THE ROLE OF TARGETING THERAPY IN CYTOREDUCTION AND SEQUENTIAL RESECTION OF UNRESECTABLE HEPATOCELLULAR CARCINOMA

ＴＨＥＲＯＬＥＯＦＴＡＲＧＥＴＩＮＧＴＨＥＲＡＰＹＩＮＣＹＴＯＲＥＤＵＣＴＩＯＮＡＮＤＳＥＱＵＥＮＴＩＡＬＲＥＳＥＣＴＩＯＮＯＦＵＮＲＥＳＥＣＴＡＢＬＥＨＥＰＡＴＯＣＥＬＬＵＬＡＲＣＡＲＣＩＮＯＭＡＴａｎｇＺｈａｏｙｏｕ汤钊猷ＹｕＹｅｑｉｎ余业勤Ｚｈ...     

Hepatocellular carcinoma: some aspects to improve long-term survival

Sixty-six patients surviving over 5 years after resection of hepatocellular carcinoma (HCC) are investigated. Of them, subclinical stage amounted to 56.1% (37/66) and moderate stage to 43.9% (29/66). There were 35 cases with small HCC (less than or equal to 5 cm). Cirrhosis was present in 81.1% (54/66). Radical resection was performed in 98.5% (65/66) and palliative resection in 1.5% (1/66). Reoperation for subclinical recurrence and solitary pulmonary metastasis was done in 14 patients, and sequential resection of huge tumors, in three patients. By the end of June 1988, follow-up varied from 60 to 319 months (mean, 115 months); 80.3% of the patients (53/66) are still alive and free of disease; 19.7% (13/66) died with disease. The majority of long-term survivors have returned to their original work; some young patients got married after resection of small HCC 10 years ago, and some can even play football again. Some aspects to improve long-term survival are discussed.     

Treatment for patients with liver metastasis from colorectal cancer--expansion of hepatic arterial infusion therapy

The treatment of patients with liver metastasis from colorectal cancer was evaluated. Although surgical resection was the most effective therapy and 5-year survival was 30%, more than two-thirds of the patients were judged unresectable at the beginning of the treatment. Those whose metastasis was judged to be unresectable received hepatic arterial infusion (HAI) of 5-FU therapy. In a comparison of the survival period, patients received more than 15 g of 5-FU were found to have a statistically significant longer survival than those who received less than 15 g. Even though the patients who revealed a PR or CR response with HAI did not survive more than 4 years, we began surgical resection in these patients after HAI therapy. As a result, the 5-year survival rate of patients whose metastasis was unresectable and who underwent surgical resection after successful HAI was 30% which was equal to the result of the patients judged resectable at the beginning of the treatment. Such treatment may become the fundamental treatment for unresectable liver metastasis in the near future.     

Small hepatocellular carcinoma (HCC) and its remote outcome

Comparative study of 92 cases of pathologically proven small HCC (less than or equal to 5 cm) and 787 clinical HCC treated and followed in Zhongshan Hospital from 1958 to 1984 demonstrated that: 1. Resection of small HCC is the best way for long survival, 26 of the 51 patients who survived for more than 5 years had had small HCC. 2. The increase of the 5 year survival rates from 1.7% (1958-1966) through 7.1% (1967-1975) to 22.6% (1976-1984) of the whole series is due to the increase of proportion of small HCC (0%, 7.2% and 15.1%) in the respective periods. 3. In comparison to clinical HCC, small HCC showed higher resection rate (28.7% vs 85.9%), lower operative mortality (9.7% vs 1.3%) and better 5 year survival (19.9% vs 70.3%). 4. Concepts of early detection, early diagnosis, surgical treatment, management of recurrence and metastasis, prognosis, natural history of HCC, early development of HCC, etc. may be changed basing on this study. Reoperation of subclinical recurrence after small HCC resection has improved the 5 year survival from 56.2% in 1981 to 70.3% in this study.     

Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma

BACKGROUND: Recently, the implementation of screening programs using alpha-fetoprotein (AFP) and ultrasonography in high risk populations has identified increasing numbers of patients with small hepatocellular carcinoma (small HCC). The aim of this study was to summarize the authors' experience in patients who underwent hepatectomy for small HCC and the factors that influence or improve long term survival. METHODS: The study included 1000 patients who underwent hepatectomy for small HCC (< or = 5 cm) and compared them with 1366 patients who underwent hepatectomy for large HCC (> 5 cm) during the same period. A Cox proportional-hazards model was used for multivariate analysis of prognostic factors. RESULTS: Comparison between patients with small HCC (n = 1000 patients) and patients with large HCC (n = 1366 patients) revealed that those with small HCC had a higher resection rate (93.6% [1000 of 1068 patients] vs. 55.7% [1366 of 2451 patients]; P < 0.01), a higher curative resection rate (80.5% [805 of 1000 patients] vs. 60.7% [829 of 1366 patients]; P < 0.01), a lower operative mortality rate (1.5% [15 of 1000 patients] vs. 3.7% [50 of 1366 patients]; P < 0.01), better differentiation of tumor cells (Edmondson Grade 3-4; 14.9% vs. 20.1%; P < 0.01), a higher incidence of single nodule tumors (82.6% vs. 64.4%; P < 0.01), a higher proportion of well encapsulated tumors (73.3% vs. 46.3%; P < 0.01), a lower incidence of tumor emboli in the portal vein (4.9% vs. 20.8%; P < 0.01), and higher survival rates after undergoing resection (5 years: 62.7% vs. 37.1%; P < 0.01; 10 years: 46.3% vs. 29.2%; P < 0.01). No significant difference was found between survival after undergoing minor resection (n = 949 patients) or lobectomy (n = 51 patients) in patients with small HCC (P > 0.05). Reresection for subclinical recurrence or solitary pulmonary metastasis after small HCC resection was undertaken in 84 patients. CONCLUSIONS: Resection is still the modality of first choice for the treatment of patients with small HCC. Minor resection instead of lobectomy was the key to increasing resectability and decreasing operative mortality, and reresection for subclinical recurrence or solitary pulmonary metastasis was important approach to prolonging survival further.     

Long-term survivors after resection for primary liver cancer. Clinical analysis of 19 patients surviving more than ten years

From July 1958 to June 1978, a total of 333 cases with pathologically proven primary liver cancer (PLC) were admitted to the Zhong Shan Hospital, Shanghai Medical University, Shanghai, the people's Republic of China. Of these, 39.6% (132 of 333) were resected and 14.4% (19 of 132) survived over 10 years after resection for PLC. These 19 patients surviving over 10 years were investigated in this paper. All 19 patients underwent radical resection, including right hemihepatectomy in two cases, left hemihepatectomy in ten cases, left lateral segmentectomy in three cases, and local resection in four cases. By the end of June 1988, follow-up varied from 10 years and 1 month to 26 years and 7 months, with a mean follow-up of 15 years and 4 months. All 19 patients are still alive with free of disease. The longest survival patient had a tumor measuring 10 X 8 X 6 cm in size and underwent local resection. Upon follow-up after 26 years and 7 months, the patient was found to be still living and well. Two patients with intraperitoneal ruptured PLC have survived for 19 years and 4 months, and 16 years and 11 months, respectively, after resection of the tumors free of disease and have returned to work. Subclinical recurrence of PLC was discovered in one patient in whom reoperation with cryosurgery was carried out. The patient has been in good condition with negative alpha-fetoprotein (AFP) for 8 years and 10 months after cryosurgery. Subclinical solitary pulmonary metastasis was detected in two patients because of a secondary rise in AFP level. Reoperations were carried out and the metastatic tumors were removed. These two patients are still in good health with negative AFP 9 years and 6 months, and 10 years and 1 months, respectively, after reoperation. These results indicate that early and radical resection are the principal factors influencing long-term survival; reoperation for subclinical recurrence and solitary metastasis remains an important approach to prolong survival further; intraperitoneal rupture of PLC does not exclude the possibility of cure; new surgical techniques, such as cryosurgery and bloodless hepatectomy, have been shown to be effective in some patients.     

Conversion of surgically verified unresectable to resectable hepatocellular carcinoma

During the period 1978–1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were determined by laparotomy to be unresectable, 155 (60.8%) out of them had their tumor mainly confined in right or left lobe and considered to be potentially resectable if remarkable tumor shrinkage appears after treatment. Second look operation was performed in 26 (16.8%) out of the 155 patients after marked reduction of tumor size, resection was done in all of these 26 patients. Triple or quadruple combination treatment with hepatic artery ligation (HAL), hepatic artery infusion (HAI) with chemotherapy, radiotherapy using linear accelerator, and radioimmunotherapy using 131-I antihuman HCC ferritin antibody yielded the highest conversion rate (29.8%, 14/47) as compared to double combination treatment with HAL+HAI, or cryosurgery+HAL (16.9%, 12/71) and single treatment with HAL or HAI or HAE (embolization) (0%, 0/37). The median tumor size of these 26 patients was reduced from 9.5 cm to 5.0 cm after combination treatment. The median interval between the first laparotomy and the subsequent resection was 5.0 (2–16) months. The survival rates calculated by life table method were: 1-year 86.5%, 2-year 74.3% and 3-year 74.3%. Nine cases have survival more than 3 years. Thus, multimodality combination treatment with subsequent resection might prolong survival significantly for some patients with unresectable HCC particularly confined in right lobe of a cirrhotic liver.     

Multimodality treatment and two-stage resection for unresectable hepatocellular carcinoma--experimental and clinical studies

During the period 1978-1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were assessed to be unresectable by laparotomy. Of them 155 had their tumors chiefly confined in the right or left lobe. Second stage resection was performed in 26 (16.8%) after marked reduction of the tumor by combination treatment with hepatic artery ligation (HAL) + hepatic artery infusion chemotherapy (HAI) + multifractionated radiotherapy (MFD) with linear accelerator, or radioimmunotherapy using 131I-anti human HCC ferritin antibody (131I-FtAb), which yielded the highest second stage resection rate (29.8%, 14/47) as compared to HAL + HAI or HAL + cryosurgery (16.9%, 12/71), HAL or HAI (0%, 0/37) alone. The 3 year survival rate of the 26 patients with second stage resection was 74.3%, comparable with those of small HCC resection (82.7%, n = 111) and radical resection of large HCC (56.1%, n = 122) in the same period. Experimental study using nude mice bearing human HCC also showed the superiority of triple (MFD or 131I-FtAb + Cisplatin PDD + mixed bacterial vaccine MBV) versus double (MFD or 131I-FtAb + PDD, or MFD or 131I-FtAb + MBV) and double versus single treatment modality. Both experimental and clinical data indicated that immunosuppression after radiotherapy was prevented by adjuvant immunotherapy (MBV). Thus, this treatment model provides an opportunity for resection or even cure in a part of patients with unresectable HCC confined in one lobe.     

What patients can survive disease free after complete resection for hepatocellular carcinoma?: A multivariate analysis

BACKGROUND: Although there have been extensive studies to determine risk factors affecting survival after resection for hepatocellular carcinoma (HCC), we still do not know which patients can survive disease free after curative resection. This study was undertaken to determine independent risk factors affecting the length of disease-free survival. METHODS: 171 patients, who survived disease free more than 1 year after curative resection, were divided into four groups according to the disease-free period: Group I (n = 96) for the patients with intrahepatic recurrence between 1 and 3 postoperative years, Group II(n = 27) for those between 3 and 5 years, Group III (n = 40) for those between 5 and 10 years and Group IV (n = 8) for those without recurrence within 10 years. The 37 variables (host factors, tumor factors, non-tumor liver factors, surgical factors) were compared among the four groups. Activity of hepatitis and hepatic fibrosis was scored by the Histological Activity Index (HAI). In a multivariate study, possible prognostic variables with a statistical difference in the disease-free survival rate among each category were preliminarily selected from the 37 variables and the independent variables were finally selected using a proportional hazard analysis. RESULTS: The patients' age, indocyanine green retention rate, microscopic tumor capsular invasion and portal invasion, cell differentiation, extent of hepatectomy, aggressiveness of chronic hepatitis and inflammatory activity assessed by HAI score were significantly different among the four groups. In the multivariate analysis, the following variables were selected as the independent determinants favorable for achieving a longer disease-free period: younger age, lower indocyanine green retention rate, solitary HCC with expansive growth, no microscopic portal invasion and lower activity of co-existing hepatitis. CONCLUSIONS: The importance of inflammatory activity in addition to aging, hepatic reserve and tumor characteristics was confirmed as a risk factor for recurrence by multivariate analysis. To achieve better disease-free survival, not only early detection but also suppression of co-existing hepatitis is necessary.     

Rules to carry out hepatic arterial infusion chemotherapy at home for patients with liver metastasis of colorectal cancer

We analyzed the effectiveness and adverse effects of hepatic arterial infusion chemotherapy (HAI) for patients with liver metastasis of colorectal cancer in order to clarify the rules of HAI. We provided HAI to 72 patients after hepatic resection and to 119 patients with unresectable liver metastases. The preventive effect on hepatic recurrence was recognized in the group administered more than 15 g of 5-FU (total dose). The response rate of patients with unresectable metastases was 60.3%. Adverse effects were observed in 65.8% of the patients. It is important to establish a follow-up system in each hospital to treat the patients as soon as possible when patients develop an adverse reaction.     

Outcome of patients with fibrolamellar hepatocellular carcinoma

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of hepatocellular carcinoma, has distinct pathologic features, and typically occurs in young patients without underlying hepatitis or cirrhosis. METHODS: Forty-one patients with the pathologic diagnosis of FL-HCC evaluated at our institution between 1986 and 2003 were identified from a prospective database. RESULTS: Median age of all patients was 27 years. None of these patients had underlying hepatitis or cirrhosis, and only 3 (7%) patients had an alpha-fetoprotein level > 200 ng/mL. Twenty-eight patients with primary disease underwent complete gross resection, and 13 patients were unresectable. In patients treated with resection, median tumor size was 9 cm (range, 3-17), 9 (36%) had vascular invasion, and 14 (50%) had lymph node metastases. There were no perioperative deaths. With a median follow-up of 34 months, 5-year overall survival for resected patients was 76%. However, 5-year recurrence-free survival was only 18%, and of the 9 resected patients with more than 5 years of follow-up, 7 had recurrences. Lymph node metastasis was the only significant negative prognostic factor. Seventeen (61%) patients underwent a second operation for recurrent disease. Median survival for unresected patients with FL-HCC was only 12 months, and no patient survived beyond 5 years. CONCLUSIONS: FL-HCC occurs in a distinctly different population of patients than common HCC, and patients with FL-HCC generally fare better after complete resection. These tumors have a relatively indolent tumor biology, and late recurrences are common. Repeat resections for recurrence should be considered given the lack of other effective treatment options.     

巨大肝癌手术切除治疗的远期疗效

背景与目的：巨大原发性肝癌(直径≥10cm)在临床上占有较大的比例,但关于其手术切除治疗的远期疗效报道较少。本研究探讨手术切除治疗巨大肝癌的远期疗效和预后影响因素。方法：回顾性分析我院1964年至1993年经手术切除的173例巨大肝癌患者的病例资料,根据随访结果计算生存率并作单因素及多因素分析。结果：术后3、5和10年累积生存率分别为31．9％、21．8％和8．3％;生存5年以上37例,生存10年以上8例;单因素分析结果表明预后影响因素为性别、术前肝功能Child-Pugh分级、术中肝硬化程度和是否根治性切除;多因素分析得出影响巨大肝癌切除术后远期疗效的独立预后因素为术中肝硬化程度和是否根治性切除。结论：巨大肝癌应积极争取手术切除治疗,术后能否长期生存取决于肝硬化程度和是否根治性切除。     

术前外周血中性粒细胞与淋巴细胞比值评估肝细胞癌根治性切除术后预后的临床价值

目的 探讨肝细胞癌(HCC)患者术前外周血中性粒细胞与淋巴细胞的比值(NLR)对根治性切除术后预后评估的临床价值.方法 收集行HCC根治性切除术的161例HCC患者的临床资料,根据患者术前NLR值情况,将患者分为高NLR组(NLR≥2.60,n=52)及低NLR组(NLR﹤2.60,n=109).应用Kaplan-Meier方法分析患者的生存率,并采用Log-rank检验差异;采用Cox回归模型分析影响HCC患者总体生存率的预后因素.结果161例HCC患者的中位随访时间为29个月,高NLR组的1、3、5年总体生存率分别为79.6%、70.8%、41.1%,中位肿瘤复发时间14.9个月;低NLR组的1、3、5年总体生存率分别为90.4%、79.6%、48.7%,中位肿瘤复发时间为20.1个月,高NLR组的1、3、5年总体生存率均低于低NLR组(P﹤0.05),中位肿瘤复发时间短于低NLR组(P﹤0.05);单因素分析结果显示:肿瘤包膜、TNM分期、术前AFP、术前高NLR、淋巴结转移、肿瘤大小与HCC根治性切除术后预后生存时间有关,差异有统计学意义(P﹤0.05);Cox多因素分析结果显示:TNM分期为Ⅲ~Ⅳ期、术前AFP﹤400 ng/ml、术前NLR≥2.60、淋巴结转移、肿瘤大小≥10 mm为影响HCC患者根治性切除术后预后的独立危险因素(P﹤0.001).结论 术前NLR是影响HCC患者根治性切除术后预后的独立危险因素,可作为评估患者预后的指标,术前高NLR者其预后较差.     

A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients

Metastasis-related recurrence often occurs in hepatocellular carcinoma (HCC) patients who receive curative therapies. At present, it is challenging to identify patients with high risk of recurrence, which would warrant additional therapies. In this study, we sought to analyze a recently developed metastasis-related gene signature for its utility in predicting HCC survival, using 2 independent cohorts consisting of a total of 386 patients who received radical resection. Cohort 1 contained 247 predominantly HBV-positive cases analyzed with an Affymetrix platform, whereas cohort 2 contained 139 cases with mixed etiology analyzed with the NCI Oligo Set microarray platform. We employed a survival risk prediction algorithm with training, test, and independent cross-validation strategies and found that the gene signature is predictive of overall and disease-free survival. Importantly, risk was significantly predicted independently of clinical characteristics and microarray platform. In addition, survival prediction was successful in patients with early disease, such as small (<5 cm in diameter) and solitary tumors, and the signature predicted particularly well for early recurrence risk (<2 years), especially when combined with serum alpha fetoprotein or tumor staging. In conclusion, we have shown in 2 independent cohorts with mixed etiologies and ethnicity that the metastasis gene signature is a useful tool to predict HCC outcome, suggesting the general utility of this classifier. We recommend the use of this classifier as a molecular diagnostic test to assess the risk that an HCC patient will develop tumor relapse within 2 years after surgical resection, particularly for those with early-stage tumors and solitary presentation.     

影响肝细胞癌术后长期生存的相关因素

通过对复旦大学肝癌研究所20世纪90年代手术治疗的2333例肝细胞癌病例的分析,旨在寻找与长期生存的相关因素.其中根治性切除1465(62.8%)例,姑息性切除868例(37.2%).随访至2003年底,术后存活5年以上者527例,其中根治性切除组454例,姑息性切除组73例.根治性切除后长期生存的相关因素为肿瘤的发现途径,肿瘤大小、包膜,肿瘤细胞的分化程度,肝硬化程度,血清γ-GT水平.姑息性切除后长期生存的相关因素为肿瘤大小、肿瘤包膜、γ-GT、肝硬化程度、术后TACE和二步切除是长期生存独立的影响因素.术后复发的病人经过综合治疗后也能达到比较理想的长期生存率.     

Cerebral metastases from malignant melanoma.

A retrospective study was undertaken of factors affecting survival in 129 patients with cerebral metastases from malignant melanoma referred to the Department of Radiation Oncology from June 1982 to January 1990. Their ages ranged from 19 to 83 years and the time interval from diagnosis of the primary tumour to development of cerebral metastases ranged from one month to 17 years. Cerebral metastases were apparently solitary in 59 (46%) and multiple in 70 (54%) patients respectively. Craniotomy with resection of tumour was performed in 49 patients, of whom 24 had a solitary cerebral metastasis as the only evidence of disease. Most patients (94%) received a course of radiotherapy. Median survival of the whole group after detection of cerebral metastases was 5 months (range less than 1-87+). Univariate analysis indicated that a solitary cerebral metastasis, absence of extracranial disease and tumour resection predicted improved survival, but only surgical intervention was of independent prognostic significance in a multivariate analysis. The effect of cranial irradiation on survival could not be assessed, but the dose of radiation did not influence survival. Of the 10 patients who survived for more than 2 years, eight had total resection of a solitary cerebral metastasis.     

经尿道切除膀胱多发肿瘤和巨大肿瘤

目的:探讨经尿道切除膀胱多发肿瘤和巨大肿瘤的治疗效果。方法:采用经尿道膀胱肿瘤切除（TUR-BT）手术治疗29例膀胱多发肿瘤和/或巨大肿瘤,术后常规膀胱灌注,5例接受系统性化疗。每3个月行膀胱镜检查,必要时再次行TUR-BT手术或全膀胱切除术。结果:术后病理结果均为膀胱癌。随访3-72月,18例存活5年以上。在所有病例中,4例术后1年内死于肿瘤转移,8例无瘤生存,17例术后1-3年复发。复发病例中14例再次或多次行TUR-BT手术,2例行全膀胱切除术,1例行单纯尿流改道手术。结论:经尿道切除膀胱多发肿瘤和巨大肿瘤可以获得较好的治疗效果,根治性TUR-BT辅以系统性化疗或许是膀胱多发肿瘤和/或巨大肿瘤而又希望保留膀胱的病人的理性选择。     

Long-term follow-up of patients of intrahepatic malignancies treated with iodine-125 brachytherapy

PURPOSE: We investigated the role of intraoperative iodine-125 (125I) brachytherapy as a treatment option for unresectable primary and metastatic liver tumors. METHODS AND MATERIALS: Between 1989 and 2002, 64 patients with unresectable or residual disease after surgical resection for intrahepatic malignancies underwent 160-Gy permanent 125I brachytherapy. RESULTS: The median length of follow-up was 13.2 years. The overall 1-year, 3-year, and 5-year actuarial intrahepatic local control rates were 44%, 22%, and 22%, respectively, with a median time to liver recurrence of 9 months (95% CI, 6-12 months). The 5-year actuarial intrahepatic control was higher for patients with solitary metastasis (38%) than for those with multiple metastases (6%, p = 0.04). The 1-year, 3-year, and 5-year actuarial overall survival rates were 73%, 23%, and 5%, respectively (median, 20 months; 95% CI, 16-24; longest survival, 7.5 years). Overall survival was higher for patients with smaller-volume implants (p = 0.003) and for patients without prior liver resection (p = 0.002). No mortality occurred. Radiation-related complications were minimal. CONCLUSIONS: For select patients with unresectable primary and metastatic liver tumors for whom curative surgical resection is not an option, 125I brachytherapy is a safe and effective alternative to other locally ablative techniques and can provide long-term local control and increased survival.     

Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors

BACKGROUND: The indication for liver resection for gastric metastases remains controversial and few previous studies have reported the outcome of surgery in the treatment of liver metastases of gastric cancer. The aim of this study is to clarify the effectiveness of surgical resection for liver metastases arising from gastric cancer. METHODS: A retrospective analysis was performed on the outcome of 42 consecutive patients with synchronous (n = 20) or metachronous (n = 22) gastric liver metastases that were curatively resected. RESULTS: The overall 1, 3 and 5 year survival rates after hepatic resection were 76, 48 and 42%, respectively, and the median survival was 34 months. Univariate analysis revealed that survival significantly differed between cases of solitary and multiple metastases (P = 0.03). Multivariate analysis revealed that solitary liver metastasis and the absence of serosal invasion by primary gastric cancer were favorable independent prognostic factors (P = 0.005 and P = 0.02, respectively). All eight patients who survived for more than 5 years after initial hepatectomy had a solitary metastasis, and six of these had no serosal invasion by the primary gastric cancer. No patient with multiple metastatic diseases survived beyond 3 years. CONCLUSIONS: Patients with a solitary liver metastasis are good candidates for surgical resection, whereas those with multiple gastric liver metastases should be treated by multimodal approaches.