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.

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.

Longer time to radical cystectomy in patients treated with neoadjuvant chemotherapy is associated with worse oncological outcomes.

BACKGROUND: Current muscle-invasive bladder cancer (MIBC) guidelines recommend not delaying radical cystectomy (RC) >3 months after diagnosis as it decreases overall survival (OS). However, literature investigating the impact of delay in RC in patients who receive NAC is limited, especially on a population-based level. OBJECTIVE: To investigate the association between time from diagnosis of MIBC to RC (TTRC) in patients with urothelial bladder cancer (UBC) treated with NAC and RC and 1) 2-year OS and 2) pathological lymph node status (pN+) in a population-based cohort. METHODS: Patients were selected from the Netherlands Cancer Registry. The study included 237 patients with cT2-T4aN0M0 UBC, treated with NAC and RC between November 2017 and October 2019. Association between TTRC and OS was assessed using multivariable Cox regression analyses. Schoenfeld and Martingale residuals were used to investigate the proportional hazards assumption and whether a cut-off in the TTRC could be identified. Association between TTRC and pN+ was assessed using multivariable logistic regression analyses. RESULTS: Median TTRC was 23 weeks (interquartile range (IQR) 19-26). 2-year OS was 67% (95%CI 59%-74%). Each week of delay in the TTRC was independently associated with 2-year OS (HR 1.06; P = 0.03) in the Cox regression analysis. The sensitivity analyses, defining TTRC as the time between last cycle of NAC and RC, revealed that each week of delay between NAC and RC was associated with 2-year OS (Hazard ratio (HR) 1.13; P < 0.0001), and with pN+ (Odds ratio (OR) 1.21; P = 0.01) in the Cox and logistic regression analyses, respectively. CONCLUSIONS: A longer TTRC is associated with worse oncological outcomes in patients treated with NAC and RC.

Global trends in the epidemiology of bladder cancer: challenges for public health and clinical practice.

Bladder cancer is among the ten most common cancers globally, causes considerable morbidity and mortality and is, therefore, a substantial burden for health-care systems. The incidence of bladder cancer is affected by demographic trends, most notably population growth and ageing, as well as exposure to risk factors, especially tobacco smoking. Consequently, the incidence has not been stable throughout the world over time, nor will it be in the near future. Further primary prevention efforts are of the utmost importance to reduce the medical and financial burden of bladder cancer on populations and health-care systems. Simultaneously, less-invasive and lower-cost approaches for the diagnosis of both primary and recurrent bladder cancers are required to address challenges posed by the increasing shortage of health-care professionals and limited financial resources worldwide. In this regard, urinary biomarkers have demonstrated promising diagnostic accuracy and efficiency. Awareness of the risk factors and symptoms of bladder cancer should also be increased in society, particularly among health-care professionals and high-risk groups. Studies investigating the associations between lifestyle factors and bladder cancer outcomes are scarce and should be a research priority. In this Review, we outline global trends in bladder cancer incidence and mortality, and discuss the main risk factors influencing bladder cancer occurrence and outcomes. We then discuss the implications, challenges and opportunities of these epidemiological trends for public health and clinical practice.

Minimum Volume Standards: An Incentive To Perform More Radical Cystectomies?

Background: Minimum volume standards (MVS) for hospitals and/or surgeons remain a subject of debate. Opponents of MVS emphasize the possible negative effects of centralization, such as an unwanted incentive to perform surgery. Objective: To evaluate whether the introduction of MVS for radical cystectomy (RC) in the Netherlands resulted in more RCs outside guideline-recommended indications. Design setting and participants: All RCs performed for bladder cancer in the Netherlands between January 1, 2006 and December 31, 2017 were identified in the Netherlands Cancer Registry. During this period, two MVS were sequentially implemented for RC. RCs in intermediate-volume hospitals (hospitals that approximated the MVS) were compared with RCs in high-volume hospitals (hospitals exceeding the MVS by ≥5 RCs/yr) in a period before and a period after implementation of each of the two MVS. Outcomes measurements and statistical analysis: Descriptive analyses were performed to evaluate whether hospitals performed more RCs outside the recommended indication (cT2-4a N0 M0) and whether an increase in the number of RCs towards the end of the year could be observed. Results and limitations: After MVS implementation, no clear shift towards disease stages outside the recommended indication for RC was observed in comparison to the period before the MVS. Results for high-volume and intermediate-volume hospitals were similar. In addition, no increase in RCs towards the end of the year was evident. Conclusions: We did not find evidence indicating an unwanted incentive to perform more RCs as a result of MVS in the Netherlands. Our results further strengthen the case for MVS implementation. Patient summary: We evaluated whether criteria for the minimum number of radical cystectomies (surgical removal of the bladder) that hospitals have to perform caused urologists to perform more of these operations than necessary in order to meet the minimum level. We found no evidence that minimum criteria led to such an unwanted incentive.

Chemoradiation for muscle-invasive bladder cancer using 5-fluorouracil versus capecitabine: A nationwide cohort study.

BACKGROUND AND PURPOSE: Oral capecitabine and intravenous 5-fluorouracil (5-FU) are both used as a radiosensitizer in chemoradiotherapy (CRT). A capecitabine-based regimen is more convenient for both patients and healthcare professionals. Since large comparative studies are lacking, we compared toxicity, overall survival (OS) and disease-free survival (DFS) between both CRT-regimens in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: All patients diagnosed with non-metastatic MIBC between November 2017-November 2019 were consecutively included in the BlaZIB study. Data on patient, tumor, treatment characteristics and toxicity were prospectively collected from the medical files. From this cohort, all patients with cT2-4aN0-2/xM0/x, treated with capecitabine or 5-FU-based CRT were included in the current study. Toxicity in both groups was compared using Fisher-exact tests. Propensity score-based inverse probability treatment weighting (IPTW) was applied to correct for baseline differences between groups. IPTW-adjusted Kaplan-Meier OS and DFS curves were compared using log-rank tests. RESULTS: Of the 222 included patients, 111 (50%) were treated with 5-FU and 111 (50%) with capecitabine. Curative CRT was completed according to treatment plan in 77% of patients in the capecitabine-based group and 62% of the 5-FU group (p = 0.06). Adverse events (14 vs 21%, p = 0.29), 2-year OS (73% vs 61%, p = 0.07) and 2-year DFS (56% vs 50%, p = 0.50) did not differ significantly between groups. CONCLUSIONS: Chemoradiotherapy with capecitabine and MMC is associated with a similar toxicity profile compared to 5-FU plus MMC and no difference in survival was found. Capecitabine-based CRT, as a more patient-friendly schedule, may be considered as an alternative to a 5-FU-based regimen.

The Impact of the COVID-19 Pandemic on Bladder Cancer Care in the Netherlands.

BACKGROUND: The COVID-19 pandemic has disrupted regular health care with potential consequences for non-COVID diseases like cancer. To ensure continuity of oncological care, guidelines were temporarily adapted. OBJECTIVE: To evaluate the impact of the COVID-19 outbreak on bladder cancer care in the Netherlands. METHODS: The number of bladder cancer (BC) diagnoses per month during 2020-2021 was compared to 2018-2019 based on preliminary data from the Netherlands Cancer Registry (NCR). Additionally, detailed data were retrieved from the NCR for the cohort diagnosed between March 1st-May 31st 2020 (first COVID wave) and 2018-2019 (reference cohort). BC diagnoses, changes in age and stage at diagnosis, and time to first-line treatment were compared between both periods. Changes in treatment were evaluated using logistic regression. RESULTS: During the first COVID wave (week 9-22), the number of BC diagnoses decreased by 14%, corresponding with approximately 300 diagnoses, but increased again in the second half of 2020. The decline was most pronounced from week 13 onwards in patients≥70 years and patients with non-muscle invasive BC. Patients with muscle-invasive disease were less likely to undergo a radical cystectomy (RC) in week 17-22 (OR = 0.62, 95% CI = 0.40-0.97). Shortly after the start of the outbreak, use of neoadjuvant chemotherapy decreased from 34% to 25% but this (non-significant) effect disappeared at the end of April. During the first wave, 5% more RCs were performed compared to previous years. Time from diagnosis to RC became 6 days shorter. Overall, a 7% reduction in RCs was observed in 2020. CONCLUSIONS: The number of BC diagnoses decreased steeply by 14% during the first COVID wave but increased again to pre-COVID levels by the end of 2020 (i.e. 600 diagnoses/month). Treatment-related changes remained limited and followed the adapted guidelines. Surgical volume was not compromised during the first wave. Altogether, the impact of the first COVID-19 outbreak on bladder cancer care in the Netherlands appears to be less pronounced than was reported for other solid tumors, both in the Netherlands and abroad. However, its impact on bladder cancer stage shift and long-term outcomes, as well as later pandemic waves remain so far unexamined.

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.

Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships.

BACKGROUND: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study. METHODS: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape. RESULTS: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely. CONCLUSIONS: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations. IMPACT: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.