The emergent role of focal liver ablation techniques in the treatment of primary and secondary liver tumours

Only 20% of patients with primary or secondary liver tumours are suitable for resection because of extrahepatic disease or the anatomical distribution of their disease. These patients could be treated by ablation of the tumour, thus preserving functioning liver. This study presents a detailed review of established and experimental ablation procedures. The relative merits of each technique will be discussed and clinical data regarding the efficacy of the techniques evaluated. A literature search from 1966 to 2003 was undertaken using Medline, Pubmed and Web of Science databases. Keywords were Hepatocellular carcinoma, liver metastases, percutaneous ethanol injection, cryotherapy, microwave coagulation therapy, radiofrequency ablation, interstitial laser photocoagulation, focused high-intensity ultrasound, hot saline injection, electrolysis and acetic acid injection. Ablative techniques offer a promising therapeutic modality to treat unresectable tumours. Large-scale randomised controlled trials are required before widespread acceptance of these techniques can occur.     

Our experience with resection of primary and secondary liver tumours

The authors retrospectively analyse the results achieved in recent years by surgical treatment of 103 malignant primary or secondary liver cancers: (Three patients have been operated on twice at different times for recurrence.) 23 hepatic resections were performed for benign lesions. The operative mortality is very low, the incidence of postoperative complications is minimal, and the survival up to 8 years is rather satisfactory. In all cases we used Ton That Tung's surgical technique, that is, "finger fracture with intraparenchymal ligature of the vasculobiliary pedicles."     

Treatment of primary and secondary liver tumours with selective internal radiation therapy

When HCC is diagnosed at an early stage or liver is affected by a solitary metastasis they can be curable by surgical resection, but this may not be feasible when an extensive tumoural involvement is present. In these cases, possible non-surgical therapies include systemic chemotherapy, chemical ablation (ethanol or acetic acid), radiofrequency ablation, microwave ablation, cryotherapy and transarterial chemoembolisation. All the above mentioned treatments have advantages and disadvantages. In the present paper we reported our experience with selective internal radiation therapy (SIRT) of non-operable HCC and metastatic liver using 99Yttrium (99Y) radioactive microspheres, and our data are compared and discussed with those reported in the literature. A MEDLINE-based review of the literature has been made in the period between 1990 and April 2007. Detailed information on patients selection criteria, SIRT procedure, dose calculation, safety and adverse reactions, follow-up schedule, and clinical efficacy are provided. On the basis of our data, in agreement with those of the literature, SIRT has added another effective method for treatment of primary and secondary liver tumours, being successful in a large number of patients in different experiences. Moreover, SIRT is well tolerated and has minimal adverse effects. Despite being regarded as non-curative, it has been associated with improved survival, reduction in tumour marker, and regression in the number and size of lesions. Follow-up with imaging is essential to assess the response to therapy, and in this respect FDG PET has been shown to be more sensitive than CT, particularly in the early stages.     

Microwave ablation in primary and secondary liver tumours: technical and clinical approaches

Abstract

Thermal ablation is increasingly being utilised in the treatment of primary and metastatic liver tumours, both as curative therapy and as a bridge to transplantation. Recent advances in high-powered microwave ablation systems have allowed physicians to realise the theoretical heating advantages of microwave energy compared to other ablation modalities. As a result there is a growing body of literature detailing the effects of microwave energy on tissue heating, as well as its effect on clinical outcomes. This article will discuss the relevant physics, review current clinical outcomes and then describe the current techniques used to optimise patient care when using microwave ablation systems.     

Effectiveness of isolated liver perfusion with mitomycin C in the treatment of liver tumours of rat colorectal cancer

Dose limiting systemic toxicity prevents sufficient exploitation of the steep dose response relationship of most anticancer agents. In our rat liver tumour model (the CC531 colorectal carcinoma), isolated liver perfusion allows administration of higher doses of mitomycin C than hepatic artery infusion, while systemic toxicity remains minimal. To determine the temporal pattern of mitomycin C induced cytokinetic changes, we analysed flow cytometric DNA histograms of CC531 liver tumours from rats treated with high dose mitomycin C (3.2 mg kg-1) via hepatic artery infusion and sacrificed at different time intervals after treatment. Between 12 and 36 h after treatment, the fraction of cells in late S and G2/M phase had markedly increased. The effects of administration of the respective maximally tolerated doses of mitomycin C in isolated liver perfusion and via hepatic artery infusion on progression of tumour cells through the cell cycle and on gross tumour growth were compared. Isolated liver perfusion with mitomycin C resulted in a significant increase in the proportion of cells in mid and late S, and in some accumulation of cells in early S and G2/M phase at 24 and 48 h after treatment. In contrast, after hepatic artery infusion a significant increase of the fraction of cells in G2/M phase was observed at 24 h after treatment. Monitoring tumour growth after isolated liver perfusion five out of seven rats showed a complete tumour remission, while after hepatic artery infusion only a minimal growth delay was detected. This study demonstrates that isolated liver perfusion in the rat CC531 liver tumour model allows the administration of a well-tolerated dose of mitomycin C being high enough to induce a marked DNA synthesis inhibition and even complete tumour remission.     

Hepatic resection for secondary tumours

The role of liver resection for secondary tumours is reviewed, with particular reference to secondary disease from primary colorectal cancer. While there are no controlled trials producing direct evidence of improved survival following resection, figures on five year survivors without resection are anecdotal. Numerous series now report five year survival of up to 50% following resection, instances of five year survival without resection are now fallen to around 5% in most major series. Factors which adversely affect survival after resection seem to be poor tumour clearance, number of metastases and possibly Dukes' C primary tumours. Other factors, including the extent of resection and size of the tumour, may affect perioperative morbidity and mortality but should not influence long-term survival. Resectional treatment is rapidly gaining an established position in the treatment of colorectal secondaries, and may be considered also for some non-colorectal lesions, particularly endocrine tumours.     

The role of focal liver ablation in the treatment of unresectable primary and secondary malignant liver tumors

Surgical resection is often the first-line treatment option for primary and select metastatic hepatic malignancies. A minority of patients with hepatocellular carcinoma undergo potentially curative resection. Similarly, patients with liver-only metastasis are candidates for resection less than 15% of the time because of bilobar disease in which resection would sacrifice too great a volume of hepatic parenchyma, tumor proximity to major vascular or biliary structures thus preventing adequate margins, or unfavorable tumor biology. Ablative techniques directed at tumor elimination while minimizing injury to the surrounding functional hepatic parenchyma may be offered to select patients with unresectable cancers. Radiofrequency ablation, percutaneous ethanol injection, transarterial chemoembolization, cryoablation, microwave coagulation, and laser-induced interstitial thermotherapy all offer potential local tumor control and occasionally achieve long-term disease-free survival. This review focuses on the indications, anticipated benefits, and limitations of these ablative techniques.     

Paediatric malignant liver tumours

Tumours and pseudotumours of the liver are a heterogeneous group of neoplasm including 60% of malignant tumours. Malignant liver tumours account for less than 2% of the lesions in children and vary considerably in incidence throughout the paediatric age range, with hepatoblastoma, rhabdoid tumour of the liver, hemangioendothelioma, biliary tract rhabdomysosarcoma and mesenchymal hamartoma in the first two years of life and hepatocellular carcinoma, focal nodular hyperplasia, and undifferentiated sarcoma in older children and adolescents. Treatment of malignant epithelial tumours is based on the surgical resection of the tumour associated with pre- and postoperative chemotherapy including cisplatinum. Modalities of the treatment are adapted to risk factors. Survival rates at three years are over 80% for localised hepatoblastoma whereas they are less than 30% in hepatocellular carcinomas. The role of targeted therapies still has to be defined.     

Imatinib in the treatment of solid tumours

The extraordinary success of imatinib in gastrointestinal stromal tumors (GIST) represents a model for molecularly targeted therapy for other solid tumors. Research is currently going to identify the molecular basis of mechanisms of action and drug resistance. In this article, we review recent advances in the clinical management of patients with GISTs treated with imatinib, but also of patients with dermatofibrosarcoma protuberans, chordoma, aggressive fibromatosis, and some other common solid tumors treated with this drug. We reviewed the knowledge of the molecular mechanisms that are basic to imatinib effects in these tumors.     

Microwave ablation of primary and secondary liver tumours: ex vivo,in vivo,and clinical characterisation

Abstract

Purpose: The aim of this study was to compare the performance of a microwave ablation (MWA) apparatus in preclinical and clinical settings.

Materials and method: The same commercial 2.45?GHz MWA apparatus was used throughout this study. In total 108 ablations at powers ranging from 20 to 130 W and lasting from 3 to 30?min were obtained on ex vivo bovine liver; 28 ablations at 60 W, 80 W and 100 W lasting 5 and 10?min were then obtained in an in vivo swine model. Finally, 32 hepatocellular carcinomas (HCCs) and 19 liver metastases in 46 patients were treated percutaneously by administering 60 W for either 5 or 10?min. The treatment outcome was characterised in terms of maximum longitudinal and transversal axis of the induced ablation zone.

Results: Ex vivo ablation volumes increased linearly with deposited energy (r²?=?0.97), with higher sphericity obtained at lower power for longer ablation times. Larger ablations were obtained on liver metastases compared to HCCs treated with 60 W for 10?min (p?<?0.003), as ablation diameters were 4.1?±?0.6?cm for metastases and 3.7?±?0.3?cm for HCC, with an average sphericity index of 0.70?±?0.04. The results on the in vivo swine model at 60 W were substantially smaller than the ex vivo and clinical results (either populations). No statistically significant difference was observed between ex vivo results at 60 W and HCC results (p?>?0.08).

Conclusions: For the selected MW ablation device, ex vivo data on bovine liver was more predictive of the actual clinical performance on liver malignancies than an in vivo porcine model. Equivalent MW treatments yielded a significantly different response for HCC and metastases at higher deposited energy, suggesting that outcomes are not only device-specific but must also be characterised on a tissue-by-tissue basis.     

Electrochemotherapy in treatment of tumours

Aim

Electrochemotherapy is a local drug delivery approach aimed at treatment with palliative intent of cutaneous and subcutaneous tumour nodules of different histologies. Electrochemotherapy, via cell membrane permeabilising electric pulses, potentiates the cytotoxicity of non-permeant or poorly permeant anticancer drugs with high intrinsic cytotoxicity, such as bleomycin or cisplatin, at the site of electric pulse application.

Methods

An overview of preclinical and clinical studies is presented, and the treatment procedure is further critically evaluated.

Results

In clinical studies electrochemotherapy has proved to be a highly efficient and safe approach for treating cutaneous and subcutaneous tumour nodules. The treatment response for various tumours (predominantly melanoma) was ∼75% complete and 10% partial response of the treated nodules.

Conclusions

Electrochemotherapy is a new, clinically acknowledged method for the treatment of cutaneous and subcutaneous tumours. Its advantages are high effectiveness on tumours with different histologies, simple application, minimal side effects and the possibility of effective repetitive treatment.     

Influence of operator experience in radiofrequency ablation of malignant liver tumours on treatment outcome.

AIMS: Radiofrequency ablation is gaining popularity as the interventional therapy of choice for unresectable hepatic malignancies. However, little attention has been paid to the importance of operator experience in this therapy. This study aims to evaluate the results of RFA treatment dependent on operator experience and learning curve. PATIENTS AND METHODS: Between 2/2000 and 11/2004 we have undertaken 116 RFA procedures to ablate 404 unresectable primary or metastatic liver tumours in 84 patients. The clinical data of all patients were recorded prospectively and treatment results of the first 42 patients (group I) and the second 42 patients (group II) were compared. All patients were treated by the same surgeon or interventional radiologist. RESULTS: RFA was performed percutaneously in 44 procedures (group I n = 35, group II n = 9), via laparotomy in 64 procedures (group I n = 27, group II n = 37) and via laparoscopy in eight procedures (group I n = 1, group II n = 7). The complication rate was comparable in both groups with 7.9% in group I and 7.5% in group II. Group II had a higher complete ablation rate (96.2 vs 93.7%) than group I. One- and two-year survival rates of 92 and 89% in group II were significantly higher than in group I with 69 and 46% (p = 0.015). CONCLUSION: By the experience conditional optimization of indication and performance by a specialized RFA team the results could be improved significantly. The data on hand speak for a considerable learning curve in the RFA and demonstrate the importance of the experience of the therapist for the outcome of the patients.     

A mouse model for developing treatment for secondary liver tumors

Metastatic colorectal cancer is the second most common cause of cancer mortality. The liver is a common site of metastasis and only a minority of patients with liver metastases are candidates for potentially curative surgical resection. The treatment of patients with unresectable liver tumors is a major clinical problem and survival remains low. Many animal models of hepatic metastasis do not result in disease which resembles the advanced cancer setting. The purpose of this study was to establish a murine model for use in the evaluation of therapy for secondary liver cancer. Human colon cancer cells were injected directly into the portal vein of nude mice. Magnetic resonance imaging (MRI), performed weekly, was used to follow the time-course and characteristics of tumor growth. As expected, tumor size increased proportionately with time, following inoculation, and the MRI images correlated well with gross pathology findings at necropsy with respect to both tumor size and location. The tumors retained important morphology and biological characteristics of human colon cancer. Mice bearing liver metastasis were treated with irinotecan or drug vehicle. MRI evaluation pre/post-therapy gave an objective measure of therapeutic response. Irinotecan therapy was able to double the survival (median 76-93 days) compared to vehicle alone (median 43-46 days). This murine model is reproducible, rapid, inexpensive and has an excellent success rate for the development of liver metastasis (100%). When used in conjunction with small animal MRI, this model allows the efficient evaluation of the therapeutics of liver metastasis without the use of repeated laparotomy or splenectomy and without requiring large numbers of animals undergoing terminal experiments.     

Electrochemotherapy on liver tumours in rabbits.

Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLM''s cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EP-dependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects. When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies.     

Diagnosis and treatment of obstructive jaundice secondary to liver metastases.

Metastatic disease to the liver and adjacent lymph nodes and may cause jaundice by compression upon the major biliary ducts. Small field relatively high dose radiotherapy after accurate localization can result in effective palliation of jaundice in selected patients.