Liver cancer: Still a long way to go
Authors: Jordi Bruix
Journal: Hepatology (2011)

This will be my last comment as Associate Editor for HEPATOLOGY with special involvement in the area of liver cancer. I was honored by the invitation to become a member of the Editorial Board directed by Keith Lindor and at the end of the term I can openly assure you that it has been a highly rewarding experience. Being in a position to evaluate manuscripts for a major journal in the field of liver diseases is a teaching experience. It allows me to understand the driving forces that dictate the outcome of submitted manuscripts from the side of the jury. We are all authors of papers submitted to journals with the hope of acceptance, and during our professional life we all undergo a variable degree of success and failure. As in any prior Editorial Board in HEPATOLOGY, the aim has always been to identify those relevant papers that provide additional knowledge in and insight to any aspect of liver biology and of the pathophyisiology and treatment of hepatic diseases. The number of valuable manuscripts far exceeds the number that can be accepted and this forces a highly stringent approach with a low acceptance rate. As a result, negative decisions exceed the number of positive ones and this implies the too frequent delivery of adverse news to the authors, a community where we all belong. All manuscripts are the result of an effort of the authors to answer a question that was felt relevant and to be timely addressed. Not surprisingly, the same question may have been raised simultaneously by several teams and the one that runs faster and delivers robust information is the winner of this competition where all clinical and laboratory investigators participate. The victory may be key to ensure grants, contracts, and recognition by peers. This last reward results in invitations to deliver talks in scientific meetings. It is funny to see how the frequently-invited express the feeling that invitations to give talks at meetings are a very demanding toll. However, it is good to retain the concept that there is only one thing worse than to be invited: not to be invited at all. All these comments serve to frame the value to invest the time needed in thinking and planning what studies are worth engaging in at a point in time and to what extent the results will come in a timely manner and will be felt valuable when the manuscript is finally submitted. This need has been there in most areas of knowledge, but was not so mandatory in the field of liver cancer until recently. The fact that liver cancer had a low incidence in Europe and America and the feeling that it was impossible to detect it at an early stage and to treat it in an effective manner was not a stimulus for intensive clinical research, while the bench research was frequently shared with interests devoted to liver regeneration and control of cell proliferation. All this has sharply changed. Liver cancer is no longer a small area of interest for a reduced number of individuals. Research in the clinical setting is a major field of activity and the availability of novel technologies for molecular profiling has triggered an exponential growth of studies in animal models or in exploiting human tissue samples. For a person entering the field, it may seem that most major unmet needs have been faced and potentially addressed, but this is far from being true. The field may be better structured than decades ago, but all advancements in knowledge at the clinical and laboratory level come together with novel questions and aspects that need further understanding. Frequently, the complexity of novel technology to assess gene expression or any component of cell biology primes the feeling that this is the sole rewarding area of research or at least the one that has the most glamor and recognition. Complex and expensive technology that is not widely accessible or easily understood appears as the path for a major breakthrough in all instances where it is applied. By contrast, research activity in areas that are not so in fashion may be seen as of limited impact. In some instances, it would even appear that the sole activity to be classified as research would be that conducted in part or in total in a laboratory facility, while the rest of the studies that obtain an answer for a relevant question at any level would not qualify as research. Several terms have been raised to divide research into separate categories — basic, laboratory, molecular, translational, epidemiology, outcomes and so on — but the division should be established between good and poor research. If focused in research about humans, and more specifically about liver cancer, it is clear that the driving force for research and publication of manuscripts should not be the mere application of costly cutting-edge technology in a specific setting ultimately leading to a descriptive manuscript. The goal should be the definition of novel concepts and creation of tools for decision-making in the management of patients and this may come both from using complex technology or by just applying the conventional armamentarium that is part of the current standard of care. Hence, intellectual ambition to develop research projects should not be deterred because of the lack of sophisticated tools used. Indeed, the assessment of the value of any novel technology and its potential impact in clinical decision-making requires that the clinical scenario to be solved or clarified is distinctly outlined by prior clinical studies. Otherwise the so-called translational results will be completely flawed. Having expressed that any study to answer a relevant question is valuable, it is worth listing the areas affecting liver cancer that are eagerly awaiting major advancement. The appeal of genomic studies to profile cancer and the impact of the benefits of sorafenib treatment in patients with advanced-stage disease have placed these areas as the apparent top priority, but there are several topics that need major attention and may have an even higher long-term impact on patients and also in the field. It is now established that liver cancer is the major cause of death in patients with cirrhosis and that preventive strategies beyond the treatment of viral infection are urgently needed. Long-term interferon administration has failed to be effective and currently, the sole approach to reduce cancer-related mortality is to attempt early detection leading to treatment. Early detection through screening is still not fully successful and there is a need to develop predictors of liver cancer with high specificity, biomarkers to detect the disease prior to imaging and obviously, imaging techniques to confidently diagnose the malignant site. Optimally, detection should take place at a premalignant stage when the pathways to malignant transformation could be abrogated. Molecular biology will help to understand the transformation process, but only the creative development of clinical projects with prospective follow-up that includes serum and tissue sampling will be able to demonstrate the feasibility and efficacy of any strategy. Major research is also needed in the field of tumor staging with an accurate definition of tumor burden and existence of undetected tumor dissemination. Current treatment failures reflect a major understaging of the disease and this implies a suboptimal use of expensive treatments. Novel imaging techniques or biomarkers may be instrumental for this purpose as well as for the evaluation of treatment efficacy. Current criteria base this assessment in the evaluation of tumor burden reduction. This is fine when the aim is to eradicate as much tumor volume as possible: all of it with resection, transplant, or ablation or part of it as with chemoembolization or radioembolization. However, molecular-targeted agents do not induce a reduction in tumor mass, but even so there is an improvement in survival as a result of a delay in tumor progression. Clearly, research is needed in this setting in order to promptly identify those who respond to therapy and to determine if treatment retains the efficacy. Ultimately, the goal will be to be able to profile the patients prior and during therapy to decide which therapeutic approach is best and at what time the disease recurrence/progression is going to take place. Indeed, recurrence after effective therapy is still a major unmet need that surely will deserve a major research investment. Fulfilling all these endpoints and others not mentioned here will not be achieved in brief; lots of efforts and proposals will fail. In most instances, the work done will be summarized in manuscripts that report the data whether the outcome is positive or negative. Those that represent a valid wealth of information that help to pave the road to ultimate success will be credited for a long time, while those with too much wishful thinking or with suboptimal strength will not pass the proof of time. As editors of journals, we will keep trying to identify those in the first category and when acting as authors, we will all want to fit there. At the very end, we all know that not all the manuscripts we produce are a milestone and we are also aware that not all manuscripts accepted will become a landmark. However, just like everybody else in the world, we will keep thinking that the rejection decisions about our own manuscripts have been unfair and not fully justified. As I step down from the role of Associate Editor, I feel that having been on both sides of the battlefield may help to better cope with the adverse news and prime a temperate acceptance of both favorable and adverse editorial decisions. As with any other author in any field, accepted manuscripts will surely deserve a celebration and hopefully, at the end of the day, these will exceed the number of rejections. Jordi Bruix MD*, * Hospital Clinic, University of Barcelona IDIPAPS, CIBERehd, Catalonia, Spain.