The Economic Cost of Thyroid Cancer in France and the Corresponding Share Associated With Treatment of Overdiagnosed Cases.

OBJECTIVES: Thyroid cancer incidence in France has increased rapidly in recent decades. Most of this increase has been attributed to overdiagnosis, the major consequence of which is overtreatment. We aimed to estimate the cost of thyroid cancer management in France and the corresponding cost proportion attributable to the treatment of overdiagnosed cases. METHODS: Multiple data sources were integrated: the mean cost per patient with thyroid cancer was estimated by using the Echantillon Généraliste des Bénéficiaires data set; thyroid cancer cases attributable to overdiagnosis were estimated for 21 departments using data from the French network of cancer registries and extrapolated to the whole country; medical records from 6 departments were used to refine the diagnosis and care pathway. RESULTS: Between 2011 and 2015, 33 911 women and 10 846 men in France were estimated to be diagnosed of thyroid cancer, with mean cost per capita of €6248. Among those treated, 8114 to 14 925 women and 1465 to 3626 men were due to overdiagnosis. The total cost of thyroid cancer patient management was €203.5 million (€154.3 million for women and €49.3 million for men), of which between €59.9 million (or 29.4% of the total cost, lower bound) and €115.9 million (or 56.9% of the total cost, upper bound) attributable to treatment of overdiagnosed cases. CONCLUSIONS: The management of thyroid cancer represents not only a relevant clinical and public health problem in France but also a potentially important economic burden. Overdiagnosis and corresponding associated treatments play an important role on the total costs of thyroid cancer management.

A new cure model that corrects for increased risk of non-cancer death: analysis of reliability and robustness, and application to real-life data.

BACKGROUND: Non-cancer mortality in cancer patients may be higher than overall mortality in the general population due to a combination of factors, such as long-term adverse effects of treatments, and genetic, environmental or lifestyle-related factors. If so, conventional indicators may underestimate net survival and cure fraction. Our aim was to propose and evaluate a mixture cure survival model that takes into account the increased risk of non-cancer death for cancer patients. METHODS: We assessed the performance of a corrected mixture cure survival model derived from a conventional mixture cure model to estimate the cure fraction, the survival of uncured patients, and the increased risk of non-cancer death in two settings of net survival estimation, grouped life-table data and individual patients' data. We measured the model's performance in terms of bias, standard deviation of the estimates and coverage rate, using an extensive simulation study. This study included reliability assessments through violation of some of the model's assumptions. We also applied the models to colon cancer data from the FRANCIM network. RESULTS: When the assumptions were satisfied, the corrected cure model provided unbiased estimates of parameters expressing the increased risk of non-cancer death, the cure fraction, and net survival in uncured patients. No major difference was found when the model was applied to individual or grouped data. The absolute bias was < 1% for all parameters, while coverage ranged from 89 to 97%. When some of the assumptions were violated, parameter estimates appeared more robust when obtained from grouped than from individual data. As expected, the uncorrected cure model performed poorly and underestimated net survival and cure fractions in the simulation study. When applied to colon cancer real-life data, cure fractions estimated using the proposed model were higher than those in the conventional model, e.g. 5% higher in males at age 60 (57% vs. 52%). CONCLUSIONS: The present analysis supports the use of the corrected mixture cure model, with the inclusion of increased risk of non-cancer death for cancer patients to provide better estimates of indicators based on cancer survival. These are important to public health decision-making; they improve patients' awareness and facilitate their return to normal life.

Health status of prevalent cancer cases as measured by mortality dynamics (cancer vs. noncancer): Application to five major cancers sites.

BACKGROUND: Cancer prevalence is heterogeneous because it includes individuals who are undergoing initial treatment and those who are in remission, experiencing relapse, or cured. The proposed statistical approach describes the health status of this group by estimating the probabilities of death among prevalent cases. The application concerns colorectal, lung, breast, and prostate cancers and melanoma in France in 2017. METHODS: Excess mortality was used to estimate the probabilities of death from cancer and other causes. RESULTS: For the studied cancers, most deaths from cancer occurred during the first 5 years after diagnosis. The probability of death from cancer decreased with increasing time since diagnosis except for breast cancer, for which it remained relatively stable. The time beyond which the probability of death from cancer became lower than that from other causes depended on age and cancer site: for colorectal cancer, it was 6 years after diagnosis for women (7 years for men) aged 75-84 and 20 years for women (18 years for men) aged 45-54 years, whereas cancer was the major cause of death for women younger than 75 years whatever the time since diagnosis for breast and for all patients younger than 75 years for lung cancer. In contrast, deaths from other causes were more frequent in all the patients older than 75 years. Apart from breast cancer in women younger than 55 years and lung cancer in women older than 55 years and men older than 65 years, the probability of death from cancer among prevalent cases fell below 1%, with varying times since diagnosis. CONCLUSIONS: The authors' approach can be used to better describe the burden of cancer by estimating outcomes in prevalent cases.

Association of Mammography Screening With a Reduction in Breast Cancer Mortality: A Modeling Study Using Population-Based Data From 2 French Departments.

Meta-analyses of randomized controlled trials that started from 1963 to 1991 reported a decrease of breast cancer mortality, associated with mammography screening. However, the effectiveness of population-based screening programs conducted currently might have changed due to the higher effectiveness of treatments for late-stage cancers and the better diagnostic performance of mammography. The main objective of this study was to predict the reduction of breast cancer mortality associated with mammography screening in the current French setting. We compared breast cancer mortality in 2 simulated cohorts of women, which differed from each other solely in a 70% biennial participation in screening from 50 to 74 years old. The microsimulation model used for predictions was calibrated with incidence rates of breast cancer according to stage that were observed in Isère and Loire-Atlantique departments, France, in 2007-2013. The model predicted a decrease of breast cancer mortality associated with mammography screening of 18% (95% CI: 5, 31) and 17% (95% CI: 3, 29) for models calibrated with data from Isère and Loire-Atlantique departments, respectively. Our results highlight the interest in biennial mammography screening from ages 50 to 74 years old to decrease breast cancer mortality in the current setting, despite improvements in treatment effectiveness.

Modeling excess hazard with time-to-cure as a parameter.

Cure models have been widely developed to estimate the cure fraction when some subjects never experience the event of interest. However, these models were rarely focused on the estimation of the time-to-cure, that is, the delay elapsed between the diagnosis and "the time from which cure is reached," an important indicator, for instance, to address the question of access to insurance or loans for subjects with personal history of cancer. We propose a new excess hazard regression model that includes the time-to-cure as a covariate-dependent parameter to be estimated. The model is written similarly to a Beta probability distribution function and is shown to be a particular case of the non-mixture cure models. Parameters are estimated through a maximum likelihood approach and simulation studies demonstrate good performance of the model. Illustrative applications to three cancer data sets are provided and some limitations as well as possible extensions of the model are discussed. The proposed model offers a simple and comprehensive way to estimate more accurately the time-to-cure.

For a sound use of health care data in epidemiology: evaluation of a calibration model for count data with application to prediction of cancer incidence in areas without cancer registry.

There is a growing interest in using health care (HC) data to produce epidemiological surveillance indicators such as incidence. Typically, in the field of cancer, incidence is provided by local cancer registries which, in many countries, do not cover the whole territory; using proxy measures from available nationwide HC databases would appear to be a suitable approach to fill this gap. However, in most cases, direct counts from these databases do not provide reliable measures of incidence. To obtain accurate incidence estimations and prediction intervals, these databases need to be calibrated using a registry-based gold standard measure of incidence. This article presents a calibration model for count data developed to predict cancer incidence from HC data in geographical areas without cancer registries. First, the ratio between the proxy measure and incidence is modeled in areas with registries using a Poisson mixed model that allows for heterogeneity between areas (calibration stage). This ratio is then inverted to predict incidence from the proxy measure in areas without registries. Prediction error admits closed-form expression which accounts for heterogeneity in the ratio between areas. A simulation study shows the accuracy of our method in terms of prediction and coverage probability. The method is further applied to predict the incidence of two cancers in France using hospital data as the proxy measure. We hope this approach will encourage sound use of the usually imperfect information extracted from HC data.

Impact of thyroid surgery volume and pathologic detection on risk of thyroid cancer: A geographical analysis in the Rhône-Alpes region of France.

OBJECTIVE: To investigate the impact of the volume of thyroid surgery and pathologic detection on the risk of thyroid cancer. METHODS: We investigated the influence of the volume of thyroid surgery in a first study that included 23 384 thyroid surgeries and 5302 thyroid cancers collected between 2008 and 2013. Standardized incidence ratios (SIRs) and thyroid intervention rates (STIRs) were used as indicators of cancer risk and surgery volume, respectively. The influence of pathologic detection, using the number of cuts per gram of tissue as the indicator, was studied in a second study that included 1257 thyroid specimens, collected in 2014. RESULTS: We found departmental variations in SIRs and a significant effect of the STIR on the SIR (men, P = 0.0008; women, P < 0.0001). A 1/100 000 increase in the STIR resulted in a 3% and 1.3% increase in the SIR in men and women, respectively. This effect was greatest for microcancers and absent for tumours >4 cm. The risk of cancer diagnosis was significantly associated with the number of cuts per gram of tissue (OR 6.1, P < 0.001), and was greater for total thyroidectomy than for lobectomy (P = 0.014) and when FNA cytology had been preoperatively performed (P < 0.001). The prevalence of incidental microcancers was highest in the centres performing the highest number of cuts per gram. CONCLUSIONS: The risk of thyroid cancer, particularly microcancer, is related to the volume of surgery and to the level of pathologist scrutiny. Both factors contribute to the increase in overdiagnosis. This further advocates for appropriate selection of patients for thyroid surgery.

Trends in the risk of second primary cancer among bladder cancer survivors: a population-based cohort of 10 047 patients.

OBJECTIVES: To determine whether the risk of second primary cancer (SPC) among patients with bladder cancer (BCa) has changed over past years. MATERIALS AND METHODS: Data from 10 French population-based cancer registries were used to establish a cohort of 10 047 patients diagnosed with a first invasive (≥T1) BCa between 1989 and 2004 and followed up until 2007. An SPC was defined as the first subsequent primary cancer occurring at least 2 months after a BCa diagnosis. Standardized incidence ratios (SIRs) of metachronous SPC were calculated. Multivariate Poisson regression models were used to assess the direct effect of the year of BCa diagnosis on the risk of SPC. RESULTS: The risk of new malignancy among BCa survivors was 60% higher than in the general population (SIR 1.60, 95% confidence interval [CI] 1.51-1.68). Male patients presented a high risk of SPC of the lung (SIR 3.12), head and neck (SIR 2.19) and prostate (SIR 1.54). In multivariate analyses adjusted for gender, age at diagnosis and follow-up, a significant increase in the risk of SPC of the lung was observed over the calendar year of BCa diagnosis (P for linear trend 0.010), with an SIR increasing by 3.7% for each year (95% CI 0.9-6.6%); however, no particular trend was observed regarding the risk of SPC of the head and neck (P = 0.596) or the prostate (P = 0.518). CONCLUSIONS: As the risk of SPC of the lung increased between 1989 and 2004, this study contributes more evidence to support the promotion of tobacco smoking cessation interventions among patients with BCa.

Risk of second primary cancer after a first potentially-human papillomavirus-related cancer: A population-based study.

Human papillomaviruses (HPV) are involved in the development of anogenital and head and neck cancers. The purpose of this study was to assess the risk of developing a second primary cancer (SPC) after a first potentially-HPV-related cancer, and to analyze the sites where SPCs most frequently occurred in these patients. All patients with a first cancer diagnosed between 1989 and 2004, as recorded by 10 French cancer registries, were followed up until December 31, 2007. Only invasive potentially-HPV-related cancers (namely, cervical, vagina, vulva, anal canal, penile, oropharynx, tongue and tonsil) were included. Standardized Incidence Ratios (SIRs) were calculated to assess the risk of SPC. A multivariate Poisson regression model was used to model SIRs separately by gender, adjusted for the characteristics of the first cancer. 10,127 patients presented a first potentially-HPV-related cancer. The overall SIR was 2.48 (95% CI, 2.34-2.63). The SIR was 3.59 (95% CI, 3.33-3.86) and 1.61 (95% CI, 1.46-1.78) in men and women respectively. The relative risk of potentially-HPV-related SPC was high among these patients (SIR=13.74; 95% CI, 8.80-20.45 and 6.78; 95% CI, 4.61-9.63 for men and women, respectively). Women diagnosed in the most recent period (2000-2004) showed a 40% increase of their relative risk of SPC as compared with women diagnosed between 1989 and 1994 (ratio of SIRs=1.40; 95% CI, 1.06-1.85). HPV cancer survivors face an increased risk of SPC, especially second cancer. Clinicians may consider this increased risk of developing HPV-related SPC during follow-up to improve subsequent cancer prevention in these patients.

Impact of socioeconomic inequalities on geographic disparities in cancer incidence: comparison of methods for spatial disease mapping.

BACKGROUND: The reliability of spatial statistics is often put into question because real spatial variations may not be found, especially in heterogeneous areas. Our objective was to compare empirically different cluster detection methods. We assessed their ability to find spatial clusters of cancer cases and evaluated the impact of the socioeconomic status (e.g., the Townsend index) on cancer incidence. METHODS: Moran's I, the empirical Bayes index (EBI), and Potthoff-Whittinghill test were used to investigate the general clustering. The local cluster detection methods were: i) the spatial oblique decision tree (SpODT); ii) the spatial scan statistic of Kulldorff (SaTScan); and, iii) the hierarchical Bayesian spatial modeling (HBSM) in a univariate and multivariate setting. These methods were used with and without introducing the Townsend index of socioeconomic deprivation known to be related to the distribution of cancer incidence. Incidence data stemmed from the Cancer Registry of Isère and were limited to prostate, lung, colon-rectum, and bladder cancers diagnosed between 1999 and 2007 in men only. RESULTS: The study found a spatial heterogeneity (p < 0.01) and an autocorrelation for prostate (EBI = 0.02; p = 0.001), lung (EBI = 0.01; p = 0.019) and bladder (EBI = 0.007; p = 0.05) cancers. After introduction of the Townsend index, SaTScan failed in finding cancers clusters. This introduction changed the results obtained with the other methods. SpODT identified five spatial classes (p < 0.05): four in the Western and one in the Northern parts of the study area (standardized incidence ratios: 1.68, 1.39, 1.14, 1.12, and 1.16, respectively). In the univariate setting, the Bayesian smoothing method found the same clusters as the two other methods (RR >1.2). The multivariate HBSM found a spatial correlation between lung and bladder cancers (r = 0.6). CONCLUSIONS: In spatial analysis of cancer incidence, SpODT and HBSM may be used not only for cluster detection but also for searching for confounding or etiological factors in small areas. Moreover, the multivariate HBSM offers a flexible and meaningful modeling of spatial variations; it shows plausible previously unknown associations between various cancers.

Anthropometric Risk Factors for Differentiated Thyroid Cancer in Young Men and Women From Eastern France: A Case-Control Study.

The incidence of thyroid cancer has risen over the past decade, along with a rise in obesity. We studied the role of anthropometric risk factors for differentiated thyroid cancer at the time of diagnosis and at age 20 years in a case-control study conducted in eastern France between 2005 and 2010. The study included 761 adults diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006. They were matched with 825 controls from the general population. Odds ratios were calculated using conditional logistic regression models and were reported for all participants, those with papillary cancer only, and women only. The risk of thyroid cancer was higher for participants with a high body surface area (BSA), great height, or excess weight and for women with a high body fat percentage. Conversely, no significant association was found between body mass index and the risk of thyroid cancer. In the present study, we provide further evidence of the role of BSA and excess weight in the risk of thyroid cancer. These epidemiologic observations should be confirmed by further exploration of the biological mechanisms responsible for the associations of obesity and BSA with thyroid cancer.

Total and partial cancer prevalence in the adult French population in 2008.

BACKGROUND: To provide estimations of partial and total prevalence of 24 cancer sites in France in 2008. The estimations of partial prevalence were compared with the previous estimations for 2002. METHODS: Nationwide estimations of incidence and survival data from cancer registries were used for partial prevalence. Nationwide incidence and mortality data were used to estimate total prevalence. RESULTS: At the end of 2008, in France, nearly 3 million people still alive had received a diagnosis of cancer. Of all prevalent cases, 36% were diagnosed 0 to 5 years earlier and 43% diagnosed 6 to 10 years earlier. The cancer sites with the highest prevalence were the prostate, the breast, and the colon-rectum. The changes in partial prevalence over 5 years (2002 to 2008) were considerable (+244,000 cases) and deemed to be highly related to changes in incidence. CONCLUSION: The present estimations update the French prevalence data and highlight the burden of cancer in the population, especially in the elderly. The methods of this study had the advantage of using recent incidence and survival data, which is necessary to show sudden changes in incidence trends and changes in survival that impact prevalence.

Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in young women in France: a population-based case-control study.

The incidence of thyroid cancer has increased in eastern Europe since the Chernobyl nuclear power plant accident. Although the radioactive fallout was much less severe and the thyroid radiation dose was much lower in France, a case-control study was initiated in eastern France. The present study included 633 young women who were diagnosed with differentiated thyroid cancer before 35 years of age between 2002 and 2006 and matched with 677 controls. Face-to-face interviews were conducted from 2005 to 2010. Odds ratios were calculated using conditional logistic regressions and were reported in the total group and by histopathological type of cancer ("only papillary" and "excluding microcarcinomas"). The risk of thyroid cancer was higher in women who had a higher number of pregnancies, used a lactation suppressant, or had early menarche. Conversely, breastfeeding, oral contraceptive use, and late age at first pregnancy were associated with a lower risk of thyroid cancer. No association was observed between thyroid cancer and having irregular menstrual cycle, undergoing treatment for menstrual cycle regularity shortly after menarche, having a cessation of menstruation, use of another contraceptive, history of miscarriage or abortion for the first pregnancy, or having had gestational diabetes. This study confirms the role of hormonal and reproductive factors in thyroid cancer, and our results support the fact that exposure to estrogens increases thyroid cancer risk.

The effect of patient characteristics on second primary cancer risk in France.

BACKGROUND: Although cancer survivors are known to be at greater risk of developing second primary cancer (SPC), SPC incidence estimates in France are thus far lacking. We used a multivariate approach to compute these estimates and analyzed the effect of patient characteristics (gender, age at diagnosis, first cancer site, year of diagnosis and follow-up) on SPC risk. METHODS: Data from ten French population-based cancer registries were used to establish a cohort of all patients diagnosed with a first cancer between 1989 and 2004 and followed up until December 31, 2007. The person-year approach was used to estimate standardized incidence ratios (SIRs) and excess absolute risks (EARs) of metachronous SPC. Multivariate Poisson regression models were then used to model SIRs and EARs separately by gender, adjusting for age, year of diagnosis, follow-up and first cancer site. RESULTS: Among the 289,967 followed-up patients with a first primary cancer, 21,226 developed a SPC. The SIR was of 1.36 (95% CI, 1.35-1.38) and the EAR was of 39.4 excess cancers per 10,000 person-years (95% CI, 37.4-41.3). Among male and female patients, multivariate analyses showed that age, year of diagnosis, follow-up and first cancer site were often independently associated with SIRs and EARs. Moreover, the EAR of SPC remained elevated during patient follow-up. CONCLUSIONS: French cancer survivors face a dramatically increased risk of SPC which is probably related to the high rate of tobacco and alcohol consumption in France. Multivariate modeling of SPC risk will facilitate the construction of a tailored prediction tool to optimize SPC prevention and early detection strategies.

Socioeconomic environment and cancer incidence: a French population-based study in Normandy.

BACKGROUND: The struggle against social inequalities is a priority for many international organizations. The objective of the study was to quantify the cancer burden related to social deprivation by identifying the cancer sites linked to socioeconomic status and measuring the proportion of cases associated with social deprivation. METHODS: The study population comprised 68 967 cases of cancer diagnosed between 1997 and 2009 in Normandy and collected by the local registries. The social environment was assessed at an aggregated level using the European Deprivation Index (EDI). The association between incidence and socioeconomic status was assessed by a Bayesian Poisson model and the excess of cases was calculated with the Population Attributable Fraction (PAF). RESULTS: For lung, lips-mouth-pharynx and unknown primary sites, a higher incidence in deprived was observed for both sexes. The same trend was observed in males for bladder, liver, esophagus, larynx, central nervous system and gall-bladder and in females for cervix uteri. The largest part of the incidence associated with deprivation was found for cancer of gall-bladder (30.1%), lips-mouth-pharynx (26.0%), larynx (23.2%) and esophagus (19.6%) in males and for unknown primary sites (18.0%) and lips-mouth-pharynx (12.7%) in females. For prostate cancer and melanoma in males, the sites where incidence increased with affluence, the part associated with affluence was respectively 9.6% and 14.0%. CONCLUSIONS: Beyond identifying cancer sites the most associated with social deprivation, this kind of study points to health care policies that could be undertaken to reduce social inequalities.

Unbiased estimates of long-term net survival of solid cancers in France.

In cancer studies, net survival (observed if cancer was the only cause of death) is a useful indicator but survival estimation at 5 years is insufficient for planning healthcare needs. We estimated the net survivals at 5 and 10 years in a cohort of 387,961 patients who had solid tumors between 1989 and 2004 and were followed-up until January 1, 2008. The cases were actively followed-up. Net survival was estimated with the unbiased Pohar-Perme method. The standardized net survival used the international cancer survival standard weights. In men, the standardized net survivals ranged from 92% at 5 years and 89% at 10 years (testis) to 6% at 5 years and 5% at 10 years (pancreas). In women, it ranged from 91% at 5 years and 88% at 10 years (thyroid) to 10% at 5 years and 7% at 10 years (pancreas). The most frequent cancers had the highest net survivals: 84% at 5 years and 71% at 10 years for prostate and 84% at 5 years and 74% at 10 years for breast cancer. Advanced age was associated with poorer prognosis. In most cancers, the net survivals at 5 and 10 years increased over periods of diagnosis. Net cancer survival is unaffected by mortalities due to other causes. It is the only indicator suitable for comparisons between countries or periods of diagnosis within a given country. The 10-year net survival confirmed the persistent unfavorable role of age in prognosis and the general improvement of cancer management over the last decade.

Breast cancer survival in the US and Europe: a CONCORD high-resolution study.

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.

Cancer incidence in a chlorochemical plant in Isère, France: an occupational cohort study, 1979-2002.

BACKGROUND: A major French chlorine chemical plant (chlor-alkali process with diaphragm cell and manufacturing of organochlorine chemicals) has used or produced known or suspected carcinogenic compounds. METHODS: A cohort study, based on the plant occupational health service and the regional cancer registry, analyzed the standardized incidence ratios of malignant tumors for the period 1979-2002. Individual exposures were estimated from workers' occupational histories in a dual division of jobs into 9 sectors and 115 workshops with known exposures. RESULTS: Men (2,742) were followed, corresponding to 52,794 person-years. Primary tumors (304) were observed for 290 expected cases, a non-significant 5% excess. A significant excess was found of pleural mesothelioma and bladder cancer in employees hired before 1964. CONCLUSION: Excesses of mesothelioma and bladder cancer were found, whereas there was no excess of hematopoietic cancers despite high benzene and dioxin exposures. Surprisingly, mesothelioma cases did not include workers who were the most exposed to asbestos.