Peter F. Orio

Incidence and Predictors of Upgrading and Up Staging among 10,000 Contemporary Patients with Low Risk Prostate Cancer

PURPOSE We determined the incidence of pathological upgrading and up staging for contemporary, clinically low risk patients, and identified predictors of having occult, advanced disease to inform the selection of patients for active surveillance. MATERIALS AND METHODS We studied 10,273 patients in the SEER database diagnosed with clinically low risk disease (cT1c/T2a, prostate specific antigen less than 10 ng/ml, Gleason 3 + 3 = 6) in 2010 to 2011 and treated with prostatectomy. The primary outcome was the incidence of upgrading to pathological Gleason score 7-10 or up staging to pathological T3-T4/N1 disease. Multivariable logistic regression of cases with complete biopsy data (5,581) identified significant predictors of upgrading or up staging, which were then used to create a risk stratification table. RESULTS At prostatectomy 44% of cases were upgraded and 9.7% were up staged. Multivariable analysis of 5,581 patients showed age, prostate specific antigen and percent positive cores (all p < 0.001) but not race were associated with occult, advanced disease. With these variables dichotomized at the median, age older than 60 years (AOR 1.39), prostate specific antigen greater than 5.0 ng/ml (AOR 1.28) and more than 25% positive cores (AOR 1.76) were significantly associated with upgrading (all p < 0.001). Similarly, age older than 60 years (AOR 1.42), prostate specific antigen greater than 5.0 ng/ml (AOR 1.44) and more than 25% positive cores (AOR 2.26) were associated with up staging (all p < 0.001). Overall 60% of 5,581 low risk cases with prostate specific antigen 7.5 to 9.9 ng/ml and more than 25% positive cores were upgraded. This study is limited by possible bias introduced by only using patients selected for prostatectomy. CONCLUSIONS Nearly half of clinically low risk patients harbor Gleason 7 or greater, or pT3 or greater disease, and should be risk stratified by prostate specific antigen and percent positive cores for consideration of further testing before deciding on active surveillance.

High-dose-rate brachytherapy for prostate cancer in a previously radiated patient with polyethylene glycol hydrogel spacing to reduce rectal dose: Case report and review of the literature

PURPOSE To describe the use of a temporary spacer to reduce rectal dose prior to prostate radiation in a man with prior pelvic radiotherapy and review the relevant literature. METHODS AND MATERIALS A healthy 57-year-old man presented with high-risk prostate cancer (Gleason score of 8, prostate-specific antigen level [PSA] 12.6 ng/mL, T3a by magnetic resonance imaging [MRI]), only 2.5 years after a low anterior resection followed by pelvic chemo-radiotherapy to 50.4 Gy for a locally advanced rectal cancer. Due to the prior radiation, he was not felt to be a candidate for surgery or external beam radiation, so he chose long-term androgen deprivation therapy (ADT) plus high-dose-rate brachytherapy to 36 Gy in 6 fractions. To reduce the radiation dose to the anterior rectal wall, 10 mL of a polyethylene glycol hydrogel spacer was injected between the prostate and rectum and created between 1.4 and 1.5 cm of separation along the length of the prostate. RESULTS Two randomized trials demonstrating that local therapy plus ADT improves overall survival compared to ADT alone provided the rationale for additional prostate radiotherapy in this otherwise healthy patient. Salvage brachytherapy is associated with a 3.4% rate of rectal fistula among the 251 cases reported in the literature from 2000-2007, with rates as high as 12% in one series. The spacer allowed the rectal dose constraint goals to be easily met. CONCLUSIONS Injecting an absorbable polyethylene glycol hydrogel to separate the prostate and rectum appears to be associated with decreased maximum and mean rectal doses, and may have particular utility in previously irradiated patients.

Use of a rectal spacer with low-dose-rate brachytherapy for treatment of prostate cancer in previously irradiated patients: Initial experience and short-term results.

BACKGROUND Salvage brachytherapy in patients with prior pelvic radiation carries a risk of rectal injury. Herein, we report our initial experience using a hydrogel spacer between the prostate and the rectum during salvage brachytherapy. METHODS AND MATERIALS A total of 11 patients with prostate cancer and prior radiotherapy (5 prostate brachytherapy, 2 prostate external beam radiation therapy [EBRT], and 4 rectal cancer EBRT) received (125)I brachytherapy after attempted placement of 10cc of a diluted hydrogel spacer between the prostate and rectum. RESULTS Spacing was achieved in 8 of the 11 (73%) patients but was not possible in 3 (1 prior brachytherapy and 2 prior EBRT) owing to fibrosis and adhesions. For the 8 patients in whom spacing was accomplished, the median space between the prostate and rectum was 10.9mm (prior EBRT) vs. 7.7mm (prior brachytherapy), p=0.048. Median followup was 15.7 months. One patient developed a prostato-rectal fistula requiring a diverting colostomy. The 16-month estimate of late Grade 3 or 4 gastrointestinal or genitourinary toxicity was 26%. One patient developed lymph node-positive recurrence. The 16-month prostate-specific antigen failure-free survival rate was 89%. Compared with baseline, Expanded Prostate Cancer Index Composite for Clinical Practice urinary quality of life (QoL) was significantly worse at 3 and 6 months but not significantly worse by 1 year. There were no significant changes throughout the study period in bowel or sexual QoL. CONCLUSION Hydrogel spacer placements may be feasible in most patients with prior pelvic radiation. Further followup is needed to determine whether spacer placement will produce long-term improvements in toxicity or QoL.

Who Bears the Greatest Burden of Aggressive Treatment of Indolent Prostate Cancer

PURPOSE The long-term prostate cancer-specific survival for patients initially managed with active surveillance for low-risk prostate cancer ranges from 97% to 100%. We characterized factors that are associated with aggressive treatment with radical prostatectomy or radiation for indolent prostate cancer (defined as screening-detected, low-risk disease). METHODS The Surveillance, Epidemiology, and End Results Program was used to extract a cohort of 39,803 men diagnosed with prostate-specific antigen-detected, low-risk prostate cancer (clinical category T1c, Gleason score ≤6, and prostate-specific antigen <10) from 2004 to 2010. After socioeconomic profiles were generated from county-linked education and income data, multivariable logistic regression was used to determine whether there were any factors associated with high rates of aggressive treatment. RESULTS The rate of aggressive treatment among all men with indolent prostate cancer was 64.3%. Greater rates of aggressive treatment were experienced by men with high socioeconomic status, Caucasian men, and married men (P < .001 for all cases). The increased adjusted odds for receipt of aggressive therapy were 1.25 (95% confidence interval [CI], 1.17-1.32; P < .001), 1.26 (95% CI, 1.21-1.32; P < .001), and 1.88 (95% CI, 1.80-1.97; P < .001) for men with high socioeconomic status, Caucasian men, and married men, respectively, compared with men with low socioeconomic status, non-Caucasian men, and unmarried men, respectively. CONCLUSIONS Although men with high socioeconomic status, Caucasian men, and married men often receive the highest quality health care and have the best outcomes for many cancers, it seems that they are most at risk for the avoidable potential harms of aggressive treatment of indolent prostate cancer. Future policy should encourage more stringent guidelines for deferred treatment and culturally and sociodemographically competent counseling of active surveillance.

Posttreatment Prostate Specific Antigen Nadir Predicts Prostate Cancer Specific and All Cause Mortality

PURPOSE We investigated whether the prostate specific antigen nadir predicts prostate cancer specific and all cause mortality in men treated in a randomized trial of radiation with or without 6 months of androgen deprivation therapy. MATERIALS AND METHODS The study included 204 men with cT1b-T2bN0M0 prostate adenocarcinoma and at least 1 unfavorable factor, including prostate specific antigen less than 10 to 40 ng/ml, Gleason 7 or greater, or T3 on magnetic resonance imaging. We performed Fine and Gray regression, and Cox multivariable analysis to determine whether an increasing prostate specific antigen nadir was associated with prostate cancer specific and all cause mortality, adjusting for treatment, age, Adult Comorbidity Evaluation 27 score and cancer prognostic factors. RESULTS At a 6.9-year median followup median prostate specific antigen nadir was 0.7 ng/ml for radiation alone and 0.1 ng/ml for radiation plus androgen deprivation therapy. The prostate specific antigen nadir (adjusted HR 1.18/ng/ml increase, 95% CI 1.07-1.31, p=0.001) and Gleason 8 or greater (adjusted HR 8.05, 95% CI 1.01-64.05, p=0.049) significantly predicted increased prostate cancer specific mortality. Moderate/severe comorbidity carried a decreased risk (adjusted HR 0.13, 95% CI 0.02-0.96, p=0.045). Higher prostate specific antigen nadir (adjusted HR 1.10/ng/ml increase, 95% CI 1.04-1.17), older age (adjusted HR 1.10/year, 95% CI 1.04-1.15) and interaction between comorbidity score and randomization arm (each p<0.001) increased the all cause mortality risk. Men who achieved a prostate specific antigen nadir of the median value or less had lower estimated prostate cancer specific and all cause mortality at 7 years (3.7% vs 18.3%, p=0.0005 and 31.5% vs 55.0%, p=0.002). CONCLUSIONS Posttreatment prostate specific antigen nadir is significantly associated with the risk of prostate cancer specific and all cause mortality after radiation with or without androgen deprivation therapy. A suboptimal prostate specific antigen nadir may identify candidates for earlier intervention to prolong survival.

Utilization of biopsy-based genomic classifier to predict distant metastasis after definitive radiation and short-course ADT for intermediate and high-risk prostate cancer

Background:We examined the ability of a biopsy-based 22-marker genomic classifier (GC) to predict for distant metastases after radiation and a median of 6 months of androgen deprivation therapy (ADT).Methods:We studied 100 patients with intermediate-risk (55%) and high-risk (45%) prostate cancer who received definitive radiation plus a median of 6 months of ADT (range 3–39 months) from 2001–2013 at a single center and had available biopsy tissue. Six to ten 4 micron sections of the needle biopsy core with the highest Gleason score and percentage of tumor involvement were macrodissected for RNA extraction. GC scores (range, 0.04–0.92) were determined. The primary end point of the study was time to distant metastasis. Median follow-up was 5.1 years. There were 18 metastases during the study period.Results:On univariable analysis (UVA), each 0.1 unit increase in GC score was significantly associated with time to distant metastasis (hazard ratio: 1.40 (1.10–1.84), P=0.006) and remained significant after adjusting for clinical variables on multivariable analysis (MVA) (adjusted hazard ratio: 1.36 (1.04–1.83), P=0.024). The c-index for 5-year distant metastasis was 0.45 (95% confidence interval: 0.27–0.64) for Cancer of the Prostate Risk Assessment score, 0.63 (0.40–0.78) for National Comprehensive Cancer Network (NCCN) risk groups, and 0.76 (0.57–0.89) for the GC score. Using pre-specified GC risk categories, the cumulative incidence of metastasis for GC>0.6 reached 20% at 5 years after radiation (P=0.02).Conclusions:We believe this is the first demonstration of the ability of the biopsy-based GC score to predict for distant metastases after definitive radiation and ADT for intermediate- and high-risk prostate cancer. Patients with the highest GC risk (GC>0.6) had high rates of metastasis despite multi-modal therapy suggesting that they could potentially be candidates for treatment intensification and/or enrollment in clinical trials of novel therapy.

The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness

PURPOSE The Canadian Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized trial showed that brachytherapy boost reduces recurrence by 50% compared to dose-escalated radiation. We examined how men with identical inclusion criteria to the ASCENDE-RT trial were being treated in the United States. METHODS AND MATERIALS We used the National Cancer Database to identify prostate cancer patients treated with radiation from 2004 through 2012 who met the inclusion criteria of the ASCENDE-RT trial (intermediate-/high-risk prostate cancer, excluding patients with prostate-specific antigen >40 or tumor stage T3b/T4). The Mantel-Haenszel test was used to investigate the trend for type of radiation modality used over the study period. RESULTS A cohort of 156,411 patients was identified. Of those, 103,188 men (66%) were treated with external beam radiation therapy (EBRT) alone, 31,129 (20%) with brachytherapy alone, and 22,094 (14%) with EBRT plus brachytherapy. EBRT plus a brachytherapy boost demonstrated a significant decrease in utilization from 2004 to 2012 in both academic and nonacademic centers, declining from 15% to 8% in academic centers and from 19% to 11% in nonacademic centers (p-Value for trend <0.0001 for both). Academic centers were significantly less likely to use brachytherapy boost than nonacademic centers (adjusted odds ratio: 0.68; 95% confidence interval: 0.66-0.70; p-Value: <0.0001). CONCLUSIONS Radiation oncology practices have demonstrated a significant reduction in the use of brachytherapy boost from 2004 to 2012, and the lowest utilization was in academic centers. In light of the superior results demonstrated for brachytherapy boost by the ASCENDE-RT trial, it is unclear whether academic centers are prepared to train the next generation of residents in this critical modality.

20 Gy versus 44 Gy of supplemental external beam radiotherapy with palladium-103 for patients with greater risk disease: results of a prospective randomized trial.

PURPOSE The necessity of external beam radiotherapy (EBRT) as a supplement to prostate brachytherapy remains unknown. We report brachytherapy outcomes for patients with higher risk features randomized to substantially different supplemental EBRT regimens. METHODS AND MATERIALS Between December 1999 and June 2004, 247 patients were randomized to 20 Gy vs. 44 Gy EBRT followed by a palladium-103 boost (115 Gy vs. 90 Gy). The eligibility criteria included clinically organ-confined disease with Gleason score 7-10 and/or pretreatment prostate-specific antigen (PSA) level 10-20 ng/mL. The median follow-up period was 9.0 years. Biochemical progression-free survival (bPFS) was defined as a PSA level of ≤0.40 ng/mL after nadir. The median day 0 prescribed dose covering 90% of the target volume was 125.7%; 80 men received androgen deprivation therapy (median, 4 months). Multiple parameters were evaluated for their effect on bPFS. RESULTS For the entire cohort, the cause-specific survival, bPFS, and overall survival rates were 97.7%, 93.2%, and 80.8% at 8 years and 96.9%, 93.2%, and 75.4% at 10 years, respectively. The bPFS rate was 93.1% and 93.4% for the 20-Gy and 44-Gy arms, respectively (p = .994). However, no statistically significant differences were found in cause-specific survival or overall survival were identified. When stratified by PSA level of ≤10 ng/mL vs. >10 ng/mL, Gleason score, or androgen deprivation therapy, no statistically significant differences in bPFS were discerned between the two EBRT regimens. On multivariate analysis, bPFS was most closely related to the preimplant PSA and clinical stage. For patients with biochemically controlled disease, the median PSA level was <0.02 ng/mL. CONCLUSION The results of the present trial strongly suggest that two markedly different supplemental EBRT regimens result in equivalent cause-specific survival, bPFS, and overall survival. It is probable that the lack of benefit for a higher supplemental EBRT dose is the result of the high-quality brachytherapy dose distributions.

Seed-based ultrasound and fluoroscopy registration using iterative optimal assignment for intraoperative prostate brachytherapy dosimetry

Prostate brachytherapy involves permanent implantation of radioactive sources into the prostate gland. Since fluoroscopy and transrectal ultrasound (TRUS) imaging modalities currently complement each other by providing good visualization of seeds and soft tissue, respectively, the registration of these two imaging modalities could lead to the intraoperative dosimetry analysis of brachytherapy procedures, thus improving patient outcome and reducing costs. Although it is desirable to register TRUS and fluoroscopy images by using the implanted seeds as fiducial markers, an operator, based on our experience, can locate only a small fraction of implanted seeds in axial TRUS images. Therefore, to perform TRUS-fluoroscopy registration in a clinical setting, there is a need for (1) a new method that can reliably perform registration at low seed detection rates and (2) a new imaging technique to enhance the seed visibility. We previously developed iterative optimal assignment (IOA), which can perform registration at seed detection rates below 20%, to address the former. In this paper, we present a new TRUS acquisition method where we acquire images of the prostate by rotating the longitudinal transducer of a biplanar probe in the clockwise/counter-clockwise direction. We acquired post-implant fluoroscopy and TRUS images from 35 patients who underwent a seed implant procedure. The results show that the combined use of IOA and rotational images makes TRUS-fluoroscopy registration possible and practical, thus our goal of intraoperative dosimetry can be realized.

National trends and determinants of proton therapy use for prostate cancer: A National Cancer Data Base study.

In the current study, the authors sought to both characterize the national trends in proton therapy use for prostate cancer and determine the factors associated with receipt of this limited resource, using what to the best of their knowledge is the largest nationwide cancer registry.