Unfavorable Intermediate-risk Research Articles

High-dose-rate brachytherapy monotherapy without androgen deprivation therapy for intermediate-risk prostate cancer

PurposeOutcomes using high-dose-rate (HDR) brachytherapy monotherapy (without androgen deprivation therapy or external beam radiation therapy) for National Comprehensive Cancer Network–defined intermediate-risk (IR) patients are limited. We report our long-term data using HDR monotherapy for this patient population. Methods and MaterialsOne-hundred ninety IR prostate cancer patients were treated 1996–2013 with HDR monotherapy. Biochemical prostate-specific antigen (PSA) failure was per the Phoenix definition. Acute and late genitourinary and gastrointestinal toxicities were graded according to Common Toxicity Criteria of Adverse Events, version 4. Kaplan–Meier (KM) biochemical progression-free survival (BPFS), cause-specific survival, and overall survival rates were calculated. Univariate analyses were performed to determine relationships with BPFS. The median patient age was 66 years (43–90), and the median initial PSA was 7.4 ng/mL. The Gleason score was ≤6 in 26%, 3 + 4 in 62%, and 4 + 3 in 12%. The median treatment BED1.5 was 254 Gy; 83% of patients were treated with a dose of 7.25 Gy × six fractions delivered in two separate implants. ResultsWith a median follow-up of 6.2 years, KM BPFS at 5/8 years was 97%/90%, cause-specific survival at 8 years was 100%, and overall survival at 5/8 years was 93%/88%. Late genitourinary toxicities were 36.3% Grade 1, 18.9% Grade 2, and 3.7% Grade 3. Late gastrointestinal toxicities were 6.3% Grade 1, 1.1% Grade 2, and no Grade ≥3. Of the patients with no sexual dysfunction before treatment, 68% maintained potency. Age, initial PSA, T stage, Gleason score, prostate volume, and percent positive cores did not correlate with BPFS. Stratifying by favorable vs. unfavorable IR groups did not affect BPFS. ConclusionsHDR brachytherapy monotherapy represents a safe and highly effective treatment for IR prostate cancer patients with long-term follow-up.

Image-guided high-dose-rate brachytherapy boost to the dominant intraprostatic lesion using multiparametric magnetic resonance imaging including spectroscopy: Results of a prospective study

PurposeTo evaluate the long-term outcomes of image-guided high-dose-rate (HDR) brachytherapy boost to the dominant intraprostatic lesion (DIL) using multiparametric magnetic resonance imaging (MRI), including spectroscopy (MRI/magnetic resonance spectroscopy [MRS]). Methods and MaterialsBetween December 2009 and March 2011, 20 patients with intermediate-risk prostate cancer underwent multiparametric MRI/MRS protocol before treatment. All patients were treated with an external beam radiotherapy dose of 40 Gy, combined with an HDR brachytherapy boost of 15 Gy. Concurrently, the DIL received a boost of 18 Gy. Missing data during followup were handled with multiple imputations. ResultsThe median followup was 62 months (range, 23–71 months). Six patients (31%) were classified as favorable intermediate risk and 13 patients (69%) as unfavorable intermediate risk. One patient experienced a prostate-specific antigen biochemical failure, and the 5-year biochemical failure-free survival rate was of 94.7%. The mean International Prostate Symptom Score rose from 7, with respect to baseline, to 10.42 1 month after treatment, and rapidly decreased to 6.97 after 3 months. Grade 1, 2, and 3 acute genitourinary toxicities were reported in 13 (68%), 3 (16%), and 1 (5%) patients, respectively. Grade 1 and 2 late genitourinary toxicities were reported in 9 (53%) and 3 (18%) patients, respectively. Only grade 1 acute and late gastrointestinal toxicities were reported in 4 (21%) and 3 (18%) patients, respectively. ConclusionsDelivering an HDR brachytherapy boost to the DIL using image-guided multiparametric MRI/MRS is feasible with good outcomes for biochemical control, acute and late toxicities, and dosimetric constraints for critical organs.

Predicting Biochemical Disease-Free Survival after Prostate Stereotactic Body Radiotherapy: Risk-Stratification and Patterns of Failure.

To determine appropriate risk-stratification factors for prostate cancer patients undergoing stereotactic body radiotherapy (SBRT). Between 2006 and 2010, 515 patients with organ-confined prostate cancer were treated with a regimen of five-fraction SBRT to dose of 35-36.25 Gy. By NCCN criteria, 324 patients were low risk, 153 were intermediate risk, and 38 were high risk. Patients were defined as unfavorable intermediate risk if Gleason 4 + 3 = 7 or >1 intermediate-risk factors (cT2b, c, PSA 10-20, Gleason 3 + 4 = 7). Cox regression analysis was used to determine risk factors significantly associated biochemical failure, and patterns of failure analyzed. With median follow-up of 84 months, the 8-year disease-free survival was 93.6, 84.3, and 65.0% for low, intermediate, and high-risk group patients, respectively. Based on the above definition, 106 favorable intermediate-risk patients had excellent outcomes, with no significant difference compared to low-risk patients (7-year DFS 95.2 vs. 93.2%, respectively). The 47 unfavorable intermediate-risk patients had worse outcomes, similar to high-risk patients (7-year DFS 68.2 vs. 65.0%, respectively). Gleason score was the only significant factor associated with biochemical failure on multivariate analysis (p = 0.0003). Patients with favorable intermediate-risk disease have excellent outcomes, comparable to low-risk patients. Patients with unfavorable intermediate-risk disease have significantly worse outcomes after SBRT, and should be considered for clinical trials or treatment intensification.

Variation in National Use of Long-Term ADT by Disease Aggressiveness Among Men With Unfavorable-Risk Prostate Cancer.

The current NCCN Clinical Practice Guidelines in Oncology for Prostate Cancer recommend long-term androgen deprivation therapy (ADT) for all men with high-risk prostate cancer treated with external-beam radiation therapy (EBRT). We determined whether the use of long-term ADT varied by the recently defined subcategories of high-risk disease (favorable, other, and very high) versus unfavorable intermediate-risk disease. We identified 5,524 patients with unfavorable-risk prostate cancer diagnosed from 2004 to 2007 and managed with EBRT using the SEER-Medicare linked database. Patients were stratified by risk group: unfavorable intermediate-risk, favorable high-risk (previously defined and validated as clinical stage T1c, Gleason score of 4 + 4 = 8, and prostate-specific antigen [PSA] level <10 ng/mL, or clinical stage T1c, Gleason score of 6, and PSA level >20 ng/mL), very-high-risk (clinical stage T3b-T4 or primary Gleason pattern 5), or other high risk (ie, neither favorable nor very high). We used multivariable competing risks regression to estimate the rates of long-term (≥2 years) ADT by group. Men with favorable high-risk prostate cancer were significantly less likely to receive long-term ADT than those with other high-risk disease (15.4% vs 24.6%, adjusted hazard ratio [AHR], 0.68; 95% CI, 0.60-0.76;P<.001), and similarly likely as those with unfavorable intermediate-risk disease (AHR, 1.10; 95% CI, 0.99-1.23;P=.087). Other high-risk disease was less likely to receive long-term ADT than very high-risk cancer (24.6% vs 30.8%; AHR, 0.83; 95% CI, 0.74-0.93;P=.002). Despite current guidelines, patients with EBRT-managed high-risk prostate cancer received significantly different rates of long-course ADT based on subclassification. Our results suggest that oncologists view these patients as a heterogeneous group with favorable high-risk cancer warranting less aggressive therapy than other high-risk or very high-risk disease.

Is supplemental external beam radiation therapy essential to maximize brachytherapy outcomes in patients with unfavorable intermediate-risk disease?

To evaluate whether supplemental external beam radiotherapy (EBRT) is essential to maximize Pd-103 brachytherapy outcomes in patients with unfavorable intermediate-risk (IR) disease. A total of 630 patients were assessed from two prospective randomized brachytherapy trials evaluating the role of supplemental EBRT in patients with higher risk features. Patients were stratified into unfavorable IR (primary Gleason pattern 4, ≥50% positive biopsies, or ≥2 IR features), favorable IR, and high-risk (HR) cohorts. Median follow-up was 7.5years. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a prostate-specific antigen >0.40ng/mL after nadir. Patients with metastatic prostate cancer or nonmetastatic castrate-resistant disease who died of any cause were classified as dead of prostate cancer. Multiple parameters were evaluated for effect on outcomes. The 10-year BF for favorable IR, unfavorable IR, and HR was 1.7%, 6.6%, and 15.5% (p < 0.001). At 10years, prostate cancer-specific mortality (PCSM) and overall mortality (OM) were 0% and 20.4%, 2.1% and 23.2%, and 4.3% and 42.4% for favorable IR, unfavorable IR, and HR. Although unfavorable IR patients had a greater incidence of BF, PCSM, and OM when compared with favorable IR, neither the addition nor dose of supplemental EBRT influenced outcome. Outcomes for favorable IR were superior to those with unfavorable IR. Within the confines of this study, neither the addition nor dose of supplemental EBRT influenced BF, PCSM, or OM in patients with IR disease.

Short-course androgen deprivation therapy and the risk of death from high-risk prostate cancer in men undergoing external beam radiation therapy and brachytherapy.

We estimated the risks of prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) in men with high-risk prostate cancer (PC) undergoing external beam radiation therapy and brachytherapy with short-course androgen deprivation therapy (ADT) (median 4 months) as compared with men with more favorable-risk PC undergoing standard of care as per the National Comprehensive Cancer Network guidelines. The prospective study cohort comprised 6595 consecutively treated men with T1-4 N0M0 PC whose treatment included brachytherapy between October 16, 1997, and May 28, 2013. Fine and Gray competing risk regression and Cox regression analyses were used to assess the risks of PCSM and ACM in men with high, unfavorable intermediate, and favorable intermediate risk as compared with low-risk PC. After median followup of 7.76 years, 820 men died (12.43%): 72 of PC (8.78%). Men with favorable intermediate-risk PC did not have significantly increased PCSM risk as compared with men with low-risk PC (adjusted hazard ratio [AHR], 1.26; 95% confidence interval [CI] 0.56, 2.88; p-Value 0.58), whereas men with high-risk PC (AHR, 3.74; 95% CI 1.12, 12.53; p-Value 0.032) and unfavorable intermediate-risk PC (AHR, 3.10; 95% CI 1.43, 6.72; p-Value 0.004) did. Based on 10-year adjusted point estimates of PCSM and ACM for men with high-risk PC being 6.01% (95% CI 3.79%, 8.94%) and 21.30% (95% CI 17.45%, 25.42%), respectively, PCSM comprised 28% of ACM. In the setting of external beam radiation therapy and brachytherapy, men with high-risk PC have low absolute adjusted estimates of PCSM (~6%) during the first decade after treatment despite receiving only short-course ADT. Whether long-term ADT can lower PCSM and improve survival in these men requires additional study.

Definition and Validation of “Favorable High-Risk Prostate Cancer”: Implications for Personalizing Treatment of Radiation-Managed Patients

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. 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. 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). 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.

Stratification of brachytherapy-treated intermediate-risk prostate cancer patients into favorable and unfavorable cohorts.

PurposeTo evaluate biochemical failure (BF) and prostate cancer specific mortality (PCSM) in intermediate-risk (IR) brachytherapy patients stratified into favorable and unfavorable cohorts, and to compare those outcomes to patients with low (LR) and high-risk (HR) disease.Material and methodsFrom March 1995 till February 2012, 2,502 consecutive patients underwent permanent interstitial brachytherapy for clinically localized prostate cancer. Patients were stratified into risk groups as per the NCCN guidelines with further stratification of the intermediate risk cohort into unfavorable (primary Gleason pattern 4, ≥ 50% positive biopsies or ≥ 2 IR features) and favorable cohorts. Median follow-up was 8.5 years. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure was defined as a PSA > 0.40 ng/ml after nadir. Patients with metastatic prostate cancer or non-metastatic castrate resistant disease who died of any cause were classified as dead of prostate cancer. Multiple parameters were evaluated for effect on outcomes.ResultsFifteen year BF for LR, favorable IR, unfavorable IR, and HR were 1.4%, 2.2%, 7.1%, and 11.1% (p < 0.001), respectively. At 15 years, PCSM for LR, favorable IR, unfavorable IR, and HR was 0.3%, 0.6%, 2.2% and 4.6% (p < 0.001), respectively. In multivariate analysis, BF was best predicted by risk group, pre-implant PSA, percent positive biopsies, prostate volume, and ADT duration, while PCSM was most closely related to risk group, percent positive biopsies and prostate volume.ConclusionsPatients with favorable IR disease have biochemical and PCSM outcomes comparable to those of patients with LR disease. Although unfavorable IR has greater than a 3-fold increased risk of BF and PCSM when compared to favorable IR, the outcomes remain superior to those men with HR disease.

Multiple Intermediate-Risk Factors as a Prognostic Tool for Men With Localized Prostate Cancer

Management of men with NCCN intermediate-risk (IR) prostate cancer (PCa) is controversial given the mixed nature of patients falling within the risk grouping. Efforts have been made to define an unfavorable-intermediate-risk (UIR) group [(i) primary Gleason pattern 4, (ii) percent of biopsy cores (PBC) with PCa ≥50%, or (iii) multiple NCCN IR factors] alongside a complementary favorable-intermediate-risk (FIR) group to aid in better prognostication and selection of therapy. Here we examine outcomes and variables important in the IR group of patients following definitive radiation therapy (RT).

A New Risk Classification System for Therapeutic Decision Making with Intermediate-risk Prostate Cancer Patients Undergoing Dose-escalated External-beam Radiation Therapy

BackgroundThe management of intermediate-risk prostate cancer (PCa) is controversial, in part due to the heterogeneous nature of patients falling within this classification. ObjectiveWe propose a new risk stratification system for intermediate-risk PCa to aid in prognosis and therapeutic decision making. Design, setting, and participantsBetween 1992 and 2007, 1024 patients with National Comprehensive Cancer Network intermediate-risk PCa and complete biopsy information were treated with definitive external-beam radiation therapy (EBRT) utilizing doses ≥81Gy. Unfavorable intermediate-risk (UIR) PCa was defined as any intermediate-risk patient with a primary Gleason pattern of 4, percentage of positive biopsy cores (PPBC) ≥50%, or multiple intermediate-risk factors (IRFs; cT2b–c, prostate-specific antigen [PSA] 10–20, or Gleason score 7). InterventionAll patients received EBRT with ≥81Gy with or without neoadjuvant and concurrent androgen-deprivation therapy (ADT). Outcome measurements and statistical analysisUnivariate and multivariate analyses were performed using a Cox proportional hazards model for PSA recurrence-free survival (PSA-RFS) and distant metastasis (DM). PCa-specific mortality (PCSM) was analyzed using a competing-risk method. Results and limitationsMedian follow-up was 71 mo. Primary Gleason pattern 4 (hazard ratio [HR]: 3.26; p<0.0001), PPBC ≥50% (HR: 2.72; p=0.0007), and multiple IRFs (HR: 2.20; p=0.008) all were significant predictors of increased DM in multivariate analyses. Primary Gleason pattern 4 (HR: 5.23; p<0.0001) and PPBC ≥50% (HR: 4.08; p=0.002) but not multiple IRFs (HR: 1.74; p=0.21) independently predicted for increased PCSM. Patients with UIR disease had inferior PSA-RFS (HR: 2.37; p<0.0001), DM (HR: 4.34; p=0.0003), and PCSM (HR: 7.39; p=0.007) compared with those with favorable intermediate-risk disease, despite being more likely to receive neoadjuvant ADT. Short follow-up and retrospective study design are the primary limitations. ConclusionsIntermediate-risk PCa is a heterogeneous collection of diseases that can be separated into favorable and unfavorable subsets. These groups likely will benefit from divergent therapeutic paradigms.