Zhao-Chong Zeng

A comparison of chemoembolization combination with and without radiotherapy for unresectable hepatocellular carcinoma.

PURPOSEThis study evaluated the effect of transcatheter arterial Chemoembolization combined with external beam radiotherapy on the response rates and survival of patients with unresectable hepato-cellular carcinoma. Transcatheter arterial Chemoembolization is frequently used for the treatment of this cancer, but complete or massive necrosis is seldom observed. Historically, radiotherapy for hepatocellular carcinoma has yielded poor long-term survival. Multimodality therapy has been initiated in an effort to improve survival statistics. PATIENTS AND METHODSWe retrospectively studied 203 patients with unresectable hepatocellular carcinoma, who were free of tumor thrombus, lymph node involvement, or extrahepatic metastasis based on computed tomography scans of the chest and abdomen. Among the 203 patients who received transcatheter arterial Chemoembolization as initial therapy, 54 also received combination therapy with external beam radiotherapy. Tumor response rate, survival, and failure patterns were analyzed and compared between the two groups. RESULTSObjective responses (complete and partial responses) on computed tomography study were observed in 31% and 76% of patients in the non-radiotherapy and radiotherapy groups, respectively. Overall survival rates in the patients in the radiotherapy group were 71.5%, 42.3%, and 24.0% at 1, 2, and 3 years, respectively, improved over the non-radiotherapy group rates of 59.6%, 26.5%, and 11.1% at 1, 2, and 3 years, respectively. Intrahepatic failure was lower in the radiotherapy group than in the non-radiotherapy group, but the difference was not significant. Side effects from radiotherapy were common, but rarely severe. CONCLUSIONSThis retrospective study suggests that the outcome of unresectable hepatocellular carcinoma can be influenced by radiation therapy, but a prospective randomized trial would be necessary to draw definitive conclusions.

A prognostic scoring system based on clinical features of intrahepatic cholangiocarcinoma: the Fudan score

BACKGROUNDnThe objectives of this study were to propose a clinical prognostic scoring system applicable for intrahepatic cholangiocarcinoma (ICC) and to evaluate the prognostic validity of the American Joint Committee on Cancer (AJCC) 7th edition staging system.nnnPATIENTS AND METHODSnRetrospective univariate and multivariate survival analyses were conducted for 344 patients with ICC who underwent hepatectomy. A simple clinical prognostic scoring system (Fudan score) was developed based on the independent predictors. The prognostic validity was assessed in 74 patients with unresected tumors and compared with the AJCC 6th and 7th edition systems.nnnRESULTSnIn the training set, serum alkaline phosphatase level, carbohydrate antigen 19-9 level, tumor boundary type, tumor size, and number of intrahepatic tumors were independent predictive factors of survival in ICC and were incorporated into the Fudan score. Three hundred forty-four patients were categorized into four subsets with 5-year overall survival rates of 48.6%, 25.6%, 10.3%, and 0.0% for low-, intermediate-, high-, and extremely high-risk groups, respectively. The discriminative ability of the Fudan score was better than that of the AJCC staging system and well applied in the unresected patient set.nnnCONCLUSIONSnA Fudan score based on clinical factors may provide a relatively accurate prognostic prediction for ICC patients regardless of resection status.

Prognostic factors for patients with hepatocellular carcinoma with macroscopic portal vein or inferior vena cava tumor thrombi receiving external-beam radiation therapy

Prognostic factors in patients with hepatocellular carcinoma (HCC) with tumor thrombosis are not well established, especially for those given external‐beam radiation therapy (EBRT). Patients (n = 136) with HCC who had portal vein (PV) or inferior vena cava (IVC) tumor thrombus received EBRT between January 1998 and October 2007. Demographic variables, laboratory values, tumor characteristics, and treatment modalities were determined at diagnosis and before EBRT. The total radiation dose ranged from 30 to 60 Gy (median, 50 Gy) and was focused on the tumor thrombi. Predictors of survival were identified using the univariate and multivariate analysis. Of the 136 patients, the tumor thrombus completely disappeared in 41 patients (30.1%), 36 patients (26.5%) had a partial response, 49 patients (36%) had stable disease, and 10 patients (7.4%) had progressive disease. On multivariate analysis, pretreatment unfavorable predictors were associated with lower albumin, higher γ‐glutamyltransferase and α‐fetoprotein levels, poorer Child–Pugh classification, intrahepatic multifocality, lymph node metastases, poorer response to EBRT, and 2‐dimension EBRT technique. Survival rates at 1, 2, and 3 years were 31.8%, 17.5%, and 8.8% for patients with PV tumor thrombi; 66.3%, 21.1%, and 15.8% for IVC tumor thrombi; and 25%, 8.3%, and 0% for PV plus IVC tumor thrombi, respectively. Overall median survival was 9.7 months. This study provides detailed information about the survival outcomes and prognostic factors of HCC with tumor thrombi in a relatively large cohort of patients treated with radiation, and the results will help in understanding the potential factors that influence survival for patients with HCC after EBRT. (Cancer Sci 2008; 99: 2510–2517)

Increased expression of vascular endothelial growth factor-C and nuclear CXCR4 in hepatocellular carcinoma is correlated with lymph node metastasis and poor outcome.

Purpose:Lymph node metastasis (LNM) is a chief cause of morbidity and mortality in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to investigate the relationship between the expression of CXCR4 and vascular endothelial cell growth factor (VEGF)-C and the clinicopathological features of HCC with LNM. Methods:Immunohistochemical staining for CXCR4 and VEGF-C was performed on tissue microarrays that were constructed using tumor specimens from patients with HCC with (N = 123) or without (N = 145) LNM. The relationship between the clinicopathological features of HCC and the expression of CXCR4 and VEGF-C was analyzed using the Pearson &khgr;2 test, logistical regression analysis, and receiver operating characteristic analysis. Results:Nuclear CXCR4 expression and VEGF-C expression were positively correlated with LNM and poor outcome in HCC. Moreover, nuclear CXCR4 expression was positively correlated with VEGF-C expression (correlation coefficient 0.256). Receiver operating characteristic analysis revealed that both factors were predictive of HCC LNM {CXCR4: area under the curve, 0.695 [95% confidence interval (CI), 0.630–0.759; VEGF-C: area under the curve, 0.629 (95% CI, 0.562–0.695]}. Patients with tumors exhibiting high nuclear CXCR4 expression or high VEGF-C expression had significantly poorer overall survival than those with low tumor expression of the corresponding factors. Multivariate analysis showed that UICC T stage [odds ratio (OR), 1.615, 95% CI, 1.306–1.997], nuclear CXCR4 expression (OR, 3.998; 95% CI, 2.706–5.907), and VEGF-C expression (OR, 1.903; 95% CI, 1.203–3.011) were independent risk factors for developing HCC LNM. Discussion:These findings suggest that nuclear CXCR4 expression and VEGF-C expression can be used to identify patients with HCC at high risk for developing LNM.

Comparison between radioimmunotherapy and external beam radiation therapy for patients with hepatocellular carcinoma

Abstract. It has previously been observed in animal studies that, at equivalent doses, radioimmunotherapy (RIT) is 2.5 times more effective than multiple fractions of external beam radiation therapy (EBRT) in inhibiting tumour growth. In this study, we compared the use of RIT and EBRT in patients with hepatocellular carcinoma (HCC), treated during the past 10 years. Of 67 patients without extrahepatic involvement, 32 were treated with hepatic artery ligation combined with RIT (the RIT group) while 35 were treated with a combination of hepatic arterial chemo-embolisation and EBRT (the EBRT group). The patients in the RIT group received 131I-Hepama-1 monoclonal antibody, which was infused through the hepatic artery catheter. The patients in the EBRT group received transcatheter arterial chemo-embolisation and limited-field EBRT using a linear accelerator. Parameters observed include tumour response, alpha-fetoprotein (AFP) level in serum, human anti-murine antibody (HAMA) assay, T lymphocyte subsets, survival rates, routine parameters, sequential resection rates and histopathological status of the resection specimens. The sequential resection rates were 53% (17/32) and 23% (8/35), and tumour response rates were 72% (23/32) and 86% (30/35) in the RIT and EBRT groups, respectively. The main side-effects in the RIT group were mild allergic reactions. The most common toxicity in the EBRT group was an increase in liver enzymes. The liver tissue in the target volume was injured by EBRT. The injured liver tissue revealed a low-attenuation area adjacent to the hepatic tumour within the target volume on follow-up computed tomography studies after EBRT. On pathological evaluation, the low-attenuation area revealed hyperaemia, distended hepatic sinusoids packed with erythrocytes and hepatic cell loss. The sequential resection specimens from both the RIT and the EBRT group showed residual cancer tissue located at the edge of the mass. The residual cancer cells presented as giant cells under microscopy. T lymphocyte subsets observed prior to treatment did not significantly change after RIT, but were significantly disturbed by EBRT. HAMA formation was the major reason for discontinuing RIT, the incidence being as high as 34% (11/32). Intrahepatic and pulmonary metastases occurred more frequently in the EBRT group (63%) than in the RIT group (22%). The 1-, 2-, 3- and 4-year survival rates were 50%, 41%, 34% and 31% in the RIT group, and 77%, 39%, 11% and 7% in the EBRT group, respectively. It is interesting that the serum AFP level showed a transient increase, the mechanism and importance of which are not known, but are discussed. Both RIT and EBRT are useful treatment modalities for unresectable HCC, serving to prolong survival. However, RIT is much less toxic than EBRT, the side-effects of which include radiation injury to the liver and disturbance of T lymphocyte subsets.

Prognostic analysis of pulmonary metastases from hepatocellular carcinoma

PurposeTo analyze the prognostic factors for the patients with lung metastases from hepatocellular carcinoma (HCC).Methods and materialsOne hundred and five patients with lung metastases from HCC were analyzed retrospectively. We analyzed the impact factors, including the gender, age, liver function, serum AFP and γ-GT level, the status of intrahepatic tumor and pulmonary metastases and treatment for them, the distant metastases beyond the lung, as well as the causes of death. The overall cumulative probability of survival was calculated by the Kaplan–Meier method, and the difference between the groups was compared using the Log-rank test. Univariate and multivariate analyses using the Cox-regression proportional hazard model were performed to evaluate the prognostic parameters for survival.ResultThe survival after the lung metastases was influenced by clinical parameters, such as the status and the treatment for both the intrahepatic tumor and the pulmonary lesions. The causes of death were respiratory failure due to metastatic lesions from HCC in 16 patients (20.0%), liver failure caused by the progressive intrahepatic lesions in 54 (67.5%). The mean and median survival times were 684 and 487xa0days after HCC diagnosis and 264 and 179xa0days after lung metastases, respectively.ConclusionIt was very important to treat the intrahepatic tumor because its worsening was still the major cause of death. The progressive treatment for pulmonary metastases may also be advised for possible prolongation of survival.

Defining prognostic factors of survival after external beam radiotherapy treatment of hepatocellular carcinoma with lymph node metastases.

PurposeTo identify independent predictors of survival in patients with lymph node (LN) metastases from hepatocellular carcinoma (HCC) after external beam radiotherapy (EBRT).MethodsThere were 191 patients with LN metastases from HCC received EBRT enrolled in the study cohort. EBRT was designed to focus on the LNs and a median dose of 50xa0Gy (range 40–60xa0Gy) was delivered. Treatment response was assessed by the WHO response criteria. Factors such as demographic data, tumor characteristics, and treatment modalities were determined before EBRT. Predictors of survival were identified by univariate and multivariate analysis.ResultsThe median survival was 8.0xa0months for all patients. Factors including Child-Pugh status (pxa0=xa00.009), intrahepatic tumor control (pxa0=xa00.015), LN location (pxa0=xa00.015), and response to EBRT (pxa0<xa00.001) were significant prognostic factors predicting for survival by multivariate analysis. The objective regression rate (ORR), which is the sum of complete and partial response rates, was as high as 79.1xa0%. As determined by multivariate analysis, the factors of LN location near liver (pxa0=xa00.002), smaller LN size (pxa0=xa00.021), and higher EBRT dose (pxa0<xa00.001) were associated with higher ORR values.ConclusionThis study provides detailed information about survival outcomes and prognostic factors. Child-Pugh B value, uncontrolled intrahepatic tumor, LN location far from liver, and no response to EBRT are the unfavorable independent predictors.

Caffeine enhances radiosensitization to orthotopic transplant LM3 hepatocellular carcinoma in vivo

The aim of this study was to determine whether caffeine enhanced radiosensitization in an orthotopic transplant of LM3 human hepatocellular cancer in nude mice. LM3 hepatocellular carcinoma cells were infected with red fluorescent protein and irradiated, and cell cycle distribution and survival fraction were detected. A nude mouse model of orthotopic transplant of red fluorescent protein‐expressing LM3 hepatocellular cancer was established. Nude mice were divided into four groups: control (NS); caffeine (Caff) alone; irradiation (IR) alone; and caffeineu2003+u2003IR (Caffu2003+u2003IR). Tumor growth curves were described. Expression of cyclin and apoptosis were evaluated by analysis of phosphorylated cyclin dependent kinase 1 (CDC2) Tyr15 (CDC2‐Tyr15‐P), cyclinB1, TUNEL staining, and caspase‐3. Caffeine abrogated IR‐induced G2 phase arrest and decreased survival of irradiated LM3 cells. Caffeine enhanced radiosensitivity of LM3 hepatocellular cancer in vivo. Tumor growth delay time in the Caffu2003+u2003IR group was 14.3u2003days compared with the NS group, 14.1u2003days compared with the Caff alone group, and 7.2u2003days compared with the IR alone group. At 15u2003Gy, expression of CDC2‐Tyr15‐P in the Caffu2003+u2003IR group (26.0u2003±u20038.9%) was significantly lower than in the IR alone group (68.4u2003±u200310.6%), expression of cyclinB1 and proportion of TUNEL‐positive cells in the Caffu2003+u2003IR group (30.4u2003±u20038.7% and 59.2u2003±u20039.5%, respectively) was significantly higher than in the IR alone group (7.0u2003±u20033.7% and 24.2u2003±u20037.2%, respectively), expression of caspase‐3 was consistent with the TUNEL staining results. This study suggested that caffeine might enhance the radiosensitivity of LM3 hepatocellular cancer in vivo, and may be feasible for further clinical applications. (Cancer Sci 2010)

A SUVmax-based propensity matched analysis of stereotactic body radiotherapy versus surgery in stage I non-small cell lung cancer: unveiling the role of 18F-FDG PET/CT in clinical decision-making

BackgroundThe value of maximum standard uptake value (SUVmax) was overlooked in current studies comparing stereotactic body radiotherapy (SBRT) versus surgery for stage I non-small cell lung cancer (NSCLC). Herein, we aimed to compare the 3-year outcomes based on patients for whom SUVmax were available, and to explore the role of SUVmax in clinical decision-making.MethodsFrom January 2010 to June 2016, data of eligible patients were collected. Patient variables and clinical outcomes were compared in both unmatched and matched groups using propensity score matching (PSM). Multivariate analysis was performed for predictors of poor outcome. The relationship between treatment approach and survival outcome was also evaluated in subgroup patients stratified by SUVmax level.ResultsA total of 425 patients treated with either surgery (325) or SBRT (100) were included. Patients receiving SBRT were significantly older, had a higher level of SUVmax and were more likely to have tumor of centrally located. Multivariate analysis showed that SUVmax and tumor size were significant predictors for 3-year OS, LRC, and PFS, while better PFS was also related to peripheral tumor and surgery. The result of PSM analysis also showed that compared to SBRT, surgery could only achieve better PFS. Subgroup analysis indicated that surgery had added advantage of 3-year LRC and PFS for patients in high SUVmax group (SUVmaxxa0>xa08), but not in low SUVmax group.ConclusionsThe study found a superior PFS after surgery while OS and LRC did not differ between SBRT and surgery. Surgery should be recommended for tumor of high SUVmax.

Radiotherapy for adrenal gland metastases from hepatocellular carcinoma

BackgroundSeveral studies have found benefits of radiotherapy for adrenal metastasis from hepatocellular carcinoma (HCC). However, the efficacy, safety and outcome issues have not yet been fully addressed. Therefore, we performed this study to further elucidate the feasibility and outcome of radiotherapy in treating adrenal metastasis from HCC.MethodsWe retrospectively analyzed 81 patients with adrenal metastasis from HCC between 2001 and 2015. Eighteen patients received helical tomotherapy and 63 patients received conventional radiotherapy, including two-dimensional (2-D) or three-dimensional conformal radiotherapy (3-D CRT). The median radiation dose was 50xa0Gy (range 26–64xa0Gy) with median fraction size of 2.0xa0Gy (range 2.0–5.0xa0Gy). Tumor responses, adverse effects, patient outcomes and prognostic factors were analyzed.ResultsAn objective response (complete and partial response) was achieved in 55.6% patients. The helical tomotherapy group showed higher objective response rate than the conventional radiotherapy group (Pxa0=xa00.031). The major adverse effects were anorexia (51.8%), nausea (41.9%), and fatigue (35.8%). Similar toxicity profile occurred in the 2-D, 3-D CRT and helical tomotherapy groups. The overall survival (OS) rate at 1, 2 and 5xa0years was 59.9, 35.0, and 12.9%, respectively, with a median survival of 15xa0months. Patients who received helical tomotherapy achieved a better OS compared to the conventional radiotherapy group (Pxa0=xa00.047). However, multivariate analysis indicated that radiotherapy technique was not an independent prognostic factor for patient outcome.ConclusionThese results suggest that radiotherapy offers a noninvasive approach in controlling adrenal metastasis from HCC with promising local control and acceptable tolerability.