Long-term biochemical progression-free survival following brachytherapy for prostate cancer: Further insight into the role of short-term androgen deprivation and intermediate risk group subclassification.
ABSTRACT: INTRODUCTION:Brachytherapy is a well-established treatment of localized prostate cancer. Few studies have documented long-term results, specifically biochemical progression-free survival (bPFS) in men with brachytherapy alone, with or without short-term androgen deprivation therapy (ADT), or in combination with external beam radiotherapy (EBRT). Our aim was to analyze long-term bPFS of brachytherapy treated patients. MATERIALS AND METHODS:Retrospective analysis of 1457 patients with low and intermediate risk prostate cancer treated with brachytherapy alone (1255) or combined with EBRT (202). Six-months ADT was administrated for all EBRT combined patients and for prostate volume downsizing when >55 cc (328). Failure was by the Phoenix definition. Kaplan-Meier analysis and multivariate Cox regression estimated and compared 10-yr and 15-yr rates of bPFS. RESULTS:Median follow-up was 6.1 yr. Ten and 15-yr bPFS rates of the entire cohort were 93.2% and 89.2%, respectively. On multivariate analysis, PSA density (PSAD), ADT and clinical stage were significantly associated with failure. The most powerful independent factor was PSAD with a HR of 3.5 (95% CI, 1.7-7.4) for PSAD above 0.15. No significant difference was found between low and intermediate risks patients regardless of treatment regimen. However, comparison of two intermediate risk groups, Gleason score (GS) 7, PSA<20 ng/ml versus GS≤6 and PSA = 10-20 ng/ml, revealed 10- and 15-yr bPFS rates of 94.2% and 94.2% compared to 88.2% and 79.9%, (P = 0.022), respectively. ADT improved bPFS rates in low risk patients. The ten and 15-yr bPFS rates were 97.6% and 94.6% compared to 92.3% and 88.2%, (P = 0.020), respectively. CONCLUSIONS:Our retrospective large scale study suggests that brachytherapy provides excellent long-term bPFS rates in low and intermediate risk disease. Combination of brachytherapy with EBRT yields favorable outcomes in GS 7 intermediate risk patients and short-term ADT has a positive effect on outcomes in low risk patients. Further prospective studies are warranted to discriminate the role of adding either EBRT and/or ADT to brachytherapy protocols.
Project description:The objective of this study was to investigate the impact of the biologically equivalent dose (BED) on treatment outcomes after iodine-125 low-dose-rate brachytherapy (LDR-BT) with or without supplemental external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for intermediate-risk prostate cancer (PCa). We retrospectively evaluated 292 Japanese patients. The impact of the BED and ADT on treatment outcomes was investigated. Cox proportional hazard models were used for univariate and multivariate analysis with biological progression-free survival (bPFS) and clinical progression-free survival (cPFS) as the primary outcome measures. The median follow-up was 66 months. The bPFS and cPFS rates at 5-/7-years were 91.6/87.7% and 95.9/94.0%, respectively. When stratified by BED levels, the bPFS rates at 5-/7-years were 92.1/89.3% for <178.0 Gy2, and 91.2/86.0% for ?178.0 Gy2 , respectively (P > 0.05). Based on ADT duration, the bPFS rates at 5-/7-years were 89.8/83.5%, 89.7/89.7%, and 97.5/97.5% for none, 1-3 months, and 4-12 months, respectively (P = 0.03). For the univariate analysis, the use of ADT and its duration were significant predictors for bPFS, whereas BED was not significant. A multivariate analysis did not indicate the use of ADT itself was significant, however, when covariates were accounted for by the duration of ADT, the longer use of ADT was found to significantly improve bPFS. Although cPFS was associated neither with the BED levels nor ADT duration (P > 0.05), ADT duration had a trend of improving cPFS (P = 0.053). The higher levels of BED did not significantly impact bPFS for intermediate-risk PCa after LDR-BT with or without supplemental EBRT and ADT. The longer duration of ADT could provide an additional benefit in the context of high-dose irradiation generated by LDR-BT.
Project description:Purpose:To assess the effectiveness of low-dose-rate (LDR) brachytherapy in patients with localized prostate cancer and to compare the outcome with predictions from Kattan and Partin nomograms at 60 months after seed implantation. Material and methods:One thousand, one hundred and eighty-seven patients with localized prostate cancer at low-, intermediate-, or high-risk of progression received LDR brachytherapy using iodine-125 seeds with curative intent, applied as monotherapy or in combination with external beam radiation therapy (EBRT), and/or androgen deprivation therapy (ADT). At 60 months after seed implantation, data of 1,064 patients (1,058 alive + 6 who died of prostate cancer) were analyzed for biochemical progression-free survival (bPFS) based on prostate-specific antigen (PSA) levels using the Phoenix definition. Five-year bPFS probabilities were determined for various risk group classifications (d'Amico, Mt. Sinai, MSKCC/Seattle, NCCN). Outcomes were also compared to patient-individualized nomogram predictions of 5-year bPFS (Kattan 2002) and probability of organ-confined disease (Kattan 2002, Partin 2007). Results:Overall, 93.3% (993/1,064) of the patients were free of biochemical progression within 5 years, while the average 5-year bPFS probability according to the Kattan nomogram was significantly lower (85%, p < 0.001). Outcomes were significantly better than Kattan nomogram predictions in the subgroup of patients with monotherapy as well as in patients additionally treated with EBRT. Comparison of the overall outcome with nomogram predictions for organ-confined disease (Kattan nomogram: 50%; Partin nomogram: 65%) revealed a significant probability of LDR brachytherapy to destroy periprostatic tumor spread (p < 0.001) in all risk group constellations, even in high-risk patients. Conclusions:The results indicate high effectiveness of LDR brachytherapy in all risk groups, significantly better than predicted with the Kattan nomogram in most subgroups. The significant superiority of LDR brachytherapy compared to nomogram predictions of organ-confined disease suggests that LDR brachytherapy effectively controls both intra- and periprostatic disease.
Project description:Introduction:There is evidence to support use of external beam radiotherapy (EBRT) in combination with both low dose rate brachytherapy (LDR-EBRT) and high dose rate brachytherapy (HDR-EBRT) to treat intermediate and high risk prostate cancer. Methods:Men with intermediate and high risk prostate cancer treated using LDR-EBRT (treated between 1996 and 2007) and HDR-EBRT (treated between 2007 and 2012) were identified from an institutional database. Multivariable analysis was performed to evaluate the relationship between patient, disease and treatment factors with biochemical progression free survival (bPFS). Results:116 men were treated with LDR-EBRT and 171 were treated with HDR-EBRT. At 5?years, bPFS was estimated to be 90.5% for the LDR-EBRT cohort and 77.6% for the HDR-EBRT cohort. On multivariable analysis, patients treated with HDR-EBRT were more than twice as likely to experience biochemical progression compared with LDR-EBRT (HR 2.33, 95% CI 1.12-4.07). Patients with Gleason ?8 disease were more than five times more likely to experience biochemical progression compared with Gleason 6 disease (HR 5.47, 95% CI 1.26-23.64). Cumulative incidence of ?grade 3 genitourinary and gastrointestinal toxicities for the LDR-EBRT and HDR-EBRT cohorts were 8% versus 4% and 5% versus 1% respectively, although these differences did not reach statistical significance. Conclusion:LDR-EBRT may provide more effective PSA control at 5?years compared with HDR-EBRT. Direct comparison of these treatments through randomised trials are recommended to investigate this hypothesis further.
Project description:The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high risk prostate cancer treated by combined definitive external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT).Between June 1995 and January 2015, 375 patients with localized prostate cancer and a National Comprehensive Cancer Network (NCCN) intermediate or high risk categories were treated by definitive EBRT and ADT. Median duration of androgen blockade was 10 months (range: 3-36 months); Median radiation dose was 72 Gy (Range: 70-78 Gy). Median follow-up time was 5.8 years (range: 0.8-16.39 years). The main study endpoint was biochemical disease free survival (BFS).Forty seven patients (12.5%) developed biochemical recurrence (BCR) during the observation period. Monovariate analysis identified baseline PSA (bPSA) (p = 0.024), T-stage (p = 0.001), Gleason's score (GS) (p = 0.042), radiation dose (p = 0.045), PSA pre-radiation therapy (p = 0.048), and nadir PSA (nPSA), (p < 0.001) as significant variables affecting BCR. The receiver operating characteristic (ROC) curve identified a nPSA of 0.06 ng/ml as optimal cut-off value significantly predicting the patients' risk of BCR (p < 0.001). Multivariate cox regression analysis revealed T-stage, GS, and nPSA as independent variable affecting BFS, while bPSA, age, and radiation dose were not.Nadir PSA at 0.06 is a strong independent predictor of BFS in patients with intermediate or high risk prostate cancer treated by definitive EBRT and ADT.
Project description:PURPOSE:Prostate brachytherapy (PB) has well-documented excellent long-term outcomes in all risk groups. There are significant uncertainties regarding the role of androgen deprivation therapy (ADT) with brachytherapy. The purpose of this report was to review systemically the published literature and summarize present knowledge regarding the impact of ADT on biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS). METHODS AND MATERIALS:A literature search was conducted in Medline and Embase covering the years 1996-2016. Selected were articles with >100 patients, minimum followup 3 years, defined risk stratification, and directly examining the role and impact of ADT on bPFS, CSS, and OS. The studies were grouped to reflect disease risk stratification. We also reviewed the impact of ADT on OS, cardiovascular morbidity, mortality, and on-going brachytherapy randomized controlled trials (RCTs). RESULTS:Fifty-two selected studies (43,303 patients) were included in this review; 7 high-dose rate and 45 low-dose rate; 25 studies were multi-institutional and 27 single institution (retrospective review or prospective data collection) and 2 were RCTs. The studies were heterogeneous in patient population, risk categories, risk factors, followup time, and treatment administered, including ADT administration and duration (median, 3-12 months);71% of the studies reported a lack of benefit, whereas 28% showed improvement in bPFS with addition of ADT to PB. The lack of benefit was seen in low-risk and favorable intermediate-risk (IR) disease and most high-dose rate studies. A bPFS benefit of up to 15% was seen with ADT use in patients with suboptimal dosimetry, those with multiple adverse risk factors (unfavorable IR [uIR]), and most high-risk (HR) studies. Four studies reported very small benefit to CSS (2%). None of the studies showed OS advantage; however, three studies reported an absolute 5-20% OS detriment with ADT. Literature suggests that OS detriment is more likely in older patients or those with pre-existing cardiovascular disease. Four RCTs with an adequate number of patients and well-defined risk stratification are in progress. One RCT will answer the question regarding the role of ADT with PB in favorable IR patients and the other three RCTs will focus on optimal duration of ADT in the uIR and favorable HR population. CONCLUSIONS:Patients treated with brachytherapy have excellent long-term disease outcomes. Existing evidence shows no benefit of adding ADT to PB in low-risk and favorable IR patients. UIR and HR patients and those with suboptimal dosimetry may have up to 15% improvement in bPFS with addition of 3-12 months of ADT, with uncertain impact on CSS and a potential detriment on OS. To minimize morbidity, one should exercise caution in prescribing ADT together with PB, in particular to older men and those with existing cardiovascular disease. Due to the retrospective nature of this evidence, significant selection, and treatment bias, no definitive conclusions are possible. RCT is urgently needed to define the potential role and optimal duration of ADT in uIR and favorable HR disease.
Project description:<h4>Background</h4> Intermediate-risk prostate cancer (PCa) is usually treated by a combination of external beam radiation therapy (EBRT) and a short course of androgen deprivation therapy (ADT). ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, anti-androgen monotherapy is generally better tolerated in spite of higher rates of gynecomastia. <h4>Objective</h4> This study assessed the effectiveness of enzalutamide monotherapy combined with hypofractionated EBRT (Hypo-EBRT) for treating intermediate risk prostate cancer. <h4>Method</h4> This trial was a multicenter, open-label phase II study of 6 months of enzalutamide monotherapy combined with Hypo-EBRT for intermediate-risk prostate cancer. Hypo-EBRT was initiated 8–12 weeks after initiating enzalutamide. The primary endpoint was PSA decline >80% measured at the 25th week of enzalutamide administration. Secondary end-points included assessment of toxicity, changes in anthropomorphic body measurements, sexual hormones, and metabolic changes. <h4>Results</h4> Sixty-two patients were included in the study from January 2018 to February 2020. A PSA decline of >80% was observed in all evaluable patients at the end of enzalutamide treatment and 92% achieved PSA values under 0.1 ngr/ml. All patients remain in PSA response (<80% reduction of the initial values) 6 months after the end of enzalutamide treatment. The most frequent adverse events were hypertension, asthenia, and gynecomastia. There were no significant changes in bone density, body mass index (BMI), or patient-reported outcomes (PROs). <h4>Conclusion</h4> Enzalutamide monotherapy is very effective along with hEBRT in reducing PSA levels for patients with intermediate-risk prostate cancer. Longer follow-up is needed to confirm the potential use of this combination in future randomized trials.
Project description:The optimal protocol for 125I-transperineal prostatic brachytherapy (TPPB) in intermediate-risk prostate cancer (PCa) patients remains controversial. Data on the efficacy of combining androgen-deprivation therapy (ADT) with 125I-TPPB in this group remain limited and consequently the guidelines of the American Brachytherapy Society (ABS) provide no firm recommendations.Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804 is a phase III, multicenter, randomized, controlled study that will investigate the impact of adjuvant ADT following neoadjuvant ADT and 125I-TPPB. Prior to the end of March, 2011, a total of 420 patients with intermediate-risk, localized PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from 20 institutions, all of which have broad experience of 125I-TPPB. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will initially undergo 3-month ADT prior to 125I-TPPB. Those randomly assigned to adjuvant therapy will subsequently undergo 9 months of adjuvant ADT. All participants will be assessed at baseline and at the following intervals: every 3 months for the first 24 months following 125I-TPPB, every 6 months during the 24- to 60-month post-125I-TPPB interval, annually between 60 and 84 months post-125I-TPPB, and on the 10th anniversary of treatment.The primary endpoint is biochemical progression-free survival (BPFS). Secondary endpoints are overall survival (OS), clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, acceptability (assessed using the international prostate symptom score [IPSS]), quality of life (QOL) evaluation, and adverse events. In the correlative study (SHIP36B), we also evaluate biopsy results at 36 months following treatment to examine the relationship between the results and the eventual recurrence after completion of radiotherapy.These two multicenter trials (SHIP0804 & SHIP36B) are expected to provide crucial data regarding the efficacy, acceptability and safety of adjuvant ADT. SHIP36B will also provide important information about the prognostic implications of PSA levels in intermediate-risk PCa patients treated with 125I-TPPB.NCT00664456, NCT00898326, JUSMH-BRI-GU05-01, JUSMH-TRIGU0709.
Project description:Objective: This study compared survival of prostate cancer patients with low prostate specific antigen level (PSA ? 10 ng/ml) and high-grades of Gleason score (GS) of 8-10 with different treatment options (i.e., radical prostatectomy [RP], external beam radiotherapy [EBRT], or external beam radiotherapy with brachytherapy [EBRT+BT]). Materials and Methods: The Surveillance, Epidemiology and End Results (SEER) database data (2004-2013), and overall survival (OS) and prostate cancer-specific mortality (PCSM), were evaluated using the Cox proportional hazards regression model and Fine and Gray competing risk model. Results: The SEER data contained 9,114 patients, 4,175 of whom received RP, 4,114 received EBRT, and 825 received EBRT+BT with a median follow-up duration of 47 months. RP patients had significantly better OS than patients with EBRT and EBRT+BT (adjusted HR [AHR]: 3.36, 95% CI: 2.43-4.64, P < 0.001; AHR: 2.15, 95% CI: 1.32-3.48, P = 0.002; respectively). There was no statistical difference in PCSM between RP and EBRT+BT (AHR: 1.31, 95% CI: 0.61-2.80, P = 0.485), while EBRT had worse OS (P < 0.05). The subgroup analysis revealed that there was no statistical difference in prognosis of patients with age of >70 years old, or PSA levels of ? 2.5 ng/ml between RP and EBRT+BT (P > 0.05). Conclusion: RP patients with low PSA levels and high GS had better OS compared to either EBRT or EBRT+BT, while RP and EBRT+BT resulted in significantly lower PCSM, compared to EBRT. Moreover, EBRT+BT and RP were associated with similar survival of patients with age of > 70 years old, or PSA levels of ? 2.5 ng/ml.
Project description:Purpose:Evaluation of clinical outcome of two-weekly high-dose-rate brachytherapy boost after external beam radiotherapy (EBRT) for localized prostate cancer. Methods:338 patients with localized prostate cancer receiving definitive EBRT followed by a two-weekly high-dose-rate brachytherapy boost (HDR-BT boost) in the period of 2002 to 2019 were analyzed. EBRT, delivered in 46 Gy (DMean) in conventional fractionation, was followed by two fractions HDR-BT boost with 9 Gy (D90%) two and four weeks after EBRT. Androgen deprivation therapy (ADT) was added in 176 (52.1%) patients. Genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated utilizing the Common Toxicity Criteria for Adverse Events (version 5.0) and biochemical failure was defined according to the Phoenix definition. Results:Median follow-up was 101.8 months. 15 (4.4%)/115 (34.0%)/208 (61.5%) patients had low-/intermediate-/high-risk cancer according to the D`Amico risk classification. Estimated 5-year and 10-year biochemical relapse-free survival (bRFS) was 84.7% and 75.9% for all patients. The estimated 5-year bRFS was 93.3%, 93.4% and 79.5% for low-, intermediate- and high-risk disease, respectively. The estimated 10-year freedom from distant metastasis (FFM) and overall survival (OS) rates were 86.5% and 70.0%. Cumulative 5-year late GU toxicity and late GI toxicity grade ≥ 2 was observed in 19.3% and 5.0% of the patients, respectively. Cumulative 5-year late grade 3 GU/GI toxicity occurred in 3.6%/0.3%. Conclusions:Two-weekly HDR-BT boost after EBRT for localized prostate cancer showed an excellent toxicity profile with low GU/GI toxicity rates and effective long-term biochemical control.
Project description:BACKGROUND:Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. METHODS:Intermediate- and high-risk PC patients treated with PBT combined with ADT for various durations were analyzed retrospectively. To assess the relationship between ADT and biochemical relapse-free (bRF) rate, Cox proportional hazards models including T stage, prostate specific antigen (PSA) level, Gleason score (GS), and total radiation dose were used. RESULTS:In the intermediate-risk PC patients (n = 520), ADT use improved bRF (HR 0.49, 95% CI 0.26-0.93; p = 0.029), especially in those with multiple intermediate-risk factors (T2b-2c, PSA 10-20 ng/mL, and GS 7). In the high-risk PC patients (n = 555), a longer ADT duration (>6 months) conferred a benefit for bRF (HR 0.54, 95% CI 0.32-0.90; p = 0.018), which was most apparent in patients with multiple high-risk factors (T3a-4, PSA > 20 ng/mL, and GS ? 8) treated with ADT for ?21 months. CONCLUSIONS:Short-term (?6 months) ADT is beneficial for intermediate-risk PC patients, but likely unnecessary for those with a single risk factor, whereas ADT for >6 months is necessary for high-risk PC patients and ADT for ?21 months might be optimal for those with multiple risk factors in combination of high-dose PBT.