Using 18F-DCFPyL Prostate-Specific Membrane Antigen-Directed Positron Emission Tomography/Magnetic Resonance Imaging to Define Intraprostatic Boosts for Prostate Stereotactic Body Radiation Therapy.

Purpose: The recently reported FLAME trial demonstrated a biochemical disease-free survival benefit to using a focal intraprostatic boost to multiparametric magnetic resonance imaging (mpMRI)-identified lesions in men with localized prostate cancer treated with definitive radiation therapy. Prostate-specific membrane antigen (PSMA)-directed positron emission tomography (PET) may identify additional areas of disease. In this work, we investigated using both PSMA PET and mpMRI in planning focal intraprostatic boosts using stereotactic body radiation therapy (SBRT). Methods and Materials: We evaluated a cohort of patients (n = 13) with localized prostate cancer who were imaged with 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-2-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/MRI on a prospective imaging trial before undergoing definitive therapy. The number of lesions concordant (overlapping) and discordant (no overlap) on PET and MRI was assessed. Overlap between concordant lesions was evaluated using the Dice and Jaccard similarity coefficients. Prostate SBRT plans were created fusing the PET/MRI imaging to computed tomography scans acquired the same day. Plans were created using only MRI-identified lesions, only PET-identified lesions, and the combined PET/MRI lesions. Coverage of the intraprostatic lesions and doses to the rectum and urethra were assessed for each of these plans. Results: The majority of lesions (21/39, 53.8%) were discordant between MRI and PET, with more lesions seen by PET alone (12) than MRI alone (9). Of lesions that were concordant between PET and MRI, there were still areas that did not overlap between scans (average Dice coefficient, 0.34). Prostate SBRT planning using all lesions to define a focal intraprostatic boost provided the best coverage of all lesions without compromising constraints on the rectum and urethra. Conclusions: Using both mpMRI and PSMA-directed PET may better identify all areas of gross disease within the prostate. Using both imaging modalities could improve the planning of focal intraprostatic boosts.

Toxicity and Patient-Reported Quality-of-Life Outcomes After Prostate Stereotactic Body Radiation Therapy With Focal Boost to Magnetic Resonance Imaging-Identified Prostate Cancer Lesions: Results of a Phase 2 Trial.

PURPOSE: In this prospective phase 2 trial, we investigated the toxicity and patient-reported quality-of-life outcomes in patients treated with stereotactic body radiation therapy (SBRT) to the prostate gland and a simultaneous focal boost to magnetic resonance imaging (MRI)-identified intraprostatic lesions while also de-escalating dose to the adjacent organs at risk. METHODS AND MATERIALS: Eligible patients included low- or intermediate-risk prostate cancer (Gleason score ≤7, prostate specific antigen ≤20, T stage ≤2b). SBRT was prescribed to 40 Gy in 5 fractions delivered every other day to the prostate, with any areas of high disease burden (MRI-identified prostate imaging reporting and data system 4 or 5 lesions) simultaneously escalated to 42.5 to 45 Gy and areas overlapping organs at risk (within 2 mm of urethra, rectum, and bladder) constrained to 36.25 Gy (n = 100). Patients without a pretreatment MRI or without MRI-identified lesions were treated to dose of 37.5 Gy with no focal boost (n = 14). RESULTS: From 2015 to 2022, a total of 114 patients were enrolled with a median follow-up of 42 months. No acute or late grade 3+ gastrointestinal (GI) toxicity was observed. One patient developed late grade 3 genitourinary (GU) toxicity at 16 months. In patients treated with focal boost (n = 100), acute grade 2 GU and GI toxicity was seen in 38% and 4% of patients, respectively. Cumulative late grade 2+ GU and GI toxicities at 24 months were 13% and 5% respectively. Patient-reported outcomes showed no significant long-term change from baseline in urinary, bowel, hormonal, or sexual quality-of-life scores after treatment. CONCLUSIONS: SBRT to a dose of 40 Gy to the prostate gland with a simultaneous focal boost up to 45 Gy is well tolerated with similar rates of acute and late grade 2+ GI and GU toxicity as seen in other SBRT regimens without intraprostatic boost. Moreover, no significant long-term changes were seen in patient-reported urinary, bowel, or sexual outcomes from pretreatment baseline.

A Phase 1 Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer.

PURPOSE: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. METHODS AND MATERIALS: Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT. RESULTS: A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume. CONCLUSIONS: SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

A Prospective Multi-Institutional Phase I/II Trial of Step-Wise Dose-per-Fraction Escalation in Low and Intermediate Risk Prostate Cancer.

PURPOSE: This phase I/II, multi-institutional trial explored the tolerance and efficacy of stepwise increasing hypofractionation (HPFX) radiation therapy regimens for fraction sizes up to 4.3 Gy in localized prostate cancer. METHODS AND MATERIALS: Three escalating dose-per-fraction schedules were designed to yield similar predicted tumor control while maintaining equivalent predicted late toxicity. HPFX levels I, II, and III were carried out sequentially and delivered schedules of 64.7 Gy/22 fx/2.94 Gy, 58.08 Gy/16 fx/3.63 Gy, and 51.6 Gy/12 fx/4.3 Gy, respectively with next level escalations contingent upon acceptable gastrointestinal (GI) toxicity. The primary endpoints were biochemical control and toxicity. RESULTS: A total of 347 patients were recruited by 5 institutions with 101, 111, and 135 patients treated on HPFX levels I, II, and III with median follow-ups of 100, 85.5, and 61.7 months, respectively (83.2 months combined). The National Comprehensive Cancer Network low- or intermediate-risk group distribution was 46% and 54%, respectively. Sixteen percent of patients, primarily intermediate risk, received 6 months of androgen deprivation therapy. The 8-year nadir + 2 actuarial biochemical control rates for HPFX levels I, II, and III were 91.1% ± 3.0%, 92.7% ± 2.7%, and 88.5% ± 4.6%, respectively (Kaplan-Meier log rank, 0.903). Among clinical covariates, only Gleason score reached near significance in multivariate analysis (P = .054). Twenty-six patients failed biochemically (crude incidence of 7.5%), and there were 5 cause-specific deaths. GI and genitourinary toxicities were acceptable and similar across the 3 HPFX levels. The combined actuarial cumulative incidence of grade 2+ GI and genitourinary toxicities at 7 years were 16.3% ± 2.1% and 22.1% ± 2.4%, respectively. CONCLUSIONS: HPFX employing fraction sizes extending into the 3.6 to 4.3 Gy/fraction range can be delivered with excellent oncologic outcomes. Such schedules, positioned between moderate and ultra-HPFX, may provide additional options for patients wishing to avoid prolonged treatment schedules associated with conventionally fractionated radiation therapy for prostate cancer.

Cardiac Toxicity in Operable Esophageal Cancer Patients Treated With or Without Chemoradiation.

PURPOSE: The purpose of this study was to evaluate predictors of cardiac events in esophageal cancer patients treated with neoadjuvant chemoradiotherapy (NA CRT) followed by surgery compared with surgery alone. MATERIALS AND METHODS: We retrospectively identified patients treated for esophageal cancer between 2006 and 2016. A total of 123 patients were identified; 70 were treated with surgery alone, and 53 were treated with NA CRT. Cardiac events were scored based on Common Terminology Criteria for Adverse Events (version 4.03), and dosimetric data was compiled for all patients who received radiation. Univariate analysis and multivariable analysis (MVA) were performed to identify predictors of cardiac events. Competing risk of death regression was performed to a model the cumulative incidence of cardiac events. RESULTS: The overall rates of grade ≥3 cardiac events were 24.5% in the NA CRT group versus 10% in the surgery group (P=0.04). On MVA, use of NA CRT (P<0.01, hazard ratio [HR]: 3.45, 95% confidence interval [CI]: 1.35-9.09) predicted for grade ≥3 cardiac events, though no dosimetric variable predicted for grade ≥3 cardiac events or overall survival. On MVA, NA CRT predicted for pericardial effusions of any grade (P<0.01, HR: 3.70, 95% CI: 1.67-8.33). The V45 Gy was the most significant predictor of pericardial effusions (P=0.012, HR: 1.03, 95% CI: 1.01-1.06) CONCLUSIONS:: NA CRT significantly increased the rate of grade ≥3 cardiac events compared with patients treated with surgery alone. Although no dosimetric parameter predicted for grade ≥3 cardiac events or survival, the V45 Gy predicted for pericardial effusions.

Semen AMACR protein as a novel method for detecting prostate cancer.

BACKGROUND: Alpha methylacyl A coenzyme racemase (AMACR) has shown to be an excellent immunohistological biomarker for prostate cancer (CaP). Given the connection between prostate and urethra, we hypothesized that semen ejaculate would be an ideal specimen for detection of CaP specific biomarkers, such as AMACR. This study explores the detection of semen AMACR protein in men with and without CaP. METHODS: Semen ejaculates from 28 biopsy proven CaP patients prior to radical prostatectomy and 15 age-comparable controls were analyzed. An indirect sandwich ELISA chemiluminescence assay was used to detect semen AMACR, PSA, and Matriptase proteins. Tissue AMACR protein was quantified in 12 corresponding prostatectomy specimens using automated quantitative analysis (AQUA). RESULTS: Semen AMACR protein was detected in 23 of 28 (82%) CaP patients and 23 of 24 (96%) CaP patients with significant tumor volume (>0.5 cc or 0.3 g). Among the 5 cancer patients with undetectable semen AMACR, 4 patients had small tumor volumes (<1% or 0.3 g). Semen AMACR protein was also detected in 7 of 15 (47%) control noncancer patients. Using 76 ng/ml as a cutoff value, 20 of 28 (71%) patients and 20 of 24 (83%) patients with significant tumor volume were positive for semen AMACR protein, whereas only 5 of 15 (33%) age-comparable controls were positive. AMACR levels degrade with time. CONCLUSIONS: This is the first study to demonstrate that AMACR protein is detectable in semen ejaculate. The higher AMACR levels detected in cancer patients suggests that semen AMACR protein may be useful as a noninvasive test for prostate cancer. Further validation is warranted.

Magnetic Resonance Imaging-Guided Adaptive Radiation Therapy: A "Game Changer" for Prostate Treatment?

Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/ß ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.

Radiation Dose Escalation in Esophageal Cancer Revisited: A Contemporary Analysis of the National Cancer Data Base, 2004 to 2012.

PURPOSE: To evaluate the effect of radiation dose escalation on overall survival (OS) for patients with nonmetastatic esophageal cancer treated with concurrent radiation and chemotherapy. METHODS AND MATERIALS: Patients diagnosed with stage I to III esophageal cancer treated from 2004 to 2012 were identified from the National Cancer Data Base. Patients who received concurrent radiation and chemotherapy with radiation doses of ≥50 Gy and did not undergo surgery were included. OS was compared using Cox proportional hazards regression and propensity score matching. RESULTS: A total of 6854 patients were included; 3821 (55.7%) received 50 to 50.4 Gy and 3033 (44.3%) received doses >50.4 Gy. Univariate analysis revealed no significant difference in OS between patients receiving 50 to 50.4 Gy and those receiving >50.4 Gy (P=.53). The dose analysis, binned as 50 to 50.4, 51 to 54, 55 to 60, and >60 Gy, revealed no appreciable difference in OS within any group compared with 50 to 50.4 Gy. Subgroup analyses investigating the effect of dose escalation by histologic type and in the setting of intensity modulated radiation therapy also failed to reveal a benefit. Propensity score matching confirmed the absence of a statistically significant difference in OS among the dose levels. The factors associated with improved OS on multivariable analysis included female sex, lower Charlson-Deyo comorbidity score, private insurance, cervical/upper esophagus location, squamous cell histologic type, lower T stage, and node-negative status (P<.01 for all analyses). CONCLUSIONS: In this large national cohort, dose escalation >50.4 Gy did not result in improved OS among patients with stage I to III esophageal cancer treated with definitive concurrent radiation and chemotherapy. These data suggest that despite advanced contemporary treatment techniques, OS for patients with esophageal cancer remains unaltered by escalation of radiation dose >50.4 Gy, consistent with the results of the INT-0123 trial. Furthermore, these data highlight that many radiation oncologists have not embraced the concept that dose escalation does not improve OS. Although local control, not investigated in the present study, might benefit from dose escalation, novel therapies are needed to improve the OS of patients with esophageal cancer.

Patient-reported quality of life after stereotactic body radiation therapy versus moderate hypofractionation for clinically localized prostate cancer.

BACKGROUND AND PURPOSE: Evaluate changes in bowel, urinary and sexual patient-reported quality of life following treatment with moderately hypofractionated radiotherapy (<5Gray/fraction) or stereotactic body radiation therapy (SBRT;5-10Gray/fraction) for prostate cancer. MATERIALS AND METHODS: In a pooled multi-institutional analysis of men treated with moderate hypofractionation or SBRT, we compared minimally detectable difference in bowel, urinary and sexual quality of life at 1 and 2years using chi-squared analysis and logistic regression. RESULTS: 378 men received moderate hypofractionation compared to 534 men who received SBRT. After 1year, patients receiving moderate hypofractionation were more likely to experience worsening in bowel symptoms (39.5%) compared to SBRT (32.5%; p=.06), with a larger difference at 2years (37.4% versus 25.3%, p=.002). Similarly, patients receiving moderate fractionation had worsening urinary symptom score compared to patients who underwent SBRT at 1 and 2years (34.7% versus 23.1%, p<.001; and 32.8% versus 14.0%, p<.001). There was no difference in sexual symptom score at 1 or 2years. After adjusting for age and cancer characteristics, patients receiving SBRT were less likely to experience worsening urinary symptom scores at 2years (odds ratio: 0.24[95%CI: 0.07-0.79]). CONCLUSIONS: Patients who received SBRT or moderate hypofractionation have similar patient-reported change in bowel and sexual symptoms, although there was worse change in urinary symptoms for patients receiving moderate hypofractionation.

Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P = .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P = .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001). CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95. © 2016 American Cancer Society.

Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer.

OBJECTIVE: This multi-institutional phase I/II trial explored patient-assessed tolerance of increasingly hypofractionated (HPFX) radiation for low/intermediate risk prostate cancer. METHODS: 347 patients enrolled from 2002 to 2010. Three increasing dose-per-fraction schedules of 64.7 Gy/22 fx, 58.08 Gy/16 fx and 51.6 Gy/12 fx were each designed to yield equivalent predicted late toxicity. Three quality of life (QoL) surveys were administered prior to treatment and annually upto 3 years. RESULTS: Bowel QoL data at 3years revealed no significant difference among regimens (p=0.469). Bowel QoL for all regimens declined transiently, largely recovering by three years, with only the 22 fraction decrement reaching significance. Bladder outcomes at 3 years were comparable (p=0.343) although, for all patients combined, a significant decline was observed from the baseline (p=0.008). Spitzer quality of life data revealed similarly excellent, 3-year means (p=0.188). International erectile function data also revealed no significant differences at 3 years although all measures except intercourse satisfaction worsened post-treatment. CONCLUSIONS: Three-year QoL changes for bowel, bladder and SQLI were modest and similar for 3 HPFX regimens spanning 2.94-4.3 Gy per fraction. These favorable patient-scored outcomes demonstrate the safety and tolerability of such regimens and may be leveraged to support further implementation of mild to moderately hypofractionated radiotherapy in the setting of low and intermediate-risk prostate cancer.

On voxel-by-voxel accumulated dose for prostate radiation therapy using deformable image registration.

Since delivered dose is rarely the same with planned, we calculated the delivered total dose to ten prostate radiotherapy patients treated with rectal balloons using deformable dose accumulation (DDA) and compared it with the planned dose. The patients were treated with TomoTherapy using two rectal balloon designs: five patients had the Radiadyne balloon (balloon A), and five patients had the EZ-EM balloon (balloon B). Prostate and rectal wall contours were outlined on each pre-treatment MVCT for all patients. Delivered fractional doses were calculated using the MVCT taken immediately prior to delivery. Dose grids were accumulated to the last MVCT using DDA tools in Pinnacle3 TM (v9.100, Philips Radiation Oncology Systems, Fitchburg, USA). Delivered total doses were compared with planned doses using prostate and rectal wall DVHs. The rectal NTCP was calculated based on total delivered and planned doses for all patients using the Lyman model. For 8/10 patients, the rectal wall NTCP calculated using the delivered total dose was less than planned, with seven patients showing a decrease of more than 5% in NTCP. For 2/10 patients studied, the rectal wall NTCP calculated using total delivered dose was 2% higher than planned. This study indicates that for patients receiving hypofractionated radiotherapy for prostate cancer with a rectal balloon, total delivered doses to prostate is similar with planned while delivered dose to rectal walls may be significantly different from planned doses. 8/10 patients show significant correlation between rectal balloon anterior-posterior positions and some VD values.

Commentary on "Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)." Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset JF, van Velthoven R, Colombel M, van de Beek C, Verhagen P, van den Bergh A, Sternberg C, Gasser T, van Tienhoven G, Scalliet P, Haustermans K, Collette L; European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-Urinary Groups. Department of Radiation Oncology, Centre Hospitalier Universitaire A Michallon, Grenoble, France.: Lancet 2012;380(9858):2018-27. doi: 10.1016/S0140-6736(12)61253-7. [Epub 2012 Oct 19].

BACKGROUND: We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression-free survival was sustained. METHODS: This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and-see policy until biochemical progression (increase in prostate-specific antigen>0·2 µg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at α = 0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511. FINDINGS: 1005 patients were randomly assigned to a wait-and-see policy (n = 503) or postoperative irradiation (n = 502) and were followed up for a median of 10·6 years (range 2 months to 16·6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39·4%] of 502 patients in postoperative irradiation group vs 311 [61·8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0·49 [95% CI 0·41-0·59]; p<0·0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70·8% [66·6-75·0] vs 59·7% [55·3-64·1]; p = 0.001). INTERPRETATION: Results at median follow-up of 10·6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. FUNDING: Ligue Nationale contre le Cancer (Comité de l'Isère, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust.

Commentary on "initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer." Aizer AA, Chen MH, Hattangadi J, D'Amico AV. Harvard Radiation Oncology program, Boston, MA.: BJU Int 2013. doi: 10.1111/j.1464-410X.2012.11789.x. [Epub ahead of print].

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The recently published Prostate Cancer Intervention versus Observation Trial (PIVOT) did not identify differences in prostate cancer-specific mortality or all-cause mortality among patients with low-risk disease managed conservatively vs those managed definitively; however, recently published data suggest that older men may harbour more aggressive disease than is identified at biopsy owing to sampling error and undergrading. Whether older men with apparent low-risk disease are placed at risk of prostate cancer-specific mortality when managed conservatively remains unknown. The study used population-level data to show that non-curative approaches for older men with low-risk prostate cancer do result in an increased risk of prostate cancer-specific mortality. Differences between our study and the PIVOT trial include the fact that we included a larger sample size, analysed the data using an 'as-treated' approach, and included a healthier cohort of men as evinced by lower 4-year all-cause mortality estimates in our study than in the PIVOT. Our results suggest that older men with apparent low-risk prostate cancer are at risk of undergrading, which probably explains the differences in prostate cancer-specific mortality observed between men managed conservatively vs those managed definitively. Our study suggests that alternative approaches to excluding occult, high grade prostate cancer are needed in such men. OBJECTIVE: To evaluate whether older age in men with low-risk prostate cancer increases the risk of prostate cancer-specific mortality (PCSM) when non-curative approaches are selected as initial management. PATIENTS AND METHODS: The study cohort consisted of 27 969 men, with a median age of 67 years, with prostate-specific antigen (PSA)-detected, low-risk prostate cancer (clinical category T1c, Gleason score≤6, and PSA≤10) identified by the Surveillance, Epidemiology and End Results programme between 2004 and 2007. Fine and Gray's competing risk regression analysis was used to evaluate whether management with non-curative vs curative therapy was associated with an increased risk of PCSM after adjusting for PSA level, age at diagnosis and year of diagnosis. RESULTS: After a median follow-up of 2.75 years, 1121 men died, 60 (5.4%) from prostate cancer. Both older age (adjusted hazard ratio [AHR] 1.05; 95% confidence interval (CI) 1.02-1.08; P<0.001) and non-curative treatment (AHR 3.34; 95% CI 1.97-5.67; P<0.001) were significantly associated with an increased risk of PCSM. Men>the median age experienced increased estimates of PCSM when treated with non-curative as opposed to curative intent (P<0.001); this finding was not seen in men≤the median age (P = 0.17). CONCLUSION: Pending prospective validation, our study suggests that non-curative approaches for older men with 'low-risk' prostate cancer result in an increased risk of PCSM, suggesting the need for alternative approaches to exclude occult, high grade prostate cancer in these men.

Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.

PURPOSE: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. METHODS AND MATERIALS: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. RESULTS: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. CONCLUSIONS: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

Analysis of urological procedures in men who died from prostate cancer using a population-based approach.

UNLABELLED: What's known on the subject? and What does the study add? Very few studies have examined end-of-life urological studies in men with prostate cancer. These studies reported fewer procedures in men who received primary therapy for prostate cancer. However, these studies were typically single institution or had a short follow-up period. The present study is the first population-based study examining end-of-life urological procedures and uses a geographic region encompassing 385 000 patients. Furthermore, this study incorporates both hospital- and office-based procedures. This approach has not been previously undertaken. OBJECTIVE: To determine using a population-based approach whether men with end-stage prostate cancer who had definitive primary therapy might require fewer urological interventions. Repeated urological procedures can impact health-related quality of life in patients dying from prostate cancer. PATIENTS AND METHODS: Using the Marshfield Epidemiological Study Area (MESA) database and tumour registry, we compared end-of-life interventions in men who died from prostate cancer between 1991 and 2009. Patient charts were queried for urological procedures using International Classification of Disease Modification, 9th edition (ICD9) codes for 3 years before death. Clinicopathological information was examined including whether the patient had a history of primary therapy (radiation or radical prostatectomy). RESULTS: Among 280 patients dying from prostate cancer, 52 (19%) required 153 urological procedures during the last 3 years of life. The frequency of procedures increased closer to death. The most common procedures involved nephrostomy tube (56%), Foley catheter (24%) and transurethral resection of the prostate (10%). Clinicopathological features did not predict the need for an end-of-life urological procedure. There was no difference in the frequency of upper or lower tract procedures in surgery or radiation patients compared with patients without primary therapy (P = 0.556 and P = 0.508). Using a Kaplan-Meier analysis, there were no differences between groups in the proportion of patients not requiring a procedure (n = 280; P = 0.179). CONCLUSIONS: This is the first population-based study to examine the frequency of urological procedures in patients with end-stage prostate cancer. A minority of patients (19%) required urological procedures during the final 3 years of life. A history of surgery or radiation did not influence the overall risk for urological intervention.

Prevalence of ATM Sequence Variants in Northern Plains American Indian Cancer Patients.

PURPOSE: To identify sequence variants of the ataxia telangiectasia mutated (ATM) gene and establish their prevalence rate among American Indian (AI) as compared with non-AI cancer patients. MATERIALS AND METHODS: DNA was isolated from blood samples collected from 100 AI and 100 non-AI cancer patients undergoing radiation therapy, and a blinded assessment of the ATM sequence was conducted. Quantitative PCR assessment of copy number for each exon was also performed. The main outcome measure was the prevalence of ATM variants in the two patient populations. RESULTS: No statistically significant differences for total prevalence of ATM variants among AI and non-AI patients were found. Of the 25 variants identified, 5 variants had a prevalence of >2%, of which 4 occurred at a rate of >5% in one or both groups. The prevalence of these four variants could meaningfully be compared between the two groups. The only statistically significant difference among the groups was the c.4138C > T variant which is predicted not to affect protein function, seen in 8% of AI versus 0% of non-AI patients (P = 0.007). No exonic copy number changes were found in these patients. CONCLUSION: This study is the first to determine the prevalence of ATM variants in AIs.