A frequentist one-step model for a simple network meta-analysis of time-to-event data in presence of an effect modifier.

INTRODUCTION: Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequentist one-step model for evaluating TE in the presence of interaction in a three-node NMA for time-to-event data. METHODS: One-step, frequentist, IPD-based Cox and Poisson generalized linear mixed models were proposed. We simulated a three-node network with or without a closed loop with (1) no interaction, (2) covariate-treatment interaction, and (3) covariate distribution heterogeneity and covariate-treatment interaction. These models were applied to the NMA (Meta-analyses of Chemotherapy in Head and Neck Cancer [MACH-NC] and Radiotherapy in Carcinomas of Head and Neck [MARCH]), which compared the addition of chemotherapy or modified radiotherapy (mRT) to loco-regional treatment with two direct comparisons. AD-based (contrast and meta-regression) models were used as reference. RESULTS: In the simulated study, no IPD models failed to converge. IPD-based models performed well in all scenarios and configurations with small bias. There were few variations across different scenarios. In contrast, AD-based models performed well when there were no interactions, but demonstrated some bias when interaction existed and a larger one when the modifier was not distributed evenly. While meta-regression performed better than contrast-based only, it demonstrated a large variability in estimated TE. In the real data example, Cox and Poisson IPD-based models gave similar estimations of the model parameters. Interaction decomposition permitted by IPD explained the ecological bias observed in the meta-regression. CONCLUSION: The proposed general one-step frequentist Cox and Poisson models had small bias in the evaluation of a three-node network with interactions. They performed as well or better than AD-based models and should also be undertaken whenever possible.

What Is the Best Treatment of Locally Advanced Nasopharyngeal Carcinoma? An Individual Patient Data Network Meta-Analysis.

Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs [95% CIs]) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.

[The frequency of cancer in France: Most recent data and trends]. / La fréquence des cancers en 2016 et leur évolution.

We present and discuss recent data on the frequency of cancer in France and on cancer survival. In the male population, the incidence of prostate and head and neck cancers diminishes rapidly and the incidence of the other common cancers: lung and colorectal diminishes less markedly; cancer mortality decreases for most sites. In the female population, the incidence of breast cancer diminishes rapidly, the incidence of colorectal and uterus cancers diminish less markedly and the incidence of lung cancer increases very fast: the mortality trends are similar. Cancer survival has improved in the last 16 years but some of the improvements are an artifact induced by overdiagnosis.

[Network meta-analyses: Interest and limits in oncology]. / Méta-analyses en réseau : intérêt et limites en oncologie.

In the last decade, a new method has emerged called 'network meta-analysis' to take into account all randomized trials in a given clinical setting to provide relative effectiveness between different treatments, whether or not they have been compared (pairwise) in randomized controlled trials. Network meta-analyses combine the results of direct comparisons from randomized trials with indirect comparisons between trials (i.e. when two treatments were not compared with each other, but have been studied in relation to a common comparator). The purpose of this note is to explain this method, its relevance and its limitations. A worked example in non-metastatic head and neck cancer is presented as illustration.

Trends in tobacco-attributable mortality in France.

BACKGROUND: In 2010, the prevalence of tobacco use in France was 33% and reached 39% in the population aged 18-44. The purpose of this article is to describe the trends in tobacco-attributable mortality in France between 1980 and 2010. METHODS: Using data from the national mortality statistics and relative risks of death, we estimated the tobacco-attributable fractions (AF) by sex and age using the method developed by Peto et al. and used recently by the World Health Organization with improved relative risk estimates. The tobacco-attributable mortality by age and sex is obtained by multiplying the AFs by the number of deaths. They are estimated in 5-year intervals from 1980 to 2010. RESULTS: In 2010, a total of 78,000 deaths were attributable to tobacco use in France. The number of deaths attributable to tobacco use among men decreased from 66,000 deaths in 1985 to 59,000 deaths in 2010, and the tobacco-AF decreased from 23% in 1985 to 21% in 2010. The number of deaths attributable to tobacco use among women increased from 2700 in 1980 (1% of all deaths) to 19,000 in 2010 (7% of all deaths). In the population aged 35-69, one in three deaths among men and one in seven deaths among women are attributable to tobacco use. CONCLUSION: While tobacco-attributable mortality among men has been declining during the past three decades, it has increased dramatically among women. Thus, effective preventive measures are urgently needed to stem the tobacco epidemic.

Deterministic modelling for transmission of Human Papillomavirus 6/11: impact of vaccination.

This paper is devoted to assess the impact of quadrivalent human papillomavirus (HPV) vaccine on the prevalence of non-oncogenic HPV 6/11 types in French males and females. For this purpose, a non-linear dynamic model of heterosexual transmission for HPV 6/11 types infection is developed, which accounts for immunity due to vaccination, in particular. The vaccinated reproduction number Rv is derived using the approach described by Diekmann et al. (2010) called the next generation operator approach. The model proposed is analysed, with regard to existence and uniqueness of the solution, steady-state stability. Precisely, the stability of the model is investigated depending on the sign of Rv-1. Prevalence data are used to fit a numerical HPV model, so as to assess infection rates. Our approach suggests that 10 years after introducing vaccination, the prevalence of HPV 6/11 types in females will be halved and that in males will be reduced by one-quarter, assuming a sustained vaccine coverage of 30% among females. Using the formula, we derived for the vaccinated reproduction number, we show that the non-oncogenic HPV 6/11 types would be eradicated if vaccine coverage in females is kept above 12%.

A critical review of cost-effectiveness analyses of vaccinating males against human papillomavirus.

A critical review of cost-effectiveness analyses of HPV vaccination in males was conducted and nine studies were identified in different countries. Due to the heterogeneity among these studies in terms of modeling approach, vaccination strategies, health outcomes considered, assumptions and parameters, limited conclusions can be drawn with regard to the absolute cost-effectiveness. Nevertheless, key drivers were identified. More favorable cost-effectiveness appeared when all HPV-related diseases outcomes were considered, a suboptimal vaccine coverage among girls and/or lower vaccine prices were assumed. There was a general lack of transparency to fully describe the details of the methodological approach of modeling and calibration. Further research should be conducted to generate robust evidence-based data sets (HPV-related diseases epidemiology, costs and quality of life). The best modeling practice for HPV vaccination and how to better capture the true economic value of vaccination beyond cost-effectiveness in a broader policy context need to be investigated.

Efficacy of vaccination against HPV infections to prevent cervical cancer in France: present assessment and pathways to improve vaccination policies.

BACKGROUND: Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and 1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has been reported to be low. METHODS: We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18, which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of cervical cancer incidence. RESULTS: In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before 14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the effect on cervical cancer incidence only moderately, compared to strategies in females only. CONCLUSION: While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary strategies in females could be considered in order to improve vaccination efficacy.

Increased risk of contralateral breast cancers among overweight and obese women: a time-dependent association.

Breast cancer (BC) survivors are at increased risk of second cancers. Obesity is commonly recognized as a risk factor of BC in postmenopausal period and a prognosis factor in BC regardless of menopausal status. Our aim was to study whether overweight BC survivors were at increased risk of contralateral BC (CBC). Our population was a large cohort of women followed since a first BC without distant spread and/or synchronous CBC. Body mass index (BMI) was assessed at diagnosis time. Binary codings of BMI were used to oppose overweight and obese patients to the others. Survival analyses were used including Cox models. Assumed hypothesis of proportional hazards was explored using graphical methods, Schoenfeld residuals and time-dependant covariates. In case of non-proportional hazards, survival models were computed over time periods. Over 15,000 patients were included in our study. Incidence of CBC was 8.8 (8.3-9.3)/1000 person-years and increased during follow-up. A significant time-dependent association between overweight and CBC was observed. After 10 years of follow-up, we found a significant increased hazard of CBC among patients with a BMI above 25 kg/m(2): the adjusted hazard ratio was 1.50(1.21-1.86), P = 0.001. After 10 years of follow-up, our study found a poorer prognosis among overweight BC survivors regarding CBC events. While benefits from diet habits and weight control may be expected during the long-term follow-up, they have yet to be established using randomized clinical trials.