Faculty Bibliography

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.

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.

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.

PURPOSE/OBJECTIVE:We report the toxicity and biochemical tumor control outcome of a prospective Phase II study using high-dose-rate brachytherapy (HDR) alone as a salvage therapy for recurrent disease after external beam radiotherapy (EBRT). METHODS:Forty-two patients with biopsy-proven recurrence were enrolled on a Phase II study of salvage HDR monotherapy using iridium-192. Median pretreatment EBRT dose was 8100 cGy (6840-8640 cGy) and the median time from completion of EBRT to salvage HDR was 73 months. The protocol prescription dose of 3200 cGy was delivered in four fractions over 30 hours in a single insertion. Median followup after salvage HDR was 36 months (6-67 months). RESULTS:The actuarial prostate-specific antigen biochemical relapse-free survival and distant metastases-free survival rates at 5 years were 68.5% and 81.5%, respectively. Cause-specific survival was 90.3%. Late genitourinary Grade 1and 2 toxicities were found in 38% and 48%, respectively, and one patient developed Grade 3 urinary incontinence. Late Grade 1 and 2 gastrointestinal toxicity was noted in 17% and 8% of patients, respectively. Three patients (7%) developed Grade 2 late urinary toxicity (urethral stricture), which were corrected with urethral dilatation, and one patient developed Grade 3 urinary incontinence. No Grade 4 toxicities were observed. CONCLUSIONS:Genitourinary toxicity was the most commonly encountered toxicity observed after salvage HDR but severe toxicities were uncommon. Salvage HDR is an effective and well-tolerated modality for locally recurrent prostate cancer and should be considered even for patients who have previously been treated with ultra-high dose levels of EBRT.

Prostate cancer survivors approach 2.8 million in number and represent 1 in 5 of all cancer survivors in the United States. While guidelines exist for timely treatment and surveillance for recurrent disease, there is limited availability of guidelines that facilitate the provision of posttreatment clinical follow-up care to address the myriad of long-term and late effects that survivors may face. Based on recommendations set forth by a National Cancer Survivorship Resource Center expert panel, the American Cancer Society developed clinical follow-up care guidelines to facilitate the provision of posttreatment care by primary care clinicians. These guidelines were developed using a combined approach of evidence synthesis and expert consensus. Existing guidelines for health promotion, surveillance, and screening for second primary cancers were referenced when available. To promote comprehensive follow-up care and optimal health and quality of life for the posttreatment survivor, the guidelines address health promotion, surveillance for prostate cancer recurrence, screening for second primary cancers, long-term and late effects assessment and management, psychosocial issues, and care coordination among the oncology team, primary care clinicians, and nononcology specialists. A key challenge to the development of these guidelines was the limited availability of published evidence for management of prostate cancer survivors after treatment. Much of the evidence relies on studies with small sample sizes and retrospective analyses of facility-specific and population databases.