Hepatocellular Carcinoma - Management

Management

• Liver transplantation to replace the diseased liver with a cadaveric liver or a living donor graft has historically low survival rates (20%-36%). During 1996–2001 the rate had improved to 61.1%, likely related to adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China resulted in overall survival and disease-free survival rates similar to the Milan criteria. Studies from the late 2000 obtained higher survival rates ranging from 67% to 91%. If the liver tumor has metastasized, the immuno-suppressant post-transplant drugs decrease the chance of survival. Considering this objective risk in conjunction with the potentially high rate of survival, some recent studies conclude that: "LTx can be a curative approach for patients with advanced HCC without extrahepatic metastasis". For those reasons, and others, it is considered nowadays that patient selection is a major key for success.
• A receptor tyrosine kinase inhibitor, Sorafenib, approved by the US FDA in December 2005 and in Europe in July 2006, may be used in patients with advanced hepatocellular carcinoma. Sorafenib is a small molecule that inhibits tumor-cell proliferation and tumor angionesis. It has been shown in a Spanish phase III clinical trial to add two months to the lifespan of late stage HCC patients with well preserved liver function. It also increases the rate of apoptosis in other tumor models. The results indicated that single-agent sorafenib might have a beneficial therapeutic effect. In this study, for instance, the median overall survival was of 9.2 months and the median time to progression was of 5.5 months. Also, the survival benefit represented a 31% relative reduction in the risk of death.
• Surgical resection to remove a tumor together with surrounding liver tissue while preserving enough liver remnant for normal body function. This treatment offers the best prognosis for long-term survival, but only 10-15% of patients are suitable for surgical resection. This is often because of extensive disease or poor liver function. Resection in cirrhotic patients carries high morbidity and mortality. The expected liver remnant should be more than 25% of the total size for a non-cirrhotic liver, while that should be more than 40% of the total size for a cirrhotic liver. The overall recurrence rate after resection is 50-60%.
• Percutaneous ethanol injection (PEI) well tolerated, high RR in small (<3 cm) solitary tumors; as of 2005, no randomized trial comparing resection to percutaneous treatments; recurrence rates similar to those for postresection. However a comparative study found that local therapy can achieve a 5-year survival rate of around 60% for patients with small HCC.
• Transcatheter arterial chemoembolization (TACE) is usually performed for unresectable tumors or as a temporary treatment while waiting for liver transplant. TACE is done by injecting an antineoplastic drug (e.g. cisplatin) mixed with a radioopaque contrast (e.g. Lipiodol) and an embolic agent (e.g. Gelfoam) into the right or left hepatic artery via the groin artery. As of 2005, multiple trials show objective tumor responses and slowed tumor progression but questionable survival benefit compared to supportive care; greatest benefit seen in patients with preserved liver function, absence of vascular invasion, and smallest tumors. TACE is not suitable for big tumors (>8 cm), presence of portal vein thrombus, tumors with portal-systemic shunt and patients with poor liver function.

• Radiofrequency ablation (RFA) uses high frequency radio-waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors (<5 cm). A large randomised trial comparing surgical resection and RFA for small HCC showed similar 4 years-survival and less morbidities for patients treated with RFA.
• Focused External Beam Radiation Stereotactic Radiotherapy (SRT) is a technique of using highly focussed radiation to small target volume. SRT has been tried successfully in the liver for treatment of metastases, and currently clinical studies are underway to evaluate its efficacy in treating Hepatocellular Carcinoma. The early results are promising. With the advent of modern computer technology, it is now possible to direct treatment to involved areas of the liver, while sparing normal healthy liver tissue.
• Selective internal radiation therapy can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). There are currently two products available, SIR-Spheres and TheraSphere The latter is an FDA approved treatment for primary liver cancer (HCC) which has been shown in clinical trials to increase survival rate of low-risk patients. SIR-Spheres are FDA approved for the treatment of metastatic colorectal cancer but outside the US SIR-Spheres are approved for the treatment of any non-resectable liver cancer including primary liver cancer. This method uses a catheter (inserted by a radiologist) to deposit radioactive particles to the area of interest.
• Intra-arterial iodine-131–lipiodol administration Efficacy demonstrated in unresectable patients, those with portal vein thrombus. This treatment is also used as adjuvant therapy in resected patients (Lau at et, 1999). It is believed to raise the 3-year survival rate from 46 to 86%. This adjuvant therapy is in phase III clinical trials in Singapore and is available as a standard medical treatment to qualified patients in Hong Kong.
• Combined PEI and TACE can be used for tumors larger than 4 cm in diameter, although some Italian groups have had success with larger tumours using TACE alone.
• High intensity focused ultrasound (HIFU) (not to be confused with normal diagnostic ultrasound) is a new technique which uses much more powerful ultrasound to treat the tumour. Still at a very experimental stage. Most of the work has been done in China. Some early work is being done in Oxford and London in the UK.
• Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed results across studies, but generally considered ineffective Octreotide (somatostatin analogue) showed 13-month MS v 4-month MS in untreated patients in a small randomized study; results not reproduced.
• Adjuvant chemotherapy: No randomized trials showing benefit of neoadjuvant or adjuvant systemic therapy in HCC; single trial showed decrease in new tumors in patients receiving oral synthetic retinoid for 12 months after resection/ablation; results not reproduced. Clinical trials have varying results.
• Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil, interferon, epirubicin, or taxol, as single agents or in combination, have not shown any survival benefit (RR, 0%-25%); a few isolated major responses allowed patients to undergo partial hepatectomy; no published results from any randomized trial of systemic chemotherapy.
• Cryosurgery: Cryosurgery is a new technique that can destroy tumors in a variety of sites (brain, breast, kidney, prostate, liver). Cryosurgery is the destruction of abnormal tissue using sub-zero temperatures. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190°C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to -190°C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 – 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery. Patients may also have insertion of a hepatic intra-arterial catheter for post-operative chemotherapy. As with liver resection, the surgeon should have experience with cryosurgical techniques in order to provide the best treatment possible.
• Interventional radiology
• Agaricus blazei mushrooms inhibited abnormal collagen fiber formation in human hepatocarcinoma cells in an in vitro experiment.
• A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all but two studies showing a response of 71% or greater.
• Gallium maltolate demonstrated in vitro efficacy against several HCC cell lines and produced very encouraging results in a clinical case of advanced HCC that had not responded to therapy with sorafenib. Gallium is known, from gallium scanning results, to be taken up preferentially by many hepatocellular carcinoma tumors. Therapeutic doses of gallium follow the same uptake pathway, causing inhibition of tumor growth and eventual apoptosis of tumor cells, while sparing healthy tissue.