Oncology
Management of liver metastases: new horizons for biologically based therapy

https://doi.org/10.1016/j.jss.2003.11.003Get rights and content

Introduction

The liver is a common site of metastatic disease, due to both anatomical and biological (“seed/soil”) factors relating to its complex metabolic and immunological functions. While many malignancies may eventually spread to the liver as part of a widely metastatic pattern, isolated colorectal metastases have been the focus of much attention and are sometimes curable. In this article we review the outcomes and limitations of the current clinical management of colorectal liver metastases. We then analyze the biology of the metastatic process with particular attention to the effects of partial hepatectomy. Upon this foundation, we then review novel biological strategies that are being developed for the treatment of patients with colorectal cancer metastatic to the liver.

Section snippets

Clinical management of colorectal liver metastases

Colorectal cancer is the third most common malignancy in the United States with 128,400 new cases and 56,600 deaths in 1999 [1]. Prognosis for patients with metastatic disease in the liver is limited. Jaffe [2] found a median survival of 5 months with no 5-year survivors in a retrospective analysis of 177 patients with colorectal metastases. Bengtsson found a median survival of 4.5 months after studying a cohort of patients that were found to have liver metastases at the time of colonic

Biology of colorectal liver metastasis

Although the genetic basis of tumorigenesis may vary greatly between different cancer types, the cellular and molecular steps required for metastasis are similar for all cancer cells. The molecular mechanisms that promote invasive growth and metastasis are also found in embryonic development, and to a lesser extent, in the repair processes of adult tissues. Metastasis is a selective, nonrandom, inefficient process consisting of a series of interrelated steps, with only 0.01% of circulating

Anti-angiogenesis agents

A growing number of anti-angiogenesis strategies have been investigated for the treatment of cancer and other angiogenesis-dependent diseases (Table 2). VEGF plays a central role in promoting angiogenesis and is the target of innovative anticancer therapies. Strategies developed for VEGF inhibition include preventing ligand-receptor interaction and blockade of signal transduction. Drugs that block endothelial cell signaling via VEGF and its receptor (VEGFR) that are currently being evaluated

Gene therapy

Gene therapy involves the transfer of genetic material into target cells. Although cancer gene therapy strategies are relatively new, they encompass a major part of this developing field. Various delivery systems are used to transfer the genetic material of interest into metastatic cells. Some of the systems include viral vectors, cationic liposomes, and protein-conjugated DNA. They are used to effect ex vivo or in vivo transfer.

Each vector system has distinct advantages and disadvantages in

Immunotherapy

In theory, immunotherapy is more appealing than chemotherapy because, when triggered appropriately, the immune system has the potential to scavenge the last tumor cell. In contrast, chemotherapy is limited by log-kill kinetics. Both monoclonal antibodies and cytokine-based cancer vaccines by themselves have shown promise for certain tumors; however, they have not yet been shown to be efficacious in patients with metastatic colorectal cancer.

Tumor cells may evade immune destruction by using

Summary

Currently, the only chance for cure in patients with colorectal liver metastases is surgical resection. Despite these encouraging results, only patients who have intrinsically favorable biology that limits spread of the disease are able to benefit from this therapy. In clinical practice, fewer than 10% of patients present with resectable disease, and only a third of resected patients enjoy long-term survival. These poor outcomes underscore the need for novel treatment strategies to manage this

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      Because considerable advances have been made in surgical techniques and perioperative care, it is now possible to provide curative treatment of clearly localized clinical metastases through partial liver resection [1]. However, this surgical procedure is only potentially curative, since 65% of all patients who undergo resection of liver metastases experience recurrence within 5 y [2–4]. Two possible sources of liver tumor recurrence have been described, in particular the development of new metastatic lesions independent of the initial seed (multifocal origin) and the existence of clinically undetectable residual intrahepatic tumor cells in the remaining organ (monofocal origin) [4].

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