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Association of Multi-Phasic MR-Based Radiomic and Dosimetric Features with Treatment Response in Unresectable Hepatocellular Carcinoma Patients following Novel Sequential TACE-SBRT-Immunotherapy. Cancers (Basel) 2023; 15:cancers15041105. [PMID: 36831445 PMCID: PMC9954441 DOI: 10.3390/cancers15041105] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
This study aims to investigate the association of pre-treatment multi-phasic MR-based radiomics and dosimetric features with treatment response to a novel sequential trans-arterial chemoembolization (TACE) plus stereotactic body radiotherapy (SBRT) plus immunotherapy regimen in unresectable Hepatocellular Carcinoma (HCC) sub-population. Twenty-six patients with unresectable HCC were retrospectively analyzed. Radiomic features were extracted from 42 lesions on arterial phase (AP) and portal-venous phase (PVP) MR images. Delta-phase (DeltaP) radiomic features were calculated as AP-to-PVP ratio. Dosimetric data of the tumor was extracted from dose-volume-histograms. A two-sided independent Mann-Whitney U test was used to assess the clinical association of each feature, and the classification performance of each significant independent feature was assessed using logistic regression. For the 3-month timepoint, four DeltaP-derived radiomics that characterize the temporal change in intratumoral randomness and uniformity were the only contributors to the treatment response association (p-value = 0.038-0.063, AUC = 0.690-0.766). For the 6-month timepoint, DeltaP-derived radiomic features (n = 4) maintained strong clinical associations with the treatment response (p-value = 0.047-0.070, AUC = 0.699-0.788), additional AP-derived radiomic features (n = 4) that reflect baseline tumoral arterial-enhanced signal pattern and tumor morphology (n = 1) that denotes initial tumor burden were shown to have strong associations with treatment response (p-value = 0.028-0.074, AUC = 0.719-0.773). This pilot study successfully demonstrated associations of pre-treatment multi-phasic MR-based radiomics with tumor response to the novel treatment regimen.
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Navin PJ, Olson MC, Mendiratta-Lala M, Hallemeier CL, Torbenson MS, Venkatesh SK. Imaging Features in the Liver after Stereotactic Body Radiation Therapy. Radiographics 2022; 42:2131-2148. [PMID: 36240077 DOI: 10.1148/rg.220084] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Historically, radiation therapy was not considered in treatment of liver tumors owing to the risk of radiation-induced liver disease. However, development of highly conformed radiation treatments such as stereotactic body radiation therapy (SBRT) has increased use of radiation therapy in the liver. SBRT is indicated in treatment of primary and metastatic liver tumors with outcomes comparable to those of other local therapies, especially in treatment of hepatocellular carcinoma. After SBRT, imaging features of the tumor and surrounding background hepatic parenchyma demonstrate a predictable pattern immediately after treatment and during follow-up. The goals of SBRT are to deliver a lethal radiation dose to the targeted liver tumor and to minimize radiation dose to normal liver parenchyma and other adjacent organs. Evaluation of tumor response after SBRT centers on changes in size and enhancement; however, these changes are often delayed secondary to the underlying physiologic effects of radiation. Knowledge of the underlying pathophysiologic mechanisms of SBRT should allow better understanding of the typical imaging features in detection of tumor response and avoid misinterpretation from common pitfalls and atypical imaging findings. Imaging features of radiation-induced change in the surrounding liver parenchyma are characterized by a focal liver reaction that can potentially be mistaken for no response or recurrence of tumor. Knowledge of the pattern and chronology of this phenomenon may allay any uncertainty in assessment of tumor response. Other pitfalls related to fiducial marker placement or combination therapies are important to recognize. The authors review the basic principles of SBRT and illustrate post-SBRT imaging features of treated liver tumors and adjacent liver parenchyma with a focus on avoiding pitfalls in imaging evaluation of response. Online supplemental material is available for this article. ©RSNA, 2022.
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Affiliation(s)
- Patrick J Navin
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Michael C Olson
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Mishal Mendiratta-Lala
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Christopher L Hallemeier
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Michael S Torbenson
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
| | - Sudhakar K Venkatesh
- From the Departments of Radiology (P.J.N., M.C.O., S.K.V.), Radiation Oncology (C.L.H.), and Pathology (M.S.T.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and Department of Radiology, University of Michigan, Ann Arbor, Mich (M.M.L.)
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LI-RADS treatment response assessment of combination locoregional therapy for HCC. Abdom Radiol (NY) 2021; 46:3634-3647. [PMID: 34120207 DOI: 10.1007/s00261-021-03165-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023]
Abstract
HCC incidence continues to increase worldwide and is most frequently discovered at an advanced stage when limited curative options are available. Combination locoregional therapies have emerged to improve patient survival and quality of life or downstage patients to curative options. The increasing options for locoregional therapy combinations require an understanding of the expected post-treatment imaging appearance in order to assess treatment response. This review aims to describe the synergy between TACE combined with thermal ablation and TACE combined with SBRT. We will also illustrate expected imaging findings that determine treatment efficacy based on the mechanism of tissue injury using the LI-RADS Treatment Response Algorithm.
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Dose escalation in radiotherapy for incomplete transarterial chemoembolization of hepatocellular carcinoma. Strahlenther Onkol 2019; 196:132-141. [DOI: 10.1007/s00066-019-01488-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 06/18/2019] [Indexed: 01/14/2023]
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. The incidence of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Sorafenib remains the only drug approved for systemic treatment for advanced HCC. However, prior to sorafenib era conventional cytotoxic chemotherapies have been studied in advanced HCC. In this review, clinical studies of systemic chemotherapy for advanced HCC will be summarized and discussed.
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Affiliation(s)
- Dae Won Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Chetasi Talati
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
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Choi C, Koom WS, Kim TH, Yoon SM, Kim JH, Lee HS, Nam TK, Seong J. A prospective phase 2 multicenter study for the efficacy of radiation therapy following incomplete transarterial chemoembolization in unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2014; 90:1051-60. [PMID: 25303890 DOI: 10.1016/j.ijrobp.2014.08.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 08/07/2014] [Accepted: 08/11/2014] [Indexed: 12/17/2022]
Abstract
PURPOSE The purpose of this study was to investigate the efficacy and toxicity of radiation therapy (RT) following incomplete transarterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). METHODS AND MATERIALS The study was designed as a prospective phase 2 multicenter trial. Patients with unresectable HCC, who had viable tumor after TACE of no more than 3 courses, were eligible. Three-dimensional conformal RT (3D-CRT) was added for HCC treatment with incomplete uptake of iodized oil, and the interval from TACE to RT was 4 to 6 weeks. The primary endpoint of this study was the tumor response after RT following incomplete TACE in unresectable HCC. Secondary endpoints were patterns of failure, progression-free survival (PFS), time to tumor progression (TTP), overall survival (OS) rates at 2 years, and treatment-associated toxicity. Survival was calculated from the start of RT. RESULTS Between August 2008 and December 2010, 31 patients were enrolled. RT was delivered at a median dose of 54 Gy (range, 46-59.4 Gy) at 1.8 to 2 Gy per fraction. A best objective in-field response rate was achieved in 83.9% of patients, with complete response (CR) in 22.6% of patients and partial response in 61.3% of patients within 12 weeks post-RT. A best objective overall response rate was achieved in 64.5% of patients with CR in 19.4% of patients and PR in 45.1% of patients. The 2-year in-field PFS, PFS, TTP, and OS rates were 45.2%, 29.0%, 36.6%, and 61.3%, respectively. The Barcelona Clinic liver cancer stage was a significant independent prognostic factor for PFS (P=.023). Classic radiation-induced liver disease was not observed. There were no treatment-related deaths or hepatic failure. CONCLUSIONS Early 3D-CRT following incomplete TACE is a safe and practical treatment option for patients with unresectable HCC.
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Affiliation(s)
- Chihwan Choi
- Department of Radiation Oncology, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae Hyun Kim
- Center for Liver Cancer, Research Institute and Hospital, National Cancer Center, Goyang-si, Republic of Korea
| | - Sang Min Yoon
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin Hee Kim
- Department of Radiation Oncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hyung-Sik Lee
- Department of Radiation Oncology, Dong-A University Hospital, Dong-A University School of Medicine, Busan, Republic of Korea
| | - Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Hospital, Gwang-Ju, Republic of Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Chen Y, Zhu J, Zhang HJ, Zhang XQ, Ju XP, Lu MZ, Liu YM, Cao YS, Yu CS, Wang XY. Short-term effects of cyberknife combined with TACE for treatment of primary liver cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:2039-2044. [DOI: 10.11569/wcjd.v22.i14.2039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the short-term clinical effects and adverse reactions of cyberknife combined with transarterial chemoembolization (TACE) for the treatment of primary liver cancer.
METHODS: The medical records for 108 patients with primary liver cancer who received cyberknife and TACE between January 2012 and May 2013 were retrospectively reviewed. Patient demographics, tumor characteristics, treatment details and post-treatment complications were recorded for each patient.
RESULTS: There were 96 males and 12 females. Intra-arterial chemoembolization and cyberknife (DT 35-60 Gy/3-6 fraction/3-7 d) were performed successfully, resulting in a substantial reduction or complete disappearance of tumors in nearly all patients, with a total effective rate (CR + PR + SD) of 100%. No major complications were encountered.
CONCLUSION: Cyberknife combined with TACE for the treatment of primary liver cancer is effective with mild adverse reactions.
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Ni S, Liu L, Shu Y. Sequential transcatheter arterial chemoembolization, three-dimensional conformal radiotherapy, and high-intensity focused ultrasound treatment for unresectable hepatocellular carcinoma patients. J Biomed Res 2012; 26:260-7. [PMID: 23554758 PMCID: PMC3596742 DOI: 10.7555/jbr.26.20120016] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 03/09/2012] [Accepted: 03/14/2012] [Indexed: 12/25/2022] Open
Abstract
The purpose of this study was to evaluate the outcome of patients with unresectable hepatocellular carcinoma (HCC) treated by sequential therapy of transcatheter arterial chemoembolization (TACE), three-dimensional conformal radiotherapy (3-DCRT) and high-intensity focused ultrasound (HIFU). From October, 2005 to September, 2010, 120 patients with unresectable HCC received the sequential treatments of several courses of TACE followed in 2-4 weeks by 3-DCRT and then a single session of HIFU with a curative intent. The median tumor irradiation dose was 40 Gy. Tumor response, toxicity and overall survival rate were analyzed. Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by univariate analysis or multivariate analysis. All 120 HCC patients were followed up by the last follow-up time. Among these patients, hepatic toxicities due to treatment were notable in 9 cases. Gastrointestinal bleeding after the overall treatment occurred in 2 cases, leukopenia of grade III was detected in 1 case, radiation-induced liver disease (RILD) was observed in 2 patients, and first- and second-degree skin burn around the HIFU treatment zone were observed in 2 patients and 1 patient, respectively. Among 120 patients, 23, 83 and 14 cases achieved partial response, stable disease and progressive disease, respectively. The overall survival rates at 1 year, 3 years and 5 years were 70%, 35% and 15%, respectively, with a median survival time of 26 months. Both Child-Pugh liver function grading and radiation dose were determined to be independent predictors for overall survival revealed by the multivariate analysis. It is concluded that the sequential therapy of TACE, 3-DCRT and HIFU is a promising therapeutic regimen for unresectable HCC.
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Affiliation(s)
- Shengfa Ni
- Department of Oncology, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
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Yuan X, Yan S, Zhao J, Shi D, Yuan B, Dai W, Jiao B, Zhang W, Miao M. Lipid metabolism and peroxisome proliferator-activated receptor signaling pathways participate in late-phase liver regeneration. J Proteome Res 2011; 10:1179-90. [PMID: 21192688 DOI: 10.1021/pr100960h] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Liver regeneration (LR) is of great clinical significance in various liver-associated diseases. LR proceeds along a sequence of three distinct phases: priming/initiation, proliferation, and termination. Compared with the recognition of the first two phases, little is known about LR termination and structure/function reorganization. A combination of "omics" techniques, along with bioinformatics, may provide new insights into the molecular mechanism of the late-phase LR. Gene, protein, and metabolite profiles of the rat liver were determined by cDNA microarray, two-dimensional electrophoresis, and HPLC-MS analysis. Pathway enrichment analysis was performed to identify the pathways: 427 differentially expressed genes extracted from the microarray experiment revealed two expression patterns representing the early and late phase of LR. Functionally, the genes expressing at a higher level at the early phase than at the late phase were mainly involved in the response to stress, proliferation, and resistance to apoptosis, while those expressing at a lower level at the early phase than at the late phase were mainly engaged in lipid metabolism. Compared with the sham-operation control (SH) group, 5 proteins in the 70% partial hepatectomy (70%PHx) group were upregulated at the protein level, and 3 proteins were downregulated at 168 h after the 70%PHx. E-FABP, an upregulated fatty acid binding protein, was found to be involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The metabolomic data confirmed the enhancement of lipid metabolism by the detection of the intermediate and final metabolites. We've concluded that increased lipid metabolism and activated PPAR signaling pathways play important roles in late-phase LR.
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Affiliation(s)
- Xing Yuan
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, People's Republic of China
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Clinical study of transarterial chemoembolization combined with 3-dimensional conformal radiotherapy for hepatocellular carcinoma. Eur J Surg Oncol 2010; 37:245-51. [PMID: 21195578 DOI: 10.1016/j.ejso.2010.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 11/18/2010] [Accepted: 12/06/2010] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Monotherapy is not very effective for intermediate or advanced stage HCC. Efficacy of combined therapy using transarterial chemoembolization (TACE) with three-dimensional conformal radiotherapy (3-DCRT) for advanced HCC should be evaluated. METHODS HCC patients were selected from our patient database. The sequence of treatments that patients underwent was several courses of TACE followed in 2-4 weeks by 3-DCRT. The median tumor irradiation dose was 44Gy. Toxicity, tumor response, and overall survival rate were analyzed. RESULTS 140 HCC patients were followed up by the last follow-up time. Among these patients, hepatic toxicities due to treatment were notable in 15 cases. Gastrointestinal bleeding after the overall treatment occurred in 3 cases. Leukopenia of grade III was detected in 1 case. Radiation-induced liver disease (RILD) was observed in 3 patients. Among 140 patients, 27, 97, and 16 cases achieved partial response, stable disease, and progressive disease, respectively. The overall survival rates of 1-year, 3-years, and 5-years were 66%, 29%, and 13%, respectively, with a median survival time of 18 months. Both Child-Pugh grade and radiation dose were determined to be independent predictors for overall survival from multivariate analysis. CONCLUSION The combined modality of TACE and 3-DCRT is a promising treatment for unresectable HCC. A large-scale, prospective randomized trial should be performed to confirm the utility of this combined therapy.
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Koo JE, Kim JH, Lim YS, Park SJ, Won HJ, Sung KB, Suh DJ. Combination of transarterial chemoembolization and three-dimensional conformal radiotherapy for hepatocellular carcinoma with inferior vena cava tumor thrombus. Int J Radiat Oncol Biol Phys 2009; 78:180-7. [PMID: 19926229 DOI: 10.1016/j.ijrobp.2009.07.1730] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 07/11/2009] [Accepted: 07/16/2009] [Indexed: 01/10/2023]
Abstract
PURPOSE To evaluate the effects of transarterial chemoembolization (TACE) and three-dimensional conformal radiotherapy (CRT) in patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT). METHODS AND MATERIALS A total of 42 consecutive patients who underwent TACE and CRT (TACE+CRT group) for the treatment of HCC with IVCTT were prospectively enrolled from July 2004 to October 2006. As historical controls, 29 HCC patients with IVCTT who received TACE alone (TACE group) between July 2003 and June 2004 were included. CRT was designed to target only the IVCTT and to deliver a median total dose of 45 Gy (range, 28-50 Gy). RESULTS Most baseline characteristics of the two groups were similar (p > 0.05). The response and progression-free rates of IVCTT were significantly higher in the TACE+CRT group than in the TACE group (42.9% and 71.4% vs. 13.8% and 37.9%, respectively; p < 0.01 for both rates). Overall, patient survival was significantly higher in the TACE+CRT group than in the TACE group (p < 0.01), with a median survival time of 11.7 months and 4.7 months, respectively. Treatment with TACE+CRT (hazard ratio [HR] = 0.38; 95% confidence interval [CI], 0.20-0.71), progression of IVCTT (HR = 4.05; 95% CI, 2.00-8.21), Child-Pugh class B (HR = 3.44; 95% CI, 1.79-6.61), and portal vein invasion (HR = 2.31; 95% CI, 1.19-4.50) were identified as independent predictors of mortality by multivariable analysis. CONCLUSIONS The combination of TACE and CRT is more effective in the control of IVCTT associated with HCC and improves patient survival compared with TACE alone.
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Affiliation(s)
- Ja Eun Koo
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Choi SB, Kim KS, Park YN, Choi JS, Lee WJ, Seong J, Han KH, Lee JT. The efficacy of hepatic resection after neoadjuvant transarterial chemoembolization (TACE) and radiation therapy in hepatocellular carcinoma greater than 5 cm in size. J Korean Med Sci 2009; 24:242-7. [PMID: 19399265 PMCID: PMC2672123 DOI: 10.3346/jkms.2009.24.2.242] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2008] [Accepted: 06/29/2008] [Indexed: 01/14/2023] Open
Abstract
In cases of large hepatocellular carcinoma (HCC), neoadjuvant treatment such as transarterial chemoembolization (TACE) and radiation therapy can be performed. The aim of this study was to evaluate the outcome of these treatments prior to hepatic resection. Between January 1994 and May 2007, 16 patients with HCC greater than 5 cm in size were treated with TACE and radiation therapy prior to hepatic resection. The clinicopathologic factors were reviewed retrospectively. Of the 16 patients, there were 14 men and two women, and the median age was 52.5 yr. TACE was performed three times in average, and the median radiation dosage was 45 Gy. The median diameter of tumor on specimen was 9.0 cm. The degree of tumor necrosis was more than 90% in 14 patients. The median survival time was 13.3 months. Five patients had survived more than 2 yr and there were two patients who had survived more than 5 yr. Although the prognosis of large HCC treated with neoadjuvant therapy is not satisfactory, some showed long-term survival loger than 5 yr. Further research will be required to examine the survival and disease control effect in a prospective randomized study.
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Affiliation(s)
- Sae Byeol Choi
- Department of Surgery, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Sik Kim
- Department of Surgery, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Jin Sub Choi
- Department of Surgery, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Woo Jung Lee
- Department of Surgery, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Jinsil Seong
- Department of Radiation Oncology, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Meidicine, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
| | - Jong Tae Lee
- Department of Radiology, Severance Hospital, Liver Cancer Special Clinic Yonsei University College of Medicine, Seoul, Korea
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Meng MB, Cui YL, Lu Y, She B, Chen Y, Guan YS, Zhang RM. Transcatheter arterial chemoembolization in combination with radiotherapy for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 2008; 92:184-94. [PMID: 19042048 DOI: 10.1016/j.radonc.2008.11.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Revised: 10/28/2008] [Accepted: 11/01/2008] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND PURPOSE To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus radiotherapy (RT) for unresectable hepatocellular carcinoma (UHCC) using meta-analysis of data from the literature involving available randomized controlled trials of TACE in combination with RT compared with that of TACE alone (Therapy I versus II) in treating UHCC. MATERIAL AND METHODS We searched the Cochrane Library, MEDLINE, CENTRAL, EMBASE, CBMdisc, and CNKI as well as employing manual searches. Meta-analysis was performed on the results of homogeneous studies. Analyses subdivided by study design were also performed. RESULTS We found 17 trials involving 1476 patients. 5 of total were Randomized Controlled Trials (RCTs) and 12 were Non-randomized Controlled Clinical Trials (CCTs). In terms of quality, 5 RCTs were graded B, and 12 CCTs were graded C. Our results showed that Therapy I, compared with Therapy II, significantly improved the survival and the tumor response of patients, and was thus more therapeutically beneficial. Serious adverse events were not increased exception for total bilirubin (TB) level. CONCLUSIONS Therapy I was more therapeutically beneficial. However, considering the strength of the evidence, additional randomized controlled trials are needed before Therapy I can be recommended routinely.
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Affiliation(s)
- Mao-Bin Meng
- Division of Thoracic Cancer, West China Hospital, West China School of Medicine, Sichuan University, #37 Guoxue Lane, Chengdu, China
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Kim W, Seong J, An JH, Oh HJ. Enhancement of tumor radioresponse by wortmannin in C3H/HeJ hepatocarcinoma. JOURNAL OF RADIATION RESEARCH 2007; 48:187-95. [PMID: 17435377 DOI: 10.1269/jrr.06077] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The objective of this study was to explore whether a specific inhibitor of PI3K, wortmannin, could potentiate the antitumor effect of radiation in vivo, particularly on radioresistant murine tumors. C3H/HeJ mice bearing syngeneic hepatocarcinoma (HCa-I) were treated with 25 Gy radiation, wortmannin, or both. Wortmannin was administered intraperitoneally (1 mg/kg) once daily for 14 days. Tumor response to treatment was determined by a tumor growth delay assay. Possible mechanisms of action were explored by examining the level of apoptosis and regulating molecules. The expression of regulating molecules was analyzed by Western blot for p53 and p21(WAF1/CIP1), and immunohistochemical staining for p21(WAF1/CIP1), CD31 and VEGF. In the tumor growth delay assay, wortmannin increased the effect of tumor radioresponse with an enhancement factor (EF) of 2.00. The level of apoptosis achieved by the combined treatments was shown to be no more than an additive effect; peak apoptotic index was 11% in radiation alone, 13% in wortmannin alone, and 19% in the combination group. Markedly increased areas of necrosis at 24 h in the combination group were noted. Western blotting showed upregulation of p21(WAF1/CIP1) in the combination treatment group, which correlated with low levels of VEGF. Microvascular density was evidently also reduced, based on low expression of CD31. In murine hepatocarcinoma, the antitumor effect of radiation was potentiated by wortmannin. The mechanism seems to involve not only the increase of induced apoptosis but also enhanced vascular injury. Wortmannin, in combination with radiation therapy, may have potential benefits in cancer treatment.
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Affiliation(s)
- Wonwoo Kim
- Department of Radiation Oncology, Brain Korea 21 Project for Medicine, Yonsei University, Seoul, South Korea
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Lambert B, De Ridder L, De Vos F, Slegers G, de Gelder V, Van de Wiele C, Thierens H. Assessment of supra-additive effects of cytotoxic drugs and low dose rate irradiation in an in vitro model for hepatocellular carcinoma. Can J Physiol Pharmacol 2007; 84:1021-8. [PMID: 17218968 DOI: 10.1139/y06-055] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The use of 5-fluorouracil, topotecan, or gemcitabine was tested for enhancement of the effects of low dose rate (LDR) irradiation in an in vitro model for hepatocellular carcinoma. For comparison, all drugs were tested in combination with high dose rate (HDR) gamma-irradiation as well. Multicellular spheroids of HepG2 cells were exposed to HDR or LDR irradiation by means of external beam cobalt-60 or rhenium-188 (188Re), respectively, dissolved in the culture medium. Secondly, exposure to irradiation was combined with the cytotoxic drug. Toxicity was evaluated by means of a quantitative spheroid outgrowth assay and histology. For 5-fluorouracil, supra-additive effects were observed in combination with HDR irradiation. With 188Re, the supra-additive toxicity was only transient. For topotecan and 188Re, no supra-additive effects were seen, whereas the addition of HDR irradiation at the end of the topotecan exposure yielded lasting supra-additive effects. Incubation with gemcitabine followed by exposure to HDR irradiation, induced a synergistic toxicity on the outgrowth. No supra-additive effects were observed when HDR irradiation was added at the start of the incubation with gemcitabine or combined with LDR irradiation. For all drugs tested, supra-additive effects were observed with HDR irradiation if the timing of the irradiation was appropriate. For 188Re, no lasting supra-additive effects were observed.
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Affiliation(s)
- Bieke Lambert
- Department of Nuclear Medicine, De Pintelaan 185, Ghent University Hospital, 9000 Ghent, Belgium
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An JH, Seong JS. Proteomics analysis of apoptosis-regulating proteins in tissues with different radiosensitivity. JOURNAL OF RADIATION RESEARCH 2006; 47:147-55. [PMID: 16819141 DOI: 10.1269/jrr.47.147] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
The aim of this study was to identify of radiosusceptibility proteins in tissues with different radiosensitivity. C3H/HeJ mice were exposed to 10 Gy. The tissues were processed for proteins extraction and were analyzed by 2-dimensional electrophoresis. The proteins were identified by matrix-assisted laser desorption ionizing time-of-flight mass spectrometry and validated by immunohistochemical staining and Western blotting. The peaks of apoptosis levels were 35.3 +/- 1.7% and 0.6 +/- 0.2% in the spleen and the liver, respectively, after ionizing radiation. Analysis of liver tissue showed that the expression level of ROS related proteins such as cytochrome c, glutathione S transferase, NADH dehydrogenase and peroxiredoxin VI increased after radiation. The expression level of cytochrome c increased to 3-fold after ionizing radiation in both tissues. However in spleen tissue, the expression level of various kinds of apoptosis regulating proteins increased after radiation. These involved iodothyronine, CD 59A glycoprotein precursor, fas antigen and tumor necrosis factor -inducible protein TSG-6n precursor after radiation. The difference in the apoptosis index between the liver and spleen tissues is closely associated with the expression of various kinds of apoptosis-related proteins. The result suggests that the expression of apoptosis-related protein and redox proteins play important roles in this radiosusceptibility.
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Affiliation(s)
- Jeung Hee An
- Department of Radiation Oncology, Brain Korea 21 Project for Medical Science, Yonsei University Medical College, Seoul Korea.
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Kim J, Seong J, Kim SH. Enhancement of tumor response by farnesyltransferase inhibitor in C3H/HeJ hepatocarcinoma. Ann N Y Acad Sci 2005; 1030:95-102. [PMID: 15659785 DOI: 10.1196/annals.1329.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Farnesyltransferase inhibitor (FTI) acts on ras, which can ultimately enhance radiosensitivity. The objective of this study was to explore whether FTI could potentiate the antitumor efficacy of radiation in vivo, particularly in radio-resistant hepatocarcinomas (HCa-I) syngeneic to C3H/HeJ mice. The presence of ras mutations was examined by PCR and DNA sequencing. C3H/HeJ mice, bearing HCa-I, were treated with FTI, LB42907, and 25 Gy radiation. FTI was orally administered, 60 mg/kg, twice daily for 30 days. The expression of regulating molecules was analyzed by Western blotting for p53, p21(WAF1/CIP1), and the Bcl-2 family, such as Bcl-2, Bax, and Bcl-X(L/s). In HCa-I, no ras mutations were detected. Downregulation of ras by FTI was most prominent at 4 h after treatment. In a tumor growth delay assay, FTI increased the effect of the tumor's radioresponse, with an enhancement factor of 1.32. Combined irradiation and FTI increased radiation-induced apoptosis; the peak apoptotic index was 3.6% with irradiation alone and with the drug alone but 7.1% in the combined treatment group. The analysis of apoptosis-regulating molecules by Western blotting showed upregulation of p53 and p21(WAF1/CIP1) in the combined treatment group compared with those in either of the single treatment groups, but the Bcl-2 family remained unchanged. FTI, in combination with radiation therapy, may have potential benefits in cancer treatment even if there are no ras mutations. FTI could inhibit ras activity but may also affect any protein that requires farnesylation for its activity.
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Affiliation(s)
- Jiyoung Kim
- Department of Radiation Oncology, Brain Korea 21 Project for Medical Science, Yonsei University Medical College, Shinchon-dong 134, Seodamun-Ku, Seoul 120-752, Korea.
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Wu DH, Liu L, Chen LH. Therapeutic effects and prognostic factors in three-dimensional conformal radiotherapy combined with transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol 2004; 10:2184-9. [PMID: 15259062 PMCID: PMC4724993 DOI: 10.3748/wjg.v10.i15.2184] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2003] [Revised: 12/23/2003] [Accepted: 02/01/2004] [Indexed: 12/15/2022] Open
Abstract
AIM To evaluate the therapeutic efficacy of three-dimensional conformal radiotherapy (3D-CRT) combined with transcatheter arterial chemoembolization (TACE) on the patients with hepatocellular carcinoma (HCC). METHODS Between 1998 and 2001, 94 patients with HCC received 3D-CRT combined with TACE. A total 63 patients had a Okuda stage I lesion and 31 patients had stage II. The median tumor size was 10.7 cm (range 3.0-18 cm), and liver cirrhosis was present in all the patients. There were 43 cases of class A and 51 class B. TACE was performed using lipiodol, 5-fluorouracil, cisplatin, doxorubicin hydrochloride and mitomycin, followed by gelatin sponge cubes. Fifty-nine patients received TACE only one time, while the others 2 to 3 times. 3D-CRT was started 3-4 wk after TACE. All patients were irradiated with a stereotactic body frame and received 4-8 Gy single high-dose radiation for 8-12 times at the isocenter during a period of 17-26 d (median 22 d). RESULTS The median follow-up was 37 mo (range 10-48 mo) after diagnosis. The response rate was 90.5%. The overall survival rate at 1-, 2-, and 3- year was 93.6%, 53.8% and 26.0% respectively, with the median survival of 25 mo. On univariate analysis, age (P=0.026), Child-Pugh classification for cirrhosis of liver (P=0.010), Okuda stage (P=0.026), tumor size (P=0.000), tumor type (P=0.029), albuminemia (P=0.035), and radiation dose (P=0.000) proved to be significant factors for survival. On multivariate analysis, age (P=0.024), radiation dose (P=0.001), and tumor size (P=0.000) were the significant factors. CONCLUSION 3D-CRT combined with TACE is an effective and feasible approach for HCC. Age, radiation dose and tumor size were found to be significant prognostic factors for survival of patients with HCC treated by 3D-CRT combined with TACE. Further study for HCC is needed to improve the treatment efficacy.
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Affiliation(s)
- De-Hua Wu
- Department of Radiation Oncology, Nanfang Hospital, First Military Medical University, Guangzhou 510515, Guangdong Province, China
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Zhang M, Boyer M, Rivory L, Hong A, Clarke S, Stevens G, Fife K. Radiosensitization of vinorelbine and gemcitabine in NCI-H460 non–small-cell lung cancer cells. Int J Radiat Oncol Biol Phys 2004; 58:353-60. [PMID: 14751503 DOI: 10.1016/j.ijrobp.2003.09.032] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
PURPOSE Results from recent clinical studies of gemcitabine and vinorelbine have encouraged the use of this combination concurrently with radiotherapy in the treatment of non-small-cell lung cancer, although preclinical data are limited. The present study aimed to quantify the in vitro interaction and radiosensitizing effect of gemcitabine and vinorelbine individually and in combination. METHODS AND MATERIALS Cytotoxicity was measured by exposing NCI-H460 cells to gemcitabine and/or vinorelbine simultaneously or sequentially, followed by irradiation at 0-10 Gy. Clonogenic cell survival assays were performed. Flow cytometry was used to measure the effects of both drug and radiation on cell cycle distribution. Apoptosis was assessed by morphologic criteria, by sub-G1 changes using flow cytometry assay, and by Annexin-V binding assay. RESULTS Both drugs showed single-agent activity against NCI-H460 cells and targeted different phases of the cell cycle. When both drugs were used in combination, they showed schedule-dependent interaction. An antagonistic effect was observed with simultaneous exposure to the two drugs. The optimum combination schedule was sequential exposure to vinorelbine followed by gemcitabine 24 h later. Both drugs showed radiosensitization effects. The radiosensitization effect of gemcitabine was evident when radiation was given immediately after 4-h incubation. However, the radiosensitization effect of vinorelbine was time dependent and observed with radiation given at 24 h postincubation. Apoptosis induced by gemcitabine increased gradually, reaching 20% at 72 h posttreatment. In contrast, apoptotic cell death was an early feature in vinorelbine-treated cells, reaching approximately 40% at 24 h. CONCLUSIONS The individual cytotoxic effects of gemcitabine and vinorelbine on NCI-H460 cells are phase specific, and the combined effect of gemcitabine and vinorelbine is sequence dependent. The radiosensitizing effects of both drugs seem to be related to enhanced apoptosis.
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Affiliation(s)
- Mei Zhang
- Department of Radiation Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
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Guo WJ, Yu EX, Liu LM, Li J, Chen Z, Lin JH, Meng ZQ, Feng Y. Comparison between chemoembolization combined with radiotherapy and chemoembolization alone for large hepatocellular carcinoma. World J Gastroenterol 2003; 9:1697-701. [PMID: 12918103 PMCID: PMC4611526 DOI: 10.3748/wjg.v9.i8.1697] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of transcatheter arterial chemoembolization (TACE) combined with radiotherapy for unresectable large hepatocellular carcinoma (HCC).
METHODS: From June 1994 to June 1999, a total of 76 patients with large unresectable HCC were treated with TACE followed by external-beam irradiation. 89 patients with large HCC, who underwent TACE alone during the same period, served as the control group. Clinical features, therapeutic modalities, acute effects and survival rates were analyzed and compared between TACE plus irradiation group and TACE alone group. A multivariate analysis of nine clinical variables and one treatment variable (irradiation) was performed by the Cox proportional hazards model.
RESULTS: The clinical features and therapeutic modalities except irradiation between the two groups were comparable (P > 0.05). The objective response rate (RR) in TACE plus irradiation group was higher than that in TACE alone group (47.4% vs 28.1%, P < 0.05). The overall survival rates in TACE plus irradiation group (64.0%, 28.6%, and 19.3% at 1, 3, 5 years, respectively) were significantly higher than those in TACE alone group (39.9%, 9.5%, and 7.2%, respectively, P = 0.0001). Cox proportional hazards model analysis showed that tumor extension and Child grade were significant and were independent negative predictors of survival, while irradiation was an independent positive predictor of survival.
CONCLUSION: TACE combined with radiotherapy is more effective than TACE alone, and is a promising treatment for unresectable large HCC.
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Affiliation(s)
- Wei-Jian Guo
- Department of Oncology, Xinhua Hospital of Shanghai Second Medical University, 1665 Kongjiang Road, Shanghai 200092, China.
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Fuchs CS, Clark JW, Ryan DP, Kulke MH, Kim H, Earle CC, Vincitore M, Mayer RJ, Stuart KE. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2002; 94:3186-91. [PMID: 12115351 DOI: 10.1002/cncr.10607] [Citation(s) in RCA: 63] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND There is no effective systemic therapy for patients with hepatocellular carcinoma. A recent trial reported a moderate antitumor activity for gemcitabine among Asian patients with advanced hepatocellular carcinoma. This led to our examination of the efficacy and tolerability of the drug in a population of U.S. patients. METHODS Thirty patients with measurable, unresectable, or metastatic hepatocellular carcinoma who had received at least one previous form of systemic therapy were enrolled. All patients were required to have adequate major organ function and performance status. Patients received gemcitabine (1000 mg/m(2) intravenously over 30 minutes weekly) for 3 consecutive weeks followed by a 1-week rest. Patients were assessed radiographically every 8 weeks. RESULTS All 30 patients were evaluable for response and toxicity. Ninety cycles of therapy were administered (median 2, range 1-8). No complete or partial responses were observed. Nine patients (30%) had stable disease (median duration 7.4 months, range 2-17). Median survival for all 30 patients was 6.9 months (95% confidence interval, 4.5-13.5) and the 1-year survival rate was 40%. Mild hematologic toxicity occurred. Two patients (7%) developed Grade 4 neutropenia and one patient (3%) experienced Grade 3 thrombocytopenia. There were no episodes of febrile neutropenia. One patient who had previously undergone orthotopic liver transplantation developed hemolytic-uremic syndrome that resolved with discontinuation of chemotherapy and plasmapheresis. CONCLUSIONS Although generally well tolerated, gemcitabine had minimal effect in patients with advanced hepatocellular carcinoma.
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Affiliation(s)
- Charles S Fuchs
- Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
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