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Chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of pooled data
180A
AASLD ABSTRACTS
HEPATOLOGY October 2001
25
26
GROWTH RATE OF PRIMARY SINGLE HEPATOCELLULAR CARCINOMA: DETERMINING THE OPTIMAL SCREENING INTERVAL W I T H CONTRAST ENHANCED COMPUTED TOMOGRAPHY. Kazunori Kubota, Hiroyasu Ina, Nakano General Hospital, Tokyo Japan; Yoichi Okada, Matsuzawa Metropolitan Hospital, Tokyo Japan; Takuji Mukai, Eri Ueda, Sunao Mae, Tetsuya Irie, Nakano General Hospital, Tokyo Japan
HISTOLOGICAL ACTIVITY IN THE NONCANCEROUS LIVER IN PATIENTS W I T H HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA CLINICOPATHOLOGICAL CORRELATION AND SURVIVAL ANALYSIS. Irene O Ng, Ronnie T Poon, Tony W Shek, Sheung T Fan, University of Hong Kong, Hong Kong Hong Kong
We reported the favorable long-term outcomes of the transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) based on the multiphasic contrast enhanced computed tomography (CECT) screening at 50th AASLD Annual Meeting, 1999, Dallas. To determine the optimal CECT screening interval for detecting small HCC, we retrospectively evaluated the growth rate of primary single HCCs. From Jan. 1995 to Apr. 2001, HCC was diagnosed in 80 patients at a single institute by the combination of two-phase CT during hepatic arteriograhy (CTA) and CT during arterial portography (CTAP). Forty-four patients had a primary single nodule and were enrolled in this study. Two experienced radiologists reviewed the past CECT films of 44 patients, and looked for the existence of the HCC nodules. The existence of the nodule in the past film was determined when an early enhancement or late / delayed attenuation was identified at the same location in the CTA and CTAP films. In 19 cases out of them, the HCC nodules were shown at least 2 times on the past CECT films, and the sizes of nodules were measured. The profile of the nineteen patients were as follows; 11 males and 8 females; mean age 68.2y, range 43-92y; 13 HCV, 2 HBV, 1 alcoholic, and 4 cryptgenic. Though serum levels of AFP and PIVKA-II were also measured at the same time with the CECT, they were of no use in detecting small HCC nodules. The existence of each nodule was observed on CECT for a mean of 266.5 days (SD 26.2, range 28-1086). The mean interval of each CECT was 146.4 days (SD 166.2, range 23-969). The nodule sizes on the last CECT ranged between 6 and 65 m m with a mean of 21.9 m m (SD 14.7), and those on the first CECT ranged between 3 and 30 m m with a mean of 13.8 m m (SD 10.1 ) in diameter. Doubling time of tumor volume (DTV) calculated from the nodule size on the first and the last CECT ranged from 34.8 to 496.4 days, with a median of 79.0 days, and a mean of 112.8 days (SD 106.7). DTV between each interval was calculated 31 times, and ranged from 25.9 to 1437 days, with a median of 86.3 days, and a mean time of 145.5 days (SD 253.3). No correlation was found between the nodule size and the doubling time (Correlation coefficient 0.30). DTV was in lognormal distribution. Geometric mean of DTV calculated from the nodule size on the first and the last CECT was 93.5 days and 95% of lower side threshold value was 27.3 day. It means that an HCC nodule less than 10 m m would not exceed 20 m m in diameter in three months. This study confirms that the CECT screening at intervals of three months is adequate for detecting small HCC.
Background: The clinicopathological and prognostic significance of the histological activity of the noncancerous liver in patients undergoing resection for hepatocellular carcinoma (HCC) is controversial. No data are available in a patient population with predominantly hepatitis B related HCC. Methods: We conducted a prospective study on 80 patients undergoing resection of HCC to evaluate the influence of the histological activity of the noncancerous liver on clinicopathological features and prognosis. Based on the histological activity index (HAD score of the nontumourous livers, the patients were classified into 3 groups: mild activity (n = 24) (with HAl score of 0-5), moderate activity (n = 31) (HAI score of 6-9), and severe activity (n = 25) (HAI score of --10). Sixty-six (82.5%) patients were hepatitis B surface antigen (HBsAg) positive and they were also analyzed separately. Results: Overall, higher HAI scores were more frequent in male patients (P = 0.025) and in patients with lower serum albumin levels (P = 0.025) and higher indocyanine green retention at 15 minutes (ICG-R15) (P = 0.025). Pathologically, the tumor size decreased with increasing HAI scores (P = 0.001), and patients with moderate activity had more frequent venous invasion (P = 0.015). However, the disease-free or overall survival rates did not differ significantly among the three groups of patients; and this was also true for the subgroup of HBsAg positive patients. Among the factors that influenced the survival rates with univariate analysis, multivariate analysis revealed that pTNM staging was the only independent risk factor for both overall and disease-free survival (P = 0.001 and 0.002 respectively). Conclusion: HAI score had significant correlation with certain clinicopathological features. However, in patients with hepatitis B related HCC, chronic hepatitic activity in the nontumorous liver does not appear to be a significant factor predisposing to shorter patient survival, and hence HAI score may not be helpful in predicting postoperative prognosis.
27
28
CHEMOEMBOLIZATION FOR UNRESECTABLE HEPATOCELLULAR CARCINOMA: META-ANALYSIS OF POOLED DATA.Josep M. Llovet,Jordi Bruix, Barcelona-Clinic Liver Cancer (BCLC) Group Liver Unit IMD Hosp Clinic IDIBAPS, Barcelona Spain
THE EXPRESSION OF NY-ESO-1, CANCER SPECIFIC ANTIGEN, IN PATIENTS W I T H HEPATOCELLULAR CARCINOMA. Shinichiro Nakamura, Kazuhiro Nouso, Mayumi Taniyama, Yoshiyuki Kobayasi, Harushige Nakatsukasa, Masayuki Uemura, Shuichiro Sato, Eiichiro Yumoto,Junko Yokoyama, Sou Tsuboi, Toshihiro Higashi, Takao Tsuji, Okayama University Graduate School of Medicine and Dentistry, Okayama-City Japan
There is no standard treatment for unresectable hepatocellular carcinoma (HCC). Arterial embolization -associated or not to chemotherapy- is widely used and has a high anti-tumoral effect, but evidences of survival benefits are lacking. However, a recent multicentre randomized controlled trial (RCT) conducted by our group has shown that chemoembolization (using gelfoam and adryamicin-lipiodol) improves survival of well-selected patients with unresectable HCC. Aims and methods.- This meta-analysis of pooled data is aimed to assess' the 2-year survival benefits of embolization/chemoembolization versus conservative management as a primary treatment ofunresectable HCC. Inclusion criteria: RCT published in English as an article, comparing embolization or chemoembolization vs conservative management/suboptimal systemic treatments, with survival as a primary end-point, and that reported 1 or 2-year death rates. Exclusion criteria: Non-RCT or RCT including a control-arm based on chemoembolization, embolization, hepatic intrarterial chemotherapy or hepatic intrarterial radioactive substances. Three sensitivity analysis were performed: 1. Assessment of the type of embolization, with or without chemotherapy 2. Studies including a control group of conservative management. 3. Studies including all trials identified, irrespective of follow-up (1-year death rates). The randomeffects model (REM) of DerSimonian and Laird and the fixed effect model (FEM) of Peto were used. The results are reported as pooled odds ratios (95% CI). Heterogeneity was computed with a chi-square-based Q statistic. Results.- Thirteen RCT were identified, seven of them were included in the meta-analysis. The core group included five studies comparing embolization (3 studies)/chemoembolization (3 studies) versus conservative management (3 studies) or suboptimal controls (2 studies, treated by systemic chemotherapy with 5-fluororacil or oral tamoxifen). Two additional studies reporting one-year survival figures were included in the sensitivity analysis. By contrast, six studies were excluded due to the use of chemoembolization, hepatic intraarterial chemotherapy or hepatic intraarterial radioactive substances as control-arm. Meta-analysis showed a trend favoring treatment using the REM model, and it reached statistical significance when using FEM. For the core group, the pooled odds ratio was of 0.60 (95% CI: 0.35 to 1.02, p=0.06) using REM, and 0.59 (95% CI: 0.39 to 0.9, p=0.014) using the Peto method. Meta-analysis specificallyassessing chemoembolization (cisplatin or adriamycin) showed a pooled OR of 0.49 (95%CI: 0.20-1.19, p=0.12) using REM, and 0.49 (95% CI: 0.29-0.84, p=0.008) using FEM. Sensitivity analysis comparing treatment vs conservative management showed an odds ratio of 0.53 (95%: 0.25 to 1.14, p=0.11), using REM, and 0.53 (95%CI: 0.33-0.86, p=0.01) using FEM. When including studies reporting 1-year survival rates, meta-analysis showed an odds ratio of 0.74 (95% CI: 0.49 to 1.10, p=0.13), with significant heterogeneity amongst the studies. Conclusions.Meta-analysis of RCT showed a trend favoring embolization/chemoembolizationin comparison to conservative management in terms of survival for patients with unresectable HCC. A meta-analysis of individual data is mandatory to identify the subgroup of patients that benefit from chemoembolization.
NY-ESO-1 is a cancer-testis antigen discovered in malignant melanoma. The protein was expressed in several cancers including bladder cancer, lung cancer and head and neck cancer. NY-ESO-1 can induce strong cellular immunity as well as humoral immunity in cancer patients and is thought to be a good candidate for cancer specific immunotherapy; however, little is known about the expression of NY-ESO-1 in h u m a n hepatocellular carcinoma (HCC). The aim of this study is to examine the expression of NY-ESO-1 in HCC and the production of the antibody against the protein and consequently to elucidate feasibility of its use in cancer immunotherapy. Methods: Forty-eight HCC samples and corresponding non-cancerous liver from surgical resections were examined for the expression of NY-ESO-1. RNA was purified from frozen HCC tissues. The cDNA was synthesized from the RNA by reverse transcriptase and amplified with either the primers for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or NY-ESO-1. The expression of NY-ESO-1 protein was examined immunohistochemically using monoclonal antibody against NY-ESO-1 (ES121). Tissue sections were treated with microwave to reactivate the antigen. Antibody production against NY-ESO-1 in patients with HCC was examined by enzyme-linked immunosorbent assay (ELISA) with 96 patients' serum. Results: The mRNA of NY-ESO-1 was expressed in 20 of 48 HCC samples (41.7%) whereas no expression was observed in non-cancerous samples. No correlation was observed between the expression of NY-ESO-1 and the grade of differentiation or tumor size. Immunohistochemical analysis revealed that NYESO-1 protein existed in the cytoplasm of cancer cells in 6 of 9 HCC samples that expressed the mRNA. Antibody against NY-ESO-1 was detected only in 2 of 96 patients with HCC (2.0%). Conclusion: NY-ESO-1 is frequently expressed in HCC in cancer specific fashion. Malignant melanoma patients who do not produce antibody against NY-ESO-1 obtain better anticancer effect by immunization of the protein than patients who has already had the antibody. Therefore lack of the antibody production in most patients with HCC as well as cancer specific production of NY-ESO-1 encourages its use in future cancer immunotherapy.
AASLD ABSTRACTS
HEPATOLOGY October 2001
25
26
GROWTH RATE OF PRIMARY SINGLE HEPATOCELLULAR CARCINOMA: DETERMINING THE OPTIMAL SCREENING INTERVAL W I T H CONTRAST ENHANCED COMPUTED TOMOGRAPHY. Kazunori Kubota, Hiroyasu Ina, Nakano General Hospital, Tokyo Japan; Yoichi Okada, Matsuzawa Metropolitan Hospital, Tokyo Japan; Takuji Mukai, Eri Ueda, Sunao Mae, Tetsuya Irie, Nakano General Hospital, Tokyo Japan
HISTOLOGICAL ACTIVITY IN THE NONCANCEROUS LIVER IN PATIENTS W I T H HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA CLINICOPATHOLOGICAL CORRELATION AND SURVIVAL ANALYSIS. Irene O Ng, Ronnie T Poon, Tony W Shek, Sheung T Fan, University of Hong Kong, Hong Kong Hong Kong
We reported the favorable long-term outcomes of the transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) based on the multiphasic contrast enhanced computed tomography (CECT) screening at 50th AASLD Annual Meeting, 1999, Dallas. To determine the optimal CECT screening interval for detecting small HCC, we retrospectively evaluated the growth rate of primary single HCCs. From Jan. 1995 to Apr. 2001, HCC was diagnosed in 80 patients at a single institute by the combination of two-phase CT during hepatic arteriograhy (CTA) and CT during arterial portography (CTAP). Forty-four patients had a primary single nodule and were enrolled in this study. Two experienced radiologists reviewed the past CECT films of 44 patients, and looked for the existence of the HCC nodules. The existence of the nodule in the past film was determined when an early enhancement or late / delayed attenuation was identified at the same location in the CTA and CTAP films. In 19 cases out of them, the HCC nodules were shown at least 2 times on the past CECT films, and the sizes of nodules were measured. The profile of the nineteen patients were as follows; 11 males and 8 females; mean age 68.2y, range 43-92y; 13 HCV, 2 HBV, 1 alcoholic, and 4 cryptgenic. Though serum levels of AFP and PIVKA-II were also measured at the same time with the CECT, they were of no use in detecting small HCC nodules. The existence of each nodule was observed on CECT for a mean of 266.5 days (SD 26.2, range 28-1086). The mean interval of each CECT was 146.4 days (SD 166.2, range 23-969). The nodule sizes on the last CECT ranged between 6 and 65 m m with a mean of 21.9 m m (SD 14.7), and those on the first CECT ranged between 3 and 30 m m with a mean of 13.8 m m (SD 10.1 ) in diameter. Doubling time of tumor volume (DTV) calculated from the nodule size on the first and the last CECT ranged from 34.8 to 496.4 days, with a median of 79.0 days, and a mean of 112.8 days (SD 106.7). DTV between each interval was calculated 31 times, and ranged from 25.9 to 1437 days, with a median of 86.3 days, and a mean time of 145.5 days (SD 253.3). No correlation was found between the nodule size and the doubling time (Correlation coefficient 0.30). DTV was in lognormal distribution. Geometric mean of DTV calculated from the nodule size on the first and the last CECT was 93.5 days and 95% of lower side threshold value was 27.3 day. It means that an HCC nodule less than 10 m m would not exceed 20 m m in diameter in three months. This study confirms that the CECT screening at intervals of three months is adequate for detecting small HCC.
Background: The clinicopathological and prognostic significance of the histological activity of the noncancerous liver in patients undergoing resection for hepatocellular carcinoma (HCC) is controversial. No data are available in a patient population with predominantly hepatitis B related HCC. Methods: We conducted a prospective study on 80 patients undergoing resection of HCC to evaluate the influence of the histological activity of the noncancerous liver on clinicopathological features and prognosis. Based on the histological activity index (HAD score of the nontumourous livers, the patients were classified into 3 groups: mild activity (n = 24) (with HAl score of 0-5), moderate activity (n = 31) (HAI score of 6-9), and severe activity (n = 25) (HAI score of --10). Sixty-six (82.5%) patients were hepatitis B surface antigen (HBsAg) positive and they were also analyzed separately. Results: Overall, higher HAI scores were more frequent in male patients (P = 0.025) and in patients with lower serum albumin levels (P = 0.025) and higher indocyanine green retention at 15 minutes (ICG-R15) (P = 0.025). Pathologically, the tumor size decreased with increasing HAI scores (P = 0.001), and patients with moderate activity had more frequent venous invasion (P = 0.015). However, the disease-free or overall survival rates did not differ significantly among the three groups of patients; and this was also true for the subgroup of HBsAg positive patients. Among the factors that influenced the survival rates with univariate analysis, multivariate analysis revealed that pTNM staging was the only independent risk factor for both overall and disease-free survival (P = 0.001 and 0.002 respectively). Conclusion: HAI score had significant correlation with certain clinicopathological features. However, in patients with hepatitis B related HCC, chronic hepatitic activity in the nontumorous liver does not appear to be a significant factor predisposing to shorter patient survival, and hence HAI score may not be helpful in predicting postoperative prognosis.
27
28
CHEMOEMBOLIZATION FOR UNRESECTABLE HEPATOCELLULAR CARCINOMA: META-ANALYSIS OF POOLED DATA.Josep M. Llovet,Jordi Bruix, Barcelona-Clinic Liver Cancer (BCLC) Group Liver Unit IMD Hosp Clinic IDIBAPS, Barcelona Spain
THE EXPRESSION OF NY-ESO-1, CANCER SPECIFIC ANTIGEN, IN PATIENTS W I T H HEPATOCELLULAR CARCINOMA. Shinichiro Nakamura, Kazuhiro Nouso, Mayumi Taniyama, Yoshiyuki Kobayasi, Harushige Nakatsukasa, Masayuki Uemura, Shuichiro Sato, Eiichiro Yumoto,Junko Yokoyama, Sou Tsuboi, Toshihiro Higashi, Takao Tsuji, Okayama University Graduate School of Medicine and Dentistry, Okayama-City Japan
There is no standard treatment for unresectable hepatocellular carcinoma (HCC). Arterial embolization -associated or not to chemotherapy- is widely used and has a high anti-tumoral effect, but evidences of survival benefits are lacking. However, a recent multicentre randomized controlled trial (RCT) conducted by our group has shown that chemoembolization (using gelfoam and adryamicin-lipiodol) improves survival of well-selected patients with unresectable HCC. Aims and methods.- This meta-analysis of pooled data is aimed to assess' the 2-year survival benefits of embolization/chemoembolization versus conservative management as a primary treatment ofunresectable HCC. Inclusion criteria: RCT published in English as an article, comparing embolization or chemoembolization vs conservative management/suboptimal systemic treatments, with survival as a primary end-point, and that reported 1 or 2-year death rates. Exclusion criteria: Non-RCT or RCT including a control-arm based on chemoembolization, embolization, hepatic intrarterial chemotherapy or hepatic intrarterial radioactive substances. Three sensitivity analysis were performed: 1. Assessment of the type of embolization, with or without chemotherapy 2. Studies including a control group of conservative management. 3. Studies including all trials identified, irrespective of follow-up (1-year death rates). The randomeffects model (REM) of DerSimonian and Laird and the fixed effect model (FEM) of Peto were used. The results are reported as pooled odds ratios (95% CI). Heterogeneity was computed with a chi-square-based Q statistic. Results.- Thirteen RCT were identified, seven of them were included in the meta-analysis. The core group included five studies comparing embolization (3 studies)/chemoembolization (3 studies) versus conservative management (3 studies) or suboptimal controls (2 studies, treated by systemic chemotherapy with 5-fluororacil or oral tamoxifen). Two additional studies reporting one-year survival figures were included in the sensitivity analysis. By contrast, six studies were excluded due to the use of chemoembolization, hepatic intraarterial chemotherapy or hepatic intraarterial radioactive substances as control-arm. Meta-analysis showed a trend favoring treatment using the REM model, and it reached statistical significance when using FEM. For the core group, the pooled odds ratio was of 0.60 (95% CI: 0.35 to 1.02, p=0.06) using REM, and 0.59 (95% CI: 0.39 to 0.9, p=0.014) using the Peto method. Meta-analysis specificallyassessing chemoembolization (cisplatin or adriamycin) showed a pooled OR of 0.49 (95%CI: 0.20-1.19, p=0.12) using REM, and 0.49 (95% CI: 0.29-0.84, p=0.008) using FEM. Sensitivity analysis comparing treatment vs conservative management showed an odds ratio of 0.53 (95%: 0.25 to 1.14, p=0.11), using REM, and 0.53 (95%CI: 0.33-0.86, p=0.01) using FEM. When including studies reporting 1-year survival rates, meta-analysis showed an odds ratio of 0.74 (95% CI: 0.49 to 1.10, p=0.13), with significant heterogeneity amongst the studies. Conclusions.Meta-analysis of RCT showed a trend favoring embolization/chemoembolizationin comparison to conservative management in terms of survival for patients with unresectable HCC. A meta-analysis of individual data is mandatory to identify the subgroup of patients that benefit from chemoembolization.
NY-ESO-1 is a cancer-testis antigen discovered in malignant melanoma. The protein was expressed in several cancers including bladder cancer, lung cancer and head and neck cancer. NY-ESO-1 can induce strong cellular immunity as well as humoral immunity in cancer patients and is thought to be a good candidate for cancer specific immunotherapy; however, little is known about the expression of NY-ESO-1 in h u m a n hepatocellular carcinoma (HCC). The aim of this study is to examine the expression of NY-ESO-1 in HCC and the production of the antibody against the protein and consequently to elucidate feasibility of its use in cancer immunotherapy. Methods: Forty-eight HCC samples and corresponding non-cancerous liver from surgical resections were examined for the expression of NY-ESO-1. RNA was purified from frozen HCC tissues. The cDNA was synthesized from the RNA by reverse transcriptase and amplified with either the primers for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or NY-ESO-1. The expression of NY-ESO-1 protein was examined immunohistochemically using monoclonal antibody against NY-ESO-1 (ES121). Tissue sections were treated with microwave to reactivate the antigen. Antibody production against NY-ESO-1 in patients with HCC was examined by enzyme-linked immunosorbent assay (ELISA) with 96 patients' serum. Results: The mRNA of NY-ESO-1 was expressed in 20 of 48 HCC samples (41.7%) whereas no expression was observed in non-cancerous samples. No correlation was observed between the expression of NY-ESO-1 and the grade of differentiation or tumor size. Immunohistochemical analysis revealed that NYESO-1 protein existed in the cytoplasm of cancer cells in 6 of 9 HCC samples that expressed the mRNA. Antibody against NY-ESO-1 was detected only in 2 of 96 patients with HCC (2.0%). Conclusion: NY-ESO-1 is frequently expressed in HCC in cancer specific fashion. Malignant melanoma patients who do not produce antibody against NY-ESO-1 obtain better anticancer effect by immunization of the protein than patients who has already had the antibody. Therefore lack of the antibody production in most patients with HCC as well as cancer specific production of NY-ESO-1 encourages its use in future cancer immunotherapy.