Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer.
ABSTRACT: To report long-term survival and toxicity outcomes with the use of high-dose intensity modulated radiation therapy (IMRT) to 86.4 Gy for patients with localized prostate cancer.Between August 1997 and December 2008, 1002 patients were treated to a dose of 86.4 Gy using a 5-7 field IMRT technique. Patients were stratified by prognostic risk group based on National Comprehensive Cancer Network risk classification criteria. A total of 587 patients (59%) were treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range, 1-14 years).For low-, intermediate-, and high-risk groups, 7-year biochemical relapse-free survival outcomes were 98.8%, 85.6%, and 67.9%, respectively (P<.001), and distant metastasis-free survival rates were 99.4%, 94.1%, and 82.0% (P<.001), respectively. On multivariate analysis, T stage (P<.001), Gleason score (P<.001), and >50% of initial biopsy positive core (P=.001) were predictive for distant mestastases. No prostate cancer-related deaths were observed in the low-risk group. The 7-year prostate cancer-specific mortality (PCSM) rates, using competing risk analysis for intermediate- and high-risk groups, were 3.3% and 8.1%, respectively (P=.008). On multivariate analysis, Gleason score (P=.004), percentage of biopsy core positivity (P=.003), and T-stage (P=.033) were predictive for PCSM. Actuarial 7-year grade 2 or higher late gastrointestinal and genitourinary toxicities were 4.4% and 21.1%, respectively. Late grade 3 gastrointestinal and genitourinary toxicity was experienced by 7 patients (0.7%) and 22 patients (2.2%), respectively. Of the 427 men with full potency at baseline, 317 men (74%) retained sexual function at time of last follow-up.This study represents the largest cohort of patients treated with high-dose radiation to 86.4 Gy, using IMRT for localized prostate cancer, with the longest follow-up to date. Our findings indicate that this treatment results in excellent clinical outcomes with acceptable toxicity.
Project description:As several recent researches focus on the importance of Gleason 9-10, we examine the role of radiotherapy dose escalation in those patients. We analyzed 476 patients with Gleason score 9-10 prostate cancer treated with radiotherapy. Of them, 127 patients were treated with conventional-dose external beam radiotherapy (Conv RT) and 349 patients were treated with high-dose radiotherapy (HDRT; 249 patients received high-dose-rate brachytherapy boost + external beam radiotherapy [HDR boost] and 100 patients received intensity-modulated radiotherapy [IMRT]). We compared these treatment groups using multi-institutional retrospective data. The patients had a median follow-up period of 66.3 months. HDRT showed superior biochemical disease-free survival (bDFS) rate (85.2%; HDR boost 84.7% and IMRT 86.6%) to Conv RT (71.1%, p < 0.0001) at 5 years, with a hazard ratio of 0.448. There were borderline difference in prostate cancer-specific mortality (PCSM; 4.3% and 2.75%, p = 0.0581), and distant metastasis-free survival (DMFS; 94.4% and 89.6%, p = 0.0916) rates at 5-years between Conv RT and HDRT group. Dose escalated radiotherapy showed better bDFS, borderline improvement in PCSM, and equivocal outcome in DMFS in with clinically localized Gleason 9-10 prostate cancer.
Project description:A phase 2 protocol was designed and implemented to assess the toxicity and efficacy of hypofractionated image guided intensity modulated radiation therapy (IG-IMRT) combined with low-dose rate 103Pd prostate seed implant for treatment of localized intermediate- and high-risk adenocarcinoma of the prostate.This is a report of an interim analysis on 24 patients enrolled on an institutional review board-approved phase 2 single-institution study of patients with intermediate- and high-risk adenocarcinoma of the prostate. The median pretreatment prostate-specific antigen level was 8.15 ng/mL. The median Gleason score was 4 + 3 = 7 (range, 3 + 4 = 7 - 4 + 4 = 8), and the median T stage was T2a. Of the 24 patients, 4 (17%) were high-risk patients as defined by the National Comprehensive Cancer Network criteria, version 2016. The treatment consisted of 2465 cGy in 493 cGy/fraction of IG-IMRT to the prostate and seminal vesicles. This was followed by a 103Pd transperineal prostate implant boost (prescribed dose to 90% of the prostate volume of 100 Gy) using intraoperative planning. Five patients received neoadjuvant, concurrent, and adjuvant androgen deprivation therapy.The median follow-up was 18 months (range, 1-42 months). The median nadir prostate-specific antigen was 0.5 ng/mL and time to nadir was 16 months. There was 1 biochemical failure associated with distant metastatic disease without local failure. Toxicity (acute or late) higher than grade 3 was not observed. There was a single instance of late grade 3 genitourinary toxicity secondary to hematuria 2 years and 7 months after radiation treatment. There were no other grade 3 gastrointestinal or genitourinary toxicities.Early results on the toxicity and efficacy of the combination of hypofractionated IG-IMRT and low-dose-rate brachytherapy boost are favorable. Longer follow-up is needed to confirm safety and effectiveness.
Project description:To give a preliminary report of clinical and treatment factors associated with toxicity in men receiving high-dose radiation therapy (RT) on a phase 3 dose-escalation trial.The trial was initiated with 3-dimensional conformal RT (3D-CRT) and amended after 1 year to allow intensity modulated RT (IMRT). Patients treated with 3D-CRT received 55.8 Gy to a planning target volume that included the prostate and seminal vesicles, then 23.4 Gy to prostate only. The IMRT patients were treated to the prostate and proximal seminal vesicles to 79.2 Gy. Common Toxicity Criteria, version 2.0, and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late morbidity scores were used for acute and late effects.Of 763 patients randomized to the 79.2-Gy arm of Radiation Therapy Oncology Group 0126 protocol, 748 were eligible and evaluable: 491 and 257 were treated with 3D-CRT and IMRT, respectively. For both bladder and rectum, the volumes receiving 65, 70, and 75 Gy were significantly lower with IMRT (all P<.0001). For grade (G) 2+ acute gastrointestinal/genitourinary (GI/GU) toxicity, both univariate and multivariate analyses showed a statistically significant decrease in G2+ acute collective GI/GU toxicity for IMRT. There were no significant differences with 3D-CRT or IMRT for acute or late G2+ or 3+ GU toxicities. Univariate analysis showed a statistically significant decrease in late G2+ GI toxicity for IMRT (P=.039). On multivariate analysis, IMRT showed a 26% reduction in G2+ late GI toxicity (P=.099). Acute G2+ toxicity was associated with late G3+ toxicity (P=.005). With dose-volume histogram data in the multivariate analysis, RT modality was not significant, whereas white race (P=.001) and rectal V70 ?15% were associated with G2+ rectal toxicity (P=.034).Intensity modulated RT is associated with a significant reduction in acute G2+ GI/GU toxicity. There is a trend for a clinically meaningful reduction in late G2+ GI toxicity with IMRT. The occurrence of acute GI toxicity and large (>15%) volumes of rectum >70 Gy are associated with late rectal toxicity.
Project description:Purpose:There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome. Methods and materials:This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0. Results:The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3?ng/mL (range, <0.01-55.4). The vast majority of patients (87%) received elective pelvic nodal irradiation (median dose: 45?Gy). Androgen deprivation therapy (ADT) was given to 39% of patients for a median of 9 months. Five-year biochemical progression-free survival and distant metastasis-free survival were 59% (95% confidence interval, 53%-66%) and 89% (95% confidence interval, 85%-93%), respectively. On multivariate analysis, higher pre-RT PSA (>0.2?ng/mL), biopsy Gleason score (?7 [4+3]), and duration of ADT (>6 months) were significantly associated (P < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively. Conclusion:Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.
Project description:Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ?5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients.All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men.Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05).NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.
Project description:The management of biochemical failure (BF) following external beam radiotherapy (EBRT) for prostate cancer is controversial, due to both the heterogeneous disease course following a BF and a lack of clinical trials in this setting.We sought to characterize the natural history and predictors of outcome for patients experiencing BF in a large cohort of men with localized prostate cancer undergoing definitive dose-escalated EBRT.This retrospective analysis included 2694 patients with localized prostate cancer treated with EBRT at a large academic center. Of these, 609 experienced BF, defined as prostate-specific antigen (PSA) nadir + 2 ng/ml. The median follow-up was 83 mo for all patients and 122 mo for BF patients.All patients received EBRT at doses of 75.6-86.4 Gy.The primary objective of this study was to determine predictors of distant progression at the time of BF. Cox proportional hazards models were used in univariate and multivariate analyses of distant metastases (DM), and a competing risks method was used to analyze prostate cancer-specific mortality (PCSM).From the date of BF, the median times to DM and PCSM mortality were 5.4 yr and 10.5 yr, respectively. Shorter posttreatment PSA doubling time, a higher initial clinical tumor stage, a higher pretreatment Gleason score, and a shorter interval from the end of radiotherapy to BF were independent predictors for clinical progression following BF. Patients with two of these risk factors had a significantly higher incidence of DM and PCSM following BF than those with zero or one risk factor. The main limitations of this study are its retrospective nature and heterogeneous salvage interventions.Clinical and pathologic factors can help identify patients at high risk of clinical progression following BF.In this report, we look at predictors of outcome for patients with prostate cancer recurrence, as determined by prostate-specific antigen (PSA) levels, following radiation treatment. We found that the approximate median times to distant metastasis and death from prostate cancer for patients in this situation were 5 yr and 10 yr, respectively. Furthermore, we found that patients with a rapid increase in PSA levels following treatment, a short time to PSA recurrence, invasion of extraprostatic organs, or a high Gleason score had worse outcomes.
Project description:Dose escalation may improve curability in intermediate-risk prostate carcinoma. A multicenter national program was developed to assess toxicity and tumor response with hypofractionated stereotactic boost after conventional radiotherapy in intermediate-risk prostate cancer.Between August 2010 and April 2013, 76 patients with intermediated-risk prostate carcinoma were included in the study. A first course delivered 46 Gy by IMRT (68.4% of patients) or 3D conformal radiotherapy (31.6% of patients). The second course delivered a boost of 18 Gy (3x6Gy) within 10 days. Gastrointestinal (GI) and genitourinary (GU) toxicities were evaluated as defined by NCI-CTCAE (v4.0). Secondary outcome measures were local control, overall and metastasis-free survival, PSA kinetics, and patient functional status (urinary and sexual) according to the IIEF5 and IPSS questionnaires.The overall treatment time was 45 days (median, range 40-55). Median follow-up was 26.4 months (range, 13.6-29.9 months). Seventy-seven per cent (n = 58) of patients presented a Gleason score of 7. At 24 months, biological-free survival was 98.7% (95% CI, 92.8-99.9%) and median PSA 0.46 ng/mL (range, 0.06-6.20 ng/mL). Grade ?2 acute GI and GU toxicities were 13.2% and 23.7%, respectively. Grade ?2 late GI and GU toxicities were observed in 6.6% and 2.6% of patients, respectively. No grade 4 toxicity was observed.Hypofractionated stereotactic boost is effective and safely delivered for intermediate-risk prostate carcinoma after conventional radiation. Mild-term relapse-free survival and tolerance results are promising, and further follow-up is warranted to confirm the results at long term.ClinicalTrials.gov NCT01596816.
Project description:No direct comparisons between extreme hypofractionation and conventional fractionation have been reported in randomized trials for the treatment of localized prostate cancer. The goal of this study is to use a propensity score matched (PSM) analysis with the National Cancer Database (NCDB) for the comparison of stereotactic body radiation therapy (SBRT) and intensity modulated radiation therapy (IMRT) for organ confined prostate cancer.Men with localized prostate cancer treated with radiation dose ?72?Gy for IMRT and ?35?Gy for SBRT to the prostate only were abstracted from the NCDB. Men treated with previous surgery, brachytherapy, or proton therapy were excluded. Matching was performed to eliminate confounding variables via PSM. Simple 1-1 nearest neighbor matching resulted in a matched sample of 5,430 (2,715 in each group). Subset analyses of men with prostate-specific antigen (PSA)?>?10, GS?=?7, and GS?>?7 yielded matched samples of 1,020, 2,194, and 247, respectively.No difference in survival was noted between IMRT and SBRT at 8?years (p?=?0.65). Subset analyses of higher risk men with PSA?>?10 or GS?=?7 histology or GS?>?7 histology revealed no difference in survival between IMRT and SBRT (p?=?0.58, p?=?0.68, and p?=?0.62, respectively). Variables significant for survival for the matched group included: age (p?<?0.0001), primary payor (p?=?0.0001), Charlson/Deyo Score (p?=?0.0002), PSA (p?=?0.0013), Gleason score (p?<?0.0001), and use of hormone therapy (p?=?0.02).Utilizing the NCDB, there is no difference in survival at 8?years comparing IMRT to SBRT in the treatment of localized prostate cancer. Subset analysis confirmed no difference in survival even for intermediate- and high-risk patients based on Gleason Score and PSA.
Project description:<h4>Importance</h4>Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear.<h4>Objectives</h4>To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools.<h4>Design, setting, and participants</h4>This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021.<h4>Exposures</h4>Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy.<h4>Main outcomes and measures</h4>PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index.<h4>Results</h4>Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database.<h4>Conclusions and relevance</h4>These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.
Project description:The aim of the study was to compare prostate cancer-specific mortality (PCSM) in young men with clinically localized prostate cancer treated by either external beam radiation (EBRT) alone or brachytherapy with or without external beam radiation.Utilizing the Surveillance, Epidemiology and End Results database, 15,505 patients ?60 years of age diagnosed with prostate cancer between 2004 and 2009 and treated with radiation therapy alone were identified. Incidence of PCSM was determined for both groups and compared using competing risk models.The overall 8-year PCSM for the study population was 1.9% (95% confidence interval [CI]: 1.6-2.2). For patients treated with EBRT or brachytherapy with or without external beam, the 8-year PCSM was found to be 2.8% (CI: 2.2-3.4) and 1.2% (CI: 0.9-1.6), respectively (p < 0.001). Univariable analysis demonstrated that brachytherapy was associated with lower PCSM risk (hazard ratio = 0.40; CI: 0.30-0.54; p < 0.001). High Gleason risk category, black race, higher Tumor (T) stage, and higher grade were all associated with greater mortality risk (p < 0.01). On multivariable analysis, brachytherapy continued to be associated with a significantly lower mortality risk (hazard ratio = 0.65; CI: 0.47-0.89; p = 0.008). Subgroup analyses found that among those with Gleason score ?8, younger patients had increased risk of PCSM (p = 0.001).In men ?60 years of age with prostate cancer, radiation therapy continues to offer excellent outcomes. After adjusting for relevant variables, the use of brachytherapy was associated with reduced PCSM compared to treatment with EBRT alone.