Fabien Subtil

Geriatric Factors Predict Chemotherapy Feasibility: Ancillary Results of FFCD 2001-02 Phase III Study in First-Line Chemotherapy for Metastatic Colorectal Cancer in Elderly Patients

PURPOSE Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patients health status to better adapt treatment. PATIENTS AND METHODS Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation. RESULTS The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52). CONCLUSION Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.

Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial

BACKGROUND Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). METHODS For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. FINDINGS Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. INTERPRETATION The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. FUNDING Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

Gender Differences in Immune Reconstitution: A Multicentric Cohort Analysis in Sub-Saharan Africa

Background In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution. Methods/Principal Findings Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub-Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART. A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85–206] for women and 125 cells/µL [IQR 63–187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/µL per year on average (95% CI 16–23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250cells/µL (difference between patients with <50 cells/µL and those with >250 was 284 cells/µL; 95% CI 272–296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150–200 cells/µL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4–2.5) and men after 4.5 years (95% CI 4.1–4.8) of ART use. Conclusion Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men.

Noninvasive diagnosis and prognosis of liver cirrhosis: a comparison of biological scores, elastometry, and metabolic liver function tests.

Background Recently, noninvasive methods for the diagnosis of liver cirrhosis have been extensively developed. We assessed the accuracy of liver stiffness measurement, aspartate aminotransferase-to-platelet ratio index (APRI) score, 13C-aminopyrine breath test, and indocyanine green plasma clearance for the diagnosis of cirrhosis in patients with chronic liver disease and for the prediction of severe complications in cirrhotic patients. Methods A total of 296 consecutive patients with chronic liver diseases of various causes were studied. Diagnostic accuracy was assessed by receiver operating characteristic curve analysis. Results Areas under the receiver operating characteristic curve for the diagnosis of cirrhosis were (95% confidence interval) 0.93 (0.90–0.96) for liver stiffness measurement, 0.82 (0.77–0.87) for 13C-aminopyrine breath test, and 0.81 (0.76–0.86) for APRI score. Using cutoff values of 14.1 kPa for liver stiffness, 4.15% dose/h for 13C-aminopyrine breath test, and 1 for APRI score, the positive predictive value was approximately 90% for the diagnosis of cirrhosis. Using cutoff values of 65.2 kPa for liver stiffness, 1.17% dose/h for 13C-aminopyrine breath test, 2.82 for APRI score, and 51.1% for indocyanine green plasma clearance, the positive predictive value was approximately 80% for the occurrence of severe complications among cirrhotic patients. Conclusion Liver stiffness measurement, 13C-aminopyrine breath test, indocyanine green plasma clearance, and APRI score are reliable noninvasive methods for the diagnosis of cirrhosis in patients with chronic liver diseases of various causes, and are also prognostic indicators for the occurrence of severe complications in cirrhotic patients.

Impact of variability in adherence to HIV antiretroviral therapy on the immunovirological response and mortality

BackgroundSeveral previous studies have shown relationships between adherence to HIV antiretroviral therapy (ART) and the viral load, the CD4 cell count, or mortality. However, the impact of variability in adherence to ART on the immunovirological response does not seem to have been investigated yet.MethodsMonthly adherence data (November 1999 to April 2009) from 317 HIV-1 infected patients enrolled in the Senegalese ART initiative were analyzed. Latent-class trajectory models were used to build typical trajectories for the average adherence and the standardized variance of adherence. The relationship between the standardized variance of adherence and each of the change in CD4 cell count, the change in viral load, and mortality were investigated using, respectively, a mixed linear regression, a mixed logistic regression, and a Cox model with time-dependent covariates. All the models were adjusted on the average adherence.ResultsThree latent trajectories for the average adherence and three for the standardized variance of adherence were identified. The increase in CD4 cell count and the increase in the percentage of undetectable viral loads were negatively associated with the standardized variance of adherence but positively associated with the average adherence. The risk of death decreased significantly with the increase in the average adherence but increased significantly with the increase of the standardized variance of adherence.ConclusionsThe impacts of the level and the variability of adherence on the immunovirological response and survival justify the inclusion of these aspects into the process of patient education: adherence should be both high and constant.

The precision–recall curve overcame the optimism of the receiver operating characteristic curve in rare diseases

OBJECTIVES Compare the area under the receiver operating characteristic curve (AUC) vs. the area under the precision-recall curve (AUPRC) in summarizing the performance of a diagnostic biomarker according to the disease prevalence. STUDY DESIGN AND SETTING A simulation study was performed considering different sizes of diseased and nondiseased groups. Values of a biomarker were sampled with various variances and differences in mean values between the two groups. The AUCs and the AUPRCs were examined regarding their agreement and vs. the positive predictive value (PPV) and the negative predictive value (NPV) of the biomarker. RESULTS With a disease prevalence of 50%, the AUC and the AUPRC showed high correlations with the PPV and the NPV (ρ > 0.95). With a prevalence of 1%, small PPV and AUPRC values (<0.2) but high AUC values (>0.9) were found. The AUPRC reflected better than the AUC the discriminant ability of the biomarker; it had a higher correlation with the PPV (ρ = 0.995 vs. 0.724; P < 0.001). CONCLUSION In uncommon and rare diseases, the AUPRC should be preferred to the AUC because it summarizes better the performance of a biomarker.

Sequential combination of gemcitabine, vinorelbine, pegylated liposomal doxorubicin and brentuximab as a bridge regimen to transplant in relapsed or refractory Hodgkin lymphoma

Among haematological malignancies, Hodgkin’s lymphoma (HL) remains a disease with a high cure rate and overall survival rate of >80% for patients under 60 years. Nevertheless, approximately 5–10% of HL patients are refractory to initial treatment and 10–30% relapse after achieving an initial

Robust non-linear mixed modelling of longitudinal PSA levels after prostate cancer treatment

The objective of this study was to develop a robust non-linear mixed model for prostate-specific antigen (PSA) measurements after a high-intensity focused ultrasound (HIFU) treatment for prostate cancer. The characteristics of these data are the presence of outlying values and non-normal random effects. A numerical study proved that parameter estimates can be biased if these characteristics are not taken into account. The intra-patient variability was described by a Student-t distribution and Dirichlet process priors were assumed for non-normal random effects; a process that limited the bias and provided more efficient parameter estimates than a classical mixed model with normal residuals and random effects. It was applied to the determination of the best dynamic PSA criterion for the diagnosis of prostate cancer recurrence, but could be used in studies that rely on PSA data to improve prognosis or compare treatment efficiencies and also with other longitudinal biomarkers that, such as PSA, present outlying values and non-normal random effects.

Can we identify response markers to antihypertensive drugs? First results from the IDEAL Trial

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25–70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was −11.5 mm Hg (indapamide) and −8.3 mm Hg (perindopril). In men, the response was significantly smaller: −4.8 mm Hg (indapamide) and −4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

Gemcitabine plus cisplatin versus chemoradiotherapy in locally advanced biliary tract cancer: Fédération Francophone de Cancérologie Digestive 9902 phase II randomised study

BACKGROUND Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH). PATIENTS AND METHODS Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ⩽ 2, bilirubinemia ⩽ 50 μM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine+oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications. RESULTS The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (± 2.8). Grade III-IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65-3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32-1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31-1.55]). CONCLUSIONS Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC.