Jordi Bruix

Antiangiogenic therapy: Not just for cancer anymore?

It has now been more than one-quarter of a century since the concept of antiangiogenic therapy as a treatment for cancer was proposed.1 Although it can be debated whether this approach has revolutionized cancer therapy, it has clearly influenced therapy and practice for patients with a variety of cancers. One notable example is hepatocellular carcinoma (HCC), which is a highly vascularized tumor that needs an intense angiogenic activity to develop and progress. In fact, one of the most effective therapies for HCC palliative therapy is chemoembolization, which can be seen as the ultimate antiangiogenic therapy. Recent studies have also delineated a beneficial effect of sorafenib in patients with HCC.2,3 Sorafenib is a receptor tyrosine kinase inhibitor with multiple targets on multiple cell types. Signaling pathways affected by sorafenib include raf, platelet-derived growth factor (PDGF), c-kit, and vascular endothelial growth factor (VEGF), but it is unknown which of these is the dominant mechanistic target for benefit in hepatocellular cancer. Likely, the efficacy is related to a balanced action on several cell systems that results in a safe and effective therapeutic intervention. It is important to be aware of the potential relevance of this fine balance because drugs with apparent pharmacologic similarities may have a different profile in vivo, both in terms of antitumoral efficacy and in terms of safety. Receptor tyrosine kinase inhibitors have also begun to receive greater attention as a potential therapy in the treatment of portal hypertension and cirrhosis. Indeed, in preclinical studies, a number of receptor tyrosine kinase inhibitors, including imatinib and sunitinib, and now sorafenib, have been shown to improve portal hypertension.4,5 The mechanistic basis for benefit is not fully elucidated; however, there is increasing and compelling evidence suggesting an intimate link between angiogenesis, fibrosis, and portal hypertension and, thus, it has been proposed that a part of the mechanism of action of these agents may be through an antiangiogenic mechanism.6-9 In the current issue of HEPATOLOGY, the article by Mejias et al.10 demonstrates a beneficial effect of the receptor tyrosine kinase inhibitor, sorafenib, on splanchnic, intrahepatic, and portocollateral circulations in cirrhotic rats with portal hypertension; these observations are reminiscent of recent work with sunitinib in this model.4 This work is exciting in many ways, especially given that sorafenib is presently approved and used in patients with existing cirrhosis and HCC. This highlights the opportunities that are available to test this agent in humans with cirrhosis and portal hypertension. In the study by Mejias and colleagues, sorafenib was administered orally once a day for 2 weeks in rats with cirrhosis and portal hypertension, and it was shown to inhibit signaling through VEGF targeted at endothelial cells, PDGF targeted at hepatic stellate cells, smooth muscle cells, and pericytes and RAF. Interestingly, the effects were observed not only in the intrahepatic circulation, but also in the systemic and collateral circulations, suggesting this therapy may have multiple benefits in portal hypertension. Indeed, the researchers observed a 25% reduction in portal pressure and a prominent improvement in liver injury, fibrosis, and angiogenesis. These results raise the compelling question of whether angiogenic therapy has an adequate rationale to be considered for therapy in patients with cirrhosis and portal hypertension. Certainly, there are some histologic similarities in the sinusoidal and parenchymal structures in the liver in cirrhosis and cancer. For example, as seen in Fig. 1, many would be hard pressed to distinguish whether this micrograph depicts a cirrhotic liver or a liver with metastasis and desmoplastic reaction. Both conditions evidence a prominent stroma with myofibroblast activation and prominent changes in the sinusoidal endothelial cells and vasculature with increased “scar vessels” traversing through the dense matrix network. So the question arises whether antiangiogenesis therapy is ready for prime time evaluation in patients with cirrhosis and portal hypertension, especially with clinical evidence that patients with cirrhosis can receive sorafenib without severe hepatic decompensation and that this agent has prominent beneficial effects in experimental models of cirrhosis and portal hypertension. Certainly, some of the analysis from histologic sections of tissue obtained during the cancer trials of sorafenib may provide some clues, especially if some antifibrotic effect can be demonstrated in the fibrotic tissues adjacent to the tumor. Abbreviations: HCC, hepatocellular carcinoma; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor. Address reprint requests to: Vijay Shah, M.D., E-mail: shah.vijay@mayo.edu; or Jordi Bruix. E-mail: JBRUIX@clinic.ub.es Copyright

Multifaceted perspective of the waiting list for liver transplantation: The value of pharmacokinetic models

Liver transplantation has become a standard procedure in the management of patients with advanced liver disease, and any referral center in liver diseases should have this intervention within its therapeutic armamentarium. It now constitutes an established field, and any news about transplantation attracts media attention. Victim of its own success, the major problem for a wide application of transplantation is no longer the need to ensure surgical, clinical, and therapeutic skills to manage the selection of candidates, the operation itself, and the postoperative period, but is the shortage of donors. Hence, in almost all health care settings, the number of candidates largely exceeds the available livers to be implanted. Even in countries with high donation rates such as Spain, the excess of candidates induces a steady expansion of the time that patients spend on the waiting list and of their likelihood of death while waiting. As in other areas of health care, there are several actors with separate interests in this complex scenario. Obviously, the central one is represented by the patients and their referring physicians. As an individual facing a life-threatening disease that might be cured by transplantation, any candidate for transplantation is mostly interested in undergoing transplantation as soon as possible. This expectation is in place even if the prospects for successful long-term survival are highly limited and do not match those required by the current criteria, a circumstance that is especially evident in patients with hepatocellular carcinoma (HCC). Because of the shortage of donors, it is usual policy to exclude from transplantation any patients with an expected suboptimal posttransplant survival. The cutoff is commonly established at less than 50% at 5 years. Nevertheless, it could be argued that if the liver donations would exceed the demand, the requested expected survival could be lowered. The second major player in the field is the transplant team who has to carefully evaluate the candidates and establish if transplant is indicated and if there are no contraindications of any class (comorbidities, failure to control alcohol and tobacco consumption, lack of understanding of the disease etiology by the patient and need to follow specific recommendations, insufficient support, and resources to sustain the demands of the posttransplantation management). Ultimately, the transplant program should have in place a clear and transparent protocol that defines all types of criteria and steps to be fulfilled in a consistent way so that the clinical management of candidates and enlisted patients does not vary arbitrarily through time if there is no robust proof of the need of such a change. One easy example to expose the challenges in the selection process is the decision to have an age limit to enter/exit the waiting list. This limit is in place in several countries but is not homogeneous at all. This demonstrates that there is no major science behind this limit, but just the willingness to use the livers in those subjects in whom the long-term life expectancy and tolerance to the procedure is higher. Should this be a mere chronological assessment or would biological age be better, even though it is not really easy to define? The same heterogeneity in the criteria for transplantation applies to HCC. Most groups adhere to the well-established and successful Milan criteria, but the pressure for expansion is present everywhere. Thus, a noticeable proportion of programs have slightly expanded the limits. In any case, the request of an acceptable outcome in patients who underwent transplantation (again, the suggested 50% at 5 years with as low as possible early mortality) should avoid that this translates into poor service to those patients of more uncertain outcome who could impair the perceived quality of the transplant program (higher mortality, longer hospitalization stay) and put it at risk of failing accreditation. Finally, the third actor comprises the community and the health care administrators. These need to have assurance that the organs provided by the community as a result of donation of any type (brain death, live donation, non beating heart donors. . .) are used in an equitable way and that the resources allocated to transplantation are Abbreviations: HCC, hepatocellular carcinoma; MELD, model for end-stage liver disease. This work was in part supported by grants of the Instituto de Salud Carlos III (grant PI 08/0146). Address reprint requests to: Jordi Bruix, BCLC Group, Liver Unit, Hospital Clı́nic of Barcelona, University of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Hepatologı́a y Enfermedades Digestivas, Villarroel 170, Barcelona 08036, Spain. E-mail: jbruix@clinic.ub.es; fax: 0034 93 227 5792. Copyright

Surgical resection for hepatocellular carcinoma: Moving from what can be done to what is worth doing

R adical resection is the mainstay of treatment for organ tumors. The same could apply to hepatocellular carcinoma (HCC) if frequent multifocality and coexisting cirrhosis did not limit its role. Current guidelines recommend resection only for single nodules of any size in patients without tumorrelated symptoms and clinically significant portal hypertension (CSPH) and with normal bilirubin ( 1 mg/dL). If this profile is not fulfilled, postoperative morbidity increases and long-term survival is significantly reduced. An extension of the recommendation has been repeatedly suggested because in patients with CSPH multiple nodules or intrahepatic vascular invasion resection can be attempted with high rates of technical success in experienced centers, even though tumor elimination by surgery translates into improved survival only in properly selected candidates. Actually, while tumor removal would be technically feasible in patients with a large tumor burden or impaired liver function, resection may not be worth attempting as survival could even be decreased. In real life the decision to resect HCC is based on individual patient components and local conditions that are not captured by guidelines. Debate about resection is fueled by several publications in which the outcome in suboptimal candidates is still felt to be acceptable because it appears to be better than with other treatment options or no treatment. The controversy will grow as improvement in surgical techniques and new drugs for hepatitis C virus will determine a reduction in postoperative morbidity, as happened with hepatitis B virus. Finally, the growing epidemic of HCC in metabolic syndrome may also prime resections in large/multifocal tumors occurring in noncirrhotic liver, although comorbidities and advanced age may preclude safe surgery in many of these patients. In this issue of HEPATOLOGY, Roayaie et al. describe the surgical management of HCC within the Bridge database, which collects information about new incident cases worldwide. In a cohort of 8656 patients the authors evaluated how frequently guidelines for resection were followed and whether straying from them impacted survival. A total of 862 (10%) patients were classified as ideal resection candidates, and more than 80% of them underwent surgery; the remaining were mostly treated by ablation or embolization and experienced a two-fold increased mortality risk. These results could be used to support the superiority of resection, but they could also reflect the fact that associated conditions (advanced age, comorbidities) excluded those less healthy subjects from surgery. The main study interest is focused in the 7794 (90%) patients who were classified as nonideal candidates, 20% of whom were resected despite a suboptimal profile. Unfortunately, the database did not register intrahepatic tumor location and type of hepatectomy performed. As known, the propensity of hepatologists to refer and that of surgeons to operate on nonideal patients with cirrhosis are influenced by the extent of planned resection and the perceived risk of the intervention. Therefore, the reader is left with the feeling that drivers of the decision to resect or not a nonideal candidate were not thoroughly recorded and, consequently, that nonideal resected patients formed a not fully reproducible cohort. The fact that just few resected cases had severe liver disease (Child-Pugh C, bilirubin >2 mg/dL, severe portal hypertension reflected by platelets <50,000/mm) or very compromised general conditions (performance status 3-4) suggests that clinicians took into account liver function, tumor location, and Abbreviations: CSPH, clinically significant portal hypertension; HCC, hepatocellular carcinoma. Received March 25, 2015; accepted April 2, 2015. Supported by the Italian Ministry of Health (to R.R., V.M.), the Italian Association for Cancer Research (to V.M.), Istituto Nazionale Tumori 5per1000 funds, and a grant from the Instituto de Salud Carlos III (to J.B., PI 14/00962); CIBERehd is funded by Instituto de Salud Carlos III. Address reprint requests to: Jordi Bruix, M.D., BCLC Group, Liver Unit, Hospital Cl ınic, c/Villaroel 170, Floor 4, Stair 11, 08036 Barcelona, Spain. E-mail: jbruix@clinic.ub.es; tel: 134 93 227 9803; fax: 134 93 227 5792. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27831 Potential conflict of interest: Dr. Mazzaferro is on the speakers’ bureau for Bayer and BTG. Dr. Bruix consults for Bayer, BTG, Syrtex, and Terumo.

Pattern of tumor progression in liver cancer: The missing partner in trial design

T he success of sorafenib has prompted a major research activity in the systemic treatment of hepatocellular carcinoma (HCC). This includes phase II and III trials, which aim to improve the benefits of sorafenib, and real-life studies to better understand the mechanisms of action and the factors associated to better or worse survival of treated patients. To date, all phase III trials in first line versus sorafenib or in combination with other agents, and trials in second line versus placebo have failed despite promising results in earlier phases of development. These negative results are deceiving, but should trigger critical thinking about the strength of the data used to gauge antitumoral activity and the safety of new drugs. At the same time, there is a need to revisit the key aspects of trial design, such as survival assumptions and stratification parameters, to ensure a balance between arms. It is critical to improve our knowledge of the natural history of patients under sorafenib treatment and the predictors of survival once it is interrupted owing to intolerance or disease progression. Understanding these aspects should provide explanations regarding trial failures, but, most important, it should lead to modification of the current methods used to evaluate new drugs or novel combinations. What are the possible explanations for the trial failures? The first ones that come to mind are that the agents were not active, not safe, or both. Sunitinib, linifanib, and brivanib had some activity according to objective response rate, disease control rate, or time to progression, but failed to improve survival, as compared to sorafenib or even placebo, as was the case in secondline studies. The potential antitumoral activity could have been counterbalanced by toxicity, but the relevant finding is that signals of activity have not translated into improved survival. Hence, criteria to detect a positive signal in phase I/II studies should be refined and move beyond the mere assessment of tumor burden measured by imaging. Cutoffs used to register response were developed because of the capacity of physicians to detect a change in tumor size by palpation, but the values defined for diameter, area, or volume have never been demonstrated to be a surrogate for a better or worse survival. Assessment of necrosis has been validated for locoregional treatments, but such usefulness for systemic therapy still awaits proper prospective validation. Time to progression may be a better parameter in the absence of a significant rate of objective responses. Sorafenib delayed tumor progression, and this was associated with improved survival. However, progression registration requires some refinement for HCC in order to make clinical sense. More important, it has to be understood that progression pattern may determine a different impact on prognosis. Hence, is there proof that an increase in the size of target lesions implies a poor prognosis? Or is there proof that development of new tumor sites has the same negative impact on survival irrespective of location? Or should progression be considered a predictor of poor short-term outcome only if associated with development/increase of cancer-related symptoms? We raised these questions when we designed a prospective study in HCC patients treated with sorafenib. We envisioned that progression pattern could be one of the main drivers of postprogression survival. This neglected concept was not so novel given that it is well known that progression pattern after resection, transplant, ablation, or chemoembolization determines outcome. The data confirmed our hypothesis: growth of existing sites or appearance of new intrahepatic nodules had no significant impact on survival, whereas the development of Abbreviations: BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PS, performance status. Received April 2, 2015; accepted May 3, 2015. J.B. is supported by a grant of the Instituto de Salud Carlos III (PI14/ 00962). Address reprint requests to: Jordi Bruix, M.D., BCLC Group, Liver Unit, Hospital Cl ınic, C/Villarroel 170, 08036 Barcelona, Spain. E-mail: jbruix@ clinic.ub.es; fax: 13493 2275792. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27881 Potential conflict of interest: Dr. Bruix consults for, advises for, and received grants from Bayer. He consults for and advises for Biocompatibles and Novartis. He consults for and received grants from Daiichi and Arqule. He consults for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lilly, and Roche. Dr. Reig advises Bayer.