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The benefit of adding neoadjuvant chemotherapy to bladder-sparing chemoradiation for muscle-invasive bladder cancer remains unclear. This retrospective, large database study of 2566 patients found no survival benefit with the addition of neoadjuvant chemotherapy to definitive chemoradiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, which should be investigated under prospective clinical trials. Background: Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. Patients and Methods: We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. Results: We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. Conclusion: These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials. [ABSTRACT FROM AUTHOR]

Radiation therapy plays a crucial role for the management of genitourinary malignancies, with technological advancements that have led to improvements in outcomes and decrease in treatment toxicities. However, better risk-stratification and identification of patients for appropriate treatments is necessary. Recent advancements in imaging and novel genomic techniques can provide additional individualized tumor and patient information to further inform and guide treatment decisions for genitourinary cancer patients. In addition, the development and use of targeted molecular therapies based on tumor biology can result in individualized treatment recommendations. In this review, we discuss the advances in precision oncology techniques along with current applications for personalized genitourinary cancer management. We also highlight the opportunities and challenges when applying precision medicine principles to the field of radiation oncology. The identification, development and validation of biomarkers has the potential to personalize radiation therapy for genitourinary malignancies so that we may improve treatment outcomes, decrease radiation-specific toxicities, and lead to better long-term quality of life for GU cancer survivors. [ABSTRACT FROM AUTHOR]

Purpose: Hypofractionated radiotherapy of prostate cancer is gaining clinical acceptance given its potential increase in therapeutic ratio and evidence for noninferiority and lack of added late toxicities compared to conventional fractionation. However, concerns have been raised that smaller number of fractions might lead to larger dosimetric influence by interfractional motion. We aim to compare the effect of these variations on hypofractionated pencil beam scanning (PBS) proton therapy and volumetric modulated arc therapy (VMAT) for localized prostate cancer. Methods: Weekly CT images were acquired for 6 patients participating in a randomized clinical trial. PBS plans featuring bilateral (BL) and a combination of lateral and anterior‐oblique beams (AOL), and VMAT plans were created. All patients were treated to a conventional 79.2 Gy total dose in 44 fractions. For this study, hypofractionated dose to the prostate gland was 51.6 Gy in 12 fractions or 36.25 Gy in 5 fractions, and 32.8, and 23.1 Gy to proximal seminal vesicles, respectively. Patients were simulated with endorectal balloons to aid gland immobilization. Three fiducial markers were implanted for setup guidance. All plans were recomputed on the weekly CT images after aligning with the simulation CT. The entire set of 9 CT images was used for dose recalculation for 12‐fraction and only 5 used for the 5‐fraction case. Adaptive range adjustments were applied to anterior‐oblique beams assuming clinical availability of in vivo range verification. Fractional doses were summed using deformable dose accumulation to approximate the delivered dose. Biologically equivalent dose to 2 Gy(EQD2) was calculated assuming α/β of 1.5 Gy for prostate and 3 Gy for bladder and rectum. Results: The median delivered prostate D98 was 0.13/0.14/0.13 Gy(EQD2) smaller than planned for PBS‐BL, 0.13/0.27/0.17 Gy(EQD2) for PBS‐AOL and 0.59/0.66/0.59 Gy(EQD2) for VMAT, for 44/12/5 fractions, respectively. The largest D98 reduction was 1.5 and 3.5 Gy(EQD2) for CTV1 and CTV2, respectively. Target dose degradation was comparable for all fractionation schemes within each modality. The maximum increase in rectum D2 was 0.98 Gy(EQD2) for a 5‐fraction PBS case. Conclusions: The robustness of PBS and VMAT were comparable for all patients for the studied fractionations. The delivered target dose generally remained within clinical tolerance and the deviations were relatively minor for both fractionation schemes. The delivered OAR dose stayed in compliance with the RTOG hypofractionation constraints for all cases. [ABSTRACT FROM AUTHOR]

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

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To analyze the location of metastatic lymph nodes in seminoma patients relative to vascular and bony anatomy and conventional radiation fields. Materials and methods: Cross-sectional scans of 90 seminoma patients with infradiaphragmatic adenopathy were analyzed. The position of each node respective to vascular anatomy was transferred to a standardized template. Conventional radiation fields were overlaid on the template and locations of metastatic nodes were assessed. Results: One hundred and forty-five nodes were radiographically positive. Eighty-four percent, 9%, and 7% of nodes were located in the para-aortic, common iliac, and pelvic regions, respectively. Ninety-nine percent of nodes were within a 2.5cm lateral and 2.1cm anterior expansion of the aorta inferior to T12/L1. No radiographically positive nodes were identified within the renal hilum or superior to L1 in left-sided seminomas. For right-sided seminomas, no radiographically positive nodes were superior to L2. Three percent of all radiographically positive nodes would have been located outside of conventional and modified fields. Conclusions: Infradiaphragmatic nodal metastases from a contemporary cohort of seminoma patients localized to a smaller area than is targeted by conventional radiation fields. Modified treatment fields based on vascular, rather than bony, anatomy are smaller and may allow for a significant decrease in normal tissue irradiation and toxicity. [Copyright &y& Elsevier]

Study Type – Prognosis (risk model) Level of Evidence 2a OBJECTIVE To design a decision-support tool to facilitate evidence-based treatment decisions in clinically localized prostate cancer, as individualized risk assessment and shared decision-making can decrease distress and decisional regret in patients with prostate cancer, but current individual models vary or only predict one outcome of interest. METHODS We searched Medline for previous reports and identified peer-reviewed articles providing pretreatment predictive models that estimated pathological stage and treatment outcomes in men with biopsy-confirmed, clinical T1-3 prostate cancer. Each model was entered into a spreadsheet to provide calculated estimates of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph node involvement (LNI). Estimates of the prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) or radiotherapy (RT), and clinical outcomes after RT, were also entered. The data are available at . RESULTS Entering a patient’s 2002 clinical T stage, Gleason score and pretreatment PSA level, and details from core biopsy findings, into the CaP Calculator provides estimates from predictive models of pathological extent of disease, four models for ECE, four for SVI and eight for LNI. The 5-year estimates of PSA relapse-free survival after RT and 10-year estimates after RP were available. A printout can be generated with individualized results for clinicians to review with each patient. CONCLUSIONS The CaP Calculator is a free, online ‘clearing house’ of several predictive models for prostate cancer, available in an accessible, user-friendly format. With further development and testing with patients, the CaP Calculator might be a useful decision-support tool to help doctors promote evidence-based shared decision-making in prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Gonadotropin-releasing hormone agonists (GnRHa) are associated with greater risk of coronary heart disease and myocardial infarction in men with prostate cancer, but little is known about their potential effects on cardiovascular mortality. We assessed the relationship between duration of GnRHa therapy and cardiovascular mortality in a large randomized trial of men treated with short-term versus longer-term adjuvant goserelin and radiation therapy (RT) for locally advanced prostate cancer. Methods: From 1992 to 1995, 1554 men with locally advanced prostate cancer (T2c–4, prostate-specific antigen [PSA] <150ng/ml) received RT and 4 mo of goserelin and then were randomized to no additional therapy (arm 1) or 24 mo adjuvant goserelin (arm 2) in a phase 3 trial (Radiation Therapy Oncology Group [RTOG] 92-02). Cox regression analyses were performed to evaluate the relationship between treatment arm and cardiovascular mortality. Covariates included age, prevalent cardiovascular disease (CVD), hypertension, diabetes (DM), race, PSA, Gleason score, and stage. Results: After median follow-up of 8.1 yr, 185 cardiovascular-related deaths had occurred. No increase in cardiovascular mortality occurred for men receiving a longer duration of goserelin. At 5 yr, cardiovascular mortality for men receiving longer-term adjuvant goserelin was 5.9% versus 4.8% with short-term goserelin (Gray''s p =0.16). In multivariate analyses, treatment arm was not significantly associated with increased risk of cardiovascular mortality (adjusted hazard ratio [HR]=1.09; 95% confidence interval [CI], 0.81–1.47; p =0.58; when censoring at time of salvage goserelin, HR=1.02, 95%CI, 0.73–1.43; p =0.9). Traditional cardiac risk factors, including age, prevalent CVD, and DM, were significantly associated with greater cardiovascular mortality. Conclusions: Longer duration of adjuvant GnRHa therapy does not appear to increase cardiovascular mortality in men with locally advanced prostate cancer. [Copyright &y& Elsevier]

The article presents a commentary on the use of postoperative radiation in the treatment of prostate cancer. The European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 showed an improvement in biochemical progression-free survival among patients with prostate cancer. The effect of the increased use of salvage therapy in the trial is indicated. The use of adjuvant therapy against prostate cancer is also discussed.

We provide the strongest evidence to date that local failure is an independent prognosticator of outcomes in high- and intermediate-risk prostate cancer patients treated with definitive radiation therapy. Distant metastasis predominantly develops from a clinical relapse-free state; however, a second wave of distant metastasis occurs subsequent to local failure, albeit less commonly. The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it. [ABSTRACT FROM AUTHOR]

Background Patterns of postoperative radiotherapy (RT) use in prostate cancer (PCa) after the publication of major randomized trials have not been well characterized. Objective To describe patterns of postoperative RT use after radical prostatectomy (RP) in patients with adverse pathologic features in the United States. Design, setting, and participants Retrospective analysis of 97 270 patients with PCa diagnosed between 2005 and 2011 whose presentation and outcomes were recorded in the National Cancer Data Base. Outcome measurements and statistical analysis Temporal changes in receipt of postoperative RT and factors associated with receipt of this treatment using the Cochran–Armitage trend test and multiple logistic regression, respectively. Results and limitations Between 2005 and 2011, receipt of postoperative RT decreased steadily from 9.1% to 7.3% ( p trend < 0.001). Use of RT with or without androgen deprivation therapy monotonically decreased with advancing age from 8.5% in patients aged 18–59 yr to 6.8% in patients aged 70–79 yr ( p trend < 0.001). Receipt of RT was higher at community cancer programs compared with teaching/research centers (14% vs 7.3%; odds ratio [OR]: 2.16; p < 0.001), in those with pT3-4 disease and positive margins compared with those with pT3-4 and negative margins (17% vs 5.9%; OR: 2.89; p < 0.001), and in patients with a Gleason score of 8–10 compared with those with a Gleason score of 2–6 (17% vs 4.2%; OR: 3.50; p < 0.001). Limitations include lack of postprostatectomy prostate-specific antigen level. Conclusions Postoperative RT use for localized PCa in patients with adverse pathologic features is declining in the United States. Patient summary In this report, we show that use of postoperative radiotherapy in patients with prostate cancer with adverse pathologic features is declining. Patients treated at community cancer programs, those with locally advanced disease and positive margins, and those with a high Gleason score were more likely to receive postoperative radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To quantify daily variations in the anatomy of patients undergoing radiation therapy for prostate carcinoma, to estimate their effect on dose distribution, and to evaluate the effectiveness of current standard planning and setup approaches employed in proton therapy. Methods: We used series of computed tomography data, which included the pretreatment scan, and between 21 and 43 in-room scans acquired on different treatment days, from 10 patients treated with intensity-modulated radiation therapy at Morristown Memorial Hospital. Variations in femur rotation angles, thickness of subcutaneous adipose tissue, and physical depth to the distal surface of the prostate for lateral beam arrangement were recorded. Proton dose distributions were planned with the standard approach. Daily variations in the location of the prescription isodose were evaluated. Results: In all 10 datasets, substantial variation was observed in the lateral tissue thickness (standard deviation of 1.7–3.6 mm for individual patients, variations of >5 mm from the planning computed tomography observed in all series), and femur rotation angle (standard deviation between 1.3° and 4.8°, with the maximum excursion exceeding 10° in 6 of 10 datasets). Shifts in the position of treated volume (98% isodose) were correlated with the variations in the lateral tissue thickness. Conclusions: Analysis suggests that, combined with image-guided setup verification, the range compensator expansion technique prevents loss of dose to target from femur rotation and soft-tissue deformation, in the majority of cases. Anatomic changes coupled with the uncertainties of particle penetration in tissue restrict possibilities for margin reduction in proton therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

Background Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT). Objective To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM). Design, setting, and participants A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo. Interventions WPRT and/or ADT in addition to PBRT. Outcome measurements and statistical analyses FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression. Results and limitation Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p < 0.001) and no ADT versus ADT (HR 1.70, p < 0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% ( p < 0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p = 0.012). No significant differences in DM cumulative incidence were found. Conclusions For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival. Patient summary We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning). [ABSTRACT FROM AUTHOR]

Background Numerous management options exist for patients with prostate cancer; however, recent trends and their influencing factors are not well described. Objective To describe modern patterns of care and factors associated with management choice using the National Cancer Database. Design, setting, and participants Patients with localized prostate cancer diagnosed between 2004 and 2012 were included and grouped according to National Comprehensive Cancer Network guidelines into low, intermediate, or high risk. Outcome measurements and statistical analysis Trend analyses and multivariate logistic regression was used to identify factors associated with management. Results and limitations There were 598 640 patients who met the study criteria; 36.3% were classified as low risk, 43.8% intermediate risk, and 20.0% high risk. Over the study period, among low-risk patients, observation increased from 9.2% to 21.3%, while radical prostatectomy (RP) increased from 29.5% to 51.1% ( p < 0.001 for both). In contrast, external beam radiotherapy decreased from 24.3% to 14.5%, while brachytherapy decreased from 31.7% to 11.1%. A similar pattern was seen for patients with intermediate-risk or high-risk disease. Among high-risk patients, RP increased from 25.1% to 43.4% replacing external beam radiotherapy as the dominant therapy. On multivariate analysis, racial minorities, the uninsured, and low-income patients were less likely to receive RP. Low-risk patients in similar subgroups were significantly more likely to be observed. Limitations include potential miscoding or misclassification of variables. Conclusions Patterns of care in localized prostate cancer are changing rapidly. While use of observation is increasing in low-risk groups, the use of RP is increasing across all risk groups with a concomitant decline in use of radiotherapy. Socioeconomic factors appear to influence management choice. Patient summary In this report we identify a recent significant increase in the use of radical prostatectomy for prostate cancer patients. Socioeconomic factors such as race, insurance type, and income may affect treatments offered to and received by patients. [ABSTRACT FROM AUTHOR]

Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ∼1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation.Methods and Materials: Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/μm) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison.Results: Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage.Conclusions: A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers. [ABSTRACT FROM AUTHOR]

Purpose: For prostate treatments, robust evidence regarding the superiority of either intensity modulated radiation therapy (IMRT) or proton therapy is currently lacking. In this study we investigated the circumstances under which proton therapy should be expected to outperform IMRT, particularly the proton beam orientations and relative biological effectiveness (RBE) assumptions.Methods and Materials: For 8 patients, 4 treatment planning strategies were considered: (A) IMRT; (B) passively scattered standard bilateral (SB) proton beams; (C) passively scattered anterior oblique (AO) proton beams, and (D) AO intensity modulated proton therapy (IMPT). For modalities (B)-(D) the dose and linear energy transfer (LET) distributions were simulated using the TOPAS Monte Carlo platform and RBE was calculated according to 3 different models.Results: Assuming a fixed RBE of 1.1, our implementation of IMRT outperformed SB proton therapy across most normal tissue metrics. For the scattered AO proton plans, application of the variable RBE models resulted in substantial hotspots in rectal RBE weighted dose. For AO IMPT, it was typically not possible to find a plan that simultaneously met the tumor and rectal constraints for both fixed and variable RBE models.Conclusion: If either a fixed RBE of 1.1 or a variable RBE model could be validated in vivo, then it would always be possible to use AO IMPT to dose-boost the prostate and improve normal tissue sparing relative to IMRT. For a cohort without rectum spacer gels, this study (1) underlines the importance of resolving the question of proton RBE within the framework of an IMRT versus proton debate for the prostate and (2) highlights that without further LET/RBE model validation, great care must be taken if AO proton fields are to be considered for prostate treatments. [ABSTRACT FROM AUTHOR]

Purpose: To quantify and compare the impact of interfractional setup and anatomic variations on proton therapy (PT) and intensity modulated radiation therapy (IMRT) for prostate cancer.Methods and Materials: Twenty patients with low-risk or intermediate-risk prostate cancer randomized to receive passive-scattering PT (n=10) and IMRT (n=10) were selected. For both modalities, clinical treatment plans included 50.4 Gy(RBE) to prostate and proximal seminal vesicles, and prostate-only boost to 79.2 Gy(RBE) in 1.8 Gy(RBE) per fraction. Implanted fiducials were used for prostate localization and endorectal balloons were used for immobilization. Patients in PT and IMRT arms received weekly computed tomography (CT) and cone beam CT (CBCT) scans, respectively. The planned dose was recalculated on each weekly image, scaled, and mapped onto the planning CT using deformable registration. The resulting accumulated dose distribution over the entire treatment course was compared with the planned dose using dose-volume histogram (DVH) and γ analysis.Results: The target conformity index remained acceptable after accumulation. The largest decrease in the average prostate D98 was 2.2 and 0.7 Gy for PT and IMRT, respectively. On average, the mean dose to bladder increased by 3.26 ± 7.51 Gy and 1.97 ± 6.84 Gy for PT and IMRT, respectively. These values were 0.74 ± 2.37 and 0.56 ± 1.90 for rectum. Differences between changes in DVH indices were not statistically significant between modalities. All volume indices remained within the protocol tolerances after accumulation. The average pass rate for the γ analysis, assuming tolerances of 3 mm and 3%, for clinical target volume, bladder, rectum, and whole patient for PT/IMRT were 100/100, 92.6/99, 99.2/100, and 97.2/99.4, respectively.Conclusion: The differences in target coverage and organs at risk dose deviations for PT and IMRT were not statistically significant under the guidelines of this protocol. [ABSTRACT FROM AUTHOR]

Purpose Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and 137 Cs γ-rays were used. To estimate the RBE of protons relative to 60 Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 ( P ≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation. [ABSTRACT FROM AUTHOR]

Abstract: We examine the quality of plans created using multicriteria optimization (MCO) treatment planning in intensity-modulated radiation therapy (IMRT) in treatment of localized prostate cancer. Nine random cases of patients receiving IMRT to the prostate were selected. Each case was associated with a clinically approved plan created using Corvus. The cases were replanned using MCO-based planning in RayStation. Dose-volume histogram data from both planning systems were presented to 2 radiation oncologists in a blinded evaluation, and were compared at a number of dose-volume points. Both physicians rated all 9 MCO plans as superior to the clinically approved plans (p<10−5). Target coverage was equivalent (p = 0.81). Maximum doses to the prostate and bladder and the V50 and V70 to the anterior rectum were reduced in all MCO plans (p<0.05). Treatment planning time with MCO took approximately 60 minutes per case. MCO-based planning for prostate IMRT is efficient and produces high-quality plans with good target homogeneity and sparing of the anterior rectum, bladder, and femoral heads, without sacrificing target coverage. [Copyright &y& Elsevier]

Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 × 1−2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior–posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior–posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy). [Copyright &y& Elsevier]

Purpose: We examined whether rectal dose–volume histogram (DVH) parameters were associated with long-term patient-reported gastrointestinal (GI) quality of life (QOL) after conventional (70.2 GyE) or high-dose (79.2 GyE) radiation for prostate cancer. Methods and Materials: Of 64 men with localized prostate cancer alive with a minimum 7-year follow-up after treatment as part of a randomized trial with either 70.2 GyE or 79.2 GyE of external beam radiation at Massachusetts General Hospital, 56 men (88%) returned a QOL questionnaire, and 50 of those men had DVH information. The DVH parameters of the anterior rectal wall were correlated with patient-reported long-term GI QOL using Pearson correlation and t tests. Results: There was a trend toward an association between increased long-term GI dysfunction and higher V60 (p = 0.07), V65 (p = 0.06), V70 (p = 0.09), and V75 (p = 0.09). When dichotomized by their medians, a V60 > 54% (p = 0.04), V70 > 44% (p = 0.06), and V75 > 39% (p = 0.06) were associated with increased long-term GI dysfunction. There was no difference in long-term GI dysfunction between men on the conventional vs. high-dose arms (p = 0.49). Conclusions: Dose–volume histogram parameters of the anterior rectal wall were associated with long-term patient-reported GI QOL after prostate radiation, whereas the dose prescribed to the prostate was not, suggesting that DVH constraints, rather than total prescribed dose, may have the greatest impact on long-term bowel dysfunction, and therefore that continued dose escalation may be feasible if appropriate dose–volume constraints are met. [ABSTRACT FROM AUTHOR]

Purpose: To assess characteristics and outcome of patients treated with radiotherapy for muscle-invasive bladder cancer at 44 community-based radiotherapy centers and compare these to those on clinical trials.Materials and Methods: We reviewed 155 patients who had been treated from 2010 to 2014. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Results were compared to a pooled analysis of 6 Radiation Therapy Oncology Group (RTOG) protocols.Results: What stood out was that our patients' characteristics were significantly inferior than those on RTOG studies: lower rate of complete transurethral resection of bladder tumor: 36.8% vs. 70% (P<0.0001), higher median age: 79 years vs. 66 (P<0.0001), more medically inoperable: (51.0%) vs. 0% in RTOG (P<0.001), and 46.9% had refused surgery. Fewer patients underwent concurrent chemotherapy: 56.1% vs. 100% (P<0.0001). It was also striking that at median follow-up 12.6 months (range: 3.1-49.2), the 36-month overall survival was 51.3% for those who refused surgery vs. 24.5% for medically inoperable (P = 0.009); 58.1% with complete transurethral resection of bladder tumor vs. 29.8% if incomplete (P = 0.07); 54.3% with chemoradiotherapy (CRT) vs. 17.2% without (P = 0.03); 66.3% for those who refused surgery and had CRT vs. 38.9% for medically inoperable who had CRT (P = 0.04).Conclusions: The cohort at community-based centers was older, more medically inoperable, and less likely to receive CRT than clinical trial patients. This suggests that we may not be able to apply trial-derived regimens for many patients in this setting. There is a pressing need to find treatment options for such patients, especially given the aging population. Survival of medically operable CRT patients was comparable to results of RTOG protocols notwithstanding this study's smaller sample size, retrospective nature and suboptimal documentation of patient characteristics. [ABSTRACT FROM AUTHOR]

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