Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

Importance: Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches. Objective: To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis. Design, Setting, and Participants: This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020. Exposures: Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy. Main Outcomes and Measures: MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio. Results: Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44). Conclusions and Relevance: Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

Functional catalytic nanoparticles (nanozymes) for sensing.

Nanoparticles exhibiting diverse shapes, high porosity and chemical stability reveal, upon appropriate chemical engineering, enzyme-like catalytic activities, "nanozymes", providing a plethora of nanomaterials for diverse applications. The present review article addresses the sensing applications of the catalytic functions of nanozymes consisting of metal nanoparticles, metal oxides, metal sulfides and cyanometallate nanoparticles, carbon-based nanomaterials and metal-organic-framework nanoparticles. The nanozymes emulate catalytic functions of oxidases or peroxidases and are employed as amplifying agents for sensing diverse analytes such as glucose, dopamine, NADH, thiols, phosphates and more. Moreover, the immobilization of nanozymes on electrodes provides versatile means to develop electrochemical sensing platforms. Different principles of the electrochemical sensing platforms, synthetic methodologies to deposit nanozymes on electrodes, and methods to establish electrical communication between the bulk conductive support and nanozyme particles are introduced. Electrochemical sensing platforms applying nanozyme-modified electrodes for the detection of analytes such as organophosphates, glucose and more are discussed. In particular, the application of nanozymes as amplifying labels for biosensor devices detecting proteins, DNA and microRNAs are addressed. Finally, the uses of nanozymes as functional constituents to design sense-and-treat systems are discussed. This is exemplified with the assembly of a bioreactor system for the sensing of glucose, the nanozyme-promoted generation of reactive oxygen species as cytotoxic agents towards cancer cells, and the autonomous nanozyme-based glucose-controlled release of insulin from nanocarrier devices. The future challenges in developing nanozyme-based sensors and sense-and-treat systems are presented.

Aptamer-Protein Structures Guide In Silico and Experimental Discovery of Aptamer-Short Peptide Recognition Complexes or Aptamer-Amino Acid Cluster Complexes.

A method to computationally and experimentally identify aptamers against short peptides or amino acid clusters is introduced. The method involves the selection of a well-defined protein aptamer complex and the extraction of the peptide sequence participating in the binding of the protein to the aptamer. The subsequent fragmentation of the peptide sequence into short peptides and the in silico docking-guided identification of affinity complexes between the miniaturized peptides and the antiprotein aptamer, followed by experimental validation of the binding features of the short peptides with the antiprotein aptamers, leads to the identification of new short peptide-aptamer complexes. This is exemplified with the identification of the pentapeptide RYERN as the scaffold that binds thrombin to the DNA thrombin aptamer (DNA TA). In silico docking studies followed by microscale thermophoresis (MST) experiments demonstrate that the miniaturized tripeptides RYE, YER, and ERN reveal selective binding affinities toward the DNA TA. In addition, docking and MST experiments show that the ribonucleotide-translated RNA TA shows related binding affinities of YER to the DNA TA. Most importantly, we demonstrate that the separated amino acids Y/E/R assemble as a three amino acid cluster on the DNA TA and RNA TA aptamers in spatial configurations similar to the tripeptide YER on the respective aptamers. The clustering phenomenon is selective for the YER tripeptide system. The method to identify binding affinities of miniaturized peptides to known antiprotein aptamers and the specific clustering of single amino acids on the aptamers is further demonstrated by in silico and experimental identification of the binding of the tripeptide RET and the selective clustering of the separated amino acids R/E/T onto a derivative of the AS1411 aptamer against the nucleolin receptor protein.

Structure-activity relationship studies on divalent naphthalene diimide G quadruplex ligands with anticancer and antiparasitic activity.

Naphthalene diimide (NDI) is a central scaffold that has been commonly used in the design of G-quadruplex (G4) ligands. Previous work revealed notable anticancer activity of a disubstituted N-methylpiperazine propyl NDI G4 ligand. Here, we explored structure-activity relationship studies around ligand bis-N,N-2,7-(3-(4-methylpiperazin-1-yl)propyl)-1,4,5,8-naphthalenetetracarboxylic diimide, maintaining the central NDI core whilst modifying the spacer and the nature of the cationic groups. We prepared new disubstituted NDI derivatives of the original compound and examined their in vitro antiproliferative and antiparasitic activity. Several N-methylpiperazine propyl NDIs showed sub-micromolar activity against Trypanosoma brucei and Leishmania major parasites with up to 30 fold selectivity versus MRC-5 cells. The best compound was a dimorpholino NDI with an IC50 of 0.17 µM against T.brucei and 40 fold selectivity versus MRC-5 cells. However, no clear correlation between G4 binding of the new NDI derivatives and antiproliferative or antiparasitic activity was observed, indicating that other mechanisms of action may be responsible for the observed biological activity.

Assembly of Dynamic Gated and Cascaded Transient DNAzyme Networks.

The dynamic transient formation and depletion of G-quadruplexes regulate gene replication and transcription. This process was found to be related to various diseases such as cancer and premature aging. We report on the engineering of nucleic acid modules revealing dynamic, transient assembly and disassembly of G-quadruplex structures and G-quadruplex-based DNAzymes, gated transient processes, and cascaded dynamic transient reactions that involve G-quadruplex and DNAzyme structures. The dynamic transient processes are driven by functional DNA reaction modules activated by a fuel strand and guided toward dissipative operation by a nicking enzyme (Nt.BbvCI). The dynamic networks were further characterized by computational simulation of the experiments using kinetic models, allowing us to predict the dynamic performance of the networks under different auxiliary conditions applied to the systems. The systems reported herein could provide functional DNA machineries for the spatiotemporal control of G-quadruplex structures perturbing gene expression and thus provide a therapeutic means for related emergent diseases.

Palliative Radiotherapy Within the Veterans Health Administration: Barriers to Referral and Timeliness of Treatment.

PURPOSE: Most Veterans Health Administration hospitals do not have radiation oncology (RO) departments on-site. The purpose of this study is to determine the impact of on-site RO on referral patterns and timeliness of palliative radiation therapy (PRT). MATERIALS AND METHODS: A survey was sent to medical directors at 149 Veterans Health Administration centers. Questions evaluated frequency of referral for PRT, timeliness of RO consults and treatment, and barriers to referral for PRT. Chi-square analysis was used to evaluate differences between centers that have on-site RO and centers that refer to outside facilities. RESULTS: Of 108 respondents, 33 (31%) have on-site RO. Chi-square analysis revealed that RO consult within 1 week is more likely at centers with on-site RO (68% v 31%; P = .01). Centers with on-site RO more frequently deliver PRT for spinal cord compression within 24 hours (94% v 70%; P = .01). Those without on-site RO were more likely to want increased radiation oncologist involvement (64% v 26%; P < .001). Barriers to referral for PRT included patient ability to travel (81%), patient noncompliance (31%), delays in consult and/or treatment (31%), difficulty contacting a radiation oncologist (14%), and concern regarding excessive number of treatments (13%). Respondents with on-site RO less frequently reported delays in consult and/or treatment (6% v 41%; P < .0001) and difficulty contacting a radiation oncologist (0% v 20%; P = .0056) as barriers. CONCLUSION: Respondents with on-site RO reported improved communication with radiation oncologists and more timely consultation and treatment initiation. Methods to improve timeliness of PRT for veterans at centers without on-site RO should be considered.

Imide Condensation as a Strategy for the Synthesis of Core-Diversified G-Quadruplex Ligands with Anticancer and Antiparasitic Activity*.

A facile imide coupling strategy for the one-step preparation of G-quadruplex ligands with varied core chemistries is described. The G-quadruplex stabilization of a library of nine compounds was examined using FRET melting experiments, and CD, UV-Vis, fluorescence and NMR titrations, identifying several compounds that were capable of stabilizing G-quadruplex DNA with interesting selectivity profiles. The best G4 ligand was identified as compound 3, which was based on a perylene scaffold and exhibited 40-fold selectivity for a telomeric G-quadruplex over duplex DNA. Surprisingly, a tetra-substituted flexible core, compound 11, also exhibited selective stabilization of G4 DNA over duplex DNA. The anticancer and antiparasitic activity of the library was also examined, with the lead compound 3 exhibiting nanomolar inhibition of Trypanosoma brucei with 78-fold selectivity over MRC5 cells. The cellular localization of this compound was also studied via fluorescence microscopy. We found that uptake was time dependant, with localization outside the nucleus and kinetoplast that could be due to strong fluorescence quenching in the presence of small amounts of DNA.

Cytotoxic (cis,cis-1,3,5-triaminocyclohexane)ruthenium(II)-diphosphine complexes; evidence for covalent binding and intercalation with DNA.

We report cytotoxic ruthenium(ii) complexes of the general formula [RuCl(cis-tach)(diphosphine)]+ (cis-tach = cis-cis-1,3,5-triaminocyclohexane) that have been characterised by 1H, 13C and 31P{1H} NMR spectroscopy, mass spectrometry, X-ray crystallography and elemental analysis. The kinetics of aquation and stability of the active species have been studied, showing that the chlorido ligand is substituted by water at 298 K with first order rate constants of 10-2-10-3 s-1, ideal for potential clinical use as anti-tumour agents. Strong interactions with biologically relevant duplex and quadruplex DNA models correlate with the activity observed with A549, A2780 and 293T cell lines, and the degree of activity was found to be sensitive to the chelating diphosphine ligand. A label-free ptychographic cell imaging technique recorded cell death processes over 4 days. The Ru(ii) cis-tach diphosphine complexes exhibit anti-proliferative effects, in some cases outperforming cisplatin and other cytotoxic ruthenium complexes.

An efficient planning technique for low dose whole lung radiation therapy for covid-19 pandemic patients.

This study aimed to establish an efficient planning technique for low dose whole lung treatment that can be implemented rapidly and safely. The treatment technique developed here relied only on chest radiograph and a simple empirical monitor unit calculation formula. The 3D dose calculation in real patient anatomy, including both nonCOVID and COVID-19 patients, which took into account tissue heterogeneity showed that the dose delivered to lungs had reasonable uniformity even with this simple and quick setup.

Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology.

We report the selective targeting of telomeric G4 DNA with a dithienylethene ligand and demonstrate the robust visible-light mediated switching of the G4 ligand binding mode and G-tetrad structure in physiologically-relevant conditions. The toxicity of the ligand to cervical cancer cells is modulated by the photoisomeric state of the ligand, indicating for the first time the potential of G4 to serve as a target for photopharmacological strategies.

Stiff-Stilbene Ligands Target G-Quadruplex DNA and Exhibit Selective Anticancer and Antiparasitic Activity.

G-quadruplex nucleic acid structures have long been studied as anticancer targets whilst their potential in antiparasitic therapy has only recently been recognized and barely explored. Herein, we report the synthesis, biophysical characterization, and in vitro screening of a series of stiff-stilbene G4 binding ligands featuring different electronics, side-chain chemistries, and molecular geometries. The ligands display selectivity for G4 DNA over duplex DNA and exhibit nanomolar toxicity against Trypasanoma brucei and HeLa cancer cells whilst remaining up to two orders of magnitude less toxic to non-tumoral mammalian cell line MRC-5. Our study demonstrates that stiff-stilbenes show exciting potential as the basis of selective anticancer and antiparasitic therapies. To achieve the most efficient G4 recognition the scaffold must possess the optimal electronics, substitution pattern and correct molecular configuration.

Quality Improvements of Veterans Health Administration Radiation Oncology Services Through Partnership for Accreditation With the ACR.

Approximately 20,000 US veterans receive radiation oncology services at a Veterans Healthcare Administration (VHA) medical facility each year. They currently have access to advanced technologies, which include image-guided intensity-modulated radiotherapy, stereotactic radiosurgery, and stereotactic body radiation therapy. Although this provides access to cancer therapies that are modern, safe, and efficient, the technical complexities of these treatments and clinical decision making that goes into the patient selection and prescriptions demand quality assurances at each VHA practice. To meet the challenges of this need, the VHA established a partnership in 2008 with the ACR's Radiation Oncology Practice Accreditation Program (ACR-ROPA). This report summarizes the experience of this ongoing partnership and demonstrates the combined impact of the VHA's mandate for ACR-ROPA accreditation and internal monitoring of all identified corrective actions at each of its radiation oncology practices.

Comparative study of late rectal toxicity in prostate cancer patients treated with low-dose-rate brachytherapy: With or without supplemental external beam radiotherapy.

PURPOSE: Supplemental external beam radiation therapy (sEBRT) is often prescribed in men undergoing low-dose-rate (LDR) brachytherapy. A population of patients was analyzed to assess the effect of sEBRT on late rectal toxicity. It was hypothesized that sEBRT + LDR would be associated with a higher risk of late rectal toxicity. METHODS AND MATERIALS: This retrospective cohort study examined LDR brachytherapy patients, treated with or without sEBRT, with a minimum of 5-year followup. Longitudinal assessments were evaluated using the computerized patient record system. The Kaplan-Meier method was used for analysis. RESULTS: Median followup was 7.5 years for 245 patients from 2004 to 2007. sEBRT was administered to 33.5%. Followup beyond 5 years was available for 89%. Overall rates of Grade ≥2 and ≥3 rectal toxicities were 6.9% and 2.9%, respectively. The risk of Grade ≥2 rectal toxicity was 2.8-fold higher for patients receiving sEBRT (95% confidence interval: 1.1-7.2; p = 0.02). The risk of Grade ≥3 rectal toxicity was 11.9-fold higher for patients who received sEBRT (1.5-97.4, 95% confidence interval; p = 0.003). Six of seven patients with a Grade ≥3 rectal toxicity received sEBRT, including one who required an abdominoperineal resection. Median post-LDR D90, V150, V200, and R100 values were 103.3%, 59.4%, 30.1%, and 0.5 cc. CONCLUSIONS: In a cohort of LDR brachytherapy patients with high rates of followup, sEBRT + LDR was associated with significantly higher risk of Grade ≥2 and ≥3 late rectal toxicity. This analysis supports previous findings and maintains concern about the supplemental use of external beam radiation therapy with LDR brachytherapy while its benefit for tumor control has yet to be prospectively validated.

Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.

PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies. PATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method. RESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively. CONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.

Availability of single-fraction palliative radiotherapy for cancer patients receiving end-of-life care within the Veterans Healthcare Administration.

BACKGROUND: Surveys demonstrate < 20% of radiation oncologists in the United States offer single-fraction palliative radiotherapy (RT) even though it is an acceptable standard of care. A study was conducted to investigate whether this held true for those practicing within the Veterans Healthcare Administration (VHA). METHODS: All radiation oncologists currently practicing at VHA medical centers were surveyed. Comparisons and associations of responses were evaluated by Fisher's exact test. RESULTS: The response rate was 90%. Half were full-time employees of the VHA, and the majority (70%) had thoroughly read guidelines on palliative RT for bone metastases recently published by either the American College of Radiology (ACR, 2009, 2012) or the American Society of Radiation Oncology (ASTRO, 2011). Single-fraction palliative RT for bone metastases had been prescribed by 76% of respondents, and 93% had prescribed a short course of ≤ 6 fractions. Respondents were less likely to have prescribed a single fraction for patients who had survival estimates of either > 6 months or > 12 months (66% versus 37%, p < 0.0001).Those not offering single-fraction palliative RT (24%) were more likely to be > 10 years out of training (37% versus 10%, p = 0.01), and to have worked in a private practice setting at some point in their career (36% versus 12%, p = 0.03). CONCLUSIONS: A majority of radiation oncologists within the VHA offer single-fraction therapy to their patients. These data ensure access to palliative RT is not limited within this health care system by a preference for prolonged treatment courses that may discourage patients and clinicians from seeking this care.

Examining the relationship between pre- and postimplant geometry in prostate low-dose-rate brachytherapy and its correlation with dosimetric quality using the similarity concept.

PURPOSE: This is a retrospective study in which we define multiple metrics for similarity and then inquire on the relationship between similarity and currently used dosimetric quantities describing preimplant and postimplant plans. METHODS AND MATERIALS: We analyzed a unique cohort of 94 consecutively performed prostate seed implant patients, associated with excellent dosimetric and clinical outcomes. For each patient, an ultrasound (US) preimplant and two CT postimplant (Day 0 and Day 30) studies were available. Measures for similarity were created and computed using feature vectors based on two classes of moments: first, invariant to rotation and translation, and the second polar-radius moments invariant to rotation, translation, and scaling. Both similarity measures were calibrated using controlled perturbations (random and systematic) of seed positions and contours in different size implants, thus producing meaningful numerical threshold values used in the clinical analysis. RESULTS: An important finding is that similarity, for both seed distributions and contours, improves significantly when scaling invariance is added to translation and rotation. No correlation between seed and contours similarity was found. In the setting of preplanned prostate seed implants using preloaded needles, based on our data, similarity between preimplant and postimplant plans does not correlate with either minimum dose to 90% of the volume of the prostate or analogous similarity metrics for prostate contours. CONCLUSIONS: We have developed novel tools and metrics, which will allow practitioners to better understand the relationship between preimplant and postimplant plans. Geometrical similarity between a preplan and an actual implant, although useful, does not seem to be necessary to achieve minimum dose to 90% of the volume of the prostate-good dosimetric implants.

Bladder preservation therapy for muscle-invading bladder cancers on Radiation Therapy Oncology Group trials 8802, 8903, 9506, and 9706: vascular endothelial growth factor B overexpression predicts for increased distant metastasis and shorter survival.

BACKGROUND: From 1988 to 1999, the Radiation Therapy Oncology Group (RTOG) conducted four prospective studies (8802, 8903, 9506, 9706) of patients with clinical stage T2-4a muscle-invasive bladder cancer. Treatment was selective bladder preservation using transurethral surgery (TURBT) plus cisplatin-based induction and consolidation chemoradiation regimens, reserving radical cystectomy for invasive tumor recurrence. We investigated vascular endothelial growth factor (VEGF) pathway biomarkers in this unique clinical dataset (median follow-up of 3.1 years). METHODS: A total of 43 patients with tissue available from the entry TURBT were included in this analysis. Expression of VEGF ligands and receptors were quantified and scored by the AQUA platform (HistoRX, now Genoptix, Carlsbad, CA) and analyzed after median split. RESULTS: VEGF expression levels were not associated with increased rates of complete response to induction chemoradiation. Higher levels of cytoplasmic VEGF-B, VEGF-C, and VEGF-R2 were associated with decreased overall survival rates. The 3-year overall survival estimates for high and low expressers were 43.7% and 75% for VEGF-B cytoplasm (p = .01), 40.2% and 86.7% for VEGF-C cytoplasm (p = .01), and 49.7% and 66.7% for VEGF-R2 cytoplasm (p = .02). Higher expression levels of cytoplasm VEGF-B were associated with higher rates of distant failure (p = .01). CONCLUSIONS: Although VEGF ligands and receptors do not appear to be associated with complete response to induction chemoradiation for muscle-invasive bladder cancer, we report significant associations with overall survival and distant failure for certain VEGF family members.

Identifying appropriate patients for early salvage radiotherapy after prostatectomy.

PURPOSE: It remains unclear whether relapsed prostate specific antigen at postprostatectomy salvage radiotherapy impacts outcomes as long it is 1.0 ng/ml or less. MATERIALS AND METHODS: We performed a retrospective cohort study of 197 patients treated with salvage radiotherapy in the setting of detectable relapsed prostate specific antigen 1.0 ng/ml or less. Patients were excluded from analysis if they had lymph node involvement or received androgen deprivation therapy. Freedom from prostate specific antigen progression after salvage radiotherapy was analyzed by a Cox regression model. RESULTS: Median relapsed prostate specific antigen was 0.33 ng/ml (range 0.07 to 1.0). There was 86% freedom from prostate specific antigen progression at a median followup of 52 months. Relapsed prostate specific antigen (HR 1.9, p = 0.004), Gleason score 8-10 (HR 5.2, p <0.001) and negative margin status (HR 2.0, p = 0.02) were independently associated with an increased risk of prostate specific antigen progression after salvage radiotherapy. We identified interaction between relapsed prostate specific antigen and Gleason score (p = 0.04) but not margin status. A significant association was noted between higher relapsed prostate specific antigen and prostate specific antigen progression after salvage radiotherapy in patients with Gleason score 8-10 but not 7 or less. In patients with Gleason score 8-10 the rate of freedom from prostate specific antigen progression at 53 months was 77% vs 26% when salvage radiotherapy was initiated at a relapsed prostate specific antigen of 0.33 or less vs 0.34 to 1.0 ng/ml (log rank p = 0.003). CONCLUSIONS: Different relapsed prostate specific antigen thresholds for unsuccessful salvage radiotherapy may exist based on Gleason score. These data suggest that patients with Gleason score 8-10 should be offered salvage radiotherapy at the earliest detectable relapsed prostate specific antigen, even 0.33 ng/ml or less. Those with Gleason score 7 or less may have the opportunity to be followed with serial prostate specific antigen measurements to improve risk stratification, and delay and/or avoid the potential toxicity of salvage radiotherapy.

Elective irradiation of pelvic lymph nodes during postprostatectomy salvage radiotherapy.

BACKGROUND: Success rates with salvage radiotherapy (SRT) in men who have a postprostatectomy biochemical relapse are suboptimal. One treatment-intensification strategy includes elective irradiation of the pelvic lymph nodes with whole pelvis radiotherapy (WPRT). METHODS: An inter-institutional retrospective cohort study compared outcomes for patients who received SRT at 2 separate academic institutions with disparate treatment paradigms: almost exclusively favoring WPRT (n = 112) versus limiting treatment to the prostate bed (PBRT) (n = 135). Patients were excluded if they had lymph node involvement or if they received androgen-deprivation therapy. The Cox proportional hazards model was used to adjust for potential confounders. RESULTS: In total, 247 patients were analyzed with a median follow-up of 4 years. The pre-SRT prostate-specific antigen (PSA) level (adjusted hazard ratio [HR], 1.58; P < .0001) and a Gleason score of 8 to 10 (adjusted HR, 3.21; P < .0001) were identified as independent predictors of increased risk of biochemical PSA progression after SRT. However, WPRT was not independently associated with biochemical progression-free survival in the multivariate model (adjusted HR, 0.79; P = .20). Neither low-risk patients nor high-risk patients (defined a priori by a preoperative PSA level ≥20 ng/mL, a pathologic Gleason score between 8 and 10, or pathologic T3 tumor classification) benefited from WPRT. Overall survival was similar between treatment groups. When restricting the analysis to patients with pre-SRT PSA levels ≥0.4 ng/mL (n = 139), WPRT was independently associated with a 53% reduction in the risk of biochemical progression (adjusted HR, 0.47; P = .031). CONCLUSIONS: WPRT did not improve outcomes among the entire group but was independently associated with improved biochemical control among patients with pre-SRT PSA levels ≥0.4 ng/mL.

Phase I/II trial of single-fraction high-dose-rate brachytherapy-boosted hypofractionated intensity-modulated radiation therapy for localized adenocarcinoma of the prostate.

PURPOSE: A Phase I/II protocol was conducted to examine the toxicity and efficacy of the combination of intensity-modulated radiation therapy (IMRT) with a single-fraction high-dose-rate (HDR) brachytherapy implant. METHODS AND MATERIALS: From 2001 through 2006, 26 consecutive patients were treated on the trial. The primary objective was to demonstrate a high rate of completion without experiencing a treatment-limiting toxicity. Eligibility was limited to patients with T stage ≤2b, prostate-specific antigen (PSA) ≤20, and Gleason score ≤7. Treatment began with a single HDR fraction of 6Gy to the entire prostate and 9Gy to the peripheral zone, followed by IMRT optimized to deliver in 28 fractions with a normalized total dose of 70Gy. Patients received 50.4Gy to the pelvic lymph node. The prostate dose (IMRT and HDR) resulted in an average biologic equivalent dose >128Gy (α/ß=3). Patients whose pretreatment PSA was ≥10ng/mL, Gleason score 7, or stage ≥T2b received short-term androgen ablation. RESULTS: Median followup was 53 months (9-68 months). There were no biochemical failures by either the American Society of Therapeutic Radiology and Oncology or the Phoenix definitions. The median nadir PSA was 0.32ng/mL. All the 26 patients completed the treatment as prescribed. The rate of Grade 3 late genitourinary toxicity was 3.8% consisting of a urethral stricture. There was no other Grade 3 or 4 genitourinary or gastrointestinal toxicities. CONCLUSIONS: Single-fraction HDR-boosted IMRT is a safe effective method of dose escalation for localized prostate cancer.