New frontiers in endovascular therapies for locally advanced hepatocellular carcinoma / Novas fronteiras em terapias endovasculares para carcinoma hepatocelular localmente avançado

Abstract Hepatocellular carcinoma is the most common primary malignant liver tumour and is a leading cause of death worldwide. Despite the advent of screening programmes, most cases of hepatocellular carcinoma are diagnosed late (in an advanced stage) which precludes curative treatments such as surgery and ablation. Therefore, intra-arterial locoregional treatments now play a central role in the management of advanced hepatocellular carcinoma, such treatments ranging from trans-arterial chemo-embolisation to the more recently developed trans-arterial radio-embolisation technique. In this essay, we discuss the state of the art of intra-arterial treatment for locally advanced hepatocellular carcinoma and the future directions for such treatment.

Resumo O carcinoma hepatocelular é o tumor hepático maligno primário mais frequentemente observado, sendo uma das principais causas de mortalidade mundial. Apesar do advento dos programas de triagem, na maioria dos casos o diagnóstico tardio está associado a um estágio avançado da doença que impede o tratamento curativo, como cirurgia ou ablação. Assim, os tratamentos locorregionais intra-arteriais têm agora um papel central no gerenciamento avançado do carcinoma hepatocelular, passando por quimioembolização transarterial e radioembolização. Neste ensaio, discutimos o estado da arte do tratamento intra-arterial atualmente disponível para o carcinoma hepatocelular localmente avançado e suas direções futuras.

Research developments of adjuvant therapies for hepatocellular carcinoma after resection / 中华放射肿瘤学杂志

Hepatocellular carcinoma (HCC) is a common malignancy with high rate of morbidity and mortality.Liver resection is the most effective curative treatment,yet subsequent recurrence and death are common,with 5-year overall survival rate remaining about 50％ and 5-year postoperative recurrence reaching as high as 60％-70％ reported by previous publications.Therefore,it is essential to identify the optimal adjuvant therapy for patients with unfavorable prognostic factors to decrease the postoperative recurrence or metastasis,thereby to deliver the promise of improved outcomes.However,there is no consensus about it and several treatment options were under investigation,including transcatheter arterial chemoembolization (TACE),radiotherapy,targeted therapy,and other treatments.Here,we review studies on the role of adjuvant therapies,to provide evidences for further research and clinical practice.

Aspects of images in magnetic resonance of liver tumors treated with transarterial selective internal radiotherapy with yttrium-90 / Aspectos de imagens em exames de ressonância magnética de tumores hepáticos tratados com radioterapia interna seletiva transarterial com ítrio-90

ABSTRACT Transarterial selective internal radiation therapy with yttrium-90, also known as radioembolization, is a therapy based on the administration of resin or glass microspheres loaded with the radioisotope yttrium-90, via selective arterial catheterization of tumor-feeding vessels. It is classified as a type of locoregional therapy and its main goal is to treat patients with primary or secondary hepatic lesions that are unresectable and not responsive to other therapies. Since it is a new technology still restricted to very few hospitals in Brazil, but used in patients throughout the country, it is necessary to demonstrate the main aspects of hepatic lesions treated with selective internal radiation therapy found in magnetic resonance imaging, and to make specific considerations on interpretation of these images. The objective of this report is to demonstrate the main aspects of magnetic resonance imaging of unresectable primary or secondary hepatic lesions, in patients submitted to transarterial selective internal radiation therapy.

RESUMO A radioterapia interna seletiva transarterial com ítrio-90, também conhecida como radioembolização, é uma terapia baseada na administração de microesferas de resina ou vidro carregadas com o radioisótopo ítrio-90, via cateterismo arterial seletivo dos vasos nutridores do tumor. É classificada como um tipo de terapia locorregional e seu principal objetivo é tratar pacientes portadores de lesões hepáticas primárias ou secundárias irressecáveis e não responsivas a outras terapias. Por se tratar de uma nova tecnologia, portanto ainda restrita a pouquíssimos hospitais no Brasil (ainda que utilizada em todo país), é necessário demonstrar os principais aspectos de imagem das lesões hepáticas tratadas com radioterapia interna seletiva transarterial encontrados em exame de ressonância magnética, além de delinear considerações específicas de interpretação destas imagens. O objetivo deste relato é demonstrar os principais aspectos encontrados em ressonância magnética de lesões hepáticas irressecáveis, primárias ou secundárias, de pacientes submetidos à radioterapia interna seletiva transarterial.

A review of updated guidelines for radiotherapy for primary liver cancer / 中华放射肿瘤学杂志

The treatment guidelines based on evidence-based medical evidence provide appropriate treatment strategies for clinical oncologists.Currently,many treatment guidelines for primary liver cancer have been published and updated by many organizations from different countries,including Barcelona Clinic Liver Cancer (BCLC),European Association for the Study of the Liver and European Organization for Research and Treatment of Cancer (EASL-EORTC),American Association for the Study of Liver Diseases (AASLD),National Comprehensive Cancer Network (NCCN),Asia-Pacific Primary Liver Cancer Expert (APPLE),Korean Liver Cancer Study Group and National Cancer Center (KLCSG-NCC),and Chinese Society for Therapeutic Radiology and Oncology (CSTRO),Chinese Medical Association.Although radiotherapy is commonly used in clinical practice,some guidelines do not accept it as a standard treatment strategy.In this article,we review the current treatment guidelines and discuss the current status and future prospects of radiotherapy in the management of primary liver cancer.

Application of 4DCT and MRI image deformation registration in the determination of primary liver cancer radiotherapy target / 中华放射肿瘤学杂志

Objective To investigate the feasibility of defining the radiotherapy target of primary liver cancer using four-dimensional computed tomography (4DCT) and T2-weighted magnetic resonance (MR-T2) deformable image registration.Methods Ten patients with hepatocellular carcinoma (HCC) who first received radiotherapy were included in this study.The 4DCT in free breathing and MR-T2 in deep breathing were acquired sequentially.4DCT were sorted into ten series of CT images according to the respiratory phase.MIM software was used for deformable image registration.The accuracy of deformable image registration was assessed by the maximal displacements in three-dimensional directions of the portal vein and the celiac trunk and the degree of liver overlapping (P-LIVER).Gross tumor volume (GTV) was delineated on different series of CT images and the internal GTV (IGTV) was merged by ten GTVs on 4DCT images in each phase.The MR-T2 image was deformably registered to 4DCT images in each phase to acquire ten GTVDR.The IGTVDRwas obtained by merging the ten GTVDR.The differences between different target volumes were compared by paired t-test.Results The maximal displacements in three-dimensional directions of the portal vein were 0.3±0.8 mm along the x-axis, 0.8±1.8 mm along the y-axis, and 0.5±1.5 mm along the z-axis.The maximal displacements in three-dimensional directions of the celiac trunk were 0.1±1.0 mm along the x-axis, 0.7±1.2 mm along the y-axis, and 0.6±2.0 mm along the z-axis.Overlapping degree was 115.4±13.8%.The volumes of GTVs obtained from 4DCT images in each phase after DR increased by an average of 8.18%(P<0.05), and were consistent with those delineated on MR-T2 images.The IGTV after DR increased by an average of 9.67%(P<0.05).Conclusions MRI image can show more information and have a higher contrast than CT image.MRI images should be combined with 4DCT images for delineating the GTV.It can better determine the scope and trajectory of the target and improve the delineation accuracy of HCC target.

Effect of independent breath-holding technology on target geometry in radiotherapy for liver cancer / 中华放射肿瘤学杂志

Objective To use the fusion image of the end-inhalation holding (EIH) phase and endexhalation holding (EEH) phase to define the target volume of individual patient with liver cancer,and to evaluate the target geometry,feasibility,and clinical significance of the technology.Methods Eighteen patients with liver caucer who were treated in our hospital from 2012 to 2013 were enrolled as subjects.With the same posture and scan range,all patients underwent contrast-enhanced three-dimensional computed tomography (3DCT) scans in the phases of free breathing (FB),EIH,and EEH.Gross tumor volume (GTV),clinical target volume (CTV),and organ of risk (OAR) were delineated on the above images.CTVFB was defined as GTV on the FB phase image (GTVFB) plus a margin of 10 mm,while planning target volume (PTVFB) was defined as CTVFB plus a margin of 10 mm in the right-left and anterior-posterior directions and a margin of 20 mm in the superior-inferior direction.GTVEI and GTVEE were defined as GTV on the EIH and EEH images,respectively.Based on the EEH images,the registered EEH and EIH images were fused to form GTVEI+EI.CTVEI+EE was defined as GTVEI+EI plus a margin of 10 mm,while PTVEI+EE was defined as CTVEI+EE plus a margin of 5 mm in the right-left and anterior-posterior directions and a margin of 10 mm in the superior-inferior direction.The Pinnacle3 v8.0m treatment planning system was used to design two 3D conformal radiotherapy plans for each patient.The volume,degree of inclusion (DI),matching index (MI),and central displacement of CTVFB and CTVEI+EE,as well as PTVFB and PTVEI+EE,were compared between the two plans.Results In the 18 patients,the mean CTVFB was significantly smaller than the mean CTVEI+EE(149.00±87.54 cm3 vs.188.17± 125.72 cm3,P=0.014);there was no significant difference between the mean PTVFB and PTVEI+EE (276.68± 146.41 cm3 vs.253.66± 117.35 cm3,P=0.080).DI of CTVFB to CTVEI+EF,PTVFB to PTVEI+EE,CTVEI+EE to CTVFB,and PTVEI+EE to PTVFB were (99.83±0.09)％,(84.55±8.45) ％,(80.83± 12.31) ％,and (99.78±0.08) ％,respectively.MI of CTVEI+EE to CTVFB and PTVEI+EE to PTVFB were 0.83± 0.07 and 0.87± 0.03,respectively.The central displacements of CTVEI+EE from CTVFB in x,y,and z axes were 0.55± 1.07 cm,0.76±3.02 cm,and-0.26± 1.98 cm,respectively (P =0.432,0.971,0.587).Conclusions In the treatment of liver cancer,the target volume delineation and image fusion using 3DCT images in EIH and EEH phases may avoid target omission due to respiratory movement,making it possible to increase radiation dose to target volume and improve the efficacy of radiotherapy.

Hypofraction radiotherapy by helical tomotherapy for unresectable but confined intrahepatic hepatocellular carcinoma is efficient and safe in comparison with conventional 3-dimension conformal radiotherapy / 中华放射肿瘤学杂志

Objective To evaluate the safety of helical tomotherapy (HT) for hepatocellular carcinoma confined to the liver,and to investigate the efficacy of HT by comparison with three-dimensional conformal radiotherapy (3DCRT).Methods In June 2011,hypofractionated HT was performed in 35 patients with unresectable hepatocellular carcinoma confined to the liver who had no distant metastasis or tumor thrombosis.The dose in each fraction increased from 2.4 Gy to 5.0 Gy with a median dose of 3.2 Gy.The median dose for the total treatment was 50.0 Gy.Within the same period,45 patients received conventionally fractionated 3DCRT with a median dose of 54.0 Gy.The adverse reactions,clinical outcomes,and survival time were compared between the two groups.The survival rate was calculated with Kaplan-Meier method,and log-rank test was used to estimate statistical significance of survival differences.Multivariate analysis of survival was carried out with Cox' s regression model.Results There were no significant differences in adversc reactions between the two groups.The objective response rate was significantly higher in the HT group than in the 3DCRT group (60％ vs.33％,P=0.024).There was no significant difference in the disease control rate between the two groups (94％ vs.89％,P=0.459).The HT group showed significantly higher 1-,2-,and 3-year overall survival rates than the 3DCRT group (97％ vs.80％,P=0.025;81％ vs.55％,P =0.008;67％ vs.50％,P =0.048).The multivariate analysis indicated that tumor smaller than 8 cm,transarterial chemoembolization before radiotherapy,and HT were associated with improved survival (P=0.005;P =0.000;P=0.002).Conclusions HT shows an advantage in precise treatment of hepatocellular carcinoma confined to the liver.With acceptable toxicity,hypofractionated HT shortens the treatment duration and improves the survival in patients.

Safety of intraoperative electron radiation therapy for primary hepatocellular carcinoma: a cohort study / 中华放射肿瘤学杂志

Objective To investigate the safety of intraoperative electron radiation therapy (IOERT) for stage Ⅰ hepatocellular carcinoma (HCC) by a cohort study.Methods From November 2010 to May 2012,16 patients who were pathologically diagnosed with stage Ⅰ HCC underwent IOERT after radical resection.With a cohort study,87 patients with stage Ⅰ HCC who underwent radical resection alone during the same period were qualified,and according to tumor size (＞ 5 cm and ≤ 5 cm) and resection margin (close margin and negative margin),32 of 87 patients made up the control group.The intraoperative and postoperative adverse events,liver function parameters,coagulogram,and routine blood parameters,as well as IOERT-related adverse reactions,were evaluated.Independent-samples t test was used for analyzing the differences between groups.Results Compared with the control group,the IOERT group had a significantly longer operative time ((275.4 ± 71.55) min vs.(184.7 ± 64.74) min,P =0.000),a slightly higher incidence of intraoperative adverse events (18.75％ vs.6.25％,P=1.000),a slightly lower incidence of operative complications (12.50％ vs.28.12％,P =0.460),and a lower perioperative mortality (0 vs.6％,P =0.440).Liver function parameters showed no significant differences between the two groups (P ＞ 0.05).There were no significant differences between the two groups in postoperative time to grade 1 or normal liver function parameters,median length of postoperative hospital stay,length of hospital stay in the surgical department,time to incision healing,and level of incision healing (P ＞ 0.05).During follow-up,no radiation hepatitis was found in the IOERT group.Conclusions As an adjuvant therapy after radical resection for early HCC,IOERT has no significant side effects on postoperative recovery and liver function,and an intraoperative dose of 15-16 Gy is safe.

The therapeutic effects of three-dimensional conformal radiation therapy combined with transcathe-ter arterial chemoembolization for stage Ⅱ primary liver cancer / 中华放射肿瘤学杂志

Objective To evaluate the therapeutic effects of three-dimensional conformal radiation therapy (3DCRT) in combination with transcatheter arterial chemoembolization (TACE) for stage Ⅱ primary liver cancer. Methods Eighty-one patients were retrospectively analyzed, including 36 received 3DCRT combined with TACE (Group A) and 45 received TACE alone (Group B). The short-term therapeutic effects and 1-, 2-, 3-year survival rates, average survival time of the dead patients, and side effects were compared between the two groups. Results The follow-up rate was 100%. The numbers of patients finished 1-, 2- and 3-year follow-up were 55,19 and 6,respectively. The reponse rates were 72% in group A, and 60% in group B, which were not significant different (χ~2= 1.32, P > 0.05). The 1-, 2- and 3-year survival rates of the dead patients were 83%, 63% and 25% in group A and 75%, 37% and 8% in group B. The corresponding average survival time was 21 months and 16 months, respectively. The differences of 2- and 3-year survival rates were significant between group A and B. (χ~2= 4.87, P < 0. 05 ). The incidence and se-verity of side effects did not differ significantly between the two groups. Conclusions In patients with stage Ⅱ primary liver cancer, 3DCRT combined with TACE, being more effective than TACE alone, can prolong the long-term survival without increasing the toxicities.

The impact factors for pathologic micro-invasion of hepatocellular carcinoma: possible application for CTV definition / 中华放射肿瘤学杂志

Objective To evaluate the microscopic characteristics of hepatocellular carcinoma (HCC) invasion,and to provide the reference for GTV-to-CTV expansion. Methods From January 2002 to January 2006,149 HCC patients treated by surgical resection were included. The pathologic slices and clinical data were reviewed, including the tumor size, capsule status, tumor edge, portal vein invasion, TNM stage, histology grade, serum alpha-fetoprotein (AFP), platelet count and the degree of liver cirrhosis. The distance between the tumor capsule and the invasion was measured by 2 senior pathologists. Results of the 149 patients evaluated,79(53.0%) patients presented micro-invasion ranged between 0.5-4.0 mm. The recurrence rate was higher in patients with micro-invasion than those without (44% vs 29%, P=0.047). The invasion extent was positively relative to the tumor size, capsule status, tumor edge, portal vein invasion, TNM stage,histology grade and AFP,while negatively relative to the platelet count. A score system was established according to five predictors of tumor size, capsule status, portal vein invasion, AFP and platelet count. The invasion distance below 2 mm was in 96.6% patients who had≤2 points and only 83.3% for those with 2 points. Conclusions For HCC patients,the invasion extent is relative to the tumor size,cap sule status,portal vein invasion, AFP and platelet count. These 5 predictors could be potentially used as a score system for GTV-to-CTV expansion.

Lyman NTCP model analysis of radiaton-induced liver disease in hypofractionated conformal radiotherapy for primary liver carcinoma / 中华放射肿瘤学杂志

Objective To-identify the factors associated with radiation-induced liver disease (RILD) and to describe the probability of RILD using the Lyman normal tissue complication(NTCP) model for primary liver carcinoma(PLC) treated with hypofractionated conformal therapy (CRT).Methods A total of 109 PLC patients treated with hypofractionated CRT were prospectively followed according to the Child-Pugh classification for liver cirrhosis,93 patients in class A and 16 in class B.The mean dose of radi- ation to the isocenter was (53.5?5.5) Gy,fractions of (4.8?0.5) Gy,with interfraction interval of 48 hours and irradiation 3 times per week.Maximal likelihood analysis yielded the best estimates of parameters of the Lyman NTCP model for all patients;Child-Pugh A and Child-Pugh B patients,respectively.Results Of all the patients,17 developed RILD (17/109),8 in Child-Pugh A(8/93 ) and 9 in Child-Pugh B(9/ 16).By multivariate analysis,only the Child-Pugh Grade of liver cirrhosis was the independent factor (P= 0.000) associated with the developing of RILD.The best estimates of the NTCP parameters for all 109 pa- tients were n=1.1,m=0.35 and TD_(50) (1)=38.5 Gy.The n,m,TD_(50) (1) estimated from patients with Child-Pugh A was 1.1,0.28,40.5 Gy,respectively,compared with 0.7,0.43,23 Gy respectively,for patients with Child-Pugh B.Conclusions Primary liver cancer patients who possess Child-Pugh B cirrho- sis would present a significantly greater susceptibility to RILD after hypofractionated CRT than patients with Child-Pugh A cirrhosis.The predominant risk factor for developing RILD is the severity of hepatic cirrhosis in the liver of PLC patients.

Hypofractionated three-dimensional conformal radiotherapy for primary liver cancer with portal vein tumor thrombosis / 中华放射肿瘤学杂志

Objective To evaluate the efficacy of hypofractionated 3DCRT for primary liver cancer(PLC) with portal vein tumor thrombosis(PVTT).Methods Between April 1999 and August 2003,34 PLC patients with PVTT received hypofractionated 3DCRT.The severity of hepatic cirrhosis was 23 in Child-Pugh gradeA and 11 gradeB.The median value of GTV was 773?cm~3(105-2097?cm~3).The radiotherapy regimen consisted of 38-63?Gy in 7-15 fractions with 4-8?Gy per fraction(median value 5?Gy),the treatment was delivered 3 times per week during every other day.Results Having response rate(CR+PR) of 76%(26/34),the overall 1-,2-,and 3-year survival rate at was 36%,19% and 13%,respectively.Conclusion Hypofractionated three-dimensional conformal radiotherapy is effective for primary liver cancer with portal vein tumor thrombosis.

Hyperfractionation radiotherapy combined with hepatic artery catheterization chemotherapy for unresectable primary liver cancer / 中华放射肿瘤学杂志

Objective To compare the effect of hyperfractionation radiotherapy combined with hepatic artery catheterization chemotherapy and hepatic artery ligation (group A, 65 patients) with conventional fractionation radiation combined with hepatic artery catheterization chemotherapy and hepatic artery ligation (group B, 65 patients) for unresectable primary liver cancer.Methods A total of 130 stage Ⅱprimary liver patients confirmed by pathology and evaluated as unresectable by exploratory laparotomy were divided evenly into group A and group B by the sequence of exploration. The two groups were comparable in age, sex, tumor type and positive fetal protein (AFP). Group A patients were treated by hepatic artery chemotherapy (PDD, 10 mg/day) 6 days a week with hepatic artery ligation followed by hyperfractionation radiotherapy (250 cGy/f, bid) 3 days a week with the scheme alternated weekly. Group B patients were treated by conventional fractionation radiotherapy with the same scheme of chemotherapy as group A. The total dose of PDD and radiotherapy for both groups were 240 mg and 45Gy. Results The AFP level was reduced to half in 89.7% of patients in group A and 67.6% in group B. The 1 , 3 and 5 year survival rates were 90.8%, 63.1%, 23.1% for group A and 73.9%, 41.5% 9.2% for group B, the difference was statistically significant (P0.05). Conclusions Hyperfractionation radiotherapy combined with hepatic artery catheterization chemotherapy and hepatic artery ligation is an effective and reasonable therapeutic scheme for unresectable liver cancer. It can effectively relieve symptoms, reduce the tumor, increase second surgical resection rate and prolong the survival. At the same time, the operation is simple and relatively easy.

Three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for inoperable primary liver cancer / 中华放射肿瘤学杂志

Objective To study the effect of transcatheter arterial chemoembolization(TACE) combined with three-dimensional conformal radiotherapy(3DCRT) for inoperable primary liver cancer.Methods Ninety-six such patients were prospectively randomized to TACE therapy alone group(TACE group-,47 patients) and TACE+3DCRT group(combined group-,49 patients).Results The overall 1-,2-,3-year survival rate was 82%,63%,43% in the combined group.It was 55%,28%,15% in the TACE group.The difference between the two groups was significant(P0.05).Conclusion Transcatheter arterial chemoembolization combined with three-dimensional conformal radiotherapy is more effective than transcatheter arterial chemoembolization therapy alone for inoperable primary liver cancer,without inflicting more treatment-related toxicities.