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Optimization of the Radiation Management of High Risk Prostate Cancer
Abstract
Radiation and androgen-deprivation therapy (ADT) are mainstays of treatment for men with high-risk prostate cancer. High-risk disease is heterogeneous and subcategories of “favorable” high risk and very high risk can identify subgroups with particularly good or poor prognosis to help personalize treatment. Overall, randomized trials show that the combination of radiation and ADT improves survival when compared with either by itself. The optimum duration of ADT remains controversial, but for most healthy men with aggressive disease, approximately 2-3 years of ADT is well supported by the literature. The role of prophylactic pelvic nodal irradiation remains controversial, and there is an ongoing trial testing whether it improves overall survival. The use of brachytherapy boost appears to improve recurrence-free survival without yet improving survival, and may come at the cost of slightly higher toxicity. The addition of docetaxel to radiation and ADT may also improve failure-free survival, but a meta-analysis did not find that it improved overall survival. Retrospective data about the relative value of surgery vs radiation for high-risk disease have yielded varied conclusions and are ultimately hampered by the major issue of selection bias in retrospective series.
... Ebbe a "nagyon magas rizikójú" csoportba azon betegek tartoznak, akikben több mint 4 biopsziás mintában a Gleason-score 8-10 közötti, vagy cT3b/T4 stádiumú a daganat. A "nagyon magas rizikójú" tumorok esetében a 10 éves daganatspecifikus mortalitás csaknem a háromszorosa a magas rizikójú esetekhez viszonyítva (6,7). Míg az alacsony rizikójú daganatok esetében elgondolkodtató, hogy a definitív kezelés valóban túlkezelés-e, addig a magas rizikójú tumorok esetében ez nem kérdés, szükséges a definitív kezelés. ...
... Ezek többsége azt igazolta, hogy az irradiáció mellett alkalmazott hosszan tartó hormonkezelés növeli a hatékonyságot (3. táblázat) (7)(8)(9)(10)(11). A radikális prostatectomiát korábban elsősorban azokban az esetekben alkalmazták, amikor a daganat csak a prosztatára lokalizálódott. ...
... First, the role of perisalvage ADT use in this setting was not clear. Previous clinical trials found that concurrent ADT has important radiosensitizing effects in the definitive RT setting [29] . Nearly all studies included in our research reported ADT use before or after salvage therapies. ...
Objective
To conduct a meta-analysis to provide the latest evidence of nonsurgical local salvage options in the first-line radiotherapy failure setting for localized prostate cancer patients.
Background
Recurrence of localized prostate cancer after primary radiotherapy (RT) remains a clinical challenge. There is no consensus on optimal nonsurgical local salvage therapies, which mainly consist of cryotherapy (CRYO), high-intensity focused ultrasound (HIFU), high/low-dose-rate brachytherapy (HDR/LDR), and stereotactic body radiotherapy (SBRT).
Methods
Our study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We systematically searched PubMed, Web of Science, Cochrane Library and ClinicalTrials.gov up to September 2023 to identify potentially relevant studies. The risk of bias was assessed using the European Association of Urology (EAU) items. Biochemical recurrence-free survival (bRFS) and genitourinary/gastrointestinal toxicities were the outcomes of interest. Pooled rates with 95% confidence intervals (CIs) were evaluated.
Results
A total of 99 studies comprising 8440 patients were included. The pooled rate of 1-year biochemical control (BC) was highest for LDR (0.88, 95%CI 0.72-0.95) and lowest for SBRT (0.68, 95%CI 0.49-0.83). The pooled rate of 5-year BC was highest for CRYO (0.52, 95%CI 0.33-0.69) and lowest for HDR (0.23, 95%CI 0.08-0.51). HIFU presented the worst outcome of grade ≥3 genitourinary toxicities (GU3), with a rate of 0.22 (95%CI 0.12-0.3). Conversely, CRYO (0.09, 95%CI 0.04-0.14), HDR (0.05, 95%CI 0.02-0.07), LDR (0.10, 95%CI 0.06-0.14) and SBRT (0.06, 95%CI 0.03-0.09) presented low rates of GU3. All subgroups induced a quite low incidence of grade ≥3 gastrointestinal toxicities (GI3).
Conclusions
Nonsurgical salvage therapies are promising modalities for prostate cancer in the local radiorecurrence setting. Based on the preliminary evidence from this study, CRYO and SBRT might present a relatively steady efficacy of BC with acceptable treatment-related toxicities.
... Radiation therapy (RT) dose-escalation for prostate cancer (PCa) has been shown to improve biochemical control in multiple randomized trials but has not been shown to improve clinical outcomes [1]. Adding or prolonging the use of concomitant androgen deprivation therapy (ADT), however, has been shown to improve clinical outcomes in multiple randomized trials [2]. These two methods of treatment intensification have generally been studied independently. ...
Background
While multiple randomized trials have evaluated the benefit of radiation therapy (RT) dose escalation and the use and prolongation of androgen deprivation therapy (ADT) in the treatment of prostate cancer, few studies have evaluated the relative benefit of either form of treatment intensification with each other. Many trials have included treatment strategies that incorporate either high or low dose RT, or short-term or long-term ADT (STADT or LTADT), in one or more trial arms. We sought to compare different forms of treatment intensification of RT in the context of localized prostate cancer.
Methods
Using preferred reporting items for systemic reviews and meta-analyses (PRISMA) guidelines, we collected over 40 phases III clinical trials comparing different forms of RT for localized prostate cancer. We performed a meta-regression of 40 individual trials with 21,429 total patients to allow a comparison of the rates and cumulative proportions of 5-year overall survival (OS), prostate cancer-specific mortality (PCSM), and distant metastasis (DM) for each treatment arm of every trial.
Results
Dose-escalation either in the absence or presence of STADT failed to significantly improve any 5-year outcome. In contrast, adding LTADT to low dose RT significantly improved 5-year PCSM (Odds ratio [OR] 0.34, 95% confidence interval [CI] 0.22–0.54, p < 0.001) and DM (OR 0.35, 95% CI 0.20–0.63. p < 0.001) over low dose RT alone. Adding STADT also significantly improved 5-year PCSM over low dose RT alone (OR 0.55, 95% CI 0.41–0.75, p < 0.001).
Conclusion
While limited by between-study heterogeneity and a lack of individual patient data, this meta-analysis suggests that adding ADT, versus increasing RT dose alone, offers a more consistent improvement in clinical endpoints.
... Multiple randomized controlled trials have demonstrated improved survival with the addition of long-duration (28-36 mo) androgen deprivation therapy (ADT) when utilizing external beam radiotherapy (EBRT) to treat patients with high-risk prostate cancer (PCa), establishing this as the standard of care [1]. Despite this, a recent population-based analysis found that only 80% of patients with high-risk PCa received concomitant ADT with EBRT in 2012 [2]. ...
Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4–5 (ie, Gleason score 8–10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4–5 PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1–6 mo of ADT, 313 (32.6) received 7–23 mo of ADT, and 126 (13.1%) received ≥24 mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1–6 mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384–0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4–5 PCa receiving <24 mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men.
Patient summary
In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.
... M ultiple randomized clinical trials have demonstrated a survival benefit to combining longduration androgen deprivation therapy (ADT) with radiotherapy (RT) for high-risk prostate cancer (PCa). 1 Androgen deprivation therapy has multiple adverse effects 2 and several trials have investigated shortening ADT duration. Although most trials conflate the outcomes for patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease, GG 5 PCa has been consistently shown to follow a more aggressive natural history, and the effect of ADT duration might differ between the two. ...
Importance:
Androgen deprivation therapy (ADT) improves survival outcomes in patients with high-risk prostate cancer (PCa) treated with radiotherapy (RT). Whether this benefit differs between patients with Gleason grade group (GG) 4 (formerly Gleason score 8) and GG 5 (formerly Gleason score 9-10) disease remains unknown.
Objective:
To determine whether the effectiveness of ADT duration varies between patients with GG 4 vs GG 5 PCa.
Design, setting, and participants:
Traditional and network individual patient data meta-analyses of 992 patients (593 GG 4 and 399 GG 5) who were enrolled in 6 randomized clinical trials were carried out.
Main outcomes and measures:
Multivariable Cox proportional hazard models were used to obtain hazard ratio (HR) estimates of ADT duration effects on overall survival (OS) and distant metastasis-free survival (DMFS). Cause-specific competing risk models were used to estimate HRs for cancer-specific survival (CSS). The interaction of ADT with GS was incorporated into the multivariable models. Traditional and network meta-analysis frameworks were used to compare outcomes of patients treated with RT alone, short-term ADT (STADT), long-term ADT (LTADT), and lifelong ADT.
Results:
Five hundred ninety-three male patients (mean age, 70 years; range, 43-88 years) with GG 4 and 399 with GG 5 were identified. Median follow-up was 6.4 years. Among GG 4 patients, LTADT and STADT improved OS over RT alone (HR, 0.43; 95% CI, 0.26-0.70 and HR, 0.59; 95% CI, 0.38-0.93, respectively; P = .03 for both), whereas lifelong ADT did not (HR, 0.84; 95% CI, 0.54-1.30; P = .44). Among GG 5 patients, lifelong ADT improved OS (HR, 0.48; 95% CI, 0.31-0.76; P = .04), whereas neither LTADT nor STADT did (HR, 0.80; 95% CI, 0.45-1.44 and HR, 1.13; 95% CI, 0.69-1.87; P = .45 and P = .64, respectively). Among all patients, and among those receiving STADT, GG 5 patients had inferior OS compared with GG 4 patients (HR, 1.25; 95% CI, 1.07-1.47 and HR, 1.40; 95% CI, 1.05-1.88, respectively; P = .02). There was no significant OS difference between GG 5 and GG 4 patients receiving LTADT or lifelong ADT (HR, 1.21; 95% CI, 0.89-1.65 and HR, 0.85; 95% CI, 0.53-1.37; P = .23 and P = .52, respectively).
Conclusions and relevance:
These data suggest that prolonged durations of ADT improve survival outcomes in both GG 4 disease and GG 5 disease, albeit with different optimal durations. Strategies to maintain the efficacy of ADT while minimizing its duration (potentially with enhanced potency agents) should be investigated.
... Prospective studies have shown that ADT improves local control and OS when combined with primary RT in the treatment of intermediate-and high-risk CaPs (26,27). However, the use of ADT combined with postoperative radiation remains less clear. ...
While radical prostatectomy (RP) has provided long-term disease control for the majority of patients with localized prostate cancer (CaP), nearly 30% of all surgical patients have disease progression. For high-risk patients, more than half of men experience disease recurrence within 10 years. Postoperative radiotherapy is the only known potentially curative treatment for a large number of patients following prostatectomy. Lately, there have been several advances with the potential to improve outcomes for patients undergoing postoperative radiotherapy. This article will give an overview of the existing literature and current controversies on: (I) timing of postoperative radiation; (II) use of concomitant androgen deprivation therapy; (III) optimal dose to the prostate bed; (IV) use of hypofractionation; (V) elective treatment of the pelvic lymph nodes; (VI) novel imaging modalities, and (VII) genomic biomarkers.
Context
Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity associated with any local salvage modality.
Objective
To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low–dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.
Evidence acquisition
We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.
Evidence synthesis
A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified.
Conclusions
Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted.
Patient summary
In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.
Background:
The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown.
Objective:
To evaluate the clinical implications of LF after definitive RT.
Design, setting, and participants:
Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials.
Outcome measurements and statistical analysis:
Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints.
Results and limitations:
Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37-2.10]), PCSS (3.10 [95% CI 2.33-4.12]), and DMFS (HR 1.92 [95% CI 1.54-2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04-0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22-4.93], p = 0.01) than those who did not.
Conclusions:
LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined.
Patient summary:
Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.
Objectives
To identify predictive factors of biochemical recurrence for patients undergoing high‐intensity focused ultrasound treatment for localized prostate cancer.
Methods
We retrospectively identified patients receiving whole‐gland prostate ablation with high‐intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre‐high‐intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate‐specific antigen, T stage, postoperative prostate‐specific antigen nadir, Gleason score, time to prostate‐specific antigen nadir and the presence of prostate‐specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan–Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut‐off values of prostate‐specific antigen nadir.
Results
Among 182 patients, 26.9% had prostate‐specific antigen biochemical recurrence after high‐intensity focused ultrasound during the median follow‐up period of 32.21 months. Gleason score ≥7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage ≥T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate‐specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate‐specific antigen. We posit that a cut‐off level of prostate‐specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate‐specific antigen biochemical recurrence in high‐intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56–15.37), and created a new nadir‐related prediction model for biochemical recurrence prediction.
Conclusions
Postoperative prostate‐specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole‐prostate gland high‐intensity focused ultrasound treatment, and the nadir‐related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score ≥7, stage ≥T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate‐specific antigen appear not to be associated with biochemical recurrence for the high‐intensity focused ultrasound treatment.
Purpose:
Androgen deprivation therapy (ADT) may contribute to depression, yet several studies have not demonstrated a link. We aimed to determine whether receipt of any ADT or longer duration of ADT for prostate cancer (PCa) is associated with an increased risk of depression.
Methods:
We identified 78,552 men older than age 65 years with stage I to III PCa using the SEER-Medicare-linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the prior year. Our primary analysis was the association between pharmacologic ADT and the diagnosis of depression or receipt of inpatient or outpatient psychiatric treatment using Cox proportional hazards regression. Drug data for treatment of depression were not available. Our secondary analysis investigated the association between duration of ADT and each end point.
Results:
Overall, 43% of patients (n = 33,882) who received ADT, compared with patients who did not receive ADT, had higher 3-year cumulative incidences of depression (7.1% v 5.2%, respectively), inpatient psychiatric treatment (2.8% v 1.9%, respectively), and outpatient psychiatric treatment (3.4% v 2.5%, respectively; all P < .001). Adjusted Cox analyses demonstrated that patients with ADT had a 23% increased risk of depression (adjusted hazard ratio [AHR], 1.23; 95% CI, 1.15 to 1.31), 29% increased risk of inpatient psychiatric treatment (AHR, 1.29; 95% CI, 1.17 to 1.41), and a nonsignificant 7% increased risk of outpatient psychiatric treatment (AHR, 1.07; 95% CI, 0.97 to 1.17) compared with patients without ADT. The risk of depression increased with duration of ADT, from 12% with ≤ 6 months of treatment, 26% with 7 to 11 months of treatment, to 37% with ≥ 12 months of treatment (P trend < .001). A similar duration effect was seen for inpatient (P trend < .001) and outpatient psychiatric treatment (P trend < .001).
Conclusion:
Pharmacologic ADT increased the risk of depression and inpatient psychiatric treatment in this large study of elderly men with localized PCa. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients before initiating treatment.
Background:
Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.
Methods:
For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).
Findings:
We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials.
Interpretation:
The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small.
Funding:
Medical Research Council UK.
Purpose:
The optimal treatment of clinically localized prostate cancer is controversial. Most studies focus on biochemical (PSA) failure when comparing radical prostatectomy (RP) with radiation therapy (RT), but this endpoint has not been validated as predictive of overall survival (OS) or cause-specific survival (CSS). We analyzed the available literature to determine whether reliable conclusions could be made concerning the effectiveness of RP compared with RT with or without androgen deprivation therapy (ADT), assuming current treatment standards.
Methods:
Articles published between February 29, 2004, and March 1, 2015, that compared OS and CSS after RP or RT with or without ADT were included. Because the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system emphasis is on randomized controlled clinical trials, a reliability score (RS) was explored to further understand the issues associated with the study quality of observational studies, including appropriateness of treatment, source of data, clinical characteristics, and comorbidity. Lower RS values indicated lower reliability.
Results:
Fourteen studies were identified, and 13 were completely evaluable. Thirteen of the 14 studies (93%) were observational studies with low-quality evidence. The median RS was 12 (range, 5-18); the median difference in 10-year OS and CSS favored RP over RT: 10% and 4%, respectively. In studies with a RS ≤12 (average RS 9) the 10-year OS and CSS median differences were 17% and 6%, respectively. For studies with a RS >12 (average RS 15.5), the 10-year OS and CSS median differences were 5.5% and 1%, respectively. Thus, we observed an association between low RS and a higher percentage difference in OS and CSS.
Conclusions:
Reliable evidence that RP provides a superior CSS to RT with ADT is lacking. The most reliable studies suggest that the differences in 10-year CSS between RP and RT are small, possibly <1%.
Purpose
To define and validate a classification of favorable high-risk prostate cancer that could be used to personalize therapy, given that consensus guidelines recommend similar treatments for all radiation-managed patients with high-risk disease.
Methods and Materials
We studied 3618 patients with cT1-T3aN0M0 high-risk or unfavorable intermediate-risk prostate adenocarcinoma treated with radiation at a single institution between 1997 and 2013. Favorable high-risk was defined as T1c disease with either Gleason 4 + 4 = 8 and prostate-specific antigen <10 ng/mL or Gleason 6 and prostate-specific antigen >20 ng/mL. Competing risks regression was used to determine differences in the risk of prostate cancer–specific mortality (PCSM) after controlling for baseline factors and treatment. Our results were validated in a cohort of 13,275 patients using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.
Results
Patients with favorable high-risk disease had significantly better PCSM than other men with high-risk disease (adjusted hazard ratio [AHR] 0.42, 95% confidence interval [CI] 0.18-0.996, P=.049) and similar PCSM as men with unfavorable intermediate-risk disease (AHR 1.17, 95% CI 0.50-2.75, P=.710). We observed very similar results within the SEER-Medicare cohort (favorable high-risk vs other high-risk: AHR 0.21, 95% CI 0.11-0.41, P<.001; favorable high-risk vs unfavorable intermediate-risk: AHR 0.67, 95% CI 0.33-1.36, P=.268).
Conclusions
Patients with favorable high-risk prostate cancer have significantly better PCSM than other patients with high-risk disease and similar PCSM as those with unfavorable intermediate-risk disease, who are typically treated with shorter-course androgen deprivation therapy. This new classification system may allow for personalization of treatment within high-risk disease, such as consideration of shorter-course androgen deprivation therapy for favorable high-risk disease.
Whether androgen deprivation therapy (ADT) for men with prostate cancer (PCa) increases the risk of cardiovascular disease (CVD) remains controversial. Pooled analyses using data from randomised controlled trials suggest no increased risk of fatal CVD following ADT, but no pooled analyses exist for observational studies.
To perform a meta-analysis using observational data on ADT and risk of CVD events in men with PCa.
PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on associations between types of ADT and nonfatal and fatal CVD outcomes using information from observational studies. Random effects meta-analyses were conducted to estimate relative risks (RRs) and 95% confidence intervals (CIs).
A total of eight observational studies were identified studying at least one type of ADT and a nonfatal or fatal CVD outcome. The RR for risk of any type of nonfatal CVD was 1.38 (95% CI, 1.29-1.48) for men with PCa on gonadotropin-releasing hormone (GnRH) agonists, compared with men not treated with ADT. When analysing nonfatal ischemic heart disease only, the RR was 1.39 (95% CI, 1.26-1.54). The associations between GnRH agonists and nonfatal or fatal myocardial infarction or stroke were even stronger: RR: 1.57 (95% CI, 1.26-1.94) and RR: 1.51 (95% CI, 1.24-1.84), respectively. The results for other types of ADT in relation to the risk of any nonfatal CVD were RR: 1.44 (95% CI, 1.28-1.62) for orchiectomy and RR: 1.21 (95% CI, 1.07-1.367) for antiandrogens.
Observational data show a consistent positive association between ADT and the risk of CVD. This finding supports the need for future randomised trials of PCa patients that include older patients and men with multiple comorbidities to better reflect the general population.
We investigated all the available data from observational studies on hormonal treatment for prostate cancer and its possible cardiovascular adverse effects. We found consistent evidence that this treatment may increase the risk of cardiovascular disease.
Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial.
We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals.
Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24).
Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).
A randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma.
From December 1997 to August 2005, 218 patients were assigned to EBRT alone (n=108) or EBRT followed by a temporary high-dose-rate implant (n=110). Patients were stratified according to tumour stage, PSA, Gleason score and androgen deprivation therapy (ADT). Biochemical/clinical relapse-free survival (RFS) was the primary endpoint. Secondary endpoints were overall survival (OS), urinary and bowel toxicity.
RFS was significantly higher in patients treated with EBRT+HDR-BTb (log rank p=0.04). In multivariate analysis treatment arm, risk category and ADT were significant covariates for risk of relapse. Differences in OS were not significant. Incidence of severe late urinary and bowel morbidity was similar.
EBRT+HDR-BTb resulted in a significant improvement in RFS compared to EBRT alone with a 31% reduction in the risk of recurrence (p=0.01) and similar incidence of severe late urinary and rectal morbidity.
Whether androgen deprivation therapy (ADT) causes excess cardiovascular deaths in men with prostate cancer is highly controversial and was the subject of a joint statement by multiple medical societies and a US Food and Drug Administration safety warning.
To perform a systematic review and meta-analysis of randomized trials to determine whether ADT is associated with cardiovascular mortality, prostate cancer-specific mortality (PCSM), and all-cause mortality in men with unfavorable-risk, nonmetastatic prostate cancer.
A search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases for relevant randomized controlled trials in English between January 1, 1966, and April 11, 2011.
Inclusion required nonmetastatic disease, intervention group with gonadotropin-releasing hormone agonist-based ADT, control group with no immediate ADT, complete information on cardiovascular deaths, and median follow-up of more than 1 year.
Extraction was by 2 independent reviewers. Summary incidence, relative risk (RR), and CIs were calculated using random-effects or fixed-effects models.
Among 4141 patients from 8 randomized trials, cardiovascular death in patients receiving ADT vs control was not significantly different (255/2200 vs 252/1941 events; incidence, 11.0%; 95% CI, 8.3%-14.5%; vs 11.2%; 95% CI, 8.3%-15.0%; RR, 0.93; 95% CI, 0.79-1.10; P = .41). ADT was not associated with excess cardiovascular death in trials of at least 3 years (long duration) of ADT (11.5%; 95% CI, 8.1%-16.0%; vs 11.5%; 95% CI, 7.5%-17.3%; RR, 0.91; 95% CI, 0.75-1.10; P = .34) or in trials of 6 months or less (short duration) of ADT (10.5%; 95% CI, 6.3%-17.0%; vs 10.3%; 95% CI, 8.2%-13.0%; RR, 1.00; 95% CI, 0.73-1.37; P = .99). Among 4805 patients from 11 trials with overall death data, ADT was associated with lower PCSM (443/2527 vs 552/2278 events; 13.5%; 95% CI, 8.8%-20.3%; vs 22.1%; 95% CI, 15.1%-31.1%; RR, 0.69; 95% CI, 0.56-0.84; P < .001) and lower all-cause mortality (1140/2527 vs 1213/2278 events; 37.7%; 95% CI, 27.3%-49.4%; vs 44.4%; 95% CI, 32.5%-57.0%; RR, 0.86; 95% CI, 0.80-0.93; P < .001).
In a pooled analysis of randomized trials in unfavorable-risk prostate cancer, ADT use was not associated with an increased risk of cardiovascular death but was associated with a lower risk of PCSM and all-cause mortality.
It is not known whether short-term androgen-deprivation therapy (ADT) before and during radiotherapy improves cancer control and overall survival among patients with early, localized prostate adenocarcinoma.
From 1994 through 2001, we randomly assigned 1979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng per milliliter or less to radiotherapy alone (992 patients) or radiotherapy with 4 months of total androgen suppression starting 2 months before radiotherapy (radiotherapy plus short-term ADT, 987 patients). The primary end point was overall survival. Secondary end points included disease-specific mortality, distant metastases, biochemical failure (an increasing level of PSA), and the rate of positive findings on repeat prostate biopsy at 2 years.
The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P=0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P=0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.
Among patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a PSA level of 20 ng per milliliter or less, the use of short-term ADT for 4 months before and during radiotherapy was associated with significantly decreased disease-specific mortality and increased overall survival. According to post hoc risk analysis, the benefit was mainly seen in intermediate-risk, but not low-risk, men. (Funded by the National Cancer Institute; RTOG 94-08 ClinicalTrials.gov number, NCT00002597.).
The combination of radiotherapy plus long-term medical suppression of androgens (> or = 2 years) improves overall survival in patients with locally advanced prostate cancer. We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer.
We randomly assigned patients with locally advanced prostate cancer who had received external-beam radiotherapy plus 6 months of androgen suppression to two groups, one to receive no further treatment (short-term suppression) and the other to receive 2.5 years of further treatment with a luteinizing hormone-releasing hormone agonist (long-term suppression). An outcome of noninferiority of short-term androgen suppression as compared with long-term suppression required a hazard ratio of more than 1.35 for overall survival, with a one-sided alpha level of 0.05. An interim analysis showed futility, and the results are presented with an adjusted one-sided alpha level of 0.0429.
A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short-term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes.
The combination of radiotherapy plus 6 months of androgen suppression provides inferior survival as compared with radiotherapy plus 3 years of androgen suppression in the treatment of locally advanced prostate cancer. (ClinicalTrials.gov number, NCT00003026.)
In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.
From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.
During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).
Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.
To assess the benefit and toxicity and quality-of-life (QOL) outcomes of pelvic nodes irradiation in nonmetastatic prostate carcinoma patients.
Between December 1998 and June 2004, 444 patients with T1b-T3, N0 pNx, M0 prostate carcinoma were randomly assigned to either pelvic and prostate radiotherapy or prostate radiotherapy only. Patients were stratified according to the prognostic factor of lymph node involvement (LNI). Short-term 6-month neoadjuvant and concomitant hormonal therapy was allowed only for patients in the high-risk group. The pelvic dose was 46 Gy. The total dose recommended to the prostate was changed during the course of the study from 66 Gy to 70 Gy. Criteria for progression-free survival (PFS) included biologic prostate-specific antigen recurrences or a local or metastatic evolution. Acute and late toxicities were recorded according to the Radiation Therapy Oncology Group and Late Effects in Normal Tissues Subjective, Objective, Management, and Analytic scales, respectively. The QOL outcome was recorded with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30, the International Prostatic Symptom Score, and the Sexual Function Index scales.
With a 42.1-month median follow-up time, the 5-year PFS and overall survival were similar in the two treatment arms for the whole series and for each stratified group. On multivariate analysis, low LNI risk and hormonal therapy were statistically associated with increased PFS. However, subgroup analyses based on these factors did not show any benefit for pelvic irradiation. There were no significant differences in acute and late digestive toxicities and in QOL outcomes.
Pelvic node irradiation was well tolerated but did not improve PFS.
In Reply We agree with Dr Voog and colleagues that combining external beam RT with ADT remains the standard of care for men with intermediate or high-risk1 prostate cancer. We also wish to highlight that across our entire study cohort there was no increase in the risk of cardiac death in men randomized to receive RT compared with RT and ADT (hazard ratio, 0.74 [95% CI, 0.40-1.39]; P = .36). This result is consistent with the study of more than 1900 men2 mentioned by Voog and colleagues and the meta-analysis3 evaluating this association.
Purpose:
To test the association of androgen deprivation therapy (ADT) in the treatment of prostate cancer with subsequent Alzheimer's disease risk.
Methods:
We used a previously validated and implemented text-processing pipeline to analyze electronic medical record data in a retrospective cohort of patients at Stanford University and Mt. Sinai hospitals. Specifically, we extracted International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, medication lists, and positive-present mentions of drug and disease concepts from all clinical notes. We then tested the effect of ADT on risk of Alzheimer's disease using 1:5 propensity score-matched and traditional multivariable-adjusted Cox proportional hazards models. The duration of ADT use was also tested for association with Alzheimer's disease risk.
Results:
There were 16,888 individuals with prostate cancer meeting all inclusion and exclusion criteria, with 2,397 (14.2%) receiving ADT during a median follow-up period of 2.7 years (interquartile range, 1.0-5.4 years). Propensity score-matched analysis (hazard ratio, 1.88; 95% CI, 1.10 to 3.20; P = .021) and traditional multivariable-adjusted Cox regression analysis (hazard ratio, 1.66; 95% CI, 1.05 to 2.64; P = .031) both supported a statistically significant association between ADT use and Alzheimer's disease risk. We also observed a statistically significant increased risk of Alzheimer's disease with increasing duration of ADT (P = .016).
Conclusion:
Our results support an association between the use of ADT in the treatment of prostate cancer and an increased risk of Alzheimer's disease in a general population cohort. This study demonstrates the utility of novel methods to analyze electronic medical record data to generate practice-based evidence.
Purpose:
A randomized trial recently found that adding brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical recurrence-free survival but not prostate cancer-specific mortality (PCSM). We investigated the relationship between BT boost and PCSM in a modern cohort from a large population-based database.
Methods and materials:
We conducted an analysis of patients in Surveillance, Epidemiology, and End Results diagnosed with intermediate- or high-risk prostate cancer in 2004-2011, treated with EBRT only or EBRT + BT. The cumulative incidence of PCSM was evaluated in the presence of other-cause mortality as a competing risk. Propensity score matching and multivariable Fine and Gray proportional hazard models were used to evaluate the association of combined modality RT on PCSM.
Results:
A total of 52,535 patients were identified, of which 19.6% were treated with EBRT + BT. One-third of cases were high-risk. On multivariable analysis, the adjusted hazard ratio (AHR) of PCSM for EBRT + BT vs. EBRT alone was 0.69 (95% confidence interval [CI], 0.55-0.87, p = 0.002), and the adjusted incidence of PCSM was 1.8% vs. 2.7% at 8 years, respectively. In subgroup analyses, the AHR for PCSM was also significantly reduced with EBRT + BT for high-risk disease (AHR 0.70; 95% CI, 0.52-0.94, p = 0.02; adjusted incidence of PCSM at 8 years, 5.4% vs. 7.6%), but not for intermediate-risk disease.
Conclusions:
BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease.
Purpose Men receiving androgen-deprivation therapy (ADT) for prostate cancer may be at risk for cognitive impairment; however, evidence is mixed in the existing literature. Our study examined the impact of ADT on impaired cognitive performance and explored potential demographic and genetic predictors of impaired performance.
Patients and Methods Patients with prostate cancer were assessed before or within 21 days of starting ADT (n = 58) and 6 and 12 months later. Age- and education-matched patients with prostate cancer treated with prostatectomy only (n = 84) and men without prostate cancer (n = 88) were assessed at similar intervals. Participants provided baseline blood samples for genotyping. Mean-level cognitive performance was compared using mixed models; cognitive impairment was compared using generalized estimating equations.
Results ADT recipients demonstrated higher rates of impaired cognitive performance over time relative to all controls (P = .01). Groups did not differ at baseline (P > .05); however, ADT recipients were more likely to demonstrate impaired performance within 6 and 12 months (P for both comparisons < .05). Baseline age, cognitive reserve, depressive symptoms, fatigue, and hot flash interference did not moderate the impact of ADT on impaired cognitive performance (P for all comparisons ≥ .09). In exploratory genetic analyses, GNB3 single-nucleotide polymorphism rs1047776 was associated with increased rates of impaired performance over time in the ADT group (P < .001).
Conclusion Men treated with ADT were more likely to demonstrate impaired cognitive performance within 6 months after starting ADT relative to matched controls and to continue to do so within 12 months after starting ADT. If confirmed, findings may have implications for patient education regarding the risks and benefits of ADT.
The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation was superior to short-term androgen deprivation when combined with high-dose radiotherapy.
In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c-T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175212.
Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% [95% CI 87-92] vs 81% [78-85]; hazard ratio [HR] 1·88 [95% CI 1·12-3·15]; p=0·01). 5-year overall survival (95% [95% CI 93-97] vs 86% [83-89]; HR 2·48 [95% CI 1·31-4·68]; p=0·009) and 5-year metastasis-free survival (94% [95% CI 92-96] vs 83% [80-86]; HR 2·31 [95% CI 1·23-3·85]; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3-4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported.
Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.
Spanish National Health Investigation Fund, AstraZeneca.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633.
Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups).
The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer.
Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.
The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results.
Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5-7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482.
802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9-11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57-0·90; p=0·003) and local progression (0·49, 0·33-0·73; p=0·0005), and improved event-free survival (0·63, 0·52-0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46-0·72; p<0·0001) and local progression (0·45, 0·30-0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42-0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60-1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60-1·23; p=0·398), or all-cause mortality (0·84, 0·65-1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31-0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32-0·74; p=0·0008), and all-cause mortality (0·63, 0·48-0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation.
6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation.
Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.
Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression.
This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787.
After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%, 0.8-18.8%), for a relative risk of 0.68 (0.52-0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; 0.12-0.20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group.
In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard.
We conducted a randomized, prospective trial comparing external irradiation with external irradiation plus goserelin (an agonist analogue of gonadotropin-releasing hormone that reduces testosterone secretion) in patients with locally advanced prostate cancer.
From 1987 to 1995, 415 patients with locally advanced prostate cancer were randomly assigned to receive radiotherapy alone or radiotherapy plus immediate treatment with goserelin. The patients had a median age of 71 years (range, 51 to 80). Patients in both groups received 50 Gy of radiation to the pelvis over a period of five weeks and an additional 20 Gy over an additional two weeks as a prostatic boost. Patients in the combined-treatment group received 3.6 mg of goserelin (Zoladex) subcutaneously every four weeks starting on the first day of irradiation and continuing for three years; those patients also received cyproterone acetate (150 mg orally per day) during the first month of treatment to inhibit the transient rise in testosterone associated with the administration of goserelin.
Data were available for analysis on 401 patients. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at five years were 79 percent (95 percent confidence interval, 72 to 86 percent) in the combined-treatment group and 62 percent (95 percent confidence interval, 52 to 72 percent) in the radiotherapy group (P=0.001). The proportion of surviving patients who were free of disease at five years was 85 percent (95 percent confidence interval, 78 to 92 percent) in the combined-treatment group and 48 percent (95 percent confidence interval, 38 to 58 percent) in the radiotherapy group (P<0.001).
Adjuvant treatment with goserelin, when started simultaneously with external irradiation, improves local control and survival in patients with locally advanced prostate cancer.
This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%.
Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause.
With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen.
WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.
This trial was designed to test the hypothesis that total androgen suppression and whole pelvic radiotherapy (WPRT) followed by a prostate boost improves progression-free survival (PFS) by > or =10% compared with total androgen suppression and prostate only RT (PORT). This trial was also designed to test the hypothesis that neoadjuvant hormonal therapy (NHT) followed by concurrent total androgen suppression and RT improves PFS compared with RT followed by adjuvant hormonal therapy (AHT) by > or =10%.
Patients eligible for the study included those with clinically localized adenocarcinoma of the prostate and an elevated prostate-specific antigen level of <100 ng/mL. Patients were stratified by T stage, prostate-specific antigen level, and Gleason score and were required to have an estimated risk of lymph node involvement of >15%.
The difference in overall survival for the four arms was statistically significant (p = 0.027). However, no statistically significant differences were found in PFS or overall survival between NHT vs. AHT and WPRT compared with PORT. A trend towards a difference was found in PFS (p = 0.065) in favor of the WPRT + NHT arm compared with the PORT + NHT and WPRT + AHT arms.
Unexpected interactions appear to exist between the timing of hormonal therapy and radiation field size for this patient population. Four Phase III trials have demonstrated better outcomes when NHT was combined with RT compared with RT alone. The Radiation Therapy Oncology Group 9413 trial results have demonstrated that when NHT is used in conjunction with RT, WPRT yields a better PFS than does PORT. It also showed that when NHT + WPRT results in better overall survival than does WPRT + short-term AHT. Additional studies are warranted to determine whether the failure to demonstrate an advantage for NHT + WPRT compared with PORT + AHT is chance or, more likely, reflects a previously unrecognized biologic phenomenon.
To determine whether adding 2 years of androgen-deprivation therapy (ADT) improved outcome for patients electively treated with ADT before and during radiation therapy (RT).
Prostate cancer patients with T2c-T4 prostate cancer with no extra pelvic lymph node involvement and prostate-specific antigen (PSA) less than 150 ng/mL were included. All patients received 4 months of goserelin and flutamide before and during RT. They were randomized to no further ADT (short-term ADT [STAD] + RT) or 24 months of goserelin (long-term ADT [LTAD] + RT). A total of 1,554 patients were entered. RT was 45 Gy to the pelvic nodes and 65 to 70 Gy to the prostate. Median follow-up of all survival patients is 11.31 and 11.27 years for the two arms.
At 10 years, the LTAD + RT group showed significant improvement over the STAD + RT group for all end points except overall survival: disease-free survival (13.2% v 22.5%; P < .0001), disease-specific survival (83.9% v 88.7%; P = .0042), local progression (22.2% v 12.3%; P < .0001), distant metastasis (22.8% v 14.8%; P < .0001), biochemical failure (68.1% v 51.9%; P <or= .0001), and overall survival (51.6% v 53.9%, P = .36). One subgroup analyzed consisted of all cancers with a Gleason score of 8 to 10 cancers. An overall survival difference was observed (31.9% v 45.1%; P = .0061), as well as in all other end points herein.
LTAD as delivered in this study for the treatment of locally advanced prostate cancer is superior to STAD for all end points except survival. A survival advantage for LTAD + RT in the treatment of locally advanced tumors with a Gleason score of 8 to 10 suggests that this should be the standard of treatment for these high-risk patients.
To evaluate the impact of adding image-guided (IG) technique to intensity-modulated radiotherapy (IMRT) on dosimetric avoidance of organs at risk (OAR) and acute toxicities.
A total of 25 consecutively treated patients (10 from National University Hospital and 15 from University of California San Francisco) with high-risk prostate cancer formed the study cohort. All received definitive IMRT with prophylactic nodal RT. Similar IMRT contouring and planning techniques were used at both centers. At the University of California, San Francisco, intraprostatic fiducial markers were used for daily pretreatment on-line corrections (IG-IMRT). In contrast, at the National University Hospital, no fiducial markers were used (IMRT). At the University of California, San Francisco, the planning target volume margins to the prostate were 2-3 mm. At the National University Hospital, they were 1 cm circumferentially, except for 0.5 cm posteriorly. The acute rectal and bladder toxicities and dosimetric endpoints to the planning target volume and organs at risk were compared.
The planning target volume dose coverage was not significantly different between IMRT and IG-IMRT for the prostate, seminal vesicles, and lymph nodes. The volume of rectum and bladder receiving >/=40, >/=60, and >/=70 Gy were all significantly less using IG-IMRT (p <0.001). IG-IMRT yielded lower acute Radiation Therapy Oncology Group Grade 2 rectal (80% vs. 13%, p = 0.004) and bladder (60% vs. 13%, p = 0.014) toxicities.
IG-IMRT, using daily target localization with fiducial markers, permits the use of smaller margins and correspondingly lower doses to the organs at risk, such as the rectum and bladder. These tangible gains appear to translate into lower clinically significant toxicities.