Altered growth patterns of colorectal liver metastases after thermal ablation

doi:10.1016/j.surg.2005.07.030

Surgery

Volume 139, Issue 1, January 2006, Pages 73-81

https://doi.org/10.1016/j.surg.2005.07.030 Get rights and content

Background

Thermal ablation by radiofrequency or laser is used increasingly for the treatment of colorectal liver metastases. Recurrence after thermal ablation is common and occurs both locally and at distant sites. One possible cause of this recurrence may be a result of growth stimulation of micrometastases in the remaining liver. This study examined the impact of thermal ablation on growth patterns of hepatic micrometastases.

Methods

Colorectal liver metastases were induced in male CBA-strain mice via an intrasplenic injection of a murine-derived cancer cell line. Subtotal thermal ablation of the left posterior lobe of the liver (30% of total liver volume) was performed by neodymium yttrium-aluminum-garnet laser 7 days after induction of metastases. The distribution, number, cross-sectional diameter, volume, and proliferation rate of established neoplasms were compared with controls at 21 days after tumor induction. The effect of thermal ablation of 7% of the total liver volume by laser on the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor 2 (FGF-2), transforming growth factor β, and cellular proliferation (Ki-67 antigen) adjacent to the ablated site was assessed by immunohistochemistry in separate groups of animals at specific time points after therapy.

Results

Thermal ablation did not alter the overall volume, number, size, and proliferation rate of neoplasms 21 days after laser ablation. There were no extrahepatic metastases after therapy. The number of neoplasms in the regenerated posterior lobe was equivalent to control despite subtotal ablation (29 ± 2 vs 27 ± 2; P = NS). A greater amount of metastases occupied the regenerated thermal-ablated lobe compared with controls (55% ± 4% vs 29% ± 3%; P < .04). Thermal ablation stimulated liver proliferation adjacent to the treatment site at 12 hours compared with untreated controls. Stimulation peaked at 72 hours (20% ± 1% vs 1% ± 1%; P < .001) and persisted to 21 days after therapy. FGF-2 and VEGF expression increased in liver tissue adjacent to the ablation site compared with baseline, peaking at 12 hours (112% ± 2% vs 102% ± 1%; P < .001) and 72 hours (114% ± 2% vs 101% ± 1%; P < .001), respectively.

Conclusions

Thermal ablation promotes the progression of micrometastases to form macroscopically detectable neoplasms in treated regenerating liver. This effect may relate to an increased expression of VEGF and FGF-2 adjacent to the treatment site.

Section snippets

Animals

Male inbred CBA-strain mice, 6 to 8 weeks of age, were used. Animals were housed in standard cages with access to irradiated food and water ad libitum and exposed to a 12-hour light/dark cycle. All procedures were performed according to the guidelines of the Austin Hospital Animal Ethics Committee.

Liver metastases model

A dimethyl hydrazine–derived primary murine colon cancer cell line was used for the induction of colorectal liver metastases by methods described previously.¹⁰ The histology, vasculature, and growth

Extrahepatic metastases

All animals killed at 21 days after induction of metastases in treatment and control groups had liver metastases without evidence of extrahepatic spread.

Control animals

Macroscopically, there was homogenous spread of neoplasms throughout the liver in the control group. There were no differences in the percentage of metastases between the anterior and posterior lobes in the control group (36% ± 3% vs 29% ± 4%; P = .451) (Fig 1). The absolute number of metastases in the left posterior liver lobe in controls was

Discussion

Cancer recurrence after operative resection of colorectal liver metastases is remarkably high despite preoperative staging using several techniques to identify all metastatic disease.1, 4, 15 The liver is the predominant site of recurrent disease in approximately 50% of patients.1, 4, 15 More recently, thermal ablation by radiofrequency and laser ablation have been used for the treatment of liver neoplasms, with data suggesting similar survival rates to operative resection in selected patients.1

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RFA, microwave or laser-based therapies cause local destruction of tumor tissue by the generation of heat. Mounting preclinical evidence indicates that locally recurring tumors following these ablative techniques, display a more aggressive growth pattern than before the ablation [10,23]. The outgrowth of micro-metastases in the periphery of the ablated lesion was four-fold higher than the outgrowth of micro metastases in non-ablated control liver tissue [10]; this was accompanied by high levels of hypoxia inducible factor (HIF)-1 and HIF-2, as a read out of hypoxia.
Metastatic colorectal cancer (mCRC) is a devastating disease causing 700.000 deaths annually worldwide. Metastases most frequently develop in the liver. Partial hepatectomy has dramatically improved clinical outcome and is the only curative treatment option for eligible patients with mCRC. Pre-clinical studies have shown that surgical procedures can have tumor-promoting local ‘side-effects’ such as hypoxia and inflammation, thereby altering the behaviour of residual tumor cells. In addition, systemically released factors following (colon or liver) surgery can act as a wakeup-call for dormant tumor cells in distant organs and/or help establish a pre-metastatic niche. Tumor handling during resection may also increase the number of circulating tumor cells. Despite the overwhelming amount of pre-clinical data demonstrating the pro-tumorigenic side effects of surgery, clinical evidence is scarce. Indications for hepatic surgery are rapidly increasing due to a rise in the incidence of mCRC and a trend towards more aggressive surgical treatment. Therefore, it is increasingly important to understand the principles of surgery-induced tumor growth, in order to devise perioperative or adjuvant strategies to further enhance long-term tumor control. In the current study we review the evidence for surgery-stimulated tumor growth and suggest strategies to assess the clinical relevance of such findings.
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A retrospective review was done of 2,032 liver tumor embolization, radioembolization, and ablation procedures performed in 1,092 patients from June 2009 to April 2016. Pathology, hepatocellular carcinoma (HCC) stage (American Joint Committee on Cancer), neuroendocrine tumor (NET) grade, initial locoregional therapy, overall survival after initial locoregional therapy, Child-Pugh score, Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index, and outpatient medications taken at the time of locoregional therapy were analyzed for each patient. Kaplan-Meier survival curves were calculated for patients taking 29 medications or medication classes (including prescription and nonprescription medications) for reasons unrelated to their primary cancer diagnosis. Kaplan-Meier curves were compared using the log-rank test.
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In addition, the cellular composition in the periablational rim involves diverse groups of cells (ie, native parenchymal, tumor, or incoming scavenger and immunogenic cells), several types of which are likely producing different proteins in response to sublethal hyperthermic exposure or other inciting processes (endothelial injury or hypoxia). Regardless, further characterization of specific cell types responsible for the various proteomic reactions in the periablational rim may be helpful in refining techniques to suppress RF ablation–induced HIF-1α expression, given that it is implicated in stimulating distant tumor growth in intrahepatic colorectal metastases in animal studies (11,20,22,23). This study also demonstrates that RF ablation resulted in periablational HIF-1α expression in normal liver parenchyma.
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View full text

Altered growth patterns of colorectal liver metastases after thermal ablation

Background

Methods

Results

Conclusions

Section snippets

Animals

Liver metastases model

Extrahepatic metastases

Control animals

Discussion

Surgery

Eur J Surg Oncol

Hepatology

Eur J Surg Oncol

J Gastrointest Surg

J Hepatol

Eur J Cancer

Adv Cancer Res

Advances in the treatment of liver tumors

Curr Probl Surg

Interstitial laser thermotherapy for liver tumours

Br J Surg

Colorectal carcinoma metastases in liver: laser-induced interstitial thermotherapy—local tumor control rate and survival data

Radiology

Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases

Ann Surg

During liver regeneration following right portal embolization the growth rate of liver metastases is more rapid than that of the liver parenchyma

Br J Surg

Promotion of hepatic metastases by liver resection in the rat

Br J Cancer

Characterization of an animal model of hepatic metastasis

J Gastroenterol Hepatol

Microvascular architecture of hepatic metastases in a mouse model

HPB Surg

A model of partial hepatectomy in mice

J Invest Surg

Current status of hepatic resection

Adv Surg

Accelerated tumour recurrence following percutaneous laser hyperthermia of colorectal liver metastases

HPB Surg