Flexible Cure Rate Modeling Under Latent Activation Schemes

With rapid improvements in medical treatment and health care, many datasets dealing with time to relapse or death now reveal a substantial portion of patients who are cured (i.e., who never experience the event). Extended survival models called cure rate models account for the probability of a subject being cured and can be broadly classified into the classical mixture models of Berkson and Gage (BG type) or the stochastic tumor models pioneered by Yakovlev and extended to a hierarchical framework by Chen, Ibrahim, and Sinha (YCIS type). Recent developments in Bayesian hierarchical cure models have evoked significant interest regarding relationships and preferences between these two classes of models. Our present work proposes a unifying class of cure rate models that facilitates flexible hierarchical model-building while including both existing cure model classes as special cases. This unifying class enables robust modeling by accounting for uncertainty in underlying mechanisms leading to cure. Issues such as regressing on the cure fraction and propriety of the associated posterior distributions under different modeling assumptions are also discussed. Finally, we offer a simulation study and also illustrate with two datasets (on melanoma and breast cancer) that reveal our framework's ability to distinguish among underlying mechanisms that lead to relapse and cure.     

A competing risks derivation of a mixture model for the analysis of survival data

Boag (1949) and Berkson and Gage (1952) proposed a mixture model for the analysis of survival time data when aproportion of treated patients are cured. This paper presents a derivation of the Boag/Berkson-Gage mixture model as well as a eneralization of the model based on the theory of competing risks. The assumptions underlying the model are stated and discussed and a general likelihood function is obtained. Use of the model is illustrated ith data from the Stanford Heart Transplant Program.     

Defective models induced by gamma frailty term for survival data with cured fraction

In this paper, we propose a defective model induced by a frailty term for modeling the proportion of cured. Unlike most of the cure rate models, defective models have advantage of modeling the cure rate without adding any extra parameter in model. The introduction of an unobserved heterogeneity among individuals has bring advantages for the estimated model. The influence of unobserved covariates is incorporated using a proportional hazard model. The frailty term assumed to follow a gamma distribution is introduced on the hazard rate to control the unobservable heterogeneity of the patients. We assume that the baseline distribution follows a Gompertz and inverse Gaussian defective distributions. Thus we propose and discuss two defective distributions: the defective gamma-Gompertz and gamma-inverse Gaussian regression models. Simulation studies are performed to verify the asymptotic properties of the maximum likelihood estimator. Lastly, in order to illustrate the proposed model, we present three applications in real data sets, in which one of them we are using for the first time, related to a study about breast cancer in the A.C.Camargo Cancer Center, São Paulo, Brazil.     

Smooth Semi‐nonparametric Analysis for Mixture Cure Models and Its Application to Breast Cancer

Mixture cure models are widely used when a proportion of patients are cured. The proportional hazards mixture cure model and the accelerated failure time mixture cure model are the most popular models in practice. Usually the expectation–maximisation (EM) algorithm is applied to both models for parameter estimation. Bootstrap methods are used for variance estimation. In this paper we propose a smooth semi‐nonparametric (SNP) approach in which maximum likelihood is applied directly to mixture cure models for parameter estimation. The variance can be estimated by the inverse of the second derivative of the SNP likelihood. A comprehensive simulation study indicates good performance of the proposed method. We investigate stage effects in breast cancer by applying the proposed method to breast cancer data from the South Carolina Cancer Registry.     

Testing for the Presence of a Cure Fraction in Clustered Interval‐Censored Survival Data

Clustered interval‐censored survival data are often encountered in clinical and epidemiological studies due to geographic exposures and periodic visits of patients. When a nonnegligible cured proportion exists in the population, several authors in recent years have proposed to use mixture cure models incorporating random effects or frailties to analyze such complex data. However, the implementation of the mixture cure modeling approaches may be cumbersome. Interest then lies in determining whether or not it is necessary to adjust the cured proportion prior to the mixture cure analysis. This paper mainly focuses on the development of a score for testing the presence of cured subjects in clustered and interval‐censored survival data. Through simulation, we evaluate the sampling distribution and power behaviour of the score test. A bootstrap approach is further developed, leading to more accurate significance levels and greater power in small sample situations. We illustrate applications of the test using data sets from a smoking cessation study and a retrospective study of early breast cancer patients.     

Assessing the prediction accuracy of cure in the Cox proportional hazards cure model: an application to breast cancer data

A cure rate model is a survival model incorporating the cure rate with the assumption that the population contains both uncured and cured individuals. It is a powerful statistical tool for prognostic studies, especially in cancer. The cure rate is important for making treatment decisions in clinical practice. The proportional hazards (PH) cure model can predict the cure rate for each patient. This contains a logistic regression component for the cure rate and a Cox regression component to estimate the hazard for uncured patients. A measure for quantifying the predictive accuracy of the cure rate estimated by the Cox PH cure model is required, as there has been a lack of previous research in this area. We used the Cox PH cure model for the breast cancer data; however, the area under the receiver operating characteristic curve (AUC) could not be estimated because many patients were censored. In this study, we used imputation‐based AUCs to assess the predictive accuracy of the cure rate from the PH cure model. We examined the precision of these AUCs using simulation studies. The results demonstrated that the imputation‐based AUCs were estimable and their biases were negligibly small in many cases, although ordinary AUC could not be estimated. Additionally, we introduced the bias‐correction method of imputation‐based AUCs and found that the bias‐corrected estimate successfully compensated the overestimation in the simulation studies. We also illustrated the estimation of the imputation‐based AUCs using breast cancer data. Copyright © 2014 John Wiley & Sons, Ltd.     

Estimating the cure fraction in population-based cancer studies by using finite mixture models

Summary.  The cure fraction (the proportion of patients who are cured of disease) is of interest to both patients and clinicians and is a useful measure to monitor trends in survival of curable disease. The paper extends the non-mixture and mixture cure fraction models to estimate the proportion cured of disease in population-based cancer studies by incorporating a finite mixture of two Weibull distributions to provide more flexibility in the shape of the estimated relative survival or excess mortality functions. The methods are illustrated by using public use data from England and Wales on survival following diagnosis of cancer of the colon where interest lies in differences between age and deprivation groups. We show that the finite mixture approach leads to improved model fit and estimates of the cure fraction that are closer to the empirical estimates. This is particularly so in the oldest age group where the cure fraction is notably lower. The cure fraction is broadly similar in each deprivation group, but the median survival of the 'uncured' is lower in the more deprived groups. The finite mixture approach overcomes some of the limitations of the more simplistic cure models and has the potential to model the complex excess hazard functions that are seen in real data.     

A weighted Poisson distribution and its application to cure rate models

The family of weighted Poisson distributions offers great flexibility in modeling discrete data due to its potential to capture over/under-dispersion by an appropriate selection of the weight function. In this paper, we introduce a flexible weighted Poisson distribution and further study its properties by using it in the context of cure rate modeling under a competing cause scenario. A special case of the new distribution is the COM-Poisson distribution which in turn encompasses the Bernoulli, Poisson, and geometric distributions; hence, many of the well-studied cure rate models may be seen as special cases of the proposed model. We focus on the estimation, through the maximum likelihood method, of the cured proportion and the properties of the failure time of the susceptibles/non cured individuals; a profile likelihood approach is also adopted for estimating the parameters of the weighted Poisson distribution. A Monte Carlo simulation study demonstrates the accuracy of the proposed inferential method. Finally, as an illustration, we fit the proposed model to a cutaneous melanoma data set.     

A Bayesian approach to mixture cure models with spatial frailties for population‐based cancer relative survival data

As the treatments of cancer progress, a certain number of cancers are curable if diagnosed early. In population‐based cancer survival studies, cure is said to occur when mortality rate of the cancer patients returns to the same level as that expected for the general cancer‐free population. The estimates of cure fraction are of interest to both cancer patients and health policy makers. Mixture cure models have been widely used because the model is easy to interpret by separating the patients into two distinct groups. Usually parametric models are assumed for the latent distribution for the uncured patients. The estimation of cure fraction from the mixture cure model may be sensitive to misspecification of latent distribution. We propose a Bayesian approach to mixture cure model for population‐based cancer survival data, which can be extended to county‐level cancer survival data. Instead of modeling the latent distribution by a fixed parametric distribution, we use a finite mixture of the union of the lognormal, loglogistic, and Weibull distributions. The parameters are estimated using the Markov chain Monte Carlo method. Simulation study shows that the Bayesian method using a finite mixture latent distribution provides robust inference of parameter estimates. The proposed Bayesian method is applied to relative survival data for colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the cure fractions. The Canadian Journal of Statistics 40: 40–54; 2012 © 2012 Statistical Society of Canada     

The negative binomial–beta Weibull regression model to predict the cure of prostate cancer

In this article, for the first time, we propose the negative binomial–beta Weibull (BW) regression model for studying the recurrence of prostate cancer and to predict the cure fraction for patients with clinically localized prostate cancer treated by open radical prostatectomy. The cure model considers that a fraction of the survivors are cured of the disease. The survival function for the population of patients can be modeled by a cure parametric model using the BW distribution. We derive an explicit expansion for the moments of the recurrence time distribution for the uncured individuals. The proposed distribution can be used to model survival data when the hazard rate function is increasing, decreasing, unimodal and bathtub shaped. Another advantage is that the proposed model includes as special sub-models some of the well-known cure rate models discussed in the literature. We derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes. We analyze a real data set for localized prostate cancer patients after open radical prostatectomy.     

Modeling survival in childhood cancer studies using two-stage non-mixture cure models

Non-mixture cure models (NMCMs) are derived from a simplified representation of the biological process that takes place after treatment for cancer. These models are intended to represent the time from the end of treatment to the time of first recurrence of cancer in studies when a proportion of those treated are completely cured. However, for many studies overall survival is also of interest. A two-stage NMCM that estimates the overall survival from a combination of two cure models, one from end of treatment to first recurrence and one from first recurrence to death, is proposed. The model is applied to two studies of Ewing's tumor in young patients. Caution needs to be exercised when extrapolating from cure models fitted to short follow-up times, but these data and associated simulations show how, when follow-up is limited, a two-stage model can give more stable estimates of the cure fraction than a one-stage model applied directly to overall survival.     

Discrete and continuous bivariate lifetime models in presence of cure rate: a comparative study under Bayesian approach

The modeling and analysis of lifetime data in which the main endpoints are the times when an event of interest occurs is of great interest in medical studies. In these studies, it is common that two or more lifetimes associated with the same unit such as the times to deterioration levels or the times to reaction to a treatment in pairs of organs like lungs, kidneys, eyes or ears. In medical applications, it is also possible that a cure rate is present and needed to be modeled with lifetime data with long-term survivors. This paper presented a comparative study under a Bayesian approach among some existing continuous and discrete bivariate distributions such as the bivariate exponential distributions and the bivariate geometric distributions in presence of cure rate, censored data and covariates. In presence of lifetimes related to cured patients, it is assumed standard mixture cure rate models in the data analysis. The posterior summaries of interest are obtained using Markov Chain Monte Carlo methods. To illustrate the proposed methodology two real medical data sets are considered.     

Standard Exponential Cure Rate Model with Noninformative or Informative Uniform-Exponential Censoring

In survival data analysis it is frequent the occurrence of a significant amount of censoring to the right indicating that there may be a proportion of individuals in the study for which the event of interest will never happen. This fact is not considered by the ordinary survival theory. Consequently, the survival models with a cure fraction have been receiving a lot of attention in the recent years. In this article, we consider the standard mixture cure rate model where a fraction p ₀ of the population is of individuals cured or immune and the remaining 1 ? p ₀ are not cured. We assume an exponential distribution for the survival time and an uniform-exponential for the censoring time. In a simulation study, the impact caused by the informative uniform-exponential censoring on the coverage probabilities and lengths of asymptotic confidence intervals is analyzed by using the Fisher information and observed information matrices.     

Estimating the turning point of the log-logistic hazard function in the presence of long-term survivors with an application for uterine cervical cancer data

The hazard function plays an important role in cancer patient survival studies, as it quantifies the instantaneous risk of death of a patient at any given time. Often in cancer clinical trials, unimodal hazard functions are observed, and it is of interest to detect (estimate) the turning point (mode) of hazard function, as this may be an important measure in patient treatment strategies with cancer. Moreover, when patient cure is a possibility, estimating cure rates at different stages of cancer, in addition to their proportions, may provide a better summary of the effects of stages on survival rates. Therefore, the main objective of this paper is to consider the problem of estimating the mode of hazard function of patients at different stages of cervical cancer in the presence of long-term survivors. To this end, a mixture cure rate model is proposed using the log-logistic distribution. The model is conveniently parameterized through the mode of the hazard function, in which cancer stages can affect both the cured fraction and the mode. In addition, we discuss aspects of model inference through the maximum likelihood estimation method. A Monte Carlo simulation study assesses the coverage probability of asymptotic confidence intervals.     

Maximum likelihood estimation for mixtures of two gompertz distributions when censoring occurs

In estimating the proportion ‘cured’ after adjuvant treatment, a population of cancer patients can be assumed to be a mixture of two Gompertz subpopulations, those who will die of other causes with no evidence of disease relapse and those who will die of their primary cancer. Estimates of the parameters of the component dying of other causes can be obtained from census data, whereas maximum likelihood estimates for the proportion cured and for the parameters of the component of patients dying of cancer can be obtained from follow-up data.

This paper examines, through simulation of follow-up data, the feasibility of maximum likelihood estimation of a mixture of two Gompertz distributions when censoring occurs. Means, variances and mean square error of the maximum likelihood estimates and the estimated asymptotic variance-covariance matrix is obtained from the simulated samples. The relationship of these variances with sample size, proportion censored, mixing proportion and population parameters are considered.

Moderate sample size typical of cooperative trials yield clinically acceptable estimates. Both increasing sample size and decreasing proportion of censored data decreases variance and covariance of the unknown parameters. Useful results can be obtained with data which are as much as 50% censored. Moreover, if the sample size is sufficiently large, survival data which are as much as 70% censored can yield satisfactory results.     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

Study design of single‐arm phase II immunotherapy trials with long‐term survivors and random delayed treatment effect

In the traditional study design of a single‐arm phase II cancer clinical trial, the one‐sample log‐rank test has been frequently used. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Such a study design may not be suitable for immunotherapy cancer trials, when both long‐term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single‐arm phase II immunotherapy cancer trials. To improve test power, we proposed a new weighted one‐sample log‐rank test and provided a sample size calculation formula for designing trials. Our simulation study showed that the proposed log‐rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well.     

A semiparametric regression cure model for interval-censored and left-truncated data

Medical advancements have made it possible for patients to be cured of certain types of diseases. In follow-up studies, the disease event time can be subject to left truncation and interval censoring. In this article, we propose a semiparametric nonmixture cure model for the regression analysis of left-truncated and interval-censored (LTIC) data. We develop semiparametric maximum likelihood estimation for the nonmixture cure model with LTIC data. A simulation study is conducted to investigate the performance of the proposed estimators.     

Standard Exponential Cure Rate Model with Informative Censoring

In this article, we consider the standard cure rate model proposed by Boag (1949 Boag , J. W. ( 1949 ). Maximum likelihood estimates of the proportion of patients cured by cancer therapy . J. Roy. Statist. Soc. B 11 : 15 – 53 . [Google Scholar]) and Berkson and Gage (1952 Berkson , J. , Gage , R. ( 1952 ). Survival curve for cancer patients following treatment . J. Amer. Statist. Assoc. 47 : 501 – 515 .[Taylor & Francis Online], [Web of Science ®] , [Google Scholar]). We present a new definition of informative censoring similar to Lawless (1982 Lawless , J. F. ( 1982 ). Statistical Models and Methods for Lifetime Data . New York : Wiley .[Crossref] , [Google Scholar]) and the corresponding likelihood function. Under informative censoring, we obtain the Fisher information matrix of the exponential standard cure rate model. We verify, with simulated data, the impact caused by informative censoring in the coverage probabilities and in the lengths of asymptotic confidence intervals of the parameters of interest. An example with real data is analyzed.     

The Large Sample Distribution of the Weighted Log Rank Statistic Under General Local Alternatives

We derive the large sample distribution of the weighted log rank statistic under a general class of local alternatives in which both the cure rates and the conditional distribution of time to failure among those who fail are assumed to vary in the two treatment arms. The analytic result presented here is important to data analysts who are designing clinical trials for diseases such as non-Hodgkins lymphoma, leukemia and melanoma, where a significant proportion of patients are cured. We present a numerical illustration comparing powers obtained from the analytic result to those obtained from simulations. This revised version was published online in July 2006 with corrections to the Cover Date.