Po-Sheng Yang

Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma

PURPOSE To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure. RESULTS In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities. CONCLUSION Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.

Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description

Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6+/-4.3Gy, in a daily fraction of 1.8-2.0Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30Gy, prediction score, and normal tissue complication probability, failed to differentiate the fatality and clinical types of this complication. Elevated transaminases are more frequently seen than ascites and elevated alkaline phosphamide are seen in patients with RILD.

A pilot study of three‐dimensional conformal radiotherapy in unresectable hepatocellular carcinoma

Background : The purpose of this study was to determine the potential role of three‐dimensional (3‐D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC).

Locoregional failure of postmastectomy patients with 1–3 positive axillary lymph nodes without adjuvant radiotherapy

PURPOSE To analyze the incidence and risk factors for locoregional recurrence (LRR) in patients with breast cancer who had T1 or T2 primary tumor and 1-3 histologically involved axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy (RT). MATERIALS AND METHODS Between April 1991 and December 1998, 125 patients with invasive breast cancer were treated with modified radical mastectomy and were found to have 1-3 positive axillary nodes. The median number of nodes examined was 17 (range 7-33). Of the 125 patients, 110, who had no adjuvant RT and had a minimum follow-up of 25 months, were included in this study. Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. Patient-related characteristics (age, menopausal status, medial/lateral quadrant of tumor location, T stage, tumor size, estrogen/progesterone receptor protein status, nuclear grade, extracapsular extension, lymphovascular invasion, and number of involved axillary nodes) and treatment-related factors (chemotherapy and hormonal therapy) were analyzed for their impact on LRR. The median follow-up was 54 months. RESULTS Of 110 patients without RT, 17 had LRR during follow-up. The 4-year LRR rate was 16.1% (95% confidence interval [CI] 9.1-23.1%). All but one LRR were isolated LRR without preceding or simultaneous distant metastasis. According to univariate analysis, age <40 years (p = 0.006), T2 classification (p = 0.04), tumor size >==3 cm (p = 0.002), negative estrogen receptor protein status (p = 0.02), presence of lymphovascular invasion (p = 0.02), and no tamoxifen therapy (p = 0.0006) were associated with a significantly higher rate of LRR. Tumor size (p = 0.006) was the only risk factor for LRR with statistical significance in the multivariate analysis. On the basis of the 4 patient-related factors (age <40 years, tumor >==3 cm, negative estrogen receptor protein, and lymphovascular invasion), the high-risk group (with 3 or 4 factors) had a 4-year LRR rate of 66.7% (95% CI 42.8-90.5%) compared with 7.8% (95% CI 2.2-13.3%) for the low-risk group (with 0-2 factors; p = 0.0001). For the 110 patients who received no adjuvant RT, LRR was associated with a 4-year distant metastasis rate of 49.0% (9 of 17, 95% CI 24.6-73.4%). For patients without LRR, it was 13.3% (15 of 93, 95% CI 6.3-20.3%; p = 0.0001). The 4-year survival rate for patients with and without LRR was 75.1% (95% CI 53.8-96.4%) and 88.7% (95% CI 82.1-95.4%; p = 0.049), respectively. LRR was independently associated with a higher risk of distant metastasis and worse survival in multivariate analysis. CONCLUSION LRR after mastectomy is not only a substantial clinical problem, but has a significant impact on the outcome of patients with T1 or T2 primary tumor and 1-3 positive axillary nodes. Patients with risk factors for LRR may need adjuvant RT. Randomized trials are warranted to determine the potential benefit of postmastectomy RT on the survival of patients with a T1 or T2 primary tumor and 1-3 positive nodes.

Targeting histone deacetylase 4/ubiquitin‐conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiations effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5‐10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin‐conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation‐induced cell death and reduced homologous recombination repair of DNA double‐strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation‐treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4‐dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation‐induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586‐599).

Targeting Histone deacetylase 4/Ubc9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells

Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiations effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5‐10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin‐conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation‐induced cell death and reduced homologous recombination repair of DNA double‐strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation‐treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4‐dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation‐induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586‐599).

Rarely Reported Liver Toxicity in Patients Who Were Hepatitis B Carrier and Underwent Chemoirradiation for Gastric Cancer

Purpose: This study is to report the clinical and dosimetric parameters of six patients who were carriers of type B chronic hepatitis and developed grade 3 or 4 hepatic toxicity after adjuvant or definitive concurrent chemoirradiation for gastric cancer. Materials and Methods: From December 1993 through July 2001, 82 patients with gastric adenocarcinoma underwent radiotherapy as adjuvant or definitive treatment. Ten patients were carriers of type B chronic hepatitis on serology test. Six of 10 patients who developed grade 3 or 4 hepatic toxicity within 4 months after radiotherapy, formed the basis of this study. Five patients underwent external-beam radiotherapy with 45 Gy/1.8 Gy/25 fractions and 18 MV photons delivered to the tumor bed and regional lymphatics Over 5 weeks. One patient had the radiotherapy with 50.4 Gy/28 fractions. Concurrent chemotherapy consisted of 3-6 (median: 5) weekly cycles of intravenous infusion with 5fluorouracil 2 gm/m2 and leucovorin 300mg/m2 for 24 hours. Dose-volume histograms of the critical organs were used for the dosimetric factors in these patients. Results: Six patients developed grade 3 or 4 hepatic toxicity, with a median interval of 38 days from completion of radiotherapy. One patient died of this complication and five patients recovered. All but one patient had either serologic or histological evidence of reactivation of chronic viral hepatitis. Mean dose of liver of the 6 patients ranged from 10.4 Gy to 22.9 Gy (mean: 17.2 Gy), while the percent volume receiving more than 30 Gy of radiation (V3o Gy) ranged from 7% to 37% (mean: 24%). Mean normal tissue complication probability (NTCP) was 3.3%, ranging from 0.03% to 6.8%. Mean hepatic dose, V30GY, and NTCP were all significantly lower than those of the 12 patients with hepatocelular carcinoma and radiation-induced liver disease after three-dimensional conformal radiotherapy. Conclusion: Hepatic toxicity after concurrent chemoirradiation, in patients who were carriers of type B chronic hepatitis and underwent treatment for gastric cancer, deserves special attention and was rarely reported in the literature. The tolerance of liver to radiation was even lower than expected in the presence of concurrent chemotherapy.

Dose-Volume Analysis for 4 Patients with Radiation-Induced Liver Disease after 3-Dimensional Conformal Radiotherapy for Hepatocellular Carcinoma

Purpose: To evaluate the feasibility and accuracy of the currently documented models for prediction of radiation -induced liver disease (RILD), for patients with hepatocellular carcinoma (HCC) treated with 3-dimensional conformal radiotherapy. Materials and Methods: From September 1994 to October 1998, four patients with HCC developed FOLD within 3 months after completion of 3-dimensional conformal radiotherapy. All patients had CT simulation with the images including the entire liver. The detailed information from the dose-volume histogram (DVH), including V(subscript 30Gy), V(subscript 50%) V (subscript off) and prediction score (PS), were calculated and assessed. The complication probabilities were compared with several documented models. Results: Two patients died of RILD-related hepatic failure and 2 recovered. Two patients had more than half of the liver with ＞ 30 cay survived but the other 2 patients died of RILD with 40% and 23% of the liver receiving ＞ 30 Gy. Three of 4 patient had the recommended doses of radiation based on the calculated V(subscript 60%). According to the normal tissue complication probability (NTCP) model, the complication probabilities were less than 5% and within 5-20% if 0.69 and 0.32 were applied for the volume effect parameters, respectively. Conclusion: All the currently documented models fail to accurately estimate the probability of FOLD for the 4 patients with HCC treated with 3-dimensional conformal radiotherapy. It is indicated to establish a model for patients with HCC in Taiwan, using the currently available fractionation and the information from the DVH.