Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial.
ABSTRACT: 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:Neoadjuvant androgen deprivation therapy (ADT) has been suggested to confer several clinical benefits in patients with prostate cancer (PCa) undergoing transperineal prostate brachytherapy (TPPB). Unlike gonadotropin-releasing hormone (GnRH) receptor agonists, a GnRH antagonist such as degarelix can achieve castrate levels of testosterone without testosterone flare. However, normalization of serum testosterone levels following completion of neoadjuvant ADT in either form of treatment has never been compared in clinical trials.This is a single-center, open-label, randomized controlled study that will compare the efficacy and safety of degarelix with those of existing GnRH agonists combined with (125)I-TPPB. A total of 56 patients with low/intermediate-risk clinically localized PCa will be enrolled and randomized to one of two treatment groups: the GnRH agonist group and the degarelix group. Patients in the GnRH agonist group will receive leuprorelin acetate or goserelin acetate, and those in the degarelix group will receive the initial dose of 240 mg as 2 subcutaneous injections of 120 mg each, and then 80 mg of maintenance doses every 4 weeks for 12 weeks. Those randomly assigned to the 12-week intervention period will subsequently undergo 48-weeks of follow-up after (125)I-TPPB. The primary endpoint is defined as normalization of serum testosterone levels (>50 ng/dL) following completion of neoadjuvant ADT. All patients will be assessed every 4 weeks for the first 24 weeks, then every 12 weeks for the next 36 weeks after administrations of these drugs. Secondary endpoints are the proportion of normalized serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the percent reduction in prostate specific antigen (PSA) compared with pretreatment levels, the percent reduction in total prostate volume (TPV) during neoadjuvant ADT, the percent increase in TPV after (125)I-TPPB, the percent reduction in hemoglobin, serum alkaline phosphatase (ALP), changes in free testosterone and bone mineral content measurement, the proportion of patients who have serum testosterone levels over 50 ng/dL at 12 weeks following completion of neoadjuvant ADT, and the improvement of quality of life (QOL).The present study will provide additional insight regarding the benefit and potency of degarelix and will examine its potential as a new option for administration in neoadjuvant ADT.Identification number: UMIN000015519 . Registration date: October 24, 2014.
Project description:Despite the many prospective randomized trials that have been available in the past decade regarding the optimization of radiation, hormonal, and surgical therapies for high-risk prostate cancer (PCa), many questions remain. There is currently a lack of level I evidence regarding the relative efficacy of radical prostatectomy (RP) followed by adjuvant radiation compared to radiation therapy (RT) combined with androgen deprivation therapy (ADT) for high-risk PCa. Current retrospective series have also described an improvement in biochemical outcomes and PCa-specific mortality through the use of augmented radiation strategies incorporating brachytherapy. The relative efficacy of modern augmented RT compared to RP is still incompletely understood. We present a narrative review regarding recent advances in understanding regarding comparisons of overall and PCa-specific mortality measures among patients with high-risk PCa treated with either an RP/adjuvant RT or an RT/ADT approach. We give special consideration to recent trends toward the assembly of multi-institutional series targeted at providing high-quality data to minimize the effects of residual confounding. We also provide a narrative review of recent studies examining brachytherapy boost and systemic therapies, as well as an overview of currently planned and ongoing studies that will further elucidate strategies for treatment optimization over the next decade.
Project description: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:Androgen deprivation therapy (ADT) is a standard treatment for metastatic, recurrent and locally advanced prostate cancer (PCa). The aim of this study is to investigate the timing and extent of testosterone recovery in clinically localized PCa patients treated with radical prostatectomy (RP) and subsequent short-term adjuvant ADT. A total of 95 localized PCa patients underwent RP and 9-month adjuvant ADT were included in this prospective study. Serum testosterone level was measured before adjuvant ADT, at ADT cessation, and at 1, 3, 6, 9 and 12 months after cessation of ADT. A Cox proportional hazards model was used to assess variables associated with the time of testosterone normalization. The results showed that median patient age was 67 years and median testosterone level before adjuvant ADT was 361 (230-905) ng dl(-1). All patients finished 9-month adjuvant ADT and achieved castrate testosterone level. At 3 months after ADT cessation, testosterone recovered to supracastrate level in 97.9% patients and to normal level in 36.9% patients. The percentage of patients who recovered to normal testosterone level increased to 66.3%, 86.3% and 92.6% at 6, 9 and 12 months, respectively. Cox regression model found that higher baseline testosterone level (≥ 300 ng dl(-1)) was the only variable associated with a shorter time to testosterone normalization (hazard ratio: 1.98; P = 0.012). In conclusion, in most patients, testosterone recovered to supracastrate level at 3 months and to normal level at 12 months after 9-month adjuvant ADT cessation. Patients with higher baseline testosterone level need shorter time of testosterone normalization.
Project description:BACKGROUND:Androgen deprivation therapy (ADT) is a standard treatment for advanced prostate cancer (PCa). However, PCa recurrence and progression rates during ADT are high. Until now, there has been no evidence regarding when progression begins. This study evaluated the gene expression of intraprostatic androgen receptor (AR) and steroidogenic enzymes in the early stages of ADT. METHODS:Prostate tissue samples were taken from PCa patients with urinary retention who received ADT (ADT-PCa; n?=?10) and were further subgrouped into ADT ?12?months (n?=?4) and ADT >?12?months (n?=?6). The ADT-PCa tissues were then compared with BPH (n?=?12) and primary (no treatment) PCa tissues (n?=?16). mRNA for gene expression analysis of AR and steroidogenic enzymes was extracted from formalin-fixed paraffin embedded (FFPE) tissues and analyzed by real-time PCR. Protein expression was evaluated by immunohistochemistry with specific antibodies. RESULTS:AR gene expression was higher in the ADT-PCa group than in the BPH or primary PCa group. Both the ADT ?12 and?>?12?months subgroups had significantly higher relative gene expression levels of AR (p?<?0.01 and 0.03, respectively) than the primary PCa group. In the ADT-PCa group, AR protein expression showed an increasing trend in the ADT ?12?months subgroup and was significantly elevated in the ADT >?12?months subgroup compared with the PCa group (100%; p?<?0.01). Half (50%) of the patients in the ADT ?12?months subgroup were found to have upregulation of AR, and one showed upregulation beginning at 3?months of ADT. A trend toward elevated relative gene expression of SRD5A3 was also apparent in the ADT groups. CONCLUSION:AR and steroidogenic enzymes are upregulated in ADT-PCa patients as early as 3?months, without PSA elevation. Steroidogenic enzymes, particularly SRD5A3, were also upregulated before PSA rose.
Project description:BACKGROUND:Retzius-sparing robot-assisted laparoscopic radical prostatectomy (rsRARP) allows entire prostatectomy procedure via the pouch of Douglas. In low- and intermediate-risk prostate cancer (PCa) there is level 1 evidence that the Retzius-sparing approach impacts early continence recovery. Since specific data on aggressive and locally advanced cancer is lacking and avoiding rsRARP is presently suggested, we investigated urinary and sexual recovery, perioperative complications and early oncologic outcomes after rsRARP in this particular cohort. METHODS:Prospectively collected data of 50 consecutive men (median age 66?years) with high-risk PCa who underwent rsRARP in a single institution was analysed retrospectively. The follow-up for all patients was 12?months after surgery. RESULTS:3 vs. 12?months after surgery, 82% vs. 98% of men used no pad or one safety pad and 50% vs. 72% used no pad. 89% of patients did not observe a decline of continence if postoperative radiotherapy was carried out. Considering the 17 preoperatively potent patients who underwent bi- or unilateral nerve-sparing surgery, 41% reported their first sexual intercourse within 1?year after rsRARP. 84% of patients had ?pT3a disease and 42% positive surgical margins. A lymphadenectomy was done in 94% of patients with a median lymph node removal of 15 and lymph node metastasis in 13%. 34% underwent adjuvant radiotherapy and 22% adjuvant androgen deprivation therapy (ADT). 1-year recurrence-free survival was 96%, including 25% of patients on adjuvant or salvage ADT. CONCLUSIONS:RsRARP in high-risk PCa is feasible and results in excellent continence rates, even after postoperative radiotherapy. The potency rates are promising but need further clarification in larger cohorts. Reliable oncologic outcomes require longterm follow-up and are awaited.
Project description:Several retrospective and a few prospective studies have shown that metastasis-directed therapy (MDT) could delay clinical progression and postpone the initiation of systemic treatment in oligorecurrent prostate cancer (PCa) patients. However, these endpoints are strongly influenced by variables such as concomitant use of androgen deprivation therapy (ADT) and follow-up imaging protocols. The aim of this manuscript was to assess palliative ADT- and metastatic castration-resistant prostate cancer (mCRPC)-free survival as long-term oncological outcomes in oligorecurrent PCa treated by MDT. We retrospectively identified consecutive post-prostatectomy oligorecurrent PCa patients treated by MDT (salvage lymphadenectomy, radiotherapy, or metastasectomy) at our tertiary referral center. Patients were eligible for inclusion if they developed recurrence following radical prostatectomy, had ?5 metastatic lesions on imaging and had a serum testosterone >50 ng/dL or a testosterone suppression therapy-free interval of >2 years prior to the first MDT as an assumption of recovered serum testosterone (if no testosterone measurement available). Patients with castration-resistant or synchronous oligometastatic PCa at the time of first MDT were excluded. Repeated MDTs were allowed, as well as a period of concomitant ADT. Kaplan-Meier analyses were performed to assess palliative ADT-free and mCRPC-free survival. We identified 191 eligible patients who underwent MDT. Median follow-up from first MDT until last follow-up or death was 45 months (IQR 27-70; mean 51 months). Estimated median palliative-ADT free survival was 66 months (95% CI 58-164) and estimated median mCRPC-free survival was not reached (mean 117 months, 95% CI 103-132). In total, 314 MDTs were performed and 25 patients (13%) received ?3 MDTs. This study demonstrated that (repeated) MDT is feasible and holds promise in terms of palliative ADT-free and mCRPC-free survival for patients with oligorecurrent PCa. However, these findings should be confirmed in prospective randomized controlled trials.
Project description:To evaluate the incidence and predictors of hip toxicity postradiotherapy for localized prostate cancer.4067 prostate cancer patients were treated with external beam radiotherapy (EBRT; n=2569; 63%) or brachytherapy with or without supplemental EBRT (n=1508; 27%). 43% (n=1738) were treated with neo-adjuvant and concurrent ADT and 57% (n=2329) with radiotherapy alone. Hip toxicity was defined as moderate or severe pain upon ambulation with or without the need for hip-revision surgery. Median follow-up was 7years (range, 3-21years).One hundred twenty-one (2.7%) patients developed moderate-to-severe hip pain after radiotherapy affecting ambulation. Of these, 73 (60%) required hip replacement secondary to persistent hip pain. Among patients with baseline degenerative joint disease (DJD) changes on scans, 10-year incidence of hip-related toxicity was 11% versus 3% for those without such changes (P<.001). The only variables on multivariate analysis associated with hip-related toxicity post-radiotherapy were baseline DJD on imaging (P<.0001) and prolonged ADT for salvage therapy (P<.0001).Prostate EBRT or brachytherapy is associated with low incidence of long-term hip-related toxicity. The only variables identified associated with hip toxicity posttherapy was the presence of baseline DJD and prolonged salvage ADT posttreatment for patients developing recurrence.
Project description:The purpose of the present study was to assess the results of two different treatment approaches for clinically localized prostate cancer: intensity-modulated radiation therapy (IMRT) followed by 125I seed-implant brachytherapy and 125I seed-implant brachytherapy alone. We studied our 30 most recent consecutive patients. The sample population consisted of 15 cases treated with IMRT (50.4 Gy) followed by 125I seed-implant boost (95 Gy), and 15 cases treated with 125I seed implant only (144 Gy). We analyzed established dosimetric indices and various clinical parameters. In addition, we also evaluated and compared the acute urinary morbidities of the two treatment approaches, as assessed by the international prostate symptom score (IPSS). In our series, acute urinary morbidity was slightly increased with IMRT followed by 125I seed-implant brachytherapy as compared with 125I seed-implant brachytherapy alone. In addition, we observed no statistically significant correlation between the IPSS and the maximum or mean urethral dose. The combination of IMRT and seed-implant brachytherapy presents an alternative opportunity to treat clinically localized prostate cancer. The full potential of the procedure needs to be further investigated.