Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment.

During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.

Accuracy and disagreement of computed tomography and magnetic resonance imaging for the diagnosis of small hepatocellular carcinoma and dysplastic nodules: role of biopsy.

UNLABELLED: Liver macronodules, ranging from benign to low-grade or high-grade dysplastic nodules (LGDNs/HGDNs) and hepatocellular carcinoma (HCC), may develop during chronic liver diseases (CLDs). Current guidelines were recently updated and the noninvasive criteria for the diagnosis of small HCC are based on a single typical radiological pattern and nonconclusive coincidental findings with two techniques. This study aimed to assess the accuracy and disagreements of noninvasive multiphasic examinations for the diagnosis of HCC and dysplastic nodules (DNs) and the role of biopsy. Seventy-four consecutive patients with CLD with ultrasound-detected 1-2-cm nodules underwent, within 1 month, multiphasic computed tomography (CT), magnetic resonance imaging (MRI), and biopsy of the nodule. Median age was 60 years; 33 patients (45%) had hepatitis C virus, 20 (27%) had hepatitis B virus, and 13 (18%) patients had no cirrhosis. Biopsy revealed 47 HCCs, 6 HGDNs, 1 LGDNs, 1 cholangiocarcinoma, and 1 epithelioid hemangioendothelioma. There were no tumors in the other 18 patients. All patients (31 of 31; 100%) who had conclusive coincidental findings (i.e., arterial enhancement and washout) on both examinations had HCC or HGDN (sensitivity, 57%; specificity, 100%). All patients (51 of 51; 100%) who had conclusive findings on at least one of the two examinations had HCC or HGDN (sensitivity, 96%; specificity, 100%). There was a disagreement regarding imaging findings between CT and MRI in 21 of 74 (28%) patients and no washout on both examinations in 23 of 74 patients (31%). In these 44 patients, liver biopsy provided an initial accurate diagnosis. CONCLUSION: The noninvasive diagnosis of HCC or HGDN can be obtained if arterial enhancement and washout are found in a single dynamic imaging examination. These findings are frequently discordant on both CT and MRI, supporting the place of biopsy for the diagnosis of small HCCs.

Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.

UNLABELLED: Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups. CONCLUSION: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures.

Incidence of liver abnormalities in Fanconi anemia patients.

Patients with Fanconi anemia (FA) are prone to liver tumors, especially after androgen treatment, but other liver abnormalities have not been described for these patients. Here, we systematically reviewed liver manifestations in a cohort of 64 adult and pediatric patients with FA followed in a single center. "Significant biological liver abnormalities(SBLA)" in the absence of any androgen treatment were found in five patients, including two children, belonging to rare FA groups; these two patients presented with a very severe chronic cytolysis pattern which may be classified as a new FA phenotype. Liver radiological abnormalities, which include hepatic tumors (n 5 4), hepatomegaly(n 5 1), hyperechogenicity (n 5 2), and a previously undescribed biliary duct dilatation as demonstrated by magnetic resonance cholangiopancreatography(MRCP) (n 5 2), were found in eight patients who received androgen treatment or who had iron overload. Lastly, we found no correlation between cytolysis intensity and high levels of alpha-fetoprotein (AFP); this common finding in FA patients cannot therefore be explained by hepatocyte regeneration.

Imaging mass spectrometry provides fingerprints for distinguishing hepatocellular carcinoma from cirrhosis.

MALDI imaging mass spectrometry (MALDI IMS) is a powerful tool for comprehending the spectrum of peptides/proteins expressed in tissue sections. The aim of the present study was to investigate, using MALDI IMS, the proteome of hepatocellular carcinomas (HCC) and to compare it with peritumoral cirrhosis so as to characterize new biomarkers of HCC. Frozen liver tissues corresponding to HCC and background cirrhosis (n = 30) were selected and subjected to MALDI IMS. We found a set of proteins/peptides with a differential intensity level that most accurately delineated cancer from adjacent cirrhotic tissue. Using a support vector machine algorithm, we generated a classification model in the train set that enabled segmenting images from the independent validation set and that in most cases matched histologic analysis. The most discriminating peak (m/z 8565) more intense in HCC was characterized as the monomeric ubiquitin. An immunohistochemical study in a large series of HCC/cirrhosis sampled on tissue microarray supported that ubiquitin was overexpressed in HCC. We demonstrated also that this increase was not related to an upregulation of ubiquitin gene transcription in HCC, thus suggesting a post-transcriptional mechanism. This approach might provide a new tool for diagnosis of difficult HCC cases and an opportunity for identifying candidate biomarkers.

Suspected interaction between sorafenib and HAART in an HIV-1 infected patient: a case report.

Sorafenib prolongs survival of patients with unresectablehepatocellular carcinoma (HCC). It is likely to be used in human immunodeficiency virus (HIV) infected patients. Interactions between sorafenib and highly active antiretroviral therapy (HAART) have not been studied yet. We report a case of serious adverse effects in anHIV-1 patient co-infected with HBV.

Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).

BACKGROUND & AIMS: The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ≥ F2) in patients with chronic viral hepatitis. METHODS: A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. RESULTS: The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). CONCLUSIONS: The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.

Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis.

UNLABELLED: Metabolic syndrome (MS) is a newly identified risk factor in chronic liver disease (CLD) and hepatocellular carcinoma (HCC). The aim of this study was to analyze the pathological characteristics of HCC and nontumoral liver in patients with MS as the only risk factor for liver disease in comparison with those that developed in the course of other CLDs in order to provide further insight into the physiopathology of HCC associated with MS. HCC patients with features of MS as the only risk factor for liver diseases (MS group, n = 31) were compared to HCC patients with overt causes of CLD (CLD group, n = 81) or without causes of CLD (cryptogenic group, n = 16) who underwent surgical resection during the same period of time. Among the patients of the MS group, there were 30 males and 1 female. In comparison with the patients with HCC of the CLD group, the patients with MS were older (mean age: 67+/- 7 versus 59 +/- 14 years, P < 0.01), and the background liver was significantly more often free of significant fibrosis (F0-F2: 65% in the MS group versus 26% in the CLD group, P < 0.001). In addition, HCCs associated with MS were more often well differentiated (65% versus 28%, P < 0.001). Five HCCs, all from the MS group, developed on a preexisting liver cell adenoma, with three of them showing typical histological features of telangiectatic adenoma. CONCLUSION: This study shows that HCCs in patients with features of MS as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver. In addition, some of them arise through malignant transformation of a preexisting liver cell adenoma.

Comparative protein expression profiles of hilar and peripheral hepatic cholangiocarcinomas.

BACKGROUND/AIMS: Hepatic cholangiocarcinomas are tumors with poor prognosis and with increasing incidence worldwide. The aim of the study was to compare morphological features and protein profiles of hilar and peripheral cholangiocarcinomas. METHODS: Clinicopathological data were collected from 111 cholangiocarcinomas (59 peripheral and 52 hilar). Protein expression, assessed on tissue samples using tissue microarray and protein array technologies, was compared between both types of tumors and with extrahepatic cholangiocarcinoma and hepatocholangiocarcinoma. RESULTS: Hilar cholangiocarcinomas were smaller in size (mean: 2.7 vs. 8 cm, p<0.001), were more often well differentiated adenocarcinomas (65% vs. 36% well differentiated, p<0.01) and carried out stronger perineural invasion (83% vs. 42%, p<0.001) than peripheral cholangiocarcinomas. Regarding protein expression, hilar cholangiocarcinomas more often expressed MUC5AC (62% vs. 22%, p<0.0001), Akt2 (54% vs. 27%, p<0.001), CK8 (98% vs. 81%, p<0.005) and annexin II (92% vs. 66%, p<0.001). Interestingly, VEGF A expression was more frequently encountered in peripheral cholangiocarcinoma (69% vs. 25%, p<0.0001) and correlated with increased vascular density. Using protein array antibody, we identified filamin A as significantly overexpressed (>2-fold) in peripheral cholangiocarcinomas. CONCLUSIONS: Our results show that hilar and peripheral cholangiocarcinomas display specific protein profiles, especially regarding VEGF expression. This suggests a potential benefit for anti-angiogenic therapies in peripheral hepatic CCs.

Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related cirrhosis: a randomized trial.

BACKGROUND & AIMS: The impact of interferon (IFN) treatment on the occurrence of complications related to hepatitis C virus (HCV)-related cirrhosis is debated because the majority of studies are retrospective. We designed a randomized controlled trial comparing the efficacy of prolonged IFN alfa-2a treatment vs nontreatment on complication-free survival in patients with compensated HCV cirrhosis. METHODS: A total of 102 patients (mean age, 60.5 +/- 9.5 y; male/female ratio, .82) with biopsy examination-proven HCV cirrhosis, Child-Pugh score A, who were hepatocellular carcinoma (HCC) free, and had at least 1 risk factor of complications were randomized to receive IFN or no therapy for 24 months. RESULTS: During the follow-up evaluation, the complication rate was 24.5%: HCC occurred in 12 and decompensation unrelated to HCC occurred in 13 patients. The number of HCC patients was similar in both groups. The probability of complication-free survival was not significantly different between treated and untreated patients (98% and 72.3% vs 90% and 70.7% at 12 and 24 mo, respectively, P = .59). The median time until complication occurrence was 17.1 months in the treated group vs 13.6 months in the untreated group (P = .2). CONCLUSIONS: This randomized controlled trial showed that a 2-year course of IFN has little or no impact on complication-free survival in patients with high-risk compensated HCV cirrhosis.

Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas.

Glypican-3 (GPC3), a member of heparan sulfate proteoglycans, plays a role in cell growth, differentiation, and migration. The objectives of this study were to assess the diagnostic value of GPC3 immunostaining in hepatocellular carcinomas (HCCs) and to analyze its expression profile in preneoplastic lesions. Tissue microarrays were built by sampling 54 HCCs and adjacent liver tissues (21 developing from cirrhosis and 33 from normal liver) and 94 cirrhotic macronodules. Fourteen typical liver cell adenomas and 5 with malignant foci were also included. Sections were assessed for GPC3 expression by immunohistochemistry. GPC3 staining was observed in 19 (90%) of 21 HCC cases with cirrhosis and in 18 (64%) of 28 HCC cases with normal liver (P < .01). When staining was positive, it was both membranous and cytoplasmic. Positive staining was observed in 1 case of nonneoplastic adjacent liver. In cases of adenomas, only malignant foci were positive. Among the 94 macronodules, GPC3 immunostaining was noted in 48% (14/29) of high-grade dysplastic or early HCC and in 3% (2/65, P < .001) of benign or low-grade dysplastic macronodules. This study shows that GPC3 is an efficient diagnostic marker of HCC, potentially useful in the differential diagnosis of liver cell adenomas and well-differentiated HCC. Our results also suggest that GPC3 may be considered as an early marker of liver carcinogenesis because it is able to identify some cirrhotic macronodules with malignant potential.

[Vaccination against hepatitis B virus]. / Vaccination contre l'hépatite B.

The vaccine against hepatitis B virus (HBV) has been widely used for the past 20 years and has demonstrated its capacity to reduce the incidence of both HBV infections and their serious complications, hepatocellular carcinoma, in particular. Vaccination schedules and targets have been well identified. Appropriate vaccination practices in France should prevent the onset of 3 cases of fulminant hepatitis, 150 of chronic HBV carriage, and 30-50 of hepatocellular carcinoma each year. Epidemiologic studies show the absence of severe complications associated with this vaccination, and a recent consensus conference recommended the wide-scale vaccination of newborns and persons at risk. It also recommended measures providing information to the general public, to respond to the many questions raised by use of this vaccine. This vaccination requires a joint effort by the health authorities, actors involved in public health, and general practitioners. It remains a medical act whose benefits must be assessed at an individual level.

[Hepatitis C infection: Therapeutic strategies]. / Infection par le virus de l'hépatite C : prise en charge thérapeutique.

The development of new direct acting antivirals has significantly modified strategies to treat chronic hepatitis C. Treatments were previously made of an interferon-based combination. This article aims to review the direct acting antivirals clinical data and to discuss the new regimens for the management of chronic hepatitis C. Direct acting antivirals combinations - with or without ribavirin - are the new chronic hepatitis C standard treatment regimen. These combinations often result in sustained viral response rate (>90%, including in patients with uncomplicated cirrhosis) after a 12-week treatment for most patients. The innovation could represent a new era for patients with unmet medical need (especially ineligible or non-responders to interferon and/or ribavirin patients). Further investigations are required to confirm the efficacy in specific population (complicated cirrhosis, pre- or post-transplantation, chronic renal failure, comorbidities, etc.) where clinical data are still limited. Other treatments are currently being developed and might lead to new perspectives, especially in terms of treatment duration or therapeutic simplification.

Serum albumin and platelet count but not portal pressure are predictive of death in patients with Child-Pugh A hepatitis C virus-related cirrhosis.

AIM: The presence of esophageal varices has been reported to be a prognostic factor in patients with compensated hepatitis viral C induced cirrhosis. We studied the prognostic value of hepatic venous pressure gradient in addition to epidemiological and clinical parameters in these patients. METHODS: Among patients with Child-Pugh A hepatitis C induced cirrhosis, prospectively followed in two Parisian centres, 100 had measurement of occluded and free hepatic venous pressures. We evaluated hepatic venous pressures as a predictive factor of death by Cox models (survival) and Fine and Gray models (liver-deaths). RESULTS: Median hepatic occluded pressure and gradient were 21.5 (15-24) and 13 mm Hg (9-15), respectively. The median duration of follow-up was 85 months (range: 70-112); 38 deaths or liver transplantation were registered. Hepatic venous pressure gradient was not significantly related to survival in the studied population but as a continuous variable was predictive of death from liver disease. On multivariable analysis serum albumin <40 g/L and platelet count <90,000 /mm(3) were the only selected prognostic factors. CONCLUSION: Hepatic venous pressure gradient has a limited value for assessing the prognosis of patients with Child-Pugh A hepatitis C virus induced cirrhosis; prognosis is accurately predicted by serum albumin and platelet count.

Standardized care management ensures similar survival rates in HIV-positive and HIV-negative patients with hepatocellular carcinoma.

OBJECTIVE: It has been suggested that HIV infection has a detrimental impact on patients with hepatocellular carcinoma (HCC). The present study sought to test this hypothesis, while controlling for tumor extension and liver disease. DESIGN AND SETTING: A case control and a cohort approach were performed in patients with HCC managed prospectively via dedicated multidisciplinary team meeting in a single tertiary institution between 2004 and 2009. SUBJECTS: Of 473 consecutive treatment-naive patients with HCC, 23 were HIV-positive (HIV) and 450 were HIV-negative (HIV). HIV patients were matched 1:2 with a control group of HIV patients in terms of the etiology of HCC, the severity of liver disease, tumor extension, and year of diagnosis. INTERVENTION: Curative or palliative treatment of HCC. MAIN OUTCOME MEASURES: Eligibility for HCC treatment, the treatment actually administered, and the survival rate. RESULTS: The HIV population was younger than the HIV population (mean age: 49 vs. 61 years, respectively; P < 0.0001). Curative treatment was recommended by the multidisciplinary team meeting and then actually performed to a similar extent in HIV patients (74% and 43%, respectively) and their matched HIV controls (74% and 56%, respectively). The HIV and their matched HIV patients did not differ significantly in terms of the 3-year survival rate [44% vs. 48%, respectively; mean (95% confidence interval) hazard ratio = 0.64 (0.3-1.3); P = 0.2]. In a cohort analysis, HIV status was not an independent predictor of survival among curatively treated patients. CONCLUSION: In an equal-access unbiased environment, HIV status does not significantly influence treatment access, delivery, and outcome.

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/ß-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.

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.

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 alpha-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.