Five-Year Patient-Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 week and a day [twice a week]) or 12 fractions (4.3Gy in 2.5 weeks [5 times a week]). Secondary objectives assessed patient-reported toxicity at 5 years using the EPIC. Chi-square tests were used to assess the proportion of patients with a deterioration from baseline of >5 points for bowel, >2 points for urinary, and >11 points for sexual score. RESULTS: The study enrolled 127 patients to 5 fractions (121 eligible) and 128 patients to 12 fractions (125 eligible). The median follow-up for all patients at the time of analysis was 5.38 years. The 5-year frequency for >5 point change in bowel score were 38.4% (P = .27) and 23.4% (P = 0.98) for 5 and 12 fractions, respectively. The 5-year frequencies for >2 point change in urinary score were 46.6% (P = .15) and 36.4% (P = .70) for 5 and 12 fractions, respectively. For 5 fractions, 49.3% (P = .007) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points; for 12 fractions, 54% (P < .001) of patients had a drop in 5-year EPIC-50 sexual score of ≥11 points. Disease-free survival at 5 years is 89.6% (95% CI: 84.0-95.2) in the 5-fraction arm and 92.3% (95% CI: 87.4-97.1) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on long-term changes in bowel and urinary domains and toxicity, the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

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.

Early Prostate-Specific Antigen Kinetics for Low- and Intermediate-Risk Prostate Cancer Treated With Definitive Radiation Therapy.

PURPOSE: This study used a patient-specific model to characterize and compare ideal prostate-specific antigen (PSA) kinetics for low- and intermediate-risk prostate cancer after definitive radiation treatment with conventionally fractionated, hypofractionated, stereotactic body radiation therapy, or brachytherapy, both high-dose and low-dose rate. METHODS AND MATERIALS: This retrospective analysis includes low- and intermediate-risk patients with prostate cancer treated between 1998 and 2018 at an National Cancer Institute-designated comprehensive cancer center. Demographics and treatment characteristics were prospectively collected. Patients had at least 2 PSA measurements within 24 months of treatment and were free from biochemical recurrence. The incidence of, time to, and risk factors for PSA nadir (nPSA) and bounce (bPSA) were analyzed at 24 months after radiation therapy. Ideal PSA kinetics were characterized for each modality and compared. RESULTS: Of 1042 patients, 45% had low-risk cancer, 37% favorable intermediate risk, and 19% unfavorable intermediate risk. nPSAs were higher for ablative modalities, both as absolute nPSA and relative to initial PSA. Median time to nPSA ranged from 14.8 to 17.1 months. Over 50% treated with nonablative therapy (conventionally fractionated, hypofractionated, and low-dose rate) reached an nPSA threshold of ≤0.5 ng/mL compared with 23% of stereotactic body radiation therapy and 33% of high-dose rate cohorts. The incidence of bPSA was 13.3% and not affected by treatment modality, Gleason score, or prostate volume. PSA decay rate was faster for ablative therapies in the 6- to 24-month period. CONCLUSIONS: Analysis of PSA within 24 months after radiation therapy revealed ablative therapies are associated with a latent PSA response and higher nPSA. Multivariable logistics modeling revealed younger age, initial PSA above the median, presence of bPSA, and ablative therapy as predictors for not achieving nPSA ≤0.5 ng/mL. PSA decay rate appears to be faster in ablative therapies after a latent period. Understanding the different PSA kinetic profiles is necessary to assess treatment response and survey for disease recurrence.

A Pooled Toxicity Analysis of Moderately Hypofractionated Proton Beam Therapy and Intensity Modulated Radiation Therapy in Early-Stage Prostate Cancer Patients.

PURPOSE: Data comparing moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) are lacking. We aim to compare late toxicity profiles of patients with early-stage prostate cancer treated with moderately hypofractionated PBT and IMRT. METHODS AND MATERIALS: This multi-institutional analysis included patients with low- or intermediate-risk biopsy-proven prostate adenocarcinoma from 7 tertiary referral centers treated from 1998 to 2018. All patients were treated with moderately hypofractionated radiation, defined as 250 to 300 cGy per daily fraction given for 4 to 6 weeks, and stratified by use of IMRT or PBT. Primary outcomes were late genitourinary (GU) and gastrointestinal (GI) toxicity. Adjusted toxicity rates were calculated using inverse probability of treatment weighting, accounting for race, National Comprehensive Cancer Network risk group, age, pretreatment International Prostate Symptom Score (GU only), and anticoagulant use (GI only). RESULTS: A total of 1850 patients were included: 1282 IMRT (median follow-up 80.0 months) and 568 PBT (median follow-up 43.9 months). Overall toxicity rates were low, with the majority of patients experiencing no late GU (56.6%, n = 1048) or late GI (74.4%, n = 1377) toxicity. No difference was seen in the rates of late toxicity between the groups, with late grade 3+ GU toxicity of 2.0% versus 3.9% (odds ratio [OR] 0.47; 95% confidence interval 0.17-1.28) and late grade 2+ GI toxicity of 14.6% versus 4.7% (OR 2.69; confidence interval 0.80-9.05) for the PBT and IMRT cohorts, respectively. On multivariable analysis, no factors were significantly predictive of GU toxicity, and only anticoagulant use was significantly predictive of GI toxicity (OR 1.90; P = .008). CONCLUSIONS: In this large, multi-institutional analysis of 1850 patients with early-stage prostate cancer, treatment with moderately hypofractionated IMRT and PBT resulted in low rates of toxicity. No difference was seen in late GI and GU toxicity between the modalities during long-term follow-up. Both treatments are safe and well tolerated.

Development and Validation of a Clinical Prognostic Stage Group System for Nonmetastatic Prostate Cancer Using Disease-Specific Mortality Results From the International Staging Collaboration for Cancer of the Prostate.

Importance: In 2016, the American Joint Committee on Cancer (AJCC) established criteria to evaluate prediction models for staging. No localized prostate cancer models were endorsed by the Precision Medicine Core committee, and 8th edition staging was based on expert consensus. Objective: To develop and validate a pretreatment clinical prognostic stage group system for nonmetastatic prostate cancer. Design, Setting, and Participants: This multinational cohort study included 7 centers from the United States, Canada, and Europe, the Shared Equal Access Regional Cancer Hospital (SEARCH) Veterans Affairs Medical Centers collaborative (5 centers), and the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (43 centers) (the STAR-CAP cohort). Patients with cT1-4N0-1M0 prostate adenocarcinoma treated from January 1, 1992, to December 31, 2013 (follow-up completed December 31, 2017). The STAR-CAP cohort was randomly divided into training and validation data sets; statisticians were blinded to the validation data until the model was locked. A Surveillance, Epidemiology, and End Results (SEER) cohort was used as a second validation set. Analysis was performed from January 1, 2018, to November 30, 2019. Exposures: Curative intent radical prostatectomy (RP) or radiotherapy with or without androgen deprivation therapy. Main Outcomes and Measures: Prostate cancer-specific mortality (PCSM). Based on a competing-risk regression model, a points-based Score staging system was developed. Model discrimination (C index), calibration, and overall performance were assessed in the validation cohorts. Results: Of 19 684 patients included in the analysis (median age, 64.0 [interquartile range (IQR), 59.0-70.0] years), 12 421 were treated with RP and 7263 with radiotherapy. Median follow-up was 71.8 (IQR, 34.3-124.3) months; 4078 (20.7%) were followed up for at least 10 years. Age, T category, N category, Gleason grade, pretreatment serum prostate-specific antigen level, and the percentage of positive core biopsy results among biopsies performed were included as variables. In the validation set, predicted 10-year PCSM for the 9 Score groups ranged from 0.3% to 40.0%. The 10-year C index (0.796; 95% CI, 0.760-0.828) exceeded that of the AJCC 8th edition (0.757; 95% CI, 0.719-0.792), which was improved across age, race, and treatment modality and within the SEER validation cohort. The Score system performed similarly to individualized random survival forest and interaction models and outperformed National Comprehensive Cancer Network (NCCN) and Cancer of the Prostate Risk Assessment (CAPRA) risk grouping 3- and 4-tier classification systems (10-year C index for NCCN 3-tier, 0.729; for NCCN 4-tier, 0.746; for Score, 0.794) as well as CAPRA (10-year C index for CAPRA, 0.760; for Score, 0.782). Conclusions and Relevance: Using a large, diverse international cohort treated with standard curative treatment options, a proposed AJCC-compliant clinical prognostic stage group system for prostate cancer has been developed. This system may allow consistency of reporting and interpretation of results and clinical trial design.

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.

Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.

PURPOSE: There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. METHODS AND MATERIALS: NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test. RESULTS: The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. CONCLUSIONS: This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.

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.

Men's health supplement use and outcomes in men receiving definitive intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND: Approximately 50% of newly diagnosed cancer patients start taking dietary supplements. Men's health supplements (MHSs), which we define as supplements that are specifically marketed with the terms men's health and prostate health (or similar permutations), are often mislabeled as having potential anticancer benefits. OBJECTIVE: We evaluated the effects of MHSs on patient outcomes and toxicities in patients who were undergoing definitive intensity-modulated radiation therapy (IMRT) for localized prostate cancer. DESIGN: This retrospective analysis included patients who were being treated at a National Cancer Institute-designated comprehensive cancer center and consented to have information stored in a prospective database. MHSs were queried online. Outcome measures were freedom from biochemical failure (FFBF) (biochemical failure was defined with the use of the prostate-specific antigen nadir + 2-ng/mL definition), freedom from distant metastasis (FFDM), cancer-specific survival (CSS), and overall survival (OS) as well as toxicities. Kaplan-Meier analysis, log-rank tests, Fine and Gray competing-risk regression (to adjust for patient and lifestyle factors), and Cox models were used. RESULTS: From 2001 to 2012, 2207 patients were treated with IMRT with a median dose of 78 Gy, and a median follow-up of 46 mo. Of these patients, 43% were low risk, 37% were intermediate risk, and 20% were high risk; 10% used MHSs. MHSs contained a median of 3 identifiable ingredients (range: 0-78 ingredients). Patients who were taking an MHS compared with those who were not had improved 5-y OS (97% compared with 92%, respectively; P = 0.01), but there were no differences in the FFBF (94% compared with 89%, respectively; P = 0.12), FFDM (96% compared with 97%, respectively; P = 0.32), or CSS (100% compared with 99%, respectively; P = 0.22). The unadjusted association between MHS use and improved OS was attenuated after adjustment for patient lifestyle factors and comorbidities. There was no difference in toxicities between the 2 groups (late-grade 3-4 genitourinary <3%; gastrointestinal <4%). CONCLUSION: The use of MHSs is not associated with outcomes or toxicities.

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.

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.

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.

Institutional clinical trial accrual volume and survival of patients with head and neck cancer.

PURPOSE: National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown. PATIENTS AND METHODS: The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models. RESULTS: Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment. CONCLUSION: OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.

The rise and fall of prostate brachytherapy: use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Data Base.

BACKGROUND: Brachytherapy has been shown to be an efficacious and cost-effective treatment among patients with localized prostate cancer. In this study, the authors examined trends in brachytherapy use for localized prostate cancer using a large national cancer registry. METHODS: In the National Cancer Data Base (NCDB), a total of 1,547,941 patients with localized prostate cancer were identified from 1998 through 2010. Excluding patients with lymph node-positive or metastatic disease, the authors examined primary treatment trends focusing on the use of brachytherapy over time. Patients with available data (2004-2009) were stratified by National Comprehensive Cancer Network risk criteria. Controlling for year of diagnosis and demographic, clinical, and pathologic characteristics, multivariate analyses were performed examining the association between patient characteristics and receipt of brachytherapy. RESULTS: In the study cohort, brachytherapy use reached a peak of 16.7% in 2002, and then steadily declined to a low of 8% in 2010. Of the 719,789 patients with available data for risk stratification, 41.1%, 35.3%, and 23.6%, respectively, met low, intermediate, and high National Comprehensive Cancer Network risk criteria. After adjustment, patients of increasing age and those with Medicare insurance were more likely to receive brachytherapy. In contrast, patients with intermediate-risk or high-risk disease, Medicaid insurance, increasing comorbidity count, and increasing year of diagnosis were less likely to receive brachytherapy. CONCLUSIONS: For patients with localized prostate cancer who are treated at National Cancer Data Base institutions, there has been a steady decline in brachytherapy use since 2003. For low-risk patients, the declining use of brachytherapy monotherapy compared with more costly emerging therapies has significant health policy implications.

Gleason scoring at a comprehensive cancer center: what's the difference?

This study attempted to determine whether the Gleason score (GS) assigned at a comprehensive cancer center better predicts risk of biochemical failure (BF) after prostate radiotherapy compared with the GS of the referring institution (RI). Between 1994 and 2007, 1649 men received radiotherapy for prostate cancer at Fox Chase Cancer Center (FCCC). The Cox proportional hazard regression was used for inferences about the relationship of time to BF and GS. Harrell's C-index (HCI) was used to assess concordance in the Cox regression between predicted and observed events. The discordance rate was 26% for any change in either major or minor Gleason pattern. In the RI GS 2 through 6 group, 79 (8%) patients were upgraded to GS 7. Twenty percent of patients with RI GS 7 were downgraded and 2% were upgraded. In the RI GS 8 through 9 group, 58% were downgraded to GS 6 (12%) or GS 7 (88%). The FCCC GS altered the NCCN risk group assignment in 144 men (9%): 92 (64%) men to lower risk and 52 (36%) to higher risk. FCCC GS was a stronger predictor of BF; the hazard ratios for GS 2 through 6 (ref), 3+4, 4+3, and 8 through 9 were 1.00 (ref), 1.82, 4.14, and 2.92, respectively. In contrast, the hazard ratios for the RI GS were 1.00 (ref), 1.53, 2.44, and 1.76, respectively. FCCC GS (HCI=0.76) had improved performance compared with RI GS (HCI=0.74). Changes in GS were common and the GS assigned by a comprehensive cancer center provided better BF risk stratification and prognostication for patients. Changes in GS may impact treatment recommendations in 9% to 26% of patients.

Assessment of the American Joint Committee on Cancer staging (sixth and seventh editions) for clinically localized prostate cancer treated with external beam radiotherapy and comparison with the National Comprehensive Cancer Network risk-stratification method.

BACKGROUND: The objective of this study was to compare the prognostic value of the sixth and seventh editions of the American Joint Cancer Committee (AJCC) Cancer Staging Manual and the risk-stratification model of the National Comprehensive Cancer Network (NCCN). METHODS: Two-thousand four hundred twenty-nine men who received definitive radiotherapy with or without androgen-deprivation therapy (median follow-up, 74 months) were analyzed. RESULTS: There was a migration of stage II patients to stage I with AJCC seventh edition (stage I increased from 1% to 38%, and stage II decreased from 91% to 55%). One pair-wise comparison (4%) of Kaplan-Meier estimates of biochemical failure, distant metastasis, prostate cancer-specific survival, and overall survival between stages was statistically significant for the AJCC sixth edition. Conversely, 16 of 24 comparisons (67%) were significant for the AJCC seventh edition. With the NCCN risk-stratification model, 9 of 12 comparisons (75%) were significant. Concordance probability estimate (CPE) and standard error (SE) analysis indicated uniform and significant improvement in the predictive power of the AJCC seventh edition versus the sixth edition for all outcomes. CPE ± SE values for the AJCC seventh edition versus the sixth edition were 0.51 ± 0.009 versus 0.59 ± 0.02, respectively, for biochemical failure; 0.54 ± 0.02 versus 0.70 ± 0.05, respectively, for distant metastasis; 0.57 ± 0.009 versus 0.76 ± 0.007, respectively, for prostate cancer-specific survival; and 0.52 ± 0.006 versus 0.57 ± 0.01, respectively, for overall survival. CPE ± SE values for the NCCN model were 0.59 ± 0.02 for biochemical failure, 0.72 ± 0.05 for distant metastasis, 0.80 ± 0.01 for prostate cancer-specific survival, and 0.57 ± 0.01 for overall survival. CONCLUSIONS: The current results indicated that the seventh edition of the AJCC Cancer Staging Manual is a major improvement over the sixth edition, because it distributes patients better among the stages and is more prognostic. However, the NCCN model was superior to the AJCC seventh edition and remains the preferred method for risk-based clinical management of prostate cancer with radiotherapy.

Does transurethral resection of prostate (TURP) affect outcome in patients who subsequently develop prostate cancer?

OBJECTIVES: Pretreatment prostate specific antigen (PSA) is a strong predictor of prostate cancer outcome after radiotherapy and is a key parameter in pretreatment risk assessment. Because PSA is secreted from both benign and malignant tissue, a prior transurethral resection of prostate (TURP) may lower pretreatment PSA levels out of proportion to the extent of cancer. The purpose of this study was to determine whether a history of TURP is associated with increased biochemical failure (BF) after definitive radiotherapy for prostate cancer. METHODS: From April 1989 to October 2001, 1135 men with low to intermediate risk T1c-2NX/0M0 (2002 AJCC) prostate cancer with a pretreatment PSA less than 20 ng/mL received three-dimensional conformal radiotherapy (median dose, 76 Gy) without androgen deprivation. The median pretreatment PSA was 7.4 ng/mL (range, 0.4 to 19.9). There were 126 men with a prior history of TURP. The Cox proportional hazards model was used for univariate and multivariate analyses for BF (nadir + 2 ng/mL definition). RESULTS: On multivariable analysis, Gleason score (GS), PSA, and T-stage were significant predictors of BF in a model containing TURP and dose. A history of TURP was not a significant independent predictor of BF on subgroup analysis. There was a trend toward significance for the subgroup of GS less than 7 (P = 0.12). CONCLUSIONS: A history of prior TURP does not affect outcome after RT for prostate cancer in low to intermediate risk patients.

Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention.

BACKGROUND: NF-kappaB and AP-1 transcriptional factors contribute to the development and progression of prostate malignancy by regulating the expression of genes involved in proliferation, apoptosis, angiogenesis, and metastasis. METHODS: NF-kappaB and AP-1 activities were examined by TransAm assay. Cytokines levels were assessed by ELISA. ICAM-1 and gp130 expression was examined by flow cytometry. Cell adhesion was examined by the ability of cells to adhere to fibronectin-coated plates. Cell viability was determined by propidium iodide staining. RESULTS: Treatment with alpha-tocopherol succinate (VES) inhibits NF-kappaB but augments AP-1 activity, reduces expression of IL-6, IL-8, and VEGF, suppresses cell adhesion, ICAM-1 and gp130 expression in androgen-independent PC-3, DU-145, and CA-HPV-10 cells. VES supplementation also decreases the expression of anti-apoptotic XIAP and Bcl-X(L) proteins and sensitizes androgen-dependent LNCaP cells to androgen deprivation. CONCLUSIONS: Our findings propose a potential mechanism of VES-mediated anti-tumor activity and support the role of vitamin E analogs as potential chemopreventative agents against prostate cancer.

Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression.

Nuclear factor-kappaB (NF-kappaB) and AP-1 nuclear transcriptional factors regulate expression of multiple genes involved in tumor growth, metastasis and angiogenesis; however, the relative contribution of each factor to cancer initiation and progression has not been established. Prostate carcinogenesis involves transformation of normal zinc-accumulating epithelial cells to malignant cells that do not accumulate zinc. Whereas activation of both NF-kappaB and AP-1 has been implicated in prostate cancer development and growth, we tested the relative effects of zinc supplementation on these important transcriptional factors. Herein, we demonstrate that physiological levels of zinc inhibit NF-kappaB but augment activities of AP-1 in DU-145 and PC-3 human prostate cancer cells. Additionally, we show that chelation of zinc with membrane-permeable zinc chelator, N,N,N',N',-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) abolishes this effect. We further propose a potential mechanism for this observation by demonstrating that zinc supplementation induces phosphorylation of the members of three major MAPK subfamilies regulating AP-1 and NF-kappaB activation (ERK 1/2, JNK and p38) while blocking TNF-alpha-mediated degradation of the inhibitory subunit I kappa B alpha and nuclear translocation of RelA in prostate cancer cells. VEGF, IL-6, IL-8 and MMP-9 are major pro-angiogenic and pro-metastatic molecules whose promoter regions contain binding sites for both NF-kappaB and AP-1. These cytokines have been associated with negative prognostic features in prostate cancer. We demonstrate that treatment of human prostate cancer cell lines with zinc reduces expression of VEGF, IL-6, IL-8 and MMP-9. We further show that zinc reduces expression of intercellular adhesion molecule-1 and functionally suppresses tumor cell invasiveness and adhesion. Therefore, the ability of zinc supplementation to inhibit NF-kappaB supercedes zinc-mediated activation of AP-1 family members. Upregulation of intracellular zinc levels may have important implications for inhibiting the angiogenic and metastatic potentials of malignant cells, predominantly through suppression of NF-kappaB signaling.