Prostate Cancer Radiation Therapy Recommendations in Response to COVID-19

Purpose: During a global pandemic, the benefit of routine visits and treatment of patients with cancer must be weighed against the risks to patients, staff, and society. Prostate cancer is one of the most common cancers radiation oncology departments treat, and efficient resource utilization is essential in the setting of a pandemic. Herein, we aim to establish recommendations and a framework by which to evaluate prostate radiation therapy management decisions. Methods and Materials: Radiation oncologists from the United States and the United Kingdom rapidly conducted a systematic review and agreed upon recommendations to safely manage patients with prostate cancer during the COVID-19 pandemic. A RADS framework was created: remote visits, and avoidance, deferment, and shortening of radiation therapy was applied to determine appropriate approaches. Results: Recommendations were provided by the National Comprehensive Cancer Network risk group regarding clinical node-positive, postprostatectomy, oligometastatic, and low-volume M1 disease. Across all prostate cancer stages, telemedicine consultations and return visits were recommended when resources/staff available. Delays in consultations and return visits of between 1 and 6 months were deemed safe based on stage of disease. Treatment can be avoided or delayed until safe for very low, low, and favorable intermediate-risk disease. Unfavorable intermediate-risk, high-risk, clinical node-positive, recurrence postsurgery, oligometastatic, and low-volume M1 disease can receive neoadjuvant hormone therapy for 4 to 6 months as necessary. Ultrahypofractionation is preferred for localized, oligometastatic, and low-volume M1, and moderate hypofractionation is preferred for postprostatectomy and clinical node positive disease. Salvage is preferred to adjuvant radiation. Conclusions: Resources can be reduced for all identified stages of prostate cancer. The RADS (remote visits, and avoidance, deferment, and shortening of radiation therapy) framework can be applied to other disease sites to help with decision making in a global pandemic

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

PURPOSE: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. MATERIALS AND METHODS: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. RESULTS: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. CONCLUSION: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).

CONTEXT: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear. OBJECTIVE: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT. EVIDENCE ACQUISITION: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states. EVIDENCE SYNTHESIS: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups. CONCLUSIONS: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis. PATIENT SUMMARY: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it

Patterns of olivocochlear axonal branches.

The olivocochlear (OC) pathway is the source of major feedback control of ascending acoustic information. Two main patterns of axonal branching are evident at this and other levels of the auditory pathway: long-distance collaterals and branches involved in feedback-control loops. Only a minority of OC neurons project to both cochlea, consistent with a role for the system in sound localization. OC branches to the ventral cochlear nucleus provide the anatomical substrate for a feedback control loop that could aid in modulating the intensity of acoustic information being conveyed to higher cortical levels while still dampening the overall intensity of signaling from the cochlea itself

A sector-based dosimetric analysis of dose heterogeneity in high-dose-rate prostate brachytherapy

Purpose: High-dose-rate (HDR) prostate brachytherapy delivers a heterogeneous dose distribution throughout the prostate gland. There is however limited information regarding the spatial distribution of this dose heterogeneity. To this end, we analyzed the magnitude and location of intraprostatic dose heterogeneity in HDR prostate brachytherapy. Methods and Materials: Five consecutive prostate cancer patients treated with HDR were analyzed. Based on CT-simulation images, each prostate was divided into three sections (apex, base, and mid-gland). These were further subdivided into eight symmetrical sections to give a total of 24 sections. Dose-volume histograms were analyzed from V100-V200% for these 24 sections comparing the means of individual regions, left vs right, apex vs base vs mid-gland, lateral vs medial, and anterior vs posterior. A separate analysis on dose as a function of individual region volume was also performed. Results: Analyses comparing the 24 regions showed a maximum 62% difference (range, 21.9-83.9%) at V130% and 19.9% (1.9-20.8%) at V200%. Seven regions were significantly decreased and one significantly elevated from V130-V180% when compared with the mean. The means for lateral sections were 1.57-fold higher than medial sections from V110-V200% (. p &lt; 0.0001). The dose at the base was significantly higher than the rest of the gland from V120-V200 (V150, 35.6±16.2% vs 20.9±13.1%, p &lt; 0.0001). Conclusions: There is significant intra-prostatic dose heterogeneity in prostate HDR brachytherapy. This is most notable in the increased dose to base and lateral portions of the gland. Further studies are needed to determine the impact of heterogeneity on clinical outcomes

A sector-based dosimetric analysis of dose heterogeneity in high-dose-rate prostate brachytherapy

Purpose: High-dose-rate (HDR) prostate brachytherapy delivers a heterogeneous dose distribution throughout the prostate gland. There is however limited information regarding the spatial distribution of this dose heterogeneity. To this end, we analyzed the magnitude and location of intraprostatic dose heterogeneity in HDR prostate brachytherapy. Methods and Materials: Five consecutive prostate cancer patients treated with HDR were analyzed. Based on CT-simulation images, each prostate was divided into three sections (apex, base, and mid-gland). These were further subdivided into eight symmetrical sections to give a total of 24 sections. Dose-volume histograms were analyzed from V100-V200% for these 24 sections comparing the means of individual regions, left vs right, apex vs base vs mid-gland, lateral vs medial, and anterior vs posterior. A separate analysis on dose as a function of individual region volume was also performed. Results: Analyses comparing the 24 regions showed a maximum 62% difference (range, 21.9-83.9%) at V130% and 19.9% (1.9-20.8%) at V200%. Seven regions were significantly decreased and one significantly elevated from V130-V180% when compared with the mean. The means for lateral sections were 1.57-fold higher than medial sections from V110-V200% (. p &lt; 0.0001). The dose at the base was significantly higher than the rest of the gland from V120-V200 (V150, 35.6±16.2% vs 20.9±13.1%, p &lt; 0.0001). Conclusions: There is significant intra-prostatic dose heterogeneity in prostate HDR brachytherapy. This is most notable in the increased dose to base and lateral portions of the gland. Further studies are needed to determine the impact of heterogeneity on clinical outcomes

Optimizing the Timing of Salvage Postprostatectomy Radiotherapy and the Use of Concurrent Hormonal Therapy for Prostate Cancer.

Context Currently, salvage radiotherapy (SRT) is the only known curative intervention for men with recurrent disease following prostatectomy. Critical issues in the optimal selection and management of men being considered for SRT include the threshold prostate-specific antigen (PSA) value at which to initiate treatment (ie, pre-SRT PSA) and the role of concurrent hormonal therapy (HT).Objective To review the published evidence pertaining to the optimal timing for SRT and the role of concurrent HT.Evidence acquisition MEDLINE (via PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, and guideline statements from professional organizations were queried from January 1, 2000 through January 10, 2018.Evidence synthesis Thirty-three independent reports, including two randomized trials evaluating HT with SRT, were identified. Retrospective data suggest that SRT initiation at lower pre-SRT PSA levels is associated with better clinical outcomes. Prospective data suggest an overall survival benefit with concurrent HT that manifests during long-term follow-up, with the caveat that hypothesis-generating subgroup analyses suggest that this benefit may be limited to patients with higher pre-SRT PSA levels. Patients with adverse risk factors, such as Gleason grade group 4-5 disease, are likely to benefit the most from earlier SRT initiation and/or the use of HT.Conclusions Given the limitations of the available data, it is imperative that physicians participate in shared decision-making, with the recommendation tailored for each man's desire to maximize oncologic benefit (with a risk of overtreatment) versus potential quality-of-life optimization (with a risk of undertreatment). Within that framework, a significant body of retrospective data supports initiation of SRT at low pre-SRT PSA values, without an arbitrary absolute threshold. Prospective data suggest a benefit of HT, but this benefit may be greatest in patients with a pre-SRT PSA that is higher than the typical level in most patients receiving "early" SRT. Further research is necessary before absolute recommendations can be made.Patient summary Two ways to potentially improve outcomes following salvage radiotherapy for prostate cancer that recurs after prostatectomy are to start treatment at a lower prostate-specific antigen level and to use concurrent hormonal therapy. Our review suggests that the available evidence is imperfect, but highlights that both measures are likely to improve clinical outcomes in general, but perhaps not uniformly and/or consistently for all patients. Physician-patient shared decision-making and further research are critical