Faculty Bibliography

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m² on day 1 and cisplatin 35 mg/m² on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

Introduction: PRECISION aimed to evaluate whether multiparametric MRI and a targeted biopsy only (MRI+/-TB) was non-inferior to TRUS biopsy in the detection of clinically significant prostate cancer in biopsy naive men. Patients & Methods: PRECISION was a randomised, non-inferiority trial, carried out in 25 centres in 11 coun-tries. 500 men were randomly allocated to 10-12 core TRUS-biopsy or MRI+/-TB. Men randomised to MRI+/-TB underwent MRI followed by targeted biopsy alone (without standard cores) if the PIRADSv2 score was >=3. Men with a PIRADSv2 score of 1-2 were not offered biopsy. The primary outcome was the proportion of men diagnosed with clinically significant cancer (Gleason grade >= 3+4). Results: One third of men avoided biopsy in the MRI arm (71/252, 28%). Clinically significant cancer was detected in 95 (38%) of 252 men in the MRI+/-TB arm compared to 64 (26%) of 248 men randomised to TRUS-biopsy (intention-to-treat analysis). Adjusting for centre effects, the absolute difference (MRI+/-TB versus TRUS-biopsy) in the proportion of men diagnosed with clinically significant prostate cancer was 11.8% (2-sided 95% CI 3.7 to 20.0; p = 0.005). The lower bound of the 95% CI for the difference is greater than-5% therefore MRI+/-TB was non-inferior to TRUS biopsy. Furthermore, the range of 95% CI was consistent with a claim of superiority of MRI+/-TB over TRUS-biopsy. Conclusion: An MRI-targeted approach in biopsy naive men resulted in greater detection of clinically significant disease, less detection of insignificant disease and required fewer biopsies

Imaging is critically important for the diagnosis, staging, and management of men with high-risk prostate cancer. Conventional imaging modalities, including computed tomography and radionuclide bone scan have been employed for local and metastatic staging, but their performance has generally been poor. Sodium fluoride positron emission tomography is recommended when there is high suspicion for bone metastases despite a negative or indeterminate bone scan. Magnetic resonance imaging has advantages in local staging but its value depends on the extent of disease. Whole body positron emission tomography/magnetic resonance imaging could provide both local and distant staging although the technology is not yet widely disseminated. None of the existing positron emission tomography agents are recommended in practice guidelines, however, among them, prostate specific membrane antigen-based tracers seem to hold the most promise based on sensitivity and specificity.

Background Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. Methods In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. Results A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). Conclusions The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).