Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate

Biochemical recurrence; Radiotherapy; Prostate adenocarcinomaRecurrència bioquímica; Radioteràpia; Adenocarcinoma de pròstataRecurrencia bioquímica; Radioterapia; Adenocarcinoma de próstataPURPOSE The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.Supported by Cancer Research UK Radiation Research Centre of Excellence at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research (grant A28724) (A.C.T.); Cancer Research UK Programme Grant (C33589/A28284)(A.C.T.); NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (A.C.T.); grant P50CA09213 from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence (A.U.K.); grant PC210066 from the Department of Defense (A.U.K.), the Prostate Cancer Foundation, and the American Society for Radiation Oncology (A.U.K.); and funding from the Chapgier, Bershad, De Silva, and McCarrick Families (A.U.K.)

The Size and Shape of Voids in Three-Dimensional Galaxy Surveys

The sizes and shapes of voids in a galaxy survey depend not only on the physics of structure formation, but also on the sampling density of the survey and on the algorithm used to define voids. Using an N-body simulation with a CDM power spectrum, we study the properties of voids in samples with different number densities of galaxies, both in redshift space and in real space. When voids are defined as regions totally empty of galaxies, their characteristic volume is strongly dependent on sampling density; when they are defined as regions whose density is 0.2 times the mean galaxy density, the dependence is less strong. We compare two void-finding algorithms, one in which voids are nonoverlapping spheres, and one, based on the algorithm of Aikio and Mahonen, which does not predefine the shape of a void. Regardless of the algorithm chosen, the characteristic void size is larger in redshift space than in real space, and is larger for low sampling densities than for high sampling densities. We define an elongation statistic Q which measures the tendency of voids to be stretched or squashed along the line of sight. Using this statistic, we find that at sufficiently high sampling densities (comparable to the number densities of galaxies brighter than L_*), large voids tend to be slightly elongated along the line of sight in redshift space.Comment: LaTex, 21 pages (including 7 figures), ApJ, submitte

Quasars Probing Quasars II: The Anisotropic Clustering of Optically Thick Absorbers around Quasars

With close pairs of quasars at different redshifts, a background quasar sightline can be used to study a foreground quasar's environment in absorption. We used a sample of 17 Lyman limit systems with column density N_HI > 10^19 cm^-2 selected from 149 projected quasar pair sightlines, to investigate the clustering pattern of optically thick absorbers around luminous quasars at z ~ 2.5. Specifically, we measured the quasar-absorber correlation function in the transverse direction, and found a comoving correlation length of r_0=9.2_{+1.5}_{-1.7} Mpc/h (comoving) assuming a power law correlation function, with gamma=1.6. Applying this transverse clustering strength to the line-of-sight, would predict that ~ 15-50% of all quasars should show a N_HI > 10^19 cm^-2 absorber within a velocity window of v < 3000 km/s. This overpredicts the number of absorbers along the line-of-sight by a large factor, providing compelling evidence that the clustering pattern of optically thick absorbers around quasars is highly anisotropic. The most plausible explanationfor the anisotropy is that the transverse direction is less likely to be illuminated by ionizing photons than the line-of-sight, and that absorbers along the line-of-sight are being photoevaporated. A simple model for the photoevaporation of absorbers subject to the ionizing flux of a quasar is presented, and it is shown that absorbers with volume densities n_H < 0.1 cm^-3 will be photoevaporated if they lie within ~ 1 Mpc (proper) of a luminous quasar. Using this simple model, we illustrate how comparisons of the transverse and line-of-sight clustering around quasars can ultimately be used to constrain the distribution of gas in optically thick absorption line systems.Comment: 14 pages of emulateapj, 7 figures, submitted to Ap

Multicriteria plan optimization in the hands of physicians: a pilot study in prostate cancer and brain tumors

Background: The purpose of this study was to demonstrate the feasibility of physician driven planning in intensity modulated radiotherapy (IMRT) with a multicriteria optimization (MCO) treatment planning system and template based plan optimization. Exploiting the full planning potential of MCO navigation, this alternative planning approach intends to improve planning efficiency and individual plan quality. Methods: Planning was retrospectively performed on 12 brain tumor and 10 post-prostatectomy prostate patients previously treated with MCO-IMRT. For each patient, physicians were provided with a template-based generated Pareto surface of optimal plans to navigate, using the beam angles from the original clinical plans. We compared physician generated plans to clinically delivered plans (created by dosimetrists) in terms of dosimetric differences, physician preferences and planning times. Results: Plan qualities were similar, however physician generated and clinical plans differed in the prioritization of clinical goals. Physician derived prostate plans showed significantly better sparing of the high dose rectum and bladder regions (p(D1) < 0.05; D1: dose received by 1% of the corresponding structure). Physicians’ brain tumor plans indicated higher doses for targets and brainstem (p(D1) < 0.05). Within blinded plan comparisons physicians preferred the clinical plans more often (brain: 6:3 out of 12, prostate: 2:6 out of 10) (not statistically significant). While times of physician involvement were comparable for prostate planning, the new workflow reduced the average involved time for brain cases by 30%. Planner times were reduced for all cases. Subjective benefits, such as a better understanding of planning situations, were observed by clinicians through the insight into plan optimization and experiencing dosimetric trade-offs. Conclusions: We introduce physician driven planning with MCO for brain and prostate tumors as a feasible planning workflow. The proposed approach standardizes the planning process by utilizing site specific templates and integrates physicians more tightly into treatment planning. Physicians’ navigated plan qualities were comparable to the clinical plans. Given the reduction of planning time of the planner and the equal or lower planning time of physicians, this approach has the potential to improve departmental efficiencies

Understanding Infrared Galaxy Populations: the SWIRE Legacy Survey

We discuss spectral energy distributions, photometric redshifts, redshift distributions, luminosity functions, source-counts and the far infrared to optical luminosity ratio for sources in the SWIRE Legacy Survey. The spectral energy distributions of selected SWIRE sources are modelled in terms of a simple set of galaxy and quasar templates in the optical and near infrared, and with a set of dust emission templates (cirrus, M82 starburst, Arp 220 starburst, and AGN dust torus) in the mid infrared. The optical data, together with the IRAC 3.6 and 4.5 mu data, have been used to determine photometric redshifts. For galaxies with known spectroscopic redshifts there is a notable improvement in the photometric redshift when the IRAC data are used, with a reduction in the rms scatter from 10% in (1+z) to 5%. While further spectroscopic data are needed to confirm this result, the prospect of determining good photometric redshifts for the 2 million extragalactic objects in SWIRE is excellent. The distribution of the different infrared sed types in the L{ir}/L{opt} versus L{ir} plane, where L{ir} and L{opt} are the infrared and optical bolometric luminosities, is discussed. Source-counts at 24, 70 and 160 mu are discussed, and luminosity functions at 3.6 and 24 mu are presented.Comment: 8 pages, 14 figures, to appear in proceedings of 'Spitzer IR Diagnostics Conference, Nov 14-16, 2005

Steep Faint-end Slopes of Galaxy Mass and Luminosity Functions at z>=6 and the Implications for Reionisation

We present the results of a numerical study comparing photometric and physical properties of simulated z=6-9 galaxies to the observations taken by the WFC3 instrument aboard the Hubble Space Telescope. Using cosmological hydrodynamical simulations we find good agreement with observations in color-color space at all studied redshifts. We also find good agreement between observations and our Schechter luminosity function fit in the observable range, Muv<= -18, provided that a moderate dust extinction effect exists for massive galaxies. However beyond what currently can be observed, simulations predict a very large number of low-mass galaxies and evolving steep faint-end slopes from alpha_L = -2.15 at z=6 to alpha_L = -2.64 at z=9, with a dependence of |alpha_L| \propto (1+z)^0.59. During the same epoch, the normalization phi* increases and the characteristic magnitude Muv* becomes moderately brighter with decreasing redshift. We find similar trends for galaxy stellar mass function with evolving low-mass end slope from alpha_M = - 2.26 at z=6 to alpha_M = -2.87 at z=9, with a dependence of |alpha_M| \propto (1+z)^0.65. Together with our recent result on the high escape fraction of ionizing photons for low-mass galaxies, our results suggest that the low-mass galaxies are important contributor of ionizing photons for the reionisation of the Universe at z>=6.Comment: Revised metadata, 16 pages, 5 tables, 17 figures. MNRAS, in pres

Patient‐reported outcomes after 3‐dimensional conformal, intensity‐modulated, or proton beam radiotherapy for localized prostate cancer

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. Prostate cancer patients who receive 3‐dimensional conformal radiotherapy, intensity‐modulated radiotherapy, or proton beam therapy report distinct patterns of treatment‐related quality of life. Although the timing of toxicity varies between cohorts, patients report similar modest quality‐of‐life decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97476/1/27956_ftp.pd

Interfractional Variations in the Setup of Pelvic Bony Anatomy and Soft Tissue, and Their Implications on the Delivery of Proton Therapy for Localized Prostate Cancer

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 set-up approaches employed in proton therapy. Methods We used series of CT data, which included the pre-treatment 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 iso-dose 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 over 5 mm from the planning CT observed in all series), and femur rotation angle (standard deviation between 1.3–4.8°, with the maximum excursion exceeding 10° in 6 out of 10 datasets). Shifts in the position of treated volume (98% iso-dose) were correlated with the variations in the lateral tissue thickness. Conclusions Analysis suggests that, combined with image-guided set-up verification, the range compensator expansion technique prevents loss of dose to target due to 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

Chandra and Spitzer unveil heavily obscured quasars in the SWIRE/Chandra Survey

Using the large multi-wavelength data set in the chandra/SWIRE Survey (0.6 square degrees in the Lockman Hole), we show evidence for the existence of highly obscured (Compton-thick) AGN, estimate a lower limit to their surface density and characterize their multi-wavelength properties. Two independent selection methods based on the X-ray and infrared spectral properties are presented. The two selected samples contain 1) 5 X-ray sources with hard X-ray spectra and column densities > 10^24 cm-2, and 2) 120 infrared sources with red and AGN-dominated infrared spectral energy distributions (SEDs). We estimate a surface density of at least 25 Compton-thick AGN per square degree detected in the infrared in the chandra/SWIRE field of which ~40% show distinct AGN signatures in their optical/near-infrared SEDs, the remainings being dominated by the host-galaxy emission. Only ~33% of all Compton-thick AGN are detected in the X-rays at our depth (F(0.3-8 keV)>10^-15 erg/cm2/s. We report the discovery of two sources in our sample of Compton-thick AGN, SWIRE_J104409.95+585224.8 (z=2.54) and SWIRE_J104406.30+583954.1 (z=2.43), which are the most luminous Compton-thick AGN at high-z currently known. The properties of these two sources are discussed in detail with an analysis of their spectra, SEDs, luminosities and black-hole masses.Comment: ApJ accepted (to appear in May 2006 issue, vol. 642, of ApJ) Figures 2, 3, and 14 have been degraded due to space consideration

Dosimetric impacts of endorectal balloon in CyberKnife stereotactic body radiation therapy (SBRT) for early‐stage prostate cancer

Abstract Purpose In SBRT for prostate cancer, higher fractional dose to the rectum is a major toxicity concern due to using smaller PTV margin and hypofractionation. We investigate the dosimetric impact on rectum using endorectal balloon (ERB) in prostate SBRT. Materials and Methods Twenty prostate cancer patients were included in a retrospective study, ten with ERB and 10 without ERB. Optimized SBRT plans were generated on CyberKnife MultiPlan for 5 × 7.25 Gy to PTV under RTOG‐0938 protocol for early‐stage prostate cancer. For the rectum and the anterior half rectum, mean dose and percentage of volumes receiving 50%, 80%, 90%, and 100% prescription dose were compared. Results: Using ERB, mean dose to the rectum was 62 cGy (P = 0.001) lower per fraction, and 50 cGy (P = 0.024) lower per fraction for the anterior half rectum. The average V50%, V80%, V90%, and V100% were lower by 9.9% (P = 0.001), 5.3% (P = 0.0002), 3.4% (P = 0.0002), and 1.2% (P = 0.005) for the rectum, and lower by 10.4% (P = 0.009), 8.3% (P = 0.0004), 5.4% (P = 0.0003), and 2.1% (P = 0.003) for the anterior half rectum. Conclusions: Significant reductions of dose to the rectum using ERB were observed. This may lead to improvement of the rectal toxicity profiles in prostate SBRT