Salvage radiotherapy (SRT) is a standard of care for men who recur postprostatectomy, and recent randomized trials have assessed the benefit and toxicity of adding hormone therapy (HT) to SRT with ...differing results.
To perform a systematic review of randomized phase III trials of the use of SRT ± HT and generate a framework for the use of HT with SRT.
Systematic literature searches were conducted on February 15, 2017 in three databases (MEDLINE via PubMed, EMBASE, and ClinicalTrials.gov) for human-only randomized clinical trials from January 30, 1990, through January 30, 2017. Only two randomized trials met all inclusion criteria.
Overall survival benefits from HT were found in one trial, which was limited to when follow-up extended to ≥10 yr, pre-SRT prostate-specific antigen (PSA) ≥0.7 ng/ml, or when higher Gleason grade or positive margins were present. Both trials demonstrated a benefit from HT in men with higher pre-SRT PSAs. Three prognostic factors appeared to discriminate improvements in meaningful clinical endpoints (eg, distant metastasis or survival): pre-SRT PSA, Gleason score, and margin status. Two years of bicalutamide monotherapy resulted in higher rates of gynecomastia with a trend for worse survival when given in favorable risk patients, and 6 mo of luteinizing hormone–releasing hormone agonist therapy resulted in higher rates of hot flashes and long-term hypertension.
Similar to the selective use of HT with radiotherapy in localized prostate cancer, not all patients appear to derive a meaningful benefit from HT with SRT. Patient, tumor, and treatment factors must be considered when recommending the use of HT with SRT. Knowledge gaps exist in the level 1 data regarding the optimal duration and type of HT, as well as the ability to use predictive biomarkers to personalize the use of HT with SRT. Important clinical trials (RADICALS and NRG GU-006) are aimed to answer these questions.
In this report, we performed a systematic review of the literature to determine the benefit and harm of adding hormone therapy to salvage radiotherapy (SRT) for recurrent prostate cancer. We found that the benefit of hormone therapy varied by important prognostic factors, including pre-SRT prostate-specific antigen, Gleason grade, and surgical margin status. Our group then developed a framework on how best to utilize hormone therapy with SRT.
The decision to add hormonal therapy to salvage radiation therapy (SRT) should be individualized. Improvements in distant metastasis or survival are most likely in patients with life expectancy of ≥10 yr with a pre-SRT prostate-specific antigen of ≥0.7, Gleason 8–10, and/or positive margins.
Abstract Background Erectile dysfunction remains the most common side effect from radical treatment of localized prostate cancer. We hypothesized that the use of vessel-sparing radiotherapy, ...analogous to the functional anatomy approach of nerve-sparing radical prostatectomy (RP), would improve erectile function preservation while maintaining tumor control for men with localized prostate cancer. Objective To determine erectile function rates after vessel-sparing radiotherapy. Design, setting, and participants Men with localized prostate cancer were enrolled in a phase 2 single-arm trial (NCT02958787) at a single academic center. Intervention Patients received vessel-sparing radiotherapy utilizing a planning MRI and MRI-angiogram to delineate and avoid the erectile vasculature. Outcome measurements and statistical analysis Both physician- and patient-reported inventories were used to capture erectile function at baseline and at 2 and 5 yr after treatment. Validated model-based comparisons were performed to compare vessel-sparing results to nerve-sparing RP and conventional radiotherapy. Results and limitations From 2001 to 2009, 135 men underwent vessel-sparing radiotherapy. After a planned interim analysis, the trial was stopped after meeting the primary endpoint. The median follow-up was 8.7 yr, with a ≥94% response rate to all inventories at each time point. At 5 yr, 88% of patients were sexually active with or without the use of sexual aids. The 2-yr erectile function rates were significantly improved with vessel-sparing radiotherapy (78%, 95% confidence interval CI 71–85%) compared to modeled rates for convention radiotherapy (42%, 95% CI 38-45%; p < 0.001) or nerve-sparing prostatectomy (24%, 95% CI 22–27%; p < 0.001). At 2 yr after treatment, 87% of baseline-potent men retained erections suitable for intercourse. The 5- and 10-yr rates of biochemical relapse–free survival were 99.3% and 89.9%, and at 5 yr the biochemical failures were limited to the National Comprehensive Cancer Network high-risk group. The single-arm design is a limitation. Conclusions Vessel-sparing radiotherapy appears to more effectively preserve erectile function when compared to historical series and model-predicted outcomes following nerve-sparing RP or conventional radiotherapy, with maintenance of tumor control. This approach warrants independent validation. Patient summary In this interim analysis we looked at using a novel approach to spare critical erectile structures to preserve erectile function after prostate cancer radiotherapy. We found that almost 90% of patients at 5 yr after treatment remained sexually active, significantly higher than previous studies with surgery or radiotherapy.
We provide the strongest evidence to date for the combined benefit of radiotherapy (RT) dose escalation and androgen deprivation therapy (ADT) use/adjuvant ADT prolongation in optimizing biochemical ...control–based outcomes. However, RT dose escalation is unlikely to improve metastasis-free survival, although ADT use and adjuvant ADT prolongation consistently will.
The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown.
To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT.
An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT.
Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence–free survival (BCRFS).
Median follow-up was 8.8 yr (interquartile range 5.7–11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio HR 0.97, 95% confidence interval CI 0.80–1.18) or with STADT (HR 0.99, 95% CI 0.8–1.23) or LTADT (HR 0.94, 95% CI 0.65–1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes.
Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT.
Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.
Metastasis-free survival (MFS), but not event-free survival, is a validated surrogate end point for overall survival (OS) in men treated for localized prostate cancer. It remains unknown if this ...holds true in biochemically recurrent disease after radical prostatectomy. Leveraging NRG/RTOG 9601, we aimed to determine the performance of intermediate clinical end points (ICEs) as surrogate end points for OS in recurrent prostate cancer.
NRG/RTOG 9601 randomly assigned 760 men with recurrence after prostatectomy to salvage radiation therapy with 2 years of placebo versus bicalutamide 150 mg daily. ICEs assessed were biochemical failure (BF) per NRG/RTOG 9601 (prostate-specific antigen nadir + 0.3-0.5 ng/mL or initiation of salvage hormone therapy; BF1) and NRG/RTOG 0534 (prostate-specific antigen nadir+2 ng/mL; BF2), distant metastasis (DM), and MFS (DM or death). Surrogacy was assessed by the Prentice criteria and a two-stage meta-analytic approach (condition one assessed at the patient level with Kendall's τ and condition two assessed by randomly dividing the entire trial cohort into 10 pseudo trial centers and calculating the average
between treatment hazard ratios for ICE and OS).
BF1, BF2, DM, and MFS satisfied the four Prentice criteria. However, with the two-condition meta-analytic approach, there was strong correlation between MFS and OS (τ = 0.86), moderate correlation between DM and OS (τ = 0.66), and weaker correlation between BF1 (τ = 0.25) or BF2 (τ = 0.40) and OS. Similarly, for condition two, the treatment effect of antiandrogen therapy on MFS and OS were correlated (
= 0.67), but this was not true for BF1 (
= 0.09), BF2 (
= 0.12), or DM (
= 0.18) and OS.
MFS is also a strong surrogate for OS in men receiving salvage radiation therapy for recurrence after prostatectomy. Caution should be used when inferring survival benefit from effects on BF in biochemically recurrent prostate cancer. Lack of comorbidity data did not allow us to assess whether BF in men with no/minimal comorbidity could serve as a surrogate for OS.
Clinically node-positive prostate cancer is often found at the time of diagnosis by cross-sectional imaging and remains poorly understood. Advanced imaging modalities such as magnetic resonance ...imaging nanoparticles or positron emission tomography-based molecular imaging stand to rapidly change the field and hopefully will bring better diagnostic clarity. This will allow for prospective clinical trials using radiographic, clinical, or molecular parameters to establish who may benefit from both localized and systemic treatment intensification and who may avoid overtreatment. Recent advances in metastatic hormone-sensitive disease may offer clues, but direct studies for nodal disease patients remain.
In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various ...oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT.
A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve.
Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio HR, 0.71 95% CI, 0.62 to 0.81), whereas the addition of BT did not significantly improve OS (HR, 1.03 95% CI, 0.78 to 1.36). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 95% CI, 0.52 to 0.89). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.
Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.
Cancer treatment delay has been reported to variably impact cancer-specific survival and coronavirus disease 2019 (COVID-19)-specific mortality during the severe acute respiratory syndrome ...coronavirus 2 pandemic. During the pandemic, treatment delay is being recommended in a nonquantitative, nonobjective, and nonpersonalized manner, and this approach may be associated with suboptimal outcomes. Quantitative integration of cancer mortality estimates and data on the consequences of treatment delay is needed to aid treatment decisions and improve patient outcomes.
To obtain quantitative integration of cancer-specific and COVID-19-specific mortality estimates that can be used to make optimal decisions for individual patients and optimize resource allocation.
In this decision analytical model, age-specific and stage-specific estimates of overall survival pre-COVID-19 were adjusted by the probability of COVID-19 (individualized by county, treatment-specific variables, hospital exposure frequency, and COVID-19 infectivity estimates), COVID-19 mortality (individualized by age-specific, comorbidity-specific, and treatment-specific variables), and delay of cancer treatment (impact and duration). These model estimates were integrated into a web application (OncCOVID) to calculate estimates of the cumulative overall survival and restricted mean survival time of patients who received immediate vs delayed cancer treatment. Using currently available information about COVID-19, a susceptible-infected-recovered model that accounted for the increased risk among patients at health care treatment centers was developed. This model integrated the data on cancer mortality and the consequences of treatment delay to aid treatment decisions. Age-specific and cancer stage-specific estimates of overall survival pre-COVID-19 were extracted from the Surveillance, Epidemiology, and End Results database for 691 854 individuals with 25 cancer types who received cancer diagnoses in 2005 to 2006. Data from 5 436 896 individuals in the National Cancer Database were used to estimate the independent impact of treatment delay by cancer type and stage. In addition, data from 275 patients in a nested case-control study were used to estimate the COVID-19 mortality rate by age group and number of comorbidities. Data were analyzed from March 17 to May 21, 2020.
COVID-19 and cancer.
Estimates of restricted mean survival time after the receipt of immediate vs delayed cancer treatment.
At the time of the study, the OncCOVID web application allowed for the selection of up to 47 individualized variables to assess net survival for an individual patient with cancer. Substantial heterogeneity was found regarding the association between delayed cancer treatment and net survival among patients with a given cancer type and stage, and these 2 variables were insufficient to discriminate the net impact of immediate vs delayed treatment. Individualized overall survival estimates were associated with patient age, number of comorbidities, treatment received, and specific local community estimates of COVID-19 risk.
This decision analytical modeling study found that the OncCOVID web-based application can quantitatively aid in the resource allocation of individualized treatment for patients with cancer during the COVID-19 global pandemic.
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