Liver transplantation and conventional surgery for advanced hepatocellular carcinoma

This study intended to discuss the roles of hepatic resection (HR) and liver transplantation (LT) in patients with advanced hepatocellular carcinoma (HCC) through our experience and literature review. For large HCC > 10 cm, HR is regarded as the treatment of choice when hepatic function is preserved. Considering frequent extrahepatic recurrence and acceptable outcome after curative HR, LT has not been recommended. For multiple HCCs, HR has been attempted in different preferences worldwide. HR can offer acceptable survival outcome for patients with small oligo‐nodular HCCs and well‐preserved liver function. Recurrence pattern lowers the applicability of salvage LT, thus primary LT is suggested. For HCC patients with major portal vein tumor thrombus, HR with thrombus removal can be performed, in contrast LT is contraindicated. For HCC with bile duct tumor thrombus, aggressive en bloc resection can lead to prolongation of survival. There is no consensus on transplantability of HCC with bile duct tumor thrombus, but complete resection may provide survival gain after LT. In conclusion, HR and LT have complementary roles, thus they should be associated to rather than being opposed. Multi‐modality treatment strategy especially, for patients with advanced HCC, provides new fields of investigation for diverse indications of HR and LT.     

不可切除和中晚期肝癌的转化切除

近年来,肝癌的药物治疗取得显著进展,成为中晚期肝癌病人延长生存的重要手段.其中仑伐替尼联合程序性死亡因子1(PD-1)抗体的临床探索在中国非常普遍.部分不可切除或中晚期肝癌病人在接受仑伐替尼联合PD-1抗体治疗的过程中出现肿瘤缩小,从不可切除肝癌转变为可切除肝癌.此文从中国肝癌的现状、不可切除肝癌的转化治疗历史和近年来...     

Aggressive resection for advanced pancreatic carcinoma

An aggressive pancreatectomy was performed on a 53 year old Japanese man with advanced cancer of the pancreas. The tumor originated from the body of the pancreas and invaded the stomach, duodenum, left kidney, transverse colon and common hepatic artery. An unexpected cancer was also found in the head of the pancreas during the operation. Therefore, total pancreatectomy, total gastrectomy, left adrenonephrectomy, resection of the left transverse colon and dissection of the regional lymph nodes were performed. Resection of the common hepatic artery was also performed, followed by an end-to-end anastomosis between the common hepatic artery and celiac trunk. The postoperative course was uneventful and the patient was doing well until nine months after the operation when multiple metastatic lesions were noted in the liver. He died 391 days after the operation from hepatic failure.     

Surgical treatment of advanced hepatocellular carcinoma]

One hundred and thirty-two patients with hepatocellular carcinoma in stages III and IV were studied. Seventy-six patients who underwent hepatectomy were divided into three groups: relative curative resection (RC: n = 30), relative noncurative resection (RNC: n = 30) and absolute noncurative resection (ANC: n = 16). Fifty-six patients were treated by non surgical procedures such as hepatic arterial infusion, transcatheter arterial embolization, ethanol injection and hyperthermia. The cumulative survival rate of hepatectomy patients was significantly better than that of non-surgically treated patients. The most significant prognostic factor was the presence of the portal venous invasion. In the patients without tumor thrombi or with tumor thrombi found microscopically, the cumulative survival rates of both RC and RNC were significantly better than those of ANC and non-surgically treated patients, but in the patients with tumor thrombi found grossly, there was no difference between hepatectomy patients and non-surgically treated patients. These results indicate that surgical treatment for advanced hepatocellular carcinoma improve the prognosis of the patients without tumor thrombi found grossly.     

Cytoreductive surgery in multidisciplinary treatment of advanced hepatocellular carcinoma

Background: Cytoreductive surgery (debulking surgery) as a multidisciplinary treatment approach for inoperable advanced hepatocellular carcinoma has been shown to prolong survival and provide symptomatic relief for good surgical risks patients in non‐randomized studies before. Methods: A non‐randomized comparative study was performed in a tertiary referral centre between January 2001 and December 2006. The outcome of a consecutive series of patients with inoperable advanced hepatocellular carcinoma who received cytoreductive surgery was compared with a control group of patients who received palliative treatment without surgery. Two techniques of cytoreductive surgery were used: (i) partial hepatectomy for the main tumour plus intraoperative local ablative therapy for the smaller tumour nodules in the liver remnant; and (ii) partial hepatectomy for the main tumour plus postoperative transarterial chemoembolization. Results: The overall survival of cytoreductive surgery group (n = 18) was significantly better than that of the palliative treatment group (n = 15) (3‐year overall survival, 54% vs 22%; median survival, 18 vs 11 months) (P =0.038). In the cytoreductive surgery group, there was no operative mortality. Postoperative morbidity rate was 16.7%. The mean hospital stay was 8 days. Conclusion: Cytoreductive treatment strategy for advanced hepatocellular carcinoma can be considered as one of the options in selected patients with low operative risks and reasonable liver function. Further prospective randomized trials are required to validate this aggressive surgical approach.     

中晚期肝细胞肝癌的靶向治疗：困境与希望

肝细胞肝癌(HCC)由于起病隐匿,大部分患者确诊时已失去根治的机会,故化学药物治疗在中晚期HCC治疗中有重要地位。随着在基因层面认识的提高和分子生物学研究的深入,对HCC的发病原因及分子通路都有了更新的了解,为靶向药物的运用提供了基础。近10余年来,HCC的靶向药物研究已取得部分成果,索拉非尼已被FDA批准用于治疗进展期HCC。然而其余靶向药物的临床试验结果却不尽人意,HCC靶向药物的研究似乎进入了瓶颈期。笔者就中晚期HCC的靶向药物治疗进展做一综述,并分析诸多临床试验失败的可能原因及可行的解决措施。     

Extended surgery for advanced colo-rectal carcinoma (stage IV and V)

Two hundred fifty-five patients with colo-rectal carcinoma underwent operations in our department between January 1980 and December 1988. The five-year survival rate of stage IV patients (30 cases) was 58%, and the three-year survival rate of stage V patients (44 cases) was 8%. The study for the expression of blood group-related cancer-associated antigens (Lea, CA19-9, etc.) in colo-rectal cancers using immunohistological method and a series of mouse monoclonal antibodies revealed that the stromal staining pattern of CA19-9 means high malignancy with poor prognosis. Nineteen patients with locally invading rectal cancer were submitted to total pelvic exenteration with urinary diversion. The operative mortality rate was 5.3%. A determinate 5-year survival rate of 4.5 was achieved. Fourteen patients with local recurrent lesions of rectal cancer following abdominoperineal resection were submitted to pelvic exenteration combined with sacral resection. Two patients are alive disease free for longer than four years at this writing. This operation assures a better quality of life, lessening of symptoms, disease control and, in selected patients, a cure.     

Aggressive surgery for carcinoma of the gallbladder

Forty patients with gallbladder cancer were admitted to our institution in a 9-year period. For two patients with Nevin's stage I carcinoma who had undergone cholecystectomy, resection of the lower portion of the fourth and fifth segments of the liver and extrahepatic bile duct with dissection of lymph nodes was carried out as a second-stage operation. Thirteen patients with stage V carcinoma underwent extensive aggressive operations. Operative procedures comprised various types of liver resection with cholecystectomy and extrahepatic bile duct resection and wide lymph node dissection in all cases, portal vein reconstruction in 3, pancreatoduodenectomy in 3, partial colectomy in 3, and right nephrectomy in 1. The operative and in-hospital mortality rates were 0%. Two patients with stage I carcinoma are both doing well. Two patients with stage V carcinoma who underwent an extended operation are working without recurrence 7 years 8 months and 8 years 5 months after surgery. From our experiences we believe that long-term survival may be achieved by aggressive surgery if it is suitably indicated.     

Reductive surgery plus percutaneous isolated hepatic perfusion for multiple advanced hepatocellular carcinoma

OBJECTIVE: To evaluate the efficacy of a novel 2-stage treatment with reductive surgery plus percutaneous isolated hepatic perfusion (PIHP) for multiple hepatocellular carcinoma (HCC), which was previously unresectable. SUMMARY BACKGROUND DATA: Surgical resection is the treatment of choice for HCC, but the majority of patients with advanced HCC are not suitable candidates. PIHP is a minimally invasive surgery that allows high-dose regional chemotherapy of the liver, and our phase II studies have shown its profound efficacy for the local control of advanced HCC. METHODS: Twenty-five patients with multiple advanced HCC were enrolled in this prospective study. In the first stage, all patients underwent reductive hepatectomy: major hepatectomy in 13 patients and segmentectomy or less in 12. In 2 patients with subsegmentectomy, the retropancreatic and periportal metastatic lymph nodes were synchronously resected. Regardless of the type of hepatectomy, all patients routinely underwent cholecystectomy, and ligations of the right gastric artery and arterial collaterals of the remnant liver to increase the safety and efficacy of PIHP. In the second stage, PIHP with doxorubicin 60-120 mg/m2/treatment was planned for a period of 1 to 3 months after surgery. RESULTS: Of 25 enrolled patients, 22 successfully underwent PIHP an average of 1.8 times for the local control of residual liver tumors. In the remaining 3 patients, PIHP was abandoned because 2 had rapid disease progression and 1 had liver failure after surgery. In 22 patients with the 2-stage treatment, 19 (86%) had objective local tumor control (10 complete remissions and 9 partial responses with a median response duration of 16 months). The actuarial survival rate of all 25 patients was 42% at 5 years. CONCLUSIONS: Reductive surgery plus PIHP produced a strong antitumoral effect on multiple advanced HCC, when liver function allows this concentrated treatment approach, and offers long-term survival in a subset of patients who were previously deemed to have unresectable disease.     

Progress in surgery for hepatocellular carcinoma

Before 1980, the surgical procedure for liver resection was limited to major hepatectomy. Anatomical resection for subsegmentectomy based on liver anatomy was established after 1980. Surgical techniques to resect nonpalpable and nonvisible tumors and devices to reduce blood loss in the resection plane of the liver are mandatory when performing subsegmentectomy. Intraoperative ultrasound has played a major role in the progress achieved. Hepatectomy procedures preservation of the inferior right hepatic vein, and preoperative portal vein embolization have also contributed to progress in the field of liver surgery.     

Aggressive surgical management of fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma (FLHC) is recognized as a distinct clinicopathologic variant of hepatocellular carcinoma. Ten consecutive patients with FLHC undergoing operative management at our institution were reviewed. At the initial presentation seven patients had stage II disease (pT₂N₀M₀), whereas three patients were in stage III (pT₂N₀M₀ or pT₃N₀M₀). Initial procedures included formal right or left hepatectomy in four patients, right or left trisegmentectomy in two patients, left lateral segmentectomy or nonanatomic resection in three patients, and in one patient considered for liver transplantation, only exploration with biopsy of positive nodes was performed. Four stage II patients required a second procedure for resection of recurrent disease from 8 months to 6 years after the initial resection and one patient required a third procedure after 13 years. Reoperations included hepatic re-resection, resection of extrahepatic disease, and liver transplantation. Overall 5- and 10-year Kaplan-Meier survival was 70%. There were no deaths among stage II patients (follow-up 96 to 180 months). All stage III patients (i.e., lymph node involvement, vascular invasion, or multiple tumors) died within 5 years. Patients with stage II disease had better survival than patients with stage III disease (P=0.011, log-rank test). Aggressive treatment of FLHC including reoperation and liver transplantation is justified, especially in patients with stage II disease.     

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在就诊的原发性肝癌病人中 ,大多数已至晚期 ,如不积极、合理地进行治疗 ,预后很差 ,生存期仅 3～ 6个月 ,对这些病人治疗的研究具有很大的社会意义。何谓晚期肝癌 ?根据 1977年我国拟定的肝癌分期标准和 1999年全国肝癌会议对分期修改讨论稿 ,Ⅲ期 (Ⅲａ、Ⅲｂ)为晚期肝癌[1 ] ,临床缺少有效治疗方法。根据国内外文献和临床多年的实践经验 ,均认为对晚期肝癌特别那些尚无黄疸、腹水 ,肝功能尚好的Ⅲａ期病人应根据不同病情 ,恰当合理的选择和联合不同方法进行多模式综合治疗 ,可获得病情缓解 ,延长生存期 ,部分病例可能获得意外的良好疗效…     

Significance of reduction surgery for stage IV hepatocellular carcinoma (HCC) and postoperative immunochemotherapy for extension of survival period]

A retrospective analysis of 35 stage IV HCC (26 IV-A case and 9 IV-B cases) which underwent reduction surgery from 1983 suggested a possibility to extend their survival period by decrease in their tumor-mass and subsequent immunochemotherapy for improvement of their depressed immunity. Their operability depended on the clinical stage of accompanying liver cirrhosis and extent of distant organ metastasis. It is of first importance for reduction surgery to select intrahepatic multiple tumors, slow-growing and not rapidly to induce distant organ metastases, among them. Intrahepatic tumors arising from multicentric origins were found in 42% in IV-A cases but 0% in IV-B. DNA ploidy analysis of the multicentric tumors in 8 cases did not show any clear indication of resectable tumors according to DNA index. The present immunochemotherapy is composed of a continuous infusion of IL2 and intermittent one-shot injections of 10mg ADR to the remnant liver by using subcutaneously implanted pump. In patients who could enhance peripheral NK and LAK activities by the immunotherapy, decreases in intra- and extra- hepatic tumors were observed. The 2 year-survival rate was 49% in IV-A, but only one case who is receiving the immunotherapy is surviving over 2 years in IV-B.     

Aggressive therapy for locoregional recurrence after mastectomy in stage II and III breast cancer patients

Background: To determine if aggressive treatment of locoregional recurrence affects survival, we retrospectively analyzed the clinical outcome of 69 breast cancer patients who developed locoregional disease as their first episode of recurrence following mastectomy and adjuvant chemotherapy. Methods: Patients were identified from among 1,707 stage II and III breast cancer patients who enrolled in five different doxorubicin-based adjuvant chemotherapy protocols at The University of Texas M. D. Anderson Cancer Center from 1975 to 1986. Sixty-nine evaluable patients who had a locoregional recurrence as the first site of relapse after mastectomy formed the study group. Multifactorial analysis of clinical and histopathological characteristics of both the primary tumor and the subsequent recurrence was performed using a logistic regression method. Survival analysis was performed using an actuarial life-table method calculated from the date of registration into the adjuvant therapy protocols. Results: Median follow-up was 6.6 years. Two factors significantly affected survival: recurrence of disease during or after adjuvant treatment of the primary and whether the patient was rendered disease free after recurrence. Conclusions: Stage II and III breast cancer patients who have locoregional recurrence after adjuvant chemotherapy and can be rendered disease free may have a better survival rate. Aggressive treatment of locoregional recurrence including complete surgical excision should be considered in this subgroup of patients.     

肝癌肝移植术后复发机制及其防治

原发性肝癌是位列中国第二位的恶性肿瘤,全世界每年新发肝癌的一半以上在我国[1].近年来,肝移植在我国发展迅速,技术日臻成熟,肝移植亦已成为治疗肝癌的一个重要手段,目前肝癌肝移植约占我国每年开展肝移植的30%～40%,比例较国外明显偏高[2].     

Factors associated with early recurrence after resection for hepatocellular carcinoma and outcomes

BACKGROUND: Early recurrence (ER) (<1 year) after liver resection is one of the most important factors that impact the prognosis of patients with hepatocellular carcinoma (HCC). We sought to determine factors associated with ER of HCC and examine the outcomes thereafter. STUDY DESIGN: From March 2001 to June 2003, 56 patients underwent hepatic resection for HCC at University of Toronto and were prospectively followed with median followup of 24 months. Patients with ER were compared with those who remained disease free for more than 1 year. Patient characteristics, tumor stage, and operative procedures were evaluated for their prognostic significance by univariate and multivariable analysis. Time to recurrence and time to death were analyzed using Kaplan-Meier survival curves and compared using log-rank analysis. RESULTS: The initial procedure in all patients was surgical hepatectomy. ER occurred in 21 patients (38%), 31 (55%) remained disease free for more than 1 year, and 4 (7%) were omitted from evaluation because of early (<30 days) death. Median survival after initial hepatic resection for those with ER was 27 months, and 2-year survival was 54%. There were no deaths in the group that remained disease free for more than 1 year (100% 2-year survival, p < 0.05). By multivariate analysis, vascular invasion and positive microscopic margins were significant predictors when all 4 variables were considered in the model (p < 0.05). After ER, 11 of 21 patients (52%) underwent additional therapy with significant improvement in median survival (33 months) compared with those not eligible for conventional therapy (18 months, p = 0.05). CONCLUSIONS: ER after liver resection for HCC is the leading cause of death during the first 2 years after potentially curative resection. ER will develop in approximately 75% of patients with either vascular invasion or positive margins. For patients with these predictive factors additional treatment might be advised.     

Extended surgery for local recurrence and advanced rectal cancer

Although much effort has been directed at reducing the incidence of local recurrence after surgical resection of rectal cancer, there remain a significant number of patients who will develop local recurrence without evidence of metastatic disease. Such patients, as well as patients with locally advanced rectal cancer at presentation, may represent a surgical challenge. Application of sound surgical principals and team work can lead to a good long term outcome. This paper sets out to discuss the philosophy and techniques involved in the surgical management of such patients.     

The indications for tumor mass reduction surgery and subsequent multidisciplinary treatments in stage IV hepatocellular carcinoma

The indications for tumor-mass reduction surgery and subsequent immunotherapy in patients with stage IV hepatocellular carcinoma (HCC) were elucidated in this study. About 42% of the resected specimens from stage IV-A patients (n=26) contained well-differentiated multicentrically occurring HCC, which was not found in any of the stage IV-B patients (n=9). The 2-year survival rate after reduction surgery was 49% for the stage IV-A patients and only 13% for the stage IV-B patients, while 6 of the stage IV-A patients who survived for more than 2 years had no vascular invasion or distant organ metastases. Some of the stage IV patients maintained normal peripheral natural killer (NK) activity and were also able to tolerate surgical insults immunologically, provided that appropriate postoperative immunotherapy was given. Thus, stage IV-A HCC has a greater possibility of containing slow-growing intrahepatic tumor clusters, and the removal of any rapidly growing tumors from among these should be undertaken by reduction surgery followed by subsequent multidisciplinary treatment for residual tumor cells, including appropriate immunotherapy.     

原发性肝癌肝切除术后复发患者的肝移植治疗

目的观察肝移植治疗原发性肝癌肝切除术后复发患者的疗效。方法回顾性分析11例原发性肝癌肝切除术后复发接受经典原位肝移植治疗的受者的临床资料,观察移植效果。结果在围手术期,1例术后发生移植肝功能不全和凝血功能障碍并发肾功能衰竭死亡;1例术后出现急性胰腺炎,给予生长抑素治疗10d缓解;2例发生急性排斥反应,行大剂量甲泼尼龙冲击治疗3d逆转。10例受者顺利出院。出院后,3例分别于术后第5个月、第7个月、第19个月死于肝癌复发,1、2年受者存活率分别为72．7％（8／11）和63．6％（7／11）,至今最长存活的1例已达4年余。获长期存活的受者肝癌肝切除术前原发病均为小肝癌,肝切除术后复发行肝移植时肝癌均符合Milan标准。结论小肝癌行肝癌肝切除术后应密切随访,如发现肝癌复发且符合Milan标准可考虑行肝移植治疗,患者仍有可能获较长时间生存。     

Intraoperative ultrasound in surgery for hepatocellular carcinoma

Imaging-guided therapeutic procedures have modified the approach to HCC both introducing new treatment modalities and also changing the policy of hepatectomies. Indeed, with intraoperative ultrasonography (IOUS) it is possible to achieve better knowledge about tumor location and staging, also with the aid of contrast-enhanced IOUS. However, IOUS also allows to minimise the rate of major hepatectomies maintaining treatment radicality and widening the indication at surgery. Indeed, precise definition of tumor-vessel relationship, intrahepatic vessel distribution and color-Doppler analysis allows performing hepatectomies otherwise not possible. This so-called "radical but conservative" policy has allowed us a safe surgical approach with minimal mortality and major morbidity and effective local treatment with no tumor relapses at the site of the resection. Techniques for safe and radical IOUS-guided liver resections for HCC are here discussed.