Neoadjuvant and Adjuvant Immune-based Approach for Renal Cell Carcinoma: Pros, Cons, and Future Directions.

CONTEXT: Immune-oncology strategies are revolutionising the perioperative treatment in several tumour types. The perioperative setting of renal cell carcinoma (RCC) is an evolving field, and the advent of immunotherapy is producing significant advances. OBJECTIVE: To critically review the potential pros and cons of adjuvant and neoadjuvant immune-based therapeutic strategies in RCC, and to provide insights for future research in this field. EVIDENCE ACQUISITION: We performed a collaborative narrative review of the existing literature. EVIDENCE SYNTHESIS: Adjuvant immunotherapy with pembrolizumab is a new standard of care for patients at a higher risk of recurrence after nephrectomy, demonstrating a disease-free survival and overall survival benefit in the phase 3 KEYNOTE-564 trial. Current data do not support neoadjuvant therapy use outside clinical trials. While both adjuvant and neoadjuvant immune-based approaches are driven by robust biological rationale, neoadjuvant immunotherapy may enable a stronger and more durable antitumour immune response. If neoadjuvant single-agent immune checkpoint inhibitors demonstrated limited activity on the primary tumour, immune-based combinations may show increased activity. Overtreatment and a risk of relevant toxicity for patients who are cured by surgery alone are common concerns for both neoadjuvant and adjuvant strategies. Biomarkers helping patient selection and treatment deintensification are lacking in RCC. No results from randomised trials comparing neoadjuvant or perioperative immune-based therapy with adjuvant immunotherapy are available. CONCLUSIONS: Adjuvant immunotherapy is a new standard of care in RCC. Both neoadjuvant and adjuvant immunotherapy strategies have potential advantages and disadvantages. Optimising perioperative treatment strategies is nuanced, with the role of neoadjuvant immune-based therapies yet to be defined. Given strong biological rationale for a pre/perioperative approach, there is a need for prospective clinical trials to determine clinical efficacy. Research investigating biomarkers aiding patient selection and treatment deintensification strategies is needed. PATIENT SUMMARY: Immunotherapy is transforming the treatment of kidney cancer. In this review, we looked at the studies investigating immunotherapy strategies before and/or after surgery for patients with kidney cancer to assess potential pros and cons. We concluded that both neoadjuvant and adjuvant immunotherapy strategies may have potential advantages and disadvantages. While immunotherapy administered after surgery is already a standard of care, immunotherapy before surgery should be better investigated in future studies. Future trials should also focus on the selection of patients in order to spare toxicity for patients who will be cured by surgery alone.

Abdominal Noncontrast Computed Tomography Scanning to Screen for Kidney Cancer and Other Abdominal Pathology Within Community-based Computed Tomography Screening for Lung Cancer: Results of the Yorkshire Kidney Screening Trial.

BACKGROUND AND OBJECTIVE: The Yorkshire Kidney Screening Trial (YKST) assessed the feasibility of adding abdominal noncontrast computed tomography (NCCT) to lung cancer screening to screen for kidney cancer and other abdominal pathology. METHODS: A prospective diagnostic study offered abdominal NCCT to 55-80-yr-old ever-smokers attending a UK randomised lung cancer screening trial (May 2021 to October 2022). The exclusion criteria were dementia, frailty, previous kidney/lung cancer, and computed tomography (CT) of the abdomen and thorax within previous 6 and 12 mo, respectively. Six-month follow-up was undertaken. KEY FINDINGS AND LIMITATIONS: A total of 4438 people attended lung screening, of whom 4309 (97%) were eligible for and 4019 (93%) accepted abdominal NCCT. Only 3.9% respondents regretted participating. The additional time to conduct the YKST processes was 13.3 min. Of the participants, 2586 (64%) had a normal abdominal NCCT, whilst 787 (20%) required an abdominal NCCT imaging review but no further action and 611 (15%) required further evaluation (investigations and/or clinic). Of the participants, 211 (5.3%) had a new serious finding, including 25 (0.62%) with a renal mass/complex cyst, of whom ten (0.25%) had histologically proven kidney cancer; ten (0.25%) with other cancers; and 60 (1.5%) with abdominal aortic aneurysms (AAAs). Twenty-five (0.62%) participants had treatment with curative intent. Of the participants, 1017 (25%) had nonserious findings, most commonly benign renal cysts (727 [18%]), whereas only 259 (6.4%) had nonserious findings requiring further tests. The number needed to screen to detect one serious abdominal finding was 18; it was 93 to detect one suspicious renal lesion and 402 to detect one histologically confirmed renal cancer. Limitations of the cohort were fixed age range and being prior lung cancer screening attendees. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this first prospective risk-stratified screening study of abdominal NCCT offered alongside CT thorax, uptake and participant satisfaction were high. The prevalence of serious findings, cancers, and AAAs, is in the range of established screening programmes such as bowel cancer. Longer-term outcomes and cost effectiveness should now be evaluated.

Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

Acceptability of adding a non-contrast abdominal CT scan to screen for kidney cancer and other abdominal pathology within a community-based CT screening programme for lung cancer: A qualitative study.

OBJECTIVES: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal malignancies to community-based CT screening for lung cancer within the Yorkshire Lung Screening Trial (YLST). This study explored the acceptability of the combined screening approach to participants and healthcare professionals (HCPs) involved in the trial. METHODS: We conducted semi-structured interviews with eight HCPs and 25 participants returning for the second round of scanning within YLST, 20 who had taken up the offer of the additional abdominal CT scan and five who had declined. Transcripts were analysed using thematic analysis, guided by the Theoretical Framework of Acceptability. RESULTS: Overall, combining the offer of a non-contrast abdominal CT scan alongside the low-dose thoracic CT was considered acceptable to participants, including those who had declined the abdominal scan. The offer of the additional scan made sense and fitted well within the process, and participants could see benefits in terms of efficiency, cost and convenience both for themselves as individuals and also more widely for the NHS. Almost all participants made an instant decision at the point of initial invitation based more on trust and emotions than the information provided. Despite this, there was a clear desire for more time to decide whether to accept the scan or not. HCPs also raised concerns about the burden on the study team and wider healthcare system arising from additional workload both within the screening process and downstream following findings on the abdominal CT scan. CONCLUSIONS: Adding a non-contrast abdominal CT scan to community-based CT screening for lung cancer is acceptable to both participants and healthcare professionals. Giving potential participants prior notice and having clear pathways for downstream management of findings will be important if it is to be offered more widely.

High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades.

BACKGROUND: Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades. METHODS: Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades. RESULTS: High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037). CONCLUSIONS: Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03741426 . Registered on 13 November 2018. RELEVANCE STATEMENT: The newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses.

Identifying the facilitators and barriers to implementation of renal tumour biopsy in the diagnostic pathway for small renal masses.

OBJECTIVES: To understand the facilitators and barriers to the implementation of renal tumour biopsy (RTB) in the diagnostic pathway for renal tumours in England. PATIENTS AND METHODS: Participants consisted of patients who had a renal tumour diagnosed and/or treated at one of five tertiary centres in England, healthcare professionals involved in the direct care of patients diagnosed with renal tumours, and clinical service managers and commissioners. The study employed a mixed-methods research methodology consisting of individual interviews and an on-line survey that explored the types of facilitators and barriers individuals perceived and experienced and the frequency in which these were reported. A public dissemination event took place following the completion of data collection; to facilitate discussion of potential solutions to implementing RTB. RESULTS: There were 50 participant interviews (23 patients, 22 clinicians, and five health service commissioners/operations managers). The patient on-line survey received 52 responses, and the clinician survey received 22 responses. Patients most frequently reported influences in choosing whether to undergo RTB pertained to wanting to know the diagnosis of their kidney mass (40%), the advice or information provided by healthcare professionals (40%), and not wishing to delay treatment (23%). Clinicians most frequently reported barriers to recommending RTB related to their uncertainty of diagnostic accuracy (56%), availability of appointments or hospital beds (52%), concerns of risk of bleeding (44%), risk of seeding (41%), and delays in meeting national cancer pathway targets (41%). The dissemination event was attended by 18 participants (seven patients and 11 clinicians). Suggestions to improve implementation included reducing variation and promotion of standardisation of practice by a consensus statement, increasing the evidence base (clinicians) and improved communication by developing better patient aids such as videos and diagrams (patients and clinicians). CONCLUSION: Implementation of RTB may be dependent on the quality of information provided, its format and perceived reliability of the information. Increased utilisation of RTB may be improved by development of a consensus statement on the role of biopsy, with patients expressing a preference for alternative information aids such as patient videos.

Fast and High-Resolution T2 Mapping Based on Echo Merging Plus k-t Undersampling with Reduced Refocusing Flip Angles (TEMPURA) as Methods for Human Renal MRI.

PURPOSE: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T2 mapping. METHODS: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors. RESULTS: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm2, resulting in improved visualization of the detailed anatomical structure. In vivo T2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59). CONCLUSION: TEMPURA provides fast and high-resolution renal T2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution.

Risk-stratified screening for the early detection of kidney cancer.

Earlier detection and screening for kidney cancer has been identified as a key research priority, however the low prevalence of the disease in unselected populations limits the cost-effectiveness of screening. Risk-stratified screening for kidney cancer may improve early detection by targeting high-risk individuals whilst limiting harms in low-risk individuals, potentially increasing the cost-effectiveness of screening. A number of models have been identified which estimate kidney cancer risk based on both phenotypic and genetic data, and while several of the former have been shown to identify individuals at high-risk of developing kidney cancer with reasonable accuracy, current evidence does not support including a genetic component. Combined screening for lung cancer and kidney cancer has been proposed, as the two malignancies share some common risk factors. A modelling study estimated that using lung cancer risk models (currently used for risk-stratified lung cancer screening) could capture 25% of patients with kidney cancer, which is only slightly lower than using the best performing kidney cancer-specific risk models based on phenotypic data (27%-33%). Additionally, risk-stratified screening for kidney cancer has been shown to be acceptable to the public. The following review summarises existing evidence regarding risk-stratified screening for kidney cancer, highlighting the risks and benefits, as well as exploring the management of potential harms and further research needs.

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.

Lithographically defined encoded magnetic heterostructures for the targeted screening of kidney cancer.

Renal cell carcinoma (RCC) is the 7th commonest cancer in the UK and the most lethal urological malignancy; 50% of all RCC patients will die from the condition. However, if identified early enough, small RCCs are usually cured by surgery or percutaneous procedures, with 95% 10 year survival. This study describes a newly developed non-invasive urine-based assay for the early detection of RCC. Our approach uses encoded magnetically controllable heterostructures as a substrate for immunoassays. These heterostructures have molecular recognition abilities and embedded patterned codes for a rapid identification of RCC biomarkers. The magnetic heterostructures developed for this study have a magnetic configuration designed for a remote multi axial control of their orientation by external magnetic fields, this control facilitates the code readout when the heterostructures are in liquid. Furthermore, the optical encoding of each set of heterostructures provides a multiplexed analyte capture platform, as different sets of heterostructures, specific to different biomarkers can be mixed together in a patient sample. Our results show a precise magnetic control of the heterostructures with an efficient code readout during liquid immunoassays. The use of functionalised magnetic heterostructures as a substrate for immunoassay is validated for urine specimen spiked with recombinant RCC biomarkers. Initial results of the newly proposed screening method on urine samples from RCC patients, and controls with no renal disorders are presented in this study. Comprehensive optimisation cycles are in progress to validate the robustness of this technology as a novel, non-invasive screening method for RCC.

Diagnosis, treatment, and survival from kidney cancer: real-world National Health Service England data between 2013 and 2019.

OBJECTIVES: To report the NHS Digital (NHSD) data for patients diagnosed with kidney cancer (KC) in England. We explore the incidence, route to diagnosis (RTD), treatment, and survival patterns from 2013 to 2019. MATERIALS AND METHODS: Data was extracted from the Cancer Data NHSD portal for International Classification of Diseases, 10th edition coded KC; this included Cancer Registry data, Hospital Episode Statistics, and cancer waiting times data. RESULTS: Registrations included 66 696 individuals with KC. Incidence of new KC diagnoses increased (8998 in 2013, to 10 232 in 2019), but the age-standardised rates were stable (18.7-19.4/100 000 population). Almost half of patients (30 340 [45.5%]) were aged 0-70 years and the cohort were most frequently diagnosed with Stage 1-2 KC (n = 26 297 [39.4%]). Most patients were diagnosed through non-urgent general practitioner referrals (n = 16 814 [30.4%]), followed by 2-week-wait (n = 15 472 [28.0%]) and emergency routes (n = 11 796 [21.3%]), with older patients (aged ≥70 years), Stage 4 KCs, and patients with non-specified renal cell carcinoma being significantly more likely to present through the emergency route (all P < 0.001). Invasive treatment (surgery or ablation), radiotherapy, or systemic anti-cancer therapy use varied with disease stage, patient factors, and treatment network (Cancer Alliance). Survival outcomes differed by Stage, histological subtype, and social deprivation class (P < 0.001). Age-standardised mortality rates did not change over the study duration, although immunotherapy usage is likely not captured in this study timeline. CONCLUSION: The NHSD resource provides useful insight about the incidence, diagnostic pathways, treatment, and survival of patients with KC in England and a useful benchmark for the upcoming commissioned National Kidney Cancer Audit. The RTD data may be limited by incidental diagnoses, which could confound the high proportion of 'emergency' diagnoses. Importantly, survival outcomes remained relatively unchanged.

Estimating the Effectiveness of Kidney Cancer Screening Within Lung Cancer Screening Programmes: A Validation in UK Biobank.

In the absence of population-based screening, addition of screening for kidney cancer to lung cancer screening could provide an efficient and low-resource means to improve early detection. In this study, we used the UK Biobank cohort (n = 442 865) to determine the performance of the Yorkshire Lung Cancer Screening Trial (YLST) eligibility criteria for selecting individuals for kidney cancer screening. We measured the performance of two models widely used to determine eligibility for lung cancer screening (PLCO[m2012] and the Liverpool-Lung-Project-v2) and the performance of the combined YLST criteria. We found that the lung cancer models have discrimination (area under the receiver operating curve) between 0.60 and 0.68 for kidney cancer. In the UK, one in four cases (25%) of kidney cancer cases is expected to occur in those eligible for lung cancer screening, and one case of kidney cancer detected for every 200 people invited to lung cancer screening. These results suggest that adding kidney cancer screening to lung cancer screening would be an effective strategy to improve early detection rates of kidney cancer. However, most kidney cancers would not be picked up by this approach. This analysis does not address other important considerations about kidney cancer screening, such as overdiagnosis. PATIENT SUMMARY: It has been proposed that adding-on kidney cancer screening to lung cancer screening (both carried out by a computed tomography scan of the chest/abdomen) would be an easy and low-cost way of detecting cases of kidney cancer earlier, when these can be treated more easily. Lung cancer screening is usually targeted at people who are at a high risk (eg, older smokers); therefore, here we look at whether the same group of people are also at a high risk of kidney cancer. Our analysis shows that one in four people later diagnosed with kidney cancer are also at a high risk of lung cancer; hence, a combined screening programme could detect up to a quarter of kidney cancers.

Patient experience of follow-up after surgery for kidney cancer: a focus group study.

OBJECTIVE: To explore patient experience of follow-up care after kidney cancer surgery and to develop recommendations for best practice. METHODS: We conducted two focus groups, including 14 participants with experience of kidney cancer follow-up after surgery, to elicit patient views on current follow-up care. Thematic analysis was used to identify unifying themes to describe the patient experience of follow-up, and the results were then used to develop a set of recommendations for best practice. RESULTS: We identified six themes (feelings of abandonment; uncertainty about the plan; anxiety about appointments; variation in care; a need for information; and a need for emotional support) that described current patient experience and areas in which current care could be improved. In particular, while most of the participants felt that their physical needs had been met, many had struggled with unmet emotional needs and a lack of information and resources. This was especially noted in the period immediately following surgery, when feelings of abandonment were common, and around follow-up scans and routine appointments, which were a source of anxiety. Our participants also described concerns about the lack of consistency between different hospitals and centres around the United Kingdom, with differences in the content and quality of follow-up care. Based on the results, we developed a list of recommendations to address some of the challenges described through relatively minor changes to the care pathway. CONCLUSIONS: We identified gaps and variability in current follow-up care after kidney cancer surgery, and have developed a set of recommendations that, if implemented, would improve the follow-up care experience for these patients.

Public Preferences for Determining Eligibility for Screening in Risk-Stratified Cancer Screening Programs: A Discrete Choice Experiment.

BACKGROUND: Risk stratification has been proposed to improve the efficiency of population-level cancer screening. We aimed to describe and quantify the relative importance of different attributes of potential screening programs among the public, focusing on stratifying eligibility. METHODS: We conducted a discrete choice experiment in which respondents selected between 2 hypothetical screening programs in a series of 9 questions. We presented the risk factors used to determine eligibility (age, sex, or lifestyle or genetic risk scores) and anticipated outcomes based on eligibility criteria with different sensitivity and specificity levels. We performed conditional logit regression models and used the results to estimate preferences for different approaches. We also analyzed free-text comments on respondents' views on the programs. RESULTS: A total of 1,172 respondents completed the survey. Sensitivity was the most important attribute (7 and 11 times more important than specificity and risk factors, respectively). Eligibility criteria based on age and sex or genetics were preferred over age alone and lifestyle risk scores. Phenotypic and polygenic risk prediction models would be more acceptable than screening everyone aged 55 to 70 y if they had high discrimination (area under the receiver-operating characteristic curve ≥0.75 and 0.80, respectively). LIMITATIONS: Although our sample was representative with respect to age, sex, and ethnicity, it may not be representative of the UK population regarding other important characteristics. Also, some respondents may have not understood all the information provided to inform decision making. CONCLUSIONS: The public prioritized lives saved from cancer over reductions in numbers screened or experiencing unnecessary follow-up. Incorporating personal-level risk factors into screening eligibility criteria is acceptable to the public if it increases sensitivity; therefore, maximizing sensitivity in model development and communication could increase uptake. HIGHLIGHTS: The public prioritized lives saved when considering changing from age-based eligibility criteria to risk-stratified cancer screening over reductions in numbers of people being screened or experiencing unnecessary follow-up.The risk stratification strategy used to do this was the least important component, although age plus sex or genetics were relatively preferable to using age alone and lifestyle risk scores.Communication strategies that emphasize improvements in the numbers of cancers detected or not missed across the population are more likely to be salient than reductions in unnecessary investigations or follow-up among some groups.Future research should focus on developing implementation strategies that maximize gains in sensitivity within the context of resource constraints and how to present attributes relating to specificity to facilitate understanding and informed decision making.

Diagnostic Performance of Biomarkers for Bladder Cancer Detection Suitable for Community and Primary Care Settings: A Systematic Review and Meta-Analysis.

Evidence on the use of biomarkers to detect bladder cancer in the general population is scarce. This study aimed to systematically review evidence on the diagnostic performance of biomarkers which might be suitable for use in community and primary care settings [PROSPERO Registration: CRD42021258754]. Database searches on MEDLINE and EMBASE from January 2000 to May 2022 resulted in 4914 unique citations, 44 of which met inclusion criteria. Included studies reported on 112 biomarkers and combinations. Heterogeneity of designs, populations and outcomes allowed for the meta-analysis of three biomarkers identified in at least five studies (NMP-22, UroVysion, uCyt+). These three biomarkers showed similar discriminative ability (adjusted AUC estimates ranging from 0.650 to 0.707), although for NMP-22 and UroVysion there was significant unexplained heterogeneity between included studies. Narrative synthesis revealed the potential of these biomarkers for use in the general population based on their reported clinical utility, including effects on clinicians, patients, and the healthcare system. Finally, we identified some promising novel biomarkers and biomarker combinations (N < 3 studies for each biomarker/combination) with negative predictive values of ≥90%. These biomarkers have potential for use as a triage tool in community and primary care settings for reducing unnecessary specialist referrals. Despite promising emerging evidence, further validation studies in the general population are required at different stages within the diagnostic pathway.