Risk factors for secondary bladder cancer following prostate cancer radiotherapy.

This review investigates the complex landscape of secondary bladder cancer (SBC) after radiotherapy for prostate cancer (PCa). External beam radiotherapy (EBRT) poses an increased risk for SBC, while brachytherapy seems to be associated with smaller increased risks for SBC due to its targeted radiation delivery, sparing the surrounding bladder tissue. Secondary cancers in the bladder are the most frequently diagnosed secondary cancers in the PCa patient population treated with radiotherapy. Patient-related factors are pivotal, with age emerging as a dual-edged factor. While advanced age is a recognized risk for bladder cancer, younger PCa patients exhibit higher susceptibility to radiation-induced cancers. Smoking, a well-established bladder cancer risk factor, increases this vulnerability. Studies highlight the synergistic effect of smoking and radiation exposure, amplifying the likelihood of genetic mutations and SBC. The latency period of SBC, which spans years to decades, remains a critical aspect. There is a strong dose-response relationship between radiation exposure and SBC risk, with higher doses consistently being associated with a higher SBC risk. While specific models for therapeutic radiation-induced SBC are lacking, insights from related studies, like the Atomic Bomb survivor research, emphasize the bladder's sensitivity to radiation-induced cancer. Chemotherapy in combination with radiotherapy, although infrequently used in PCa, emerges as a potential risk for bladder cancer. Bladder cancer's complex epidemiology, encompassing risk factors, treatment modalities, and cancer types, provides a comprehensive backdrop. As research refines understanding, we hope that this review contributes to guide clinicians, inform patient care, and shape preventive strategies on SBC.

The impact of baseline health factors on second primary cancer risk after radiotherapy for prostate cancer.

PURPOSE: In evaluating second primary cancers (SPCs) following External Beam Radiotherapy (EBRT), the role of lifestyle factors is frequently not considered due to data limitations. We investigated the association between smoking, comorbidities, and SPC risks within EBRT-treated patients for localized prostate cancer (PCa). PATIENTS & METHODS: The study included 1,883 PCa survivors aged 50-79, treated between 2006 and 2013, with intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). Clinical data were combined with SPC and survival data from the Netherlands Cancer Registry with a 12-month latency period. Standardized Incidence Ratios (SIRs) were calculated comparing the EBRT cohort with the general Dutch population. To explore the effect of patient and treatment characteristics on SPCs we conducted a Cox regression analysis. Lastly, we estimated cumulative incidences of developing solid SPC, pelvis SPC, and non-pelvis SPC using a competing risk analysis. RESULTS: Significantly increased SIRs were observed for all SPC (SIR = 1.21, 95% confidence interval [CI]: 1.08-1.34), pelvis SPC (SIR = 1.46, 95% CI: 1.18-1.78), and non-pelvis SPC (SIR = 1.18, 95% CI [1.04-1.34]). Smoking status was significantly associated with pelvic and non-pelvic SPCs. Charlson comorbidity index (CCI) ≥ 1 (Hazard Ratio [HR] = 1.45, 95% CI: 1.10-1.91), cardiovascular disease (HR = 1.41, 95% CI: 1.05-1.88), and chronic obstructive pulmonary disease (COPD) (HR = 1.91, 95% CI: 1.30-2.79) were significantly associated with non-pelvis SPC. The proportion of active smoking numbers in the cohort was similar to the general population. INTERPRETATION: We conclude that the presence of comorbidities in the EBRT population might be a relevant factor in observed excess non-pelvis SPC risk, but not for excess pelvis SPC risk.

Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit.

OBJECTIVE: To evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. METHODS: All Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20-50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry. Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). RESULTS: A total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80-0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85-1.07]). CONCLUSIONS: In a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

The impact of the COVID-19 pandemic on renal cancer care.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on renal cell carcinoma (RCC) care in the Netherlands. METHODS: Newly diagnosed RCCs between 2018 and 2021 were selected from the Netherlands Cancer Registry; 2020-2021 was defined as COVID period and 2018-2019 as reference period. Numbers of RCCs were evaluated using 3-week-moving averages, overall and by disease stage and age. Changes in treatment were evaluated with logistic regression analyses. To evaluate possible delays in care, time to start of treatment was assessed. The cumulative number of metastatic RCC (mRCC) over time was assessed to evaluate stage shift. RESULTS: During the 1st COVID wave (weeks 9-22, 2020), the number of new RCC diagnoses decreased with 15%. Numbers restored partially in 2020, but remained 10% lower compared to 2018/2019. The decline was mostly due to a drop in T1a/T1b RCCs and in age > 70 years. 2021 showed similar numbers of new RCC diagnoses compared to 2018/2019 without an increase due to previously missed RCCs. Treatment-related changes during the 1st COVID wave were limited and temporarily; less surgery in T1a RCCs in favor of more active surveillance, and in mRCC targeted therapy was preferred over immunotherapy. Time to start of firstline treatment was not prolonged during the 1st COVID wave. No increase in mRCC was found until the end of 2021. CONCLUSIONS: The COVID-19 pandemic resulted in fewer RCC diagnoses, especially T1a/T1b tumors. Treatment-related changes appeared to be limited, temporarily and in accordance with the adapted guidelines. The diagnostic delay could lead to more advanced RCCs in later years but there are no indications for this yet.

Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.

Background and objective: The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

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.

Treatment Patterns and Use of Immune Checkpoint Inhibitors Among Patients with Metastatic Bladder Cancer in a Dutch Nationwide Cohort.

Since 2017, two immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of metastatic urothelial carcinoma in Europe: pembrolizumab as second-line therapy and avelumab as maintenance therapy. Our aim was to describe the use of ICIs as first and later lines of treatment in patients with metastatic bladder cancer (mBC) in the Netherlands. We identified all patients diagnosed with primary mBC between 2018 and 2021 in the Netherlands from the Netherlands Cancer Registry (NCR). NCR data were supplemented with data from the Dutch nationwide Prospective Bladder Cancer Infrastructure (ProBCI) collected from medical files, with follow-up until death or end of data collection on January 1, 2023. A total of 1525 patients were diagnosed with primary mBC between 2018 and 2021 in the Netherlands. Of these, 34.7% received at least one line of systemic treatment with chemotherapy or ICI. After first-line platinum-based chemotherapy, 34.1% received second-line ICI and 3.9% received maintenance ICI. Among patients who completed or discontinued first-line cisplatin- or carboplatin-based chemotherapy after approval of maintenance ICI in the Netherlands, 40.7% and 19.7% received second-line ICI, and 9.3% and 14.1% received maintenance ICI, respectively. ICI use for mBC treatment has not increased considerably since their introduction in 2017. Future research should assess whether the introduction of maintenance avelumab (available since April 2021 in the Netherlands) has led to increases in the proportion of patients with mBC patients receiving systemic treatment and the proportion receiving ICI. Patient summary: We assessed the rate of immunotherapy use for patients with metastatic bladder cancer in the Netherlands. Since its introduction, immunotherapy has been used in a minority of patients, mostly as second-line treatment after platinum-based chemotherapy.

Health-related Quality of Life During the First 4 Years After Non-Muscle-invasive Bladder Cancer Diagnosis: Results of a Large Multicentre Prospective Cohort.

BACKGROUND: The health-related quality of life (HRQoL) of patients with non-muscle-invasive bladder cancer (NMIBC) may be impaired due to the chronic and burdensome disease course, but longitudinal data are limited. OBJECTIVE: To evaluate HRQoL outcomes during the first 4 yr after NMIBC diagnosis, and to compare HRQoL across patient characteristics and with a normative population. DESIGN, SETTING, AND PARTICIPANTS: Patients with NMIBC (n = 1019) were included from the multicentre prospective cohort UroLife. Data were collected at 6 wk (baseline), and 3, 15, and 51 mo after diagnosis. Longitudinal reference data were obtained from an age- and sex-matched normative population (n = 490). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer- and NMIBC-specific HRQoL outcomes (range 0-100) were evaluated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-NMIBC24 questionnaires, respectively. Linear mixed modelling was used to analyse within-group changes and between-group differences. RESULTS AND LIMITATIONS: The majority of HRQoL outcomes remained stable over time. Observed changes were only of small clinical relevance. Improvements were noted in insomnia, social functioning, and three NMIBC-specific symptoms, while minor deteriorations in appetite and diarrhoea lasted until 51 mo. HRQoL in some domains was worse for high-grade NMIBC, high European Association of Urology (EAU) risk group, initial Bacillus Calmette-Guérin (BCG) treatment, being female, and being younger (<65 yr); yet differences were few, small, and temporary. No differences were observed across recurrence status. Compared with a normative population, clinically relevant worse scores were observed for six of 15 outcomes, which mostly recovered at 51 mo, except for minor symptoms of appetite loss and diarrhoea. CONCLUSIONS: No remarkable changes in HRQoL were observed during the first 4 yr after NMIBC diagnosis. Grade, EAU risk group, initial treatment, recurrence, sex, and age did not importantly affect HRQoL. HRQoL was largely comparable with that of the general population, especially after 4 yr. PATIENT SUMMARY: Quality of life is not largely affected during the first 4 yr after non-muscle-invasive bladder cancer diagnosis.

Body mass index and waist circumference in relation to risk of recurrence and progression after non-muscle invasive bladder cancer.

BACKGROUND: Obesity may be associated with increased risk of recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), but evidence is limited and inconsistent. We examined the associations of body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) with risk of recurrence and progression among patients with NMIBC. METHODS: This prospective study included 1029 patients diagnosed with primary NMIBC between 2014 and 2017. Patients reported weight 2 years before diagnosis at baseline, and weight, waist and hip circumference at 3 months postdiagnosis. Associations were quantified using Cox proportional hazard analyses, adjusted for clinical and lifestyle characteristics. RESULTS: More than half of patients were overweight (49%) or obese (19%) after diagnosis. During a median follow-up time of 3.6 years, 371 patients developed ≥1 recurrence and 53 experienced progression. No associations with recurrence were observed for BMI (HRper 5 kg/m2 0.94; 95% CI 0.82, 1.07), waist circumference (HRper 10 cm 0.95; 95% CI 0.86, 1.05), or WHR (HRper 0.1 unit 0.90; 95% CI 0.76, 1.06). In contrast, higher BMI was associated with a 40% increased risk of progression, with only the 2-year prediagnosis association reaching statistical significance (HRper 5 kg/m2 1.42; 95% CI 1.09, 1.84). No associations for pre-to-postdiagnosis weight change were found. CONCLUSION: General and abdominal obesity were not associated with recurrence risk among patients with NMIBC, but might be associated with increased risk of progression. Studies with sufficient sample size to stratify by tumor stage and treatment are needed to better understand whether and how obesity could influence prognosis.

Estimating Treatment Effect of Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer Using Bayesian Networks.

PURPOSE: While adjuvant therapy with capecitabine and oxaliplatin (CAPOX) has been proven to be effective in stage III colon cancer, capecitabine monotherapy (CapMono) might be equally effective in elderly patients. Unfortunately, the elderly are under-represented in clinical trials and patients included may not be representative of the routine care population. Observational data might alleviate this problem but is sensitive to biases such as confounding by indication. Here, we build causal models using Bayesian Networks (BNs), identify confounders, and estimate the effect of adjuvant chemotherapy using survival analyses. METHODS: Patients 70 years and older were selected from the Netherlands Cancer Registry (N = 982). We developed several BNs using constraint-based, score-based, and hybrid algorithms while precluding noncausal relations. In addition, we created models using a limited set of recurrence and survival nodes. Potential confounders were identified through the resulting graphs. Several Cox models were fitted correcting for confounders and for propensity scores. RESULTS: When comparing adjuvant treatment with surgery only, pathological lymph node classification, physical status, and age were identified as potential confounders. Adjuvant treatment was significantly associated with survival in all Cox models, with hazard ratios between 0.39 and 0.45; CIs overlapped. BNs investigating CAPOX versus CapMono did not find any association between the treatment choice and survival and thus no confounders. Analyses using Cox models did not identify significant association either. CONCLUSION: We were able to successfully leverage BN structure learning algorithms in conjunction with clinical knowledge to create causal models. While confounders differed depending on the algorithm and included nodes, results were not contradictory. We found a strong effect of adjuvant therapy on survival in our cohort. Additional oxaliplatin did not have a marked effect and should be avoided in elderly patients.

The PRO-RCC study: a long-term PROspective Renal Cell Carcinoma cohort in the Netherlands, providing an infrastructure for 'Trial within Cohorts' study designs.

BACKGROUND: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs). METHODS: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician. TRIAL REGISTRATION: Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620). DISCUSSION: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Changes to Primary End Points in Randomized Clinical Trials on Immune Checkpoint Inhibitors in Urothelial, Renal Cell, and Lung Cancers: A Systematic Review.

This systematic review investigates how often and to what extent primary end points are changed and reported in immune checkpoint inhibitor clinical trials.

A comparison of machine learning models for predicting urinary incontinence in men with localized prostate cancer.

Introduction: Urinary incontinence (UI) is a common side effect of prostate cancer treatment, but in clinical practice, it is difficult to predict. Machine learning (ML) models have shown promising results in predicting outcomes, yet the lack of transparency in complex models known as "black-box" has made clinicians wary of relying on them in sensitive decisions. Therefore, finding a balance between accuracy and explainability is crucial for the implementation of ML models. The aim of this study was to employ three different ML classifiers to predict the probability of experiencing UI in men with localized prostate cancer 1-year and 2-year after treatment and compare their accuracy and explainability. Methods: We used the ProZIB dataset from the Netherlands Comprehensive Cancer Organization (Integraal Kankercentrum Nederland; IKNL) which contained clinical, demographic, and PROM data of 964 patients from 65 Dutch hospitals. Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM) algorithms were applied to predict (in)continence after prostate cancer treatment. Results: All models have been externally validated according to the TRIPOD Type 3 guidelines and their performance was assessed by accuracy, sensitivity, specificity, and AUC. While all three models demonstrated similar performance, LR showed slightly better accuracy than RF and SVM in predicting the risk of UI one year after prostate cancer treatment, achieving an accuracy of 0.75, a sensitivity of 0.82, and an AUC of 0.79. All models for the 2-year outcome performed poorly in the validation set, with an accuracy of 0.6 for LR, 0.65 for RF, and 0.54 for SVM. Conclusion: The outcomes of our study demonstrate the promise of using non-black box models, such as LR, to assist clinicians in recognizing high-risk patients and making informed treatment choices. The coefficients of the LR model show the importance of each feature in predicting results, and the generated nomogram provides an accessible illustration of how each feature impacts the predicted outcome. Additionally, the model's simplicity and interpretability make it a more appropriate option in scenarios where comprehending the model's predictions is essential.

Staging fluorodeoxyglucose positron emission tomography/computed tomography for muscle-invasive bladder cancer: a nationwide population-based study.

OBJECTIVE: To provide insight into the use and staging information on lymph-node involvement added by fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with muscle-invasive bladder cancer (MIBC), based on a nationwide population-based cohort study. PATIENTS AND METHODS: We analysed a nationwide cohort of patients with MIBC without signs of distant metastases, newly diagnosed in the Netherlands between November 2017 and October 2019. From this cohort, we selected patients who underwent pre-treatment staging with CT only or CT and FDG-PET/CT. The distribution of patients, disease characteristics, imaging findings, nodal status (clinical nodal stage cN0 vs cN+) and treatment were described for each imaging modality group (CT only vs CT and FDG-PET/CT). RESULTS: We identified 2731 patients with MIBC: 1888 (69.1%) underwent CT only; 606 (22.2%) underwent CT and FDG-PET/CT, 237 (8.6%) underwent no CT. Of the patients who underwent CT only, 200/1888 (10.6%) were staged as cN+, vs 217/606 (35.8%) who underwent CT and FDG-PET/CT. Stratified analysis showed that this difference was found in patients with clinical tumour stage (cT)2 as well as cT3/4 MIBC. Of patients who underwent both imaging modalities and were staged with CT as cN0, 109/498 (21.9%) were upstaged to cN+ based on FDG-PET/CT. Radical cystectomy (RC) was the most common treatment within both imaging groups. Preoperative chemotherapy was more frequently applied in cN+ disease and in FDG-PET/CT-staged patients. Concordance of pathological N stage after upfront RC was higher among patients staged as cN+ with CT and FDG-PET/CT (50.0% pN+) than those staged as cN+ with only CT (39.3%). CONCLUSION: Patients with MIBC who underwent pre-treatment staging with FDG-PET/CT were more often staged as lymph node positive, regardless of cT stage. In patients with MIBC who underwent CT and FDG-PET/CT, FDG-PET/CT led to clinical nodal upstaging in approximately one-fifth. Additional imaging findings may influence subsequent treatment strategies.

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.

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review.

BACKGROUND: To summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa). METHODS: We searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle-Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed. RESULTS: Nineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported. CONCLUSIONS: Evidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

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.

Advances in radiotherapy and its impact on second primary cancer risk: A multi-center cohort study in prostate cancer patients.

BACKGROUND: Modelling studies suggest that advanced intensity-modulated radiotherapy may increase second primary cancer (SPC) risks, due to increased radiation exposure of tissues located outside the treatment fields. In the current study we investigated the association between SPC risks and characteristics of applied external beam radiotherapy (EBRT) protocols for localized prostate cancer (PCa). METHODS: We collected EBRT protocol characteristics (2000-2016) from five Dutch RT institutes for the 3D-CRT and advanced EBRT era (N = 7908). From the Netherlands Cancer Registry we obtained patient/tumour characteristics, SPC data, and survival information. Standardized incidence ratios (SIR) were calculated for pelvis and non-pelvis SPC. Nationwide SIRs were calculated as a reference, using calendar period as a proxy to label 3D-CRT/advanced EBRT. RESULTS: From 2000-2006, 3D-CRT with 68-78 Gy in 2 Gy fractions, delivered with 10-23 MV and weekly portal imaging was the most dominant protocol. By the year 2010 all institutes routinely used advanced EBRT (IMRT, VMAT, tomotherapy), mainly delivering 78 Gy in 2 Gy fractions, using various kV/MV imaging protocols. Sixteen percent (N = 1268) developed ≥ 1 SPC. SIRs for pelvis and non-pelvis SPC (all institutes, advanced EBRT vs 3D-CRT) were 1.17 (1.00-1.36) vs 1.39 (1.21-1.59), and 1.01 (0.89-1.07) vs 1.03 (0.94-1.13), respectively. Nationwide non-pelvis SIR was 1.07 (1.01-1.13) vs 1.02 (0.98-1.07). Other RT protocol characteristics did not correlate with SPC endpoints. CONCLUSION: None of the studied RT characteristics of advanced EBRT was associated with increased out-of-field SPC risks. With constantly evolving EBRT protocols, evaluation of associated SPC risks remains important.