Multidimensional penalized splines for survival models: illustration for net survival trend analyses.

BACKGROUND: In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. METHODS: The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990-2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. RESULTS: For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. CONCLUSIONS: MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

Is the Social Gradient in Net Survival Observed in France the Result of Inequalities in Cancer-Specific Mortality or Inequalities in General Mortality?

BACKGROUND: In cancer net survival analyses, if life tables (LT) are not stratified based on socio-demographic characteristics, then the social gradient in mortality in the general population is ignored. Consequently, the social gradient estimated on cancer-related excess mortality might be inaccurate. We aimed to evaluate whether the social gradient in cancer net survival observed in France could be attributable to inaccurate LT. METHODS: Deprivation-specific LT were simulated, applying the social gradient in the background mortality due to external sources to the original French LT. Cancer registries' data from a previous French study were re-analyzed using the simulated LT. Deprivation was assessed according to the European Deprivation Index (EDI). Net survival was estimated by the Pohar-Perme method and flexible excess mortality hazard models by using multidimensional penalized splines. RESULTS: A reduction in net survival among patients living in the most-deprived areas was attenuated with simulated LT, but trends in the social gradient remained, except for prostate cancer, for which the social gradient reversed. Flexible modelling additionally showed a loss of effect of EDI upon the excess mortality hazard of esophagus, bladder and kidney cancers in men and bladder cancer in women using simulated LT. CONCLUSIONS: For most cancers the results were similar using simulated LT. However, inconsistent results, particularly for prostate cancer, highlight the need for deprivation-specific LT in order to produce accurate results.

Factors influencing access to specialised haematology units during acute myeloblastic leukaemia patient care: A population-based study in France.

BACKGROUND: The excess mortality observed in Acute Myeloblastic Leukaemia (AML) patients, partly attributed to unequal access to curative treatments, could be linked to care pathways. METHODS: We included 1039 AML incident cases diagnosed between 2012-2016 from the 3 French blood cancer registries (3,625,400 inhabitants). We describe patients according to age, the medical entry unit and access to the specialised haematology unit (SHU) during follow-up. Multivariate logistic regression model was done to determine the association between covariables and access to SHU. A total of 713 patients (69%) had access to SHU during care. RESULTS: The most common care pathway concerned referral from the general practitioner to SHU, n = 459(44%). The univariate analysis observed a downward trend for the most deprived patients. Patients who consulted in SHU were younger (66 years vs. 83, p < 0.001), and 92% had access to cytogenetic analysis (vs. 54%, p < 0.001). They also had less poor prognosis AML-subtypes (AML-MRC, t-AML/MDS and AML-NOS) (38% vs. 69%); 77% with de novo AML (vs. 67%, p < 0.003)], more favourable cytogenetic prognostic status (23% vs. 6%, p < 0.001), less comorbidities (no comorbidity = 55% vs. 34%, p < 0.001) and treatments proposed were curative 68% (vs. 5.3%, p < 0.001). Factors limiting access to SHU were age over 80 years (OR, 0.14; 95% CI, 0.04-0.38), severe comorbidities (OR, 0.39; 95% CI, 0.21-0.69), emergency unit referral (OR, 0.28; 95% CI, 0.18-0.44) and non-SHU referral (OR, 0.12; 95% CI, 0.07-0.18). Consultation in an academic hospital increased access to SHU by 8.87 times (95% CI, 5.64-14.2). CONCLUSION: The high proportion of access to cytogenetic testing and curative treatment among patients admitted to SHU, and the importance of early treatment in AML underlines the importance of access to SHU for both diagnosis and treatment.

Socioeconomic Environment and Survival in Patients with Digestive Cancers: A French Population-Based Study.

Social inequalities are an important prognostic factor in cancer survival, but little is known regarding digestive cancers specifically. We aimed to provide in-depth analysis of the contextual social disparities in net survival of patients with digestive cancer in France, using population-based data and relevant modeling. Digestive cancers (n = 54,507) diagnosed between 2006-2009, collected through the French network of cancer registries, were included (end of follow-up 30 June 2013). Social environment was assessed by the European Deprivation Index. Multidimensional penalized splines were used to model excess mortality hazard. We found that net survival was significantly worse for individuals living in a more deprived environment as compared to those living in a less deprived one for esophageal, liver, pancreatic, colon and rectal cancers, and for stomach and bile duct cancers among females. Excess mortality hazard was up to 57% higher among females living in the most deprived areas (vs. least deprived) at 1 year of follow-up for bile duct cancer, and up to 21% higher among males living in the most deprived areas (vs. least deprived) regarding colon cancer. To conclude, we provide a better understanding of how the (contextual) social gradient in survival is constructed, offering new perspectives for tackling social inequalities in digestive cancer survival.

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.

Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

BACKGROUND: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. METHODS: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. RESULTS: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) (p = 0.79)). CONCLUSION: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.

How to produce sound predictions of incidence at a district level using either health care or mortality data in the absence of a national registry: the example of cancer in France.

BACKGROUND: In many countries, epidemiological surveillance of chronic diseases is monitored by local registries (LR) which do not necessarily cover the whole national territory. This gap has fostered interest in using non-registry databases (e.g., health care or mortality databases) available for the whole territory as proxies for incidence at the local level. However, direct counts from these databases do not provide reliable incidence measures. Accordingly, specific methods are needed to correct proxies and assess their epidemiological usefulness. METHODS: This study's objective was to implement a three-stage turnkey methodology using national non-registry data to predict incidence in geographical areas without an LR as follows: constructing a calibration model to make predictions including accurate prediction intervals; accuracy assessment of predictions and rationale for the criteria to assess which predictions were epidemiologically useful; mapping after spatial smoothing of the latter predictions. The methodology was applied to a real-world setting, whereby we aimed to predict cancer incidence, by gender, at the district level in France over the 2007-15 period for 24 different cancer sites, using several health care indicators and mortality. In the present paper, the spatial smoothing performed on predicted incidence of epidemiological interest is illustrated for two examples. RESULTS: Predicted incidence of epidemiological interest was possible for 27/34 solid site-gender combinations and for only 2/8 haematological malignancies-gender combinations. Mapping of smoothed predicted incidence provided a clear picture of the main contrasts in incidence between districts. CONCLUSIONS: The methodology implemented provides a comprehensive framework to produce valuable predictions of incidence at a district level, using proxy measures and existing LR.

Multidimensional penalized splines for incidence and mortality-trend analyses and validation of national cancer-incidence estimates.

BACKGROUND: Cancer-incidence and mortality-trend analyses require appropriate statistical modelling. In countries without a nationwide cancer registry, an additional issue is estimating national incidence from local-registry data. The objectives of this study were to (i) promote the use of multidimensional penalized splines (MPS) for trend analyses; (ii) estimate the national cancer-incidence trends, using MPS, from only local-registry data; and (iii) propose a validation process of these estimates. METHODS: We used an MPS model of age and year for trend analyses in France over 1990-2015 with a projection up to 2018. Validation was performed for 22 cancer sites and relied essentially on comparison with reference estimates that used the incidence/health-care ratio over the period 2011-2015. Alternative estimates that used the incidence/mortality ratio were also used to validate the trends. RESULTS: In the validation assessment, the relative differences of the incidence estimates (2011-2015) with the reference estimates were <5% except for testis cancer in men and < 7% except for larynx cancer in women. Trends could be correctly derived since 1990 despite incomplete histories in some registries. The proposed method was applied to estimate the incidence and mortality trends of female lung cancer and prostate cancer in France. CONCLUSIONS: The validation process confirmed the validity of the national French estimates; it may be applied in other countries to help in choosing the most appropriate national estimation method according to country-specific contexts. MPS form a powerful statistical tool for trend analyses; they allow trends to vary smoothly with age and are suitable for modelling simple as well as complex trends thanks to penalization. Detailed trend analyses of lung and prostate cancers illustrated the suitability of MPS and the epidemiological interest of such analyses.

Preoperative Topical Estrogen Treatment vs Placebo in 244 Children With Midshaft and Posterior Hypospadias.

PURPOSE: Urethral fistula and dehiscence are common after hypospadias surgery. Preoperative androgens have been considered to reduce these complications although this consideration is not evidence-based. Dermatologists have reported the benefits of topical estrogens on skin healing. We investigated whether the preoperative use of topical promestriene could reduce healing complications in hypospadias surgery. Our primary objective was to demonstrate a reduction of healing complications with promestriene vs placebo. Impact on reoperations and other complications, clinical tolerance, bone growth, and biological systemic effects of the treatment were also considered. METHODS: We conducted a prospective, randomized, placebo-controlled, double-blind, parallel group trial between 2011 and 2015 in 4 French centers. One-stage transverse preputial island flap urethroplasty (onlay urethroplasty) was selected for severe hypospadias. Promestriene or placebo was applied on the penis for 2 months prior to surgery. The primary outcome was the presence of postoperative urethral fistula or dehiscence in the first year postsurgery. For safety reasons, hormonal and anatomical screenings were performed. RESULTS: Out of 241 patients who received surgery, 122 patients were randomized to receive placebo, and 119 patients received promestriene. The primary outcome was unavailable for 11 patients. Healing complications were assessed at 16.4% (19/116) in the placebo vs 14.9% (17/114) in the promestriene arm, and the odds ratio adjusted on center was 0.93 (95% confidence interval 0.45-1.94), P = 0.86. CONCLUSIONS AND RELEVANCE: Although we observed an overall lower risk of complications compared to previous publications, postsurgery complications were not different between promestriene and placebo, because of a lack of power of the study or the inefficacy of promestriene.

Time-to-cure and cure proportion in solid cancers in France. A population based study.

BACKGROUND: In cancer care, the cure proportion (P) and time-to-cure (TTC) are important indicators for practitioners, patients, and healthcare policy makers. The recent definition of TTC as the time at which the probability of belonging to the cured group reaches 95% was used for the first time. METHODS: The data stem from the common database of French cancer registries including 335,358 solid tumours diagnosed between 1995 and 2009 at 27 sites. P and TTC were estimated through a flexible parametric net survival cure model for each cancer site, sex, and age at diagnosis with acceptable assumption of cure (excess mortality rate ≤0.05). RESULTS: TTC was ≤5 years and P was >80% for skin melanoma and thyroid and testis cancers. It was 0 for testis cancer in men <55 and for thyroid cancer in men <45 and women <65. TTC was between 5 and 10 years for all digestive cancers except small intestine and all gynaecologic cancers except breast. It was ≥10 years in prostate, breast, and urinary tract. The range of P according to age and sex was 37-79% for urinary tract 72-88% for prostate and breast, 4-16% for pancreatic and 47-62% for colorectal cancer. CONCLUSION: Time-to-cure was estimated for the first time from a large national database and individual probabilities of cure. It was 0 in the younger patients with testis or thyroid cancer and <12 years in most cancer sites. These results should help improve access to credit and insurance for patients still alive past the estimated TTCs.

Trends in probabilities of death owing to cancer and owing to other causes in patients with colon cancer.

BACKGROUND: It is of interest to both the clinicians and patients to estimate the probability of death owing to cancer in the presence of other causes as time elapses since diagnosis. The objective of this study was to depict for patients diagnosed with colon cancer between 1990 and 2010 in France, the probability of surviving up to 10 years after diagnosis and to disentangle the probability of death owing to cancer from that of death owing to other causes. PATIENTS AND METHODS: Individuals with cancer were described, up to 10 years after diagnosis, as belonging to one of three categories: those who died owing to a cause related to cancer, those who died owing to another cause and those who survived. Net survival, crude probabilities of death related to colon cancer, death related to another cause and survival were estimated by modeling excess mortality hazard. RESULTS: In women of all ages, 5 and 10-year net survival improved over calendar time. The 10-year probability of survival decreased when age increased in both sexes. It was higher in women than in men, and this difference increased with age. Crude probabilities of death related to colon cancer decreased between 1990 and 2010 for men and women, although this was not observed in the eldest men. CONCLUSION: Crude probability of death related to colon cancer is an important indicator for patients and health policy makers. Results of cancer screening should be faced to trends in probability of death related to colorectal cancer.

On a general structure for hazard-based regression models: An application to population-based cancer research.

The proportional hazards model represents the most commonly assumed hazard structure when analysing time to event data using regression models. We study a general hazard structure which contains, as particular cases, proportional hazards, accelerated hazards, and accelerated failure time structures, as well as combinations of these. We propose an approach to apply these different hazard structures, based on a flexible parametric distribution (exponentiated Weibull) for the baseline hazard. This distribution allows us to cover the basic hazard shapes of interest in practice: constant, bathtub, increasing, decreasing, and unimodal. In an extensive simulation study, we evaluate our approach in the context of excess hazard modelling, which is the main quantity of interest in descriptive cancer epidemiology. This study exhibits good inferential properties of the proposed model, as well as good performance when using the Akaike Information Criterion for selecting the hazard structure. An application on lung cancer data illustrates the usefulness of the proposed model.

Flexible and structured survival model for a simultaneous estimation of non-linear and non-proportional effects and complex interactions between continuous variables: Performance of this multidimensional penalized spline approach in net survival trend analysis.

Cancer survival trend analyses are essential to describe accurately the way medical practices impact patients' survival according to the year of diagnosis. To this end, survival models should be able to account simultaneously for non-linear and non-proportional effects and for complex interactions between continuous variables. However, in the statistical literature, there is no consensus yet on how to build such models that should be flexible but still provide smooth estimates of survival. In this article, we tackle this challenge by smoothing the complex hypersurface (time since diagnosis, age at diagnosis, year of diagnosis, and mortality hazard) using a multidimensional penalized spline built from the tensor product of the marginal bases of time, age, and year. Considering this penalized survival model as a Poisson model, we assess the performance of this approach in estimating the net survival with a comprehensive simulation study that reflects simple and complex realistic survival trends. The bias was generally small and the root mean squared error was good and often similar to that of the true model that generated the data. This parametric approach offers many advantages and interesting prospects (such as forecasting) that make it an attractive and efficient tool for survival trend analyses.

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.

Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study.

BACKGROUND: Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy-naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. METHODS: In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18-75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score ≤2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. FINDINGS: Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert ≤2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29·9%, 95% CI 24·3-36·0) and targeted biopsy (32·3%, 26·5-38·4) did not differ significantly (p=0·38). csPCa-A would have been missed in 5·2% (95% CI 2·8-8·7) of patients had systematic biopsy not been done, and in 7·6% (4·6-11·6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). INTERPRETATION: There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. FUNDING: French National Cancer Institute.

Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French Network of Cancer Registries (FRANCIM) data.

Social inequalities are concerning along the cancer continuum. In France, social gradient in health is particularly marked but little is known about social gradient in cancer survival. We aimed to investigate the influence of socioeconomic environment on cancer survival, for all cancers reported in the French Network of Cancer Registries. We analyzed 189,657 solid tumors diagnosed between 2006 and 2009, recorded in 18 registries. The European Deprivation Index (EDI), an ecological index measuring relative poverty in small geographic areas, assessed social environment. The EDI was categorized into quintiles of the national distribution. One- and five-year age-standardized net survival (ASNS) were estimated for each solid tumor site and deprivation quintile, among men and among women. We found that 5-year ASNS was lower among patients living in the most deprived areas compared to those living in the least deprived ones for 14/16 cancers among men and 16/18 cancers among women. The extent of cancer survival disparities according to deprivation varied substantially across the cancer sites. The reduction in ASNS between the least and the most deprived quintile reached 34% for liver cancer among men and 59% for bile duct cancer among women. For pancreas, stomach and esophagus cancer (among men), and ovary and stomach cancer (among women), deprivation gaps were larger at 1-year than 5-year survival. In conclusion, survival was worse in the most deprived areas for almost all cancers. Our results from population-based cancer registries data highlight the need for implementing actions to reduce social inequalities in cancer survival in France.

Describing the association between socioeconomic inequalities and cancer survival: methodological guidelines and illustration with population-based data.

BACKGROUND: Describing the relationship between socioeconomic inequalities and cancer survival is important but methodologically challenging. We propose guidelines for addressing these challenges and illustrate their implementation on French population-based data. METHODS: We analyzed 17 cancers. Socioeconomic deprivation was measured by an ecological measure, the European Deprivation Index (EDI). The Excess Mortality Hazard (EMH), ie, the mortality hazard among cancer patients after accounting for other causes of death, was modeled using a flexible parametric model, allowing for nonlinear and/or time-dependent association between the EDI and the EMH. The model included a cluster-specific random effect to deal with the hierarchical structure of the data. RESULTS: We reported the conventional age-standardized net survival (ASNS) and described the changes of the EMH over the time since diagnosis at different levels of deprivation. We illustrated nonlinear and/or time-dependent associations between the EDI and the EMH by plotting the excess hazard ratio according to EDI values at different times after diagnosis. The median excess hazard ratio quantified the general contextual effect. Lip-oral cavity-pharynx cancer in men showed the widest deprivation gap, with 5-year ASNS at 41% and 29% for deprivation quintiles 1 and 5, respectively, and we found a nonlinear association between the EDI and the EMH. The EDI accounted for a substantial part of the general contextual effect on the EMH. The association between the EDI and the EMH was time dependent in stomach and pancreas cancers in men and in cervix cancer. CONCLUSION: The methodological guidelines proved efficient in describing the way socioeconomic inequalities influence cancer survival. Their use would allow comparisons between different health care systems.

A new approach to estimate time-to-cure from cancer registries data.

BACKGROUND: Cure models have been adapted to net survival context to provide important indicators from population-based cancer data, such as the cure fraction and the time-to-cure. However existing methods for computing time-to-cure suffer from some limitations. METHODS: Cure models in net survival framework were briefly overviewed and a new definition of time-to-cure was introduced as the time TTC at which P(t), the estimated covariate-specific probability of being cured at a given time t after diagnosis, reaches 0.95. We applied flexible parametric cure models to data of four cancer sites provided by the French network of cancer registries (FRANCIM). Then estimates of the time-to-cure by TTC and by two existing methods were derived and compared. Cure fractions and probabilities P(t) were also computed. RESULTS: Depending on the age group, TTC ranged from to 8 to 10 years for colorectal and pancreatic cancer and was nearly 12 years for breast cancer. In thyroid cancer patients under 55 years at diagnosis, TTC was strikingly 0: the probability of being cured was >0.95 just after diagnosis. This is an interesting result regarding the health insurance premiums of these patients. The estimated values of time-to-cure from the three approaches were close for colorectal cancer only. CONCLUSIONS: We propose a new approach, based on estimated covariate-specific probability of being cured, to estimate time-to-cure. Compared to two existing methods, the new approach seems to be more intuitive and natural and less sensitive to the survival time distribution.

Focus on an unusual rise in pancreatic cancer incidence in France.

Background: Pancreatic cancer is one of the most lethal. Most countries have exhibited a stable or decreasing incidence over time. The aim of this study was to provide updated French temporal trends in pancreatic cancer incidence and mortality over the past three decades. Methods: Incidence was estimated using the French National Network of Cancer Registries (FRANCIM) and mortality using the French Mortality Statistics Office. World age-standardized incidence and mortality were modelled by age-period-cohort models. The net cumulative risk of developing pancreatic cancer by birth cohort was calculated, as were annual percentage changes (APCs) in incidence and mortality. Results: Between 1982 and 2012, age-standardized incidence increased from 4.8 in 1980 to 9.6 per 100 000 in men and from 2.3 to 6.8 in women. The mean APC was 2.3% (2.1-2.6) and 3.6% (3.3-3.9), respectively. The cumulative risk of developing pancreatic cancer before age 75 rose from 0.62% for males born around 1920 to 1.17% for those born around 1950. It was respectively 0.31% and 0.86% for women. Mortality did not vary in men (8.1 per 100 000). It slightly increased in women from 4.0 in 1982 to 5.4 in 2012. Conclusion: Pancreatic cancer incidence and mortality exhibited diverging trends. Incidence increased over the last 30 years in France whereas mortality did not vary in men and moderately increased in women. Incidence remained lower than mortality up to 2002. One cannot exclude the possibility that a similar trend may appear in other countries. Etiological studies are required to further explain this increase.

Survival of solid cancer patients in France, 1989-2013: a population-based study.

This study provides updates of net survival (NS) estimates at 5, 10, and 15 years as well as survival trends for 35 solid cancers in France using data from 19 population-based cancer registries. The study considered all cases of solid cancer diagnosed between 1989 and 2010 in patients older than 15 years of age who were actively followed up until 30 June 2013. NS was estimated using the Pohar-Perme method. The age-standardized NS used the international cancer survival standard weights. The 5-year age-standardized NSs ranged from 4% (pleural mesothelioma) to 93% (prostate) in men and from 10% (pancreas) to 97% (thyroid) in women. The 10-year age-standardized NSs ranged from 2% (pleural mesothelioma) in both sexes to 95% (testis) in men and 91% (thyroid) in women. The most frequent cancers (namely, breast and prostate cancers) had the highest NSs: 87 and 93% at 5 years and 78 and 84% at 10 years, respectively. Several cancers (especially lung, pancreas, and liver cancer) had very poor prognoses (5-year NSs under 20%). Fifteen-year NSs remained high for testis cancer. In most cancers, 5- and 10-year age-standardized NSs increased between 1989 and 2010. Advanced age was associated with a poor prognosis and little improvement in survival. The increases in cancer survival are probably related to earlier diagnosis and therapeutic advances over the last decade. However, poor prognoses are still found in some alcohol-related and tobacco-related cancers and in elderly patients, highlighting the need for more prevention, diagnosis, and treatment efforts.