Symptomatic and functional recovery after transurethral resection of bladder tumor: Data from ecological momentary symptom assessment.

OBJECTIVES: To quantitatively describe the nature, severity, and duration of symptoms and functional impairment during recovery from transurethral resection of bladder tumors. MATERIALS AND METHODS: All patients scheduled for transurethral resection were approached for enrollment in a text-message based ecological momentary symptom assessment platform. Nine patients reported outcomes were measured 7 days before surgery and on postoperative days 1, 2, 3, 5, 7, 10, and 14 using a 5-point Likert scale. Self-reported degree of hematuria was collected using a visual scale. Clinical data was collected via retrospective chart review. RESULTS: A total of 159 patients were analyzed. Postoperative symptoms were overall mild, with the largest differences from baseline to postoperative day 1 seen in dysuria (median 0/5 vs. 3/5) and ability to work (median 5/5 vs. 4/5). Recovery was generally rapid, with 76% of patients reporting ≥4/5 agreement with the statement "I feel recovered from surgery" by postoperative day 2, although 15% of patients reported persistently lower levels of agreement on postoperative day 10 or 14. Patients undergoing larger resections (≥2cm) did take longer to return to baseline in multiple symptom domains, but the difference of medians vs. those undergoing smaller resections was less than 1 day across all domains. Multivariable analysis suggested that receiving perioperative intravesical chemotherapy was associated with longer time to recovery. 84% of patients reported clear yellow urine by postoperative day 3. CONCLUSION: In this population, hematuria and negative effects on quality of life resulting from transurethral resection of bladder tumors were generally mild and short-lived, although a small number of patients experienced longer recoveries.

Transition to Value-based Healthcare: Development, Implementation, and Results of an Optimal Surgical Care Framework at a National Cancer Institute-designated Comprehensive Cancer Center.

BACKGROUND: The continued rise in healthcare expenditures has not produced commensurate improvements in patient outcomes, leading US healthcare stakeholders to emphasize value-based care. Transition to such a model requires all team members to adopt a new strategic and organizational framework. OBJECTIVE: To describe and report a strategy for the implementation of a novel patient-centered value-based "optimal surgical care" (OSC) framework, with validation and cost analysis in kidney surgery. DESIGN, SETTING, AND PARTICIPANTS: An observational study of care episodes at a single institution from 2014 to 2019 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multidisciplinary teams defined OSC by core and procedure-specific metrics using a combination of provider-based ("bottom-up") and "clinical leadership"-based ("top-down") strategies. Baseline OSC rates across were established, while identifying proportions of OSC achieved by coefficient of variation (CV) in total direct costs. Multivariable linear regression comparing cost between OSC and non-OSC encounters was performed, adjusting for patient characteristics. RESULTS AND LIMITATIONS: An analysis of 30 261 perioperative care episodes was performed. Following the implementation of an OSC framework, there was an increase in OSC rates across all procedure buckets using core (25%) and procedure-specific (26%) metrics. Among the tumors tested, kidney cancer surgical episodes held the highest OSC rate improvement (67%) with lowest variability in cost (CV 0.5). OSC was associated with significant total cost savings across all tumor types after adjusting for inflation (p < 0.05). Compared with non-OSC episodes, a significant reduction in the cost ratio of OSC was noted for renal surgery (p < 0.01), with estimated costs savings of $2445.87 per OSC encounter. CONCLUSIONS: Institutional change directing efforts toward optimizing surgical care and emphasizing value rather than focusing solely on expense reduction is associated with improved outcomes, while potentially reducing costs. The strategy for implementation requires serial performance analyses, engaging and educating providers, and continuous ongoing adjustments to achieve durable results. PATIENT SUMMARY: In this study, we report our strategy and outcomes for transitioning to a value-based healthcare model using a novel "optimal surgical care" framework at a National Cancer Institute-designated comprehensive cancer center. We observed an increase in optimal surgical care episodes across all specialties after 5 yr, with a potential associated reduction in cost expenditure. We conclude that the key to a successful and sustained transition is the implementation strategy, focusing on continual review and provider engagement.

Adverse Events Reported by Patients With Cancer After Administration of a 2-Dose mRNA COVID-19 Vaccine.

BACKGROUND: Most safety and efficacy trials of the SARS-CoV-2 vaccines excluded patients with cancer, yet these patients are more likely than healthy individuals to contract SARS-CoV-2 and more likely to become seriously ill after infection. Our objective was to record short-term adverse reactions to the COVID-19 vaccine in patients with cancer, to compare the magnitude and duration of these reactions with those of patients without cancer, and to determine whether adverse reactions are related to active cancer therapy. PATIENTS AND METHODS: A prospective, single-institution observational study was performed at an NCI-designated Comprehensive Cancer Center. All study participants received 2 doses of the Pfizer BNT162b2 vaccine separated by approximately 3 weeks. A report of adverse reactions to dose 1 of the vaccine was completed upon return to the clinic for dose 2. Participants completed an identical survey either online or by telephone 2 weeks after the second vaccine dose. RESULTS: The cohort of 1,753 patients included 67.5% who had a history of cancer and 12.0% who were receiving active cancer treatment. Local pain at the injection site was the most frequently reported symptom for all respondents and did not distinguish patients with cancer from those without cancer after either dose 1 (39.3% vs 43.9%; P=.07) or dose 2 (42.5% vs 40.3%; P=.45). Among patients with cancer, those receiving active treatment were less likely to report pain at the injection site after dose 1 compared with those not receiving active treatment (30.0% vs 41.4%; P=.002). The onset and duration of adverse events was otherwise unrelated to active cancer treatment. CONCLUSIONS: When patients with cancer were compared with those without cancer, few differences in reported adverse events were noted. Active cancer treatment had little impact on adverse event profiles.

Adjuvant therapy in patients with sarcomatoid renal cell carcinoma: post hoc analysis from Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2805.

OBJECTIVES: To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805. PATIENTS AND METHODS: The original trial (E2805) was a randomised, double-blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805. RESULTS: A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3-4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very-high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5-year disease-free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.45-1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53-1.28 for sorafenib vs placebo). CONCLUSIONS: Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.

Concordance of confirmatory prostate biopsy in active surveillance with national guidelines: An analysis from the multi-institutional PURC cohort.

PURPOSE: National Comprehensive Cancer Network (NCCN) guidelines recommend confirmatory biopsy within 12 months of active surveillance (AS) enrollment. With <10 cores on initial biopsy, re-biopsy should occur within 6 months. Our objective was to determine if patients on AS within practices in the Pennsylvania Urologic Regional Collaborative (PURC) receive guideline concordant confirmatory biopsies. MATERIALS AND METHODS: Within PURC, a prospective collaborative of diverse urology practices in Pennsylvania and New Jersey, we identified men enrolled in AS after first biopsy, analyzing time to re-biopsy and factors associated with various intervals of re-biopsy. RESULTS: In total, 1,047 patients were enrolled in AS for a minimum of 12 months after initial biopsy. Four hundred seventy-seven (45%) underwent second biopsy at 1 of the 9 PURC practices. The number of patients undergoing re-biopsy within 6 months, 6 to 12 months, 12 to 18 months, and >18 months was 71 (14%), 218 (45.7%), 134 (28%), and 54 (11%), respectively. Sixty percent underwent confirmatory biopsy within 12 months. On multivariate analysis, re-biopsy interval was associated with number of positive cores, perineural invasion, and practice ID (all P < 0.05). Adjusted multivariable regression did not identify factors predictive of re-biopsy interval. CONCLUSION: Of patients who underwent confirmatory biopsy at PURC practices, 60.5% were within 12 months per NCCN guidelines. This suggests area for improvement in guideline adherence after enrollment in AS. All practices that offer AS should periodically perform similar analyses to monitor their performance. In an era of value-based care, adherence to guideline based active surveillance practices may eventually comprise national quality metrics affecting provider reimbursement.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS: Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS: Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION: H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

Angiogenic Factor and Cytokine Analysis among Patients Treated with Adjuvant VEGFR TKIs in Resected Renal Cell Carcinoma.

PURPOSE: The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial. EXPERIMENTAL DESIGN: Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels. RESULTS: VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status. CONCLUSIONS: Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.

Active Surveillance as Initial Management of Newly Diagnosed Prostate Cancer: Data from the PURC.

PURPOSE: We describe contemporary active surveillance utilization and variation in a regional prostate cancer collaborative. We identified demographic and disease specific factors associated with active surveillance in men with newly diagnosed prostate cancer. MATERIALS AND METHODS: We analyzed data from the PURC (Pennsylvania Urologic Regional Collaborative), a cooperative effort of urology practices in southeastern Pennsylvania and New Jersey. We determined the rates of active surveillance among men with newly diagnosed NCCN® (National Comprehensive Cancer Network®) very low, low or intermediate prostate cancer and compared the rates among participating practices and providers. Univariate and multivariable analyses were used to identify factors associated with active surveillance utilization. RESULTS: A total of 1,880 men met inclusion criteria. Of the men with NCCN very low or low risk prostate cancer 57.4% underwent active surveillance as the initial management strategy. Increasing age was significantly associated with active surveillance (p <0.001) while adverse clinicopathological variables were associated with decreased active surveillance use. Substantial variation in active surveillance utilization was observed among practices and providers. CONCLUSIONS: More than 50% of men with low risk disease in the PURC collaborative were treated with active surveillance. However, substantial variation in active surveillance rates were observed among practices and providers in academic and community settings. Advanced age and favorable clinicopathological factors were strongly associated with active surveillance. Analysis of regional collaboratives such as the PURC may allow for the development of strategies to better standardize treatment in men with prostate cancer and offer active surveillance in a more uniform and systematic fashion.

Patterns of Relapse and Implications for Post-Nephrectomy Surveillance in Patients with High Risk Nonclear Cell Renal Cell Carcinoma: Subgroup Analysis of the Phase 3 ECOG-ACRIN E2805 Trial.

PURPOSE: The natural history of nonclear cell renal cell carcinoma following surgery with curative intent remains poorly defined with postoperative surveillance informed by guidelines largely intended for clear cell renal cell carcinoma. We evaluated relapse patterns and potential implications for post-nephrectomy surveillance in patients with nonclear cell renal cell carcinoma enrolled in the E2805 trial, the largest randomized trial of adjuvant antiangiogenic therapy of high risk renal cell carcinoma. MATERIALS AND METHODS: We retrospectively analyzed the records of patients with completely resected nonclear cell renal cell carcinoma. Participants received up to 54 weeks of postoperative therapy with sunitinib, sorafenib or placebo and underwent surveillance imaging at standardized intervals for 10 years. For recurrence rates by site the cumulative incidence was estimated, accounting for competing risks. The adequacy of strict adherence to post-nephrectomy surveillance guidelines was evaluated. RESULTS: A total of 403 patients with nonclear cell renal cell carcinoma were enrolled in the study. During a median followup of 6.2 years 36% of nonclear cell renal cell carcinomas recurred. Five-year recurrence rates were comparable for nonclear and clear cell renal cell carcinoma in the 1,541 patients, including 34.6% (95% CI 29.8-39.4) and 39.5% (95% CI 36.9-42.1), respectively. However, patients with nonclear cell renal cell carcinoma were significantly more likely to have abdominal sites of relapse (5-year recurrence rate 26.4% vs 18.2%, p = 0.0008) and significantly less likely to experience relapse in the chest (5-year recurrence rate 13.7% vs 20.9%, p = 0.0005). Current surveillance guidelines would potentially capture approximately 90% of relapses at any site. CONCLUSIONS: Nonclear cell renal cell carcinoma may show a distinct pattern of relapse compared to clear cell renal cell carcinoma. Our findings emphasize the importance of cross-sectional, long-term imaging in patients with high risk, resected, nonclear cell renal cell carcinoma.

Treatment Trends and Outcomes for Patients With Lymph Node-Positive Cancer of the Penis.

Importance: Penile cancer is an uncommon disease with minimal level I evidence to guide therapy. The National Comprehensive Cancer Network (NCCN) guidelines advocate a lymph node dissection (LND) or radiotherapy with consideration of perioperative chemotherapy for all patients with lymph node-positive (LN+) penile cancer without metastasis. Objectives: To determine temporal trends in use of chemotherapy for patients with LN+ penile cancer without metastasis and to evaluate outcomes between those who did or did not receive LND, chemotherapy, and radiotherapy. Design, Setting, and Participants: The US National Cancer Database (NCDB) was queried for all 1123 patients with LN+, squamous cell carcinoma of the penis without metastasis from January 1, 2004, through December 31, 2014. Temporal trends were assessed using Cochran-Armitage tests. Multivariable logistic models were used to examine the association between treatments, clinicopathologic variables, and receipt of chemotherapy. Kaplan-Meier analyses with log-rank tests and multivariable Cox regressions were used to analyze overall survival. Data were analyzed between January 2017 and September 2017. Main Outcomes and Measures: Use of chemotherapy over time. Survival outcomes by receipt or nonreceipt of LND, radiotherapy, and chemotherapy. Results: Of 1123 patients identified, most were white (924 [82.3%]) vs African American (141 [12.6%]) or of other or unknown race (58 [5.2%]). The age of most patients (727 [64.7%]) was between 50 and 75 years, and 750 patients (66.8%) underwent an LND. From 2004 to 2014, the use of systemic therapy significantly increased (26 of 68 patients, 38.2% vs 65 of 136, 47.8%; P < .001). However, only 177 of 335 patients with N3 disease (52.8%) received chemotherapy (N1: 106 of 338, 31.4%; N2: 178 of 450, 39.6%). Following adjustment, older patients (>76 years: OR, 0.28; 95% CI, 0.15-0.50; P < .001) were less likely to receive chemotherapy. Patients who received radiotherapy (OR, 4.38; 95% CI, 3.10-6.18; P < .001) and those patients with N2 (OR, 1.62; 95% CI, 1.16-2.27; P = .005) or N3 (OR, 2.32; 95% CI, 1.67-3.22; P < .001) cancer were more likely to receive chemotherapy. On multivariable analysis, LND (HR, 0.64; 95% CI, 0.52-0.78; P < .001) was associated with better overall survival, while neither chemotherapy (HR, 1.01; 95% CI, 0.80-1.26; P = .95) nor radiotherapy (HR, 0.85; 95% CI, 0.70-1.04; P = .11) was associated with overall survival. Conclusions and Relevance: In hospitals reporting to the NCDB, only 66.8% of patients with LN+ penile cancer received an LND. While chemotherapy use has increased since 2004, rates remain low (52.8% for patients with N3 cancer). Receipt of LND, but not chemotherapy or radiotherapy, is associated with overall survival. This may reflect the aggressive natural history of penile cancer as well as the inherent analysis limitation of a relatively small sample size. These data highlight opportunities to improve adherence to guideline-recommended care.

Differences in Survival Associated with Performance of Lymph Node Dissection in Patients with Invasive Penile Cancer: Results from the National Cancer Database.

PURPOSE: Inguinal lymphadenectomy remains under performed in patients with invasive penile cancer. Using a large national cancer registry we assessed temporal trends in inguinal lymphadenectomy performance and evaluated the impact of the procedure on survival in patients in whom inguinal lymphadenectomy was an absolute indication (T1b-4 N0/x-1) according to NCCN® (National Comprehensive Cancer Network®) Guidelines®. MATERIALS AND METHODS: We queried the National Cancer Database for all cases of nonmetastatic, T1b-4 N0/x-1 squamous cell carcinoma of the penis from 2004 to 2014. Multivariable logistic regression models adjusting for patient, demographic, and clinicopathological characteristics were used to examine the association between available covariates and receipt of inguinal lymphadenectomy. Cox proportional hazards regression analysis was then done to assess the impact of clinical and pathological variables on overall survival. Propensity score weighted analysis was performed to assess the effect of inguinal lymphadenectomy on overall survival. RESULTS: A total of 2,224 patients met analysis criteria, of whom 606 (27.2%) underwent inguinal lymphadenectomy. Following adjustment the procedure was more likely in younger patients, those who presented with palpable adenopathy (cN1), those treated at an academic facility and those with a more contemporary diagnosis. On survival analysis controlling for all known and measured confounders inguinal lymphadenectomy was associated with improved overall survival (HR 0.79, 95% CI 0.74-0.84, p <0.001). CONCLUSIONS: At hospitals that report to the National Cancer Database the overall rate of inguinal lymphadenectomy in patients with invasive penile cancer was only 27.2%. Inguinal lymphadenectomy was associated with increased overall survival, justifying the procedure as an important quality metric for performance reporting in patients with invasive penile cancer.

Effects of interruptions of external beam radiation therapy on outcomes in patients with prostate cancer.

INTRODUCTION: To evaluate if interruptions of external beam radiation therapy impact outcomes in men with localized prostate cancer (PCa). METHODS: We included men with localized PCa treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) of escalated dose (≥74 Gy in 1.8 or 2 Gy fractions) between 1992 and 2013 at an NCI-designated cancer centre. Men receiving androgen deprivation therapy were excluded. The non-treatment day ratio (NTDR) was defined as the number of non-treatment days divided by the total elapsed days of therapy. NTDR was analysed for each National Comprehensive Cancer Network (NCCN) risk group. RESULTS: There were 1728 men included (839 low-risk, 776 intermediate-risk and 113 high-risk), with a median follow up of 53.5 months (range 12-185.8). The median NTDR was 31% (range 23-71%), translating to approximately 2 breaks (each break represents a missed treatment that will be made up) for 8 weeks of RT with 5 treatments per week. The 75 percentile of NTDR was 33%, translating to approximately 4 breaks, which was used as the cutoff for analysis. There were no significant differences in freedom from biochemical failure, freedom from distant metastasis, cancer specific survival, or overall survival for men with NTDR ≥33% compared to NTDR<33% for each risk group. Multivariable analyses including NTDR, age, race, Gleason score, T stage, and PSA were performed using the proportional hazards regression procedure. NTDR≥33% was not significantly associated with increased hazard ratio for outcomes in each risk group compared to NTDR<33%. CONCLUSION: Unintentional treatment breaks during dose escalated external beam radiation therapy for PCa did not cause a significant difference in outcomes, although duration of follow up limits the strength of this conclusion.

Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial.

IMPORTANCE: Given recently published results of a 750-patient adjuvant sunitinib trial showing improved disease-free survival (DFS), the appropriate strategy for treating high-risk patients is unclear. We sought to determine whether there is improved disease-free survival benefit to taking the active drug in patients with high-risk (pT3, pT4, node-positive) clear cell renal cancer (ccRCC) in the ASSURE trial (adjuvant sunitinib or sorafenib vs placebo in resected unfavorable renal cell carcinoma [RCC]), the largest adjuvant trial published to date. OBJECTIVE: To evaluate DFS and overall survival (OS) in ccRCC high-risk patients randomized to sunitinib or sorafenib vs placebo among patients with stages comparable to other high-risk adjuvant trials. DESIGN, SETTING, AND PARTICIPANTS: The DFS and OS at 10 years postactivation were calculated for 1069 patients in US and Canadian cooperative groups with high-risk patients who had ccRCC histology and pT3, pT4, or node-positive disease accrued between 2006 and 2010 to the double-blind randomized placebo-controlled phase 3 trial. Outcome analyses by dose quartiles of these patients receiving sunitinib or sorafenib were also performed. INTERVENTIONS: Patients received 1 year of adjuvant sunitinib (50 mg), sorafenib (800 mg) daily, or equivalent placebo. The study was amended for patient intolerance to sunitinib (37.5 mg), sorafenib (400 mg) daily, or equivalent placebo with mandatory dose escalation if no serious adverse effects were experienced. MAIN OUTCOMES AND MEASURES: Disease-free survival, defined as time from randomization to recurrence, second primary cancer, or death. RESULTS: Of 1069 patients, 358 (243 [67.9%] men, 115 [32.1%] women) received sunitinib, 355 (248 [69.9%] men, 107 [30.1%] women) received sorafenib, and 356 (254 [71.3%] men, 102 [28.7%] women) received placebo as adjuvant therapy. The mean (SD) age for each group was 58.3 (10.6) years, 56.8 (10.3) years, and 57.5 (10.4) years, respectively. Five-year DFS rates were 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo (HR, 0.94 for sunitinib vs placebo; and HR, 0.90; 97.5% CI, 0.71-1.14 for sorafenib vs placebo), with 5-year OS of 75.2%, 80.2%, and 76.5% (HR, 1.06; 97.5% CI, 0.78-1.45; P = .66, sunitinib vs placebo; and HR, 0.80; 97.5% CI, 0.58-1.11; P = .12 for sorafenib vs placebo). There was no difference by dose quartile. CONCLUSIONS AND RELEVANCE: Neither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccRCC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00326898.

Effects of Time to Treatment on Biochemical and Clinical Outcomes for Patients With Prostate Cancer Treated With Definitive Radiation.

INTRODUCTION: The purpose of this study was to evaluate if time to treatment (TTT) has an effect on outcomes for patients with localized prostate cancer treated with definitive external beam radiation therapy (EBRT). PATIENTS AND METHODS: We included 4064 patients (1549 low-risk, 1612 intermediate-risk, and 903 high-risk) treated with EBRT. For each National Comprehensive Cancer Network (NCCN) risk group, TTT (defined as the time between initial positive prostate biopsy and start of RT) was analyzed in 4 intervals: < 3, 3-6, 6-9, and 9-24 months. We recorded the use of androgen deprivation therapy among patients with intermediate-risk and high-risk disease. RESULTS: The median TTT was 3.3 months (range, 0.6-23.5 months), and it was similar for each risk group (range, 3.3-3.4 months). The median follow up was 64 months. There were no significant differences in biochemical failure, distant metastasis, or overall survival for patients with TTT < 3, 3-6, 6-9, or 9-24 months for each risk group. There were also no significant differences in the outcomes at 5 years when patients with TTT > 3.3 months were compared with those with TTT ≤ 3.3 months for each risk group. For high-risk men, 328 of 450 (72.9%) with TTT > 3.3 months were on androgen deprivation therapy (ADT) versus 299 of 453 (66%) with TTT ≤ 3.3 months. Among men with high-risk cancer treated without ADT, there remained no significant difference in outcomes between TTT > 3.3 months and TTT ≤ 3.3 months. CONCLUSION: TTT was not associated with significant differences in outcomes among each risk group of men with localized prostate cancer treated with EBRT. Among the high-risk patients, there were no observed detriments in outcomes with TTT > 3.3 months regardless of androgen deprivation therapy use.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Fox Chase Cancer Center's Genitourinary Division: a national resource for research, innovation and patient care.

Founded in 1904, Fox Chase Cancer Center remains committed to its mission. It is one of 41 centers in the country designated as a Comprehensive Cancer Center by the National Cancer Institute, is a founding member of the National Comprehensive Cancer Network, holds the magnet designation for nursing excellence, is one of the first to establish a family cancer risk assessment program, and has achieved national distinction because of the scientific discoveries made there that have advanced clinical care. Two of its researchers have won Nobel prizes. The Genitourinary Division is nationally recognized and viewed as one of the top driving forces behind the growth of Fox Chase due to its commitment to initiating and participating in clinical trials, its prolific contributions to peer-reviewed publications and presentations at scientific meetings, its innovations in therapies and treatment strategies, and its commitment to bringing cutting-edge therapies to patients.

Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate Cancer.

IMPORTANCE: In 5 published randomized clinical trials, dose-escalated external-beam radiation therapy (EBRT) for prostate cancer resulted in improved biochemical and local control. However, scarce evidence addresses whether dose escalation improves overall survival. OBJECTIVE: To examine the association between dose-escalated EBRT and overall survival among men with nonmetastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective, nonrandomized comparative effectiveness study of dose-escalated vs standard-dose EBRT for prostate cancer diagnosed from 2004 to 2006 using the National Cancer Database (NCDB), which includes data from patients treated at Commission on Cancer-accredited community, academic, and comprehensive cancer facilities. Three cohorts were evaluated: men with low-risk (n = 12,229), intermediate-risk (n = 16,714), or high-risk (n = 13,538) prostate cancer. EXPOSURES: We categorized patients in each risk cohort into 2 treatment groups: standard-dose (from 68.4 Gy to <75.6 Gy) or dose-escalated (≥75.6 Gy to 90 Gy) EBRT (1 Gy = 100 rad). MAIN OUTCOMES AND MEASURES: We compared overall survival between treatment groups in each analytic cohort using Cox proportional hazard models with an inverse probability weighted propensity score (IPW-PS) approach. In secondary analyses, we evaluated dose response for survival. RESULTS: Dose-escalated EBRT was associated with improved survival in the intermediate-risk (IPW-PS adjusted hazard ratio [HR], 0.84; 95% CI, 0.80-0.88; P < .001) and high-risk groups (HR, 0.82; 95% CI, 0.78-0.85; P < .001) but not the low-risk group (HR, 0.98; 95% CI, 0.92-1.05; P = .54). For every incremental increase of about 2 Gy in dose, there was a 7.8% (95% CI, 5.4%-10.2%; P < .001) and 6.3% (95% CI, 3.3%-9.1%; P < .001) reduction in the hazard of death for intermediate- and high-risk patients, respectively. CONCLUSIONS AND RELEVANCE: Dose-escalated EBRT is associated with improved overall survival in men with intermediate- and high-risk prostate cancer but not low-risk prostate cancer. These results add to the evidence questioning aggressive local treatment strategies in men with low-risk prostate cancer but supporting such treatment in men with greater disease severity.

Use of Postprostatectomy Radiation Therapy at an NCI-Designated Comprehensive Cancer Center.

PURPOSE: Characterize use of postprostatectomy radiation (PPRT) for patients with prostate cancer at an NCI-designated comprehensive cancer center. METHODS: We queried our prospective prostate cancer database for patients treated with 60 to 68 Gy of radiation therapy (RT) to the prostate bed after prostatectomy from 2003 to 2011. Prostatectomy cases were obtained from billing records. Patients with an intact prostate treated with definitive RT served as a control for the change in volume of patients with prostate cancer treated in the department. Chi-square analysis assessed differences between adjuvant and salvage RT cohorts. Spearman correlation assessed yearly trends in prostate-specific antigen (PSA) level at the time of referral for RT. Linear regression models tested trends for number of PPRT cases, prostatectomies, and patients with intact prostate receiving radiation across years. RESULTS: PPRT was used to treat 475 men at Fox Chase Cancer Center from 2003 to 2011 (83 adjuvant and 392 salvage). Over time, an increased proportion of patients receiving RT to the prostate were treated with PPRT. No increase was seen in the proportion of patients treated with adjuvant RT compared with salvage RT (P=.5). Patients receiving adjuvant RT were younger, had higher pathologic Gleason score, pathologic T stage, and rates of positive margins than those receiving salvage RT. Pre-RT PSA values were inversely correlated with year (P=.005). The number of patients referred for salvage RT with a PSA of 0.5 ng/mL or less increased significantly from 7.9% in 2003 to 26.6% in 2011 (P=.002). CONCLUSIONS: A larger proportion of patients treated with RT for localized prostate cancer are now receiving PPRT. No increase was seen in the proportion of patients treated with adjuvant RT. Over time, patients with lower PSAs were referred for salvage RT.

Effects of Adjuvant Sorafenib and Sunitinib on Cardiac Function in Renal Cell Carcinoma Patients without Overt Metastases: Results from ASSURE, ECOG 2805.

PURPOSE: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents. EXPERIMENTAL DESIGN: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE). RESULTS: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups. CONCLUSIONS: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population.

Increasing use of dose-escalated external beam radiation therapy for men with nonmetastatic prostate cancer.

PURPOSE: To examine recent practice patterns, using a large national cancer registry, to understand the extent to which dose-escalated external beam radiation therapy (EBRT) has been incorporated into routine clinical practice for men with prostate cancer. METHODS AND MATERIALS: We conducted a retrospective observational cohort study using the National Cancer Data Base, a nationwide oncology outcomes database in the United States. We identified 98,755 men diagnosed with nonmetastatic prostate cancer between 2006 and 2011 who received definitive EBRT and classified patients into National Comprehensive Cancer Network (NCCN) risk groups. We defined dose-escalated EBRT as total prescribed dose of ≥75.6 Gy. Using multivariable logistic regression, we examined the association of patient, clinical, and demographic characteristics with the use of dose-escalated EBRT. RESULTS: Overall, 81.6% of men received dose-escalated EBRT during the study period. The use of dose-escalated EBRT did not vary substantially by NCCN risk group. Use of dose-escalated EBRT increased from 70.7% of patients receiving treatment in 2006 to 89.8% of patients receiving treatment in 2011. On multivariable analysis, year of diagnosis and use of intensity modulated radiation therapy were significantly associated with receipt of dose-escalated EBRT. CONCLUSIONS: Our study results indicate that dose-escalated EBRT has been widely adopted by radiation oncologists treating prostate cancer in the United States. The proportion of patients receiving dose-escalated EBRT increased nearly 20% between 2006 and 2011. We observed high utilization rates of dose-escalated EBRT within all disease risk groups. Adoption of intensity modulated radiation therapy was strongly associated with use of dose-escalated treatment.