Laurent Roche

Estimating net survival: the importance of allowing for informative censoring

Net survival, the one that would be observed if cancer were the only cause of death, is the most appropriate indicator to compare cancer mortality between areas or countries. Several parametric and non-parametric methods have been developed to estimate net survival, particularly when the cause of death is unknown. These methods are based either on the relative survival ratio or on the additive excess hazard model, the latter using the general population mortality hazard to estimate the excess mortality hazard (the hazard related to net survival). The present work used simulations to compare estimator abilities to estimate net survival in different settings such as the presence/absence of an age effect on the excess mortality hazard or on the potential time of follow-up, knowing that this covariate has an effect on the general population mortality hazard too. It showed that when age affected the excess mortality hazard, most estimators, including specific survival, were biased. Only two estimators were appropriate to estimate net survival. The first is based on a multivariable excess hazard model that includes age as covariate. The second is non-parametric and is based on the inverse probability weighting. These estimators take differently into account the informative censoring induced by the expected mortality process. The former offers great flexibility whereas the latter requires neither the assumption of a specific distribution nor a model-building strategy. Because of its simplicity and availability in commonly used software, the nonparametric estimator should be considered by cancer registries for population-based studies.

HIV-1 Load Comparison Using Four Commercial Real-Time Assays

ABSTRACT The HIV-1 RNA viral load is commonly used for the monitoring of disease progression and antiretroviral treatment of HIV-1-infected patients. Since the misestimating of values could lead to inappropriate therapeutical management, the comparative performances, especially the ability to span the genetic diversity of HIV-1, of available automated real-time assays need to be evaluated. We conducted a prospective study with 74 consenting patients enrolled between March 2007 and November 2008. A blood sample was obtained at the time of diagnosis of HIV seropositivity and blindly tested for HIV-1 RNA by at least 4 commercial tests: the Abbott m2000 RealTime HIV-1, bioMérieux NucliSens EasyQ HIV-1, version 1.2 (v1.2), and Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) v1.0 and v2.0 assays. The means of difference were null between CAP/CTM v2.0 and Abbott for CRF02_AG subtypes but positive in favor of CAP/CTM v2.0 for genotype B and negative in favor of NucliSens for all genotypes. The standard deviation (SD) of difference ranged from 0.3 to 0.59, depending on the considered couples of assays. Reliabilities of these four tests, appreciated by the standard deviation of difference between the measurement and the estimated “true” viral load and by the coefficient of reliability, were significantly different (P < 10−4) among each other. Significant differences were also observed within each group of HIV-1 genotype. The global disparity was higher for CRF02_AG than for B subtypes. This study indicates a risk of viral load misestimating or discrepancies between techniques, depending on the HIV-1 subtype, and speaks in favor of using the same assay for the monitoring of HIV-1-infected patients.

Cancer net survival on registry data: use of the new unbiased Pohar-Perme estimator and magnitude of the bias with the classical methods.

Net survival, the survival which might occur if cancer was the only cause of death, is a major epidemiological indicator required for international or temporal comparisons. Recent findings have shown that all classical methods used for routine estimation of net survival from cancer‐registry data, sometimes called “relative‐survival methods,” provide biased estimates. Meanwhile, an unbiased estimator, the Pohar‐Perme estimator (PPE), was recently proposed. Using real data, we investigated the magnitude of the errors made by four “relative‐survival” methods (Ederer I, Hakulinen, Ederer II and a univariable regression model) vs. PPE as reference and examined the influence of time of follow‐up, cancer prognosis, and age on the errors made. The data concerned seven cancer sites (2,51,316 cases) collected by FRANCIM cancer registries. Net survivals were estimated at 5, 10 and 15 years postdiagnosis. At 5 years, the errors were generally small. At 10 years, in good‐prognosis cancers, the errors made in nonstandardized estimates with all classical methods were generally great (+2.7 to +9% points in prostate cancer) and increased in age‐class estimations (vs. 5‐year ones). At 15 years, in bad‐ or average‐prognosis cancers, the errors were often substantial whatever the nature of the estimation. In good‐prognosis cancers, the errors in nonstandardized estimates of all classical methods were great and sometimes very important. With all classical methods, great errors occurred in age‐class estimates resulting in errors in age‐standardized estimates (+0.4 to +3.2% points in breast cancer). In estimating net survival, cancer registries should abandon all classical methods and adopt the new Pohar‐Perme estimator.

Changes in the dynamics of the excess mortality rate in chronic phase-chronic myeloid leukemia over 1990-2007: a population study

Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.

The Net Chance of a Longer Survival as a Patient-Oriented Measure of Treatment Benefit in Randomized Clinical Trials.

IMPORTANCE Time to events, or survival end points, are common end points in randomized clinical trials. They are usually analyzed under the assumption of proportional hazards, and the treatment effect is reported as a hazard ratio, which is neither an intuitive measure nor a meaningful one if the assumption of proportional hazards is not met. OBJECTIVE To demonstrate that a different measure of treatment effect, called the net chance of a longer survival, is a meaningful measure of treatment effect in clinical trials whether or not the assumption of proportional hazards is met. DESIGN In this simulation study, the net chance of a longer survival by at least m months, where m months is considered clinically worthwhile and relevant to the patient, was calculated as the probability that a random patient in the treatment group has a longer survival by at least m months than does a random patient in the control group minus the probability of the opposite situation. The net chance of a longer survival is equal to zero if treatment does not differ from control and ranges from -100% if all patients in the control group fare better than all patients in the treatment group up to 100% in the opposite situation. We simulated data sets for realistic trials under various scenarios of proportional and nonproportional survival hazards and plotted the Kaplan-Meier survival curves as well as the net chance of a longer survival as a function of m. Data analysis was performed from August 14 to 18, 2015. MAIN OUTCOMES AND MEASURES The net chance of a longer survival calculated for values of m ranging from 0 to 40 months. RESULTS When hazards are proportional, the net chance of a longer survival approaches zero as m increases. The net chance of a longer survival (Δ) was 13% (95% CI, 6.5%-19.4%; P < .001) when any survival difference was considered clinically relevant (m = 0 months). When survival differences larger than 20 months were considered relevant (m = 20), the net chance of a longer survival was very close to zero (Δ[20] = 0.5%; 95% CI, -0.1% to 1.1%; P = .09). In contrast, when treatment effects are delayed or when some patients are cured by treatment, the net chance of a longer survival benefit remains high and tends to the cure rate. For crossing hazards, the Δ was negative (Δ = -6.9%; 95% CI, -14.0% to -0.5%; P = .047). However when large survival differences were considered (m = 20), the Δ(m) was positive (Δ[20] = 8.9%; 95% CI, 6.7%-11.1%; P < .001). CONCLUSIONS AND RELEVANCE The net chance of a longer survival is useful whether or not the assumption of proportional hazards is met in the analysis of survival end points and may be helpful as a measure of treatment benefit that has direct relevance to patients and health care professionals.

Assessing the benefit-risk of new treatments using generalised pairwise comparisons: the case of erlotinib in pancreatic cancer.

Background:Efficacy and safety are the two considerations when characterising the effects of a new therapy. We sought to apply an innovative method of assessing the benefit–risk balance using data from a completed randomised controlled trial that compared erlotinib vs placebo added to gemcitabine in patients with advanced pancreatic cancer (NCIC CTG PA.3).Methods:We applied generalised pairwise comparisons with several prioritised outcome measures (e.g., one or more benefit outcomes and one or more risk outcomes). Here, the first priority outcome was overall survival (OS) time. Differences in OS that exceeded 2 months were considered clinically meaningful. The second priority outcome was toxicity. The overall treatment effect was quantified using the proportion in favour of erlotinib, which can be interpreted as the net proportion of patients who have a better overall outcome with erlotinib as compared with placebo. Sensitivity analyses were performed.Results:In this trial 569 patients were randomly assigned in a 1 : 1 ratio to receive gemcitabine plus either erlotinib or a matched placebo. Overall, the method indicated no statistically significant overall treatment effect in favour of erlotinib; if anything, the point estimate of the net proportion leaned in favour of the placebo group (overall proportion in favour of erlotinib=−3.6%, 95% CI, −14.2– 7.1%; P=0.51). The net proportion was never in favour of the erlotinib group throughout all sensitivity analyses.Conclusions:Generalised pairwise comparisons make it possible to assess the benefit–risk balance of new treatments using a single statistical test for any number of prioritised outcomes. The benefit–risk assessment was not in favour of adding erlotinib to gemcitabine for the treatment of patients with advanced pancreatic cancer.

A multilevel excess hazard model to estimate net survival on hierarchical data allowing for non‐linear and non‐proportional effects of covariates

The excess hazard regression model is an approach developed for the analysis of cancer registry data to estimate net survival, that is, the survival of cancer patients that would be observed if cancer was the only cause of death. Cancer registry data typically possess a hierarchical structure: individuals from the same geographical unit share common characteristics such as proximity to a large hospital that may influence access to and quality of health care, so that their survival times might be correlated. As a consequence, correct statistical inference regarding the estimation of net survival and the effect of covariates should take this hierarchical structure into account. It becomes particularly important as many studies in cancer epidemiology aim at studying the effect on the excess mortality hazard of variables, such as deprivation indexes, often available only at the ecological level rather than at the individual level. We developed here an approach to fit a flexible excess hazard model including a random effect to describe the unobserved heterogeneity existing between different clusters of individuals, and with the possibility to estimate non-linear and time-dependent effects of covariates. We demonstrated the overall good performance of the proposed approach in a simulation study that assessed the impact on parameter estimates of the number of clusters, their size and their level of unbalance. We then used this multilevel model to describe the effect of a deprivation index defined at the geographical level on the excess mortality hazard of patients diagnosed with cancer of the oral cavity. Copyright

An assessment of the benefit-risk balance of FOLFIRINOX in metastatic pancreatic adenocarcinoma

Background We sought to assess the benefit-risk balance of FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic adenocarcinoma. Methods We used generalized pairwise comparisons. This statistical method permits the simultaneous analysis of several prioritized outcome measures. The first priority outcome was survival time (OS). Differences in OS that exceeded two months were considered clinically relevant. The second priority outcome was toxicity. The overall treatment effect was quantified using the net chance of a better outcome, which can be interpreted as the net probability for a random patient treated in the FOLFIRINOX group to have a better overall outcome than a random patient in the gemcitabine group. Results In this trial 342 patients received either FOLFIRINOX or gemcitabine. The net chance of a better outcome favored strongly and significantly the FOLFIRINOX group (24.7; P<.001), suggesting a favorable benefit-risk balance of FOLFIRINOX versus gemcitabine. The positive benefit-risk balance of FOLFIRINOX was observed throughout all sensitivity analyses. Conclusions Generalized pairwise comparisons are useful to perform a quantitative assessment of the benefit-risk balance of new treatments. It provides a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. Overall the benefit-risk balance of FOLFIRINOX was strongly positive.

An extension of generalized pairwise comparisons for prioritized outcomes in the presence of censoring

Generalized pairwise comparisons have been proposed to permit a comprehensive assessment of several prioritized outcomes between two groups of observations. This procedure estimates Δ, the net chance of a better outcome with treatment than with control by comparing the patients outcomes among all possible pairs taking one patient from the treatment group and one patient from the control group. For time to event outcomes, the standard procedure of generalized pairwise comparisons is analogous to the Gehan’s modification of the Mann-Whitney test which is biased in presence of censored observation and less powerful than Efron’s modification of this test. We adapt Efron’s modification to generalized pairwise comparisons. We show how a pairwise contribution to Δ can be calculated from the estimates of the survival function in the presence of right-censored data. We performed a simulation study to assess the bias, the type I error and the power of the new procedure. The estimate of Δ with the new procedure is only slightly biased even in presence of heavy censoring. We also show how this bias can be corrected when only one time-to-event outcome is analyzed. The new procedure has higher power in most cases compared to the standard procedure.

One-step partial or complete caries removal and bonding with antibacterial or traditional self-etch adhesives: study protocol for a randomized controlled trial

BackgroundCurrent concepts in conservative dentistry advocate minimally invasive dentistry and pulp vitality preservation. Moreover, complete removal of carious dentin in deep carious lesions often leads to pulp exposure and root canal treatment, despite the absence of irreversible pulp inflammation. For years, partial caries removal has been performed on primary teeth, but little evidence supports its effectiveness for permanent teeth. Furthermore, the recent development of new antibacterial adhesive systems could be interesting in the treatment of such lesions. The objectives of this study are to compare the effectiveness of partial versus complete carious dentin removal in deep lesions (primary objective) and the use of an antibacterial versus a traditional two-step self-etch adhesive system (main secondary objective).Methods/DesignThe DEep CAries Treatment (DECAT) study protocol is a multicenter, randomized, controlled superiority trial comparing partial versus complete caries removal followed by adhesive restoration. The minimum sample size required is 464 patients. Two successive randomizations will be performed (allocation ratio 1:1): the first for the type of excavation (partial versus complete) and the second (if no root canal treatment is required) for the type of adhesive (antibacterial versus traditional). For the two objectives, the outcome is the success of the treatment after 1 year, measured according to a composite outcome of five FDI criteria: material fracture and retention, marginal adaptation, radiographic examination (including apical pathologies), postoperative sensitivity and tooth vitality, and carious lesion recurrence.DiscussionThe study will investigate the interest of a conservative approach for the management of deep carious lesions in terms of dentin excavation and bioactive adhesive systems. The results may help practitioners achieve the most efficient restorative procedure to maintain pulp vitality and increase the restoration longevity.Trial registrationClinicalTrials.gov Identifier NCT02286388. Registered in November 2014.