Carlo Sposito

Milan criteria in liver transplantation for hepatocellular carcinoma: An evidence-based analysis of 15 years of experience†‡

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third most common cause of cancer-related deaths; the number of new cases per year is approaching 750,000. The magnitude of the incidence of HCC has discouraged any attempts to apply liver transplantation (LT) as the prevailing curative therapy for HCC worldwide because of the limited sources of donated organs (deceased and living donors) and the poor access to sophisticated health care systems in some geographical areas. If these limitations continue to prevail throughout the world, any attempt to significantly reduce HCC-related mortality rates through the application of LT will be delusional. International experiences have confirmed, however, the potential of LT to definitively cure HCC because it presents a unique opportunity to remove both the tumor (HCC is associated with 695,000 deaths per year) and the underlying cirrhosis. Despite its limited access, LT has become the standard of care for patients with small HCCs and the main driving force for alternative strategies offered to patients with intermediate HCCs. In 1996, a prospective cohort study defined restrictive selection criteria that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. Since then, these selection criteria have become universally known as the Milan criteria (MC) in recognition of their origin. Ever since their adoption in clinical practice, the MC have helped doctors to single out early-stage HCC as a prognostic category of cancer presentation that is amenable to curative treatments. After their implementation, the favorable posttransplant outcomes that were observed in cohort series were so convincing that the MC immediately became the standard of care for early HCC, and further validation by randomized controlled trials (RCTs) was prevented. After the passage of approximately a decade, researchers began to challenge the MC with other proposals designed to capture those patients not meeting the MC who could achieve similar posttransplant survival rates through the expansion of the accepted tumor limits for transplant eligibility. None of these expanded criteria have become the new reference standard for selecting LT candidates with HCC; any broadening of the selection criteria for transplantation is inevitably hampered by severe

Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: a phase 2 study.

Yttrium‐90 radioembolization (Y90RE) is a novel approach to radiation therapy for hepatocellular carcinoma (HCC), never tested in phase 2 studies. Fifty‐two patients with intermediate (n.17) to advanced (n.35) HCC were prospectively recruited to assess, as the primary endpoint, efficacy of Y90RE on time‐to‐progression (TTP). Secondary endpoints were tumor response, safety, and overall survival (OS). All patients were Eastern Cooperative Oncology Group (ECOG) score 0‐1, Child‐Pugh class A‐B7. Y90RE treatments aimed at a lobar delivery of 120 Gy. Retrospective dosimetric correlations were conducted and related to response. Fifty‐eight treatments were performed on 52 patients. The median follow‐up was 36 months. The median TTP was 11 months with no significant difference between portal vein thrombosis (PVT) versus no PVT (7 versus 13 months). The median OS was 15 months (95% confidence interval [CI], 12‐18 months) with a nonsignificant trend in favor of non‐PVT versus PVT patients (18 versus 13 months). Five complete responses occurred (9.6%), and the 2 year‐progression rate was 62%. Objective response was 40.4%, whereas the disease control rate (78.8%) significantly affected survival (responders versus nonresponders: 18.4% versus 9.1%; P = 0.009). Tumor response significantly correlated with absorbed dose in target lesions (r = 0.60, 95% CI, 0.41‐0.74, P < 0.001) and a threshold of 500 Gy predicted response (area under the curve, 0.78). Mortality at 30‐90 days was 0%‐3.8%. Various grades of reduction in liver function occurred within 6 months in 36.5% of patients, with no differences among stages. On multivariate analysis, tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child‐Pugh class). Conclusion: Y90RE is an effective treatment in intermediate to advanced HCC, particularly in the case of PVT. Further prospective evaluations comparing Y90RE with conventional treatments are warranted. (HEPATOLOGY 2013)

Resection of hepatocellular cancer ≤2 cm: results from two Western centers

Asian series have shown a 5‐year survival rate of ≈70% after resection of hepatocellular carcinoma (HCC) ≤2 cm. Western outcomes with resection have not been as good. In addition, ablation of HCC ≤2 cm has been shown to achieve competitive results, leaving the role of resection in these patients unclear. Records of patients undergoing resection at two Western centers between January 1990 and December 2009 were reviewed. Patients with a single HCC ≤2 cm on pathologic analysis were included. Thirty clinical variables including demographics, liver function, tumor characteristics, nature of the surgery, and the surrounding liver were examined. An exploratory statistical analysis was conducted to determine variables associated with recurrence and survival. The study included 132 patients with a median follow‐up of 37.5 months. There was one (<1%) 90‐day mortality. There were 32 deaths with a median survival of 74.5 months and a 5‐year survival rate of 70% (63% in patients with cirrhosis). The median time to recurrence was 31.6 months and the 5‐year recurrence rate was 68%. Presence of satellites (hazard ratio [HR], 2.46; P = 0.031) and platelet count <150,000/μL (HR, 2.37; P = 0.026) were independently associated with survival. Presence of satellites (HR, 2.79; P = 0.003), cirrhosis (HR, 2.3; P = 0.010), and nonanatomic resection (HR, 1.79; P = 0.031) were independently associated with recurrence. Patients with a single HCC ≤2 cm and platelet count ≥150,000/μL achieved a median survival of 138 months and a 5‐year survival rate of 81%, respectively. Conclusion: Resection of HCC ≤2 cm is safe and achieves excellent results in Western centers. Recurrence continues to be a significant problem. Presence of satellites, platelet count, anatomic resection, and cirrhosis are associated with outcomes after resection, even among such early tumors. Resection should continue to be considered a primary treatment modality in patients with small HCC and well‐preserved liver function. (HEPATOLOGY 2013)

Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: A proof of principle

BACKGROUND & AIMS The advent of molecular medicine that targets specific pathways is changing the therapeutic approach to hepatocellular carcinoma. For several aberrantly activated pathways in hepatocarcinoma, surrogate markers of activation can be assessed by immunohistochemistry, although associations with in vivo response to targeted therapies are still lacking. METHODS A patient, who presented with hepatic and extra-hepatic hepatocarcinoma recurrence 11 years after liver transplantation, was assessed for beta-catenin, pERK, and pS6 in primary and secondary tumor specimens, in order to define a possible activation of the Wnt, Ras/MAPK and Akt/mTOR pathways and design a personalized targeted therapy in absence of alternative treatment options. Moreover, mutation analysis of the beta-catenin gene (CTNNB1) and DNA microsatellite analyses were performed. RESULTS The identification of the same mutation in the beta-catenin gene, as well as the same microsatellite pattern in tumor tissues taken 11 years apart, proved that the observed hepatocarcinoma was a true recurrence. Nuclear beta-catenin and pS6 in tumor cells were positive, whereas pERK was positive only in the peritumoral endothelium. This pattern of immunohistochemistry, after failure of sorafenib alone, lead to the choice to add the mTOR inhibitor, everolimus, to sorafenib. Three months later a 50% tumor reduction was observed, and after 6 months a further reduction of tumor vital components was confirmed, while a grade II gastrointestinal bleeding episode occurred. CONCLUSIONS A personalized approach aimed to treat recurrent hepatocarcinoma is possible through analysis of tumoral molecular pathways. Partial success of the selected combination of sorafenib and everolimus supports the pivotal role of mTOR signalling and highlights the importance of reliable biomarkers to route the best molecular-based therapeutic options in HCC.

Propensity score analysis of outcomes following laparoscopic or open liver resection for hepatocellular carcinoma

Liver resection is a potentially curative approach for hepatocellular carcinoma (HCC). Laparoscopic liver resections may reduce complication rates, especially in patients with cirrhosis. The aim of this study was to compare the results of laparoscopic liver resection with those of open liver resection for HCC.

The challenges of liver transplantation for hepatocellular carcinoma on cirrhosis.

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and liver transplantation (LT) has potentials to improve survival for patients with HCC. However, expansion of indications beyond Milan Criteria (MC) and use of bridging/downstaging procedures to convert intermediate‐advanced stages of HCC within MC limits are counterbalanced by graft shortage and increasing use of marginal donors, partially limited by the use of donor‐division protocols applied to the cadaveric and living‐donor settings. Several challenges in technique, indications, pre‐LT treatments and prioritization policies of patients on the waiting list have to be precised through prospective investigations that have to include individualization of prognosis, biological variables and pathology surrogates as stratification criteria. Also, liver resection has to be rejuvenated in the general algorithm of HCC treatment in the light of salvage transplantation strategies, while benefit of LT for HCC should be determined through newly designed composite scores that are able to capture both efficiency and equity endpoints. Innovative treatments such as radioembolization for HCC associated with portal vein thrombosis and molecular targeted compounds are likely to influence future strategies. Accepting this challenge has been part of the history of LT and will endure so also for the future.

Drug‐eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma

Solid demonstrations of superior efficacy of drug‐eluting beads transarterial chemoembolization with respect to conventional chemoembolization in hepatocellular carcinoma patients are lacking. The aim of the study was to compare these two techniques in two large cohorts of unresectable hepatocellular carcinoma patients.

A prospective policy development to increase split-liver transplantation for 2 adult recipients: Results of a 12-year multicenter collaborative study

Objective:To analyze in a multicenter study the potential benefit of a new prospective policy development to increase split-liver procedures for 2 adult recipients. Background:Split-liver transplantation is an important means of overcoming organ shortages. Division of the donor liver for 1 adult and 1 pediatric recipient has reduced the mortality of children waiting for liver transplantation but the benefits or disadvantages to survival when the liver is divided for 2 adults (adult-to-adult split-liver transplant, AASLT) compared with recipients of a whole graft have not been fully investigated. Methods:We developed a computerized algorithm in selected donors for 2 adult recipients and applied it prospectively over a 12-year period among 7 collaborative centers. Patient and graft outcomes of this cohort receiving AASLT either as full right grafts or full left grafts were analyzed and retrospectively compared with a matched cohort of adults who received a conventional whole-liver transplant (WLT). Univariate and multivariate analysis was done for selected clinical variables in the AASLT group to assess the impact on the patient outcome. Results:Sixty-four patients who received the AASLT had a high postoperative complication rate (64.1% grade III and IV) and a lower 5-year survival rate than recipients of a WLT (63.3% and 83.1%) Conclusions:AASLT should be considered a surgical option for selected smaller-sized adults only in experimental clinical studies in experienced centers.

Effect of age on survival in patients undergoing resection of hepatocellular carcinoma.

The benefit of surgical intervention for cancer should be estimated in relation to the life expectancy of the general population. The aim of this study was to provide a measure of relative survival after hepatectomy for hepatocellular carcinoma (HCC).

Hierarchic Interaction of Factors Associated With Liver Decompensation After Resection for Hepatocellular Carcinoma.

IMPORTANCE Liver resection is the treatment of choice for hepatocellular carcinoma (HCC) in well-compensated liver cirrhosis. Postoperative liver decompensation (LD) is the most representative and least predictable cause of morbidity and mortality. OBJECTIVES To determine the hierarchy and interaction of factors associated with the risk for LD and to define applicable risk classes among surgical candidates. DESIGN, SETTING, AND PARTICIPANTS This retrospective review collected data from 543 patients with chronic liver disease who underwent hepatic resection for HCC from January 1, 2000, through December 31, 2013, in a tertiary comprehensive cancer center. Final follow-up was completed on January 31, 2015, and data were assessed from February 1 to 28, 2015. MAJOR OUTCOMES AND MEASURES Preoperative prognostic factors and risk stratification for postoperative LD. Multivariate logistic regression was performed, and the independent risk factors for LD were included in a recursive partitioning analysis model. Results were validated by means of 10-fold cross-validation. RESULTS The analysis included 543 patients, of whom 411 (75.7%) were male, 132 (24.3%) were female, and the median age was 68 (interquartile range, 62-73) years. An independent association with LD was found for major hepatectomy (odds ratio [OR], 2.41; 95% CI, 1.17-4.30; P = .01), portal hypertension (OR, 2.20; 95% CI, 1.13-4.30; P = .01), and Model for End-Stage Liver Disease (MELD) score greater than 9 (OR, 2.26; 95% CI, 1.10-4.58; P = .02). Recursive partitioning analysis confirmed portal hypertension as the most important factor (OR, 2.99; 95% CI, 1.93-4.62; P < .001), followed by extension of hepatectomy with (OR, 2.76; 95% CI, 1.85-4.77; P = .03) and without (OR, 2.98; 95% CI, 1.97-4.52; P < .001) portal hypertension, and MELD score (OR, 1.79; 95% CI, 1.23-2.13; P < .001). Low-risk patients (LD rate, 4.9% [11 of 226]) without portal hypertension underwent minor resection with a MELD score of 9 or less; intermediate-risk patients (LD rate, 28.6% [85 of 297]) had no portal hypertension and underwent major resections or, in case of minor resections, had portal hypertension or a MELD score greater than 9; and high-risk patients (LD rate, 60.0% [12 of 20]) underwent major resection with portal hypertension. Risk-class progression paralleled median length of stay (7, 8, and 11 days, respectively; P < .001) and liver-related mortality (4.4% [10 of 226], 9.0% [27 of 297], and 25.0% [5 of 20], respectively; P = .001). A 10-fold cross-validation of the model resulted in a C index of 0.78 (95% CI, 0.74-0.82) and an overall error rate of 0.06. CONCLUSIONS AND RELEVANCE The risk for postoperative LD after resection for HCC in chronic liver disease is associated with preoperative hierarchic interaction of portal hypertension, planned extension of hepatectomy, and the MELD score.