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Salvage cystectomy is required for some patients with intravesical recurrence after trimodality therapy. We compared postoperative outcomes between salvage cystectomy post-trimodality therapy, primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy.We included 265 patients who underwent radical cystectomy at Massachusetts General Hospital for cT1-T4 bladder cancer between 2003 and 2013. Patients were grouped as salvage cystectomy post-trimodality therapy, primary cystectomy or primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Early (≤90 days) and late (90 days) complications were compared. Disease-specific survival and overall survival were calculated using a Cox regression model, and adjusted survival curves were generated.The median followup from the time of cystectomy was 65.5 months. There was no difference in intraoperative and early complications between the groups. The detection of late complications was higher in salvage cystectomy post-trimodality therapy compared to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy (p=0.03). In multivariable Cox regression analysis, salvage cystectomy post-trimodality therapy was associated with a higher incidence of any late (HR 2.3, p=0.02) and major late complications (HR 2.1, p0.05). There was no difference in disease-specific survival (p=0.8) or overall survival (p=0.9) between the groups.Salvage cystectomy post-trimodality therapy for intravesical recurrence post-trimodality therapy has an intraoperative and early complication rate comparable to primary cystectomy and primary cystectomy with prior history of nontrimodality therapy abdominal or pelvic radiotherapy. Salvage cystectomy post-trimodality therapy is associated with a higher risk of overall and major late complications than primary cystectomy. The disease-specific survival and overall survival of patients who require salvage cystectomy post-trimodality therapy are comparable to both groups.

Background Bladder-sparing trimodality therapy (TMT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), and biomarkers to inform therapy selection are needed. Objective To evaluate the prognostic value of immune and stromal signatures in MIBC treated with TMT. Design, setting, and participants We used a clinical-grade platform to perform transcriptome-wide gene expression profiling of primary tumors from 136 MIBC patients treated with TMT at a single institution. We observed 60 overall survival events at 5 yr, and median follow-up time for patients without an event was 5.0 yr (interquartile range 3.1, 5.0). Expression data from another cohort of 223 MIBC patients treated with neoadjuvant chemotherapy (NAC) and RC were also analyzed. Outcome measurements and statistical analysis Molecular subtype, immune, and stromal signatures were evaluated for associations with disease-specific survival (DSS) and overall survival (OS) in TMT patients, and in patients treated with NAC and RC. Results and limitations Gene expression profiling of TMT cases identified luminal (N = 40), luminal-infiltrated (N = 26), basal (N = 54), and claudin-low (N = 16) subtypes. Signatures of T-cell activation and interferon gamma signaling were associated with improved DSS in the TMT cohort (hazard ratio 0.30 [0.14–0.65], p = 0.002 for T cells), but not in the NAC and RC cohort. Conversely, a stromal signature was associated with worse DSS in the NAC and RC cohort (p = 0.006), but not in the TMT cohort. This study is limited by its retrospective nature. Conclusions Higher immune infiltration in MIBC is associated with improved DSS after TMT, whereas higher stromal infiltration is associated with shorter DSS after NAC and RC. Additional studies should be conducted to determine whether gene expression profiling can predict treatment response. Patient summary We used gene expression profiling to study the association between tumor microenvironment and outcomes following bladder preservation therapy for invasive bladder cancer. We found that outcomes varied with immune and stromal signatures within the tumor. We conclude that gene expression profiling has potential to guide treatment decisions in bladder cancer.

PURPOSE Radiotherapy (RT) plus long-term androgen suppression (AS) are a standard treatment option for patients with high-risk localized prostate cancer. We hypothesized that docetaxel chemotherapy (CT) could improve overall survival (OS) and clinical outcomes among patients with high-risk prostate cancer. PATIENTS AND METHODS The multicenter randomized NRG Oncology RTOG 0521 study enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned to receive standard long-term AS plus RT with or without adjuvant CT. RESULTS A total of 612 patients were enrolled; 563 were evaluable. Median prostate-specific antigen was 15.1 ng/mL; 53% had a Gleason score 9 to 10 cancer; 27% had cT3 to cT4 disease. Median follow-up was 5.7 years. Treatment was well tolerated in both arms. Four-year OS rate was 89% (95% CI, 84% to 92%) for AS + RT and 93% (95% CI, 90% to 96%) for AS + RT + CT (hazard ratio [HR], 0.69; 90% CI, 0.49 to 0.97; one-sided P = .034). There were 59 deaths in the AS + RT arm and 43 in the AS + RT + CT arm, with fewer deaths resulting from prostate cancer in the AS + RT + CT arm versus AS + RT (23 v 16 deaths, respectively). Six-year rate of distant metastasis was 14% for AS + RT and 9.1% for AS + RT + CT, (HR, 0.60; 95% CI, 0.37 to 0.99; two-sided P = .044). Six-year disease-free survival rate was 55% for AS + RT and 65% for AS + RT + CT (HR, 0.77; 95% CI, 0.59 to 1.00; two-sided P = .053). CONCLUSION For patients with high-risk nonmetastatic prostate cancer, CT with docetaxel improved OS from 89% to 93% at 4 years, with improved disease-free survival and reduction in the rate of distant metastasis. The trial suggests that docetaxel CT may be an option to be discussed with selected men with high-risk prostate cancer.

To provide a comprehensive overview and update of the Joint Societe Internationale d’Urologie–International Consultation on Urological Diseases (SIU–ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3–4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

Purpose/objective(s) To conduct the first global individual patient data (IPD) meta-analysis of randomized trials to assess the impact of androgen deprivation therapy (ADT) use and duration with definitive radiotherapy (RT) in localized prostate cancer. Materials/methods The MARCAP Consortium was formed from international trial groups (NRG/RTOG, EORTC, TROG, DART/GICOR, and ICORG). IPD for 10,131 patients enrolled across 11 RT trials were available for three pre-specified meta-analyses: addition of ADT to RT (5 trials; n = 4736), addition of long-term adjuvant ADT (12-30 months) to short-term ADT (4 trials; n = 3674), and addition of longer neoadjuvant ADT (3-7 months) to short-term ADT (3 trials; n = 2213). The primary endpoint of all meta-analyses was overall survival (OS), with metastasis-free survival (MFS) as a secondary endpoint. Interaction tests between treatment and receipt of dose-escalated RT (≥74 Gy in 2 Gy fractions) were performed. Results After a median follow-up of 12.0 years, the addition of ADT to RT improved 12-year OS (absolute 7.2%, HR 0.87, 95% CI 0.8-0.95) and 12-year MFS (absolute 8.3%, HR 0.85, 95% CI 0.79-0.92). After a median follow-up of 10.9 years, prolongation of adjuvant ADT improved 12-year OS (absolute 6.3%, HR 0.86, 95% CI 0.78-0.94) and 12-year MFS (absolute 6.3%, HR 0.83, 95% CI 0.77-0.90). After a median follow-up of 10.3 years, prolongation of neoadjuvant ADT was not associated with a significant benefit in any endpoint (MFS HR 0.95, 95% CI 0.83-1.09; OS HR 0.94, 95% CI 0.82-1.09). On subgroup analysis, there was no evidence of a treatment effect interaction between RT dose and ADT use (OS P-interaction 0.59) or adjuvant ADT prolongation (OS P-interaction 0.13). In the setting of dose-escalated RT, adjuvant ADT prolongation significantly improved OS (HR 0.70, 95% CI 0.53-0.92). Conclusion This study represents the strongest evidence to support ADT use and prolongation of adjuvant ADT to at least 18 months in localized prostate cancer in conjunction with definitive RT. The relative benefit of ADT use and adjuvant ADT prolongation was consistent irrespective of RT dose-escalation. In contrast, prolongation of neoadjuvant ADT beyond 2 months did not improve survival outcomes and should not routinely be employed.

Summary Although muscle-invasive bladder cancer is commonly treated with radical cystectomy, a standard alternative is bladder preservation therapy, consisting of maximum transurethral bladder tumour resection followed by radiotherapy with concurrent chemotherapy. Although no successfully completed randomised comparisons are available, the two treatment paradigms seem to have similar long-term outcomes; however, clinicopathologic parameters can be insufficient to provide clear guidance in the selection of one treatment over the other. Recent advances in the molecular understanding of bladder cancer have led to the identification of new predictive biomarkers that ultimately might help guide the tailored selection of therapy on the basis of the intrinsic biology of the tumour. In this Review, we discuss the existing evidence for molecular alterations and genomic signatures as prognostic or predictive biomarkers for bladder preservation therapy. If validated in prospective clinical trials, such biomarkers could enable the identification of subgroups of patients who are more likely to benefit from one treatment over another, and guide the use of combination therapies that include other modalities, such as immunotherapy, which might act synergistically with radiotherapy.

PURPOSE There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Importance In men with recurrent prostate cancer, addition of long-term antiandrogen therapy to salvage radiotherapy (SRT) was associated with overall survival (OS) in the NRG/RTOG 9601 study. However, hormone therapy has associated morbidity, and there are no validated predictive biomarkers to identify which patients derive most benefit from treatment. Objective To examine the role of pre-SRT prostate-specific antigen (PSA) levels to personalize hormone therapy use with SRT. Interventions Men were randomized to SRT plus high-dose nonsteroidal antiandrogen (bicalutamide, 150 mg/d) or placebo for 2 years. Design, Setting, and Participants In this secondary analysis of the multicenter RTOG 9601 double-blind, placebo-controlled randomized clinical trial conducted from 1998 to 2003 by a multinational cooperative group, men with a positive surgical margin or pathologic T3 disease after radical prostatectomy with pre-SRT PSA of 0.2 to 4.0 ng/mL were included. Analysis was performed between March 4, 2019, and December 20, 2019. Main Outcomes and Measures The primary outcome was overall survival (OS). Secondary end points included distant metastasis (DM), other-cause mortality (OCM), and grades 3 to 5 cardiac and neurologic toxic effects. Subgroup analyses were performed using the protocol-specified PSA stratification variable (1.5 ng/mL) and additional PSA cut points, including test for interaction. Competing risk analyses were performed for DM and other-cause mortality (OCM). Results Overall, 760 men with PSA elevation after radical prostatectomy for prostate cancer were included. The median (range) age of particpants was 65 (40-83) years. Antiandrogen assignment was associated with an OS benefit in the PSA stratum greater than 1.5 ng/mL (n = 118) with a 25% 12-year absolute benefit (hazard ratio [HR], 0.45; 95% CI, 0.25-0.81), but not in the PSA of 1.5 ng/mL or less stratum (n = 642) (1% 12-year absolute difference; HR, 0.87; 95% CI, 0.66-1.16). In a subanalysis of men with PSA of 0.61 to 1.5 (n = 253), there was an OS benefit associated with antiandrogen assignment (HR, 0.61; 95% CI, 0.39-0.94). In those receiving early SRT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in OS (HR, 1.16; 95% CI, 0.79-1.70), an increased OCM hazard (subdistribution HR, 1.94; 95% CI, 1.17-3.20;P = .01), and an increased odds of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio, 3.57; 95% CI, 1.09-15.97;P = .05). Conclusions and Relevance These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA >0.6 ng/mL, hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤0.6 ng/mL), long-term antiandrogen treatment was not associated with improved OS. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population. Trial Registration ClinicalTrials.gov Identifier:NCT00002874

PURPOSE/OBJECTIVE(S) Decipher is a prognostic 22-gene genomic classifier (GC) prospectively validated post-prostatectomy. Herein, we validate the performance of the GC in pre-treatment biopsy samples within the context of three randomized phase III high-risk definitive radiotherapy trials. MATERIALS/METHODS Following a pre-specified and approved CTEP-CCSC analysis plan (NRG-GU-TS006), we obtained all available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on NRG/RTOG 9202, 9413, and 9902 phase III randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability of GC for distant metastases (DM), and secondary was prostate cancer-specific mortality (PCSM) and overall survival (OS), with Cox multivariable analyses (MVA). RESULTS GC scores were obtained on 385 samples (n = 90 on 9202, n = 172 on 9413, and n = 123 on 9902), of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9, 13). On MVA, the GC (per 0.1 unit) was independently associated with DM (HR 1.24, 95% CI 1.11-1.39), PCSM (HR 1.27, 95% CI 1.13-1.43), and OS (HR 1.12, 95% CI 1.05-1.20) after adjusting for age, PSA, Gleason score, cT-stage, trial, and randomized treatment arm. For categorical GC, on MVA, GC score ≥ 0.45 (representing the intermediate and high GC categories) had worse DM (HR 2.18, 95% CI 1.25-3.80), PCSM (HR 2.34, 95% CI 1.31-4.16), and OS (HR 1.45, 95% CI 1.03-2.04) outcomes as compared to those with low GC. Cumulative incidence of distant-metastasis at 10-years was 29% (95% CI 20-38%) for intermediate/high GC vs 13% (95% CI 7-18%) for low GC. For the subset with GC > 0.85, the threshold for inclusion in the intensification study of NRG GU009 (PREDICT-RT), at 5-years and 10-years DM was 29% (95% CI 7-52%) and 41% (95% CI 17-66%). GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy (ADT). CONCLUSION This is the first validation of any gene expression biomarker on pre-treatment biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT will further determine the optimal therapy based on GC score. NCT04513717.

Background Trimodality bladder-sparing therapy (TMT) is an acceptable treatment for selected patients with muscle-invasive urothelial cancer. Outcomes of TMT in histologic variants remains largely unknown. Objective To compare outcomes of pure urothelial carcinoma (PUC) to variant urothelial carcinoma (VUC) after TMT. Design, setting, and participants Retrospective study of patients treated with TMT at a single cancer center from 1993 until 2013. Outcome measurements and statistical analysis Kaplan-Meier survival probabilities, and univariate and multivariable Cox regression analysis. Results and limitations Of 303 patients treated with TMT, 66 (22%) had VUC. Fifty (76%) had VUC with squamous and/or glandular differentiation and 16 (24%) had other forms. Complete response rate after induction TMT was 83% in PUC and 82% in VUC ( p =0.9). The 5-yr and 10-yr disease-specific survival (DSS) was 75% and 67% in PUC versus 64% and 64% in VUC. The 5-yr and 10-yr overall survival (OS) was 61% and 42% in PUC versus 52% and 42% in VUC. On multivariable analysis VUC was not associated with DSS (hazard ratio: 1.3, 95% confidence interval: 0.8–2.2, p =0.3) or OS (hazard ratio: 1.2, 95% confidence interval: 0.8–1.7, p =0.4). Salvage cystectomy rates were similar (log-rank p =0.3). Limitations include retrospective design and restriction to variants of urothelial cancer. Conclusions VUC responded to TMT, and there was no significant difference in complete response, OS, DSS, or salvage cystectomy rates compared with PUC. The presence of VUC should not exclude patients from TMT. Patient summary The response of histologic variants of bladder cancer to bladder-sparing chemoradiation is largely unknown. We compared the outcomes of histologic variants of urothelial cancer to pure urothelial cancer in a large series of patients from a single institution. We found that variant histology does not significantly influence outcomes.

Background Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC). Objective Report long-term outcomes of patients with MIBC treated by TMT. Design, setting, and participants Four hundred and seventy-five patients with cT2–T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013. Intervention Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy. Outcome measurements and statistical analysis Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results and limitations Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44–0.75, DSS HR: 0.51, 95% CI: 0.36–0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46–0.81, DSS HR: 0.49, 95% CI: 0.34–0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17–2.08, DSS HR: 1.50, 95% CI: 1.03–2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986–1995 to 2005–2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%. Conclusions These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients. Patient summary Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.

Purpose Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival. Results A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.

Purpose The purpose of this study was to evaluate freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS) after adjuvant radiation therapy (ART) versus early salvage radiation therapy (ESRT) in men with prostate cancer and adverse pathologic features (pT3 and/or positive surgical margins). Methods and materials Of 718 patients consecutively treated with postoperative radiation therapy (RT) for prostate cancer between 1992 and 2013, we retrospectively identified 171 men receiving ART and 230 receiving ESRT (RT delivered at a prostate-specific antigen level ≤0.5 ng/mL) who had adverse pathologic features. Postirradiation FFBF (BF was defined as prostate-specific antigen level rise to ≥0.2 ng/mL), FFADT, FFDM, and OS were compared using Kaplan-Meier and Cox regression methods. Propensity score (PS)-matching was performed to estimate treatment effects while accounting for covariates predicting treatment allocation. Results Median follow-up was 7.4 and 8.0 years for patients treated with ART and ESRT, respectively. Ten-year FFBF (69% vs 56%, P = .003) and 10-year FFADT (88% vs 81%, P = .046) rates were higher after ART; however, FFDM and OS did not significantly differ. After PS-matching, ART was associated with improved FFBF ( P P = .0001), and FFDM ( P = .02). Findings were confirmed in multivariable analyses in unmatched and PS-matched cohorts. Sensitivity analyses showed that FFBF benefit associated with ART lost statistical significance only after 38% of ART patients were assumed to have been cured by surgery and excluded from the model. This corresponds to the upper bound of patients with adverse pathologic features who did not recur after observation in prior randomized trials. Conclusions Postoperative RT confers excellent long-term cancer control. These results suggest ART may be associated with improved FFBF, FFADT, and FFDM, but comparable OS. Given the retrospective study design, these findings should be interpreted with caution. Optimal timing of postoperative RT further awaits results of ongoing trials.

IMPORTANCE: Black men are more likely to die of prostate cancer than white men. In men with similar stages of disease, the contribution of biological vs nonbiological differences to this observed disparity is unclear. OBJECTIVE: To quantify the association of black race with long-term survival outcomes after controlling for known prognostic variables and access to care among men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This multiple-cohort study included updated individual patient-level data of men with clinical T1-4N0-1M0 prostate cancer from the following 3 cohorts: Surveillance, Epidemiology, and End Results (SEER [n = 296 273]); 5 equal-access regional medical centers within the Veterans Affairs health system (VA [n = 3972]); and 4 pooled National Cancer Institute–sponsored Radiation Therapy Oncology Group phase 3 randomized clinical trials (RCTs [n = 5854]). Data were collected in the 3 cohorts from January 1, 1992, through December 31, 2013, and analyzed from April 27, 2017, through April 13, 2019. EXPOSURES: In the VA and RCT cohorts, all patients received surgery and radiotherapy, respectively, with curative intent. In SEER, radical treatment, hormone therapy, or conservative management were received. MAIN OUTCOMES AND MEASURES: Prostate cancer–specific mortality (PCSM). Secondary measures included other-cause mortality (OCM). To adjust for demographic-, cancer-, and treatment-related baseline differences, inverse probability weighting (IPW) was performed. RESULTS: Among the 306 100 participants included in the analysis (mean [SD] age, 64.9 [8.9] years), black men constituted 52 840 patients (17.8%) in the SEER cohort, 1513 (38.1%) in the VA cohort, and 1129 (19.3%) in the RCT cohort. Black race was associated with an increased age-adjusted PCSM hazard (subdistribution hazard ratio [sHR], 1.30; 95% CI, 1.23-1.37; P

Purpose Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy. Methods and Materials We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4. Results We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of β-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells. Conclusions Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancer patients to individualize treatment.

Purpose Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. Methods Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder-intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. Results From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. Conclusion Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy.

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .

276 Background: Decipher is a genomic classifier (GC) that estimates risk of prostate cancer (PCa) distant metastases (DM) post-radical prostatectomy (RP). Herein, we validate the GC within the context of a randomized phase 3 trial. Methods: RP specimens from patients on the NRG/RTOG 9601 phase 3 placebo-controlled randomized trial of salvage radiotherapy (sRT) +/- 2 years of bicalutamide (NCT00002874) were centrally reviewed and the highest-grade tumor underwent RNA extraction. Samples passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to assign the GC score (scale 0-1). Our NCTN-CCSC approved pre-specified statistical plan (NRG-GU-TS002 CSC0075) included the primary objective of validating the ability of the GC to independently prognosticate the cumulative incidence of DM, with secondary endpoints of prostate cancer-specific mortality (PCSM) and overall survival (OS). Results: Of patients with tissue available, 352 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 13 years. On multivariable analysis, the GC (continuous variable) was independently associated with DM (HR 1.19 [95%CI 1.06-1.35], p=0.003), PCSM (HR 1.37 [95%CI 1.18-1.61], p

Background Multidisciplinary clinics integrate the expertise of several specialties to provide effective treatment to patients. This exposure is especially relevant in the management of muscle-invasive bladder cancer (MIBC), which requires critical input from urology, radiation oncology, and medical oncology, among other supportive specialties. Materials and Methods In the present study, we sought to catalog the different styles of multidisciplinary care models used in the management of MIBC and to identify barriers to their implementation. We surveyed providers from academic and community practices regarding their currently implemented multidisciplinary care models, available resources, and perceived barriers using the Bladder Cancer Advocacy Network and the Genitourinary Medical Oncologists of Canada e-mail databases. Results Of the 101 responding providers, most practiced at academic institutions in the United States (61%) or Canada (29%), and only 7% were from community practices. The most frequently used model was sequential visits on different days (57%), followed by sequential same-day (39%) and concurrent (1 visit with all providers; 22%) models. However, most practitioners preferred a multidisciplinary clinic involving sequential same-day (41%) or concurrent (26%) visits. The lack of clinic space (58%), funding (41%), staff (40%), and time (32%) were the most common barriers to implementing a multidisciplinary clinic. Conclusion Most surveyed practitioners at academic centers use some form of a multidisciplinary care model for patients with MIBC. The major barriers to more integrated multidisciplinary clinics were limited time and resources rather than a lack of provider enthusiasm. Future studies should incorporate patient preferences, further evaluate practice patterns in community settings, and assess their effects on patient outcomes.

Purpose To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer. Patients and Methods One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up. Results There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen–based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively. Conclusion Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.

Although bladder cancer (BC) is a significant health threat to the US population, integrated clinical and laboratory investigations of this disease lag behind those of other types of cancer. Advances in BC are especially challenged due in part to a general decreased level of funding over the past 5 years. It is ironic that despite the awareness that BC is the 5th most commonly diagnosed solid malignancy in the United States, and one of the most costly to treat, funding for this organ site lags far behind that of other less common malignancies. Moreover, BC offers several unique opportunities for translational research that make it an ideal candidate for investigation. One distinct advantage over other solid tumor sites is that urine and tissue are readily available for translational studies that can direct the development of novel therapy for this disease. The NCI sponsored “Novel Neoadjuvant Therapy for Bladder Cancer” forum held in brought leading clinical and laboratory-based scientists together with the advocacy community to lay the groundwork for collaborative discovery and translation. The goal of the meeting was to bridge the gaps in translational science and develop the concepts for two novel biomarker-driven clinical trials, one in the neoadjuvant presurgical setting and the other in the setting of bladder preservation with chemoradiation. The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapy for UC. Herein, we summarize the proceedings of this meeting, and the future plans resulting from this forum.

We describe the incidence, clinicopathological risk factors, management and outcomes of recurrent nonmuscle invasive bladder cancer after a complete response to trimodality therapy of muscle invasive bladder cancer.We retrospectively reviewed the records of 342 patients with cT2-4aN0M0 muscle invasive bladder cancer and a complete response after trimodality therapy from 1986 to 2013. Using competing risks analyses we examined the association between baseline clinicopathological variables and nonmuscle invasive bladder cancer outcomes. Kaplan-Meier and the generalized Fleming-Harrington test were used to compare disease specific and overall survival.At a median followup of 9 years nonmuscle invasive bladder cancer recurred in 85 patients (25%) who had had a complete response. On Kaplan-Meier analysis baseline carcinoma in situ was associated with recurrent nonmuscle invasive bladder cancer (p = 0.02). However, on multivariate analysis carcinoma in situ and other baseline clinicopathological characteristics did not predict such recurrence. Patients with recurrent nonmuscle invasive bladder cancer had worse 10-year disease specific survival than those without recurrence (72.1% vs 78.4%, p = 0.002), although overall survival was similar (p = 0.66). Of the 39 patients (46%) who received adjuvant intravesical bacillus Calmette-Guérin 29 (74%) completed induction therapy and 19 (49%) reported bacillus Calmette-Guérin toxicity. Three-year recurrence-free and progression-free survival after induction bacillus Calmette-Guérin was 59% and 63%, respectively.After a complete response to trimodality therapy nonmuscle invasive bladder cancer recurred in 25% of patients, developing in some of them more than a decade after trimodality therapy. No baseline clinicopathological characteristics were associated with such recurrence after a complete response. Patients with nonmuscle invasive bladder cancer recurrence had worse disease specific survival than those without such recurrence but similar overall survival. Adjuvant intravesical bacillus Calmette-Guérin had a reasonable toxicity profile and efficacy in this population. Properly selected patients with recurrent nonmuscle invasive bladder cancer after a complete response may avoid immediate salvage cystectomy.

To examine the accuracy of clinical staging and its effects on outcome in bladder cancer (BC) patients treated with radical cystectomy (RC), using a large national database.A total of 16,953 patients with BC without distant metastases treated with RC from 1998 to 2009 were analyzed. Factors associated with clinical-pathologic stage discrepancy were assessed by multivariate generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (n=7270) using the Kaplan-Meier method and Cox proportional hazards models.At RC 41.9% of patients were upstaged, whereas 5.9% were downstaged. Upstaging was more common in females, the elderly, and in patients who underwent a more extensive lymphadenectomy. Downstaging was less common in patients treated at community centers, in the elderly, and in Hispanics. Receipt of preoperative chemotherapy was highly associated with downstaging. Five-year overall survival rates for patients with clinical stages 0, I, II, III, and IV were 67.2%, 62.9%, 50.4%, 36.9%, and 27.2%, respectively, whereas those for the same pathologic stages were 70.8%, 75.8%, 63.7%, 41.5%, and 24.7%, respectively. On multivariate analysis, upstaging was associated with increased 5-year mortality (hazard ratio [HR] 1.80, P.001), but downstaging was not associated with survival (HR 0.88, P=.160). In contrast, more extensive lymphadenectomy was associated with decreased 5-year mortality (HR 0.76 for ≥10 lymph nodes examined, P.001), as was treatment at an National Cancer Institute-designated cancer center (HR 0.90, P=.042).Clinical-pathologic stage discrepancy in BC patients is remarkably common across the United States. These findings should be considered when selecting patients for preoperative or nonoperative management strategies and when comparing the outcomes of bladder sparing approaches to RC.

This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT).Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance.IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P.01), presence of sarcomatoid features (HR 3.7-6.9, P.05), and higher IORT dose (HR 1.3, P.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS.We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.

Purpose of review The management of nonmuscle invasive bladder cancer (NMIBC) recurrent after bacillus Calmette-Guerin therapy is complex and further complicated by high numbers of patients who are not candidates for cystectomy. This article reviews data supporting the use of chemoradiation in NMIBC and discusses emerging biomarkers of treatment response. Recent findings Radiotherapy, especially when combined with chemotherapy, has shown great promise for treating bladder cancer. Recent studies have identified that many patients with bladder cancer do not receive potentially curative therapies. Many such patients are elderly or infirm and represent an unmet need for curative therapeutic alternatives to radical cystectomy. Although radiotherapy alone does not appear superior to intravesical therapy in NMIBC, at least one series with long-term follow-up has shown excellent results in patients treated with radiation and concurrent chemotherapy. A clinical trial investigating the role for chemoradiation in T1 disease that has recurred is underway. Biomarkers able to predict radiotherapy response may allow for personalized therapy in the near future. Summary Chemoradiation is an emerging treatment option for selected patients with NMIBC. Prospective validation of currently identified biomarkers is needed along with further research to identify which patients may benefit the most from such therapy.

Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.

Urothelial tumors represent a spectrum of diseases with a range of prognosis. After a diagnosis is established at any point within the urothelial tract, the patient remains at risk for developing a new lesion at a different or the same location and at a similar or more advanced stage. Continued monitoring for recurrence is an essential part of management, because most recurrences are superficial and can be managed endoscopically. Within each category of disease, more refined methods to determine prognosis and guide management, based on molecular staging, are under development with the goal of optimizing the individual patient's likelihood of cure and chance for organ preservation. For patients with more extensive disease, newer treatments typically involve combined-modality approaches, using recently developed surgical procedures, or three-dimensional treatment planning for more precise delivery of radiation therapy. Although these are not appropriate in all cases, they do offer the promise of an improved quality of life and prolonged survival. Finally, within the category of metastatic disease, a number of new agents have been identified that appear to be superior to those currently considered to be standard therapies. Experts believe, therefore, that the treatment of urothelial tumors will evolve rapidly over the next few years, with improved outcomes for patients at all stages of disease.

Purpose Assess the impact of PSA-complete response (PSA-CR), measured at the end of external beam radiotherapy (EBRT) and short-term hormonal therapy (STHT), on treatment outcomes.

BACKGROUND There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved ≤ 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. Cancer 2013;119:1994–1998. © 2013 American Cancer Society.

BACKGROUND: Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT). METHODS: The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months. RESULTS: At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post-treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL. CONCLUSIONS: Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences. Cancer 2013. © 2013 American Cancer Society.

324 Background: Historically, radiation therapy for testicular seminoma has targeted the retroperitoneal (RPLN) and pelvic lymph nodes via standard anterior-posterior/posterior-anterior fields based upon skeletal anatomy. This study was undertaken to identify the location of involved lymph nodes and their relationship to both bony and vascular anatomy in stage II patients. Methods: Scans of 69 patients with stage II seminoma diagnosed between 1996 and 2011 were reviewed. 55% of patients had left-sided, 44% right-sided, and 1% bilateral primaries. The position of each node was recorded and then transferred to a standardized CT template scan based upon its relation to skeletal and vascular anatomy. Para-aortic fields were overlaid on the template, extending from T10/T11 to L5/S1 and bounded laterally by the contralateral transverse processes and ipsilateral renal hilum. Extended fields included ipsilateral iliac lymph node chains. The location of involved nodes within these conventional fields was assessed. Results: 113 nodes were identified as radiographically positive. 88% of involved nodes were located in the RPLN region with the remaining 12% in the pelvis. 98% of positive RPLN nodes were within a 2.2cm lateral and 1.8cm anterior expansion of the aorta between L1/L2 and L5/S1. No positive nodes were identified within the renal hilar region or superior to L1 for patients with left-sided seminomas. For right-sided seminomas, no positive nodes were superior to L2, though there was one renal hilar node. Conclusions: Nodal metastases from a contemporary cohort of stage II seminoma patients generally localized to a smaller area than is targeted using conventional fields. Notably, no positive nodes were identified superior to L1, on the contralateral side of vertebral bodies, or in the left renal hilum. Modified treatment fields based on vascular rather than bony anatomy may allow for a significant decrease in normal tissue irradiation and its associated toxicities. Validation of these results may inform guidelines for a redefined clinical target volume and allow for more targeted radiation delivery in the treatment of seminoma.

Context New guidelines of the International Consultation on Urological Diseases for the treatment of muscle-invasive bladder cancer (MIBC) have recently been published. Objective To provide a comprehensive overview of the current role of radical cystectomy (RC) in MIBC. Evidence acquisition A detailed Medline analysis was performed for original articles addressing the role of RC with regard to indication, timing, surgical extent, perioperative morbidity, oncologic outcome, and follow-up. The analysis also included radiation-based bladder-preserving strategies. Evidence synthesis The major findings are presented in an evidence-based fashion and are based on large retrospective unicenter and multicenter series with some prospective data. Conclusions Open RC is the standard treatment for locoregional control of MIBC. Delay of RC is associated with reduced cancer-specific survival. In males, standard RC includes the removal of the bladder, prostate, seminal vesicles, and distal ureters; in females, RC includes an anterior pelvic exenteration including the bladder, entire urethra and adjacent vagina, uterus, and distal ureters. A procedure sparing the urethra and the urethra-supplying autonomous nerves can be performed in case of a planned orthotopic neobladder. Further technical variations (ie, seminal-sparing or vaginal-sparing techniques) aimed at improving functional outcomes must be weighed against the risk of a positive margin. Laparoscopic surgery is promising, but long-term data are required prior to accepting it as an option equivalent to the open procedure. Lymphadenectomy should remove all lymphatic tissue around the common iliac, external iliac, internal iliac, and obturator region bilaterally. Complications after RC should be reported according to the modified Clavien grading system. In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC.

Health-related quality of life (QOL) has not been well-studied in survivors of muscle-invasive bladder cancer (MIBC). The present study compared long-term QOL in MIBC patients treated with radical cystectomy (RC) versus bladder-sparing trimodality therapy (TMT).This cross-sectional bi-institutional study identified 226 patients with nonmetastatic cT2-cT4 MIBC, diagnosed in 1990 to 2011, who were eligible for RC and were disease free for ≥2 years. Six validated QOL instruments were administered: EuroQOL EQ-5D, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire and EORTC MIBC module, Expanded Prostate Cancer Index Composite bowel scale, Cancer Treatment and Perception Scale, and Impact of Cancer, version 2. Multivariable analyses of the mean QOL scores were conducted using propensity score matching.The response rate was 77% (n=173). The median follow-up period was 5.6 years. Of the 173 patients, 64 received TMT and 109, RC. The median interval from diagnosis to questionnaire completion was 9 years after TMT and 7 years after RC (P=.009). No significant differences were found in age, gender, comorbidities, tobacco history, performance status, or tumor stage. On multivariable analysis, patients who received TMT had better general QOL by 9.7 points of 100 compared with those who had received RC (P=.001) and higher physical, role, social, emotional, and cognitive functioning by 6.6 to 9.9 points (P≤.04). TMT was associated with better bowel function by 4.5 points (P=.02) and fewer bowel symptoms by 2.7 to 7.1 points (P≤.05). The urinary symptom scores were similar. TMT was associated with better sexual function by 8.7 to 32.1 points (P≤.02) and body image by 14.8 points (P.001). The patients who underwent TMT reported greater informed decision-making scores by 13.6 points (P=.01) and less concern about the negative effect of cancer by 6.8 points (P=.006). The study limitations included missing baseline QOL data and different follow-up times.Both TMT and RC result in good long-term QOL outcomes in MIBC survivors, supporting TMT as a good alternative to RC for selected patients. Whether TMT leads to superior QOL requires prospective validation.

Introduction To estimate the contribution of the prostate gland and prostatic urethral inflammation to urinary symptoms after radiation therapy for prostate cancer, we performed a secondary analysis of urinary toxicity after primary radiation to an intact prostate vs. postprostatectomy radiation to the prostatic fossa in protocols RTOG 94-08 and 96-01, respectively. Materials and methods Patients randomized to the radiation-alone arms (without hormone therapy) of the 2 trials were evaluated, including 104 men receiving primary prostate radiation to 68.4 Gy on RTOG 94-08 and 371 men receiving 64.8 Gy to the prostatic fossa on RTOG 96-01. Acute and late urinary toxicity were scored prospectively by RTOG scales. Chi-square test/logistic regression and cumulative incidence approach/Fine-Gray regression model were used for analyses of acute and late toxicity, respectively. Results Grade≥2 acute urinary toxicity was significantly higher after primary prostatic radiation compared with postprostatectomy radiation (30.8% vs. 14.0%; P P = 0.54). After adjusting for age, primary radiation resulted in significantly higher grade≥2 acute urinary toxicity (odds ratio = 3.72; 95% CI: 1.65–8.37; P = 0.02). With median follow-up of 7.1 years, late urinary toxicity was not significantly different with primary vs. postprostatectomy radiation (5-year grade≥2: 16.7% vs. 18.3%; P = 0.65; grade≥3: 6.0% vs. 3.3%; P = 0.24). Conclusions Primary radiation to an intact prostate resulted in higher grade≥2 acute urinary toxicity than radiation to the prostatic fossa, with no difference in late urinary toxicity. Thus, a proportion of acute urinary toxicity in men with an intact prostate may be attributable to inflammation of the prostatic gland or urethra.

Purpose The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. Methods and Materials Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b-T2b and prostate-specific antigen concentrations of ≤20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. Results A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3-2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease-specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score ≥7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). Conclusions Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors.

Whether organ-conserving treatment by combined-modality therapy (CMT) achieves comparable long-term survival to radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) is largely unknown.Report long-term outcomes of patients with muscle-invasive BCa treated by CMT.We conducted an analysis of successive prospective protocols at the Massachusetts General Hospital (MGH) treating 348 patients with cT2-4a disease between 1986 and 2006. Median follow-up for surviving patients was 7.7 yr.Patients underwent concurrent cisplatin-based chemotherapy and radiation therapy (RT) after maximal transurethral resection of bladder tumor (TURBT) plus neoadjuvant or adjuvant chemotherapy. Repeat biopsy was performed after 40 Gy, with initial tumor response guiding subsequent therapy. Those patients showing complete response (CR) received boost chemotherapy and RT. One hundred two patients (29%) underwent RC-60 for less than CR and 42 for recurrent invasive tumors.Disease-specific survival (DSS) and overall survival (OS) were evaluated using the Kaplan-Meier method.Seventy-two percent of patients (78% with stage T2) had CR to induction therapy. Five-, 10-, and 15-yr DSS rates were 64%, 59%, and 57% (T2=74%, 67%, and 63%; T3-4=53%, 49%, and 49%), respectively. Five-, 10-, and 15-yr OS rates were 52%, 35%, and 22% (T2: 61%, 43%, and 28%; T3-4=41%, 27%, and 16%), respectively. Among patients showing CR, 10-yr rates of noninvasive, invasive, pelvic, and distant recurrences were 29%, 16%, 11%, and 32%, respectively. Among patients undergoing visibly complete TURBT, only 22% required cystectomy (vs 42% with incomplete TURBT; log-rank p0.001). In multivariate analyses, clinical T-stage and CR were significantly associated with improved DSS and OS. Use of neoadjuvant chemotherapy did not improve outcomes. No patient required cystectomy for treatment-related toxicity.CMT achieves a CR and preserves the native bladder in70% of patients while offering long-term survival rates comparable to contemporary cystectomy series. These results support modern bladder-sparing therapy as a proven alternative for selected patients.

Given concerns of excess malignancies following adjuvant radiation for seminoma, we evaluated photon and proton beam therapy (PBT) treatment plans to assess dose distributions to organs at risk and model rates of second cancers.Ten stage I seminoma patients who were treated with conventional para-aortic AP-PA photon radiation to 25.5 Gy at Massachusetts General Hospital had PBT plans generated (AP-PA, PA alone). Dose differences to critical organs were examined. Risks of second primary malignancies were calculated.PBT plans were superior to photons in limiting dose to organs at risk. PBT decreased dose by 46% (8.2 Gy) and 64% (10.2 Gy) to the stomach and large bowel, respectively (p0.01). Notably, PBT was found to avert 300 excess second cancers among 10,000 men treated at a median age of 39 and surviving to 75 (p0.01).In this study, the use of protons provided a favorable dose distribution with an ability to limit unnecessary exposure to critical normal structures in the treatment of early-stage seminoma. It is expected that this will translate into decreased acute toxicity and reduced risk of second cancers, for which prospective studies are warranted.

Objectives High-dose external radiation for localized prostate cancer results in favorable clinical outcomes and low toxicity rates. Here, we report long-term quality of life (QOL) outcome for men treated with conformal protons. Methods QOL questionnaires were sent at specified intervals to 95 men who received proton radiation. Of these, 87 men reported 3- and/or 12-month outcomes, whereas 73 also reported long-term outcomes (minimum 2 years). Symptom scores were calculated at baseline, 3 months, 12 months, and long-term follow-up. Generalized estimating equation models were constructed to assess longitudinal outcomes while accounting for correlation among repeated measures in an individual patient. Men were stratified into functional groups from their baseline questionnaires (normal, intermediate, or poor function) for each symptom domain. Long-term QOL changes were assessed overall and within functional groups using the Wilcoxon signed-rank test. Results Statistically significant changes in all four symptom scores were observed in the longitudinal analysis. For the 73 men reporting long-term outcomes, there were significant change scores for incontinence (ID), bowel (BD) and sexual dysfunction (SD), but not obstructive/irritative voiding dysfunction (OID). When stratified by baseline functional category, only men with normal function had increased scores for ID and BD. For SD, there were significant changes in men with both normal and intermediate function, but not poor function. Conclusions Patient reported outcomes are sensitive indicators of treatment-related morbidity. These results quantitate the long-term consequences of proton monotherapy for prostate cancer. Analysis by baseline functional category provides an individualized prediction of long-term QOL scores. High dose proton radiation was associated with small increases in bowel dysfunction and incontinence, with more pronounced changes in sexual dysfunction.

Purpose To report a case-matched analysis comparing high-dose external-beam radiation (EBRT) for prostate cancer delivered on Proton Radiation Oncology Group (PROG) 95-09, a randomized trial, with permanent prostate brachytherapy over the same era. Methods From 1996 to 1999, 196 patients were accrued to the high-dose arm (79.2 Gray equivalent (GyE) using photons and protons) of PROG 95-09 at the Massachusetts General Hospital and Loma Linda University Medical Center. Entry criteria specified T1–2 and prostate-specific antigen ≤15 ng/mL. When Gleason score >7 was excluded, 177 men were left for case matching. At Massachusetts General Hospital, 203 similar patients were treated by a single brachytherapist from 1997 to 2002. Minimum follow-up was 3 years. Case matching, based on T stage, Gleason score, prostate-specific antigen, and age resulted in 141 matches (282 patients). Median follow-up was 8.6 and 7.4 years for EBRT and brachytherapy, respectively. The primary endpoint was biochemical failure (BF). Results Using the Phoenix definition, the 8-year BF rates were 7.7% and 16.1% for EBRT and brachytherapy, respectively ( p = 0.42). A stratified analysis was performed by risk group. In the EBRT group, 113 and 28 patients were low and intermediate risk, respectively. In the brachytherapy group, 118 and 23 were. When stratified by risk group, the BF rates were similar by either technique. Conclusions High-dose EBRT and brachytherapy result in similar BF rates for men with localized prostate cancer. Comparative quality-of-life and cost-effectiveness studies are warranted.

343 Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was >1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.

Purpose Several randomized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer. Single-institution data suggest a benefit with even higher doses. American College of Radiology 03-12 is a Phase II trial testing the safety and efficacy of 82 GyE (Gray equivalent) delivered with conformal proton radiation. Methods and Materials From 2003–2006, 85 men with localized prostate cancer were accrued to American College of Radiology 03-12. Eighty-four were eligible for analysis. They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was designed to test whether the rate of 18-month Grade 3+ late toxicity was greater than 10%. Results The median follow-up was 31.6 months. Regarding treatment-related acute toxicity, there were 39 Grade 1 cases (46%), 19 Grade 2 cases (23%) and 2 Grade 3 cases (2%). Regarding genitourinary/gastrointestinal toxicity, there were 42 Grade 1 cases (50%), 12 Grade 2 cases (14%) and 1 Grade 3 case (1%). Regarding late toxicity, there were 28 Grade 1 cases (33%), 22 Grade 2 cases (26%), 6 Grade 3 cases (7%), and 1 Grade 4 case (1%). The late genitourinary/gastrointestinal rates were the same. The estimated rate of Grade 3+ late toxicity at 18 months was 6.08%. Conclusions Although not free of late toxicity, 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial. There was sufficient morbidity, however, that this may be the maximal dose that can be delivered safely with this technique and fractionation.

Purpose: The purpose of this study was to evaluate the effect on freedom from biochemical failure (bNED) or disease-free survival (DFS) by adding hormone therapy (HT) to dose-escalated radiation therapy (HDRT). Methods and Materials: We used 883 analyzable prostate cancer patients who enrolled on Radiation Therapy Oncology Group (RTOG) 94-06, a Phase I/II dose escalation trial, and whose mean planning target volume dose exceeded 73.8 Gy (mean, 78.5 Gy; maximum, 84.3 Gy). We defined biochemical failure according to the Phoenix definition. Results: A total of 259 men started HT 2 to 3 months before HDRT, but not longer than 6 months, and 66 men with high-risk prostate cancer received HT for a longer duration. At 5 years, the biochemical failure rates after HDRT alone were 12%, 18%, and 29% for low-, intermediate-, and high-risk patients, respectively (p < 0.0001). Cox proportional hazards regression analysis adjusted for covariates revealed that pretreatment PSA level was a significant factor, whereas risk group, Gleason score, T-stage, and age were not. When the patients were stratified by risk groups, the Cox proportion hazards regression model (after adjusting for pretreatment PSA, biopsy Gleason score, and T stage) did not reveal a significant effect on bNED ormore » DFS by adding HT to HDRT Conclusion: The addition of HT did not significantly improve bNED survival or DFS in all prostate cancer patients receiving HDRT, but did approach significance in high-risk patient subgroup. The result of this study is hypothesis generating and requires testing in a prospective randomized trial.« less

408 Background: To assess GD or FCT as the chemoradiation (CRT) component of a bladder sparing regimen. Methods: Patients with T2-4a bladder cancer were randomized. Patients had a maximal transurethral resection and induction CRT to 40 Gy followed by cystoscopic assessment. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others were offered cystectomy and no further CRT. Adjuvant gemcitabine/cisplatin chemotherapy was subsequently administered. The primary endpoint was the rate of distant metastasis at 3 years (DM3). Toxicity and other efficacy related endpoints including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3) were also assessed. Using the Clopper-Pearson method, the study required 32 patients per arm, with a benchmark DM3 of 25% and a 1-sided significance level of 0.1. If both arms meet this benchmark, toxicity will be used to select a regimen for future study. This study was not designed to compare arms. Results: From 12/2008 to 4/2014, 70 patients were enrolled; 66 were eligible for analysis (33 per arm). Median follow-up was 4.3 years. DM3 was 22% and 16% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. CR rates were 88% and 78%, respectively. Of 33 patients in the FCT group, 32 (97%) completed induction, 27 (93%) completed induction and consolidation, and 18 (55%) completed the entire protocol. Of 33 patients in the GD group, these figures were 31 (94%), 23 (92%), and 16 (49%), respectively. Of 33 patients in the FCT group, 21 (64%) had grade 3-4 toxicity during protocol treatment with 18 (55%), 2 (6%) and 2 (6%) experiencing hematologic, GI and GU toxicity, respectively. For 33 patients in the GD group, these figures were 18 (55%) overall and 14 (43%), 3 (9%) and 2 (6%), respectively. Conclusions: Both regimens are promising, given DM3 rates < 25%. As there was less toxicity in the GD arm, it would be reasonable to consider a gemcitabine based option as well as a cisplatin based regimen for future trials. Daily radiation may be as effective as twice-daily radiation, which may broaden appeal. Clinical trial information: NCT00777491.