Trends in lung cancer survival in the Nordic countries 1990-2016: The NORDCAN survival studies.

OBJECTIVES: The aim of this study was to evaluate if the previously reported improvements in lung cancer survival were consistent across age at diagnosis and by lung cancer subtypes. MATERIALS AND METHODS: Data on lung cancers diagnosed between 1990 and 2016 in Denmark, Finland, Iceland, Norway and Sweden were obtained from the NORDCAN database. Flexible parametric models were used to estimate age-standardized and age-specific relative survival by sex, as well as reference-adjusted crude probabilities of death and life-years lost. Age-standardised survival was also estimated by the three major subtypes; adenocarcincoma, squamous cell and small-cell carcinoma. RESULTS: Both 1- and 5-year relative survival improved continuously in all countries. The pattern of improvement was similar across age groups and by subtype. The largest improvements in survival were seen in Denmark, while improvements were comparatively smaller in Finland. In the most recent period, age-standardised estimates of 5-year relative survival ranged from 13% to 26% and the 5-year crude probability of death due to lung cancer ranged from 73% to 85%. Across all Nordic countries, survival decreased with age, and was lower in men and for small-cell carcinoma. CONCLUSION: Lung cancer survival has improved substantially since 1990, in both women and men and across age. The improvements were seen in all major subtypes. However, lung cancer survival remains poor, with three out of four patients dying from their lung cancer within five years of diagnosis.

Have the recent advancements in cancer therapy and survival benefitted patients of all age groups across the Nordic countries? NORDCAN survival analyses 2002-2021.

BACKGROUND: Since the early 2000s, overall and site-specific cancer survival have improved substantially in the Nordic countries. We evaluated whether the improvements have been similar across countries, major cancer types, and age groups. MATERIAL AND METHODS: Using population-based data from the five Nordic cancer registries recorded in the NORDCAN database, we included a cohort of 1,525,854 men and 1,378,470 women diagnosed with cancer (except non-melanoma skin cancer) during 2002-2021, and followed for death until 2021. We estimated 5-year relative survival (RS) in 5-year calendar periods, and percentage points (pp) differences in 5-year RS from 2002-2006 until 2017-2021. Separate analyses were performed for eight cancer sites (i.e. colorectum, pancreas, lung, breast, cervix uteri, kidney, prostate, and melanoma of skin). RESULTS: Five-year RS improved across nearly all cancer sites in all countries (except Iceland), with absolute differences across age groups ranging from 1 to 21 pp (all cancer sites), 2 to 20 pp (colorectum), -1 to 36 pp (pancreas), 2 to 28 pp (lung), 0 to 9 pp (breast), -11 to 26 pp (cervix uteri), 2 to 44 pp (kidney), -2 to 23 pp (prostate) and -3 to 30 pp (skin melanoma). The oldest patients (80-89 years) exhibited lower survival across all countries and sites, although with varying improvements over time. INTERPRETATION: Nordic cancer patients have generally experienced substantial improvements in cancer survival during the last two decades, including major cancer sites and age groups. Although survival has improved over time, older patients remain at a lower cancer survival compared to younger patients.

Survival trends for patients diagnosed with cutaneous malignant melanoma in the Nordic countries 1990-2016: The NORDCAN survival studies.

BACKGROUND: The survival in patients diagnosed with cutaneous malignant melanoma (CMM) has improved in the Nordic countries in the last decades. It is of interest to know if these improvements are observed in all ages and for both women and men. METHODS: Patients diagnosed with CMM in the Nordic countries in 1990-2016 were identified in the NORDCAN database. Flexible parametric relative survival models were fitted, except for Iceland where a non-parametric Pohar-Perme approach was used. A range of survival metrics were estimated by sex, both age-standardised and age-specific. RESULTS: The 5-year relative survival improved in all countries, in both women and men and across age. While the improvement was more pronounced in men, women still had a higher survival at the end of the study period. The survival was generally high, with age-standardised estimates of 5-year relative survival towards the end of the study period ranging from 85% in Icelandic men to 95% in Danish women. The age-standardised and reference-adjusted 5-year crude probability of death due to CMM ranged from 5% in Danish and Swedish women to 13% in Icelandic men. CONCLUSION: Although survival following CMM was relatively high in the Nordic countries in 1990, continued improvements in survival were observed throughout the study period in both women and men and across age.

Health outcomes after myocardial infarction: A population study of 56 million people in England.

BACKGROUND: The occurrence of a range of health outcomes following myocardial infarction (MI) is unknown. Therefore, this study aimed to determine the long-term risk of major health outcomes following MI and generate sociodemographic stratified risk charts in order to inform care recommendations in the post-MI period and underpin shared decision making. METHODS AND FINDINGS: This nationwide cohort study includes all individuals aged ≥18 years admitted to one of 229 National Health Service (NHS) Trusts in England between 1 January 2008 and 31 January 2017 (final follow-up 27 March 2017). We analysed 11 non-fatal health outcomes (subsequent MI and first hospitalisation for heart failure, atrial fibrillation, cerebrovascular disease, peripheral arterial disease, severe bleeding, renal failure, diabetes mellitus, dementia, depression, and cancer) and all-cause mortality. Of the 55,619,430 population of England, 34,116,257 individuals contributing to 145,912,852 hospitalisations were included (mean age 41.7 years (standard deviation [SD 26.1]); n = 14,747,198 (44.2%) male). There were 433,361 individuals with MI (mean age 67.4 years [SD 14.4)]; n = 283,742 (65.5%) male). Following MI, all-cause mortality was the most frequent event (adjusted cumulative incidence at 9 years 37.8% (95% confidence interval [CI] [37.6,37.9]), followed by heart failure (29.6%; 95% CI [29.4,29.7]), renal failure (27.2%; 95% CI [27.0,27.4]), atrial fibrillation (22.3%; 95% CI [22.2,22.5]), severe bleeding (19.0%; 95% CI [18.8,19.1]), diabetes (17.0%; 95% CI [16.9,17.1]), cancer (13.5%; 95% CI [13.3,13.6]), cerebrovascular disease (12.5%; 95% CI [12.4,12.7]), depression (8.9%; 95% CI [8.7,9.0]), dementia (7.8%; 95% CI [7.7,7.9]), subsequent MI (7.1%; 95% CI [7.0,7.2]), and peripheral arterial disease (6.5%; 95% CI [6.4,6.6]). Compared with a risk-set matched population of 2,001,310 individuals, first hospitalisation of all non-fatal health outcomes were increased after MI, except for dementia (adjusted hazard ratio [aHR] 1.01; 95% CI [0.99,1.02];p = 0.468) and cancer (aHR 0.56; 95% CI [0.56,0.57];p < 0.001). The study includes data from secondary care only-as such diagnoses made outside of secondary care may have been missed leading to the potential underestimation of the total burden of disease following MI. CONCLUSIONS: In this study, up to a third of patients with MI developed heart failure or renal failure, 7% had another MI, and 38% died within 9 years (compared with 35% deaths among matched individuals). The incidence of all health outcomes, except dementia and cancer, was higher than expected during the normal life course without MI following adjustment for age, sex, year, and socioeconomic deprivation. Efforts targeted to prevent or limit the accrual of chronic, multisystem disease states following MI are needed and should be guided by the demographic-specific risk charts derived in this study.

Including uncertainty of the expected mortality rates in the prediction of loss in life expectancy.

PURPOSE: This study introduces a novel method for estimating the variance of life expectancy since diagnosis (LEC) and loss in life expectancy (LLE) for cancer patients within a relative survival framework in situations where life tables based on the entire general population are not accessible. LEC and LLE are useful summary measures of survival in population-based cancer studies, but require information on the mortality in the general population. Our method addresses the challenge of incorporating the uncertainty of expected mortality rates when using a sample from the general population. METHODS: To illustrate the approach, we estimated LEC and LLE for patients diagnosed with colon and breast cancer in Sweden. General population mortality rates were based on a random sample drawn from comparators of a matched cohort. Flexible parametric survival models were used to model the mortality among cancer patients and the mortality in the random sample from the general population. Based on the models, LEC and LLE together with their variances were estimated. The results were compared with those obtained using fixed expected mortality rates. RESULTS: By accounting for the uncertainty of expected mortality rates, the proposed method ensures more accurate estimates of variances and, therefore, confidence intervals of LEC and LLE for cancer patients. This is particularly valuable for older patients and some cancer types, where underestimation of the variance can be substantial when the entire general population data are not accessible. CONCLUSION: The method can be implemented using existing software, making it accessible for use in various cancer studies. The provided example of Stata code further facilitates its adoption.

Using temporal recalibration to improve the calibration of risk prediction models in competing risk settings when there are trends in survival over time.

We have previously proposed temporal recalibration to account for trends in survival over time to improve the calibration of predictions from prognostic models for new patients. This involves first estimating the predictor effects using data from all individuals (full dataset) and then re-estimating the baseline using a subset of the most recent data whilst constraining the predictor effects to remain the same. In this article, we demonstrate how temporal recalibration can be applied in competing risk settings by recalibrating each cause-specific (or subdistribution) hazard model separately. We illustrate this using an example of colon cancer survival with data from the Surveillance Epidemiology and End Results (SEER) program. Data from patients diagnosed in 1995-2004 were used to fit two models for deaths due to colon cancer and other causes respectively. We discuss considerations that need to be made in order to apply temporal recalibration such as the choice of data used in the recalibration step. We also demonstrate how to assess the calibration of these models in new data for patients diagnosed subsequently in 2005. Comparison was made to a standard analysis (when improvements over time are not taken into account) and a period analysis which is similar to temporal recalibration but differs in the data used to estimate the predictor effects. The 10-year calibration plots demonstrated that using the standard approach over-estimated the risk of death due to colon cancer and the total risk of death and that calibration was improved using temporal recalibration or period analysis.

Fair comparisons of cause-specific and relative survival by accounting for the systematic removal of patients from risk-sets.

BACKGROUND: In population-based cancer studies it is common to try to isolate the impact of cancer by estimating net survival. Net survival is defined as the probability of surviving cancer in the absence of any other-causes of death. Net survival can be estimated either in the cause-specific or relative survival framework. Cause-specific survival considers deaths from the cancer as the event of interest. Relative survival incorporates general population expected mortality rates to represent the other-cause mortality rate. Estimation approaches in both frameworks are impacted by the systematic removal of patients from the risk-set, commonly referred to as informative censoring in the cause-specific framework. In the relative survival framework, the Pohar Perme estimator combats the effect of this systematic removal of patients through weighting. When the two frameworks have been compared, informative censoring is rarely accounted for in the cause-specific framework. METHODS: We investigate the use of weighted cause-specific Kaplan-Meier estimates to overcome the impact of informative censoring and compared approaches to defining weights. Individuals remaining in the risk-set are upweighted using their predicted other-cause survival obtained through various model-based approaches. We also compare weights derived from expected mortality rates. We applied the approaches to US cancer registry data and conducted a simulation study. RESULTS: Using weighted cause-specific estimates provides a better estimate of marginal net survival. The unweighted Kaplan-Meier estimates have a similar bias to the Ederer II method for relative survival. Weighted Kaplan-Meier estimates are unbiased and similar to the Pohar Perme estimator. There was little variation between the several weighting approaches. CONCLUSION: In comparisons of cause-specific and relative survival, it is important to compare "like-with-like", therefore, a weighted approach should be considered for both frameworks. If researchers are interested in obtaining net measures in a cause-specific framework, then weighting is needed to account for informative censoring.

Improving communication of cancer survival statistics-feasibility of implementing model-based algorithms in routine publications.

BACKGROUND: Routine reporting of cancer patient survival is important, both to monitor the effectiveness of health care and to inform about prognosis following a cancer diagnosis. A range of different survival measures exist, each serving different purposes and targeting different audiences. It is important that routine publications expand on current practice and provide estimates on a wider range of survival measures. We examine the feasibility of automated production of such statistics. METHODS: We used data on 23 cancer sites obtained from the Cancer Registry of Norway (CRN). We propose an automated way of estimating flexible parametric relative survival models and calculating estimates of net survival, crude probabilities, and loss in life expectancy across many cancer sites and subgroups of patients. RESULTS: For 21 of 23 cancer sites, we were able to estimate survival models without assuming proportional hazards. Reliable estimates of all desired measures were obtained for all cancer sites. DISCUSSION: It may be challenging to implement new survival measures in routine publications as it can require the application of modeling techniques. We propose a way of automating the production of such statistics and show that we can obtain reliable estimates across a range of measures and subgroups of patients.

Survival Extrapolation Incorporating General Population Mortality Using Excess Hazard and Cure Models: A Tutorial.

BACKGROUND: Different parametric survival models can lead to widely discordant extrapolations and decision uncertainty in cost-effectiveness analyses. The use of excess hazard (EH) methods, which incorporate general population mortality data, has the potential to reduce model uncertainty. This review highlights key practical considerations of EH methods for estimating long-term survival. METHODS: Demonstration of methods used a case study of 686 patients from the German Breast Cancer Study Group, followed for a maximum of 7.3 y and divided into low (1/2) and high (3) grade cancers. Seven standard parametric survival models were fit to each group separately. The same 7 distributions were then used in an EH framework, which incorporated general population mortality rates, and fitted both with and without a cure parameter. Survival extrapolations, restricted mean survival time (RMST), and difference in RMST between high and low grades were compared up to 30 years along with Akaike information criterion goodness-of-fit and cure fraction estimates. The sensitivity of the EH models to lifetable misspecification was investigated. RESULTS: In our case study, variability in survival extrapolations was extensive across the standard models, with 30-y RMST ranging from 7.5 to 14.3 y. Incorporation of general population mortality rates using EH cure methods substantially reduced model uncertainty, whereas EH models without cure had less of an effect. Long-term treatment effects approached the null for most models but at varying rates. Lifetable misspecification had minimal effect on RMST differences. CONCLUSIONS: EH methods may be useful for survival extrapolation, and in cancer, EHs may decrease over time and be easier to extrapolate than all-cause hazards. EH cure models may be helpful when cure is plausible and likely to result in less extrapolation variability. HIGHLIGHTS: In health economic modeling, to help anchor long-term survival extrapolation, it has been recommended that survival models incorporate background mortality rates using excess hazard (EH) methods.We present a thorough description of EH methods with and without the assumption of cure and demonstrate user-friendly software to aid researchers wishing to use these methods.EH models are applied to a case study, and we demonstrate that EHs are easier to extrapolate and that the use of the EH cure model, when cure is plausible, can reduce extrapolation variability.EH methods are relatively robust to lifetable misspecification.

Impact of a Prior Cancer Diagnosis on Quality of Care and Survival Following Acute Myocardial Infarction: Retrospective Population-Based Cohort Study in England.

BACKGROUND: An increasing proportion of patients with cancer experience acute myocardial infarction (AMI). We investigated differences in quality of AMI care and survival between patients with and without previous cancer diagnoses. METHODS: A retrospective cohort study using Virtual Cardio-Oncology Research Initiative data. Patients aged 40+ years hospitalized in England with AMI between January 2010 and March 2018 were assessed, ascertaining previous cancers diagnosed within 15 years. Multivariable regression was used to assess effects of cancer diagnosis, time, stage, and site on international quality indicators and mortality. RESULTS: Of 512 388 patients with AMI (mean age, 69.3 years; 33.5% women), 42 187 (8.2%) had previous cancers. Patients with cancer had significantly lower use of ACE (angiotensin-converting enzyme) inhibitors/angiotensin receptor blockers (mean percentage point decrease [mppd], 2.6% [95% CI, 1.8-3.4]) and lower overall composite care (mppd, 1.2% [95% CI, 0.9-1.6]). Poorer quality indicator attainment was observed in patients with cancer diagnosed in the last year (mppd, 1.4% [95% CI, 1.8-1.0]), with later stage disease (mppd, 2.5% [95% CI, 3.3-1.4]), and with lung cancer (mppd, 2.2% [95% CI, 3.0-1.3]). Twelve-month all-cause survival was 90.5% in noncancer controls and 86.3% in adjusted counterfactual controls. Differences in post-AMI survival were driven by cancer-related deaths. Modeling improving quality indicator attainment to noncancer patient levels showed modest 12-month survival benefits (lung cancer, 0.6%; other cancers, 0.3%). CONCLUSIONS: Measures of quality of AMI care are poorer in patients with cancer, with lower use of secondary prevention medications. Findings are primarily driven by differences in age and comorbidities between cancer and noncancer populations and attenuated after adjustment. The largest impact was observed in recent cancer diagnoses (<1 year) and lung cancer. Further investigation will determine whether differences reflect appropriate management according to cancer prognosis or whether opportunities to improve AMI outcomes in patients with cancer exist.

Exploring different research questions via complex multi-state models when using registry-based repeated prescriptions of antidepressants in women with breast cancer and a matched population comparison group.

BACKGROUND: Multi-state models are used to study several clinically meaningful research questions. Depending on the research question of interest and the information contained in the data, different multi-state structures and modelling choices can be applied. We aim to explore different research questions using a series of multi-state models of increasing complexity when studying repeated prescriptions data, while also evaluating different modelling choices. METHODS: We develop a series of research questions regarding the probability of being under antidepressant medication across time using multi-state models, among Swedish women diagnosed with breast cancer (n = 18,313) and an age-matched population comparison group of cancer-free women (n = 92,454) using a register-based database (Breast Cancer Data Base Sweden 2.0). Research questions were formulated ranging from simple to more composite ones. Depending on the research question, multi-state models were built with structures ranging from simpler ones, like single-event survival analysis and competing risks, up to complex bidirectional and recurrent multi-state structures that take into account the recurring start and stop of medication. We also investigate modelling choices, such as choosing a time-scale for the transition rates and borrowing information across transitions. RESULTS: Each structure has its own utility and answers a specific research question. However, the more complex structures (bidirectional, recurrent) enable accounting for the intermittent nature of prescribed medication data. These structures deliver estimates of the probability of being under medication and total time spent under medication over the follow-up period. Sensitivity analyses over different definitions of the medication cycle and different choices of timescale when modelling the transition intensity rates show that the estimates of total probabilities of being in a medication cycle over follow-up derived from the complex structures are quite stable. CONCLUSIONS: Each research question requires the definition of an appropriate multi-state structure, with more composite ones requiring such an increase in the complexity of the multi-state structure. When a research question is related with an outcome of interest that repeatedly changes over time, such as the medication status based on prescribed medication, the use of novel multi-state models of adequate complexity coupled with sensible modelling choices can successfully address composite, more realistic research questions.

Acute heart failure presentation, management, and outcomes in cancer patients: a national longitudinal study.

AIMS: Currently, little evidence exists on survival and quality of care in cancer patients presenting with acute heart failure (HF). The aim of the study is to investigate the presentation and outcomes of hospital admission with acute HF in a national cohort of patients with prior cancer. METHODS AND RESULTS: This retrospective, population-based cohort study identified 221 953 patients admitted to a hospital in England for HF during 2012-2018 (12 867 with a breast, prostate, colorectal, or lung cancer diagnosis in the previous 10 years). We examined the impact of cancer on (i) HF presentation and in-hospital mortality, (ii) place of care, (iii) HF medication prescribing, and (iv) post-discharge survival, using propensity score weighting and model-based adjustment. Heart failure presentation was similar between cancer and non-cancer patients. A lower percentage of patients with prior cancer were cared for in a cardiology ward [-2.4% age point difference (ppd) (95% CI -3.3, -1.6)] or were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists (ACEi/ARB) for heart failure with reduced ejection fraction [-2.1 ppd (-3.3, -0.9)] than non-cancer patients. Survival after HF discharge was poor with median survival of 1.6 years in prior cancer and 2.6 years in non-cancer patients. Mortality in prior cancer patients was driven primarily by non-cancer causes (68% of post-discharge deaths). CONCLUSION: Survival in prior cancer patients presenting with acute HF was poor, with a significant proportion due to non-cancer causes of death. Despite this, cardiologists were less likely to manage cancer patients with HF. Cancer patients who develop HF were less likely to be prescribed guideline-based HF medications compared with non-cancer patients. This was particularly driven by patients with a poorer cancer prognosis.

Age-specific survival trends and life-years lost in women with breast cancer 1990-2016: the NORDCAN survival studies.

BACKGROUND: A recent overview of cancer survival trends 1990-2016 in the Nordic countries reported continued improvements in age-standardized breast cancer survival among women. The aim was to estimate age-specific survival trends over calendar time, including life-years lost, to evaluate if improvements have benefited patients across all ages in the Nordic countries. METHODS: Data on breast cancers diagnosed 1990-2016 in Denmark, Finland, Iceland, Norway, and Sweden were obtained from the NORDCAN database. Age-standardized and age-specific relative survival (RS) was estimated using flexible parametric models, as was reference-adjusted crude probabilities of death and life-years lost. RESULTS: Age-standardized period estimates of 5-year RS in women diagnosed with breast cancer ranged from 87% to 90% and 10-year RS from 74% to 85%. Ten-year RS increased with 15-18 percentage points from 1990 to 2016, except in Sweden (+9 percentage points) which had the highest survival in 1990. The largest improvements were observed in Denmark, where a previous survival disadvantage diminished. Most recent 5-year crude probabilities of cancer death ranged from 9% (Finland, Sweden) to 12% (Denmark, Iceland), and life-years lost from 3.3 years (Finland) to 4.6 years (Denmark). Although survival improvements were consistent across different ages, women aged ≥70 years had the lowest RS in all countries. Period estimates of 5-year RS were 94-95% in age 55 years and 84-89% in age 75 years, while 10-year RS were 88-91% in age 55 years and 69-84% in age 75 years. Women aged 40 years lost on average 11.0-13.8 years, while women lost 3.8-6.0 years if aged 55 and 1.9-3.5 years if aged 75 years. CONCLUSIONS: Survival for Nordic women with breast cancer improved from 1990 to 2016 in all age groups, albeit with larger country variation among older women where survival was also lower. Women over 70 years of age have not had the same survival improvement as women of younger age.

Standardised survival probabilities: a useful and informative tool for reporting regression models for survival data.

BACKGROUND: When interested in studying the effect of a treatment (or other exposure) on a time-to-event outcome, the most popular approach is to estimate survival probabilities using the Kaplan-Meier estimator. In the presence of confounding, regression models are fitted, and results are often summarised as hazard ratios. However, despite their broad use, hazard ratios are frequently misinterpreted as relative risks instead of relative rates. METHODS: We discuss measures for summarising the analysis from a regression model that overcome some of the limitations associated with hazard ratios. Such measures are the standardised survival probabilities for treated and untreated: survival probabilities if everyone in the population received treatment and if everyone did not. The difference between treatment arms can be calculated to provide a measure for the treatment effect. RESULTS: Using publicly available data on breast cancer, we demonstrated the usefulness of standardised survival probabilities for comparing the experience between treated and untreated after adjusting for confounding. We also showed that additional important research questions can be addressed by standardising among subgroups of the total population. DISCUSSION: Standardised survival probabilities are a useful way to report the treatment effect while adjusting for confounding and have an informative interpretation in terms of risk.

Estimating causal effects in the presence of competing events using regression standardisation with the Stata command standsurv.

BACKGROUND: When interested in a time-to-event outcome, competing events that prevent the occurrence of the event of interest may be present. In the presence of competing events, various estimands have been suggested for defining the causal effect of treatment on the event of interest. Depending on the estimand, the competing events are either accommodated or eliminated, resulting in causal effects with different interpretations. The former approach captures the total effect of treatment on the event of interest while the latter approach captures the direct effect of treatment on the event of interest that is not mediated by the competing event. Separable effects have also been defined for settings where the treatment can be partitioned into two components that affect the event of interest and the competing event through different causal pathways. METHODS: We outline various causal effects that may be of interest in the presence of competing events, including total, direct and separable effects, and describe how to obtain estimates using regression standardisation with the Stata command standsurv. Regression standardisation is applied by obtaining the average of individual estimates across all individuals in a study population after fitting a survival model. RESULTS: With standsurv several contrasts of interest can be calculated including differences, ratios and other user-defined functions. Confidence intervals can also be obtained using the delta method. Throughout we use an example analysing a publicly available dataset on prostate cancer to allow the reader to replicate the analysis and further explore the different effects of interest. CONCLUSIONS: Several causal effects can be defined in the presence of competing events and, under assumptions, estimates of those can be obtained using regression standardisation with the Stata command standsurv. The choice of which causal effect to define should be given careful consideration based on the research question and the audience to which the findings will be communicated.

On the choice of timescale for other cause mortality in a competing risk setting using flexible parametric survival models.

In competing risks settings where the events are death due to cancer and death due to other causes, it is common practice to use time since diagnosis as the timescale for all competing events. However, attained age has been proposed as a more natural choice of timescale for modeling other cause mortality. We examine the choice of using time since diagnosis versus attained age as the timescale when modeling other cause mortality, assuming that the hazard rate is a function of attained age, and how this choice can influence the cumulative incidence functions ( C I F $CIF$ s) derived using flexible parametric survival models. An initial analysis on the colon cancer data from the population-based Swedish Cancer Register indicates such an influence. A simulation study is conducted in order to assess the impact of the choice of timescale for other cause mortality on the bias of the estimated C I F s $CIFs$ and how different factors may influence the bias. We also use regression standardization methods in order to obtain marginal C I F $CIF$ estimates. Using time since diagnosis as the timescale for all competing events leads to a low degree of bias in C I F $CIF$ for cancer mortality ( C I F 1 $CIF_{1}$ ) under all approaches. It also leads to a low degree of bias in C I F $CIF$ for other cause mortality ( C I F 2 $CIF_{2}$ ), provided that the effect of age at diagnosis is included in the model with sufficient flexibility, with higher bias under scenarios where a covariate has a time-varying effect on the hazard rate for other cause mortality on the attained age scale.

Generating high-fidelity synthetic time-to-event datasets to improve data transparency and accessibility.

BACKGROUND: A lack of available data and statistical code being published alongside journal articles provides a significant barrier to open scientific discourse, and reproducibility of research. Information governance restrictions inhibit the active dissemination of individual level data to accompany published manuscripts. Realistic, high-fidelity time-to-event synthetic data can aid in the acceleration of methodological developments in survival analysis and beyond by enabling researchers to access and test published methods using data similar to that which they were developed on. METHODS: We present methods to accurately emulate the covariate patterns and survival times found in real-world datasets using synthetic data techniques, without compromising patient privacy. We model the joint covariate distribution of the original data using covariate specific sequential conditional regression models, then fit a complex flexible parametric survival model from which to generate survival times conditional on individual covariate patterns. We recreate the administrative censoring mechanism using the last observed follow-up date information from the initial dataset. Metrics for evaluating the accuracy of the synthetic data, and the non-identifiability of individuals from the original dataset, are presented. RESULTS: We successfully create a synthetic version of an example colon cancer dataset consisting of 9064 patients which aims to show good similarity to both covariate distributions and survival times from the original data, without containing any exact information from the original data, therefore allowing them to be published openly alongside research. CONCLUSIONS: We evaluate the effectiveness of the methods for constructing synthetic data, as well as providing evidence that there is minimal risk that a given patient from the original data could be identified from their individual unique patient information. Synthetic datasets using this methodology could be made available alongside published research without breaching data privacy protocols, and allow for data and code to be made available alongside methodological or applied manuscripts to greatly improve the transparency and accessibility of medical research.

Survival trends in patients diagnosed with colon and rectal cancer in the nordic countries 1990-2016: The NORDCAN survival studies.

BACKGROUND: Survival of patients with colon and rectal cancer has improved in all Nordic countries during the past decades. The aim of this study was to further assess survival trends in patients with colon and rectal cancer in the Nordic countries by age at diagnosis and to present additional survival measures. METHODS: Data on colon and rectal cancer cases diagnosed in the Nordic countries between 1990 and 2016 were obtained from the NORDCAN database. Relative survival was estimated using flexible parametric models. Both age-standardized and age-specific measures for women and men were estimated from the models, as well as reference-adjusted crude probabilities of death and life-years lost. RESULTS: The five-year age-standardized relative survival of colon and rectal cancer patients continued to improve for women and men in all Nordic countries, from around 50% in 1990 to about 70% at the end of the study period. In general, survival was similar across age and sex. The largest improvement was seen for Danish men and women with rectal cancer, from 41% to 69% and from 43% to 71%, respectively. The age-standardized and reference-adjusted five-year crude probability of death in colon cancer ranged from 30% to 36% across countries, and for rectal cancer from 20% to 33%. The average number of age-standardized and reference-adjusted life-years lost ranged between six and nine years. CONCLUSION: There were substantial improvements in colon and rectal cancer survival in all Nordic countries 1990-2016. Of special note is that the previously observed survival disadvantage in Denmark is no longer present.

Reference-Adjusted Loss in Life Expectancy for Population-Based Cancer Patient Survival Comparisons-with an Application to Colon Cancer in Sweden.

BACKGROUND: The loss in life expectancy, LLE, is defined as the difference in life expectancy between patients with cancer and that of the general population. It is a useful measure for summarizing the impact of a cancer diagnosis on an individual's life expectancy. However, it is less useful for making comparisons of cancer survival across groups or over time, because the LLE is influenced by both mortality due to cancer and other causes and the life expectancy in the general population. METHODS: We present an approach for making LLE estimates comparable across groups and over time by using reference expected mortality rates with flexible parametric relative survival models. The approach is illustrated by estimating temporal trends in LLE of patients with colon cancer in Sweden. RESULTS: The life expectancy of Swedish patients with colon cancer has improved, but the LLE has not decreased to the same extent because the life expectancy in the general population has also increased. When using a fixed population and other-cause mortality, that is, a reference-adjusted approach, the LLE decreases over time. For example, using 2010 mortality rates as the reference, the LLE for females diagnosed at age 65 decreased from 11.3 if diagnosed in 1976 to 7.2 if diagnosed in 2010, and from 3.9 to 1.9 years for women 85 years old at diagnosis. CONCLUSIONS: The reference-adjusted LLE is useful for making comparisons across calendar time, or groups, because differences in other-cause mortality are removed. IMPACT: The reference-adjusted approach enhances the use of LLE as a comparative measure.

Obtaining long-term stage-specific relative survival estimates in the presence of incomplete historical stage information.

BACKGROUND: Completeness of recording for cancer stage at diagnosis is often historically poor in cancer registries, making it challenging to provide long-term stage-specific survival estimates. Stage-specific survival differences are driven by differences in short-term prognosis, meaning estimated survival metrics using period analysis are unlikely to be sensitive to imputed historical stage data. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) Program for lung, colon and breast cancer. To represent missing data patterns in less complete registry data, we artificially inflated the proportion of missing stage information conditional on stage at diagnosis and calendar year of diagnosis. Period analysis was applied and missing stage at diagnosis information was imputed under four different conditions to emulate extreme imputed stage distributions. RESULTS: We fit a flexible parametric model for each cancer stage on the excess hazard scale and the differences in stage-specific marginal relative survival were assessed. Estimates were also obtained from non-parametric approaches for validation. There was little difference between the 10-year stage-specific marginal relative survival estimates, regardless of the assumed historical stage distribution. CONCLUSIONS: When conducting a period analysis, multiple imputation can be used to obtain stage-specific long-term estimates of relative survival, even when the historical stage information is largely incomplete.