Volume 39, Issue 4 , Pages 367-368, August 2012
http://www.seminoncol.org/current
Introduction: Hepatocellular Carcinoma
Article Outline
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Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, with 80% being in the developing world, in which the incidence is starting to decline, in part due to hepatitis B virus (HBV) vaccination. By contrast, HCC is increasing in the developed world, with hepatitis C virus (HCV) and obesity being contributing factors. Only a minority of patients present with tumors small enough to be amenable to potentially curative resection and the remaining patients have a typical survival of less than 12 months. Incidence-to-death ratios are thus almost 1. Although liver transplantation is potentially curative for two diseases simultaneously—namely, for HCC and for the underlying cirrhosis—it is not curative for most patients with advanced HCC and is not available to many patients with limited-stage disease due to poor availability of donor organs or, in the less developed world, due to its high cost. The reasons for the disappointing survival in patients with large HCCs are not entirely clear, unless they have concomitant portal vein invasion, which provides a route to vascular dissemination of the tumor. There are huge geographical variations in incidence and, for patients with cirrhosis, a male to female predominance. The reasons for the large gender disparity are far from clear. Geography may relate to the incidence of predisposing hepatitis and also to dietary contamination with mycotoxic and other hepatocarcinogens. Many of the predisposing causes are known, unlike with most other cancers, and include cirrhosis from any cause, hepatitis B and C chronic carrier status, aflatoxin B1 contamination of stored rice and grains in non-refrigerated conditions, and chronic alcoholism. These factors provide the potential for prevention strategies, including hepatitis virus vaccination or treatment, refrigeration of rural stored food grains, and psychological interventions for chronic alcohol abuse. The large number of years needed for a patient with a predisposing risk such as chronic hepatitis B or C or alcoholism to develop HCC makes it feasible to implement screening for early detection of those known to be at risk, similar to Pap smears for cancer of the cervix uteri.
All of the aforementioned data have been known for decades, with ultrasound screening,
percutaneous ethanol injection (PEI), surgical resection, liver transplant, or chemoembolization being the mainstay of the clinical practice. Why then the need for a special edition of Seminars in Oncology that is devoted to HCC? As summarized in the first article by this guest editor, the last 5 years have seen a great number of advances in a wide array of investigative areas, some of which did not even exist 10 years ago, including proteomics and genomic analyses of clinical samples in treatment decision-making, availability of targeted, non-cytotoxic (chemotherapy) kinase inhibitor therapies (sorafenib, regorafenib, brivanib, linifanib, erlotinib, bevacizumab, and temsirolimus, to name only a few) against specific steps in the cellular proliferation pathways, a vast array of potential new therapies directed against various aspects of cellular protein turnover and against metabolic pathways, newer internal radiation agents (yttrium 90, holmium 66, rhenium 88) and external radiation imaging techniques (IMRT) and particle types (protons), increasing availability of peripheral blood circulating tumor cells as substrates for genomics analysis, a whole array of potential new tumor markers, several of which are becoming part of clinical practice (L3 (fucosylated) form of alpha fetoprotein [AFP-L3], des-gamma-carboxyprothrombin [DCP], glypican-3) and newer diagnostic imaging modalities (contrast-enhanced ultrasound, flow magnetic resonance imaging).
The introduction of sorafenib into routine clinical practice has obliged us to re-evaluate some previously held views, due to some of the associated clinical trial findings. In particular, there are two. First, that survival was enhanced in treated patients compared to control patients, without meaningful tumor shrinkage. Thus decades of oncology thinking that tumor shrinkage was a key to a treatment's usefulness (and our discussions with our patients) needs to be re-appraised. Second, this agent, and many in its class, has the tumor vasculature as a prime target. Given that tumor size can remain unchanged and can be associated with enhanced survival, tumor stability (measured in part as time to tumor progression) becomes increasingly useful as a goal in its own right. We have spent decades in the clinic measuring tumor size and using this as a hallmark for the effectiveness of our therapy.
We now need to develop for clinical use semiquantitative techniques for measuring tumor blood flow and vascularity, and this is in process. Three other new general ideas have recently found support in recent experimental work. They are that patient subsets with likely different prognoses can be identified by molecular probing of tumor biopsy samples and that gene expression patterns of the underlying non-tumor liver may be important in predicting, and likely influencing, HCC growth. A consequence of these two ideas is the importance for clinical decision-making of tumor (and perhaps non-tumor) biopsy. We have entered a very exciting era in HCC clinical and basic research, with profound changes resulting in HCC clinical practice. This series of articles gives us a glimpse of the cornucopia that is unfolding in both diagnostics and therapy. The field of HCC studies promises to be different again in another 5 years, based upon what is unfolding now, especially as a consensus emerges as to which gene signature patterns are reliable and useful, together with the results of the many clinical trials that are just beginning or are being planned, using combinations of therapies that target differing pathways, or combinations of these agents with either chemotherapy or regional radiotherapy.
PII: S0093-7754(12)00119-4
doi:10.1053/j.seminoncol.2012.06.001
© 2012 Elsevier Inc. All rights reserved.
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