Darren M. Mitchell

Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation.

PURPOSE To compare postprostatectomy clinical target volume (CTV) delineation before and after the introduction of a contouring protocol and to investigate its effect on interphysician variability METHODS AND MATERIALS Six site-specialized radiation oncologists independently delineated a CTV on the computed tomography (CT) scans of 3 patients who had received postprostatectomy radiotherapy. At least 3 weeks later this was repeated, but with the physicians adhering to the contouring protocol from the Medical Research Councils Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial. The volumes obtained before and after the protocol were compared and the effect of the protocol on interphysician variability assessed. RESULTS An increase in mean CTV for all patients of 40.7 to 53.9 cm(3) was noted as a result of observing the protocol, with individual increases in the mean CTV of 65%, 15%, and 24% for Patients 1, 2, and 3 respectively. A reduction in interphysician variability was noted when the protocol was used. CONCLUSIONS Substantial interphysician variation in target volume delineation for postprostatectomy radiotherapy exists, which can be reduced by the use of a contouring protocol. The RADICALS contouring protocol increases the target volumes when compared with those volumes typically applied at our center. The effect of treating larger volumes on the therapeutic ratio and resultant toxicity should be carefully monitored, particularly if the same dose-response as documented in radical prostate radiotherapy applies to the adjuvant and salvage setting. Prostate cancer, Postprostatectomy, Radiotherapy, Target volume.

Assessing the daily consistency of bladder filling using an ultrasonic Bladderscan device in men receiving radical conformal radiotherapy for prostate cancer

OBJECTIVE Consistency in target organ and organ at risk position from planning to treatment is an important basic principle of radiotherapy. This study evaluates the effectiveness of bladder-filling instructions in achieving a consistent and reproducible bladder volume at the time of planning CT and daily during the course of radical radiotherapy for prostate cancer. It also assessed the rate of bladder filling before and at the end of radiotherapy. METHODS 30 men attending for radiation therapy planning for prostate cancer received written and verbal bladder-filling instructions. They had their bladder volume assessed using a bladder ultrasound scanner post-void, immediately prior to planning CT scan and then daily immediately prior to treatment while in the therapy position. The inflow was calculated using the void and full bladder volumes and the time for the bladder to fill. RESULTS The mean bladder volume at the time of planning was 282 ml (range 89-608 ml, standard deviation (SD) = 144.5 ml). This fell during treatment, with a mean value for all treatments of 189 ml (range 11-781 ml, SD = 134 ml). During radiotherapy, 76% (828/1090), 53% (579/1090) and 36% (393/1090) of bladder volumes had >50 ml, >100 ml and >150 ml difference, respectively when compared with their volume at the time of planning. Inflow reduced from 4.6 ml min(-1), SD = 2.9 min(-1) at planning to 2.5 min(-1), SD = 1.8 min(-1) after radiotherapy. CONCLUSION The Bladderscan device (BVI 6400 Bladderscan, Verathon Medical UK, Sandford, UK) provides an effective means of assessing bladder volume prior to radiotherapy for prostate cancer. The evaluated bladder-filling protocol does not produce consistent, reproducible bladder volumes for radiotherapy.

Sector analysis of 125I permanent prostate brachytherapy provides a rapid and effective method of evaluating and comparing pre- and post-implant dosimetry

PURPOSE To evaluate a sector analysis program in the assessment and comparison of pre- and post-implant dosimetric parameters during the development of an (125)I permanent prostate brachytherapy service. METHODS AND MATERIALS A total of 50 consecutive men being treated with permanent prostate brachytherapy had dose-volume analysis in 12 sectors of their pre-implant ultrasound (USpre) and post-implant CT (CTpost) studies. Individual sectors were created by dividing prostate into three equal lengths, namely base, midgland, and apex. Each of these volumes was then divided into four axial sectors. Dosimetric parameters were compared in adjoining sectors within each study and between studies. RESULTS There were statistically significant differences between individual sectors on USpre and CTpost volumes with CTpost higher than USpre (p=0.001). Statistically significant differences were found in corresponding sectors on USpre and CTpost for all dosimetric parameters. The dosimetric parameters were significantly lower on CTpost in the anterior base and midgland (p=0.001) and significantly higher at the posterior apex and midgland (p=0.05). Dose homogeneity was demonstrated in adjoining sectors in all USpre and most adjoining sectors on CTpost. CONCLUSIONS Sector analysis allows rapid assessment of USpre and CTpost dosimetry. It offers a scientific method of identifying areas of increased and reduced dosing on CTpost when compared with USpre, providing a learning tool to refine dosimetric analysis and highlight sectors where implant quality could be improved.

Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy

Abstract Background Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35–7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11–6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22–8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52–6.77); P = 0.332]. A high concordance [100% (61.5–100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

UK & Ireland Prostate Brachytherapy Practice Survey 2014-2016

Purpose To document the current prostate brachytherapy practice across the UK and Ireland and compare with previously published audit results. Material and methods Participants from 25 centers attending the annual UK & Ireland Prostate Brachytherapy Conference were invited to complete an online survey. Sixty-three questions assessed the center’s experience and staffing, clinician’s experience, clinical selection criteria and scheduling, number of cases per modality in the preceding three years, low-dose-rate (LDR) pre- and post-implant technique and high-dose-rate (HDR) implant technique. Responses were collated, and descriptive statistical analysis performed. Results Eighteen (72%) centers responded with 17 performing LDR only, 1 performing HDR only, and 6 performing both LDR and HDR. Seventy-one percent of centers have > 10 years of LDR brachytherapy experience, whereas 71% centers that perform HDR brachytherapy have > 5 years of experience. Thirteen centers have 2 or more clinicians performing brachytherapy with 61% of lead consultants performing > 25 cases (LDR + HDR) in 2016. The number of implants (range), that includes LDR and HDR, performed by individual practitioners in 2016 was > 50 by 21%, 25-50 by 38%, and < 25 by 41%. Eight centers reported a decline in LDR monotherapy case numbers in 2016. Number of center’s performing HDR brachytherapy increased in last five years. Relative uniformity in patient selection is noted, and LDR pre- and post-implant dosimetry adheres to published quality guidelines, with an average post-implant D90 of > 145 Gy in 69% of centers in 2014 and 2015 compared to 63% in 2016. The median CT/US volume ratios were > 0.9 ≤ 1.0 (n = 4), > 1.0 ≤ 1.1 (n = 7), and > 1.1 (n = 2). Conclusion There is considerable prostate brachytherapy experience in the UK and Ireland. An apparent fall in LDR case numbers is noted. Maintenance of case numbers and ongoing compliance with published quality guidelines is important to sustain high quality outcomes.

Single institution, retrospective comparison of toxicity and outcome for static 5-field IMRT versus VMAT in the delivery of prostate and pelvic nodal irradiation in high-risk prostate cancer.

147 Background: There is emerging evidence for the role of pelvic nodal irradiation in high-risk prostate cancer. We have assessed the toxicity rates and outcomes with 2 different radiotherapy techniques. Methods: The baseline disease metrics, toxicity and outcome data for men treated at our institution with prostate and pelvic nodal irradiation during a 2 year period were retrospectively collected. The radiotherapy technique, either 5-field IMRT or VMAT was recorded along with a single dose-level to indicate normal tissue exposure (V50 to bowel and rectum, that is the percentage of total organ receiving ≥ 50Gy). Results: 67 men with a median age of 64 years were identified; 83.6% were Gleason ≥ 8, 82.1% were ≥ T3a, 50.7% were N1, 4.5% were M1a/M1b. All had neoadjuvant and concurrent hormone therapy. All received 74Gy to prostate; 70.1% received 60Gy to pelvic nodes, 28.4% received 55Gy to pelvic nodes (1 patient received 56Gy). 55.2% were treated with static IMRT and 44.8% with VMAT with no significant d...

A sector-based postimplant dosimetric comparison of sagittal and axial ultrasound-guided source placement during I-125 permanent prostate brachytherapy

262 Background: To use sector based pre- and postimplant dosimetric analysis to evaluate the effect of changes in implant technique in a developing I-125 permanent prostate brachytherapy program (PPB). Methods: 109 men treated with PPB were divided into two groups by implant technique. The first 50 patients (group 1) had needle-by-needle seed deposition under axial ultrasound (USS) guidance and subsequent 59 patients (group 2) having needle placement row-by-row then seed deposition under sagittal USS guidance. Twelve sector dose volume analysis of pre-implant ultrasound (USpre) and postimplant CT (CTpost) study was performed in all cases. Individual sectors were created by dividing the cranio-caudal prostate into three equal lengths creating prostate base, midgland and apex. Each of these volumes was then divided into four axial sectors (right and left anterior, right and left posterior). The difference in the minimum dose delivered to 90% of prostate volume (D90) and the prostate volume receiving 100%, 1...

Bicalutamide (150 mg) monotherapy versus LHRHa as neoadjuvant treatment in intermediate- and high-risk prostate cancer: A case matched study.

226 Background: The role of neo-adjuvant Lutenising Hormone Releasing Hormone Agonist (LHRHa) therapy prior to radical radiotherapy of intermediate and high risk prostate cancer (PC) has been clearly defined. Anti-androgen (AA) monotherapy is often used as an alternative to castration therapy in this setting due to a more favorable toxicity profile, however the evidence base is weaker. We compared biochemical failure free survival (BFFS) and prostate-specific antigen (PSA) kinetics in men receiving radical radiotherapy for localised prostate cancer and neo-adjuvant hormones with either AA or LHRHa therapy. Methods: All men with intermediate and high risk PC treated with AA monotherapy prior to radical prostate radiotherapy between April 2004 and December 2008 were individually case matched for key prognostic factors with men treated with neoadjuvant LHRHa monotherapy at our institution. BFFS, PSA kinetics, and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level were analyzed. Results: Sixty fi...

Neoadjuvant hormone therapy for radical prostate radiotherapy: A case-matched study comparing bicalutamide to LHRH agonist therapy.

88 Background: To assess and compare the biochemical failure free survival (BFFS), PSA kinetics and absolute PSA responses in men receiving radical radiotherapy for localized prostate cancer (RT) receiving either neoadjuvant bicalutamide or neoadjuvant LHRH agonist therapy. METHODS A retrospective review of consecutive cases with prostate cancer treated with BC monotherapy prior to radical radiotherapy was individually case matched to men treated with neoadjuvant LHRHa monotherapy from April 2004 to December 2008. PSA kinetics and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level and subsequent BFFS were analyzed. RESULTS 65 men treated with BC monotherapy were individually matched with 65 men treated with LHRHa. The median follow-up was 44 months and 54 months respectively. There were no significant differences in pre-treatment patient or tumour characteristics. Statistically significant differences were noted between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 - 11.2ng/ml) for BC patients and 1.0ng/ml (range 0.1 - 11.1ng/ml) for LHRHa patients (p<0.001). The geometric mean PSA halving time during the neo-adjuvant period of 14.6weeks (range 2 - 160weeks) in the BC treated group was statistically significantly different when compared to the mean of 16.1 weeks (range 2.1-96.8 weeks) for LHRHa patients (p=0.056). There were however no differences in PSA velocity. A PRPH-PSA of <1.0ng/ml and <0.1ng/ml was seen in 16(24.6%) and 2 (3%) of the BC patients and 34(52.3%) and 3(4.6%) of LHRHa patients respectively. Phoenix biochemical failure was seen in 10(15.4%, 95%CI [8.6%, 26.1%]) and 8(12.3%, [6.4%, 22.5%) of BC and LHRHa patients respectively. Neither PRPH-PSA level nor PSA kinetics during the neo-adjuvant period predict for subsequent BFFS at this duration of follow-up. CONCLUSIONS In this case-matched study, we found that although neo-adjuvant BC therapy did not result in equivalent PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone, there was no difference in biochemical failure rates between the cohorts at an overall median follow-up of 44 months. Longer follow-up is required.

Use of sector analysis of I-125 permanent prostate brachytherapy to evaluate and compare pre- and postimplant dosimetry.

242 Background: To evaluate 12 sector analysis in the assessment and comparison of pre- and post- implant dosimetric parameters during the development of an I-125 prostate brachytherapy (PPB) service. METHODS 50 consecutive men being treated with PPB had dose volume analysis in 12 sectors of their pre implant ultrasound (PIUS) and post implant CT (PICT) data using a Variseed 8.0 treatment planning system. PIUS dosimetry was performed 2 weeks prior to implantation and PICT dosimetry 4 weeks post implant. Individual sectors were created by dividing the cranio-caudal prostate length into 3 equal lengths creating prostate base (PB), midgland (PM) and apex (PA). Each of these volumes was then divided into four axial sectors (right and left anterior, right and left posterior). The planning target volume (PTV), dose to 90% of prostate (D90), prostate volume enclosed by 100% (V100), 150% (V150) and 200% (V200) dose were recorded in each sector on PIUS and PICT. Adjacent sectors on PIUS were assessed for dose-volume homogeneity as were adjacent sectors on PICT. Differences in individual sectors on PIUS and PICT were evaluated. RESULTS Adjacent sector analysis demonstrated dose homogeneity in all sectors of PIUS and the majority of sectors on PICT. Statistically significant differences between PIUS and PICT were noted in target volume, particularly in PB with PICT >PIUS. When individual sectors on PIUS and PICT were compared, statistically significant differences were noted in the majority of dosimetric parameters. The anterior PB and PM were significantly lower on PICT (p value < 0.001) and significantly higher at the posterior PM and PA (p value < 0.05). These changes were consistent across all analysed parameters. In particular, significant absolute differences in D90 in equivalent sectors on PIUS and PICT were seen. CONCLUSIONS 12 sector analysis allows rapid assessment of PIUS and PICT dose and volume homogeneity. It offers a scientific method of identifying areas of relative over and under dosing on PICT when compared with PIUS providing both clinicians and physicists with a learning tool to refine dosimetric analysis and highlight sectors where implant quality could be improved.