Postoperative Prostate Cancer Research Articles

Development of New Prognostic Model for Predicting Biochemical Failure in Prostate Cancer Patients After Radical Prostatectomy With Adverse Pathological Features

Adjuvant radiotherapy after radical prostatectomy (RP) with adverse pathological features (APFs) has a significant decrease biochemical failure (BF) and local recurrence. Three published randomized trials showed overtreatment 40-60% and these patients did expose to unnecessary radiation toxicities. Thus, we developed a new prognostic model to predict the probability of BF after RP to select more appropriate patients for adjuvant treatment. DESIGN: Multivariable Cox regression of a retrospective cohort of postoperative prostate cancer patients. SETTING: One university hospital. PATIENTS: 292 consecutive prostate cancer patients in 2005 to 2009 after RP with pT2-3N0M0 and at least one of APFs (extracapsular extension, seminal vesicle involvement, close or positive margin) without any adjuvant radiotherapy or hormonal therapy. OUTCOME: BF defined as rising of PSA ≥ 0.2 ng/ml with a second confirmatory level (apart at least 2 week) or start any salvage treatment. The median follow up time was 82 months and 99 of 292 (34%) patients who underwent RP alone had BF with median time to BF 24 months. Preoperative PSA risk group, postoperative PSA level, perineural invasion, sum of Gleason score were strongest predictor of BF. Other predictors included in the final model were extracapsular extension, seminal vesicle invasion and surgical margin status. Discrimination of new model was satisfactory, with C statistics 0.78 (95% CI: 0.74-0.83), compared with C statistics from the conventional three standard APFs 0.60 (95% CI: 0.55-0.66). Calibration plot was performed by dividing patients into 4 risk groups and comparing the survival curves between predicted BF-free survival probability and observed outcome from Kaplan-Meier method. These two curves were fitted by visual analysis. A simple chart was constructed to easily provide 5-year probability of BF from sum of risk score from all predictors and web-based calculator is also available. If criteria were set to have 10% of 5 year probability of BF, this prediction rule can decrease overtreatment by 12%. This new prediction model can predict 5-year probability of BF in localized prostate cancer patients with APFs after treated with RP. In addition, this new model can assist in decision making between patient and doctor to tailor the individually appropriate treatment. Cautiously, internal and external validation should be performed in the near future.

Postoperative radiotherapy for prostate cancer: the sooner the better and potential to reduce toxicity even further

To evaluate biochemical relapse-free survival (bRFS), overall survival (OS), late rectal and bladder toxicities in a retrospective single institution series, also applying an in-house software for biological dose calculation. 258 patients submitted to radiotherapy after prostatectomy were considered. Differences between groups were calculated using the log-rank test and the relevant clinical and therapeutic variables were considered for multivariate analysis. PRODVH is an in-house system able to calculate mean dose-volume histograms (DVHs) of a series of patients, to convert them in biologically effective DVHs (BEDVHs) and allowing to compare them with ANOVA and t Student test. Adjuvant radiotherapy (ART) and salvage radiotherapy (SRT) were performed in 131 (50.8%) and 127 patients (49.2%). At multivariate analysis advanced T stage, androgen deprivation total (ADT) and SRT resulted as independent variables related to a worst bRFS (p=0.019, 0.001 and 0.02), while GS>7 and SRT affected negatively OS (p 0.047 and 0.039). High grade toxicity events occurred mainly in patients treated with 3-dimensional conformal radiotherapy (3DCRT) (proctitis p=0.006; cystitis: p=0.041). A significantly more favorable mean rectum BEDVH for patients with G0 or G1 rectal toxicity was shown (p<0.001). Mean BEDVH for both bladder (p<0.01) and rectum (p<0.05) were also significantly better for volumetric modulated arc therapy-image guided radiotherapy (VMAT-IGRT) plans than for 3DCRT plans. ART is better than SRT in terms of bRFS and OS, particularly for more aggressive cases, advanced T stage and higher Gleason Score. Postoperative prostate cancer radiotherapy should be applied as soon as possible after surgery. The use of modern techniques such as VMAT-IGRT significantly reduces toxicity.

Tissue-based analytics provide the next generation of prostate cancer risk models.

236 Background: Quantitative analysis of formalin-fixed paraffin-embedded (FFPE) prostate samples post radical-prostatectomy (RP) can help guide management of post-operative prostate cancer (PCa) patients. We have previously published on the results of our systems (precise) pathology platform which includes integration of clinical data with immunofluorescent (IF) morphology and biomarkers to predict disease progression in post-RP patients. We extended this approach by developing quantitative image features that further refine risk discrimination by directly competing with Gleason through the incorporation of biological attributes. Methods: Tissue microarrays representing a 892 RP population from Roswell Park Cancer Institute and the Henry Ford Hospital, with median 8 years follow-up were stained with a multiplex IF assay incorporating CK18 (epithelial cells), CK5/6 (basal cells), AMACR, the Androgen Receptor (AR), and Ki67. Images were captured with a Nikon i90 microscope / CRI multiplex camera and a Bayesian probabilistic approach was used to derive micro-anatomic quantitative image attributes. We generated a 50:50 balanced training / test cohort and optimized feature construction using clinical variables. Multivariate models were produced on the 324 training set to predict disease progression (i.e. clinical failure) which included a PSA rise post-adjuvant therapy, metastasis or death from PCa. The concordance index (CI), sensitivity and specificity were used to assess performance of the model. Results: A multivariate training model yielded a CI of 0.80, sensitivity 85% and specificity 74% with a hazard ratio of 9.8. By comparison a clinical only model produced a CI of 0.77, sensitivity 80% and specificity 73%, with a hazard ratio of 6. The IF model consisted of 3 features including pathologic stage and two imaging features that combine morphometry integrated with levels of AR and Ki67. Neither the Gleason score nor PSA were selected. Conclusions: Tissue-based models which incorporate objective and biological attributes accurately predict disease progression. Once validated, such approaches may replace the subjective Gleason grading system and provide an additional tool for pathologists when assigning risk.

Comparison of Automated Atlas-Based Segmentation Software for Postoperative Prostate Cancer Radiotherapy.

Automated atlas-based segmentation (ABS) algorithms present the potential to reduce the variability in volume delineation. Several vendors offer software that are mainly used for cranial, head and neck, and prostate cases. The present study will compare the contours produced by a radiation oncologist to the contours computed by different automated ABS algorithms for prostate bed cases, including femoral heads, bladder, and rectum. Contour comparison was evaluated by different metrics such as volume ratio, Dice coefficient, and Hausdorff distance. Results depended on the volume of interest showed some discrepancies between the different software. Automatic contours could be a good starting point for the delineation of organs since efficient editing tools are provided by different vendors. It should become an important help in the next few years for organ at risk delineation.

EP-1359: A randomized trial comparing bladder volume consistency during EBRT in postoperative prostate cancer

EP-1359: A randomized trial comparing bladder volume consistency during EBRT in postoperative prostate cancer

Evaluation of a new transperineal ultrasound probe for inter-fraction image-guidance for definitive and post-operative prostate cancer radiotherapy

PurposeThe aim of this study was to evaluate a new system based on transperineal ultrasound (TP-US) acquisitions for prostate and post-prostatectomy pre-treatment positioning by comparing this device to cone-beam computed tomography (CBCT). MethodsThe differences between CBCT/CT and TP-US/TP-US registrations were analyzed on 427 and 453 sessions for 13 prostate and 14 post-prostatectomy patients, respectively. The inter-operator variability (IOV) of the registration process, and the impact and variability of the probe pressure were also evaluated. ResultsCBCT and TP-US shift agreements at ± 5 mm were 76.6%, 95.1%, 96.3% and 90.3%, 85.0%, 97.6% in anterior-posterior, superior-inferior and left-right directions, for prostate and post-prostatectomy patients, respectively. IOV values were similar between the 2 modalities. Displacements above 5 mm due to strong pressures were observed on both localizations, but such pressures were rarely reproduced during treatment courses. ConclusionsHigh concordance between CBCT/CT and TP-US/TP-US localization of prostates or prostatic beds was found in this study. TP-US based prepositioning is a feasible method to ensure accurate treatment delivery, and represents an attractive alternative to invasive and/or irradiating imaging modalities.

The effect of bladder contrast on dose calculation in volumetric modulated arc therapy planning in patients treated for postoperative prostate cancer

The aim of this study was to evaluate the effect of contrast agent on dose calculation in volumetric modulated arc therapy (VMAT) in the post-prostatectomy setting. Ten patients were studied. Each patient received planning computed tomography (CT) images with contrast agent. All of the plans were done on virtually simulated contrast-free CT scans. The plan approved by the radiation oncologist was replicated to the contrast CT series. In both of the plans the same monitor unit was used. The doses calculated from the two plans were compared in regard to target volumes and organs at risk. A paired sample t-test was used to evaluate the differences in cumulative dose volume histogram between the two plans. We showed that the use of contrast agent may cause significant differences in dose distribution. There was a significant decrease in doses received by planning target volume (PTV70), rectum V65Gy, rectum V40Gy, bladder V65Gy, penile bulb V40Gy in plans with contrast-enhanced CT sets. The decrease in mean, maximum and minimum doses received by PTV70 also contributed to the significant decrease in conformity index. Using a contrast agent at the time of CT simulation may cause significant differences in dose distribution. For this reason, the plan should always be carried out on non-contrast CT data sets to avoid additional errors in the treatment planning process.

Endoscopic, Transperitoneal Radical Prostatectomy with 3.0-T mpMRI Stratifies Patients with Advanced Prostate Cancer

Objective: Recent years have brought a significant shift in case selection for the surgical treatment of prostate cancer (PCa). Primary surgical management is increasingly implemented in more aggressive tumors, however the role of radical prostatectomy (RP) in advanced cases remains controversial. The aim of the present study is to explore cancer diversity in patients who were subjected to endoscopic, transperitoneal RP due to very high-risk advanced PCa. Methods: Our database was screened for prostate cancer patients with clinically diagnosed seminal vesicles infiltration and/or invasion of other adjacent structures (cT3b-4 N0) and/or suspected nodal involvement (cT1-4 N1) who underwent ERP. Twenty cases were identified: 11 patients with cT3b-4 N0 disease and 9 patients with suspected nodal involvement. The preoperative tumor stage was assessed with the use of multiparametric magnetic resonance (mpMRI) in all cases. Results: Although the accuracy of mpMRI in the assessement of local tumor stage was 85%, the lymph node status was properly assessed preoperatively in 45% cases only. The pT3b-4 PCa was diagnosed in 13 cases (65%). Of them, 9 had lymph nodes metastases. Three patients (15%) were diagnosed with pT3a cancer, among them nodal metastases were confirmed in 2 cases. In the remaining 4 patients (20%), the tumor was confined to the prostate but in 1 of them pelvic lymph nodes were involved. Early, postoperative PSA was lower than 0.2 ng/ml in 13 patients (65%). Seventeen patients (85%) received additional treatment: androgen deprivation therapy in 7 cases (35%), radiation therapy in 10 cases (50%). No pad use was declared by 14 patients (70%). Conclusion: Radical prostatectomy thoroughly stratifies patients diagnosed with advanced prostate cancer. In more than a half of cases the clinical stage differs from the pathological disease status. Correct, postoperative prostate cancer stratification allows to personalize multidisciplinary treatment to reduce toxicity and improve oncological outcome.

Incorporation of advanced image analysis in novel post-prostatectomy systems pathology models as an approach to replace the clinical Gleason and provide robust risk stratification.

e16134 Background: Quantitative analysis of formalin-fixed paraffin-embedded prostatectomy tissue can help guide management of post-operative prostate cancer (PCa) patients. We have previously publ...

MP78-04 INFLUENCE OF RADICAL PROSTATECTOMY ON SERUM BIOAVAILABLE TESTOSTERONE LEVEL IN JAPANESE PATIENTS WITH LOCALIZED PROSTATE CANCER: A LONGITUDINAL STUDY

You have accessJournal of UrologyProstate Cancer: Localized VIII1 Apr 2015MP78-04 INFLUENCE OF RADICAL PROSTATECTOMY ON SERUM BIOAVAILABLE TESTOSTERONE LEVEL IN JAPANESE PATIENTS WITH LOCALIZED PROSTATE CANCER: A LONGITUDINAL STUDY Shoichiro Iwatsuki, Shoichi Sasaki, Yasue Kubota, Hiroki Kubota, Hiroyuki Kamiya, Yukihiro Umemoto, and Kenjiro Kohri Shoichiro IwatsukiShoichiro Iwatsuki More articles by this author , Shoichi SasakiShoichi Sasaki More articles by this author , Yasue KubotaYasue Kubota More articles by this author , Hiroki KubotaHiroki Kubota More articles by this author , Hiroyuki KamiyaHiroyuki Kamiya More articles by this author , Yukihiro UmemotoYukihiro Umemoto More articles by this author , and Kenjiro KohriKenjiro Kohri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2820AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES It is widely accepted that prostate cancer (PCa) is affected by serum testosterone (T). Interestingly, several authors have reported that serum total testosterone (TT) level had elevated after radical prostatectomy. However, TT consists of free testosterone, albumin-bound T, and sex hormone binding globulin (SHBG)-bound T. Only free T and albumin-bound T have biological activity (bioavailable T). However, the change of T activity before and after prostatectomy is unknown. In this study, we longitudinally measured serum bioavailable T levels before and after radical prostatectomy and evaluated the effect of prostatectomy on serum T activity. METHODS A total of 262 patients with prostate cancer who underwent robot-assisted laparoscopic prostatectomy (RALP) between May 2011 and April 2014 were enrolled in this study. Patients who received hormonal therapy during the observation period were excluded. Serum luteinizing hormone (LH), TT, and SHBG were measured before and 1 and 3 months after operation. Bioavailable T levels were calculated according to the ISSAM webpage (www.issam.ch/freetesto.htm) (abbreviated as cBAT). RESULTS Serum LH, TT, SHBG, and cBAT before and 1 and 3 months after radical prostatectomy are shown in the Table. Serum LH, TT, and cBAT levels were significantly increased both 1 and 3 months after operation (paired t-test). Postoperative serum SHBG level was also significantly higher than the preoperative value (paired t-test). There were no significant correlations between the rate of increase of hormone value and patients' age, prostatic volume, and the severity of prostate cancer (Pearson□fs correlation coefficient). CONCLUSIONS This study clarified that not only LH and TT but also bioavailable T significantly increase after radical prostatectomy in patients with PCa. Because this increased testosterone activity may affect postoperative PCa, postoperative monitoring of serum T activity should be performed, especially in patients in whom the resection margin is positive. preoperative postoperative 1 month (p value) postoperative 3 months (p value) LH [mIU/mL] 5.4 ± 3.2 6.4 ± 3.4 (< 10^-12) 6.3 ± 3.4 (< 10^-10) TT [ng/mL] 4.01 ± 1.39 4.37 ± 1.44 (< 10^-7) 4.33 ± 1.39 (< 10^-5) cBAT [ng/mL] 1.29 ± 0.41 1.34 ± 0.38 (< 0.05) 1.36 ± 0.39 (< 0.01) SHBG [nmol/L] 61.2 ± 23.2 64.7 ± 23.9 (< 0.05) 64.3 ± 26.8 (< 0.05) © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e1003 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shoichiro Iwatsuki More articles by this author Shoichi Sasaki More articles by this author Yasue Kubota More articles by this author Hiroki Kubota More articles by this author Hiroyuki Kamiya More articles by this author Yukihiro Umemoto More articles by this author Kenjiro Kohri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Dosimetric effects of the acuros XB and anisotropic analytical algorithm on volumetric modulated arc therapy planning for prostate cancer using an endorectal balloon.

BackgroundTo compare the dosimetric effects of Acuros XB (AXB) and Anisotropic Analytical Algorithm (AAA) on volumetric modulated arc therapy (VMAT) planning for postoperative prostate cancer patients irradiated using an endorectal balloon (ERB).MethodsWe measured central axis doses with film in a phantom containing an air cavity, and compared measurements with calculations of the AAA and AXB. For clinical study, 10 patients who had undergone whole pelvic radiotherapy (WPRT) followed by prostatic bed-only radiotherapy (PBRT) using VMAT were enrolled. An ERB was used for PBRT but not for WPRT. To compare dosimetric parameters, the cumulative dose-volume histograms, mean, maximum, and minimum doses were measured for the planning target volume. Homogeneity of plans were confirmed using V95%, V107% (VX%, percentage volumes receiving at least X% of prescribed doses) and conformity indices (homogeneity index [HI], conformity index [CI], and conformation number [CN]). We compared volumes of the organ-at-risk receiving 10% to 100% (10-tier at 10% interval) of prescribed doses (V10% – V100%).ResultsIn the phantom study, the AAA showed larger disagreement with the measurements, and overestimated the dose in the air cavity, comparing with the AXB. For WPRT planning, the AAA predicted a lower maximum dose and V107% than the AXB. For PBRT planning, the AAA estimated a higher minimum dose, lower maximum dose, and smaller V107%, and larger V95% than the AXB. Regarding the conformity indices, the AAA was estimated to be more homogenous than the AXB for PBRT planning (HI, 0.088 vs. 0.120, p = 0.005; CI, 1.052 vs. 1.038, p = 0.022; and CN, 0.920 vs. 0.900, p = 0.007) but not for WPRT planning. Among V10% to V100% of the rectum, the PBRT exhibited significant discrepancies in V30%, V40%, V70%, V80%, and V90%; while the WPRT did in V20% and V30%.ConclusionsThe phantom study demonstrated that the AXB calculates more accurately in the air cavity than the AAA. In the clinical setting, the AXB exhibited different dosimetric distributions in the VMAT plans for PBRT containing an ERB. The AXB should be considered for prostate cancer patients irradiated with an ERB for better applying of heterogeneous condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0346-3) contains supplementary material, which is available to authorized users.

Co-occurring gland angularity in localized subgraphs: predicting biochemical recurrence in intermediate-risk prostate cancer patients.

Quantitative histomorphometry (QH) refers to the application of advanced computational image analysis to reproducibly describe disease appearance on digitized histopathology images. QH thus could serve as an important complementary tool for pathologists in interrogating and interpreting cancer morphology and malignancy. In the US, annually, over 60,000 prostate cancer patients undergo radical prostatectomy treatment. Around 10,000 of these men experience biochemical recurrence within 5 years of surgery, a marker for local or distant disease recurrence. The ability to predict the risk of biochemical recurrence soon after surgery could allow for adjuvant therapies to be prescribed as necessary to improve long term treatment outcomes. The underlying hypothesis with our approach, co-occurring gland angularity (CGA), is that in benign or less aggressive prostate cancer, gland orientations within local neighborhoods are similar to each other but are more chaotically arranged in aggressive disease. By modeling the extent of the disorder, we can differentiate surgically removed prostate tissue sections from (a) benign and malignant regions and (b) more and less aggressive prostate cancer. For a cohort of 40 intermediate-risk (mostly Gleason sum 7) surgically cured prostate cancer patients where half suffered biochemical recurrence, the CGA features were able to predict biochemical recurrence with 73% accuracy. Additionally, for 80 regions of interest chosen from the 40 studies, corresponding to both normal and cancerous cases, the CGA features yielded a 99% accuracy. CGAs were shown to be statistically signicantly () better at predicting BCR compared to state-of-the-art QH methods and postoperative prostate cancer nomograms.

Comparative Review of Consensus-Based Clinical Target Volume Definitions For Prostate Radiotherapy

Background: A major obstacle in the delivery of postoperative radiation therapy (RT) for prostate cancer is accurate delineation of the tumor targets and organs at risk. Although postoperative prostate cancer contouring atlases are quite common, there is still no widely accepted contouring guideline. The purpose of this study is to critically review the various postoperative prostate RT treatment planning consensus guidelines or atlases currently available. Methods: A literature search was conducted using various electronic databases with the key terms: prostate, contour, planning tumour volume, clinical target volume, delineation or definition, guidelines or atlas, and radiation oncology. The search was limited to English publications from the years 1985 to 2011. Results: A total of seven publications relating to contouring guidelines for postoperative prostate radiotherapy were identified. There are four distinct consensus guidelines developed by major institutions: Princess Margaret Hospital, the Australian and New Zealand Radiation Oncology Genito-Urinary Group, the European Organization for Research and Treatment of Cancer, and the Radiation Therapy Oncology Group. Conclusions: After reviewing the consensus contouring guidelines for postoperative prostate cancer radiation therapy that were available in the literature, it is clear that there disagreement with regards to what anatomical borders should be used for delineating an appropriate prostate bed CTV. Additional studies comparing the reproducibility of the various guidelines as well as the performance of these guidelines on clinically important outcomes are needed.

PO-0709: Acute toxicity in post-operative prostate cancer: hypofractionation-vmat versus conventional-3DCRT

PO-0709: Acute toxicity in post-operative prostate cancer: hypofractionation-vmat versus conventional-3DCRT

Patient benefit from salvage radiation for prostate cancer.

175 Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Methods: Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Results: Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetectable nadir following RP had 55% 3-year bPFS compared with 79% in those who did achieve an undetectable PSA (p=0.041). Multivariate analysis demonstrated that GS of 8 and pre-RT PSA were significant predictors. A separate analysis was performed on a subgroup of 8 patients with node-positive disease. Five patients failed at a median of 24 months (range 12-64). Of the remaining 3 patients, 2 had been maintained on long-term ADT, and 1 patient was 11 months out from treatment. Conclusions: Patients with node-positive disease are unlikely to achieve long-term biochemical control from SRT due to extra-prostatic disease spread. Although various factors may influence outcome, no other group demonstrated a very low chance of benefit. Patients with rising PSA benefit from early treatment before PSA rises above 1.0 ng/mL. [Table: see text]

The PROCAINA (PROstate CAncer INdication Attitudes) Project (Part I): a survey among Italian radiation oncologists on postoperative radiotherapy in prostate cancer

Radiotherapy (RT) has an established role in the postoperative treatment of prostate cancer patients with extracapsular extension, positive surgical margins or a detectable post-operative prostate-specific antigen (PSA). Despite the large number of patients treated with postoperative RT, some issues about optimal technique, doses, volumes, timing and association with androgen deprivation are still subject of debate. The aim of this survey was to determine the patterns of choice of Italian radiation oncologists in two different clinical cases of postoperative prostate cancer patients. During the 2010 National Congress of the Italian Association of Radiation Oncology (AIRO), four clinical cases were presented to the attending radiation oncologists. Two of them were cases of postoperative prostate cancer, differing in T stage of the primary tumour according to the TNM classification, preoperative staging procedures, preoperative PSA (iPSA), Gleason score of biopsies and definitive pathological specimen after surgery and postoperative PSA. For each clinical case, the radiation oncologists were asked to: (a) give indication to new pre-treatment procedures for staging; b) give indication to postoperative treatment; (c) to define specifically, where indicated, the total dose, type of fractionation, treatment volumes, type of technique, type of image-guided setup control; (d) indicate whether adjuvant hormonal therapy should be prescribed; (e) define criteria that mostly influenced the prescription. A descriptive statistical analysis was then performed. A total of 300 questionnaires were distributed amongst radiation oncologists attending the congress; 128 were completed and considered for this analysis (41%). Some important differences were shown in prescribing and performing postoperative radiotherapy, and some significant differences with international guidelines and data available from the literature were also reviewed and discussed. Despite the results of clinical trials, significant differences still exist among Italian radiation oncologists in deciding postoperative treatment in prostate cancer patients. These patients probably deserve a more uniform approach based on updated, detailed and evidence-based recommendations.

Magnitude and Agreement of Cone Beam Computed Tomography Shifts for Patients With Intact and Postoperative Prostate Cancer

To assess the magnitude and variability of pre-treatment alignment shifts between therapists for prostate cancer patients treated with IGRT/IMRT and positioned using CBCT. Eighteen patients treated for intact (IP, n = 8) and postoperative (PP, n = 10) prostate cancer during 2010 were selected. Patients with prostate markers were excluded. For each patient, daily CBCT images were reviewed and two representative images were selected, one in which the bladder resembled the planning CT (B0) and one in which the bladder was different from the planning CT (B1). Therapists viewed each of the 36 images in scanning acquisition position and aligned the cone beam to the planning CT as if they were preparing to treat the patient. Shifts in the AP, SI and LR dimensions were recorded. One-way ANOVA was used to compare the magnitude of shifts in the SI, AP, and LR directions. Repeated measures ANOVA was used to assess the variability between therapists in positioning the same images. Two way ANOVA was used to compare ranges between IP and PP patients and between B0 and B1. Eight therapists participated in the study (mean years experience with CBCT: 3.6, range: 2-6). Eighteen patients, each with two images, were included for a total of 288 shifts. Average magnitude of shifts was greater in the AP (3.6 mm) and LR (3.4 mm) direction than in the SI direction (1.2 mm, p<0.001). There was no difference between the average magnitudes in the AP vs. LR direction (p = 0.66). There was significant variation among therapists for shifts in the AP direction (p<0.001), but not in the SI (p = 0.29) and LR (p = 0.10) directions. There were no significant differences in the average AP, SI, or LR shifts for IP vs. PP (p = 0.23, 0.58, 0.09) or for B0 vs. B1 (p = 0.50, 0.43,0.56). The mean range to encompass the shifts for all 8 therapists in the AP, SI, and LR directions were 7.7 (min: 3, max: 19), 4.7 (min: 1, max: 11), and 2.7 mm (min: 1, max: 5). The mean range was smaller for the B0 image in the AP (6.7 vs. 8.6 mm, p = 0.09), SI (4.2 vs. 5.1 mm, p = 0.27) and LR (2.3 vs. 3.1 mm, p = 0.04) directions, but this was only statistically significant in the LR direction. The mean range was smaller for IP patients in the AP (7.5 vs. 7.8 mm, p = 0.81), SI (4.5 vs. 4.9 mm, p = 0.63), and LR directions (2.5 vs. 2.9 mm, p = 0.36), but this was not statistically significant. Significant variation exists in the AP direction between different therapists making CBCT shifts of the same images. Greater variation in the AP direction may be due to deformation of the rectal wall by varying amounts of stool or bowel gas, which can create uncertainty in the match. Careful evaluation of bladder filling to resemble sim CT may decrease shifts. Larger PTV margins may be needed to account for variation between therapists when using CBCT for IGRT.

Rectum and Bladder Dose Variations During the Course of Image Guided Radiation Therapy for Postoperative Prostate Cancer

The Value of Dose Constraints in Minimizing Rectal Toxicity in Patients Receiving Radiation Therapy for Prostate Cancer: Threeyear Analysis of Toxicity Outcomes in 2 Prospective Trials of Image Guided Proton Therapy for Earlyand Intermediate-Risk Prostate Cancer N.P. Mendenhall, Z. Li, B.S. Hoppe, R.B. Marcus, W.M. Mendenhall, R.C. Nichols, C.G. Morris, C.R. Williams, J. Costa, and R. Henderson; University of Florida Proton Therapy Institute, Jacksonville, FL, Division of Urology, College of Medicine, University of Florida, Jacksonville, FL

Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794

BackgroundComposite endpoints can be problematic in the presence of competing risks when a treatment does not affect events comprising the endpoint equally. MethodsWe conducted secondary analysis of SWOG 8794 trial of adjuvant radiation therapy (RT) for high-risk post-operative prostate cancer. The primary outcome was metastasis-free survival (MFS), defined as time to first occurrence of metastasis or death from any cause (competing mortality (CM)). We developed separate risk scores for time to metastasis and CM using competing risks regression. We estimated treatment effects using Cox models adjusted for risk scores and identified an enriched subgroup of 75 patients at high risk of metastasis and low risk of CM. ResultsThe mean CM risk score was significantly lower in the RT arm vs. control arm (p=0.001). The effect of RT on MFS (HR 0.70; 95% CI, 0.53–0.92; p=0.010) was attenuated when controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58–1.00; p=0.049), and the effect of RT on overall survival (HR 0.73; 95% CI, 0.55–0.96; p=0.02) was no longer significant when controlling for metastasis and CM risk (HR 0.80; 95% CI, 0.60–1.06; p=0.12). Compared to the whole sample, the enriched subgroup had the same 10-year incidence of MFS (40%; 95% CI, 22–57%), but a higher incidence of metastasis (30% (95% CI, 15–47%) vs. 20% (95% CI, 15–26%)). A randomized trial in the subgroup would have achieved 80% power with 56% less patients (313 vs. 709, respectively). ConclusionStratification on competing event risk may improve the efficiency of clinical trials.

Competing event risk stratification may improve the design and efficiency of clinical trials: Secondary analysis of SWOG 8794.

6121 Background: Efficiency of clinical trials may be improved by stratifying according to competing event risk. We aimed to test whether effect and sample size estimates would be altered when adjusting for competing event risk, using data from the SWOG 8794 trial of adjuvant radiation therapy (RT) for high-risk post-operative prostate cancer. Methods: The primary outcome was metastasis-free survival (MFS), defined as time to first occurrence of metastasis or death from any cause (i.e., competing mortality (CM)). We developed separate risk scores for time to metastasis and CM using backward stepwise competing risks regression. Risk factors for metastasis were PSA, Gleason score, and seminal vesicle invasion, and for CM were age, performance status, and Charlson comorbidity index. Treatment effects were estimated using Cox models adjusted for risk scores. We identified an enriched subgroup of 75 patients at high risk of metastasis and low risk of CM, based on risk score cutoffs. Sample size estimates assumed type I and II error of 0.10 and 0.20, and accrual and follow-up times of 6 and 6 years. Results: The mean CM risk score was significantly lower in the RT vs. control arm (p=0.001). The effect of RT on MFS (HR 0.70; 95% CI, 0.53-0.92; p=0.010) was attenuated when controlling for metastasis and CM risk (HR 0.76; 95% CI, 0.58-1.00; p=0.049). The hazard for CM was reduced by RT (HR 0.82; 95% CI, 0.59-1.14; p=0.24), but this effect was attenuated when controlling for CM risk (HR 0.94; 95% CI, 0.67-1.31; p=0.71). In contrast, there was no difference in the adjusted and unadjusted HRs for metastasis (0.50; 95% CI, 0.31-0.81; p=0.005 and 0.49; 95% CI, 0.30-0.81; p=0.005). Compared to the whole cohort, the enriched subgroup had the same baseline 10-year incidence of MFS (40%; 95% CI 22-57%), but a higher incidence of metastasis (30% (95% CI, 15-47%) vs. 20% (95% CI, 15-26%)). A randomized trial in an enriched population could have achieved 80% power with 44% less patients (313 vs. 709 patients, respectively), due to the differing event composition. Conclusions: Stratification based on competing event risk may improve the design and efficiency of clinical trials. These findings should be externally validated.