Faculty Bibliography

PURPOSE/OBJECTIVE:To investigate the association between statin use and prostate cancer outcomes in intermediate- and high-risk patients treated with brachytherapy for prostate cancer. METHODS AND MATERIALS/METHODS:Between 1998 and 2010, 754 men with National Comprehensive Cancer Network intermediate- (n = 627) and high-risk (n = 127) prostate cancer were treated with prostate brachytherapy at our institution. Patients received either low-dose-rate or high-dose-rate brachytherapy as monotherapy or in combination with supplemental external beam radiotherapy. Two hundred eighty-five patients (37.8%) also received androgen-deprivation therapy. Two hundred seventy-three men (36.2%) were identified as taking statin medication before initiating radiation therapy. Prostate-specific antigen relapse-free survival (PSA-RFS), distant metastasis-free survival (DMFS), and overall survival were compared using log-rank tests. Associations of patient and treatment characteristics with outcomes were analyzed with univariate and multivariate regression. The median followup was 48 months. RESULTS:The 8-year PSA-RFS for intermediate-risk, high-risk, and all patients was 92.2%, 64.1%, and 87.7%, respectively. The 8-year DMFS was 97.1%, 82.9%, and 94.9%, respectively. The 8-year overall survival for the entire cohort was 86.6%. There were no significant differences between statin users and nonusers when stratified by risk group, nor when analyzed as a full cohort. On multivariate analysis, Gleason score 4 + 3 = 7 and >7 were significantly associated with worse PSA-RFS (p ≤ 0.003 and <0.001, respectively). Gleason score > 7 (p = 0.008) and the use of neoadjuvant androgen-deprivation therapy (p = 0.03) was associated with worse DMFS. Statin use did not significantly impact PSA-RFS or DMFS. CONCLUSIONS:Pretreatment statin use is not associated with improved outcomes in intermediate- and high-risk patients undergoing prostate brachytherapy-based regimens for prostate cancer.

PURPOSE/OBJECTIVE:To identify an anatomic structure predictive for acute (AUT) and late (LUT) urinary toxicity in patients with prostate cancer treated with low-dose-rate brachytherapy (LDR) with or without external beam radiation therapy (EBRT). METHODS AND MATERIALS/METHODS:From July 2002 to January 2013, 927 patients with prostate cancer (median age, 66 years) underwent LDR brachytherapy with Iodine 125 (n=753) or Palladium 103 (n=174) as definitive treatment (n=478) and as a boost (n=449) followed by supplemental EBRT (median dose, 50.4 Gy). Structures contoured on the computed tomographic (CT) scan on day 0 after implantation included prostate, urethra, bladder, and the bladder neck, defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. AUT and LUT were assessed with the Common Terminology Criteria for Adverse Events, version4. Clinical and dosimetric factors associated with AUT and LUT were analyzed with Cox regression and receiver operating characteristic analysis to calculate area under the receiver operator curve (ROC) (AUC). RESULTS:Grade ≥2 AUT and grade ≥2 LUT occurred in 520 patients (56%) and 154 patients (20%), respectively. No grade 4 toxicities were observed. Bladder neck D2cc retained a significant association with AUT (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.03-1.04; P<.0001) and LUT (HR, 1.01; 95% CI, 1.00-1.03; P=.014) on multivariable analysis. In a comparison of bladder neck with the standard dosimetric variables by use of ROC analysis (prostate V100 >90%, D90 >100%, V150 >60%, urethra D20 >130%), bladder neck D2cc >50% was shown to have the strongest prognostic power for AUT (AUC, 0.697; P<.0001) and LUT (AUC, 0.620; P<.001). CONCLUSIONS:Bladder neck D2cc >50% was the strongest predictor for grade ≥2 AUT and LUT in patients treated with LDR brachytherapy. These data support inclusion of bladder neck constraints into brachytherapy planning to decrease urinary toxicity.

PURPOSE/OBJECTIVE:To assess outcomes and toxicity of high-dose-rate intraoperative radiation therapy (HDR-IORT) in the management of pediatric sarcoma. METHODS AND MATERIALS/METHODS:Seventy-five pediatric patients underwent HDR-IORT for sarcoma from May 1993 to November 2013. The median age was 9 years old (36 patients were ≤ 6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR-IORT and postoperative external beam RT (PORT), and 22 patients (29%) were previously treated with external beam radiation therapy to the IORT site. Local control (LC), overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier methods. RESULTS:At a median follow-up of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% confidence interval [CI] 50%-76%), 33% (95% CI 21%-45%), and 43% (95% CI 30%-55%), with a median survival of 3.1 years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28%-64%), 30% (95% CI, 13%-46%), and 36% (95% CI, 18%-54%). Acute toxicity ≥ grade 3 occurred in 2 (2.5%) treatments; late toxicity ≥ grade 3 occurred in 4 (5.3%) patients 0.3-9.9 years after HDR-IORT. The incidence of toxicity ≥ grade 3 was not associated with HDR-IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, but all toxicity ≥ grade 3 occurred in patients ≤ 6 years treated with HDR-IORT doses ≥ 12 Gy. CONCLUSIONS:HDR-IORT is a well-tolerated component of multimodality therapy for pediatric sarcoma, allowing additional local treatment while reducing external beam exposure. Taking clinical considerations into account, doses between 8-12 Gy are appropriate for HDR-IORT in patients ≤ 6 years of age.

OBJECTIVE:To compare tumour control and toxicity outcomes with the use of high-dose intensity-modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo-RT) for patients with intermediate-risk prostate cancer. PATIENTS AND METHODS/METHODS:Between 1997 and 2010, 870 consecutive patients with intermediate-risk prostate cancer were treated at our institution with either 86.4 Gy of IMRT alone (n = 470) or combo-RT consisting of brachytherapy combined with 50.4 Gy of IMRT (n = 400). Brachytherapy consisted of low-dose-rate permanent interstitial implantation in 260 patients and high-dose-rate temporary implantation in 140 patients. The median (range) follow-up for the entire cohort was 5.3 (1-14) years. RESULTS:For IMRT alone vs combo-RT, 7-year actuarial prostate-specific antigen (PSA)-relapse-free survival (PSA-RFS) rates were 81.4 vs 92.0% (P < 0.001), and distant metastases-free survival (DMFS) rates were 93.0 vs 97.2% (P = 0.04), respectively. Multivariate analysis showed that combo-RT was associated with better PSA-RFS (hazard ratio [HR], 0.40 [95% confidence interval, 0.24-0.66], P < 0.001), and better DMFS (HR, 0.41 [0.18-0.92], P = 0.03). A higher incidence of acute genitourinary (GU) grade 2 (35.8 vs 18.9%; P < 0.01) and acute GU grade 3 (2.3 vs 0.4%; P = 0.03) toxicities occurred in the combo-RT group than in the IMRT-alone group. Most acute toxicity resolved. Late toxicity outcomes were similar between the treatment groups. The 7-year actuarial late toxicity rates for grade 2 gastrointestinal (GI) toxicity were 4.6 vs 4.1% (P = 0.89), for grade 3 GI toxicity 0.4 vs 1.4% (P = 0.36), for grade 2 GU toxicity 19.4 vs 21.2% (P = 0.14), and grade 3 GU toxicity 3.1 vs 1.4% (P = 0.74) for the IMRT vs the combo-RT group, respectively. CONCLUSIONS:Enhanced dose escalation using combo-RT was associated with superior PSA-RFS and DMFS outcomes for patients with intermediate-risk prostate cancer compared with high-dose IMRT alone at a dose of 86.4 Gy. While acute GU toxicities were more prevalent in the combo-RT group, the incidence of late GI and GU toxicities was similar between the treatment groups.

PURPOSE/OBJECTIVE:We studied adjuvant daily sildenafil citrate during and after radiotherapy for prostate cancer for erectile function preservation. MATERIALS AND METHODS/METHODS:We performed a randomized, prospective trial of 279 patients with localized prostate cancer treated with radiotherapy who received sildenafil citrate (50 mg daily) or placebo (2:1 randomization). Medication/placebo was initiated 3 days before treatment and continued daily for 6 months. Before therapy and 3, 6, 9, 12, 18 and 24 months after radiotherapy patients completed the IIEF questionnaire, including the erectile function domain, the I-PSS questionnaire and the RAND SF-36®. All IIEF domains were scored. RESULTS:At 12 months erectile function scores were better for sildenafil citrate than placebo (p = 0.018), 73% of patients on sildenafil citrate vs 50% on placebo had mild/no erectile dysfunction (p = 0.024) and the sildenafil citrate arm had superior overall satisfaction (p = 0.027) and IIEF total scores (p = 0.043). At 24 months erectile function and IIEF scores were no longer significantly better for sildenafil citrate (p = 0.172 and 0.09, respectively) and yet overall satisfaction scores were higher (p = 0.033). Sexual desire scores in patients who received sildenafil citrate were higher at 24 months although they had completed drug therapy 18 months previously (p = 0.049). At 24 months 81.6% of patients on sildenafil citrate and 56.0% of those on placebo achieved functional erection with or without erectile dysfunction medication (p = 0.045). CONCLUSIONS:Daily sildenafil citrate during and after radiotherapy for prostate cancer was associated with improved overall sexual function compared with placebo for various sexual function domains. To our knowledge this is the largest randomized, prospective, controlled trial to show the usefulness of a phosphodiesterase-5 inhibitor as a rehabilitation strategy in patients with prostate cancer who received radiation therapy.

BACKGROUND:Fluorodeoxyglucose (FDG) positron emission tomography (PET) has well-characterized limitations in prostate adenocarcinoma (PCA). However, data assessing the utility of PET in neuroendocrine prostate cancer (NEPC) is limited to isolated case reports. Herein, we describe the first case series to assess the utility of FDG-PET in NEPC. METHODS:Inclusion criteria consisted of clinically progressive metastatic PCA in the setting of a chromogranin-A levels >1.5× the upper limit of normal, and ≥1 FDG-PET scan after the diagnosis of NEPC, which yielded 23 patients. All metastatic lesions on CT, PET, and bone scan were read by two independent physicians. RESULTS:Five hundred ninety two unique lesions were identified across all imaging modalities, 510 were bone metastases, and 82 were soft tissue metastases. Of bone lesions, 22.2%, 92.7%, and 77.6% were detected by PET, CT, and bone scan, respectively. Of soft tissue lesions, 95.1% and 97.5% were detected by PET and CT, respectively. Stratified by the median survival from NEPC diagnosis, patients who survived <2.2 versus ≥2.2 years had more PET avid bone (8 vs. 2, P = 0.06) and soft tissue lesions (7 vs. 1, P = 0.01), and higher average SUVmax of bone (5.49 vs. 3.40, P = 0.04) and soft tissue lesions (8.02 vs. 3.90, P = 0.0002). CONCLUSIONS:In patients with clinical NEPC, we demonstrate that FDG-PET has clinical utility in the detection of metastatic disease. In addition to detection, PET allows for treatment response to determine tumor viability. With novel therapies on the horizon to treat NEPC, consideration to investigate the use of FDG-PET to monitor response is warranted.

CONTEXT/BACKGROUND:Depending on the pathologic tumour stage, up to 60% of prostate cancer patients who undergo radical prostatectomy will develop biochemical relapse and require further local treatment. OBJECTIVES/OBJECTIVE:We reviewed the results of early salvage radiation therapy (RT), defined as prostate-specific antigen (PSA) values prior to RT ≤ 0.5 ng/ml in the setting of lymph node-negative disease. EVIDENCE ACQUISITION/METHODS:Ten retrospective studies, including one multicentre analysis, were used for this analysis. Among them, we received previously unpublished patient characteristics and updated outcome data from five retrospective single-centre trials to perform a subgroup analysis for early salvage RT. EVIDENCE SYNTHESIS/RESULTS:Patients treated with early salvage RT have a significantly improved biochemical recurrence-free survival (BRFS) rate compared with those receiving salvage RT initiated after PSA values are >0.5 ng/ml. Similarly, within the cohort of patients with pre-RT PSA values <0.5 ng/ml, improved BRFS rates were noted among those with lower rather higher pre-RT PSA levels. It is possible that higher RT dose levels and the use of adjunctive androgen-deprivation therapy improve biochemical control outcomes in the salvage setting. CONCLUSIONS:Based on a literature review, improved 5-yr BRFS rates are observed for patients who receive early salvage RT compared with patients treated with salvage RT with a pre-RT PSA value >0.5 ng/ml. Whether the routine application of early salvage RT in patients with initially undetectable PSA levels will be associated with demonstrable clinical benefit awaits the results of ongoing prospective trials.

PURPOSE/OBJECTIVE:To determine the potential association between genitourinary (GU) toxicity and planning dose-volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. METHODS AND MATERIALS/METHODS:A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose-volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. RESULTS:Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). CONCLUSIONS:The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.

PURPOSE/OBJECTIVE:To investigate the influence of treatment plan data and image guidance (IG) on positioning uncertainty during prostate cancer (PCa) radiotherapy (RT). METHODS:Body mass index (BMI), planning target volume (PTV), bladder volume (BV), and rectal cross section area (RCS) were collected for 267 consecutive PCa patients undergoing daily IGRT. Radiographic isocenter corrections to intra-prostatic fiducials for 12,490 treatment fractions were used to derive random (RE) and systematic (SE) inter-fraction uncertainties for the cardinal axes. These data were used to simulate RE and SE for weekly IG and Action Level (AL)-IG treatment protocols. RESULTS:SE and RE were 2-5 and 3-4mm in the cardinal axes, respectively, during simulation of no IG. Without IG, positive correlations (p<0.01) were noted for (1) anterior-posterior RE vs. RCS and BV and (2) cranio-caudal RE vs. RCS, BV and BMI. The RE increase was 3mm for the highest quartile of RCS, BV and BMI. Daily IGRT eliminated this relationship. 3D IG corrections of 1cm or more occured in 27% of treatment fractions and in 97% of patients. CONCLUSION/CONCLUSIONS:PCa patients with elevated pre-treatment BV, RCS and BMI have increased inter-fractionation positioning uncertainty and appear the primary candidates for daily IGRT.