Bladder-sparing Therapy for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: International Bladder Cancer Group Recommendations for Optimal Sequencing and Patient Selection.

BACKGROUND AND OBJECTIVE: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. METHODS: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC.

Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

PURPOSE: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. METHODS: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). RESULTS: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. CONCLUSION: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

International Bladder Cancer Group Consensus Statement on Clinical Trial Design for Patients with Bacillus Calmette-Guérin-exposed High-risk Non-muscle-invasive Bladder Cancer.

CONTEXT: A large proportion of patients with non-muscle-invasive bladder cancer (NMIBC) fall in the gap between bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive disease. As multiple therapeutic agents move into this gray area, there is a critical need to define the disease state and establish recommendations for optimal trial design. OBJECTIVE: To develop a consensus on optimal trial design for patients with BCG-exposed NMIBC, defined as high-grade recurrence after BCG treatment that does not meet the criteria for BCG-unresponsive disease. EVIDENCE ACQUISITION: We conducted a literature review using the Cochrane Library, Medline, and Embase and a review of clinical trials in ClinicalTrials.gov as a basis to generate consensus recommendations for clinical trial design in BCG-exposed NMIBC. EVIDENCE SYNTHESIS: BCG-exposed NMIBC encompasses BCG resistance (presence of high-grade Ta or carcinoma in situ [CIS] at 3-mo evaluation after induction BCG) and delayed relapse. Randomized controlled trials are required to compare experimental therapies to a control arm receiving additional BCG, although ongoing BCG shortages may impact our ability to follow an optimal trial design. A placebo should be used in combination with BCG if the treatment arm includes BCG plus a study drug. Trials will either need to separate patients with and without CIS into two cohorts, or stratify by the presence of CIS at the time of randomization. If two cohorts are used, the primary endpoint for CIS patients should be complete response within a predetermined time. The primary endpoint in a cohort with Ta/T1 only, or if a single combined cohort is used, should be the duration of event-free survival. Suggested efficacy thresholds and corresponding sample sizes are provided. CONCLUSIONS: The International Bladder Cancer Group has developed recommendations regarding definitions, endpoints, and clinical trial design for BCG-exposed NMIBC to encourage uniformity among studies in this disease state. PATIENT SUMMARY: Our consensus provides a precise definition of the disease state for bladder cancer not invading the bladder muscle and exposed to bacillus Calmette-Guérin (BCG) treatment. Clear guidance for conducting optimal clinical trials in this disease setting was established and we believe that this will promote further progress in this field.

Metastatic progression following multimodal therapy for unfavorable-risk prostate cancer.

INTRODUCTION: Identifying the optimal management of unfavorable-risk (Prostate Cancer Risk Stratification [ProCaRS] high intermediate-, high-, and very high-risk categories) non-metastatic prostate cancer is an important public health concern given the large burden of this disease. We compared the rate of metastatic progression-free survival among men diagnosed with unfavorable-risk non-metastatic prostate cancer who were initially treated with radiation therapy or radical prostatectomy. METHODS: Information was obtained from medical records at two academic centers in Canada from 333 men diagnosed with unfavorable-risk non-metastatic prostate cancer between 2007 and 2012. Median followup was 90.4 months. Men were eligible for the study if they received either primary radiation therapy (n=164) or radical prostatectomy (n=169), in addition to various adjuvant and salvage therapies when deemed clinically appropriate. Patients were matched on prognostic covariates using two matching techniques. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HR) and confidence intervals (CI) for metastatic progression-free survival between groups. RESULTS: After matching, treatment groups were balanced on prognostic variables except for percent core positivity. Hazard ratios from all Cox proportional hazards models (i.e., before and after matching, and with and without multivariable adjustment) showed no difference in the rate of metastatic progression-free survival between groups (adjusted unmatched HR 1.16, 95% CI 0.63, 2.13, p=0.64). CONCLUSIONS: Metastatic progression-free survival did not differ between men diagnosed with unfavorable risk non-metastatic prostate cancer who were treated with either radiation therapy or radical prostatectomy.

Incidence of kidney stones in pregnancy and associations with adverse obstetrical outcomes: a systematic review and meta-analysis of 4.7 million pregnancies.

BACKGROUND: Renal stones are a common cause of non-obstetrical abdominal pain in pregnant women. Though the management of renal stones in pregnancy is challenging, it remains unclear how the incidence of kidney stones may affect the course of pregnancy and delivery. OBJECTIVE: To determine the incidence of renal stones in pregnancy and its impact on adverse obstetrical outcomes. DATA SOURCES: We conducted a systematic literature search of three databases: Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL Plus. After the selection of articles, an additional hand-search of their citations was completed to maximize sensitivity. Databases were examined from the last four decades (19 March 1970) up to the search date (19 March 2020). STUDY ELIGIBILITY CRITERIA: Articles were excluded if they were not relevant to kidney stones or did not report outcomes related to pregnancy. Case reports, animal studies, and cadaveric studies were excluded. Conference abstracts, gray literature, and unpublished data were not eligible. STUDY APPRAISAL AND SYNTHESIS METHODS: All screening, extraction, and synthesis were completed in duplicate with two independent reviewers. All outcomes reported in the included studies were systematically evaluated to determine suitability for meta-analysis. Random-effects models and sensitivity analyses were used to account for interstudy variation. Renal stone incidence rates were pooled to generate summary proportions. Risk of bias assessment was completed using the Risk of Bias Assessment tool for Non-randomized Studies. RESULTS: Twenty-one studies were included through systematic review and approximately 4.7 million pregnancies across nine studies were included for meta-analysis. There are three major findings of this review regarding renal stone incidence in pregnancy and maternal, child, and birth-related outcomes associated with renal stones. First, we found pooled incidence of renal stones was 0.49%, or one case for every 204 pregnancies. Second, renal stones during pregnancy were significantly associated with the development of preeclampsia and urinary tract infection, as well as increased likelihood of low birth weight, preterm labor, and C-section deliveries. However, renal stones were not significantly associated with premature rupture of membranes or infant mortality. Third, there were limited obstetrical complications reported with either medical or surgical therapies although comparative outcomes were not provided in the majority of studies, precluding formal meta-analysis. CONCLUSIONS: Although renal stones in pregnancy are relatively rare, there may be an associated risk of serious adverse obstetrical outcomes. However, further research is required to understand whether these obstetrical outcomes are causal or due to other confounders. Interdisciplinary care and pregnancy-specific counseling should be advised for pregnant women with kidney stones.

The association between renal stones and fasting: A systematic review.

INTRODUCTION: Fasting is a common cultural practice worldwide for both religious and dietary reasons. However, there is concern that fasting may be a risk factor for the development of renal stones. To date, there has not been a systematic assessment of the literature regarding the association between renal stones and fasting. METHODS: We conducted a systematic review following PRISMA guidelines of three databases: Medline-OVID, EMBASE, and CINAHL. All screening and extraction was completed in parallel with two independent reviewers. RESULTS: Of the 1501 database citations, a total of 10 observational studies with a total of 9906 participants were included. Nine of the studies were conducted in the context of Islamic fasting during Ramadan, with the majority (7/9) finding that renal colic incidence was unaffected by the month of fasting. In contrast, two studies noted an increased incidence among fasting populations. Two other studies noted that urine metabolites and density were altered with fasting but did not translate into clinical outcomes. CONCLUSIONS: Based on the available evidence, it is unlikely that fasting significantly increases the risk of renal stones. Physicians should counsel higher-risk patients on safe fasting practices.

Implementing and evaluating the efficacy of an acute care urology model of care in a large community hospital.

INTRODUCTION: We implemented an acute care urology (ACU) model at a large Canadian community hospital to determine the impacts on safe and timely care of patients with renal colic. The model includes a dedicated ACU surgeon, a clinic for emergency department (ED) referrals, and additional daytime operating room (OR) blocks for urgent cases. METHODS: We conducted a chart review of 579 patients presenting to the ED with renal colic. Data was collected before (pre-intervention, September to November 2015) and after (post-intervention, September to November 2016) implementation of the ACU model. Secondary methods of evaluation included surveying patients and 20 ED physicians to capture subjective feedback. RESULTS: Of the 579 patients presenting with renal colic,194 were diagnosed with an obstructing kidney stone and were referred to urology for outpatient care. The ED-to-clinic time was significantly lower for those in the ACU model (p<0.001). Furthermore, the ACU clinic resulted in significantly more patients being referred for outpatient care (p=0.0004). There was also higher likelihood that patients would successfully obtain an appointment post-referral (p=0.0242). The number of after-hours and weekend surgeries decreased significantly after dedicated ACU daytime OR blocks were added in September 2015 (p<0.0001). All surveyed patients rated the care as either "excellent" or "very good," and all physicians believed the ACU model has improved patient care. CONCLUSIONS: The ACU model has shown benefit in ensuring timely followup for ED patients, reducing use of after-hour OR time, and improving patient and physician satisfaction.

Risk-adapted management of low-grade bladder tumours: recommendations from the International Bladder Cancer Group (IBCG).

OBJECTIVE: To provide a contemporary update and recommendations for the diagnosis and management of low-grade non-muscle-invasive bladder cancer (BCa) based on current literature and expert consensus of the International Bladder Cancer Group. METHODS: We reviewed published trials, guidelines, meta-analyses and reviews (up to March 2019) and provide recommendations on baseline evaluations, treatment, endpoints, study design and surveillance protocols. RESULTS: Low-grade Ta BCa poses minimal risk to patients in terms of progression and disease-specific survival. Thus, to minimize patient morbidity, this entity should be managed appropriately. After initial diagnosis of low-grade Ta tumour, subsequent stable, low-grade-appearing recurrences can be managed conservatively with office cystoscopy and fulguration or even followed using an active surveillance protocol. Intravesical therapy other than single-dose peri-operative chemotherapy instillation should be used judiciously, and only after assigning appropriate risk points. Routine use of urinary cytology - other than at initial risk stratification, or for patients on active surveillance without therapy - is not recommended; and surveillance cystoscopy may be discontinued after 5 years. Clinical studies in this group of patients should focus on recurrence rates, and time to recurrence, rather than progression events. CONCLUSIONS: The International Bladder Cancer Group has developed formal recommendations regarding the diagnosis, treatment and surveillance of low-grade non-muscle-invasive BCa to minimize morbidity and encourage uniformity among studies in this disease.

Transperineal Prostate Biopsies Using Local Anesthesia: Experience with 1,287 Patients. Prostate Cancer Detection Rate, Complications and Patient Tolerability.

PURPOSE: We report our experience with transperineal prostate biopsy as well as the cancer diagnosis rate, complications and patient tolerability in 1,287 consecutive patients at risk for prostate cancer. MATERIALS AND METHODS: Beginning in October 2016 transperineal prostate biopsy was performed using local anesthesia in all patients undergoing prostate biopsy. Data on prebiopsy characteristics and results, including the cancer detection rate, complications and patient tolerability scores, were collected retrospectively from patient records. RESULTS: The cancer detection rate of transperineal prostate biopsy was 49.8% (641 of 1,287 patients). Clinically significant prostate cancer was detected in 385 patients and 62 (9.7%) had exclusively anterior zone pathology findings. Urinary retention developed in 20 patients (1.6%) following transperineal prostate biopsy, requiring temporary catheterization. In 4 patients (0.3%) lower urinary tract symptoms were suggestive of infection but only 1 had a positive urine culture. The only hospital admission was for a patient with persistent hypotension after biopsy. Patients tolerated transperineal prostate biopsy reasonably well and generally reported only mild levels of discomfort on a pain visual analogue scale. Infiltration of the anesthesia was rated more painful than the biopsy. CONCLUSIONS: Transperineal prostate biopsy with the patient under local anesthesia is a feasible alternative to transrectal biopsy in the detection of prostate cancer. Transperineal prostate biopsy has an acceptable cancer detection rate with additional detection of anterior zone cancers. It is a safer alternative in patients due to the low risk of complications, in particular urosepsis, and it is well tolerated. Transperineal prostate biopsy using local anesthesia could be considered a standard modality for the initial diagnosis of prostate cancer.

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation.

BACKGROUND: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described. METHODS: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis. RESULTS: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis. CONCLUSIONS: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

Estimating basal tear osmolarity in normal and dry eye subjects.

PURPOSE: Tear osmolarity (tOsm) is used as a measure of severity in dry eye disease (DED) and has been proposed as an index of body hydration. In DED the level of tear hyperosmolarity is compared with that of a control population. It is proposed here that a better index of body hydration and a more valid reference point in DED can be acquired by measuring the tOsm after a period of evaporative suppression. METHOD: 8 normal and DED subjects were recruited, their tOsm measured in uncontrolled environmental 'clinic conditions'. Then in experiment 1 they entered a controlled environment chamber and had tOsm measured after 45 minutes of eye closure and then, with the eyes open, at 15 minute intervals for a further 45 minutes, at a relative humidity (RH) of 45%. Alternatively, in experiment 2, they had tOsm measured every 15 minutes for 45 minutes during exposure to 70% RH, as a separate measure to suppress evaporation. RESULTS: A significant decrease in tOsm occurred in both normal and DED subjects after lid closure in experiment 1 (normal RE p=0.015; normal LE p=0.006; DED RE p=0.0002; DED LE p=0.01). The tOsm also fell slightly after exposure to 70% RH in experiment 2 significant in the LE of normal group only (normal LE p=0.045). CONCLUSIONS: Suppression of tear evaporation resulted in a fall in tOsm, close to that of plasma osmolarity (285-295mOsm/L). It is proposed that this new measure, termed Basal Tear Osmolarity (BTO), could provide a valuable index of plasma osmolarity and hence of body hydration and in DED, a personal baseline against which to gauge the severity of tear hyperosmolarity.

Central Connections of the Lacrimal Functional Unit.

PURPOSE: To study the contribution of each eye to the reflex tear response, after unilateral and bilateral topical anesthesia. METHOD: A closed-eye, modified Schirmer test was performed bilaterally in 8 normal subjects, in a controlled environment chamber set to 23°C, 45% relative humidity, and 0.08 m/s airflow. Eye drops were instilled into each eye 10 minutes before the Schirmer test. Experiments were as follows: 1) bilateral saline (control), 2) unilateral anesthesia (ipsilateral anesthetic; contralateral saline), and 3) bilateral anesthesia. RESULTS: There was no difference in between-eye wetting lengths in the saline control eyes (P = 0.394) or the bilaterally anesthetized eyes (P = 0.171). The wetting length was reduced in both eyes after bilateral anesthesia compared with saline controls (P = 0.001; P ≤ 0.0005). After unilateral anesthesia, the wetting length was reduced in the anesthetized eye compared with its saline control by 51.4% (P ≤ 0.0005) and compared with its fellow, unanesthetized eye (P = 0.005). The fellow eye value was also reduced compared with its saline control (P = 0.06). CONCLUSIONS: The wetting length was reduced by topical anesthesia, when instilled bilaterally and ipsilaterally. The latter response implies an ipsilateral, reflex sensory drive to lacrimal secretion. In the unanesthetized fellow eye, the reduction compared with its saline control was not quite significant. This implies a relative lack of central, sensory, reflex cross-innervation, although the possibility cannot entirely be ruled out. These results are relevant to the possibility of reflex lacrimal compensation from a normal fellow eye, in cases of unilateral corneal anesthesia.

Improving prostate cancer care collaboratively - a multidisciplinary, formal, consensus-based approach.

INTRODUCTION: There are numerous standard treatment options for men diagnosed with localized prostate cancer. Multidisciplinary consultation before decision-making is a consensus- and quality-based objective in Ontario. With the goals of working together more collaboratively and to provide higher quality information for patients at the time of decision-making, a prostate cancer community partnership consensus (PCPC) panel was formed among six partnering centers in the Greater Toronto Area. MATERIALS AND METHODS: Five iterative meetings were held among 40 prostate cancer specialists (32 urologists and 8 radiation oncologists) who participate in multidisciplinary clinics. The meetings defined the goals of the partnership as well as the topics and questions the group would address together. Answers to these questions were developed by formal consensus: >= 75% of participants had to agree with wording based on secret ballots to achieve consensus. RESULTS: All six groups wanted to participate to improve patient care/decision-making. Forty-one questions addressing 30 issues were derived from the literature and the group's collective experience. These issues were cross-tabbed against five management options: active surveillance, radical prostatectomy, low dose rate brachytherapy, high dose rate brachytherapy boost and external beam radiation. Answers common to all modalities were coalesced. Eighty-six issues were subjected to formal consensus. After three rounds of secret ballots, consensus was achieved for the answers to all issues. CONCLUSIONS: A formal consensus-based partnership between urology and radiation oncology to support newly diagnosed prostate cancer patients was feasible and resulted in a patient information guide which may improve decision-making.

BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG.

Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.

Diagnosis, referral, and primary treatment decisions in newly diagnosed prostate cancer patients in a multidisciplinary diagnostic assessment program.

INTRODUCTION: We aimed to report on data from the multidisciplinary diagnostic assessment program (DAP) at the Gale and Graham Wright Prostate Centre (GGWPC) at North York General Hospital (NYGH). We assessed referral, diagnosis, and treatment decisions for newly diagnosed prostate cancer (PCa) patients as seen over time, risk stratification, and clinic type to establish a deeper understanding of current decision-making trends. METHODS: From June 2007 to April 2012, 1277 patients who were diagnosed with PCa at the GGWPC were included in this study. Data was collected and reviewed retrospectively using electronic patient records. RESULTS: 1031 of 1260 patients (81.8%) were seen in a multidisciplinary clinic (MDC). Over time, a decrease in low-risk (LR) diagnoses and an increase intermediate-risk (IR) diagnoses was observed (p<0.0001). With respect to overall treatment decisions 474 (37.1%) of patients received primary radiotherapy, 340 (26.6%) received surgical therapy, and 426 (33.4%) had conservative management; 57% of patients who were candidates for active surveillance were managed this way. No significant treatment trends were observed over time (p=0.8440). Significantly, different management decisions were made in those who attended the MDC compared to those who only saw a urologist (p<0.0001). CONCLUSIONS: In our DAP, the vast majority of patients presented with screen-detected disease, but there was a gradual shift from low- to intermediate-risk disease over time. Timely multidisciplinary consultation was achievable in over 80% of patients and was associated with different management decisions. We recommend that all patients at risk for prostate cancer be worked up in a multi-disciplinary DAP.

Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group.

PURPOSE: To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer Group. METHODS: We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size. RESULTS: NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies. CONCLUSION: The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.