Implementing combined approach with radiotherapy in surgical strategy for advanced HCC

Jinsil SEONG 한국간담췌외과학회 2022 Annals of hepato-biliary-pancreatic surgery Vol.26 No.-

Optimizing Therapeutic Efficacy with Systemic Therapy & Radiotherapy in Hepatocellular Carcinoma

( Jinsil Seong ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

For most solid cancers, multimodality treatment is a general principle particularly for locally advanced ones while single modality reserved for early cancers. However, this notion hasn’t been well reflected in current therapeutic guidelines for hepatocellular carcinoma (HCC), which show a single modality as a standard of care for each stage of HCC. HCC shows significant heterogeneity particularly in advanced stage. Although current guidelines recommend systemic agent as a standard of care, efficacy has been limited with gaining only a few months of survival. Recent studies on phylogenetic analysis reported that sorafenib-targeted genetic alteration was identified in only limited case, explaining why response was less than satisfactory. It also suggests that combination strategy needs to be adopted particularly in advanced HCC. Applying a single agent to a disease with extreme heterogeneity can hardly produce therapeutic success, warranting subclassification of the disease and optimal therapy accordingly. Advanced HCC needs to be classified into 2 catogories; advanced but confined to liver and advanced to beyond liver. In advanced HCC confined to liver, combination strategy may involve maximizing local control by local modality as well as systemic agent preventing tumor spread either intrahepatically or extrahepatically. Our group has long been practicing local radiotherapy concurrently with hepatic arterial chemotherapy (liver-directed CCRT) followed by adjuvant hepatic arterial chemotherapy for substantial period. More recently we reported a phase 2 trial results of liver-directed CCRT followed by sorafenib. The result was quite encouraging with 24.6 months of median survival time, which corresponds to double the time in those with sorafenib alone. The beauty of this approach is that 19% of the patients underwent curative surgery by tumor downsizing/downstaging. In advanced HCC beyond liver, systemic therapy is a mainstay without any argument. Now, a concept discriminating oligometastasis from full metastasis has been proposed, which has been well established in most solid cancers. While systemic therapy is undergoing, local treatment, either radiotherapy or surgery, can effectively control oligometastasis that can result in prolonged overall survival. Taken together, systemic therapy and radiotherapy can be combined in various scenario, ultimately aiming at improved therapeutic efficacy in advanced Hepatocellular Carcinoma.

A multicenter retrospective cohort study of practice patterns and clinical outcome on radiotherapy for hepatocellular carcinoma in Korea

Seong, Jinsil,Lee, Ik Jae,Shim, Su Jung,Lim, Do Hoon,Kim, Tae Hyun,Kim, Jong Hoon,Jang, Hong Seok,Kim, Mi Sook,Chie, Eui Kyu,Kim, Jin Hee,Nam, Taek-Keun,Lee, Hyung Sik,Han, Chul Joo Blackwell Publishing Ltd 2009 Liver International Vol.29 No.2

<P>Abstract</P><P>Aim</P><P>To determine the national practice processes of care and outcomes of radiotherapy for hepatocellular carcinoma (HCC) in Korea.</P><P>Patients and Methods</P><P>A national survey of 53 institutions nationwide was conducted by requesting data on their experience of radiotherapy for HCC. Among them, 10 institutions were selected for performing more detailed analysis, based on the radiotherapy experience of at least five HCC patients between 2004 and 2005.</P><P>Results</P><P>This study covered the treatment of 398 HCC patients for 2 years. Most patients (78%) were in stage III or IV. Radiotherapy was chosen after the failure of other treatments, most frequently transarterial chemoembolization. Radiotherapy was performed predominantly using the three-dimensional conformal technique (3D-CRT, 81.9%) mostly with a total dose of ≥45 Gy. In 9.3% of the patients, radiotherapy was performed using radiosurgery. In a biologically effective dose (BED) with 10 Gy of α/β, 4.2–124.3 Gy<SUB>10</SUB> was delivered. The median survival time was 12 months, and the 2-year overall survival rate was 27.9%. A tumour size <5 cm, a negative lymph node and BED >53.1 Gy<SUB>10</SUB> were shown by multivariate analysis to be significant factors for a better prognosis. In a subset analysis for the 326 patients treated with 3D-CRT, better liver function with Child–Pugh class A was shown to be an additional factor for a better prognosis.</P><P>Conclusions</P><P>Radiotherapy has been used to treat advanced HCC in various modes, but mostly as a salvage treatment. Although this study was retrospective, it indicates that radiotherapy is a quite effective modality for HCC patients.</P>

Overview of Technical Advance in Radiation Therapy of HCC

Jinsil Seong 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

Liver-Directed CCRT for Locally Advanced Hepatocellular Carcinoma

( Jinsil Seong ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

According to the staging system of hepatocellular carcinoma (HCC), advanced stage involves a group of diseases with either portal vein invasion (PVI) or metastases. Despite the wide scope of advanced HCC, sorafenib is recommended as an only treatment in BCLC guideline. This notion has thrown many debates particularly on the treatment for advanced but liver confined HCC as shown in recent publications reporting a pattern of care of HCC in Asia as well as survival benefit of surgical resection for HCC with PVI in Japan. In our institute, liver-directed concurrent chemoradiotherapy (CCRT) has long been performed, combining local radiotherapy (RT) with concurrent hepatic arterial infusion chemotherapy (HAIC) of 5-Fu followed by monthly HAIC no longer than 6 months. Liver-directed CCRT CCRT was designed not only to maximize local antitumor effect through interaction between chemotherapy and radiotherapy but also to minimize intrahepatic metastasis through HAIC in the patients with major vascular invasion (MVI), mostly portal vein in major or the first branch. Following the first pilot study reporting a median survival time of 13 months, CCRT has been applied to the most HCC patients with MVI. Improved survival was observed in a recent study comparing CCRT to non-CCRT RT group by propensity score matching analysis (11.4 vs. 6.6 months of median survival time, p<0.007). CCRT has also given a chance for cure by converting to resectable condition and allowing R0 resection in some patients (16.9%). However, this approach lacks of systemic treatment component. Hence we modified CCRT scheme by replacing HAIC to sorafenib and performed a prospective study. Interim result seems quite promising with increased median survival time. Further details will be discussed.

Identification of Proteins that Regulate Radiation-induced Apoptosis in Murine Tumors with Wild Type p53

SEONG, Jinsil,OH, Hae Jin,KIM, Jiyoung,AN, Jeung Hee,KIM, Wonwoo Journal of Radiation Research Editorial Committee 2007 JOURNAL OF RADIATION RESEARCH Vol.48 No.5

<P>In this study, we investigated the molecular factors determining the induction of apoptosis by radiation. Two murine tumors syngeneic to C3H/HeJ mice were used: an ovarian carcinoma OCa-I, and a hepatocarcinoma HCa-I. Both have wild type p53, but display distinctly different radiosensitivity in terms of specific growth delay (12.7 d in OCa-I and 0.3 d in HCa-I) and tumor cure dose 50% (52.6 Gy in OCa-I and > 80 Gy in HCa-I). Eight-mm tumors on the thighs of mice were irradiated with 25 Gy and tumor samples were collected at regular time intervals after irradiation. The peak levels of apoptosis were 16.1 ± 0.6% in OCa-I and 0.2 ± 0.0% in HCa-I at 4 h after radiation, and this time point was used for subsequent proteomics analysis. Protein spots were identified by peptide mass fingerprinting with a focus on those related to apoptosis. In OCa-I tumors, radiation increased the expression of cytochrome c oxidase and Bcl2/adenovirus E1B-interacting 2 (Nip 2) protein higher than 3-fold. However in HCa-I, these two proteins showed no significant change. The results suggest that radiosensitivity in tumors with wild type p53 is regulated by a complex mechanism. Furthermore, these proteins could be molecular targets for a novel therapeutic strategy involving the regulation of radiosensitivity.</P>

Adaptive response to ionizing radiation induced by low dose of gamma ray in human hepatoma cell lines

Seong, Jinsil,Kim, Gwi Eon Yonsei University, College of Medicine 1994 Yonsei medical journal Vol.35 No.1

마우스 종양에서 저선량 방사선이 Apoptosis의 유도에 미치는 영향

성진실(Jinsil Seong),표홍렬(Hong Ryull Pyo),정은지(Eun Ji Chung),김성희(Sung Hee Kim),서창옥(Chang Ok Suh) 대한방사선종양학회 1999 Radiation Oncology Journal Vol.17 No.4

목 적 : 방사선에 의한 apoptosis 유도에 저선량 방사선이 미치는 영향을 관찰하여 adaptive response 현상이 관계되는지를 마우스 종양에서 분석하고 관련되는 기전에 관하여 연구하고자 하였다. 대상 및 방법 : 마우스 동종암인 HCa-I, OCa-I에서 저선량 (0.05 Gy) 방사선 조사 후 고선량 (25 Gy)을 조사하여 이로부터 일정시간 후 종양에서 유도된 apoptosis 수준을 비교분석하였다. 또한, apoptosis의 조절 물질인 p53, Bcl-2, Bax, Bcl-X 등의 발현을 Western blotting으로 분석하여 관련된 기전을 연구하였다. 결 과 : OCa-I에서 0.05 Gy 를 전처치 후에 25 Gy 를 조사한 군에서 apoptosis의 유도 수준은 세포 1000개당 229로서 예상되는 값인 324 에 비하면 약 30%정도 감소된 결과로 나타나서( p<0.05) 저선량의 방사선에 의하여 apoptosis의 유도 수준이 감소한 것으로 나타났다. 반면 HCa-I에서는 예상된 apoptosis수준과 실제 관찰치간에 변화가 없었다. 유전물질의 발현에서 p53은 두 종양 공히 0.05 Gy 조사군, 25 Gy 조사군 및 0.05+25 Gy 조사군에서 발현이 증가되었다. Bcl-2와 Bax는 두 종양 모두 발현 수준의 등락이 현저하지는 않았으나 OCa-I의 0.05+25 Gy 조사군에서 Bcl-2의 발현이 Bax 를 상회하는 결과를 보였다. Bcl-X는 HCa-I에서 0.05 Gy 정도의 저선량에서부터 높은 상승을 보인 반면, OCa-I에서는 전혀 발현되지 않았다. 결 론 : 마우스 종양의 일부에서 0.05 Gy 의 저선량이 고선량 방사선에 의한 apoptosis 유도에 대하여 adaptive response를 보이는 것으로 나타났다. 이는 Bcl-2, Bax의 발현 수준과 Bcl-X 등이 관련되는 것으로 보였다. 본 연구는 방사선에 의한 apoptosis에서 adaptive response의 관련성이 일정치 않다는 것을 마우스 종양에서 보여주었다. Purpose : To investigate the presence of adaptive response by low dose radiation in murine tumors in relation to radiation induced apoptosis as well as related mechanism. Materials and Methods : Syngeneic murine tumors, OCa -I and HCa-I, were given 0.05 Gy pretreatment followed by therapeutic dose of 25 Gy radiation. Induction of apoptosis was analyzed for each treatment group. Regulating molecules of apoptosis, p53, Bcl-2, Bax, Bcl-X, were also analyzed by Western blotting. Results : In 0.05 Gy pretreatment group of OCa -I, 25 Gy -induced apoptosis per 1000 cells was 229, which was estimated at 30% lower level than the expected ( p<0.05). In contrast, this reduction in radiation induced apoptosis was not seen in HCa-I. In the expression of apoptosis regulating molecules, p53 increased in both tumors in response to radiation. Bcl-2 and Bax did not show significant change in both tumors however, the expression of Bcl-2 surpassed that of Bax in 0.05 Gy pretreatment group of OCa -I. Bcl - X was not expressed in OCa -I. In HCa -I, Bcl-X showed increased expression even with 0.05 Gy. Conclusion : Adaptive response by low dose radiation is shown in one murine tumor, OCa -I, in relation to radiation induced apoptosis. Apoptosis regulating molecules including Bcl -2/Bax and Bcl-X, appear to related. This study shows an evidence that adaptive response is present, but not a generalized phenomenon in vivo.

방사선의 항암작용에 대한 재조합 TNF-α의 효과

성진실(Jinsil Seong),신항철(Hang Chul Shin),김귀언(Gwi Eon Kim),서창옥(Chang Ok Suh) 대한방사선종양학회 1998 Radiation Oncology Journal Vol.16 No.3

목 적 : 마우스 동종암에 TNF-α와 방사선을 병용하여 방사선의 항암 효과가 TNF-α에 의하여 증강될 수 있는지 연구하고자 하였다. 대상 및 방법 : C3Hf/HeJ 마우스에 유방암인 MCa-K, MCa-4, 난소암인 OCa- I, 그리고 간암인 HCa- I 등 종양을 이식하였다. 종양의 크기가 6 mm에 이를 때 TNF-α, 방사선, 또는 병용군 등 실험군을 나누어 적절한 치료를 하였다. 방사선조사는 Cobalt-60 방사선 조사기를 이용하여 HCa- I 에는 30 Gy를, 나머지 종양에는 15 Gy를 단일 조사하였다. TNF-α는 실험실 마우스당 하루 10 μg씩 7일간 연속 주사하였다. 치료 결과는 종양성장지연 분석법으로 평가하였다. 결 과 : TNF-α 단독 투여시 네가지 종양 중 MCa-K 및 OCa- I 종양에서 absolute growth delay(AGD)가 각각 5.0일, 6.5일로 유의한 항암 효과가 있었다. TNF-α와 방사선을 병용한 경우 OCa- I에서는 AGD가 TNF-α 단독의 6.5일, 방사선의 26.9일에 비하여 TNF-α와 방사선 병용시 41.1일로 의의있게 증가하였다 (p<0.05). EF는 1이상으로서 (EF: 1.29) TNF-α와 방사선 병용시 증강효과가 있는 것으로 나타났다. 나머지 세 종양에서는 TNF-α 단독 및 방사선 단독에 비하여 TNF-α와 방사선 병용시 AGD의 유의한 증가는 관찰되지 않았다. 결 론 : TNF-α는 마우스 동종암 중 일부 종양 (MCa-K 및 OCa- I)에서 항암 효과를 보였다. 방사선과 병용한 경우에도 일부 종양에서만 (OCa- I) 방사선의 항암 효과를 증강시키는 것으로 나타났다. 이같이 종양에 따라 방사선과 TNF-α의 병용치료 효과의 정도가 다르다는 점은 향 후 임상적 적용에 대비한 유용한 기초자료로 쓰일 것으로 기대된다. Purpose : To determine whether TNF-α increases the antitumor effect of radiotherapy in murine syngeneic tumor system. Materials and Methods : Syngeneic murine tumors of MCa-K or MCa-4 (mammary carcinoma), OCa-I (ovarian carcinoma), or HCa-I(hepatocarcinoma were grown in hind legs of C3Hf/HeJ mice. When tumors were grown to 6 mm in mean diameter, mice were treated with TNF-α, radiation, or combination of the both. Gamma-radiation was given as a single dose of 30 Gy for HCa-I and 15 Gy for other tumors using Cobalt-60 teletherapy unit. A novel TNF-α mutein developed in Korea, was intraperitoneally administered daily at a dose of 10 μg per mouse for 7 days. In combination of radiation and TNF-α, the drug was started 1 hour after radiation. Tumor growth delay assay was used to measure the tumor response to the treatment. Results : Among 4 tested tumors, TNF-α alone showed significant antitumor activity in MCa-K and OCa-I tumors, which showed absolute growth delay (AGD) of 5.0 days and 6.5 days, respectively. In combination with radiation, TNF-α showed significant delay of AGD (41.1 days) in OCA-I compared to AGDs of TNF-α alone and radiation, i.e., 6.5 days and 26.9 days, respectively(p<0.05). Enhancement factor was 1.29 in OCa- I, which showed supraadditive effect. TNF-α did not show significant delay of AGDs in the remaining 3 tumors compared to AGDs of TNF-α alone and radiation. Conclusions: TNF-α alone showed antitumor effects in MCa-K and OCa-I. In combination with radiation, TNF-α acted in supraadditive way in OCa-I only. The results of this study imply that the combination of TNF-α and radiation has different therapeutic potential depending on tumor model and further study is advocated.

절제불가능 원발성 간암에서 경간동맥 항암 색전술과 국소 방사선의 병용요법

성진실(Jinsil Seong),금기창(Ki Chang Keum),한광협(Kwang Hyub Han),이도연(Do Yun Lee),이종태(Jong Tae Lee),전재윤(Chae Yoon Chon),문영명(Young Myoung Moon),김귀언(Gwi Eon Kim),서창욱(Chang Ok Suh) 대한방사선종양학회 1998 Radiation Oncology Journal Vol.16 No.2

목 적 : 간암의 최적치료는 수술적 절제로 알려져 있으나 진행성 병변 또는 동반된 간질환 등으로 인해 실제적인 절제는 매우 제한되고 있다. 이에 본 연구에서는 절제불가능 원발성 간암에서 경간동맥 항암 색전술과 국소 방사선의 병용요법을 시행하여 그 결과를 보고하는 바이다. 대상 및 방법 : 1992년 3월부터 1994년 8월까지 진행성 병변 및 간경변증 동반 등으로 절제 불가능으로 판정된 30명의 간암 환자가 본 연구에 포함되었다. 간외 전이가 있거나 간경변증의 정도가 Child’s C군으로 악화된 경우, 종양이 전체 간 용적의 2/3 이상을 차지하는 경우, 수행 능력이 ECOG 3기 이상인 경우 들은 제외되었다. 환자들의 특성은; 종양의 평균 직경이 8.95±3.4cm, UICC 병기 Ⅲ, ⅣA가 각각 10명, 20명, 간경변증 동반이 22명, 간문맥혈전증 동반이 11명, 혈중 alpha fetoprotein(AFP)은 모든 예에서 양성이었다. TACE는 리피오돌 5 ml와 항암제(Adriamycin 50mg)을 혼합하여 도관을 통하여 간동맥내 주입하고 이어서 교질 스폰지 입자(Gelfoam)로 색전술을 시행하였다. 방사선 치료는 TACE 후 7-10일 이내에 시작하였고 평균 조사량은 44.0±9.3 Gy로 전통적인 분할 방식으로 조사하였다. 결 과 : 30명중 19명에서 종괴의 부분관해를 보여서, 관해율은 63.3%를 보였다. 생존율은 1, 2, 3년에 각각 67, 33.3, 22.2%를 나타내었고, 중앙 생존기간은 17개월이었다. 부분관해를 보인 19명의 환자중 6명은 3년이상은 생존하였다. 치료로 인한 독성은 경미하였다. 일시적인 간기능 검사의 변화나 열감은 회복되었고 혈소판 감소증과 심한 오심 및 구토가 각각 4명, 1명에서 나타났으나 1-2 주의 치료 중단과 약물로써 회복되었다. 치료로 인한 독성과 관계되는 사망은 없었다. 결 론 : 절제불가능 원발성 간암에서 경간동맥 항암 색전술과 국소 방사선의 병용요법은 실질적으로 생존율 향상을 유도하면서 독성이 낮은 안전한 치료인 것으로 나타나, 향후 적극적인 임상적 적용으로 치료율의 향상이 기대된다. Purpose : The best prognosis for hepatocellular carcinoma can be achieved with surgical resection. However, the number of resected cases is limited due to the advanced lesion or associated liver disease. A trial of combined transcatheter arterial chemoembolization(TACE) and local radiotherapy(RT) for unresectable hepatocellular carcinoma(HCC) was prospectively conducted and its efficacy and toxicity were investigated. Materials and Methods : From 1992 to 1994, 30 patients with unresectable HCC due either to advanced lesion or to associated cirrhosis were entered in the study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child’s class C, tumors occupying more than two- thirds of the whole liver, and an ECOG scale of more than 3. Patient characteristics were : mean tumor size 8.95±3.4cm, serum AFP+ in all patients, portal vein thrombosis in 11 patients, liver cirrhosis in 22 patients, and UICC stage III and IVA in 10 and 20 patients, respectively. TACE was performed with the mixture of Lipiodol(5ml) and Adriamycin(50mg) and Gelfoam embolization. RT(mean dose 44.0±9.3Gy) was followed within 7- 10 days with conventional fractionation. Results : An objective response was observed in 19 patients(63.3%). Survival rates at 1, 2, and 3 years were 67%, 33.3% and 22.2%, respectively. Median survival was 17 months. There were 6 patients surviving more than 3 years. Distant metastasis occurred in 10 patients, with 8 in the lung only and 2 in both lung and bone. Toxicity included transient elevation of liver function test in all patients, fever in 20, thrombocytopenia in 4, and nausea and vomiting in 1. There was no treatment-related death. Conclusion : Combined TACE and RT appear to produce a favorable response and survival results with minimal toxicity.