Advances in clinical research of hepatocellular carcinoma in China

Abstract

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TEXT

Based on the survey in 1990/1992, hepatocellular carcinoma (HCC) has become the second cancer killer in China, the mortality rate was 20.37/100000[1]. The etiological background of HCC in China includes: Viral hepatitis-around 90% of HCC in China had evidence of hepatitis B virus (HBV) infection, whereas hepatitis C virus infection was found in only 10%-30% of HCC patients. HGV-RNA was less important as compared to HBV/HCV. The second factor was aflatoxin B1 (AFB1), particularly in areas with high temperature-humidity index. In the rural areas, contamination of drinking water was claimed correlates with high HCC mortality, and microcystin was found to be promoter of hepatocarci nogenesis. The others include alcohol, smoking and genetic factors. Using trees hrew experiment, synergetic effect was found between HBV and AFB1, the incidence of HCC in HBV + AFB1 group was 52.9%, whereas it was only 12.5% in AFB1 group, 11.1% in HBV group, and 0% in the control[2]. For primary prevention, “control of water, control of crops, and prevention of hepatitis” has been advocated, and being proved to be effective since the 1970s[3]. It was reported, during the period of 1993/1994, HB vaccination has been given in 96.9% of new born babies in the cities, and 50.8% in the rural areas. It is predicted that a decline of HCC incidence will probably happen in decades later.

In clinical aspect, lobectomy for large HCC in the 1950s has benefited to 5%-10% of HCC patients. Liver transplantation appeared in the 1960s. In the 1970s, as a result of alpha fetoprotein (AFP) serosurvey, the study of small HCC has benefited to the second part of 5%-10% of HCC patients. Diagnostic level of HC C has been greatly improved due to the rapid progress of medical imaging. The advances in regional cancer therapies and multimodality combination treatment have resulted in cytoreduction and sequential resection for initially unresectable HCC, which will benefit to the third part of 5%-10% of HCC patients. In the 1990s, the rapid progress of molecular biology will be certainly of implication in the diagnosis and treatment of HCC, and the study of recurrence and metastasis have become an attractive field of study. Unfortunately, the prognosis of HCC remains disappointed. The relative 5-year survival rates reported in the United States during 1974/1976-1980/1982 and 1986/1993 were 4%, 4% and 6% in white, and being 1%, 2% and 4% in black[4]. The relative 5-year survival rates in a high risk area of China-Qidong county in the period of 1972/1981 and 1982/1991 were only 2.2% and 2.3% respectively[5].

DIAGNOSIS OF HCC

No remarkable progress was made in the field of tumor marker for HCC. A report said that detection of fragment of fibronectin in plasma was helpful for diagnosis of HCC, the value in HCC patients was 28.91 g/mL ± 1.96 g/mL, being 9.60 g/mL ± 2.42 g/mL for chronic liver disease, and 4.32 g/mL ± 3.10 g/mL in normal control[6]. Spiral CT was claimed of value for diagnosis, the sensitivity was 89% in the arterial phase, 72% in portal phase and being 91% for double phase[7].

LONG-TERM SURVIVORS RELATED TREATMENT

By the end of 1992, at the Liver Cancer Institute of Shanghai Medical University (author′s institution), 320 HCC patients have survived more than 5 years, 100 of them survived more than 10 years. Most of the long-term survivors came from small HCC resection, the second source being large HCC resection, and cytoreduct ion and sequential resection ranked third, palliative surgery other than resection ranked fourth. At the author′s institution, treatment modalities that result ed in prolonging survival included: (1) Small HCC resection, the 5-year survival was 63.4% in 806 cases. (2) Large HCC resection, the 5-year survival was 39 .6% in 1061 cases. (3) Cytoreduction and sequential resection for initially unresectable HCC, the 5-year survival was 64.7% in 93 cases who had tumor cytor eduction by hepatic artery ligation and cannulation; in another 70 cases, sequential resection was done after cytoreduction by transcatheter arterial chemoembolization (TACE), the 5-year survival was 56.0%. (4) Reresection for recurrence , the 5-year survival of 155 patients was 50.9% calculated from the first resection. (5) Palliative surgery other than resection, the 5-year survival of 784 cases (including some patients who had sequential resection) was 21.6%. Cheng et al[8] reported that the 5-year survival of 240 patients treated by TACE was 18.9% (including some patients who had sequential resection. Other treatment that resulted in long-term survivor included radiotherapy combined wi th Chinese traditional medicine, etc. In short, surgery played the most important role, however, the role of regional cancer therapies seems increasing

SURGICAL TREATMENT

The advances of surgical treatment for HCC in China might include: Early resection, first stage resection for HCC in difficult location, re-resection, cytoreduction and sequential resection for unresectable HCC, and palliative surgery other than resection[9]. The 5-year survival of 2051 HCC resections was 36.1% reported by Wu et al[10], and being 50.6% at the author′s ins titution (n = 1866).

Small HCC resection: The encouraging result of small HCC resection was mainly a result of screening in high risk population and yearly checkup using AFP and ultrasonography. At the author′s institution, a prospective controlled trial of screening every 6 months indicated that the percentage of subclinical HCC, resectability rate, and 2-year survival rate were 76.3%, 70.8%, and 77.5% respectively, much higher than that in the control group (0%)[11]. However, the retrospective analysis in Qidong County demonstrated that screening group was only slightly superior to that of nonscreening group, the 5-year survival was 4.0% (being 8.3% for subclinical HCC) versus 1.6%[12]. In the recent years, the 5-year survival of small HCC resection reported in China were around 50%: being 52% (n = 50) reported by Feng et al[13], 79.8% reported b y Wu et al[10], and 63.4% at the author′s institution (n = 806).

Large HCC resection: The 5-year survival rates reported in the recent literature were: 32.9% reported by Du et al (n = 407, including small HCC)[14], 36.1% reported by Wu et al (n = 2051, including small HCC)[10], and 39.6% at the author′s institution(n = 1061). Aggressive surgical approach was also reported for the management of tumor emboli in the main trunk of portal vein[15]. In the technical aspect of HCC resection, unilateral inflow occlusion has been employed more frequently[16,17].

Re-resection for recurrence: As reported, the 5-year survival rates calculated from the first resection were 41.5% (n = 49, DU et al)[14], 53.2% (n = 95, Wu et al)[10], and 50.9% (n = 155, author′s institute).

Cytoreduction and sequential resection for unresectable HCC: At the author′s in stitution, during 1958/1994, 663 patients with HCC were verified to be unr esectable, of them, 72 patients received sequential resection when tumor shrank after treatment; the median tumor diameter reduced from 10 cm (maximum 24 cm) to 5 cm at the sequential resection; the pre-resection treatment includi ng hepatic artery ligation (HAL) plus cannulation (HAI) (38.9%), HAL + HAI + radioi mmunotherapy/regional hyperfractionated radiotherapy (58.3%), single treatment only accounted for 2.8%; the median duration between the first and the second resection was 5 months (1-16 months); operative mortality of sequential resection was 1.4%[18,19]. The 5-year survival rates of sequential resection were 64.7% at the author′s institution (n = 93), 61.5% reported by Wu et al (n = 73 )[10], and 25% in Du et al′s series (n = 20)[14]. Besides , cytoreduction by TACE and followed by resection was also reported: the 5-year survival was 56% (n = 59 at the author′s institution)[20], 39.2% (n = 33, Wang et al)[21], 60.5% (n = 11, after operative hepatic artery cannulation HACE/TAE, Peng et al)[22], and 62.3% (n = 13, after HACE/TAC-E, Yuan et al)[23].

Palliative surgery other than resection: Palliative surgery for HCC includes hepatic artery ligation (HAL), hepatic artery cannulation (HAI), cryotherapy, microwave, intralesional ethanol injection during operation, etc. At the author′s institution, the 5-year survival of 235 patient with HCC treated by cryotherapy w as 39.8%, and being 55.4% for small HCC (n = 80); further analysis revealed that it was 26.9% in single cryotherapy subgroup (n = 78), 39.6% for cryothe rapy+-HAL/HAI(n = 58),46.0% for cryotherapy of residual cancer after resection (n = 27), and 60.4% for resection after cryotherapy (n = 72)[24]. Experimental study demonstrated that high intensive focussed ultrasound (HIFU) was one of the hopeful approach for regional therapy of HCC, and Lipiodol could enhance the response of HIFU[25,26]

NONSURGICAL TREATMENT

Regional cancer therapy is a recent trend for the treatment of HCC, which includes surgical approach as mentioned above, and nonsurgical approach. Interventional radiology and percutaneous ultrasound guided intervention are two major parts of nonsurgical approach. Recently, TACE has surpassed radioherapy to be the first choice of treatment for unresectable HCC. The 5-year survival rate reported by Cheng et al[8]was 18.9% (n = 240, including patients with sequential resection); another series was 7.5% (n = 621), reported by Liu et al[27], and patients with single HCC and without tumor emboli in the portal vein had better prognosis. The commonly used internal radiotherpy was 1311 labeled lipiodol. Radioimmunotherapy is currently under clinical trial, effective tumor shrinkage and followed by sequential resection had been reported using 1311-antiferritin/1311-anti human HCC mAb[28,29]. However, human anti-murine antibody appeared in one third of the patients even administrated intra hepatic arterially[30]. At the author′s institution, chimeric human-mouse antibody has been reconstructed, and radioimmunoimaging obtained in nude mice model[31,32]. In the field of biotherapy, response observed in author ′s institution when LAK/IL-2 plus TAE were used[33]. For drug therapy, Zheng et al[34]reported that tamoxifen is a treatment choice for HCC patients with expression of estrogen receptor[34].

PREVENTION AND TREATMENT OF RECURRENCE AND METASTASIS

At the author′s institution, the previous report indicated that the 5-year recurrent rate after curative resection was 61.5%, and being 43.5% for small HCC; using analysis of HBV-DNA integration and p53 genotype, we also demonstrated that there are both unicentric origin and multicentric origin for recurrent HCC[35]. In this paper, only invasiveness related recurrence will be discussed.

Prediction of recurrence: Predictive markers include serum marker and examination of surgical specimens, which cover molecular and cellular levels. Proliferating cell nucleus antigen (PCNA) and overexpression of p53 in immunohistochemistry indicate poor prognosis[36]. At the author′s institution, poor prognosis has been observed in patients who had higher expression of matrix metalloprote inase-2 (MMP-2) in HCC than that in the surrounding liver[37].

Prevention of recurrence: Peng et al[38] reported that preoperative TACE was only good for HCC > 8 cm but not for HCC < 8 cm. Zhou et al[39] claimed that postoperative immunochemotherapy was helpful to reduce recurrent rate. Han et al[40] reported that postoperative intraarterial chemotherapy decreased 5-year recurrent rate, being 72.0% versus 80.7% when compared to the control, and was only 67.8% in double cannulation group.At the author′s institution, 68 patients with curative resection verified by postoperative lipiodol-CT received TACE and interferon therapy, the 3-year recur rent rate was lower than that reported previously, being 14.7% vs 32.5%; a nother group comprised 105 patients with curative resection and treated with transhepatic arterial/portal vein chemotherapy, the 3-year recurrent rate was also lower than that reported previously, being 18% vs 32.5%.

Experimental model of metastasis: At the author′s institution, we established a metastatic model of human HCC in nude mice (LCI-D20) after orthotopic implantation of intact HCC tissue from 30 patients′ surgical specimens, the metastatic rates to lung, liver and lymph node were extremely high, and 90% of cells were a neuploid, with expression of invasive related genes, the biological characteristics remained unchanged after 50 passages[41,42]; recently, a high metastatic potential HCC cell line-MHCC97 was also established, and lung metastasis appeared after innoculation into liver of nude mice.

Molecular mechanism of HCC metastasis: At the author′s institution, the followings were found to be positively related to HCC invasiveness: p16 (CDKN2) mutation, p53 mutation, p21 (ras), mdm-2, c-erbB-2, TGF EGFR, VEGF, MMP-2, ICAM-1, etc; whereas the followings were negatively related to invasiveness; nm 23-H1, Kai-1, TIMP-2, E-cadherin, etc. However, the difference between expression in small HCC and large HCC was not significant, indicating that even small HCC still facing the problem of biological characteristics[43-54].

Experimental intervention of metastasis:Experimental interventions have been done in metastatic model of human HCC in nude mice (LCI-D20), including: antisense H-ras, anti-HBx/anti CD3 bispecific antibody, BB94-inhibitor of MMP, a ntiangiogenic TNP-470, Suramin, CAI, and antisense VEGsF, and inhibition of tumor growth as well as inhibition of lung metastasis were observed[55-60].

PROSPECTS IN THE 21^ST CENTURY

The followings are important issues to be studied: the “cost effectiveness” of screening, early diagnosis of AFP nonproducing HCC, the better combination mo de of surgery and other therapies, the problem of inadequacy of regional cancer therapies for HCC, the balance of inadequate-treatment and over-treatment, the high recurrent rate after curative resection, the multicentric origin of recurrence, the invasion to blood vessel and distant spreading, the coexisted Child C cirrhosis, etc. It is expected that molecular biology will certainly play an important role, however, it also take time to translate into clinical application. Therefore, prospective control trial using clinically available approaches, particularly multimodality combination treatment, remains important to improve prognosis of HCC.