Low adherence to recommended use of neoadjuvant chemotherapy for muscle-invasive bladder cancer.

PURPOSE: To evaluate guideline adherence and variation in the recommended use of neoadjuvant chemotherapy (NAC) and the effects of this variation on survival in patients with non-metastatic muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: In this nationwide, Netherlands Cancer Registry-based study, we identified 1025 patients newly diagnosed with non-metastatic MIBC between November 2017 and November 2019 who underwent radical cystectomy. Patients with ECOG performance status 0-1 and creatinine clearance ≥ 50 mL/min/1.73 m2 were considered NAC-eligible. Interhospital variation was assessed using case-mix adjusted multilevel analysis. A Cox proportional hazards model was used to evaluate the association between hospital specific probability of using NAC and survival. All analyses were stratified by disease stage (cT2 versus cT3-4a). RESULTS: In total, of 809 NAC-eligible patients, only 34% (n = 277) received NAC. Guideline adherence for NAC in cT2 was 26% versus 55% in cT3-4a disease. Interhospital variation was 7-57% and 31-62%, respectively. A higher hospital specific probability of NAC might be associated with a better survival, but results were not statistically significant (HRcT2 = 0.59, 95% CI 0.33-1.05 and HRcT3-4a = 0.71, 95% CI 0.25-2.04). CONCLUSION: Guideline adherence regarding NAC use is low and interhospital variation is large, especially for patients with cT2-disease. Although not significant, our data suggest that survival of patients diagnosed in hospitals more inclined to give NAC might be better. Further research is warranted to elucidate the underlying mechanism. As literature clearly shows the potential survival benefit of NAC in patients with cT3-4a disease, better guideline adherence might be pursued.

The influence of multidisciplinary team meetings on treatment decisions in advanced bladder cancer.

OBJECTIVES: To investigate the role of specialised genitourinary multidisciplinary team meetings (MDTMs) in decision-making and identify factors that influence the probability of receiving a treatment plan with curative intent for patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: Data relating to patients with cT2-4aN0/X-1 M0 urothelial cell carcinoma, diagnosed between November 2017 and October 2019, were selected from the nationwide, population-based Netherlands Cancer Registry ('BlaZIB study'). Curative treatment options were defined as radical cystectomy (RC) with or without neoadjuvant chemotherapy, chemoradiation or brachytherapy. Multilevel logistic regression analyses were used to examine the association between MDTM factors and curative treatment advice and how this advice was followed. RESULTS: Of the 2321 patients, 2048 (88.2%) were discussed in a genitourinary MDTM. Advanced age (>80 years) and poorer World Health Organization performance status (score 1-2 vs 0) were associated with no discussion (P < 0.001). Being discussed was associated with undergoing treatment with curative intent (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.9-4.9), as was the involvement of a RC hospital (OR 1.70, 95% CI 1.09-2.65). Involvement of an academic centre was associated with higher rates of bladder-sparing treatment (OR 2.05, 95% CI 1.31-3.21). Patient preference was the main reason for non-adherence to treatment advice. CONCLUSIONS: For patients with MIBC, the probability of being discussed in a MDTM was associated with age, performance status and receiving treatment with curative intent, especially if a representative of a RC hospital was present. Future studies should focus on the impact of MDTM advice on survival data.

Non-metastatic muscle-invasive bladder cancer: the role of age in receiving treatment with curative intent.

OBJECTIVES: To evaluate which patient and tumour characteristics are associated with remaining untreated in patients with potentially curable, non-metastatic muscle-invasive bladder cancer (MIBC), and to compare survival of untreated vs treated patients with similar characteristics. PATIENTS AND METHODS: For this cohort study, 15 047 patients diagnosed with cT2-T4aN0/xM0/x urothelial MIBC between 2005 and 2019 were identified in the Netherlands Cancer Registry. Factors associated with remaining untreated were identified using logistic regression analyses. Interhospital variation was assessed using multilevel analysis. Using a propensity score, the median overall survival (mOS) of untreated and treated patients was evaluated. Analyses were stratified by age (<75 vs ≥75 years). RESULTS: One-third of patients aged ≥75 years remained untreated; increasing age, worse performance status, worse renal function, cT4a stage and previous radiotherapy in the abdomen/pelvic area increased the odds of remaining untreated. One in 10 patients aged <75 years remained untreated; significant associations were only found for performance status, renal function and cT4a stage. Interhospital variation for remaining untreated was largest for patients aged ≥75 years, ranging from 37% to 69% (case-mix-adjusted). Irrespective of age, mOS was significantly worse for untreated patients: 6.4 months (95% confidence interval [CI] 5.1-7.3) vs 16.0 months (95% CI 13.5-19.1) for treated patients. CONCLUSION: On average, one in five patients with non-metastatic MIBC remained untreated. Untreated patients were generally older and had a more unfavourable prognostic profile. Untreated patients had significantly worse overall survival, regardless of age. Age alone should therefore not affect treatment decision-making. Considering the large interhospital variation, a proportion of untreated patients might be wrongfully denied life-prolonging treatment.

Validation and reliability of the Dutch version of the EORTC QLQ-NMIBC24 Questionnaire Module for patients with non-muscle-invasive bladder cancer.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire for non-muscle invasive bladder cancer (QLQ-NMIBC24) has been available and applied for some years now, but has yet to undergo a full comprehensive psychometric evaluation. The aim of this study was to investigate the psychometric properties of the Dutch version of the EORTC QLQ-NMIBC24 questionnaire in patients with low, intermediate and high risk NMIBC. METHODS: We included patients newly diagnosed with NMIBC participating in the multicenter, population-based prospective cohort studies UroLife or BlaZIB. Psychometric evaluation included examination of the structural validity, reliability (i.e. internal consistency and test-retest reliability), construct validity (i.e. divergent validity and known-groups validity), responsiveness and interpretability. RESULTS: A total of 1463 patients who completed the baseline questionnaire of UroLife (n = 541, response rate 50%) or BlaZIB (n = 922, response rate 58%) were included. The percentage of missing responses were low for all non-sex related scales (< 1%) and ranged between 6.9% to 50.0% for sex-related scales. More than 15% of the patients obtained the lowest possible scores on nearly each scale (floor effect). The structural validity was adequate; the confirmatory factor analysis showed satisfactory results and all items of multiple items scales had higher within- than between-scale correlations. Reliability of the questionnaire was adequate for most multiple item scales (Cronbach's α ≥ 0.70 and intraclass correlation coefficient ≥ 0.70), with exception of the scales 'malaise' and 'bloating and flatulence'. The questionnaire also showed good construct validity; it showed low correlations with the items of the EORTC core questionnaire and was able to measure differences between risk-based subgroups. The responsiveness of the questionnaire was good, but the interpretability, i.e. minimal important change, could not be determined. CONCLUSIONS: This study shows that the measurement properties of the EORTC QLQL-NMIBC24 are good; it has a good structural validity, reliability (i.e. internal consistency and test-retest reliability), construct validity (i.e. divergent validity and known-group validity), and responsiveness. Interpretability could not be assessed. This questionnaire can be used to measure and monitor health-related quality of life of patients with NMIBC.

Hospital volume is associated with postoperative mortality after radical cystectomy for treatment of bladder cancer.

OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered.

Low Risk of Severe Complications After a Single, Post-Operative Instillation of Intravesical Chemotherapy in Patients with TaG1G2 Urothelial Bladder Carcinoma.

BACKGROUND: EAU guidelines recommend a single instillation (SI) of intravesical chemotherapy (e.g. Mitomycin C) within 24 hours after transurethral resection of a bladder tumour (TURBT) in patients with low- to intermediate risk non-muscle invasive bladder cancer without (suspected) bladder perforation or bleeding requiring bladder irrigation. However, remarkable variation exists in the use of SI. The risk of severe complications is likely to contribute to this variation, but evidence is limited. OBJECTIVE: To investigate the absolute severe complication and mortality risk after SI in low- and intermediate risk bladder cancer. METHODS: In this observational, historic cohort study, data on 25,567 patients diagnosed with TaG1G2 urothelial bladder carcinoma (UBC) between 2009 and 2018 who underwent TURBT were collected from the Netherlands Cancer Registry. Data were supplemented with information on cause of death and severe complications after cancer treatment by re-examining the electronic health records and the 14-day complication risk and the 30-day mortality risk were evaluated. RESULTS: On average, 55% of patients had a SI after TURBT, varying from 0->80% between hospitals. The 30-day mortality risk was 0.02% and the 14-day risk of severe complications was 1.6%. CONCLUSIONS: As the absolute risk of mortality and severe complications is very low, SI after TURBT can be considered a safe treatment in patients with low- to intermediate UBC without contraindications for SI. These results imply that a part of eligible patients is denied effective treatment.

Hospital-specific probability of cystectomy affects survival from muscle-invasive bladder cancer.

OBJECTIVES: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival. METHODS AND MATERIALS: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival. RESULTS: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98). CONCLUSION: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume criteria. Future research is needed to identify patient, tumor, and hospital characteristics affecting utilization of curative treatment as this may benefit overall survival.

Quantifying Overdiagnosis in Cancer Screening: A Systematic Review to Evaluate the Methodology.

Background: Overdiagnosis is the main harm of cancer screening programs but is difficult to quantify. This review aims to evaluate existing approaches to estimate the magnitude of overdiagnosis in cancer screening in order to gain insight into the strengths and limitations of these approaches and to provide researchers with guidance to obtain reliable estimates of overdiagnosis in cancer screening. Methods: A systematic review was done of primary research studies in PubMed that were published before January 1, 2016, and quantified overdiagnosis in breast cancer screening. The studies meeting inclusion criteria were then categorized by their methods to adjust for lead time and to obtain an unscreened reference population. For each approach, we provide an overview of the data required, assumptions made, limitations, and strengths. Results: A total of 442 studies were identified in the initial search. Forty studies met the inclusion criteria for the qualitative review. We grouped the approaches to adjust for lead time in two main categories: the lead time approach and the excess incidence approach. The lead time approach was further subdivided into the mean lead time approach, lead time distribution approach, and natural history modeling. The excess incidence approach was subdivided into the cumulative incidence approach and early vs late-stage cancer approach. The approaches used to obtain an unscreened reference population were grouped into the following categories: control group of a randomized controlled trial, nonattenders, control region, extrapolation of a prescreening trend, uninvited groups, adjustment for the effect of screening, and natural history modeling. Conclusions: Each approach to adjust for lead time and obtain an unscreened reference population has its own strengths and limitations, which should be taken into consideration when estimating overdiagnosis.

Breast cancer screening effect across breast density strata: A case-control study.

Breast cancer screening is known to reduce breast cancer mortality. A high breast density may affect this reduction. We assessed the effect of screening on breast cancer mortality in women with dense and fatty breasts separately. Analyses were performed within the Nijmegen (Dutch) screening programme (1975-2008), which invites women (aged 50-74 years) biennially. Performance measures were determined. Furthermore, a case-control study was performed for women having dense and women having fatty breasts. Breast density was assessed visually with a dichotomized Wolfe scale. Breast density data were available for cases. The prevalence of dense breasts among controls was estimated with age-specific rates from the general population. Sensitivity analyses were performed on these estimates. Screening performance was better in the fatty than in the dense group (sensitivity 75.7% vs 57.8%). The mortality reduction appeared to be smaller for women with dense breasts, with an odds ratio (OR) of 0.87 (95% CI 0.52-1.45) in the dense and 0.59 (95% CI 0.44-0.79) in the fatty group. We can conclude that high density results in lower screening performance and appears to be associated with a smaller mortality reduction. Breast density is thus a likely candidate for risk-stratified screening. More research is needed on the association between density and screening harms.

The relative effect of mammographic screening on breast cancer mortality by socioeconomic status.

Breast cancer incidence and mortality are higher in women with a high socioeconomic status (SES). The potential to prevent death from breast cancer is therefore greater in the high SES group. This does, however, require that the effectiveness of screening in the high SES group is equal to or greater than the effectiveness in the low SES group. The aim of this study is to assess the relative effectiveness of mammographic screening on breast cancer mortality by SES.In Nijmegen, the Netherlands, women are invited to participate in biennial mammographic screening since 1975. Postal code is collected at each round and is used to calculate the SES of each woman based on the SES indicator of the Netherlands Institute for Social Research. The Dutch average was used to classify the SES score of each woman as either high or low. We designed a case-control study to investigate the effect of mammographic screening in women aged 50 to 75, 40 to 75, and 50 to 69 years, and calculated the odds ratios (ORs) and 95% confidence intervals (CIs).Among the women invited to the mammographic screening program in Nijmegen, 10% had a high SES. In women aged 50 to 75 years, the breast cancer death rate was 38% lower in screened women than in unscreened women. The ORs for women with high SES (OR 0.82, 95% CI 0.31-2.19) and low SES did not differ significantly (OR 0.61, 95% CI 0.47-0.78).Mammographic screening reduces breast cancer mortality, but we did not observe a significant difference in the relative effectiveness of screening by SES. If the effectiveness of mammographic screening is indeed not dependent on SES status, the absolute number of breast cancer deaths prevented by mammographic screening will be greater in the high SES than low SES group, because women with a high SES have a greater risk of breast cancer death.

Statistical Methods for Estimating the Cumulative Risk of Screening Mammography Outcomes.

BACKGROUND: This study illustrates alternative statistical methods for estimating cumulative risk of screening mammography outcomes in longitudinal studies. METHODS: Data from the US Breast Cancer Surveillance Consortium (BCSC) and the Nijmegen Breast Cancer Screening Program in the Netherlands were used to compare four statistical approaches to estimating cumulative risk. We estimated cumulative risk of false-positive recall and screen-detected cancer after 10 screening rounds using data from 242,835 women ages 40 to 74 years screened at the BCSC facilities in 1993-2012 and from 17,297 women ages 50 to 74 years screened in Nijmegen in 1990-2012. RESULTS: In the BCSC cohort, a censoring bias model estimated bounds of 53.8% to 59.3% for false-positive recall and 2.4% to 7.6% for screen-detected cancer, assuming 10% increased or decreased risk among women screened for one additional round. In the Nijmegen cohort, false-positive recall appeared to be associated with subsequent discontinuation of screening leading to overestimation of risk of a false-positive recall based on adjusted discrete-time survival models. Bounds estimated by the censoring bias model were 11.0% to 19.9% for false-positive recall and 4.2% to 9.7% for screen-detected cancer. CONCLUSION: Choice of statistical methodology can substantially affect cumulative risk estimates. The censoring bias model is appropriate under a variety of censoring mechanisms and provides bounds for cumulative risk estimates under varying degrees of dependent censoring. IMPACT: This article illustrates statistical methods for estimating cumulative risks of cancer screening outcomes, which will be increasingly important as screening test recommendations proliferate.

Overdiagnosis in cancer screening: the need for a standardized denominator.

It is widely accepted that overdiagnosis is a major harm of screening, but its extent is still topic of controversy. This is partly the result of incomparable overdiagnosis estimates in scientific literature, as a variety of denominators are used to calculate the percentage of overdiagnosis in cancer screening. We propose to use the following denominator to calculate the percentage of overdiagnosis: 'all cancers detected during the screening period, both interval and screen-detected, in participants of a screening programme'. This denominator is more appropriate than existing denominators because it presents overdiagnosis as a real percentage, is unaffected by attendance percentages, is applicable to all observational study designs, and can be easily recalculated to absolute numbers. This denominator can be widely applied and increases comparability between overdiagnosis estimates, which is needed to correctly present the balance between the benefits and harms of screening.

Breast cancer diagnosis and death in the Netherlands: a changing burden.

BACKGROUND: Lifetime risks are often used in communications on cancer to the general public. The most-cited estimate for breast cancer risk (1 in 8 women), however, appears to be outdated. Here we describe the breast cancer burden in the Netherlands over time by means of lifetime and age-conditional risks. The aim is to identify changes in absolute risk of primary breast cancer diagnosis and death. METHODS: Data on breast cancer incidence, mortality and size of the female population were retrieved from the Netherlands Cancer Registry and Statistics Netherlands. Lifetime and age-conditional risks were calculated for 1990, 2000 and 2010 using the life-table method (DevCan software). RESULTS: The lifetime risk of developing breast cancer (ductal carcinoma in situ and invasive) in 1990, 2000 and 2010 was estimated at 10.8 (1 in 9.3 women), 13.5 (1 in 7.4) and 15.2% (1 in 6.6), respectively. Most women were still diagnosed after the age of 50, with the highest risk between 60 and 70 years in 2010. The lifetime risk of breast cancer death was 3.8% (1 in 27) in 2010, which is lower than in 1990 (4.5%; 1 in 22) and 2000 (4.2%; 1 in 24). CONCLUSION: Breast cancer risk has increased to 1 in 6.6 women being diagnosed during their lifetime (invasive cancer only: 1 in 7.4), whereas risk of breast cancer death has decreased from 1 in 22 to 1 in 27 women. To keep cancer management and prevention up-to-date, it remains important to closely monitor the ever-changing breast cancer burden.