Men with locally advanced prostate cancer who undergo radical prostatectomy (RP) often develop recurrence and require postoperative radiotherapy. We aimed to determine the safety of neoadjuvant ...stereotactic body radiotherapy (SBRT) before RP in this population.
A single-institution phase 1 trial (NCT02946008) of men with high-risk or node-positive prostate cancer were enrolled between March and October 2017. The primary endpoint was to determine the maximum tolerated dose of SBRT based on a composite 30-day post-RP toxicity goal of ≤28% of patients experiencing a dose-limiting toxicity (DLT). Secondary outcomes included toxicity, efficacy, and multiple quality of life (QoL) inventories. SBRT (30-35 Gy/5 fractions) was delivered to the prostate and seminal vesicles, and 25 Gy/5 fractions to the pelvic lymph nodes. RP was performed for a median of 6 weeks post-SBRT. Hormone therapy was not allowed.
Median follow-up was 40 months (range, 33-44). Twenty-five percent of the patients (n = 4) experienced a DLT within 30 days post-RP; however, the trial was stopped early (n = 16 of planned 38 patients) owing to the proportion and severity of the late adverse events. Post-RP grade 3 genitourinary and gastrointestinal toxicities occurred in 75% (n = 12) and 25% (n = 4) of patients, respectively. Two patients required cystectomy and urinary diversion ≥2 years post-RP. At 24 months post-RP, 75% (n = 12) of men used ≥1 pad/d and 0% had erections suitable for intercourse. Surgical margins were negative in all patients and 31% (n = 5) had complete or partial (pre-RP) MRI-response to SBRT. Three-year biochemical recurrence and distant metastasis were 45% (95% CI, 5%-68%) and 28% (95% CI, 0%-49%), respectively.
Neoadjuvant SBRT followed by RP resulted in unacceptably high toxicity and severe QoL declines.
An altitude-based background correction strategy was developed for use in the application of pattern recognition methods to the classification of gamma-ray spectra collected during airborne surveys. ...Application of this methodology helped to suppress the background spectral variation that serves to obscure the photopeaks associated with low levels of gamma-ray emission. The correction method was implemented by optimizing a database of background gamma-ray spectra collected at various locations and altitudes. Given this background database, a field-collected spectrum was corrected by performing linear regression onto a background spectrum from the database at a matching altitude. The residuals about the regression fit were then digitally filtered and submitted to nonparametric linear discriminant analysis for the purpose of computing classification models for targeted radioisotopes. The resulting classifiers were applied to predict the presence or absence of specific radioisotope signatures in data acquired during airborne surveys. Employing data provided by the U.S Environmental Protection Agency Airborne Spectral Photometric Environmental Collection Technology (ASPECT) program, classification models were computed to detect the presence of cesium-137 (137Cs) and cobalt-60 (60Co). The optimized classifiers were tested over 12 diverse locations, with nine of these data sets containing the target radioisotopes. Correct classification percentages of 99.4% and 99.8% were obtained for the 137Cs and 60Co classifiers, respectively, on the basis of comparisons to visual inspections of the corresponding spectra.
•Altitude-based background correction for gamma-ray spectra.•Enhances pattern recognition of radioisotopes in airborne surveys.•Automated detection of 137Cs and 60Co.•Methodology tested with aerial surveys of 12 independent field sites.•Ability to detect weak radioisotope signals is improved.
Regional nodal irradiation, including radiation therapy (RT) to the internal mammary node (IMN) region, improves oncologic outcomes in patients with node-positive breast cancer. Concern remains, ...however, given the proximity of the IMNs to the heart and the association between cardiac RT exposure and toxicity. The objective of the study was to evaluate rates of ischemic cardiac events (ICEs) and associated risk with treatment of the IMN region.
The cardiac outcomes of 2126 patients treated with adjuvant breast RT or breast and nodal RT from 1984 to 2007 at a single institution were reviewed. The primary endpoint was an ICE following RT initiation. The association between IMN RT and ICEs was assessed using Cox proportional hazards models. Treatment with both IMN RT and 3-dimensional (3D) conformal radiation therapy (CRT) began in 1997; therefore, subset analyses of patients with only 3D CRT were performed to minimize bias associated with improved treatment technique.
The median follow-up period was 9.3 years. An ICE occurred in 87 patients (4.1%). No increased 10-year rate of ICEs was observed with IMN RT compared with no IMN RT in the total cohort (3.2% 95% confidence interval (CI), 2.4%-4.3% vs 3.4% 95% CI, 1.5%-7.5%; hazard ratio HR, 0.88; P=.73). Similarly, no statistically significant difference was noted in the 3D CRT-planned, left-sided disease subset (5.1% 95% CI, 1.8%-14.1% vs 4.0% 95% CI, 2.0%-8.0%; HR, 1.18, P=.76). On multivariate analysis, adjusting for cardiac risk factor imbalances, no significantly increased hazard was noted with IMN RT (HR, 1.84; P=.28) in the 3D CRT-planned, left-sided disease subset.
No statistically significant association between IMN RT and ICEs was demonstrated in a review of patients treated at a single institution from 1984 to 2007. Given the long natural history and low overall rate of ICEs, continued follow-up of this study, as well as additional studies in the 3D CRT era, is warranted to confirm these results. Minimizing cardiac exposure, when treating a limited IMN field, is critical to limit excess risk of ICEs.
Purpose
The synergy of combining androgen receptor-signaling inhibition (ARSI) to radiotherapy (RT) in prostate cancer has been largely attributed to non-homologous end joining (NHEJ) inhibition. ...However, this mechanism is unlikely to explain recently observed trial results that demonstrated the sequencing of ARSI and RT significantly impacts clinical outcomes, with adjuvant ARSI following RT yielding superior outcomes to neoadjuvant/concurrent therapy. We hypothesized this is driven by differential effects on AR-signaling and alternative DNA repair pathway engagement based on ARSI/RT sequencing.
Methods
We explored the effects of ARSI sequencing with RT (neoadjuvant vs concurrent vs adjuvant) in multiple prostate cancer cell lines using androgen-deprived media and validation with the anti-androgen enzalutamide. The effects of ARSI sequencing were measured with clonogenic assays, AR-target gene transcription and translation quantification, cell cycle analysis, DNA damage and repair assays, and xenograft animal validation studies.
Results
Adjuvant ARSI after RT was significantly more effective at killing colony forming cells and decreasing the transcription and translation of downstream AR-target genes across all prostate cancer models evaluated. These results were reproduced in xenograft studies. The differential effects of ARSI sequencing were not fully explained by NHEJ inhibition alone, but by the additional disruption of homologous recombination specifically with adjuvant sequencing of ARSI.
Conclusion
We demonstrate that altered sequencing of ARSI and RT mediates differential anti-AR-signaling and anti-cancer effects, with the greatest benefit from adjuvant ARSI following RT. These results, combined with our prior clinical findings, support the superiority of an adjuvant-based sequencing approach when using ARSI with RT.
Patients with lymph node positive (pN+) disease found at the time of radical prostatectomy with pelvic lymphadenectomy for clinically localized prostate cancer (CaP) are at high risk of disease ...persistence and progression. Contemporary management trends of pN+ CaP are not well described.
Patients in the Michigan Urologic Surgery Improvement Collaborative (MUSIC) with clinically localized prostate cancer who underwent radical prostatectomy between 2012 and 2023 with cN0/pN+ disease were identified. The primary outcome was to evaluate patient and practice-level factors associated with time to secondary post-RP treatment. Secondary outcomes included practice-level variation in management of pN+ CaP and rates of secondary treatment modality. To assess factors associated with secondary treatment, a Cox proportional hazards model of a 60-day landmark analysis was performed.
We identified 666 patients with pN+ disease. Overall, 66% underwent secondary treatment within 12 months post-RP. About 19% of patients with detectable post-RP PSA did not receive treatment. Of patients receiving secondary treatment after 60-days post-RP, 34% received androgen deprivation therapy (ADT) alone, 27% received radiation (RT) alone, 36% received combination, and 4% received other systemic therapies. In the multivariable model, pathologic grade group (GG)3 (HR 1.5; 95%CI: 1.05-2.14), GG4-5 (HR 1.65; 95%CI: 1.16-2.34), positive margins (HR 1.46; 95%CI: 1.13-1.88), and detectable postoperative PSA ≥0.1 ng/ml (HR 3.46; 95%CI: 2.61-4.59) were significantly associated with secondary post-RP treatment. There was wide variation in adjusted practice-level 12-month secondary treatment utilization (28%-79%).
The majority pN+ patients receive treatment within 12 months post-RP which was associated with high-risk pathological features and post-RP PSA. Variation in management of pN+ disease highlights the uncertainty regarding the optimal management. Understanding which patients will benefit from secondary treatment, and which type, will be critical to minimize variation in care.
Androgen deprivation therapy (ADT) is an integral component in the management of prostate cancer across multiple disease states. Traditionally, luteinizing hormone-releasing hormone (LHRH) agonists ...constituted the backbone of ADT. However, gonadotropin-releasing hormone receptor hormone (GnRH) antagonists also are available, which offer faster testosterone suppression and reduced likelihood of ADT-related adverse effects compared with LHRH agonists, including the potential for fewer ADT-associated major cardiac events. Until recently, all forms of LHRH agonists and GnRH antagonist formulations were of parenteral administration. However, recently relugolix gained Food and Drug Administration approval as the first oral GnRH antagonist. Relugolix achieves faster and more complete testosterone suppression compared with an LHRH agonist. This translates to more rapid prostate-specific antigen response compared with LHRH agonists. After discontinuation of relugolix, testosterone recovers faster than after GnRH agonists or injectable GnRH antagonist therapy. Overall, these factors provide opportunities for more precisely defined ADT duration when combined with radiation therapy. The rapid onset and offset of testosterone suppression with relugolix may require physicians to rethink the mechanism and goals of ADT when prescribing. As an oral formulation, relugolix enables patients to avoid pain and injection site reactions, limit extra office visits for injections, and achieve a shorter duration of experiencing the side effects of castrate testosterone levels. This convenience and tolerability may enhance physicians' willingness to prescribe ADT and patients' feeling of control during their ADT course, but the potential advantages are accompanied by the risks of patients choosing to discontinue therapy to escape side effects of ADT. This article focuses on different aspects of what is known and unknown regarding the optimal use of ADT and radiation therapy, and how relugolix, due to its properties, fit into our current treatment paradigms for localized prostate cancer.
Breast-conserving surgery (BCS) and radiotherapy reduce breast cancer recurrence but can cause functional deficits in breast cancer survivors. A cross-sectional study quantified the long-term ...pathophysiological impact of these treatments on biomechanical measures of shoulder stiffness and ultrasound shear wave elastography measures of the shear elastic modulus of the pectoralis major (PM). Nine node-positive patients treated with radiotherapy to the breast and regional nodes after BCS and axillary lymph node dissection (Group 1) were compared to nine node-negative patients treated with radiotherapy to the breast alone after BCS and sentinel node biopsy (Group 2) and nine healthy age-matched controls. The mean follow-up for Group 1 and Group 2 patients was 988 days and 754 days, respectively. Shoulder stiffness did not differ between the treatment groups and healthy controls (p = 0.23). The PM shear elastic modulus differed between groups (p = 0.002), with Group 1 patients exhibiting a stiffer PM than Group 2 patients (p < 0.001) and healthy controls (p = 0.027). The mean prescribed radiotherapy dose to the PM was significantly correlated with passive shear elastic modulus (p = 0.018). Breast cancer patients undergoing more extensive axillary surgery and nodal radiotherapy did not experience long-term functional deficits to shoulder integrity but did experience long-term mechanical changes of the PM.
Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific ...mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear.
This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression.
Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 95% CI, 0.57-3.75; P = .42) or DM (sHR, 0.72, 95% CI, 0.30-1.71; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 95% CI, 0.48-5.81; P = .42; DM: sHR, 0.56 95% CI, 0.15-2.04; P = .38).
In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.
Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design.
To identify a ...potential ICE for men receiving PORT.
We performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr.
Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination.
OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio HR 2.32, 95% confidence interval CI 1.45–3.71; p<0.001), DM (HR 6.52, 95% CI 4.20–10.1; p<0.001), and CRPC (HR 2.47, 95% CI 1.56–3.92; p<0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data.
While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design.
We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.
We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival.
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