Cell-cycle risk score more accurately determines the risk for metastases and death in prostatectomy patients compared with clinical features alone.

BACKGROUND: Prostate cancer treatment aims to prevent metastases and disease-specific mortality. Pathologic parameters have limited ability to predict these outcomes, but biomarkers can improve risk discrimination. We evaluated the ability of cell-cycle progression and combined cell-cycle risk scores to predict metastases and disease-specific mortality after prostatectomy. METHODS: Eligibility included (1) treatment with radical prostatectomy (1985-1997); (2) cell-cycle progression score; (3) preoperative prostate-specific antigen; (4) no neoadjuvant therapy; and (5) clinical follow-up (N = 360). Cancer of the prostate risk assessment postsurgical score was combined with cell cycle progression into the prespecified combined cell-cycle risk score. Hazard ratios (HRs) are reported per unit score. RESULTS: In total, 11% (41/360) developed metastases and 9% (33/360) experienced disease-specific mortality. Combined cell-cycle risk score predicted metastases and disease-specific mortality post-radical prostatectomy (p < 1 × 10-8 ). Adjusting for cancer of the prostate risk assessment postsurgical score, the combined cell-cycle risk score remained a predictor of metastases (HR = 3.03 [95% confidence interval (CI): 1.49, 6.20]; p = .003] and disease-specific mortality (HR = 3.40 [95% CI: 1.52, 7.59]; p = .004). Of patients with biochemical recurrence, 25% (41/163) developed metastases. Cancer of the prostate risk assessment postsurgical score was predictive of metastases postbiochemical recurrence but was improved by the addition of cell cycle progression (HR = 1.70 [95% CI: 1.14, 2.53]; p = .012). The combined cell-cycle risk was also prognostic of metastases post-biochemical recurrence (HR = 1.56 [95% CI: 1.20, 2.03]; p = .001). CONCLUSION: Combined cell-cycle risk and cell cycle progression scores predict metastases and disease-specific mortality post-radical prostatectomy and should help identify patients at greatest risk of treatment failure who might benefit from earlier intervention.

The effect of radiation therapy on post-prostatectomy urinary function.

AIM: We sought to evaluate the effect of radiation therapy on post-prostatectomy urinary quality of life in prostate cancer patients. BACKGROUND: In some men with non-metastatic prostate cancer, radiation therapy is indicated following prostatectomy. The radiation toxicity and quality of life considerations are unique in the post-prostatectomy setting. MATERIALS AND METHODS: A total of 106 patients receiving post-prostatectomy radiation therapy completed the Expanded Prostate Cancer Index Composite questionnaire before radiation and at 2-year follow-up. The primary outcomes of this study were the urinary domain summary score and subscale scores. Planned analysis was performed based on time interval from prostatectomy to radiation therapy. RESULTS: Among the 106 patients analyzed, the mean urinary domain summary score worsened at 2-year follow-up after radiation therapy, lowering from 77.23-72.51 (p = 0.0085). Similar worsening was observed in the subscales of function (p = 0.003), bother (p = 0.0397), and incontinence (p = 0.0003). Urinary incontinence showed the greatest observable change among subscales. While the summary score worsened (p = 0.0031) among patients receiving radiation therapy more than 1 year after prostatectomy, it did not show statistically significant change in those treated 1 year or less after prostatectomy. CONCLUSION: Our results demonstrate that post-prostatectomy radiation therapy is associated with modest declines in reportable urinary quality of life. Patients receiving radiation therapy more than 1 year after prostatectomy showed greater worsening of urinary quality of life, which indicates that there may be no functional advantage to delaying radiation therapy beyond the initial postoperative period.

Long term clinical toxicity of radiation therapy in prostate cancer patients with Inflammatory Bowel Disease.

AIM: The study's aim was to examine the clinical impact of radiation therapy (RT) on GI toxicity in Inflammatory Bowel Disease (IBD) patients. BACKGROUND: IBD has long been considered a risk factor for increased bowel toxicity from RT; however, minimal evidence exists on patients with prostate cancer (PC) and IBD. MATERIALS AND METHODS: The tumor registry was queried for patients with IBD and PC from the years 1990-2013. A retrospective review was conducted for patients who received RT. Radiation treatment and toxicity data were collected. RESULTS: Average length of follow-up was 12 years (median 9.54, range 0.42-19.9). The majority had well controlled baseline bowel function on medical management. Prior to radiation, 60% of patients (9/15) and 40% (6/15) reported grade 0 (G0) and grade (G1) diarrhea at baseline, respectively. No baseline proctitis existed. Following radiation treatment, 78% (14/18) of patients experienced G0 diarrhea while 22% (4/18) reported G1 diarrhea. No patients suffered from greater than G1 diarrhea. Sixty-six percent (12/18), 17% (3/18) and 17% (3/18) of patients experienced G0, G1, and G2 proctitis, respectively. No patients suffered post-radiation stricture formation, and all patients with G2 proctitis received 3dCRT. CONCLUSIONS: Limited published data is available exploring RT for patients with PC and IBD. This analysis offers valuable insight into appropriate counseling for a rare patient subset. Radiation improved late G1 diarrhea rates. Grade 2 proctitis was only encountered in 3dCRT patients. No post-radiation complications occurred. Our findings suggest that IBD patients experience minimal toxicity in the era of IMRT based RT.

Pathological characteristics of low risk prostate cancer based on totally embedded prostatectomy specimens.

BACKGROUND: Surveillance and focal therapy are increasingly considered for low risk prostate cancer (PC). We describe pathological characteristics of low risk PC at radical prostatectomy in contemporary patients. METHODS: Five-hundred-fifty-two men from 2008 to 2012 with low risk (stage T1c/T2a, PSA ≤ 10 ng/ml, Gleason score ≤6) PC underwent radical prostatectomy. Slides were re-reviewed to grade and stage the tumor, map separate tumor nodules, and calculate their volumes. RESULTS: Ninety-three (16.9%) men had prostatectomy Gleason score 3 + 4 = 7 or higher and were excluded. Five (0.9%) men had no residual carcinoma. Remaining 454 patients composed the study cohort. The median age was 57 years (36-73) and median PSA 4.4 ng/ml (0.4-9.9). Racial distribution was 77.5% Caucasian, 15.5% African American, and 7% other. The median total tumor volume was 0.38 cm(3) (0.003-7.22). Seventy percent of the patients had bilateral tumor and 34% had a tumor nodule >0.5 cm(3) . The index lesion represented 89% (median) of the total tumor volume. Extraprostatic extension and positive margin were present in 5.7% and 9% of cases, respectively. The tumor nodules measuring >0.5 cm(3) were located almost equally between the anterior (53%) and peripheral (47%) gland. The relationship between PSA and total tumor volume was weak (r = 0.13, P = 0.005). The relationship between PSA density and total tumor volume was slightly better (r = 0.26, P < 0.001). CONCLUSIONS: Low risk prostate cancer is generally a low volume disease. Gleason score upgrade is seen in 16.9% of cases at radical prostatectomy. While the index lesion accounts for the bulk of the disease, the cancer is usually multifocal and bilateral. Neither PSA nor PSA density correlates well with the total tumor volume. Prostate size has a significant contribution to PSA level. These factors need to be considered in treatment planning for low risk prostate cancer.

Tolerance of Phellodendron amurense bark extract (Nexrutine®) in patients with human prostate cancer.

Phellodendron amurense bark extract (Nexrutine®) has shown a favorable effect on prostate cancer in vivo and in vitro. We evaluated its tolerance in patients undergoing surgery or radiation for prostate cancer. Patients received Nexrutine® orally (500 mg tid) either 1 to 2 months preoperatively or 1 to 2 months prior to and with radiation therapy. Common Terminology Criteria for Adverse Events were used to measure tolerance. In total, 21 patients (9 surgery and 12 radiation) underwent treatment. During the Nexrutine® alone component, there were two transient grade 3 toxicities (hypokalemia and urinary incontinence). There was no grade 4 toxicity. For the combined Nexrutine® and radiation component, no additional patients suffered a grade 3 toxicity. All the toxicities were transient. By the end of the neoadjuvant treatment, 81% of the patients had a decline in prostate-specific antigen. This is the first report of patients with prostate cancer being treated with P. amurense bark extract, and it was very well tolerated. Toxicities were minimal and self-limited. This compound can be safely used in further evaluation of a treatment effect on cancer.

NTCP Modeling and Dose-Volume Correlations of Significant Hematocrit Drop 3 Months After Prostate Radiation Therapy.

Purpose: Our purpose was to determine and model the dose-response relations of different parts of the pelvis regarding the endpoint of hematocrit level drop after pelvic radiation therapy (RT). Methods and Materials: Two hundred and twenty-one patients treated with RT for prostate adenocarcinoma between 2014 and 2016 were included. All patients had complete blood counts collected at baseline and 3 months post-RT. The net difference of hematocrit level post-RT versus baseline was calculated, and the level of the 15th percentiles defined the thresholds of response in each case. The doses to 8 different pelvic structures were derived and fitted to the hematocrit levels using the relative seriality normal tissue complication probability model and the biologically equivalent uniform dose (D=). Results: Pelvic structures that correlated with significant decreases in hematocrit were the os coxae bilaterally superior to the acetabulum (OCUB), the total os coxae bilaterally, and the bone volume of the whole pelvis. The structure showing the highest correlation was OCUB with a maximum area under the curve (AUC) of 0.74. For V20 Gy < 30% the odds ratio was 9.8 with 95% CI of 2.9 to 32.9. For mean dose (Dmean) to OCUB, an AUC of 0.73 was observed where the dose threshold was 23 Gy and the odds ratio was 2.7 and 95% CI 1.3 to 5.6. The values for the D50, γ, and s parameters of the relative seriality model were 26.9 Gy (25.9-27.9), 1.3 (1.2-2.2), and 0.12 (0.10-0.83), respectively. The AUC of D= was 0.73 and patients with D= to OCUB ≥ 27 Gy had 8.2 times higher rate of significant hematocrit drop versus <27 Gy. Conclusions: These findings confirm the association of radiation-induced damage to pelvic bone marrow with a drop in hematocrit. A threshold of V20 Gy < 30%, Dmean < 23 Gy, or D= < 27 Gy to OCUB may significantly reduce the risk for this endpoint.

Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524-A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation.

BACKGROUND: Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil-based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered. OBJECTIVE: To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study. DESIGN, SETTING, AND PARTICIPANTS: Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival. RESULTS AND LIMITATIONS: Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2. CONCLUSIONS: In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy. PATIENT SUMMARY: Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.

Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI (P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773).

Salvage prostate bed plus elective pelvic node radiation without androgen deprivation therapy.

BACKGROUND AND PURPOSE: In men with biochemical recurrence (BCR) of prostate cancer (PCA) after radical prostatectomy (RP), there is limited data on the effectiveness of adding elective pelvic nodal radiation (EPNI) to salvage prostate bed radiation (PBRT) without androgen deprivation therapy (ADT) to prevent progression. MATERIALS AND METHODS: Retrospective chart review of 326 patients treated for BCR of PCA from a single institution was performed to capture baseline pre-operative PSA, pathologic details, post-operative PSA, treatment details (radiation and ADT), subsequent failure (rising PSA), response to radiation, and subsequent outcomes after radiation. RESULTS: Between 2004 through 2017, 326 patients received PBRT. Majority (n = 253; 78%) did not receive ADT. Majority received EPNI (n = 227; 90%) with salvage PBRT (n = 213; 94%). The median pre-PBRT PSA was 0.50 ng/ml (0.10-75.60 ng/ml). Of the patients that did not receive ADT, 83% (210/253) achieved an undetectable (< 0.2 ng/ml) PSA after salvage PBRT. After a median follow-up of 87 months, 172 (53%) patients were without a rising PSA and 50 (15%) developed metastatic disease. CONCLUSION: Outcomes with salvage PBRT plus EPNI without ADT appear comparable to salvage PBRT plus EPNI plus ADT. These results need confirmation in a randomized setting.

Investigating the dosimetric and tumor control consequences of prostate seed loss and migration.

PURPOSE: Low dose-rate brachytherapy is commonly used to treat prostate cancer. However, once implanted, the seeds are vulnerable to loss and movement. The goal of this work is to investigate the dosimetric and radiobiological effects of the types of seed loss and migration commonly seen in prostate brachytherapy. METHODS: Five patients were used in this study. For each patient three treatment plans were created using Iodine-125, Palladium-103, and Cesium-131 seeds. The three seeds that were closest to the urethra were identified and modeled as the seeds lost through the urethra. The three seeds closest to the exterior of prostatic capsule were identified and modeled as those lost from the prostate periphery. The seed locations and organ contours were exported from Prowess and used by in-house software to perform the dosimetric and radiobiological evaluation. Seed loss was simulated by simultaneously removing 1, 2, or 3 seeds near the urethra 0, 2, or 4 days after the implant or removing seeds near the exterior of the prostate 14, 21, or 28 days after the implant. RESULTS: Loss of one, two or three seeds through the urethra results in a D(90) reduction of 2%, 5%, and 7% loss, respectively. Due to delayed loss of peripheral seeds, the dosimetric effects are less severe than for loss through the urethra. However, while the dose reduction is modest for multiple lost seeds, the reduction in tumor control probability was minimal. CONCLUSIONS: The goal of this work was to investigate the dosimetric and radiobiological effects of the types of seed loss and migration commonly seen in prostate brachytherapy. The results presented show that loss of multiple seeds can cause a substantial reduction of D(90) coverage. However, for the patients in this study the dose reduction was not seen to reduce tumor control probability.

Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study.

BACKGROUND: Optimum management of clinically localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease. To predict disease aggressiveness, clinicians combine clinical variables to create prognostic models, but the models have limited accuracy. We assessed the prognostic value of a predefined cell cycle progression (CCP) score in two cohorts of patients with prostate cancer. METHODS: We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour samples, and created a predefined score and assessed its usefulness in the prediction of disease outcome. The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy, and in a cohort of randomly selected men with clinically localised prostate cancer diagnosed by use of a transurethral resection of the prostate (TURP) in the UK who were managed conservatively. The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy, and time to death from prostate cancer for the TURP cohort. FINDINGS: After prostatectomy, the CCP score was useful for predicting biochemical recurrence in the univariate analysis (hazard ratio for a 1-unit change [doubling] in CCP 1·89; 95% CI 1·54-2·31; p=5·6×10(-9)) and the best multivariate analysis (1·77, 1·40-2·22; p=4·3×10(-6)). In the best predictive model (final multivariate analysis), the CCP score and prostate-specific antigen (PSA) concentration were the most important variables and were more significant than any other clinical variable. In the TURP cohort, the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis (2·92, 2·38-3·57, p=6·1×10(-22)) and the final multivariate analysis (2·57, 1·93-3·43; p=8·2×10(-11)), and was stronger than all other prognostic factors, although PSA concentration also added useful information. Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables. INTERPRETATION: The results of this study provide strong evidence that the CCP score is a robust prognostic marker, which, after additional validation, could have an essential role in determining the appropriate treatment for patients with prostate cancer. FUNDING: Cancer Research UK, Queen Mary University of London, Orchid Appeal, US National Institutes of Health, and Koch Foundation.

Long-Term Effects of Radiation on Lymphocytes and Risk of Opportunistic Infections.

Objectives Lymphocytes are very sensitive to ionizing radiation. The long-term effects and the risk of permanent immune compromise are not well defined in spite of more than a century of therapeutic radiation. The contemporary analysis is made more difficult in that most patients also receive immunosuppressive chemotherapy. Methods Cohort-all patients that underwent a prostate biopsy from 2002 to 2007. Those (n=1118) with at least two blood counts, with one at a minimum of 10 years after biopsy, were included. We identified three groups: those that received no treatment (due to benign biopsy findings or active surveillance), those undergoing prostate cancer surgery, and those undergoing radiation therapy. Blood counts were collected and analyzed for differences with a median follow-up of 178 months. Also evaluated was the risk of opportunistic infections. Results The median granulocyte count gradually increased with time, with no difference between the groups. Overall, the median lymphocyte count decreased from baseline over time (with a slight rise at 20 years). For the no treatment and surgery groups, the lymphocyte counts declined, but due to the initial decline after radiation therapy, that group saw a slow improvement. By 20 years, there was no difference between the groups. Most patients' counts remained in the normal range throughout. The risk of defined opportunistic infections was low (12%) with no difference between the groups. Conclusion Pelvic radiation has minimal lasting effects on lymphocyte and granulocyte counts. In addition, patients receiving radiation do not appear to be significantly immunocompromised.

Reference Results for Blood Parameter Changes and Recovery after Pelvic Radiation without Chemotherapy.

Introduction: There are few reports on the effect of radiation alone on blood cells (without chemotherapy). We sought to develop a single source as a reference. Materials and Methods: For over 300 prostate cancer patients treated with radiation alone, we collected the baseline, end-of-treatment and three-month post-therapy complete blood counts (CBC). Results: The hemoglobin dropped by a mean of 1.00 g/dL (−7.1%), with an RBC count of 0.40 × 1012 (−8.6%) at the end of treatment and remained significantly (but <5%) below baseline at follow-up. Significant declines were seen in the levels of the granulocytes (−12.2%; −0.67 × 109), monocytes (−2.2%; −0.05 × 109) and platelets (−12.7%; −30.31 × 109) at the end of treatment, but all returned to baseline on follow-up. The neutrophils and basophils (the primary components of the granulocytes) suffered a significant decline but returned to baseline by the follow-up. The other granulocyte components, the eosinophils, did not decline significantly. The most dramatic decline was in the levels of lymphocytes −62.5% (−1.29 × 109), which were still significantly below baseline (−38%) after two years. Conclusion: The effect of radiation is mostly transitory, with some persistence in hemoglobin/erythrocyte levels (<5%). Lymphocytes are slower to recover, remaining significantly below baseline after two years. It is noteworthy that of the patients whose lymphocytes were in the normal range at the start of therapy, only 14% were below normal at follow-up. Radiation alone has negligible-to-modest long-term effects on blood counts.

The Effect of High-Dose Radiation Therapy on Healthy Vertebral Bone Density.

Objective Increased rates of insufficiency fractures are reported after radiation therapy without well-defined causality. Here, we conduct a cross-sectional study on the density change of a non-lesioned vertebral bone after irradiation relative to a control bone in patients with spinal metastases. Methods Patients were identified who received radiation therapy for spinal metastases to a region, including an adjacent vertebra without identifiable malignancy on pre-treatment CT. Every patient had an untreated vertebra of a similar type available as a control. A Hounsfield-density calibration curve was used to measure the vertebral body density before and after treatment. Analysis of covariance was used to model vertebral bone density changes with respect to treatment status. Significance was established as p < 0.05. Results We identified 36 patients who fit the study criteria. The irradiated healthy bone received a median dose of 30 Gy. The median biologically effective dose (BED) was 60 Gy (α/ß = 3) and 39 Gy (α/ß = 10). Median follow-up imaging intervals between pre-treatment and follow-up CT scans was 13.4 months. Levene's test was used to confirm the equality of error variance assumption of ANCOVA (p = 0.093). The mean change in the density of the irradiated vertebral bone was -3.59% (95% CI = -8.51% - 1.32%, p = 0.149). Conclusions We found no significant change in vertebral bone density attributable to radiation treatment. Further work is needed to elucidate if increased fracture rates after radiation are due to factors other than bone density.

The cost of elective nodal coverage in prostate cancer: Late quality of life outcomes and dosimetric analysis with 0, 45 or 54 Gy to the pelvis.

Purpose: Elective pelvic lymph node radiotherapy (PLNRT) in prostate cancer is often omitted from definitive (n = 267) and post prostatectomy (n = 160) radiotherapy (RT) due to concerns regarding toxicity and efficacy. Data comparing patient-reported outcome measures (PROMs) with or without PLNRT is limited. Our long-term supposition is that PLNRT, particularly to higher doses afforded by IMRT, will decrease pelvic failure rate in select patients. We aim to establish the impact of two different PLNRT doses on long term quality of life (QOL). Methods and materials: Prostate cancer patients (n = 428) recorded baseline scores using the Expanded Prostate Cancer Index Composite (EPIC), prior to definitive or post-prostatectomy RT. PLNRT, if given, was prescribed to 45 or 54 Gy at 1.8 Gy per fraction. New EPIC scores were recorded 20-36 months after radiotherapy. Absolute change in each domain subscale and summary score was recorded, along with if these changes met minimally important difference (MID) criteria. A separate multivariate analysis (MVA) was performed for each measure. Subsequent dosimetric analysis was performed. Results: Frequency of a MID decline was significantly greater with PLNRT to 54 Gy for urinary function, incontinence, and overall. No urinary decline was correlated with PLNRT to 45 Gy. PLNRT to 54 Gy was significant for decline in urinary function, bother, irritative, incontinence, and overall score in one or both MVA models while 45 Gy was not. Postoperative status was significant for decline in urinary function, incontinence, and overall. Amongst postoperative patients, there was significantly greater decline in urinary function score in the salvage setting. Neither 54 nor 45 Gy significantly affected bowel subscale or overall score decline. Conclusions: Using conventional fractionation, adding PLNRT to 54 Gy, but not 45 Gy, correlates with worse urinary QOL, with postoperative patients experiencing a steeper decline. PLNRT had no significant impact on bowel QOL with either dose.

Ad Astra - telomeres in space!

PURPOSE: My journey to the stars began as I - along with the whole world - stood still and watched Neil Armstrong take those first small steps on the Moon. Fast forward 50 years and NASA astronauts Scott Kelly and Christina Koch each spend nearly a year in space aboard the International Space Station (ISS), a remarkable multinational collaborative project and floating U.S. National Laboratory that has supported continuous human presence in low Earth orbit for the past 20 years. Marking a new era of human space exploration, the first commercial rocket, SpaceX Falcon 9, recently launched NASA astronauts Doug Hurley and Bob Behnken in the Crew Dragon spacecraft Endeavor to the ISS and returned safely to Earth. NASA and its commercial partners are rapidly advancing innovative space technologies, and with the recently announced Artemis team of astronauts, plans to send the first woman and next man back to the moon and establish sustainable exploration by the end of the decade. Humankind will then be poised to take the next giant leap - pioneering human exploration of Mars. CONCLUSIONS: Historically, fewer than 600 individuals have participated in spaceflight, the vast majority of whom have been middle aged males (35-55 years) on short duration missions (less than 20 days). Thus, as the number and diversity of space travelers increase, a better understanding of how long-duration spaceflight affects human health is essential to maintaining individual astronaut performance during, and improving disease and aging trajectories following, future exploration missions. Here, I review findings from our NASA Twins Study and Telomeres investigations, highlighting potential mechanistic roles of chronic space radiation exposure in changes in telomere length and persistent DNA damage responses associated with long-duration spaceflight. Importantly, similar trends were observed in prostate cancer patients undergoing intensity-modulated radiation therapy (IMRT), additional support specifically for the role of radiation exposure. Individual differences in response were also observed in both cohorts, underscoring the importance of developing personalized approaches for evaluating human health effects and long-term outcomes associated with radiation exposures, whether on Earth or living in the extreme environment of space.

Bone Density Changes Following Radiotherapy to Vertebral Metastases.

Introduction Patients have increasing longevity and time for bone healing following radiotherapy (RT) for treatment of bone metastases (BM). Attempts to assess the treatment response of bone metastases have been either limited or heavily subjective. Our goal was to try to quantitate cancer-involved bone changes after RT using changes in bone mineral density (BMD) from computer tomographic (CT) imaging. Methods Retrospectively, 117 spinal metastases were identified that received RT with follow-up CT scans >9 months following CT simulation. Contoured volumes included: the metastasis (gross tumor volume; GTV); the involved vertebra (gross bone volume; GBV); a total lytic volume (Lyt); a dominant lytic volume (Domlyt); a control volume, and the nearest uninvolved, unirradiated vertebra (control bone volume; CBV). The Hounsfield-density calibration curve was used to measure the density of these volumes before and after treatment. Results Whether using raw or control-adjusted changes, the absolute and percent change in density of the GBV, GTV, Lyt, and Domlyt volumes all significantly increased (each p<0.0001). The increase in the density of Domlyt volumes was greater than that of Lyt volumes (p=0.0465), which were greater than GTV (p=0.0065), which were greater than GBV (p<0.0001). On multivariate analysis, only the biologically effective dose (BED) dose significantly correlated with GTV density change (p=0.0175). K means clustering created groups by initial lesion size, GTV, or GBV density. A significant difference in GTV density change was not detected between any groups. Conclusion Increases in BMD are associated with healing regardless of lesion size or initial density. A prospective study to determine whether long-term control is related to early density measurements is needed.

C-Reactive Protein Is a Poor Marker of Baseline Inflammation in Prostate Cancer and Response to Radiotherapy or Androgen Ablation.

Introduction C-reactive protein (CRP) is an acute-phase reactant used as a general marker for inflammation. Isolated levels have been associated with prostate cancer development, prostate-specific antigen (PSA), Gleason score, and treatment response. We seek to establish whether CRP levels reflect inflammation caused by prostate cancer by comparing levels at various points of time before, during, and after therapy. Materials and methods A total of 209 patients had a complete blood count (CBC), PSA, and CRP taken at up to four different time points. Labs were performed up to one week prior to androgen ablation via leuprolide injection (pre-AA), up to one week prior to radiotherapy (RT) (pre-RT), within one week of RT completion (post-RT), and three months following RT completion (FU [follow-up]). Results Significant relationships were found between CRP and WBC pre-AA (p-value=0.0050), pre-RT (p-value=0.0170), and post-RT (p-value=0.0113), but not at FU (p=.096). CRP had no significant relationship with PSA or lymphocytes at any time points. PSA was significantly affected by androgen ablation but lymphocytes, WBCs, and CRP were not. No CRP levels were associated with risk groups or FU-PSA. Lymphatic radiation fields significantly decreased WBCs and lymphocytes but not CRP. PSA, WBC, and lymphocytes all significantly decreased from pre-RT to post-RT, followed by a significant recovery. CRP did not significantly change during any of these periods and was not significantly related to changes in PSA, WBCs, or lymphocytes. Conclusion CRP is not a sensitive marker of the acute inflammatory effects of non-metastatic prostate cancer and treatment response with androgen ablation or radiation therapy.

Gleason Score Evolution and the Effect on Prostate Cancer Outcomes.

OBJECTIVES: We evaluated how the changes in Gleason grading affected the long-term outcomes of a large prostatectomy cohort. METHODS: We obtained long-term follow-up (16.7 years) in 581 patients having undergone radical retropubic prostatectomy between 1985 and 1995. We excluded those with seminal vesicle and/or lymphatic involvement. We regraded the specimens according to contemporary guidelines and compared how this affected outcomes compared with their original (pre-1995) Gleason scoring. In total, 499 patients were evaluable. RESULTS: A Gleason score of 6 or less declined from 73% to 29%, and the number increased from 25% to 63% for a Gleason score of 7 and from 5% to 8% for a Gleason score of 8 to 9. As a result, for a Gleason score less than 7, biochemical failure decreased from 28% to 23%, metastatic disease 5% to 2%, and prostate cancer death from 5% to 3%. The same results were 50% to 37%, 11% to 7%, and 10% to 6% for a Gleason score of 7 and 86% to 71%, 43% to 32%, and 29% to 26% for a Gleason score more than 7, respectively. With the most recent grade grouping, for groups 1 to 5, biochemical failure occurred in 23%, 32%, 45%, 69%, and 78%, respectively. Metastatic disease occurred in 2%, 4%, 12%, 24%, and 56%, respectively. Prostate cancer-related death occurred in 2%, 4%, 9%, 21%, and 44%, respectively. CONCLUSIONS: The revised Gleason scores improved the outcomes in all risk groups. Based on Gleason score, patients with prostate cancer will appear to have better outcomes than they did before 2005, making any comparison tenable. The current grading system shows a consistent increased risk in biochemical failure, metastatic disease, and prostate cancer-related death with each successive grade.

Telomere Length Dynamics and Chromosomal Instability for Predicting Individual Radiosensitivity and Risk via Machine Learning.

The ability to predict a cancer patient's response to radiotherapy and risk of developing adverse late health effects would greatly improve personalized treatment regimens and individual outcomes. Telomeres represent a compelling biomarker of individual radiosensitivity and risk, as exposure can result in dysfunctional telomere pathologies that coincidentally overlap with many radiation-induced late effects, ranging from degenerative conditions like fibrosis and cardiovascular disease to proliferative pathologies like cancer. Here, telomere length was longitudinally assessed in a cohort of fifteen prostate cancer patients undergoing Intensity Modulated Radiation Therapy (IMRT) utilizing Telomere Fluorescence in situ Hybridization (Telo-FISH). To evaluate genome instability and enhance predictions for individual patient risk of secondary malignancy, chromosome aberrations were assessed utilizing directional Genomic Hybridization (dGH) for high-resolution inversion detection. We present the first implementation of individual telomere length data in a machine learning model, XGBoost, trained on pre-radiotherapy (baseline) and in vitro exposed (4 Gy γ-rays) telomere length measurements, to predict post radiotherapy telomeric outcomes, which together with chromosomal instability provide insight into individual radiosensitivity and risk for radiation-induced late effects.