Current status of yttrium-90 microspheres radioembolization in primary and metastatic liver cancer

Liver malignancy,including primary liver cancer and metastatic liver cancer has become one of the most common causes of cancer-related death worldwide due to the high malignant degree and limited systematic treatment strategy.Radioembolization with yttrium-90(^(90)Y)-loaded microspheres is a relatively novel technology that has made significant progress in the local treatment of liver malignancy.The different steps in the extensive work-up of radioembolization for patients with an indication for treatment with^(90)Y microspheres,from patient selection to follow up,both technically and clinically,are discussed in this paper.It describes the application and development of^(90)Y microspheres in the treatment of liver cancer.

Radioembolization with Yttrium-90 microspheres in hepatocellular carcinoma:Role and perspectives

Transarterial radioembolization(TARE) is a form of brachytherapy in which intra-arterially injected yttrium-90-loaded microspheres serve as a source for internal radiation purposes.On the average,it produces disease control rates exceeding 80% and it is a consolidated therapy for hepatocellular carcinoma(HCC);however,current data are all based on retrospective series or non-controlled prospective studies since randomized controlled trials comparing it with the other liver-directed therapies for intermediate and locally advanced stage HCC are still underway.The data available show that TARE provides similar or even better survival rates when compared to transarterial chemoembolization(TACE).First-line TARE is best indicated for both intermediatestage patients(staged according to the barcelona clinic liver cancer staging classification) who have lesions which respond poorly to TACE due to multiple tumors or a large tumor burden,and for locally advanced-stage patients with solitary tumors,and segmental or lobar portal vein tumor thrombosis.In addition,emerging data have suggested the use of TARE in patients who are classified slightly beyond the Milan criteria regarding radical treatment for downstaging purposes.As a secondline treatment,TARE can also be applied in patients progressing to TACE or sorafenib;a large number of phase Ⅱ/Ⅲ trials are ongoing with the purpose of evaluating the best association with systemic therapies.Transarterial radioembolization is very well tolerated and has a low rate of complications which are mainly related to unintended non-target tissue irradiation,including the surrounding liver parenchyma.The complications can be additionally reduced by accurate patient selection and a strict pre-treatment evaluation including dosimetry and assessment of the vascular anatomy.Since a correct treatment algorithm for potential TARE candidates is not clear and standardized,this comprehensive review analyzes the best selection criteria for patients who really benefit from TARE and also the new advances of this therapy,which can be a very important weapon against HCC.

Radiation segmentectomy for hepatic malignancies: Indications, devices,dosimetry, procedure, clinical outcomes, and toxicity of yttrium-90 microspheres

Radiation segmentectomy(RS) is a new approach to90 Y radioembolization that has been designed to increase the safety and efficacy of radioembolization in patients with unresectable hepatic malignancies. With this technique,high doses(>190 Gy) of radiation are delivered to the tumor through radioembolization performed in a segmental fashion, potentially increasing the radiation dose to the tumor while minimizing injury to the liver parenchyma. The aim of this review is to provide a summary of the indications, device choice, dosimetry, procedure, clinical outcomes, and toxicity of RS based on the clinical series currently available.

Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report

Hepatocellular carcinoma (HCC) recurs with a reported frequency of 12%-18% after liver transplantation. Recurrence is associated with a mortality rate exceeding 75%. Approximately one-third of recurrences develop in the transplanted liver and are therefore amenable to local therapy. A variety of treatment modalities have been reported including resection, transarterial chemo- embolization (TACE), radiofrequency ablation (RFA), ethanol ablation, cryoablation, and external beam irradiation. Goals of treatment are tumor control and the minimization of toxic effect to functional parenchyma. Efficacy of treatment is mitigated by the need for ongoing immunosuppression. Yttrium-90 microspheres have been used as a treatment modality both for primary HCC and for pre-transplant management of HCC with promising results. Twenty-two months after liver transplantation for hepatitis C cirrhosis complicated by HCC, a 42-year old man developed recurrence of HCC in his transplant allograft. Treatment of multiple right lobe lesions with anatomic resection and adjuvant chemotherapy was unsuccessful. Multifocal recurrence in the remaining liver allograft was treated with hepatic intra-arterial infusion of yttrium-90 microspheres (SIR-Spheres, Sirtex Medica Inc., Lake Forest, IL, USA). Efficacy was demonstrated by tumor necrosis on imaging and a decrease in alpha-fetoprotein (AFP) level. There were no adverse consequences of initial treatment.

Factors associated with increased incidence of severe toxicities following yttrium-90 resin microspheres in the treatment of hepatic malignancies

AIM: To further define variables associated with increased incidences of severe toxicities following administration of yttrium-90(^(90)Y) microspheres. METHODS: Fifty-eight patients undergoing 79 treatments were retrospectively assessed for development of clinical and laboratory toxicity incidence following ^(90)Y administration. Severe toxicity events were defined using Common Terminology Criteria for Adverse Events version 4.03 and defined as grade ≥ 3. Univariate logistic regression analyses were used to evaluate the effect of different factors on the incidence of severe toxicity events. Multicollinearity was assessed for all factors with P < 0.1 using Pearson correlation matrices. All factors not excluded due to multicollinearity were included in a multivariate logistic regression model for each measurement of severe toxicity.RESULTS: Severe(grade ≥ 3) toxicities occurred following 21.5% of the 79 treatments included in our analysis. The most common severe laboratory toxicities were severe alkaline phosphatase(17.7%), albumin(12.7%), and total bilirubin(10.1%) toxicities. Decreased pre-treatment albumin(OR = 26.2, P = 0.010) and increased pre-treatment international normalized ratio(INR)(OR = 17.7, P = 0.048) were associated with development of severe hepatic toxicity. Increased pre-treatment aspartate aminotransferase(AST; OR = 7.4, P = 0.025) and decreased pre-treatment hemoglobin(OR = 12.5, P = 0.025) were associated with severe albumin toxicity. Increasing pre-treatment model for end-stage liver disease(MELD) score(OR = 1.8, P = 0.033) was associated with severe total bilirubin toxicity. Colorectal adenocarcinoma histology was associated with severe alkaline phosphatase toxicity(OR = 5.4, P = 0.043).CONCLUSION: Clinicians should carefully consider pre-treatment albumin, INR, AST, hemoglobin, MELD, and colorectal histology when choosing appropriate candidates for ^(90) Y microsphere therapy.

钇-90树脂微球选择性内放射治疗后切除肝右叶巨块型肝癌1例

1临床资料患者男,48岁,因“右侧腹痛2年余”入院。入院查体:腹部未扪及包块,肝Murphy征(-)。肝浊音界存在,无肝区和脾区叩击痛,移动性浊音阴性。实验室检查:甲胎蛋白(AFP)66840 ng/m L,白蛋白(ALB)39.7 g/L,乙肝病毒表面抗原(HBs Ag)阴性,丙氨酸转氨酶(ALT)69 U/L,天冬氨酸转氨酶(AST)88 U/L,总胆红素(TBil)23.9μmol/L,余无异常。

Yttrium-90 microsphere selective internal radiation therapy for liver metastases following systemic chemotherapy and surgical resection for metastatic adrenocortical carcinoma

Adrenocortical carcinoma(ACC)is a rare malignancy with generally poor outcomes and limited treatment options.While surgical resection can be curative for early local disease,most patients present with advanced ACC owing to nonspecific symptoms.For those patients,treatment options include systemic chemotherapy and locoregional therapies including radiofrequency ablation and transarterial chemoembolization.We present the first reported case of utilizing yttrium-90 microsphere selective internal radiation therapy(SIRT)in combination with first line EDP-M(Etoposide,Doxorubicin,Cisplatin,Mitotane)chemotherapy and debulking surgical primary tumor resection for treatment of metastatic ACC.Stable complete radiologic response has been maintained after twelve months with resolution of clinical symptoms.These findings prompt the need for further consideration and studies to elucidate the role of SIRT in combination with systemic and surgical treatment for metastatic ACC.

钇⁃90微球放射栓塞联合靶向和免疫治疗后成功肝移植:一例报道并文献复习

目的探讨晚期肝癌经钇⁃90微球放射栓塞(Y90⁃RE)联合靶向和免疫治疗后成功肝移植治疗的临床资料并复习相关文献。方法回顾性分析我中心一例晚期肝癌患者经Y90⁃RE联合靶向和免疫治疗后成功行肝移植治疗,对相关治疗方法及术后病情变化特点进行分析,并总结国内外最新文献进展。结果患者为41岁中年男性,经Y90⁃RE联合靶免治疗后行肝移植术,围手术期予人免疫球蛋白冲击治疗,术后早期予他克莫司+糖皮质激素联合免疫抑制方案。患者术后2周内肝功能逐渐好转后,在术后第15天和第68天出现转氨酶轻度升高,肝穿刺病理提示轻度急性排斥反应,均通过予加强免疫抑制治疗后好转。现随访6月余,肝功能正常,未见肿瘤复发。结论Y90⁃RE联合靶免治疗可为晚期肝癌患者提供一种治疗选择方案。

Effects of Yttrium-90 selective internal radiation therapy on non-conventional liver tumors

The liver is a common site of metastasis, with essentially all metastatic malignancies having been known to spread to the liver. Nearly half of all patients with extrahepatic primary cancer have hepatic metastases. The severe prognostic implications of hepatic metastases have made surgical resection an important first line treatment in management. However, limitations such as the presence of extrahepatic spread or poor functional hepatic reserve exclude the majority of patients as surgical candidates, leaving chemotherapy and locoregional therapies as next best options. Selective internal radiation therapy(SIRT) is a form of catheter-based locoregional cancer treatment modality for unresectable tumors, involving trans-arterial injection of microspheres embedded with a radioisotope Yttrium-90. The therapeutic radiation dose is selectively delivered as the microspheres permanently embed themselves within the tumor vascular bed. Use of SIRT has been conventionally aimed at treating primary hepatic tumors(hepatocellular carcinoma) or colorectal and neuroendocrine metastases. Numerous reviews are available for these tumor types. However, little is known or reviewed on non-colorectal or nonneuroendocrine primaries. Therefore, the aim of this paper is to systematically review the current literature to evaluate the effects of Yttrium-90 radioembolization on non-conventional liver tumors including those secondary to breast cancer, cholangiocarcinoma, ocular and percutaneous melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

Yttrium-90 radioembolization for unresectable hepatic metastases of breast cancer: A systematic review

BACKGROUND Liver metastases secondary to breast cancer are associated with unfavourable prognosis.Radioembolization with ytrrium-90 is an emerging option for management of liver metastases of breast cancer when other systemic therapies have failed to achieve disease control.However,unlike the case of other liver tumours(colorectal/melanoma metastases/cholangiocarcinoma),its role in the management of breast liver metastases is yet to be elucidated.AIM The aims of this systematic review were to(1)assess the effect of radioembolization with yttrium-90 on tumour response;and(2)to estimate patient survival post radioembolization.METHODS The review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.A systematic literature search was performed using the PubMed and EMBASE databases from January 2007 to December 2018.The initial search yielded 265 reports which were potentially suitable for inclusion in this review.Studies published in English reporting at least one outcome of interest were considered to be suitable for inclusion.Conference abstracts;case reports,animal studies and reports not published in English were excluded from this review.Data was retrieved from each individual report on the name of primary author,year of publication,patient demographics,type of microspheres used,radiation dose delivered to tumour,duration of follow-up,disease control rate(%),tumour response,and overall patient survival.RESULTS The final number of studies which met the inclusion criteria was 12 involving 452 patients.There were no randomized controlled trials identified after the literature search.The age of the patients included in this review ranged from 52 to 61 years.The duration of the follow up period post-radioembolization ranged from 6 to 15.7 mo.The total number of patients with breast metastases not confined to the liver was 236(52.2%).Cumulative analysis revealed that radioembolization with yttrium-90 conferred tumour control rate in 81%of patients.Overall survival post-radioembolization ranged from 3.6 to 20.9 mo with an estimated mean survival of 11.3 mo.CONCLUSION Radioembolization with ytrrium-90 appears to confer control of tumour growth rate in most patients,however its effect on patient survival need to be elucidated further.Furthermore,quality evidence in the form of randomized trials is needed in order to assess the effect of radioembolization in more depth.

Same day yttrium-90 radioembolization with single photon emission computed tomography/computed tomography: An opportunity to improve care during the COVID-19 pandemic and beyond

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has made it more challenging for patients to undergo yttrium-90(Y-90)radioembolization(RE).Same day Y-90 RE provides an opportunity to minimize logistical challenges and infection risk associated with COVID-19,thus improving patient access.AIM To describe the use of same day Y-90 RE with routine single photon emission computed tomography/computed tomography(SPECT/CT)in order to optimize therapy.METHODS All patients were selected for Y-90 RE through a multidisciplinary tumor board,and were screened and tested for COVID-19 infection per institutional protocol.A same day procedure was developed,consisting of angiography,imaging,and Y-90 resin particle delivery.Routine SPECT/CT after technetium-99m macroaggregated albumin(Tc-99m MAA)administration was performed for assessment of arterial supply,personalized dosimetry,and extrahepatic activity.Post-treatment Y-90 bremsstrahlung SPECT/CT was performed for confirmation of particle delivery,by utilization of energy windowing to limit signal from previously administered Tc-99m MAA particles.RESULTS A total of 14 patients underwent same day Y-90 RE between March and June 2020.Mean lung shunt fraction was 6.13%(range 3.5%-13.1%).Y-90 RE was performed for a single lesion in 7 patients,while the remaining 7 patients had treatment of multifocal lesions.The largest lesion measured 8.3 cm.All patients tolerated the procedure well and were discharged the same day.CONCLUSION Same day Y-90 RE with resin-based microspheres is feasible,and provides an opportunity to mitigate infection risk and logistical challenges associated with the COVID-19 pandemic and beyond.We recommend consideration of SPECT/CT,especially among patients with complex malignancies,for the potential to improve outcomes and eligibility of patients to undergo same day Y-90 RE.

钇90微球放射栓塞治疗肝脏恶性肿瘤研究的全球现状与发展趋势:一项文献计量学分析

目的:通过文献计量学分析探讨钇90微球放射栓塞治疗肝脏恶性肿瘤研究的全球现状与发展趋势。方法:以Web of Science数据库中1991-2021年收录的钇90微球放射栓塞治疗肝脏恶性肿瘤相关文献为对象,应用VOS viewer软件对国家、机构、作者、期刊、关键词进行文献计量学分析,并绘制可视化的合作关系网络图谱。结果:根据检索策略和筛选标准,共989篇钇90微球放射栓塞治疗肝脏恶性肿瘤的相关文献纳入本研究,来自47个国家1055个机构4406名研究人员参与其中。该领域发表文献数量整体呈明显上升趋势,2021年达到峰值。美国在国家合作和发表文献数量上占据主导地位。在机构中,美国的西北大学发表文献数量最多,西班牙的纳瓦拉大学和美国的华盛顿大学次之。发表文献数量和总被引频次前3位的作者分别是Salem R、Lewandowski RJ和Mulcahy MF。Journal of Vascular and Interventional Radiology等期刊在推动该领域发展中发挥了重要作用。出现频次最高的10个关键词是放射栓塞、肝细胞癌、钇90、钇90微球、生存、癌症、肝转移、微球、选择性内放射治疗和内放射治疗。结论:目前钇90微球放射栓塞治疗肝脏恶性肿瘤是重要研究热点之一,中国的研究人员不仅需要关注该领域的前沿研究,还应积极开展多中心临床研究项目。

Neutron-activated biodegradable samarium-153 acetylacetonate-poly-L-lactic acid microspheres for intraarterial radioembolization of hepatic tumors

BACKGROUND Liver cancer is the 6 th most common cancer in the world and the 4 th most common death from cancer worldwide.Hepatic radioembolization is a minimally invasive treatment involving intraarterial administration of radioembolic microspheres.AIM To develop a neutron-activated,biodegradable and theranostics samarium-153 acetylacetonate(153SmAcAc)-poly-L-lactic acid(PLLA)microsphere for intraarterial radioembolization of hepatic tumors.METHODS Microspheres with different concentrations of 152SmAcAc(i.e.,100%,150%,175%and 200%w/w)were prepared by solvent evaporation method.The microspheres were then activated using a nuclear reactor in a neutron flux of 2×10^12n/cm^2/s^1,converting 152Sm to Samarium-153(153)Sm)via 152Sm(n,γ) 153Sm reaction.The SmAcAc-PLLA microspheres before and after neutron activation were characterized using scanning electron microscope,energy dispersive X-ray spectroscopy,particle size analysis,Fourier transform infrared spectroscopy,thermo-gravimetric analysis and gamma spectroscopy.The in-vitro radiolabeling efficiency was also tested in both 0.9% sodium chloride solution and human blood plasma over a duration of 550 h.RESULTS The SmAcAc-PLLA microspheres with different SmAcAc contents remained spherical before and after neutron activation.The mean diameter of the microspheres was about 35μm.Specific activity achieved for 153SmAcAc-PLLA microspheres with 100%,150%,175%and 200%(w/w)SmAcAc after 3 h neutron activation were 1.7±0.05,2.5±0.05,2.7±0.07,and 2.8±0.09 GBq/g,respectively.The activity of per microspheres were determined as 48.36±1.33,74.10±1.65,97.87±2.48,and 109.83±3.71 Bq for 153SmAcAc-PLLA microspheres with 100%,150%,175%and 200%(w/w)SmAcAc.The energy dispersive X-ray and gamma spectrometry showed that no elemental and radioactive impurities present in the microspheres after neutron activation.Retention efficiency of 153Sm in the SmAcAc-PLLA microspheres was excellent(approximately 99%)in both 0.9%sodium chloride solution and human blood plasma over a duration of 550 h.CONCLUSION The 153SmAcAc-PLLA microsphere is potentially useful for hepatic radioembolization due to their biodegradability,favorable physicochemical characteristics and excellent radiolabeling efficiency.The synthesis of the formulation does not involve ionizing radiation and hence reducing the complication and cost of production.

钇-90微球治疗不可切除或复发性肝内胆管癌的应用进展

肝内胆管癌作为一种进展快速的恶性肿瘤,只有少数患者可以行根治性切除术,并且姑息性治疗方案大多疗效有限。钇-90经动脉放射性栓塞是在传统的经导管动脉化疗栓塞术的基础上结合肿瘤近程精准放射治疗技术衍生而来一种新型治疗手段。钇-90经动脉放射性栓塞是经微创切口利用导管将钇-90微球定向、足量投放于目标位置进行选择性内照射治疗。该治疗方法不仅可以有效延长患者生存期、提高患者生存率,而且可以显著降低肿瘤分期,实现降期、转化的功效,创造潜在手术机会,改善患者的远期预后,是一种安全的治疗方法,其并发症及不良反应均小于全身化学治疗和经导管动脉化疗栓塞术治疗。钇-90微球放射性栓塞治疗为不可切除或复发性肝内胆管癌患者提供了治疗选择。

关于钇-90树脂微球核素治疗中的辐射防护研究

本文以钇-90核素体内放射治疗新方法为例,梳理分析其涉源环节,将DSA机房外辐射剂量的实际辐射监测结果与钇-90核素注入过程中所致DSA机房外辐射剂量估算结果叠加,数据表明注入过程中DSA机房屏蔽体外辐射剂量率可以满足相应的限值要求。同时对近台操作医生操作位辐射剂量率进行估算,并以典型钇-90核素体内放射治疗方案为例,选取常见的曝光时间和注入时间,对职业人员和公众的年有效剂量进行估算,结果显示可以满足《电离辐射防护与辐射源安全基本标准》(GB 18871-2002)中规定的剂量约束值要求和管理限值,上述分析方法和结果可为同类项目辐射环境影响评价提供技术参考。

Poly(Vinyl Alcohol)/Collagen/Hydroxyapatite Nanoparticles Hybrid System Containing Yttrium-90 as a Potential Agent to Treat Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumors, affecting mostly children, adolescents and young adults. This is an aggressive tumor that results in a high mortality rate and poor prognosis. Due to the low sensitivity of osteosarcoma to ionizing radiation, such treatment is not used very often and it can be recommended only to postsurgical therapy. As an alternative therapy, functionalized nanomaterials allow their accumulation in tumor tissues due to their unique properties, making them good agents to act as stable carriers for radionuclides. In this work, mesoporous hydroxyapatite nanoparticles were synthesized and the functionalization process with poly(vinyl alcohol) and collagen was investigated. The samples were characterized by X-ray diffraction (XRD), N2 adsorption, elemental analysis (CHN), Fourier Transform Infrared Spectroscopy (FTIR), Nitrogen Adsorption, Transmission Electron Microscopy (TEM), and Thermal Analysis. Also, the yttrium incorporation potential and its release kinetics in the hydroxyapatite matrix were evaluated to study the capacity of this system to treat osteosarcomas. The results indicate that this material has a promisor potential to treat this kind of tumor.

某医院钇90应用核医学科改建辐射防护探讨

文章通过某医院钇90微球治疗应用的核医学科改造项目,根据该应用的主要特点,对其放射性工作场所的平面布局、人员流动、辐射防护等方面的设计进行分析,并总结一些案例经验,为其他医疗机构建设该类科室提供参考。

钇-90微球的特性、放射栓塞的操作技术及安全防护——钇-90微球放射栓塞系列回顾(一)

钇-90(90Y)微球放射栓塞是一种局部治疗方法 ,它将载有发射β射线的90Y树脂或玻璃微球选择性地注射到肝动脉。90Y微球随血流被阻塞在肿瘤血管床,其发出的射线对靶肿瘤具有细胞毒性作用。该方法的安全性和有效性已经在不可切除的肝脏恶性肿瘤患者中得到证实。本文作为90Y微球放射栓塞系列综述的第一部分,将讨论90Y和90Y微球的基本特性,90Y微球放射栓塞的基本操作方法 ,以及放射性安全与防护。

^(90)Y微球选择性内放射治疗在肝细胞癌中的应用及研究进展

肝细胞癌(hepatocellular carcinoma,HCC)是中国癌症相关死亡第二大常见原因。中国约85%的HCC患者在确诊时已是中晚期,系统治疗(包括化疗、靶向治疗、免疫治疗)联合局部微创治疗(如介入治疗、放射治疗等)是目前主要的治疗方式。钇-90(yttrium-90,^(90)Y)微球选择性内放射治疗(selective internal radiation therapy,SIRT)作为主要局部微创治疗手段在国外已有近20年的临床使用经验,临床研究证明了其治疗肝脏肿瘤的疗效和安全性。相关研究证实了^(90)Y微球SIRT单用在HCC中的局部控制作用,以及其与手术、免疫药物、靶向药物联用的有效性及安全性,同时,^(90)Y微球SIRT对于肝段产生的“放射性切除”效应初步显示出其在HCC根治性治疗方面的应用前景。从HCC姑息治疗、转化治疗、放射性肝段切除等方面综述SIRT在HCC中的应用及研究进展。

钇-90微球放疗栓塞在原发性肝癌治疗中的应用

原发性肝癌是常见的恶性肿瘤,其治疗效果特别是中晚期肝癌的治疗效果仍不理想。钇-90放射微球放疗栓塞是一种综合了介入治疗与局部放疗的新兴非手术治疗技术,能高选择性地将具有肿瘤杀伤效应剂量的放射微球打入癌组织,而对正常组织影响较小。前期临床研究显示其在内放射肝段/叶切除、肝移植前过渡/降级治疗、肝切除后肝癌复发和中晚期肿瘤的姑息治疗等方面具有广阔的前景,该治疗方式日益得到人们关注。本文简要介绍钇-90微球放疗栓塞的原理及特点,并将其在原发性肝癌治疗中的应用予以综述。