Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

A prospective case series to evaluate subcostal nerve injury with high-resolution ultrasound in posterior retroperitoneoscopic adrenalectomy.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has several advantages over transabdominal laparoscopic adrenalectomy regarding operating time, blood loss, postoperative pain, and recovery. However, postoperatively several patients report chronic pain or hypoesthesia. We hypothesized that these symptoms may be the result of damage to the subcostal nerve, because it passes the surgical area. METHODS: A prospective single-center case series was performed in adult patients without preoperative pain or numbness of the abdominal wall who underwent unilateral posterior retroperitoneoscopic adrenalectomy. Patients received pre- and postoperative questionnaires and a high-resolution ultrasound scan of the subcostal nerve and abdominal wall muscles was performed before and directly after surgery. Clinical evaluation at 6 weeks was performed with repeat questionnaires, physical examination, and high-resolution ultrasound. Long-term recovery was evaluated with questionnaires, and photographs from the patients were examined for abdominal wall asymmetry. RESULTS: A total of 25 patients were included in the study. There were no surgical complications. Preoperative visualization of the subcostal nerve was possible in all patients. At 6 weeks, ultrasound showed nerve damage in 15 patients, with no significant association between nerve damage and postsurgical pain. However, there was a significant association between nerve damage and hypoesthesia (p = 0.01), sensory (p < 0.001), and motor (p < 0.001) dysfunction on physical examination. After a median follow-up of 18 months, 5 patients still experienced either numbness or muscle weakness, and one patient experienced chronic postsurgical pain. CONCLUSION: In this exporatory case series the incidence of postoperative damage to the subcostal nerve, both clinically and radiologically, was 60% after posterior retroperitoneoscopic adrenalectomy. There was no association with pain, and the spontaneous recovery rate was high.

Longitudinal associations of adherence to lifestyle recommendations and health-related quality of life in patients with non-muscle invasive bladder cancer.

Although the role of lifestyle in health-related quality of life (HRQoL) outcomes has been increasingly recognized for various types of cancer, evidence in patients with non-muscle invasive bladder cancer (NMIBC) is very limited. We aimed to evaluate the longitudinal association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations and HRQoL in patients with NMIBC. This study included 1029 patients with NMIBC recruited between May 2014 and April 2017 from the Dutch multi-centre prospective cohort study UroLife. Lifestyle and HRQoL data were collected at 6 weeks (baseline), 3 months and 15 months after diagnosis. Information on body mass index (BMI), physical activity, diet and alcohol was used to compute the standardized WCRF/AICR adherence score (0-7). HRQoL outcomes were evaluated by the EORTC QLQ-C30. Linear mixed models were used to assess longitudinal confounder-adjusted associations between the WCRF/AICR adherence score and HRQoL outcomes. Adherence to each additional WCRF/AICR recommendation was associated with better global quality of life, physical, role and social functioning, and less fatigue. We found stronger inter-individual than intra-individual associations, suggesting that associations were mainly driven by between-subject differences. Higher adherence to the BMI, physical activity and dietary recommendations was associated with better scores for most HRQoL outcomes, while adherence to the alcohol recommendation (ie, non-consumption) was associated with worse HRQoL. Following the WCRF/AICR lifestyle recommendations may improve HRQoL in patients with NMIBC. Intervention studies are needed to establish whether the association between lifestyle and HRQoL is causal.

Incidence of significant prostate cancer after negative MRI and systematic biopsy in the FUTURE trial.

OBJECTIVES: To assess the proportion of clinically significant (cs) prostate cancer (PCa) found during follow-up in patients with negative systematic biopsy (SB) followed by non-suspicious multiparametric magnetic resonance imaging (mpMRI) and persistent clinical suspicion of PCa compared to the general population. PATIENTS AND METHODS: A prospective study in a subgroup of patients from a multicentre randomized controlled trial was conducted between 2014 and 2017, including 665 men with prior negative SB with a persistent elevated prostate-specific antigen and/or suspicious digital rectal examination undergoing mpMRI. All patients with negative SB and Prostate Imaging-Reporting and Data System (PI-RADS) ≤2 on mpMRI entered biochemical follow-up. Follow-up data until December 2021 were collected by reviewing institutional hospital records and the Dutch Pathology Registry (PALGA). The primary outcome was the observed number of csPCa (Gleason ≥3 + 4/International Society of Urological Pathology grade group ≥2) cases during follow-up compared to the expected number in the general population (standardized incidence ratio [SIR]). RESULTS: In total, 431 patients had non-suspicious mpMRI and entered biochemical follow-up. After a median (interquartile range) follow-up of 41 (23-57) months, 38 patients were diagnosed with PCa, of whom 13 (3.0%) had csPCa. The SIR for csPCa was 4.3 (95% confidence interval 2.3-7.4; total excess of eight cases). A higher risk of a positive biopsy for (cs)PCa based on the European Randomized Study of Screening for Prostate Cancer risk calculator and a suspicious repeat MRI (PI-RADS ≥3) were significant predictive factors for csPCa. CONCLUSION: After negative prior biopsy and non-suspicious mpMRI the risk of csPCa is low. However, compared to the general population, the risk of csPCa is increased despite the high negative predictive value of mpMRI. More research focusing on biochemical and image-guided risk-adapted diagnostic surveillance strategies is warranted.

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.

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.

Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer.

PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

Intra-therapeutic dosimetry of [177Lu]Lu-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer patients and correlation with treatment outcome.

INTRODUCTION: While [177Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [177Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. METHODS: Ten mHSPC patients underwent two cycles of [177Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values. RESULTS: Kinetics of [177Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047). CONCLUSIONS: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.

[68Ga]Ga-PSMA-11 PET imaging as a predictor for absorbed doses in organs at risk and small lesions in [177Lu]Lu-PSMA-617 treatment.

INTRODUCTION: Patient eligibility for [177Lu]Lu-PSMA therapy remains a challenge, with only 40-60% response rate when patient selection is done based on the lesion uptake (SUV) on [68Ga]Ga-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver). METHODS: Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic [68Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [177Lu]Lu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions (n = 22) was determined according to the MIRD scheme. Absorbed dose prediction based on [68Ga]Ga-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume. RESULTS: PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4-2.7, correlation coefficient r = 0.69, p < 0.01). CONCLUSION: A single time point [68Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [177Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [177Lu]Lu-PSMA therapy.

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

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

Predicting surgical outcome in posterior retroperitoneoscopic adrenalectomy with the aid of a preoperative nomogram.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) has several advantages over transperitoneal laparoscopic adrenalectomy (TLA) regarding operative time, blood loss, postoperative pain, and recovery. However, it can be a technically challenging procedure. To improve patient selection for PRA, we developed a preoperative nomogram to predict operative time. METHODS: All consecutive patients with tumors of ≤ 7 cm and a body mass index (BMI) of < 35 kg/m2 undergoing unilateral PRA between February 2011 and March 2020 were included in the study. The primary outcome was operative time as surrogate endpoint for surgical complexity. Using ten patient variables, an optimal prediction model was created, with a best subsets regression analysis to find the best one-variable up to the best seven-variable model. RESULTS: In total 215 patients were included, with a mean age of 52 years and mean tumor size of 2.4 cm. After best subsets regression analysis, a four-variable nomogram was selected and calibrated. This model included sex, pheochromocytoma, BMI, and perinephric fat, which were all individually significant predictors. This model showed an ideal balance between predictive power and applicability, with an R2 of 38.6. CONCLUSIONS: A four-variable nomogram was developed to predict operative time in PRA, which can aid the surgeon to preoperatively identify suitable patients for PRA. If the nomogram predicts longer operative time and therefore a more complex operation, TLA should be considered as an alternative approach since it provides a larger working space. Also, the nomogram can be used for training purposes to select patients with favorable characteristics when learning this surgical approach.

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

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

External validation of the Memorial Sloan Kettering Cancer Centre and Briganti nomograms for the prediction of lymph node involvement of prostate cancer using clinical stage assessed by magnetic resonance imaging.

OBJECTIVES: To evaluate the impact of using clinical stage assessed by multiparametric magnetic resonance imaging (mpMRI) on the performance of two established nomograms for the prediction of pelvic lymph node involvement (LNI) in patients with prostate cancer. PATIENTS AND METHODS: Patients undergoing robot-assisted extended pelvic lymph node dissection (ePLND) from 2015 to 2019 at three teaching hospitals were retrospectively evaluated. Risk of LNI was calculated four times for each patient, using clinical tumour stage (T-stage) assessed by digital rectal examination (DRE) and by mpMRI, in the Memorial Sloan Kettering Cancer Centre (MSKCC; 2018) and Briganti (2012) nomograms. Discrimination (area under the curve [AUC]), calibration, and the net benefit of these four strategies were assessed and compared. RESULTS: A total of 1062 patients were included, of whom 301 (28%) had histologically proven LNI. Using DRE T-stage resulted in AUCs of 0.71 (95% confidence interval [CI] 0.70-0.72) for the MSKCC and 0.73 (95% CI 0.72-0.74) for the Briganti nomogram. Using mpMRI T-stage, the AUCs were 0.72 (95% CI 0.71-0.73) for the MSKCC and 0.75 (95% CI 0.74-0.76) for the Briganti nomogram. mpMRI T-stage resulted in equivalent calibration compared with DRE T-stage. Combined use of mpMRI T-stage and the Briganti 2012 nomogram was shown to be superior in terms of AUC, calibration, and net benefit. Use of mpMRI T-stage led to increased sensitivity for the detection of LNI for all risk thresholds in both models, countered by a decreased specificity, compared with DRE T-stage. CONCLUSION: T-stage as assessed by mpMRI is an appropriate alternative for T-stage assessed by DRE to determine nomogram-based risk of LNI in patients with prostate cancer, and was associated with improved model performance of both the MSKCC 2018 and Briganti 2012 nomograms.

Comparison of the performances of the ADXBLADDER test and urinary cytology in the follow-up of non-muscle-invasive bladder cancer: a blinded prospective multicentric study.

OBJECTIVE: To compare directly the performance of the ADXBLADDER test with that of cytology in the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences. BACKGROUND: ADXBLADDER is a urine test based on the detection of MCM5, a DNA licensing factor expressed in all cells capable of dividing. Expression is usually restricted to the basal stem cell compartment; however, in malignancy, MCM5-expressing cells can be found throughout the epithelium. Detection of MCM5 in urine sediment can be indicative of the presence of a bladder tumour. PATIENTS AND METHODS: A multicentre prospective, blinded study was carried out from August 2017 and July 2019 at 21 European Union centres, 14 of which collected matching cytology data. Urine was collected from patients prior to cystoscopy. Urine cytology and ADXBLADDER were performed and compared to the diagnosis obtained by cystoscopy. The performance of cytology and ADXBLADDER were then compared. RESULTS: The overall performance of ADXBLADDER demonstrated a sensitivity of 51.9%, a specificity of 66.4%, and a negative predictive value (NPV) of 92%. The sensitivity of ADXBLADDER for low- and high-grade recurrences was 44.1% and 58.8%, respectively. By contrast, cytology sensitivity was 16.7%, specificity was 98% and NPV was 90.7%. Cytology sensitivity for both low- and high-grade disease was 17.6%. CONCLUSIONS: ADXBLADDER detection of both low- and high-grade NMIBC recurrence is superior to that of cytology, with ADXBLADDER able to exclude the presence of high-grade recurrence in 97.8% of cases compared to 97.1% with cytology. These results show that ADXBLADDER has promise as a more reliable alternative to urine cytology in the follow-up of NMIBC.

Follow-up in non-muscle invasive bladder cancer: facts and future.

Patients with non-muscle invasive bladder cancer (NMIBC) have high recurrence and progression rates in spite of tumor resection and adjuvant instillation therapy. To detect recurrences and progression, these patients remain under frequent follow-up. Follow-up, however, is not well defined. Frequency and duration of follow recommendations are based on low levels of evidence, which is illustrated by clear differences in these recommendations per guideline, even when specified per risk group. Additionally, follow-up is recommended with cystoscopy and cytology in selected patients, which both have clear limitations. Fact is that follow-up in NMIBC is too frequent, with low levels of evidence and suboptimal tools, and it is patient unfriendly and costly. Improved cystoscopy techniques are unproven or impractical in the outpatient follow-up setting. Urinary markers have been around for decades, but never widely used in clinical practice. New (epi)genetic markers, however, could play a significant role in future follow-up of NMIBC. They have been shown to have very high negative predictive values for recurrences in follow-up of NMIBC, especially high-grade recurrences. Several studies suggested that these markers could be used to adapt follow-up cystoscopy frequency. What still needs study and confirmation is the cost-effectiveness of the use of these markers, which is highly dependent on health care costs per country and marker price. In all, however, implementation of these new urinary markers after confirmation of current results might significantly reduce patient burden and health care costs in the near future without reducing quality.

Patient-reported outcomes and health-related quality of life after urinary diversions.

PURPOSE OF REVIEW: To study the recent literature on health-related quality of life (HRQOL) in patients after radical cystectomy followed by urinary diversion. RECENT FINDINGS: General consensus regarding, which urinary diversion is superior in terms of HRQOL has not been reached. Although there is an increase in studies favoring the orthotopic neobladder, overall quality of these studies is poor. Other studies suggest that HRQOL outcomes in different types of urinary diversions is similar and that other factors, such as age, comorbidities and sex are more important instead. Patient choice, in consultation with the treating surgeon should be the determinant of which urinary diversion is performed. Furthermore, sexual function can play an important role in HRQOL. However, practice shows that counselling on the option of sexual-preserving techniques is still not implemented in routine clinical practice. Furthermore, studies regarding differences in HRQOL after urinary diversion between male and female individuals are lacking. SUMMARY: Thorough preoperative counselling on the different types of urinary diversion and options for sexual-preserving techniques decreases decision regret and increases HRQOL in patients after radical cystectomy.

Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303.

Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (ClinicalTrials.gov).

DPPG2-based thermosensitive liposomes as drug delivery system for effective muscle-invasive bladder cancer treatment in vivo.

PURPOSE: Recommended treatments for muscle-invasive bladder cancer (MIBC) come with considerable morbidity. Hyperthermia (HT) triggered drug release from phosphatidylglycerol-based thermosensitive liposomes (DPPG2-TSL) might prevent surgical bladder removal and toxicity from systemic chemotherapy. We aimed to assess the efficacy of DPPG2-TSL with HT in a syngeneic orthotopic rat urothelial carcinoma model. METHODS: A total of 191 female Fischer F344 rats were used. Bladder tumors were initiated by inoculation of AY-27 cells and tumor-bearing rats were selected with cystoscopy and semi-randomized over treatment groups. On days 5 and 8, animals were treated with DOX in different treatment modalities: intravenous (iv) DPPG2-TSL-DOX with HT, iv free DOX without HT, intravesical DOX without HT, intravesical DOX with HT or no treatment (control group), respectively. Animals were euthanized on day 14 and complete tumor response was assessed by histopathological evaluation. RESULTS: Iv DPPG2-TSL-DOX + HT resulted in a favorable rate of animals with complete tumor response (70%), compared to iv free DOX (18%, p = .02), no treatment (0%, p = .001), and intravesical DOX with (43%, p = .35) or without HT (50%, p = .41). All rats receiving intravesical DOX with HT and 24% of rats treated with DPPG2-TSL-DOX containing the same DOX dose with HT had to be euthanized before day 14 because of substantial bodyweight loss, which was associated with dilated ureters urine retention in a few rats. CONCLUSION: Treatment with DPPG2-TSL-DOX combined with intravesical HT outperformed systemic and intravesical DOX in vivo. There might be a role for DPPG2-TSL encapsulating chemotherapeutics in the treatment of MIBC in the future.

Platinum exposure and cause-specific mortality among patients with testicular cancer.

BACKGROUND: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. METHODS: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. RESULTS: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. CONCLUSIONS: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.