Mohamed Bouattour

Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

Tolerance and outcome of patients with unresectable hepatocellular carcinoma treated with sorafenib.

Background Sorafenib is the standard treatment for patients with an advanced stage of hepatocellular carcinoma (HCC). The aims of this study were (i) to evaluate the tolerance and survival of sorafenib-treated patients, in a nonselected population, especially in Child–Pugh B patients; and (ii) to identify potential prognostic factors of survival. Patients and methods From April 2007 to December 2008, 50 patients received sorafenib for advanced HCC. Seventeen (34%) were Child–Pugh B patients. We recorded adverse events and the duration of treatment and survival. For 34 patients with histopathologically proven HCC, immunophenotypical analysis was carried out using antibodies against cluster differentiation 34, vascular endothelial growth factor, phosphorylated ERK, cytokeratin 19, and phosphorylated stat3. Results Patients with Child–Pugh B cirrhosis had a more advanced stage of the disease compared with Child–Pugh A patients. The occurrence of adverse events was similar in Child–Pugh A and Child–Pugh B patients. Duration of treatment until discontinuation for bad tolerance was lower in Child–Pugh B patients (1.8 vs. 5 months, P=0.02). Survival of Child–Pugh A patients was higher compared with Child–Pugh B patients (8.9 vs. 2 months, P=0.004). Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group Performance Status, portal vein impairment, extra-hepatic spread, and α-foetoprotein were also prognostic factors. In multivariate analysis, the sole factor associated with survival was the Barcelona Clinic Liver Cancer stage. None of the immunohistological markers used was associated with tolerance and survival. Conclusion Occurrence of adverse events is similar in Child–Pugh A and Child–Pugh B patients. Nevertheless, the survival of Child–Pugh B patients is very low. Whether liver function or tumor spread is responsible for mortality is unclear. Opportunity of treatment for Child–Pugh B patients is questionable. The immunophenotype of tumoral tissue was not predictive of survival.

Alternative Response Criteria (Choi, European Association for the Study of the Liver, and Modified Response Evaluation Criteria in Solid Tumors [RECIST]) Versus RECIST 1.1 in Patients With Advanced Hepatocellular Carcinoma Treated With Sorafenib

INTRODUCTION Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), may underestimate activity and does not predict survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib. This study assessed the value of alternative radiological criteria to evaluate response in HCC patients treated with sorafenib. PATIENTS AND METHODS A retrospective blinded central analysis was performed of computed tomography (CT) scans from baseline and the first tumor evaluation in consecutive patients treated with sorafenib over a 2-year period in a single institution. Four different evaluation criteria were used: Choi, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), and RECIST 1.1. RESULTS Among 82 HCC patients, 64 with Barcelona Clinic Liver Cancer stage B-C were evaluable with a median follow-up of 22 months. Median duration of sorafenib treatment was 5.7 months, and median overall survival was 12.8 months. At the time of the first CT scan, performed after a median of 2.1 months, Choi, EASL, mRECIST, and RECIST 1.1 identified 51%, 28%, 28%, and 3% objective responses, respectively. Responders by all criteria showed consistent overall survival >20 months. Among patients with stable disease according to RECIST 1.1, those identified as responders by Choi had significantly better overall survival than Choi nonresponders (22.4 vs. 10.6 months; hazard ratio: 0.43, 95% confidence interval: 0.15-0.86, p = .0097). CONCLUSION Choi, EASL, and mRECIST criteria appear more appropriate than RECIST 1.1 to identify responders with long survival among advanced HCC patients benefiting from sorafenib.

Sunitinib in Hepatocellular Carcinoma: Redefining Appropriate Dosing, Schedule, and Activity End Points

TO THE EDITOR: In a recent article, Zhu et al reported the results of a phase II study with sunitinib in patients with advanced hepatocellular carcinoma (HCC) and concluded that “sunitinib shows evidence of modest antitumor activity in advanced HCC.” Interpretation of current data from Zhu et al as well as those of other published trials with sunitinib in HCC might not be so straightforward. The dose and the schedule of sunitinib may not derive easily from previous dosefinding studies in patients with HCC who also frequently suffer from several hepatic disorders. Furthermore, although RECIST (Response Evaluation Criteria in Solid Tumors) criteria have been extensively used for evaluating efficacy of several targeted therapies, response rate evaluation in HCC on the basis of the measurement of largest diameters before and after treatment may not be the only reliable tool to detect activity in HCC using antiangiogenic agents in phase II trials. Herein we provide some clues that may help understanding why we believe current data justify additional development of sunitinib in HCC despite low response rates in most trials. In their article, Zhu et al reported the safety and activity of sunitinib administered at the dose of 37.5 mg/d for 4 weeks every 6 weeks in patients with HCC. In this article, the authors reported a 2.9% response rate, a median progression-free survival (PFS) of 3.9 months, and a median overall survival (OS) of 9.8 months. At a higher dose of 50 mg/d sunitinib administered on the same schedule, we recently reported similar results, yielding 2.7% response rate, a median PFS of 3.7 months, and a median OS of 8.0 months. The trial by Zhu et al included only Western patients, whereas our trial included both Eastern and Western populations, which may partly explain PFS and OS survival differences. When subgroup analysis was performed in our trial, we found that European and Asian populations showed median PFS and OS of 5.1 months (95% CI, 1.4 to 7.8 months) and 9.3 months (95% CI, 3.4 to 15.8 months) in Europe, as compared with 2.7 months (95% CI, 1.2 to 7.5 months) and 6.0 months (95% CI, 4.3 to 19.1 months) in Asia, respectively. Combined together, our data seem consistent with those of Zhu et al and are similar to those previously reported with sorafenib in patients with HCC in European and Asian populations. However, those data also raised two important questions: (1) on the basis of current safety data, what is the appropriate dose and schedule for sunitinib in patients with HCC? (2) Are efficacy data from reported phase II trials convincing enough to justify additional development of sunitinib in HCC? In a phase I trial, we established the dose of sunitinib at 50 mg/d for 4 consecutive weeks every 6 weeks in patients with cancer who have normal liver function. Previous studies in patients with impaired hepatic functions revealed no significant change in exposure for sunitinib and its active metabolite, suggesting that daily doses are not influenced by limited changes of routine hepatic tests. However, sticking evidence from our phase II trial demonstrated that the daily dose of 50 mg, routinely used in patients with other tumor types, was not suitable for patients with advanced HCC. Common sunitinibrelated toxicities were consistent with those reported in previous studies in other tumor types, such as renal cancer and gastrointestinal stromal tumor—that is, asthenia, hand-foot syndrome, and thrombocytopenia. Moreover, the dose of 50 mg/d sunitinib also induced a high level of complications usually observed in patients undergoing decompensated hepatic fibrosis and cirrhosis, including encephalopathy, portal hypertension with esophageal varice bleeding, ascites, and thrombocytopenia. It is likely that vascular endothelial growth factor receptor– and platelet-derived growth factor receptor–related angiogenesis, which plays an important role in the physiopathology of compensated hepatic fibrosis and cirrhosis, might be impaired during sunitinib treatment. Identifying this source of toxicity may seem of particular importance in this disease, given that appearance of signs of decompensated liver function is usually associated with sunitinib discontinuation and may jeopardize efficacy results. The dose used in our trial was also associated with more pronounced grade 3 to 4 toxicities and a higher under-therapy death rate. Overall, dose reductions were required in 43.2% of patients, strongly suggesting that the dose of 50 mg/d sunitinib was inappropriate in this patient population. Consistent with this hypothesis, Zhu et al found that sunitinib displayed a better toxicity profile when daily dose exposure was reduced by using a 37.5 mg/d schedule. However, this dose and schedule is subject to two criticisms. First, the dose used by Zhu et al accounts for a 25% dose reduction, which may have an impact in the overall efficacy of the drug. Second, the intermittent schedule, regardless of dosing, allows potential tumor angiogenesis recovery during the 2-week washout period, which may also impair efficacy of sunitinib. Recent data generated in patients with gastrointestinal stromal tumors indicated that continuous daily dose of 37.5 mg without a washout period was associated with a safe toxicity profile and did not impair the overall PFS and survival results of sunitinib. This later schedule was recently evaluated by Koeberle et al in 45 European patients with HCC, allowing achieving a median PFS of 2.8 months and an overall survival of 9.3 months. Importantly, this continuous low-dose schedule displayed a safe toxicity profile and did not alter underlying hepatic functions. Thereby, it was decided that the optimal compromise for safety and efficacy would be testing a daily dose of 37.5 mg sunitinib administered continuously without any washout period in an ongoing phase III trial comparing sunitinib with sorafenib (NTC00699374). Phase II trials are usually aimed detecting hints of antitumor activity and providing information that could be used for the setting of phase III trials. Phase II studies with sunitinib in HCC were designed using response rate according to RECIST criteria as a primary end point for efficacy. However, regardless of doses and the schedules used in the recently reported phase II trials, response rates of sunitinib in HCC barely reached the 5% level that is usually acknowledged to define a potentially active anticancer agent. This feature was also observed with sorafenib, despite additional evidence showing that this drug improved survival of patients with HCC. Despite limited JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 27 NUMBER 35 DECEMBER 1

Novel molecular therapies in hepatocellular carcinoma

The approval of sorafenib as the standard of care (SOC) for advanced hepatocellular carcinoma (HCC) fostered interest to further evaluate several other targeted therapies and extend the positioning of sorafenib alone and in combination with other drugs and local therapies at earlier stages and in an adjuvant setting. This review highlights current research using targeted therapies in HCC. Information for this review was compiled by searching PubMed and MEDLINE databases for articles published until September 2010. Several small molecules and humanized antibodies with anti‐angiogenic and antiproliferative properties are currently being investigated in preclinical and/or clinical trials. Results are awaited from these clinical trials and offer promise for extending the current treatment options in HCC. Currently published data suggest that substantial progress may be achieved in the treatment of patients with HCC in the next 10 years.

Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma.

BACKGROUND & AIMS Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib. METHODS Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression. RESULTS In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6 months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high α-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells. CONCLUSION This case report suggests the occurrence of an epithelial-to-mesenchymal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib.

Prospective evaluation of the management of hepatocellular carcinoma in the elderly.

BACKGROUND An increasing proportion of patients with hepatocellular carcinoma are older than 75 years. Previous studies suggested that ageing does not adversely impact survival but they have the drawback of being retrospective and spanning a prolonged period of time. GOALS Evaluate management and prognosis of hepatocellular carcinoma in elderly. PATIENTS AND METHODS A multidisciplinary oncology meeting prospectively evaluated all patients with hepatocellular carcinoma. Management were standardised according to European and American guidelines. Forty patients older than 75 years were matched with younger patients for tumour extension and liver function. Both groups were compared for the type of treatment and survival. RESULTS Male/female ratio was 1.2 as compared to 7 in controls. Cirrhosis was related mostly to hepatitis C virus in elderly, and equally to hepatitis C or B virus and alcohol in controls. Curative treatments were recommended in 55% of elderly and 75% of controls. Treatment actually performed was curative in 25% in elderly as compared to 63% in controls. Median survival (30 months) was identical in both groups. CONCLUSION Despite more restricted access to curative treatments, survival of elderly patients with hepatocellular carcinoma is comparable to that of younger patients.

Macrotrabecular‐massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance

We recently identified a histological subtype of hepatocellular carcinoma (HCC), designated as “macrotrabecular‐massive” (MTM‐HCC) and associated with specific molecular features. In order to assess the clinical relevance of this variant, we investigated its prognostic value in two large series of patients with HCC treated by either surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM‐HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than six cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM‐HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, alpha‐fetoprotein level, satellite nodules, and vascular invasion). Multivariate analysis showed that MTM‐HCC subtype was an independent predictor of early and overall recurrence (surgical series: hazard ratio, 3.03; 95% confidence interval, 1.38‐6.65; P = 0.006; and 2.76; 1.63‐4.67; P < 0.001; RFA series: 2.37; 1.36‐4.13; P = 0.002; and 2.19; 1.35‐3.54; P = 0.001, respectively). Its prognostic value was retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness. No other baseline parameter was independently associated with recurrence in the RFA series. Conclusion: The MTM‐HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103‐112).

Recent Developments of c‐Met as a Therapeutic Target in Hepatocellular Carcinoma

Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.