Liver cancer: An evolving challenge reaching research maturity
Authors: Jordi Bruix
Journal: Hepatology (2008)

Hepatology has emerged in recent decades as an area of expertise and potentially as an independent medical specialty. This review will not recount the events that prompted the recognition of liver diseases as a distinct field of active clinical and laboratory research, but it is worth mentioning that creation of associations devoted to sharing knowledge and results of clinical and research projects related to liver disease is relatively recent, compared to other disciplines within medicine and biology. Knowledge of the mechanisms of liver disease and of the agents inducing liver damage allowed the transition from mostly observational studies with descriptions of events and development of diagnostic tools to an era where the need to assess and dissect the benefits of potentially effective interventions is critical. Hence, high-impact research is based on carefully designed studies that imply prospective investigations with validated definitions and methods to reach robust conclusions that move the field further forward. This applies both to laboratory and clinical research, and it must be stressed that this is only a division according to the place where the activity is done. Research of any kind would be better divided into good or poor, with the consequences of the latter in the clinical arena being more deleterious for the population. These comments are meant to frame the evolution of liver cancer research as a growing area of interest. The existence of liver tumors was already acknowledged centuries ago. However, until very recently primary liver cancer as an entity usually associated with underlying liver disease has been considered a malignancy that would affect only some specific areas of Asia and sub-Saharan Africa. The consideration of primary liver cancer as an uncommon condition has been maintained until very recently. In addition, it was also common to state that diagnosis was almost impossible at an early stage and that the prognosis was always dismal. Some of the current hepatologists (me among them) were taught in medical school that small hepatocellular carcinoma was only observed in Japan or China, while in the West the tumor would emerge always as multifocal and very aggressive, thus implying death in the short term. Advancements in diagnosis and knowledge have shown that not all these concepts were correct. It is likely that years ago a large proportion of liver cancers were not even suspected, and the deaths of patients with cirrhosis were wrongly attributed to progressive liver failure. The relationship between chronic viral infection and chronic liver disease leading to cancer was not known (hepatitis B virus was discovered in 1967 by Blumberg, and the first tests to recognize hepatitis C virus infection were available in 1989). Thirty years ago, the best imaging tool was hepatic scintigraphy using different isotopes. Its diagnostic accuracy was suboptimal, and as soon as ultrasonography was validated, the diagnosis of liver cancer experienced a major change. Computed tomography and magnetic resonance imaging also came on board; fortunately, it is now feasible to detect and diagnose liver cancer at an early asymptomatic stage where treatment can be highly effective. These clinical developments have been paralleled by major advances in the knowledge of molecular events that determine malignant transformation and progression. A vast amount of data about gene abnormalities, gene expression, pathway derangement, and protein expression have been generated in cell lines and animal models and then evaluated in human samples. Computer-based systems have gathered a massive amount of data in a large collection of specimens and as a result, it is expected that we will finally be able to differentiate liver cancer into separate categories according to molecular profiling. This should be the first step to a more specific therapeutic approach to cancer treatment, ultimately leading to personalized medicine. According to this evolution, we are no longer at the time where retrospective clinical studies reporting the characteristics and outcome of patients with liver cancer represent a major advance in knowledge. As in other areas of biomedical research, the advancement will come from translational research in which the hypothesis developed in the laboratory must be validated in the clinical scenario. Proper identification and validation of any relevant mechanism in liver cancer should open the path for studies assessing the impact of pharmacologic interventions targeting the specific pathway. Laboratory research should again precede human testing; such a step-by-step action will move the field forward. It is important to note that today we are still reaching diagnosis when cancer traits are fully displayed. Major effort will have to be undertaken to develop strategies for early detection, even prior to overt malignant transformation. Studies of blood samples for protein profiling or as-yet unconceived new technology may, in years to come, allow improvements in imaging techniques. These ideally will be able to accurately identify premalignant and malignant sites. At the same time, imaging techniques will have to be refined to assess the efficacy of therapeutic interventions based on molecular targeted agents. Up to now, the therapeutic efficacy is established by measuring tumor burden reduction, but new agents have shown that survival benefit may come from preventing tumor progression by blocking angiogenesis, proliferation, and dissemination. Hence, recognition of response to therapy and decision to modify dosing or establish multiagent treatment will be decided on the basis of functional imaging with criteria still to be developed. Successful conduct of these efforts will require an efficient networking between several areas of interest converging in the field of liver cancer. Only the teams able to mount this collaboration will be fit to properly design the investigations to carry out and interpret the data. Expertise from specialties that may have evolved separately will have to be properly assembled with the generous contribution from all participants. Major research institutions have already constructed such structures for effective interaction between separate fields of knowledge and expertise. At these institutions, the recruitment of enough critical mass is never driven by administrative specialty origin but rather by the degree of intellectual capacity and competence. Scientific journals are also a reflection of this diverse origin of research contributions, as is the case with HEPATOLOGY. Even if the journal is owned by a specialty-based association, the submitted manuscripts come from any research group that has produced a relevant piece of work irrespective of their administrative location. Thereby, whereas a simplistic analysis by administrative bodies may induce some groups to establish barriers for a fruitful and constructive exchange of knowledge among specialties in order to retain the "ownership" of the field, the creative intellectual approach should indeed prime this effort, because only through this joint venture will we be able to advance faster in the battle against cancer in general, and liver cancer in particular. Hepatologists surely have a major role in the study of liver cancer, but input and expert knowledge from surgeons, radiologists, pathologists, epidemiologists, oncologists, as well as several others has to be seen as a need rather than as a competition within the field. Leadership and hence "ownership" of any field of knowledge and research is not based on administrative decisions or origin, but rather in the capacity to evolve, to incorporate novel concepts from any origin, and to team up with others to produce advance. If this is not the case, the final outcome will be personal failure, and what is worse, lack of intellectual reward that in the end is the driving force for all those actively involved in research, either clinical or basic.