Faculty Bibliography

PURPOSE/OBJECTIVE:To analyze the effect of primary Gleason (pG) grade among a large cohort of Gleason 7 prostate cancer patients treated with external beam radiation therapy (EBRT). METHODS AND MATERIALS/METHODS:From May 1989 to January 2011, 1190 Gleason 7 patients with localized prostate cancer were treated with EBRT at a single institution. Of these patients, 613 had a Gleason 7 with a minimum of a sextant biopsy with nonfragmented cores and full biopsy core details available, including number of cores of cancer involved, percentage individual core involvement, location of disease, bilaterality, and presence of perineural invasion. Median follow-up was 6 years (range, 1-16 years). The prognostic implication for the following outcomes was analyzed: biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific mortality (PCSM). RESULTS:The 8-year bRFS rate for pG3 versus pG4 was 77.6% versus 61.3% (P<.0001), DMFS was 96.8% versus 84.3% (P<.0001), and PCSM was 3.7% versus 8.1% (P=.002). On multivariate analysis, pG4 predicted for significantly worse outcome in all parameters. Location of disease (apex, base, mid-gland), perineural involvement, maximum individual core involvement, and the number of Gleason 3+3, 3+4, or 4+3 cores did not predict for distant metastases. CONCLUSIONS:Primary Gleason grade 4 independently predicts for worse bRFS, DMFS, and PCSM among Gleason 7 patients. Using complete core information can allow clinicians to utilize pG grade as a prognostic factor, despite not having the full pathologic details from a prostatectomy specimen. Future staging and risk grouping should investigate the incorporation of primary Gleason grade when complete biopsy core information is used.

BACKGROUND:In vitro data and early clinical results suggest that metformin has desirable antineoplastic effects and has a theoretical benefit on castration-resistant prostate cancer (CRPC). OBJECTIVE:To determine whether the use of metformin would be associated with improved clinical outcomes and a reduction in the development of CRPC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Data from 2901 consecutive patients (157 metformin, 162 diabetic non-metformin, and 2582 nondiabetic) with localized prostate cancer treated with external-beam radiation therapy from 1992 to 2008 were collected from a single institution in the United States. INTERVENTION/METHODS:Use of metformin in localized prostate cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:Univariate and multivariate regression models utilizing k-sample, Fine and Gray, Cox regression, log-rank, and Kaplan-Meier methods to assess prostate-specific antigen-recurrence-free survival (PSA-RFS), distant metastases-free survival (DMFS), prostate cancer-specific mortality (PCSM), overall survival (OS), and development of CRPC. RESULTS AND LIMITATIONS/CONCLUSIONS:With a median follow-up of 8.7 yr, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic patients for PCSM were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 0.001), respectively. Metformin use independently predicted (correcting for PSA, T stage, Gleason score, age, diabetic status, and androgen-deprivation therapy use) improvement in all outcomes compared with the diabetic non-metformin group; PSA-RFS (hazard ratio [HR]: 1.99 [1.24-3.18]; p=0.004), DMFS (adjusted HR: 3.68 [1.78-7.62]; p<0.001), and PCSM (HR: 5.15 [1.53-17.35]; p=0.008). Metformin use was also independently associated with a decrease in the development of CRPC in patients experiencing biochemical failure compared with diabetic non-metformin patients (odds ratio: 14.81 [1.83-119.89]; p=0.01). The retrospective study design was the primary limitation of the study. CONCLUSIONS:To our knowledge, our results are the first clinical data to indicate that metformin use may improve PSA-RFS, DMFS, PCSM, OS, and reduce the development of CRPC in prostate cancer patients. Further validation of metformin's potential benefits is warranted.

PURPOSE/OBJECTIVE:We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. METHODS AND MATERIALS/METHODS:The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. RESULTS:The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. CONCLUSIONS:Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

PURPOSE/OBJECTIVE: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. METHODS AND MATERIALS/METHODS: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). RESULTS: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. CONCLUSIONS: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.

PURPOSE:To test the feasibility of using proposed quality indicators to assess radiotherapy quality in prostate cancer management based on a 2007 stratified random survey of treating academic and non-academic US institutions. METHODS AND MATERIALS:414 patients with clinically localized prostate cancer treated with external beam radiotherapy (EBRT) or brachytherapy were selected from 45 institutions. Indicators used as specific measurable clinical performance measures to represent surrogates for quality of radiotherapy delivery included established measures, such as the use of prescription doses ≥75 Gy for intermediate- and high-risk EBRT patients and androgen-deprivation therapy (ADT) in conjunction with EBRT for patients with high-risk disease, and emerging measures, including daily target localization (image-guidance) to correct for organ motion for EBRT patients. RESULTS:167 patients (47%) were treated with 6 MV photons, 31 (9%) were treated with 10 MV, 65 (18%) received 15 MV, and the remaining 90 (26%) 16-23 MV. For intermediate- plus high-risk patients (n=181), 78% were treated to ≥75 Gy. Among favorable-risk patients, 72% were treated to ≥75 Gy. Among high-risk EBRT patients, 60 (87%) were treated with ADT in conjunction with EBRT and 13% (n=9) with radiotherapy alone. Among low- and intermediate-risk patients, 10% and 42%, respectively, were treated with ADT plus EBRT. For 24% of EBRT patients (85/354), weekly electronic portal imaging was obtained as verification films without daily target localization and the remaining 76% were treated with daily localization of the target using various methods. CONCLUSIONS:Adherence to defined quality indicators was observed in a majority of patients. ≈90% of high-risk patients are treated with ADT plus EBRT and ≈80% of intermediate- and high-risk patients receive prescription doses >=75 Gy, consistent with the published results of randomized trials.

PURPOSE/OBJECTIVE:Intraoperative radiation therapy (IORT) allows delivery of tumoricidal doses of radiation to areas of potential residual microscopic disease while minimizing doses to normal tissues. IORT using high-dose-rate (HDR) brachytherapy allows dose modulation and delivery of concomitant boosts to high-risk areas. This study describes a novel technique of HDR-IORT with dose painting (DP) (HDR-IORT-DP) and evaluates the clinical outcomes. METHODS AND MATERIALS/METHODS:Sixteen patients with recurrent cancers received HDR-IORT-DP at the time of radical resection. Of these patients, 13 had colorectal cancer, 2 had head and neck cancer, and 1 had a gynecologic malignancy. All received external beam radiation previously. Negative margin (R0) was obtained in 12 patients (75%) and microscopically positive margins (R1) in 4 patients (25%). RESULTS:The median total target and boost area were 45 and 8.5cm(2), and HDR-IORT and boost dose were 1500 and 1750cGy, respectively. Median followup was 14.9 months. The 2-year local control and overall survival were 80% and 20%, respectively. Eleven patients (69%) developed distant metastasis and were deceased at the time of the last followup. A total of 13 patients (19%) developed Grade 3 toxicity related to HDR-IORT; no grade 4+ toxicities were observed. CONCLUSIONS:HDR-IORT-DP technique is feasible, safe, and allows for dose escalation in locally advanced or recurrent previously irradiated tumors. To our knowledge, this is the first clinical report on HDR-IORT-DP. Further studies are warranted to evaluate efficacy in a larger patient cohort. Local control was encouraging in our patients.

PURPOSE/OBJECTIVE:We report on quality of dose delivery to target and normal tissues from low-dose-rate prostate brachytherapy using postimplantation dosimetric evaluations from a random sample of U.S. patients. METHODS AND MATERIALS/METHODS:Nonmetastatic prostate cancer patients treated with external beam radiotherapy or brachytherapy in 2007 were randomly sampled from radiation oncology facilities nationwide. Of 414 prostate cancer cases from 45 institutions, 86 received low-dose-rate brachytherapy. We collected the 30-day postimplantation CT images of these patients and 10 test cases from two other institutions. Scans were downloaded into a treatment planning system and prostate/rectal contours were redrawn. Dosimetric outcomes were reanalyzed and compared with calculated outcomes from treating institutions. RESULTS:Median prostate volume was 33.4cm(3). Reevaluated median V(100), D(90), and V(150) were 91.1% (range, 45.5-99.8%), 101.7% (range, 59.6-145.9%), and 53.9% (range, 15.7-88.4%), respectively. Low gland coverage included 27 patients (39%) with a D(90) lower than 100% of the prescription dose (PD), 12 of whom (17% of the entire group) had a D(90) lower than 80% of PD. There was no correlation between D(90) coverage and prostate volume, number of seeds, or implanted activity. The median V(100) for the rectum was 0.3cm(3) (range, 0-4.3cm(3)). No outcome differences were observed according to the institutional strata. Concordance between reported and reevaluated D(90) values (defined as within ±10%) was observed in 44 of 69 cases. CONCLUSIONS:Central review of postimplantation CT scans to assess the quality of prostate brachytherapy is feasible. Most patients achieved excellent dosimetric outcomes, yet 17% had less than optimal target coverage by the PD. There was concordance between submitted target-coverage parameters and central dosimetric review in 64% of implants. These findings will require further validation in a larger cohort of patients.

PURPOSE/OBJECTIVE:To report prostate-specific antigen (PSA) relapse-free survival and treatment-related toxicity outcomes after combining high-dose-rate (HDR) brachytherapy with external beam radiotherapy (EBRT) for patients with clinically localized prostate cancer. METHODS AND MATERIALS/METHODS:Between 1998 and 2009, 229 patients were treated with HDR brachytherapy followed 3 weeks later by supplemental EBRT. The HDR brachytherapy boost consisted of three fractions of (192)Ir (5.5-7.5Gy per fraction), and EBRT consisted of intensity-modulated radiotherapy delivering an additional 45.0-50.4Gy directed to the prostate gland and seminal vesicles. Median follow-up was 61 months. RESULTS:Seven-year PSA relapse-free survival for low-, intermediate-, and high-risk patients were 95%, 90%, and 57%, respectively (p<0.001). Among high-risk patients treated with biological equivalent doses in excess of 190Gy, 7-year PSA relapse-free survival was 81%. In multivariate analysis, Gleason scores of ≥8 predicted for increased risk of biochemical failure, whereas the use of short-term neoadjuvant androgen deprivation therapy did not influence tumor-control outcomes even among intermediate- or high-risk patients. Seven-year incidence of distant metastases for low-, intermediate-, and high-risk patients were 5%, 3%, and 17%, respectively. Seven-year incidence of late Grade 2 and 3 genitourinary toxicities were 22.1% and 4.9%, respectively and the 7-year incidence of Grade 2 and 3 gastrointestinal toxicities were 1% and 0.4%, respectively. CONCLUSION/CONCLUSIONS:HDR prostate brachytherapy in conjunction with supplemental EBRT results in excellent biochemical relapse-free survival rates with a low incidence of severe late genitourinary or gastrointestinal toxicities. The use of short-term neoadjuvant androgen deprivation did not influence long-term biochemical tumor control in this cohort.