was 2.9 AE 1.0 in those treated with Y90-RS and 2.3 AE 0.9 for MWA (p < 0.05).Lesions were located adjacent to the following structures: dome (n ¼ 22), capsule (n ¼ 16), hilum (n ¼ 9), and gallbladder (n ¼ 6).There was no difference in the distribution of lesions (►Table 1, p > 0.05).Nineteen (63%) MWA patients were treated in combination with prior conventional TACE.

Discussion
4][25] Recent landmark single-arm studies have demonstrated the efficacy of Y90-RS for unresectable early-stage HCC. 4,6,23The RASER study described the first prospective cohort of very-early to early HCC (mean 2.1 cm) treated with Y90-RS in which 90% of patients achieved CR after one treatment with a median response duration of 635 days. 7Target lesion progression had a cumulative incidence of 4% after 1 year and 12% after 2 years and actuarial overall survival was 96% at 2 years.7][28] Our smaller retrospective cohort shows similar CR rates of 96% with Y90-RS and 77% with MWA AE TACE.Furthermore, disease progression occurred after 23.5 months following Y90-RS and 6.7 months following MWA AE TACE, with a longer TTP following Y90-RS.
There is a paucity of literature directly comparing Y90-RS to percutaneous ablation. 6,7,26Arndt et al evaluated the outcomes of MWA versus Y90-RS in 68 treatment-naive unresectable lesions < 4 cm.Response rates were comparable between treatment groups with 87.5% (MWA) and 88.0% (Y90-RS) achieving CR at 3 months (p ¼ 0.565) as was overall survival (RS 46.1 months, MWA 46.0 months) and adverse events.All clinical and laboratory CTCAE toxicities were grade 3 with no significant difference in laboratory toxicities, although there was a higher incidence of clinical toxicities, that is, ascites (p ¼ 0.048), fatigue (p ¼ 0.028), and abdominal pain (p ¼ 0.035) following Y90-RS.Notably, these differences were eliminated after propensity score matching and progression-free survival was longer following Y90-RS (59.0 vs. 44.3months; p ¼ 0.021).The authors attributed this to Y90-RS achieving negative margins more frequently, corroborating the results in our study. 6Therefore, our difference in CR may be attributed to Y90-RS obtaining better negative margins compared with MWA for lesions that are adjacent to critical structures.
Biederman et al performed a propensity score-matched study in which 121 locoregional treatment-naive patients with lesions 3 cm were treated with Y90-RS or combined TACE/MWA.No statistically significant differences were observed in procedure-related complications (8.9% TACE/MWA vs. 4.9% Y90-RS; p ¼ 0.46), yet major CTCAE clinical toxicities only occurred following TACE/MWA, including pneumothorax (n ¼ 3), TACE access site hematoma (n ¼ 2), biloma (n ¼ 1), and subcapsular hematoma (n ¼ 1).The Y90-RS group experienced two access site hematomas during pretreatment mapping angiography.Grade 3 to 4 elevations in bilirubin and AST occurred infrequently and with similar incidence in both treatment groups.Overall and target lesion CR was comparable regardless of propensity score matching. 16However, in contrast to our study, lesions treated with MWA in this study were in favorable locations.
0][31] Gozzo et al investigated recurrence following percutaneous thermal ablation for 213 patients, where local recurrence occurred in 12.4% at 1 year and 19.7% over the total follow-up period. 32Lesions in suboptimal locations may be more prone to incomplete ablation margins.In our study, 23% of the patients had disease recurrence after MWA, which was not statistically different from that of Y90-RS (17%; p ¼ 0.6), however, there are considerations with respect to assessing response rates.The tumoricidal impact of MWA is mediated by hyperthermal damage resulting in coagulative necrosis, which becomes quickly visible on imaging, whereas radioembolization causes delayed hemorrhagic necrosis and edema, with persistent enhancement of the exposed area.Therefore, follow-up imaging within 3 months may result in underestimation of response, and larger tumors may even require > 6 months to fully appreciate tumor necrosis. 10,20ith respect to safety, our study found Y90-RS to be a comparable treatment strategy compared with MWA for lesions adjacent to critical structures; there were no clinical complications following Y90-RS and a rate of 33% following MWA.A review from 2019 assessed the clinical outcomes and toxicity of 155 cases of Y90-RS, in which only two patients developed radiation-induced liver injury, the most commonly reported side effect was fatigue, and all CTCAE events were grade 3. 33 Similarly, the LEGACY and RASER trials reported grade 3 events in 19.1 and 24.1% of patients, respectively, with the most common being transient fatigue and leukopenia. 7,26Transient laboratory toxicities were the only adverse events noted in our cohort of Y90-RS patients.In contrast, our study showed a higher minor and major complication rate for MWA, with 7 major complications including arterioportal fistula (n ¼ 1), pneumothorax (n ¼ 1), liver infarction (n ¼ 2), capsular burn (n ¼ 1), rectus sheath hematoma (n ¼ 1), and hepatic vasculature injury (n ¼ 1).
Reported complication rates following MWA are between 2.2 and 61.5%, with major complications ranging from 2.6 to 4.6%. 34,357][38] The challenges presented by lesions within 1 cm of critical structures are twofold: (1) critical structures are susceptible to mechanical damage or delayed complications if ablated, and (2) the avoidance of damaging these structures can result in incomplete ablation of the lesion. 39,40uncture-related complications include pneumothorax, pleural effusion, hemothorax, intraperitoneal bleeds, and tumor seeding. 41,42Damage during probe placement can be mitigated by CT and US guidance or by reducing motion artifact with decreased ventilated tidal volume or the Valsalva maneuver. 12,43Cauterization of the intraparenchymal tract reduces the risk of seeding and direct puncture of the tumor can be avoided by creating an overlapping ablation zone with multiple probes. 12,44The endovascular approach of Y90-RS offers a theoretical advantage over percutaneous ablation by eliminating the risk of damage to surrounding structures or tract seeding.
Thermal-related complications include damage to gastrointestinal or biliary structures (e.g., gallbladder perforation, bile duct stenosis, cholecystitis, biloma), liver abscesses, or portal vein thromboses. 41,45Additionally, large caliber vessels can alter the ablation zone away from the vessel, termed heat sink effect, leading to incomplete tumor ablation, although MWA has been shown to be less susceptible to this phenomenon than RFA. 45,46Hydrodissection provides thermal protection by physically separating the lesion from critical structures; it can also reduce heat sink effect by displacing large vessels. 17,18A recent study detailed 66 patients with subcapsular tumors and tumors near critical structures who underwent hydrodissection-assisted MWA; although CR occurred in 91.4%, 3.0% had a major complication (two hepatic abscesses, one biliary injury). 17Additional disadvantages of hydrodissection include fluid overload, diffusion from the injection site, risk of peritoneal seeding, and perihepatic bleeding from forceful dissection. 47,48emperature monitoring can monitor for thermal damage to surrounding structures or achievement of threshold temperature when placed adjacent to the tumor margin. 49In a study of 89 patients with 96 lesions adjacent to the diaphragm, thermal monitoring needles placed between the lesion and diaphragm allowed for temperature control between 50 and 60°C.There was no difference in complete ablation rate (94.8%) when compared with control lesions, although the study group had statistically insignificant, yet higher, incidence of shoulder pain, pleural effusion, nausea, and vomiting. 50Although such adjunct techniques can mitigate MWA complications, they lead to increased procedure time and complexity and are not without inherent risks.
Limitations of this study include its small size, single-center and retrospective design, limited follow-up period, and inconsistent MWA pretreatment with TACE.In addition, this study was not randomized and therefore there is a potential for bias to have been introduced during case selection.A longer followup period (> 3 months) may be beneficial to avoid underestimation of treatment response following Y90-RS.Future studies necessitate a multi-institutional comparison of treatmentnaive lesions with a longer follow-up period.Additionally, comparison using radiology-pathology correlation and an expanded characterization of toxicities will be prudent.The use of TACE prior to MWA has been postulated to increase response rates, however, we did not examine if prior TACE improved efficacy of MWA.Despite its limitations, our study directly compared Y90-RS and MWA for lesions in particular locations, demonstrating comparability in safety and efficacy between the treatment modalities.

Conclusion
Y90-RS is a suitable alternative to MWA as a first-line therapy for early-stage HCC, particularly where regional anatomy presents challenges for percutaneous ablation.Y90-RS offers both a favorable treatment response and an excellent safety profile, supporting its use as an important curative therapy for early-stage HCC.

Ethical Approval Statement
This study was conducted in accordance with ethical standards as defined in the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals guidelines, and approved by the relevant institutional review boards.The protocol (Pro2023002524) for this study was approved by the Institutional Review Board at Rutgers New Jersey Medical School.

Fig. 2
Fig. 2 Example case of microwave ablation (MWA).(A) Pretreatment axial contrast-enhanced computed tomography (CT) demonstrates Liver Imaging Reporting and Data System (LI-RADS) 5 lesion measuring 1.7 Â 1.5 in segment 1 close to the hilum of the liver.(B) Intraprocedural image of MWA probe placement in segment 1 lesion.(C) Follow-up axial contrast-enhanced T1 magnetic resonance imaging (MRI) demonstrating necrosis of the tumor and infarction of the left lobe of the liver.

Table 1
Patient demographics and clinical status before treatment initiation

Table 2
Tumor response and complications Abbreviations: CR, complete response; mRECIST, modified Response Evaluation Criteria in Solid Tumors; MWA, microwave ablation; PD, progressive disease; PR, partial response; SD, stable disease; TACE, transarterial chemoembolization; TTP, time to progression; Y90, yttrium-90.Note: Parenthetical values are percentages unless otherwise indicated.Complications were categorized by the CTCAE (Common Terminology Criteria for Adverse Events) with minor events defined as grades 1-3 and major events as grades 4-5.