Improved survival for patients with prostate cancer receiving high-dose-rate brachytherapy boost to EBRT compared with EBRT alone.

PURPOSE: High-dose-rate (HDR) brachytherapy boost is a treatment of intermediate- to high-risk prostate cancer, but long-term clinical outcome data are sparse. We report long-term survival and toxicity data in a cohort of patients treated in a single institution. METHODS: Between 1998 and 2004, 654 patients with localized prostate cancer received either 3-dimensional conformal radiotherapy (median 46 Gy) with an HDR (median 18 Gy in three fractions) boost ("3-D conformal radiotherapy [3DCRT] + HDR"; 215 patients) or 3DCRT alone ("3DCRT"; median 70 Gy; 439 patients) with curative intent. Men with National Comprehensive Cancer Network intermediate risk were offered neoadjuvant androgen deprivation and with high risk were also offered adjuvant androgen deprivation. Data collection included patient-reported outcome measures. RESULTS: The 3DCRT + HDR group was older (72.3 vs. 68.9 yrs), had higher presenting PSAs (iPSA) (15.66 and 12.57 ng/mL, respectively), higher proportion of Gleason scores >7 (15.3% vs. 12.4%), and higher proportions of extracapsular disease (29.3% vs. 25.5%). 3DCRT + HDR men had lower proportions of low-risk patients (3.3% vs. 19.4%) and higher proportions of high-risk patients (50.7% vs. 37.4%) than the 3DCRT group. The 5-, 10-, and 15-year overall survival was superior at 92%, 81%, and 67%, respectively, for the 3DCRT + HDR group, compared with 88%, 71%, and 53%, respectively, in the 3DCRT group (p < 0.001). The 5-, 10-, and 15-year cause specific survival also favored the HDR boost group with survival of 96%, 93%, and 87% (3DCRT + HDR) and 95% 88% and 79% (3DCRT), respectively (p < 0.037). CONCLUSIONS: HDR brachytherapy boost in conjunction with 3DCRT offered superior overall survival and cause-specific survival in our patient population.

An integrated system for clinical treatment verification of HDR prostate brachytherapy combining source tracking with pretreatment imaging.

PURPOSE: High-dose-rate (HDR) prostate brachytherapy treatment is usually delivered in one or a few large dose fractions. Poor execution of a planned treatment could have significant clinical impact, as high doses are delivered in seconds, and mistakes in an individual fraction cannot be easily rectified. Given that most potential errors in HDR brachytherapy ultimately lead to a geographical miss, a more direct approach to verification of correct treatment delivery is to directly monitor the position of the source throughout the treatment. In this work, we report on the clinical implementation of our treatment verification system that uniquely combines the 2D source-tracking capability with 2D pretreatment imaging, using a single flat panel detector (FPD). METHODS AND MATERIALS: The clinical brachytherapy treatment couch was modified to allow integration of the FPD into the couch. This enabled the patient to be set up in the brachytherapy bunker in a position that closely matched that at treatment planning imaging. An anteroposterior image was acquired of the patient immediately before treatment delivery and was assessed by the Radiation Oncologist online, to reestablish the positions of the catheters relative to the prostate. Assessment of catheter positions was performed in the left-right and superior-inferior directions along the entire catheter length and throughout the treatment volume. Source tracking was then performed during treatment delivery, and the measured position of the source dwells were directly compared to the treatment plan for verification. RESULTS: The treatment verification system was integrated into the clinical environment without significant change to workflow. Two patient cases are presented in this work to provide clinical examples of this system, which is now in routine use for all patient treatments in our clinic. The catheter positions were visualized relative to the prostate, immediately before treatment delivery. For one of the patient cases presented in this work, they agreed with the treatment plan on average by 1.5 mm and were identifiable as a predominantly inferior shift. The source tracking was performed during treatment delivery, and for the same case, the mean deviation from the planned dwell positions was 1.9 mm (max = 4.9 mm) for 280 positions across all catheters. CONCLUSION: We have implemented our noninvasive treatment verification system based on an FPD in the clinical environment. The device is integrated into a patient treatment couch, and the process is now included in the routine clinical treatment procedure with minor impact on workflow. The system which combines both 2D pretreatment imaging and HDR 2D source tracking provides a range of information that can be used for comprehensive treatment verification. The system has the potential to meaningfully improve safety standards by allowing widespread adoption of routine treatment verification in HDR brachytherapy.

Decline in acute urinary toxicities with increased institutional experience: 15-year experience of permanent seed prostate brachytherapy in a single Australasian institution.

PURPOSE: To evaluate the incidence of acute urinary toxicity after permanent seed prostate brachytherapy (BT) over a 15-year period. METHODS AND MATERIALS: The study consisted of 782 prostate cancer patients treated with BT. All patients completed self-administered International Prostate Symptoms Score (IPSS) at baseline and during regular follow-up. We evaluated the risk of acute urinary retention (AUR) up to 3 months post-BT and lower urinary tract symptom (LUTS) resolution (defined as return to within two points of baseline IPSS score) at regular intervals, up to 24 months post-BT. Univariate and multivariate logistic regressions were used to evaluate the effect of various patient, tumor, and treatment factors on the risk of AUR and the likelihood of LUTS resolution. RESULTS: Ninety-six patients (12%) developed AUR at a median of 1 day post-BT. Increased peak urinary flow is independently associated with lower risk of AUR (odds ratio [OR] = 0.94; 95% confidence interval [CI] = 0.91-0.97). Decline in incidence of AUR was observed over time with increased institutional experience (p = 0.03). Of the 646 patients with a minimum of 24-month follow-up, 29%, 49%, and 72% had LUTS resolution at 6, 12, and 24 months, respectively. Patients who had pre-BT transurethral resection of prostate (OR = 2.4; 95% CI = 1.5-4.0), cytoreductive neo-adjuvant androgen deprivation (OR = 2.0; 95% CI = 1.0-4.0), and higher baseline IPSS (OR = 1.1; 95% CI = 1.07-1.19) are more likely to report LUTS resolution at 24 months. CONCLUSIONS: We reported decline in AUR over time with increased institutional experience in one of the largest Australasian BT series. Approximately three-quarters of patients achieved LUTS resolution at 24-month follow-up.

Long-term outcomes following post-operative radiotherapy for Stage I/II testicular seminoma - an Australasian single-institution experience.

INTRODUCTION: The aim of the study is to review the long-term oncological outcomes and adverse effects of post-operative radiotherapy (PORT) for Stage I/II seminoma patients in an Australian radiation treatment centre. METHODS: This is a retrospective study of 125 patients with Stage I/II seminoma treated with PORT at the Alfred Health Radiation Oncology Service between 1992 and 2013. Patients were linked to the Victorian Cancer Registry to enable confirmation of survival and diagnosis of secondary malignancies (SM). The relapse-free survival (RFS), testicular-cancer-specific survival (TCSS), overall survival (OS) and SM-free survival (SMFS) were estimated with Kaplan-Meier methods. RESULTS: The median age at diagnosis was 36 (range 20-62). The median time between diagnosis and PORT was 1.6 months (range: 0.5-4.5). Fifty patients (40%) had PORT to the para-aortic (PA) target alone, while the remaining had PORT to PA and ipsilateral or bilateral iliac lymph nodes. There were no acute adverse effects requiring admission. The median follow-up after PORT was 7.8 years (range = 0.1-19.1). There were two relapses, both of which occurred within 1 year of PORT (estimated 10-year RFS = 98.4%). Five deaths were reported, none of which were testicular cancer-related death (estimated 10-year TCSS = 100%, 10-year OS = 97.3%). There were seven SM (one lower lip cancer, one upper shoulder melanoma, one mesothelioma, two prostate cancer, one acute myeloid leukaemia and one contralateral testicular seminoma) reported in six patients, with estimated 10-year SMFS of 92.9%. CONCLUSION: Our series confirms excellent oncological outcomes among patients with Stage I/II seminoma treated with PORT, with uncommon occurrence of SM.

Urethral strictures following high-dose-rate brachytherapy for prostate cancer: analysis of risk factors.

PURPOSE: High-dose-rate brachytherapy is an established technique to deliver a conformal dose of radiation to patients with prostate cancer. The William Buckland Radiotherapy Center has been performing high-dose-rate brachytherapy with external beam radiation treatment for prostate cancer since 1998 and has an extensive prospective database on all patients treated. The purpose of this analysis was to assess the risk of stricture formation and identify the predictive or causative factors. METHODS AND MATERIALS: Three hundred fifty-four patients were treated between 1998 and 2008. Patients received one of three differing dose schedules: 20Gy in four treatments (20Gy/4), 18Gy/3, and 19Gy/2 during three sequential time periods. Nelson-Aalen cumulative hazard modeling was used to estimate risk of events over time. Potential risk factors, including dose, were identified and used in the analysis. RESULTS: There were 45 patients who developed at least one stricture, an overall risk of 8.2% at 2 years. The 2-year risk of stricture formation was 3.4%, 2.3%, and 31.6% for 18Gy/3, 20Gy/4, and 19Gy/2, respectively. Most strictures occurred in the bulbomembranous urethra (50%) or external sphincter region (33%). On multivariable analysis, the dose schedule used was the only significant predictor for increased stricture formation. CONCLUSIONS: In our patients, those who received 19Gy/2 were at a significantly higher risk of stricture formation. Most of these strictures were mild, requiring only one intervention but a 2-year stricture risk of 31.6% was striking, and we have modified our protocol.

Prostate-specific antigen bounce after permanent iodine-125 prostate brachytherapy--an Australian analysis.

PURPOSE: To report on prostate-specific antigen (PSA) "bounces" after (125)I prostate brachytherapy to review the relationship to biochemical control and correlate both clinical and dosimetric variables. METHODS AND MATERIALS: We analyzed 194 hormone-naive patients with a follow-up of ≥ 3 years. Four bounce definitions were applied: an increase of ≥ 0.2 ng/mL (definition I), ≥ 0.4 ng/mL (definition II), ≥ 15% (definition III), and ≥ 35% (definition IV) of a previous value with spontaneous return to the prebounce level or lower. RESULTS: Using definition I, II, III, and IV, a bounce was detected in 50%, 34%, 11%, and 9% of patients, respectively. The median time to onset was 14-16 months, the duration was 12-21.5 months, and the magnitude of the increase was 0.5-2 ng/mL. A magnitude of >2 ng/mL, fulfilling the criteria for biochemical failure (BF) according to the American Society for Therapeutic Radiology and Oncology Phoenix definition, was detected in 11.3%, 16.9%, 47.6%, and 50% using definitions I, II, III, and IV, respectively; 11 patients (5.7%) had true BF. The PSA bounces occurred earlier than BF (p < 0.001). The prediction of BF remains controversial and is probably unrelated to biochemical control. The only statistically significant factor predictive of a PSA bounce was younger age (definitions I and II). CONCLUSION: PSA bounces are common after brachytherapy. All definitions resulted in a high number of false-positive calls for BF during the first 2 years. The definition of an increase of ≥ 0.2 ng/mL should be preferred because of the lowest number of false-positive results for BF. Patients experiencing a PSA bounce during the first 2 years after brachytherapy should undergo surveillance every 3-6 months. Additional investigations are recommended for elevated postimplant PSA levels that have not corrected by 3 years of follow-up.

High-dose-rate brachytherapy in combination with conformal external beam radiotherapy in the treatment of prostate cancer.

PURPOSE: To report long-term outcomes for treatment of prostate cancer using dose escalation with high-dose-rate (HDR) brachytherapy and 3-dimensional conformal external beam radiotherapy (3DCRT), and compare them with outcomes for treatment of prostate cancer with 3DCRT alone at the same institution. METHODS AND MATERIALS: From 1998 to 2003, 587 patients were treated for clinically localized prostate cancer. Patients received either 3DCRT (median, 46Gy) with a single HDR brachytherapy implant (196 patients) delivering a fractionated dose of 18Gy (combined group) or 3DCRT (median, 70Gy; 387 patients; "3DCRT alone"). There were 41.9% patients with intermediate-risk and 42.6% with high-risk disease. In all, 441 patients (75.1%) received neoadjuvant and 116 patients (19.8%) received adjuvant androgen deprivation therapy. The American Society of Therapeutic Radiology and Oncology Phoenix definition for biochemical failure was used. RESULTS: The median followup was 5.5 years. The 5- and 7-year biochemical control (BC) rates were 82.5% and 80.3%, respectively, for the combined group and 81.3% and 71%, respectively, for 3DCRT alone; for overall survival, they were 91.9% and 89.5% vs. 88.7% and 86.2%, respectively, whereas for cause-specific survival, they were 96.9% and 96.1% vs. 97.6% and 96.2%, respectively. Cox proportional hazard regression analysis for BC revealed that low Gleason grade, HDR brachytherapy combined with 3DCRT, and adjuvant androgen deprivation therapy were significant in predicting BC. Radiation Therapy Oncology Group Grade 3 late urinary and rectal morbidity rates were 7.1% and 0%, respectively. No Grade > or =4 reactions were detected. CONCLUSIONS: HDR brachytherapy combined with 3DCRT was associated with improved BC and minimal toxicity in patients with unfavorable prostate cancer compared with conventional 3DCRT.

Identification of a Cis-acting regulatory polymorphism in a Eucalypt COBRA-like gene affecting cellulose content.

Populations with low linkage disequilibrium (LD) offer unique opportunities to study functional variants influencing quantitative traits. We exploited the low LD in forest trees to identify functional polymorphisms in a Eucalyptus nitens COBRA-like gene (EniCOBL4A), whose Arabidopsis homolog has been implicated in cellulose deposition. Linkage analysis in a full-sib family revealed that EniCOBL4A is the most strongly associated marker in a quantitative trait locus (QTL) region for cellulose content. Analysis of LD by genotyping 11 common single-nucleotide polymorphisms (SNPs) and a simple sequence repeat (SSR) in an association population revealed that LD declines within the length of the gene. Using association studies we fine mapped the effect of the gene to SNP7, a synonymous SNP in exon 5, which occurs between two small haplotype blocks. We observed patterns of allelic expression imbalance (AEI) and differential binding of nuclear proteins to the SNP7 region that indicate that SNP7 is a cis-acting regulatory polymorphism affecting allelic expression. We also observed AEI in SNP7 heterozygotes in a full-sib family that is linked to heritable allele-specific methylation near SNP7. This study demonstrates the potential to reveal functional polymorphisms underlying quantitative traits in low LD populations.