Flexible Parametric Survival Models Research Articles

Association of Medicaid expansion with timely receipt of treatment and survival among patients with HER2-enriched breast cancer.

6539 Background: HER2-enriched breast cancer (estrogen and progesterone receptors negative and HER2-positive) has no worse prognosis than other breast cancers if it is treated with HER2-targeted therapy. Medicaid expansion under the Affordable Care Act (ACA) has been shown to be associated with improved access to care and outcomes for many cancers, but its impact on care for HER2-enriched breast cancer is unknown. To fill this gap, we examined the association of Medicaid expansion with receipt of guideline-concordant treatment, time to treatment, and survival among newly diagnosed nonelderly women with HER2-enriched breast cancer. Methods: Women aged 18-62 years newly diagnosed with HER2-enriched breast cancer between 2010 and 2018 were identified from the National Cancer Database. Our primary outcomes included receipt of stage-based guideline-concordant treatment, initiation of treatment <60 days, and stage-specific 2-year overall survival. A difference-in-differences (DD) approach compared outcome changes following the expansion in Medicaid expansion vs. non-expansion states. A linear probability model estimated treatment outcome, and a flexible parametric survival model evaluated survival. All models were clustered at the state level and adjusted for age group, race/ethnicity, rurality of residence, zip code-level income, comorbidity, and diagnosis year. Results: A total of 31,354 patients with HER2-enriched breast cancer were included, including 19,255 in expansion states and 12,099 in non-expansion states. Compared to patients in expansion states, patients in non-expansion states were more likely to be racial/ethnic minorities, uninsured, and diagnosed at late-stage. Medicaid expansion was not significantly associated with changes in receipt of surgery for stage I-III disease but was associated with an increase of 4.42 percentage points (ppt, 95% CI: 0.09, 8.74) in receipt of chemotherapy/targeted therapy for stage IV disease, with an increase from 90.4% pre-expansion to 92.8% post-expansion in expansion states and a decrease from 93.7% to 91.9% in non-expansion states. Medicaid expansion was also significantly associated with a 2.41 ppt increase in initiating guideline-concordant treatment within 60 days (95% CI: 0.66, 4.17; 83.5% to 82.5% in expansion states vs. 86.6% to 83.7% in non-expansion states), and a 1.18 ppt increase in two-year survival rate (95% CI: 0.03, 2.33; 94.0% to 94.9% in expansion states vs. 94.3% to 94.1% in non-expansion states). The increase in two-year survival associated with Medicaid expansion was most prominent for stage III patients (DD=3.63 ppt; 95% CI: 0.64, 6.62). Conclusions: Medicaid expansion was associated with increased receipt of timely treatment and improved 2-year survival among nonelderly women newly diagnosed with HER2-enriched breast cancer.

Association of Cardiovascular Health Assessed by the New Life's Essential 8 Metrics With Years Lived Without Cardiovascular Disease.

Background The American Heart Association recently proposed an updated definition of cardiovascular health (CVH) named as Life's Essential 8. We aimed to explore the association between this latest published CVH measurement and years lived without cardiovascular disease (CVD) among the Chinese population. Methods and Results We included 89 755 adults free of CVD at baseline from the Kailuan study. The CVH of each participant was scored (from 0 point to 100 points) and classified (low [0-49 points], moderate [50-79 points], and high [80-100 points]) according to Life's Essential 8, which incorporated 8 components covering health behaviors and health factors. Incident CVD was documented through follow-ups from baseline (June 2006 to October 2007) until December 31, 2020. CVD-free life years from age 30 to 80 years associated with different CVH scores were estimated using flexible parametric survival models. A total of 9977 incident CVDs were recorded. We observed a gradient relationship between CVH score and years lived without CVD. The age- and sex-adjusted CVD-free life years (95% CI) were 40.7 (40.3-41.0) years for low CVH, 43.3 (43.0-43.5) years for moderate CVH, and 45.5 (45.1-45.9) years for high CVH. Similar trends were noted when individual subtypes of CVD were investigated, and high CVH evaluated by health behaviors and health factors was also related to longer CVD-free life years. Conclusions A higher CVH evaluated by the updated Life's Essential 8 metrics was significantly associated with a greater number of life years without CVD, indicating the importance of promoting CVH for healthy aging in China.

Labour market status and mortality risk: The Finnmark cohort study 1987-2017.

The aim of this study was to investigate the age-varying mortality risk associated with different labour market status categories. Data from a population-based survey carried out among adults aged 30-62 years in Finnmark in 1987/1988 were linked to the Norwegian Cause of Death Registry to identify all deaths occurring by December 2017. We used flexible parametric survival models to examine the age-varying associations between different labour market status categories (no paid work/homemaker, part-time work, full-time work, unemployment benefits, sick leave/rehabilitation allowance, and disability pension) and mortality. Men with part-time work, unemployment benefits, sick leave/rehabilitation allowance, or disability pension had an increased mortality risk compared with men with full-time work; however, these findings were restricted to ages below 60-70 years, varying with labour market status category. For women, excess mortality was linked to disability pension in the younger age groups; in older age groups it was linked to the labour market status category no paid work/homemaker. Non-employment was associated with low education level compared with full-time employment. The study showed increased mortality risk for some non-employment categories, with decreasing relative risk with age. Our findings suggest that the increased mortality risk is partly explained by health, pre-existing illnesses, and health-related behaviour and partly by other factors, such as social network and economic factors.

Preterm Birth, Small for Gestational Age, and Large for Gestational Age and the Risk of Atrial Fibrillation Up to Middle Age

Adverse birth outcomes, including preterm birth, small for gestational age (SGA), and large for gestational age (LGA) are associated with increased risks of hypertension, ischemic heart disease, stroke, and heart failure, but knowledge regarding their associations with atrial fibrillation (AF) is limited and inconsistent. To investigate whether preterm birth, SGA, or LGA are associated with increased risks of AF later in life. This multinational cohort study included Danish, Swedish, and Finnish national health registries. Live singleton births in Denmark from 1978 through 2016, in Sweden from 1973 through 2014, and in Finland from 1987 through 2014, who were followed up until December 31, 2016, in Denmark, December 31, 2021, in Sweden, and December 31, 2014, in Finland were included. Data analyses were performed between January 2021 and August 2022. Preterm birth (less than 37 gestational weeks), SGA (less than 10th percentile birth weight for gestational age), and LGA (more than 90th percentile birth weight for gestational age) identified from medical birth registers. Diagnosis of AF obtained from nationwide inpatient and outpatient registers. The study team ran multivariable Cox proportional hazard models and flexible parametric survival models to estimate hazard ratios (HRs) and 95% CIs for AF according to preterm birth, SGA, and LGA. Sibling analyses were conducted to control for unmeasured familial factors. The cohort included 8 012 433 study participants (maximum age, 49 years; median age, 21 years; male, 51.3%). In 174.4 million person-years of follow-up, 11 464 participants had a diagnosis of AF (0.14%; median age, 29.3 years). Preterm birth and LGA were associated with increased AF risk in both the full population cohort and in the sibling analyses; the multivariate HRs from the cohort analyses were 1.30 (95% CI, 1.18-1.42) and 1.55 (95% CI, 1.46-1.63), respectively. Preterm birth was more strongly associated with AF in childhood than in adulthood. Children born SGA had an increased risk of AF in the first 18 years of life but not afterwards. Preterm births and LGA births were associated with increased risks of AF up to middle age independently of familial confounding factors. Individuals born SGA had an increased AF risk only during childhood.

Body composition and mortality from middle to old age: a prospective cohort study from the UK Biobank.

How the association between adiposity and the risk of death changes with age, and which is the optimal level of adiposity to reduce mortality in older ages, is still not completely understood. We aimed to ascertain the age-specific risks of mortality associated with different measures of adiposity. This was a prospective UK Biobank cohort study. Participants were categorized based on five different adiposity and body composition metrics. We explored the age-varying associations between body composition indices and all-cause mortality from 45 to 85 years of age at follow-up using hazard ratios (HR) from flexible parametric survival models with multivariable adjustment and age as timescale. Participants were followed from baseline (2006-2010) through 31 March 2020. We included 369,752 participants (mean baseline age = 56.3 ± 8.1 years; range 38.9-73.7 years; 54.1% women) and 10,660 deaths during a median follow-up of 11.4 years. Associations between body mass index and mortality were similar when using the fat mass index in magnitude and shape. Compared to participants with normal weight, overweight was not associated with the risk of death regardless of age and the adiposity measure used. Participants with obesity class I showed an HR of 1.20 (95% confidence interval [CI]: 1.08, 1.33) and 1.14 (95%CI: 0.98, 1.30) at ages 60 and 80, respectively, and participants with obesity class II an HR about 1.55 across all age. More attenuated associations with higher age were found in individuals with the highest obesity using the fat mass index. Very high lean mass was associated with an increased risk of mortality in those aged 55-75 years (HR about 1.20 across all ages). Obesity should be prevented at any age. Attenuated associations with older age were observed only among the individuals with the highest obesity, but the risk remained higher compared to normal-weight participants. Lean mass did not reduce mortality risk at any age.

Influence of Hemorrhagic Complications of Pancreatoduodenectomy in Patients with Cancer on Short- and Long-Term Mortality.

With a mortality rate of up to 30%, post-pancreatectomy hemorrhage (PPH) remains a serious complication after pancreatoduodenectomy (PD) for cancer. Little is known about the long-term survival of patients after PPH. This retrospective study aimed to evaluate the impact of PPH on long-term survival after PD. The study included 830 patients (PPH, n = 101; non-PPH, n = 729) from two centers, who underwent PD for oncological indications. PPH was defined as any bleeding event occurring within 90 days after surgery. A flexible parametric survival model was used to determine the evolution of the risk of death over time. At postoperative day 90, PPH significantly increased the mortality rate (PPH vs. non-PPH: 19.8% vs. 3.7%, p < 0.0001) and severe postoperative complication rate (85.1% vs. 14.1%, p < 0.0001), and decreased median survival (18.6 months vs. 30.1 months, p = 0.0001). PPH was associated with an increased mortality risk until the sixth postoperative month. After this 6-month period, PPH had no more influence on mortality. PPH had a negative impact on the short-term overall survival beyond postoperative day 90 and up to six months after PD. However, compared to non-PPH patients, this adverse event had no impact on mortality after a 6-month period.

Life expectancy following a cardiovascular event in individuals with and without type 2 diabetes: A UK multi-ethnic population-based observational study

Background and aimsWe aimed to evaluate the life expectancy following the first cardiovascular disease (CVD) event by type 2 diabetes (T2D) status and ethnicity. Methods and resultsWe used the Clinical Practice Research Datalink database in England (UK), linked to the Hospital Episode Statistics information, to identify individuals with and without T2D who survived a first CVD event between 1st Jan 2007 and 31st Dec 2017; subsequent death events were extracted from the Office for National Statistics database. Ethnicity was categorised as White, South Asian (SA), Black, or other. Flexible parametric survival models were used to estimate survival and predict life expectancy. 59,939 individuals with first CVD event were included: 7596 (12.7%) with T2D (60.9% men; mean age at event: 69.7 years [63.2 years in SA, 65.9 in Black, 70.2 in White]) and 52,343 without T2D (56.7% men; 65.9 years [54.7 in Black, 58.2 in SA, 66.3 in White]). Accounting for potential confounders (sex, deprivation, lipid-lowering medication, current smoking, and pre-existing hypertension), comparing individuals with vs without T2D the mortality rate was 53% higher in White (hazard ratio [HR]: 1.53 [95% CI: 1.44, 1.62]), corresponding to a potential loss of 3.87 (3.30, 4.44) life years at the age of 50 years in individuals with T2D. No evidence of a difference in life expectancy was observed in individuals of SA (HR: 0.82 [0.52, 1.29]; −1.36 [-4.58, 1.86] life years), Black (HR: 1.26 [0.59, 2.70]; 1.21 [-2.99, 5.41] life years); and other (HR: 1.64 [0.80, 3.39]; 3.89 [-2.28, 9.99] life years) ethnic group. ConclusionFollowing a CVD event, T2D is associated with a different prognosis and life years lost among ethnic groups.

The effect of monthly vitamin D supplementation on fractures: a tertiary outcome from the population-based, double-blind, randomised, placebo-controlled D-Health trial

Low serum 25-hydroxy vitamin D concentration is associated with increased fracture risk. It is uncertain whether vitamin D supplementation reduces fractures, or whether intermittent doses are harmful. We aimed to investigate if supplementing adults living in Australia with monthly doses of 60 000 international units (IU) vitamin D3 for 5 years or less altered the rate of fractures. We did a population-based, double-blind, randomised, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) for up to 5 years in adults aged 60-84 years living in Australia. We randomly assigned (1:1) 21 315 participants to either vitamin D or placebo. We ascertained fractures through linkage with administrative datasets. The main outcome was total fractures. Additional outcomes were non-vertebral, major osteoporotic (hip, wrist, proximal humerus, and spine), and hip fractures. We excluded participants (989 [4·6%]) without linked data, and estimated hazard ratios (HRs) and 95% CIs using flexible parametric survival models. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763, and the trial intervention ended in February, 2020. Between Feb 14, 2014, and June 17, 2015, we recruited 21 315 participants. For the current analysis, we included 20 326 participants (vitamin D 10 154 [50·0%]; placebo 10 172 [50·0%]). 9295 (45·7%) of 20 326 participants were women and the mean age was 69·3 years (SD 5·5). Over a median follow-up of 5·1 years (IQR 5·1-5·1), 568 (5·6%) participants in the vitamin D group and 603 (5·9%) in the placebo group had one or more fractures. There was no effect on fracture risk overall (HR 0·94 [95% CI 0·84-1·06]), and the interaction between randomisation group and time was not significant (p=0·14). However, the HR for total fractures appeared to decrease with increasing follow-up time. The overall HRs for non-vertebral, major osteoporotic, and hip fractures were 0·96 (95% CI 0·85-1·08), 1·00 (0·85-1·18), and 1·11 (0·86-1·45), respectively. These findings do not support concerns that bolus doses of vitamin D administered monthly increase fracture risk. Long-term supplementation might reduce the incidence of total fractures, but additional research is needed to clarify this effect. Australian National Health and Medical Research Council.

The Survival Outcomes, Prognostic Factors and Adverse Events following Systemic Chemotherapy Treatment in Bone Sarcomas: A Retrospective Observational Study from the Experience of the Cancer Referral Center in Northern Thailand.

This study aimed to assess survival outcomes, prognostic factors, and adverse events following chemotherapy treatment for osteosarcoma and Ewing's sarcoma. This retrospective observational study was conducted to collect the data of the patients with osteosarcoma or Ewing's sarcoma who received chemotherapy treatment between 2008 and 2019. The flexible parametric survival model was performed to explore the adjusted survival probability and the prognostic factors. A total of 102 patients (79 with osteosarcoma and 23 with Ewing's sarcoma) were included. The estimated 5-year disease-free survival (DFS) and 5-year overall survival (OS) probabilities in patients with resectable disease were 60.9% and 63.3% for osteosarcoma, and 54.4% and 88.3% for Ewing's sarcoma, respectively, whereas the 5-year DFS and 5-year OS for those with unresectable/metastatic disease remained below 25%. Two prognostic factors for osteosarcoma included a response to neoadjuvant chemotherapy and female gender. Ewing's sarcoma patients aged 25 years and older were significantly associated with poorer survival outcomes. Of 181 chemotherapy treatment cycles, common self-reported adverse symptoms included tumor pain (n = 32, 17.7%), fever (n = 21, 11.6%), and fatigue (n = 16, 8.8%), while common grade III adverse events included febrile neutropenia (n = 13, 7.3%) and neutropenia (n = 9, 5.1%). There was no chemotherapy-related mortality (grade V) or anaphylaxis events.

Abstract P2-03-04: Long-Term Benefit from Adjuvant Tamoxifen in Luminal A and Luminal B Breast Cancer Patients

Abstract Background: The risk for patients with estrogen receptor (ER)-positive breast cancer remains stable decades after primary diagnosis, with a large proportion of distant metastatic events occurring late. Thus, long-term follow-up studies are essential to understand true treatment benefit. Tamoxifen (TAM) therapy is a fundamental endocrine treatment for ER-positive breast cancer. We have previously shown a long-term tamoxifen therapy benefit for patients with less aggressive tumor characteristics in ER-positive/HER2-negative patients. However, ER-positive breast cancer is highly heterogenous and can be separated into different molecular subpopulations that behave differently during extended follow-up. The long-term tamoxifen benefit by molecular subtype is largely unexplored. We therefore aimed to investigate the long-term benefit from tamoxifen by clinically used tumor characteristics in Luminal A vs Luminal B patients in the Stockholm tamoxifen (STO)-trials with complete 20-years follow-up. Methods: Secondary analysis of ER-positive/HER2-negative patients with Luminal A or B molecular subtype (n=952) from the STO-trials (1976-1997) randomized to TAM (40 mg) vs no endocrine therapy (control). Gene expression data was generated using custom designed Agilent arrays from FFPE breast cancer tumor tissue and was used to define PAM50 molecular subtypes. The clinically used markers were reannotated in 2014 and 2020. Complete 20-year follow-up was obtained from Swedish high-qualitative registries. The long-term distant recurrence-free interval (DRFI) was assessed by Kaplan-Meier, multivariable Cox proportional hazard regression and time-varying analysis, using flexible parametric modelling. Results: Multivariable analysis showed significantly improved long-term DRFI from TAM vs control for both Luminal A (HR=0.59; 95% CI, 0.44-0.81) and Luminal B (HR=0.67; 95% CI, 0.46-0.99) patients. Time-varying analysis showed that patients with Luminal A subtype significantly benefitted from TAM for 15 years (HR=0.60, 95% CI, 0.39-0.94 at year 15), whereas patients with Luminal B subtype had a significant TAM benefit for 5 years (HR=0.64, 95% CI, 0.42-0.98 at year 5), see Table. Furthermore, a significant long-term TAM benefit for patients with large tumor size (pT&amp;gt;20mm: HR=0.46; 95% CI, 0.25-0.84), tumor grade 1-2 (HR=0.55; 95% CI, 0.40-0.77), lymph node-negative (HR=0.51, 95% CI, 0.34-0.78), PR-positive (HR=0.57, 95% CI, 0.40-0.81) and Ki-67-low tumors (HR=0.55, 95% CI, 0.39-0.77) was seen for Luminal A patients. In Luminal B patients, significantly improved long-term DRFI from TAM vs control was seen for small tumor size (pT≤20mm: HR=0.44; 95% CI, 0.24-0.80), tumor grade 1-2 (HR=0.51; 95% CI, 0.29-0.90), lymph node-negative (HR=0.40, 95% CI, 0.19-0.83), PR-positive (HR=0.59, 95% CI, 0.38-0.93) and Ki-67-low tumors (HR=0.45, 95% CI, 0.25-0.84). Conclusions: This study suggests a 15 years tamoxifen benefit for patients with Luminal A subtype tumors, whereas the benefit for patients with Luminal B tumors is up to five years after diagnosis. Furthermore, our study suggests a long-term tamoxifen benefit for patients with less aggressive tumor characteristics regardless of tumor subtype, except for tumor size in Luminal A patients. ER-positive breast cancer is a heterogeneous disease and long-term follow-up studies in molecular subtypes are essential to understand differences in treatment benefit. Table. Time-varying analysis of long-term tamoxifen therapy benefit by PAM50 molecular subtype. Time-varying analysis of distant recurrence-free interval (DRFI) to assess how tamoxifen benefit varied over the 20 year of follow-up using flexible parametric survival modelling. Patients included in analyses with no missing values. Estimated hazard ratios (HR) at year 5, 10, 15 and 20 for patients with Luminal A or Luminal B molecular subtype tumors randomized to tamoxifen therapy, as compared with patients randomized to no endocrine therapy (control). Adjusted for age, period of primary breast cancer diagnosis, tumor size, tumor grade, lymph node status, PR status, Ki-67 status, chemotherapy, radiotherapy, type of surgery, and menopausal status. *indicates significant findings P&amp;lt;0.05 Citation Format: Huma Dar, Annelie Johansson, Anna Nordenskjöld, Gizeh Perez-Tenorio, Christina Yau, Christopher C. Benz, Laura J. Esserman, Bo Nordenskjöld, Olle Stål, Tommy Fornander, Linda S. Lindström. Long-Term Benefit from Adjuvant Tamoxifen in Luminal A and Luminal B Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-04.

Cancer Survival and Travel Time to Nearest Reference Care Center for 10 Cancer Sites: An Analysis of 21 French Cancer Registries

The impact of several non-clinical factors on cancer survival is poorly understood. The aim of this study was to investigate the influence of travel time to the nearest referral center on survival of patients with cancer. The study used data from the French Network of Cancer Registries that combines all the French population-based cancer registries. For this study, we included the 10 most common solid invasive cancer sites in France between 1 January 2013 and 31 December 2015, representing 160,634 cases. Net survival was measured and estimated using flexible parametric survival models. Flexible excess mortality modelling was performed to investigate the association between travel time to the nearest referral center and patient survival. To allow the most flexible effects, restricted cubic splines were used to investigate the influence of travel times to the nearest cancer center on excess hazard ratio. Among the 1-year and 5-year net survival results, lower survival was observed for patients residing farthest from the referral center for half of the included cancer types. The remoteness gap in survival was estimated to be up to 10% at 5 years for skin melanoma in men and 7% for lung cancer in women. The pattern of the effect of travel time was highly different according to tumor type, being either linear, reverse U-shape, non-significant, or better for more remote patients. For some sites restricted cubic splines of the effect of travel time on excess mortality were observed with a higher excess risk ratio as travel time increased. For numerous cancer sites, our results reveal geographical inequalities, with remote patients experiencing a worse prognosis, aside from the notable exception of prostate cancer. Future studies should evaluate the remoteness gap in more detail with more explanatory factors.

Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials

BackgroundThe Keynote-045 trial illustrates that the long-term benefit (LTB) of treatment does not always translate to improved progression-free survival (PFS). Milestone survival and flexible parametric survival model with cure (FPCM) have been proposed as complementary statistical approaches to more comprehensively evaluate LTBs of treatments. ObjectiveThe current study compares milestone survival and FPCM analyses to evaluate treatment effects of immune checkpoint inhibitor (ICI) phase III trials. Design, setting, and participantsIndividual patient data, from initial and follow-up analyses of Keynote-045 (urothelial cancer) and Checkmate-214 (advanced renal cell carcinoma), were reconstructed for PFS. Outcome measurements and statistical analysisEach trial was reanalyzed using the Cox proportional hazard regression and two complementary methods (milestone survival and FPCM) to estimate treatment impact on the LTB. Results and limitationsFor each trial, there was evidence of nonproportional hazards. For the long-term analysis of the Keynote-045 trial, FPCM identified a time-dependent effect on PFS, but the Cox model found no statistical difference in PFS (hazard ratio, 0.90; 95% confidence interval, 0.75–1.08). Milestone survival and FPCM identified improvements in the LTB fractions. This was consistent with the results from the reanalysis of Keynote-045, based on the shorter follow-up, although the LTB fraction was not retained. The increase in PFS in Checkmate-214 was identified by both Cox model and FPCM. Experimental treatment-dependent improvement in the LTB fraction was demonstrated using milestone survival and FPCM. The LTB fraction estimated with FPCM was consistent with the results from the reanalysis of the shorter follow-up period. ConclusionsAlthough ICIs show substantial shifts toward LTBs in terms of PFS, based on a conventional Kaplan-Meier or Cox model analysis, our approach provides an alternative assessment of benefit-risk ratios for new therapeutics and facilitates communicating risk to patients. Kidney patients treated with ICIs can be counseled that they are potentially cured, but future work will need to definitively validate this conclusion. Patient summaryAlthough immune checkpoint inhibitor treatments show substantial shifts toward long-term benefits in terms of progression-free survival, a more rigorous attempt to quantify this shift, rather than simply using a Kaplan-Meier estimate or comparing progression-free survival curves using the classic Cox model, is warranted. Our results suggest that advanced renal cell carcinoma patients who had not received a previous treatment are functionally cured by nivolumab and ipilimumab, which is not the case for second-line urothelial carcinoma.

Mitigating disparities in breast cancer treatment at an academic safety-net hospital.

Among women with non-metastatic breast cancer, marked disparities in stage at presentation, receipt of guideline-concordant treatment and stage-specific survival have been shown in national cohorts based on race, ethnicity, insurance and language. Little is published on the performance of safety-net hospitals to achieve equitable care. We evaluate differences in treatment and survival by race, ethnicity, language and insurance status among women with non-metastatic invasive breast cancer at a single, urban academic safety-net hospital. We conducted a retrospective study of patients with invasive ductal or lobular breast cancer, diagnosed and treated between 2009 and 2014 at an urban, academic safety-net hospital. Demographic, tumor and treatment characteristics were obtained. Stage at presentation, stage-specific overall survival, and receipt of guideline-concordant surgical and adjuvant therapies were analyzed. Chi-square analysis and ANOVA were used for statistical analysis. Unadjusted survival analysis was conducted by Kaplan-Meier method using log-rank test; adjusted 5 year survival analysis was completed stratified by early and late stage, using flexible parametric survival models incorporating age, race, primary language and insurance status. 520 women with stage 1-3 invasive breast cancer were identified. Median age was 58.5years, 56.1% were non-white, 31.7% were non-English-speaking, 16.4% were Hispanic, and 50.1% were Medicaid/uninsured patients. There were no statistically significant differences in stage at presentation between age group, race, ethnicity, language or insurance. The rate of breast conserving surgery (BCS) among stage 1-2 patients did not vary by race, insurance or language. Among patients indicated for adjuvant therapies, the rates of recommendation and completion of therapy did not vary by race, ethnicity, insurance or language. Unadjusted survival at 5 years was 93.7% for stage 1-2 and 73.5% for stage 3. Adjusting for age, race, insurance status and primary language, overall survival at 5 years was 93.8% (95% CI 86.3-97.2%) for stage 1-2 and 83.4% (95% CI 35.5-96.9%) for stage 3 disease. Independently, for patients with early- and late-stage disease, age, race, language and insurance were not associated with survival at 5-years. Among patients diagnosed and treated at an academic safety-net hospital, there were no differences in the stage at presentation or receipt of guideline-concordant treatment by race, ethnicity, insurance or language. Overall survival did not vary by race, insurance or language. Additional research is needed to assess how hospitals and healthcare systems mitigate breast cancer disparities.

The Association Between Survival and Receipt of Post-mastectomy Radiotherapy According to Age at Diagnosis Among Women With Early Invasive Breast Cancer: A Population-Based Cohort Study

AimsClinical trials of post-mastectomy radiotherapy (PMRT) for early invasive breast cancer (EIBC) have included few older women. This study examined whether the association between overall survival or breast cancer-specific survival (BCSS) and receipt of PMRT for EIBC altered with age. Materials and methodsThe study used patient-level linked cancer registration, routine hospital and radiotherapy data for England and Wales. It included 31 243 women aged ≥50 years diagnosed between 2014 and 2018 with low- (T1-2N0), intermediate- (T3N0/T1-2N1) or high-risk (T1-2N2/T3N1-2) EIBC who received a mastectomy within 12 months from diagnosis. Patterns of survival were analysed using a landmark approach. Associations between overall survival/BCSS and PMRT in each risk group were analysed with flexible parametric survival models, which included patient and tumour factors; whether the association between PMRT and overall survival/BCSS varied by age was assessed using interaction terms. ResultsAmong 4711 women with high-risk EIBC, 86% had PMRT. Five-year overall survival was 70.5% and BCSS was 79.3%. Receipt of PMRT was associated with improved overall survival [adjusted hazard ratio (aHR) 0.75, 95% confidence interval 0.64–0.87] and BCSS (aHR 0.78, 95% confidence interval 0.65–0.95) compared with women who did not have PMRT; associations did not vary by age (overall survival, P-value for interaction term = 0.141; BCSS, P = 0.077). Among 10 814 women with intermediate-risk EIBC, 59% had PMRT; 5-year overall survival was 78.4% and BCSS was 88.0%. No association was found between overall survival (aHR 1.01, 95% confidence interval 0.92–1.11) or BCSS (aHR 1.16, 95% confidence interval 1.01–1.32) and PMRT. There was statistical evidence of a small change in the association with age for overall survival (P = 0.007), although differences in relative survival were minimal, but not for BCSS (P = 0.362). ConclusionsThe association between PMRT and overall survival/BCSS does not appear to be modified by age among women with high- or intermediate-risk EIBC and, thus, treatment recommendations should not be modified on the basis of age alone.

Incipient dementia and avoidable hospital admission in persons with osteoarthritis

ObjectiveTo investigate the associations between incipient dementia (ID) and hospitalization for ambulatory care sensitive conditions (ACSCs) among people with osteoarthritis (OA) of the peripheral joints. MethodsAmong individuals aged 51–99 years residing in Skåne, Sweden, in 2009, we identified those with a doctor-diagnosed OA and no dementia during 1998–2009 (n ​= ​57,733). Treating ID as a time-varying exposure, we followed people from January 1, 2010 or their 60th birthday (whichever occurred last) until hospitalization for ACSCs, death, 100th birthday, relocation outside Skåne, or December 31, 2019 (whichever occurred first). Using age as time scale, we applied flexible parametric survival models, adjusted for confounders, to assess the associations between ID and hospitalization for ACSCs. ResultsThere were 58 and 33 hospitalizations for ACSCs per 1000 person-years among OA people with and without ID, respectively. The association between ID and hospitalization for any ACSCs was age-dependent with higher risk in ages<86 years and lower risks in older ages. Between ages 60 and 100 years, persons with ID had, on average, 5.8 (95% CI 0.9, 10.7), 1.6 (−2.6, 5.9) and 3.1 (2.3, 4.0) fewer hospital-free years for any, chronic and acute ACSCs, respectively, compared with persons without ID. ConclusionsAmong persons with OA, while ID was associated with increased risks of hospitalization for ACSCs in younger ages, it was associated with decreased risk in oldest ages. These results suggest the need for improvement in quality of ambulatory care including the continuity of care for people with OA having dementia.

Twenty years of melanoma in Victoria, Queensland, and South Australia (1997 – 2016)

BackgroundGiven the high incidence of melanoma in Australia alongside high mortality with later stage disease, we investigated the populations and locations most at risk, to optimise public health activities in areas where intervention is most needed. This study examines trends and identifies significant prognostic factors and potential disparities in incidence, mortality and survival between population groups in Victoria, Queensland and South Australia. MethodsThe analysis includes data from the population-based cancer registries of the three states over a twenty-year period (1997–2016). Age-standardized and age-specific incidence rates were calculated, and long-term trends analysed using Joinpoint Regression. Five-year relative survival estimates for the study population were calculated using the cohort method and multivariable flexible parametric survival models were applied for each jurisdiction to calculate adjusted excess mortality hazard ratios for the key characteristics. ResultsThere were more males with melanoma than females in all the three states. Over 60% of the cases occurred in the 40–74 years age group. Most melanomas had a Breslow thickness less than or equal to 1.0 mm. For males, Victoria and Queensland had a statistically significant increasing trend whereas in South Australia there was a decreasing trend. For females, the incidence rate trend was stable in Victoria but significantly decreasing in South Australia. In Queensland there was an increasing and statistically significant trend from 2006 to 2016. Across all three states there was a reducing incidence rate in the youngest cohort, stabilizing incidence in the 40–59-year-old age group, and increasing in the oldest cohorts. Five-year relative survival decreased with increasing age and with Breslow thickness across all three jurisdictions. Males had between 43%− 46% excess mortality compared to females in all the three states. There was higher risk with increasing age and Breslow thickness, with the largest risk among the 75 + age group and those with a Breslow thickness of > 4 mm. ConclusionIt is the first time that data from these three registries has been analysed together in a uniform way, covering more than half of the Australian population. This study compares the epidemiology of melanoma across three states and provides a better understanding of trends and factors affecting outcome for Australians with melanoma. While there has been some improvement in aspects of incidence and mortality, this has not been evenly achieved across Australia.

Treatment-Related Circulatory Diseases and Mortality in Hodgkin Lymphoma Patients Using Multi-State Modelling and Relative Survival

Introduction Diseases of the circulatory system (DCS) are some of the most common late effects of Hodgkin lymphoma (HL), primarily due to mediastinal radiotherapy and/or anthracycline-containing chemotherapy (e.g., ABVD and BEACOPP). As DCS is very common in the general population, modelling DCS attributable to HL therapy versus that expected in the general population is relevant to understand the magnitude of DCS reduction that could be achieved with less cardiotoxic therapies. This real-world data study used multi-state modelling and relative survival to estimate treatment-related DCS risk in HL survivors. Material and methods All HL patients registered in the Swedish Lymphoma Register 2000-2018, aged 18-80 years at diagnosis, and treated with anthracycline-containing therapy were included. DCS events were identified in the Swedish National Inpatient Register (ICD-10 codes I00-I99) and defined as the first admission for DCS after HL diagnosis. Sex-, year-, and age-specific DCS incidence rates in the general population were retrieved from public records. Patients were followed from treatment initiation through a series of states: alive and DCS-free, alive and with (excess or expected) DCS, dead without DCS, and dead after DCS. Follow-up ended on date of death, emigration, or December 31st, 2019, whichever came first. All state transitions were modelled separately using flexible parametric survival models, yielding hazard ratios (HR) with 95% confidence intervals (CI). A relative survival model incorporating the expected DCS rates was fitted to allow for estimation of excess DCS, which was then interpreted as treatment-related. Transition probabilities (i.e., the likelihood of being in a state) were predicted for specific patient groups, by sex and low/high (≤200/>200 mg/m2) cumulative anthracycline dose. Results In a total of 1,929 HL patients, the mean age at diagnosis was 42 years, 54% were males, and 49% were treated with high dose anthracycline (Table 1). The distribution of treatments was 66% ABVD, 20% CHOP-like, and 14% BEACOPP. During a median follow-up of 7.6 years (IQR: 4.5-11.0), 145 (7.5%) died without DCS, 377 patients (20%) were diagnosed with DCS, and 87 (5%) died after DCS. Figure 1a shows the sex-specific transition probabilities for a patient with advanced stage disease, diagnosed in 2000, at age 50, and treated with a cumulative anthracycline dose of >200mg/m2 in a ABVD regimen. The probability of being in the treatment-related (excess) DCS state at 10 years after first line treatment was 0.35 (95% CI: 0.09-0.75) for males and 0.41 (95% CI: 0.10-0.81) for females in this patient group. Figure 1b shows the probabilities for limited stage male patients diagnosed in 2000 at age 50, treated with ABVD, by low/high anthracycline dose. Here, the probability of being in the treatment-related (excess) DCS state at 10 years was 0.44 (95% CI: 0.16-0.76) and 0.53 (95% CI: 0.25-0.80) for low and high dose anthracycline patients, respectively. There were no significant differences in treatment-related (excess) DCS incidence rates or post DCS all-cause mortality rates (Table 1). Females had a significantly lower non-DCS mortality rate than males (adj. HR=0.69, 95% CI: 0.49-0.97), as did patients treated with high compared to low anthracycline dose (adj. HR=0.28, 95% CI: 0.18-0.44). Conclusion After 10 years, females had higher risks of treatment-related (excess) DCS compared to males, although not statistically significant and likely due to superior survival. The same was seen for high compared to low cumulative doses of anthracycline. Female sex and high dose anthracycline reduced the non-DCS mortality rate, but not the excess DCS incidence rate. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Maternal Preeclampsia With Offspring Risks of Ischemic Heart Disease and Stroke in Nordic Countries

An association between maternal preeclampsia and an increased risk of cardiovascular disease in the offspring is plausible, but evidence in this area is limited. To investigate (1) the association between maternal preeclampsia and risks of ischemic heart disease (IHD) and stroke in the offspring, (2) whether the association varies by severity or timing of onset of preeclampsia, and (3) the role of preterm birth and small for gestational age (SGA) birth, both of which are related to preeclampsia and cardiovascular diseases, in this association. This multinational population-based cohort study obtained data from Danish, Finnish, and Swedish national registries. Live singleton births from Denmark (1973-2016), Finland (1987-2014), and Sweden (1973-2014) were followed up until December 31, 2016, in Denmark and December 31, 2014, in Finland and Sweden. Data analyses were performed between September 2020 and September 2022. Preeclampsia and its subtypes, including early onset (<34 gestational weeks) and late onset (≥34 gestational weeks), severe and mild or moderate, and with and without SGA birth. Diagnoses of IHD and stroke were extracted from patient and cause-of-death registers. Cox proportional hazards regression models and flexible parametric survival models were used to analyze the associations. Sibling analyses were conducted to control for unmeasured familial factors. The cohort included of 8 475 819 births (2 668 697 [31.5%] from Denmark, 1 636 116 [19.3%] from Finland, and 4 171 006 [49.2%] from Sweden, comprising 4 350 546 boys [51.3%]). Of these offspring, 188 670 (2.2%) were exposed to maternal preeclampsia, 7446 (0.1%) were diagnosed with IHD, and 10 918 (0.1%) were diagnosed with stroke during the median (IQR) follow-up of 19.3 (9.0-28.1) years. Offspring of individuals with preeclampsia had increased risks of IHD (adjusted hazard ratio [HR], 1.33; 95% CI, 1.12-1.58) and stroke (adjusted HR, 1.34; 95% CI, 1.17-1.52). These associations were largely independent of preterm or SGA birth. Severe forms of preeclampsia were associated with a higher stroke risk than less severe forms (severe vs mild or moderate: adjusted HR, 1.81 [95% CI, 1.41-2.32] vs 1.22 [95% CI, 1.05-1.42]; early vs late onset: adjusted HR, 2.55 [95% CI, 1.97-3.28] vs 1.18 [95% CI, 1.01-1.39]; with vs without SGA birth: adjusted HR, 1.84 [95% CI, 1.44-2.34] vs 1.25 [95% CI, 1.07-1.48]). Sibling analyses suggested that the associations were partially explained by unmeasured familial factors. Results of this study suggest that offspring born to individuals with preeclampsia had increased IHD and stroke risk that were not fully explained by preterm or SGA birth, and that the associated risks for stroke were higher for severe forms of preeclampsia.

Predictors of Adverse Clinical Outcome in Diffuse Large B-Cell Lymphoma Richter Transformation of CLL/SLL: A Consortium of Richter Transformation Investigators (CORTI) Multicenter Study across 8 US, UK, and Australian Academic Centers

Background Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a known but uncommon complication with dismal prognosis despite improvements in CLL outcomes with novel agents. Previously published studies are characterized by cohort heterogeneity with respect to CLL treatments (predating the rituximab era and novel agents) and RT histology [diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL)], limiting their generalizability in the modern era. To this end, we examined characteristics and outcomes in 222 DLBCL-RT cases, enriching for patients treated with novel agents. Methods We collected 247 RT cases diagnosed between 1995-2022 across eight academic institutions, excluding 23 with cHL-RT and 2 with "pseudo-transformation" after BTKi withdrawal (final n = 222; 41% of cases post-2010). We analyzed > 65 CLL/RT biologic, pathologic, and clinical parameters. Primary outcomes included complete response (CR) to first line of therapy [in CLL (iwCLL 2008/2018) and RT (Lugano 2014)] and 5-year overall survival (5yr-OS) after RT, estimated using Cox proportional hazards [yielding hazard ratios (HRs) and 95% confidence intervals (CIs)] and flexible parametric survival models (for prediction of standardized survival). Results The antecedent CLL included: 11% cases with atypical CLL, 84% IGHVUM, and 70% ZAP70+ with 46% and 43% of patients harboring del(13q) and del(17p), respectively. CLL/RT was synchronous (CLL diagnosis within 2 months of RT diagnosis) in 13% of cases. Only del(17p) correlated with C/HC (≥ 3 / ≥ 5 chromosome abnormalities) karyotype (p < 0.0001), and ZAP70/CD38 had no association with IGHV status. RT was primarily nodal (47.3%), non-GCB (90.3%), and EBV-negative (95%) with p53 IHC-positive large cells in 60% of cases and MYC translocation in 10%. Preceding CLL was treated with a median of 2 lines of therapy (range: 1-7) with 53% heavily-treated (≥ 2 lines). The most common first lines (LOT1) were chemotherapy (fludarabine-based or bendamustine/CHOP equivalents; 73.6%) and BTKi/novel agents (17%); 37% received BTKi as any LOT, while 44% received any novel agent (BTKi, BCL2i, PI3Ki, or SYKi). CLL CRLOT1 was achieved in 41.2% with overall response of 77%. Median time to RT from CLL diagnosis (sequential group) was 47.6 months pre-2010 (IQR: 87.8) vs. 21.8 months post-2010 (IQR: 34.6, p < 0.0001). During a median follow up of 10.2 months (IQR: 27.1 months) post-RT, 59% of patients died. Median OS was 17.4 months (range: 11.3-24.2) with 28% 5yr-OS. In the pre-rituximab era (i.e. prior to 2010), median OS was significantly shorter compared to the present era (8 vs. 19.9 months). Indicators of inferior 5yr-OS on univariable analysis included: sequential transformation (HR: 2.34 [95% CI: 1.25-4.35]), not achieving CRLOT1 for CLL (HR: 1.62 [95% CI: 1.01-2.58]), heavily-treated CLL (HR: 1.98 [95% CI: 1.36-2.88]), and C/HC karyotype (HR: 1.59 [95% CI: 1.02-2.46]). While trisomy 12 predicted superior outcome (HR: 0.54 [95% CI: 0.32-0.94]), del(13q) and del(17p) had no impact. Adverse baseline covariates at RT diagnosis were low (< 3.5 g/dL) serum albumin (HR: 3.13 [95% CI: 2.09-4.69]), low (< 150x103/uL) platelet count (HR: 2.38 [95% CI: 1.64-3.47]), LDH > 1.5x ULN (HR: 1.63 [95% CI: 1.12-1.38]), and ECOG-PS ≥ 2 (HR: 2.4 [95% CI: 1.51-3.81]). Notably, p53 IHC positivity in RT predicted increased all-cause mortality (HR: 2.13 [95% CI: 1.27-3.5]), retaining significance in both minimally- and heavily-treated CLL subsets. RT was treated using CHOP-R or EPOCH-R in 62%. Not achieving CRLOT1 for RT predicted worse 5yr-OS (HR: 3.90 [95% CI: 2.09-7.29]). A multivariable, main effects Cox model was constructed using five variables (age at transformation, CLL treatment number, LDH > 1.5x ULN, albumin, and p53 IHC). In this age-adjusted model, all variables retained adverse prognostic significance (Figure 1). Marginal OS was predicted by p53 IHC, standardizing over remaining covariates, and with a trend towards inferior 5yr-OS in p53-positive vs. -negative RT (13% vs. 38%; Figure 2). Conclusion This multicenter, international study is the largest cohort of RT in the era of novel therapies with solely DLBCL histology. We confirmed the utility of several traditional predictors. In addition, we identified p53 IHC as a promising predictor of adverse outcome (in univariable and multivariable analyses) based on these preliminary analyses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modelling multiple time-scales with flexible parametric survival models

BackgroundThere are situations when we need to model multiple time-scales in survival analysis. A usual approach in this setting would involve fitting Cox or Poisson models to a time-split dataset. However, this leads to large datasets and can be computationally intensive when model fitting, especially if interest lies in displaying how the estimated hazard rate or survival change along multiple time-scales continuously.MethodsWe propose to use flexible parametric survival models on the log hazard scale as an alternative method when modelling data with multiple time-scales. By choosing one of the time-scales as reference, and rewriting other time-scales as a function of this reference time-scale, users can avoid time-splitting of the data.ResultThrough case-studies we demonstrate the usefulness of this method and provide examples of graphical representations of estimated hazard rates and survival proportions. The model gives nearly identical results to using a Poisson model, without requiring time-splitting.ConclusionFlexible parametric survival models are a powerful tool for modelling multiple time-scales. This method does not require splitting the data into small time-intervals, and therefore saves time, helps avoid technological limitations and reduces room for error.