F. Bonnetain

Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials

OBJECTIVEnThe objective of this study was to assess the performance of three staging systems [Okuda, Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer group (BCLC)], for predicting survival in patients with hepatocellular carcinoma (HCC) and to explore how to improve prognostic classification among French patients with HCC whose main etiology is alcoholic cirrhosis.nnnMETHODSnWe have pooled two randomized clinical trials in palliative condition from the Fédération Francophone de Cancerologie Digestive. They had included 416 and 122 patients. Performances of Okuda, CLIP and BCLC scores have been compared using Akaike information criterion, discriminatory ability (Harrells C and the Roystons D statistics), monotonicity of gradients and predictive accuracy (Schemper statistics Vs). To explore how to improve classifications, univariate and multivariate Cox model analyses were carried out.nnnRESULTSnThe pooled database included 538 patients. The median survival was 5.3 months (95% confidence interval 4.6-6.2). For all statistics CLIP staging system had a better prognostic ability. Performances of all staging systems were rather disappointing. World Health Organization performance status (WHO PS) for CLIP or alpha-fetoprotein for BCLC allowed a significant improvement of prognostic information.nnnCONCLUSIONnOur results indicate that CLIP staging seems to be most adapted to palliative setting and that it could be better by associating WHO PS.

Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial

BACKGROUNDnIn resectable rectal cancer trials, pathological parameters are early preoperative treatment efficacy measures. Their validation as surrogate end points for long-term clinical outcomes would allow to reduce trial duration. The aim was to evaluate potential surrogates for overall survival (OS) and local control (LC) in preoperative T3/T4 rectal cancer trials. Candidate variables included ypT and ypN stages, T downstaging, tumor regression grade (TRG), and circumferential resection margin (CRM) status.nnnPATIENTS AND METHODSnIn the Fédération Francophone de Cancérologie Digestive (FFCD) 9203 trial, 742 eligible patients were randomly assigned to receive preoperative radiotherapy with or without concurrent chemotherapy. Surrogacy was evaluated using Prentice criteria and the proportion of treatment effect (PTE) explained by each potential surrogate.nnnRESULTSnNone of the candidate surrogates fulfilled all Prentice criteria. Data analyses did not provide interpretable PTE measures for OS. Regarding LC, the highest PTE was reached by TRG, which explained 12% of the effect on local recurrence. This proportion may not exceed 41% [95% confidence interval (CI) -1% to 41%]. PTE explained by the CRM status was associated with a wide uncertainty (95% CI -81% to 105%), which does not exclude a potentially high degree of surrogacy.nnnCONCLUSIONnIn the FFCD 9203 trial, pathological parameters were not surrogate for OS or LC.

Estimating the cost related to surveillance of colorectal cancer in a French population

Little is known about costs related to the surveillance of patients that have undergone curative resection of colorectal cancer. The aim of this study was to calculate the observed surveillance costs for 385 patients followed-up over a 3-year period, to estimate surveillance costs if French guidelines are respected, and to identify the determinants related to surveillance costs to derive a global estimation for France, using a linear mixed model. The observed mean surveillance cost was €xa0713. If French recommendations were strictly applied, the estimated mean cost would vary between €xa0680 and €xa01,069 according to the frequency of abdominal ultrasound. The predicted determinants of cost were: age, recurrence, duration of surveillance since diagnosis, and adjuvant treatments. For France, the surveillance cost represented 4.4% of the cost of colorectal cancer management. The cost of surveillance should now be balanced with its effectiveness and compared with surveillance alternatives.

RAS mutation analysis in circulating tumor DNA from patients with metastatic colorectal cancer: the AGEO RASANC prospective multicenter study

BackgroundnRAS mutations are currently sought for in tumor samples, which takes a median of almost 3u2009weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort.nnnPatients and methodsnPlasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precisionu2009±u20090.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary.nnnResultsnFrom July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratiou2009=u20090.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers.nnnConclusionnThis prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients.nnnClinical Trial registrationnClinicaltrials.gov, NCT02502656.

Publication de l'étude CHOC (Carcinome Hépatocellulaire OCtréotide) Traitement du carcinome hépatocellulaire évolué par octréotide-retard: essai multicentrique phase III randomisé en double aveugle octréotide-retard vs placebo

Un essai randomise comparant octreotide et absence de traitement specifique chez des malades atteints de carcinome hepatocellulaire (CHC) evolue avait precedemment montre un benefice en termes de survie globale chez les patients traites [1]. Le but de letude ici relatee a ete devaluer ce benefice dans un essai randomise multicentrique incluant un nombre suffisant de patients.