Percentage grade 4 tumour predicts outcome for prostate adenocarcinoma in needle biopsies from patients with advanced disease: 10-year data from the TROG 03.04 RADAR trial.

Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).

Validation of International Society of Urological Pathology (ISUP) grading for prostatic adenocarcinoma in thin core biopsies using TROG 03.04 'RADAR' trial clinical data.

In 2014 a consensus conference convened by the International Society of Urological Pathology (ISUP) adopted amendments to the criteria for Gleason grading and scoring (GS) for prostatic adenocarcinoma. The meeting defined a modified grading system based on 5 grading categories (grade 1, GS 3+3; grade 2, GS 3+4; grade 3, GS 4+3; grade 4, GS 8; grade 5, GS 9-10). In this study we have evaluated the prognostic significance of ISUP grading in 496 patients enrolled in the TROG 03.04 RADAR Trial. There were 19 grade 1, 118 grade 2, 193 grade 3, 88 grade 4 and 79 grade 5 tumours in the series, with follow-up for a minimum of 6.5 years. On follow-up 76 patients experienced distant progression of disease, 171 prostate specific antigen (PSA) progression and 39 prostate cancer deaths. In contrast to the 2005 modified Gleason system (MGS), the hazards of the distant and PSA progression endpoints, relative to grade 2, were significantly greater for grades 3, 4 and 5 of the 2014 ISUP grading scheme. Comparison of predictive ability utilising Harrell's concordance index, showed 2014 ISUP grading to significantly out-perform 2005 MGS grading for each of the three clinical endpoints.

The development of practice standards for radiation oncology in Australia: a tripartite approach.

In many areas of health care, practice standards have become an accepted method for professions to assess and improve the quality of care delivery. The aim of this work is to present the development of practice standards for radiation oncology in Australia, highlighting critical points and lessons learned. Following a review of radiotherapy services in Australia, a multidisciplinary group with support from the Australian Government developed practice standards for radiation oncology in Australia. The standards were produced in a multistep process including a nationwide survey of radiotherapy centres and piloting of the standards in a representative subset of all Australian radiotherapy centres. The standards are grouped into three sections: Facility management (covering staffing, data management, equipment and processes); Treatment planning and delivery (providing more detailed guidance on prescription, planning and delivery); Safety and quality management (including radiation safety, incident monitoring and clinical trials participation). Each of the 16 standards contains specific criteria, a commentary and suggestions for the evidence required to demonstrate compliance. The development of the standards was challenging and time consuming, but the collaborative efforts of the professions resulted in standards applicable throughout Australia and possibly further afield.

Efficacy of high-dose palliative radiotherapy for localised, castration-resistant prostate cancer.

AIMS: There are limited outcome data after radiotherapy treatment for clinically localised, castration-resistant prostate cancer. We report our single institution experience on patient outcomes in this group using high-dose palliative radiotherapy (HDPRT). MATERIALS AND METHODS: A retrospective review of patient hospital records was conducted in prostate cancer patients treated with palliative intent radiotherapy and restricted to those who had castration-resistant disease, no evidence of regional or distant disease and who received a local radiotherapy dose equivalent to 40 Gy or greater. RESULTS: Fifty-one patients met the study criteria, 88% of these had high-risk disease at initial diagnosis. The median time to delivery of HDPRT was 66 months and the median follow-up from HDPRT was 54 months. Grade 3 or worse toxicity was experienced in 8%. The estimated freedom from local failure, cause-specific survival and overall survival at 5 years were 81, 65 and 35%, respectively. Local procedures were a significant contributor to local morbidity, with the most common procedure a transurethral resection of the prostate (27% patients). Only two patients died from complications of local failure. CONCLUSION: HDPRT was well tolerated and provided a high rate of local control in a clinically localised castration-resistant prostate cancer population. Although prostate cancer remained the most frequent cause of death, some patients had extended survival without evidence of disease progression.

Patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy.

OBJECTIVES: To report on complications from transrectal ultrasound-guided insertion of fiducial markers for prostate image-guided radiotherapy. METHODS: 234 patients who underwent transrectal fiducial marker insertion for prostate cancer image-guided radiotherapy were assessed retrospectively by questionnaire with regard to the duration and severity of eight symptoms experienced following the procedure. Pain during the implantation procedure was assessed according to the Wong-Baker faces pain scale. RESULTS: Of 234 patients, 32% had at least one new symptom after the procedure. The commonest new symptom following the procedure was urinary frequency affecting 16% of patients who had not been troubled by frequency beforehand. Haematuria, rectal bleeding, dysuria and haematospermia affected 9-13% of patients, mostly at Grade 1 or 2. Pain, obstruction, and fever and shivers affected 3-4% of patients. Grade 3 rectal bleeding, haematuria, fever and shivers, and urinary frequency affected 0.5-1.5% of patients. Only one patient had a Grade 4 complication (i.e. fever and shivers). Overall, 9% of patients had symptoms lasting more than 2 weeks. The commonest symptoms that lasted more than 2 weeks were frequency, dysuria, obstructive symptoms and rectal bleeding. Mean pain score during the procedure was 1.1 (range 0-5). CONCLUSION: Transrectal ultrasound-guided fiducial marker insertion for image-guided radiotherapy is well tolerated in the majority of prostate cancer patients. Most symptoms were Grade 1 or 2 in severity. Symptoms in the majority of patients last under 2 weeks. The most serious complication was sepsis in our study.

Electronic portal imaging vs kilovoltage imaging in fiducial marker image-guided radiotherapy for prostate cancer: an analysis of set-up uncertainties.

OBJECTIVES: The purpose of this study was to compare interfraction prostate displacement data between electronic portal imaging (EPI) and kilovoltage imaging (KVI) treatment units and discuss the impact of any difference on margin calculations for prostate cancer image-guided radiotherapy (IGRT). METHODS: Prostate interfraction displacement data was collected prospectively for the first 4 fractions in 333 patients treated with IGRT with daily pre-treatment EPI or KVI orthogonal imaging. Displacement was recorded in the anteroposterior (AP), left-right (LR) and superoinferior (SI) directions. The proportion of displacement <3 mm and the difference in median absolute displacements were calculated in all directions. RESULTS: 1088 image pairs were analysed in total, 448 by EPI and 640 by KVI. There were 23% (95% confidence interval [CI] 18-28%) more displacements under 3 mm for EPI than for KVI in the AP direction, 14% (95% CI 10-19%) more in the LR direction and 10% (95% CI 5-15%) more in the SI direction. The differences in absolute median displacement (KVI>EPI) were AP 1 mm, LR 1 mm and SI 0.5 mm. Wilcoxon rank-sum test showed that distributions were significantly different for all three dimensions (p<0.0001 for AP and LR and p=0.02 for SI). CONCLUSION: EPI has a statistically significant smaller set-up error distribution than KVI. We would expect that, because fiducial marker imaging is less clear for EPI, the clinical target volume to planning target volume margin would be greater when using IGRT; however, relying wholly on displacement data gives the opposite result. We postulate that this is owing to observer bias, which is not accounted for in margin calculation formulas.

Interfraction patient motion and implant displacement in prostate high dose rate brachytherapy.

PURPOSE: To quantify movement of prostate cancer patients undergoing treatment, using an in-house developed motion sensor in order to determine a relationship between patient movement and high dose rate (HDR) brachytherapy implant displacement. METHODS: An electronic motion sensor was developed based on a three axis accelerometer. HDR brachytherapy treatment for prostate is delivered at this institution in two fractions 24 h apart and 22 patients were monitored for movement over the interval between fractions. The motion sensors functioned as inclinometers, monitoring inclination of both thighs, and the inclination and roll of the abdomen. The implanted HDR brachytherapy catheter set was assessed for displacement relative to fiducial markers in the prostate. Angle measurements and angle differences over a 2 s time base were binned, and the standard deviations of the resulting frequency distributions used as a metric for patient motion in each monitored axis. These parameters were correlated to measured catheter displacement using regression modeling. RESULTS: The mean implant displacement was 12.6 mm in the caudal direction. A mean of 19.95 h data was recorded for the patient cohort. Patients generally moved through a limited range of angles with a mean of the exception of two patients who spent in excess of 2 h lying on their side. When tested for a relationship between movement in any of the four monitored axes and the implant displacement, none was significant. CONCLUSIONS: It is not likely that patient movement influences HDR prostate implant displacement. There may be benefits to patient comfort if nursing protocols were relaxed to allow patients greater freedom to move while the implant is in situ.

Prospective development of an individualised predictive model for treatment coverage using offline cone beam computed tomography surrogate measures in post-prostatectomy radiotherapy.

The aim of this study is to prospectively evaluate and model surrogate explanatory variables (SEVs) of target coverage and rectal dose pertaining to soft tissue anatomy visualised on cone beam computed tomography (CBCT) for incorporation into post-prostatectomy treatment coverage verification protocols. Twenty post-prostatectomy patients treated with conformal prostate bed radiotherapy (64-74 Gy) underwent CBCT daily at fractions 1 to 5, and then weekly. Treatment coverage was defined on each CBCT using 'PTV95', percentage of the CBCT PTV covered by original treatment fields, and 'RECTD50', dose delivered to 50% of CBCT rectal volume by original treatment fields. Three candidate SEVs for treatment coverage were defined for each scan: anterior rectal wall movement, change in bladder length and bladder base movement. Both anterior rectal wall movement and increase in bladder length predicted for the decreased PTV95 (P < 0.001 for each). Anterior movement of the anterior rectal wall predicted for increased RECTD50 (P < 0.001). Predictive models for the PTV95 and RECTD50 that accept the significant SEVs as inputs were developed. We developed simple CBCT-acquired soft tissue anatomic surrogate measures that signal changes in target coverage and rectal dose during post-prostatectomy radiotherapy. Conventional bony anatomy patient position verification protocols were inadequate in accounting for soft tissue target and organ variation seen with CBCT.

Rectal filling at planning does not predict stability of the prostate gland during a course of radical radiotherapy if patients with large rectal filling are re-imaged.

AIMS: It has been suggested that large rectal filling is associated with an increased risk of prostate motion in radiotherapy. The aim of the present study was to determine if there is a correlation between rectal distension on planning computed tomography and the intrafraction and interfraction stability of the prostate gland during a course of radical radiotherapy for prostate cancer if a protocol was used to rescan patients with excessive rectal diameter during planning. MATERIALS AND METHODS: The computed tomography planning scans of 89 patients with adenocarcinoma of the prostate treated with conformal radiotherapy were reviewed. All patients had three gold seed fiducial markers implanted into the prostate before planning computed tomography. About one in five patients had repeat computed tomography because their rectum was judged to be too large at the time of the first planning computed tomography. Rectal distension was assessed on planning computed tomography using outlines following European Organization for Research and Treatment of Cancer guidelines by measuring the rectal volume, the average cross-sectional area and the mean anterior-posterior diameter of the rectum. Daily kV images were obtained before and after treatment delivery to determine positional matching of the fiducial markers in the superior-inferior, anterior-posterior and right-left dimensions. RESULTS: In total, 2860 pre- and post-treatment daily kV image pairs were obtained of 89 patients (average 32.1 image pairs per patient). The median rectal cross-sectional area was 7.3cm(2) (range 2.8-17.1), the median rectal volume was 54.8cm(3) (range 20.9-128.2), and the median anterior-posterior rectal diameter was 3.03cm (range 1.58-8.30). Unifactor linear regression models showed no statistically significant relationship between intra- and interfraction prostate stability and rectal volume on planning computed tomography. CONCLUSIONS: No statistically significant relationship between rectal distension on planning computed tomography and the intra- and interfraction stability of the prostate gland was identified if patients with a large rectal volume were rescanned for planning.

Verification of target position in the post-prostatectomy cancer patient using cone beam CT.

We present the results of a pilot study designed to investigate methods that may be applied to develop a patient position correction protocol for the post-prostatectomy patient receiving radiotherapy. Imaging was carried out with cone beam CT (CBCT) to investigate its suitability for detecting changes in rectal and bladder volumes and movements of these organs relative to the treatment planning CT. Eligible patients were imaged daily during the first week of treatment and weekly thereafter. Surrogate explanatory variables, including distance from the isocentre to the anterior rectum and bladder length, were tested for their potential to substitute for contouring entire organs and predict for changes in coverage of the planning treatment volume (PTV) by the 95% isodose (PTV95) and the maximum dose delivered to 50% of the rectal volume (RECTD50). The PTV defined on the CBCT images was larger than that defined on the planning CT and resulted in a decrease in the PTV95. Bladder length correlated with bladder volume and changes in bladder volume were associated with a decrease in PTV95. Rectal volumes changed randomly during treatment. There was a trend for the rectum to move anteriorly as treatment progressed. CBCT may be used to define the PTV, rectum and bladder though the reason for an apparent increase in PTV on CBCT requires further investigation. The bladder length and distance to the anterior rectal wall are potential surrogate explanatory variables. Further studies will be designed to test values of these surrogates that predict the need for a change in isocentre position.

Offline adaptive radiotherapy for bladder cancer using cone beam computed tomography.

We investigated if an adaptive radiotherapy approach based on cone beam CT (CBCT) acquired during radical treatment was feasible and resulted in improved dosimetric outcomes for bladder cancer patients compared to conventional planning and treatment protocol. A secondary aim was to compare a conventional plan with a theoretical online process where positioning is based on soft tissue position on a daily basis and treatment plan choice is based on bladder size. A conventional treatment plan was derived from a planning CT scan in the radical radiotherapy of five patients with muscle invasive bladder cancer. In this offline adaptive protocol using CBCT, the patients had 10 CBCT: daily CBCT for the first five fractions and then CBCT scan on a weekly basis. The first five daily CBCT in each patient were used to create a single adaptive plan for treatment from fraction eight onwards. A different process using the planning CT and the first five daily CBCT was used to create small, average and large bladder volumes, giving rise to small, average and large adaptive bladder treatment plans, respectively. In a retrospective analysis using the CBCT scans, we compared the clinical target volume (CTV) coverage using three protocols: (i) conventional; (ii) offline adaptive; and (iii) online adaptive with choice of 'plan of the day'. Daily CBCT prolonged treatment time by an average of 7 min. Two of the five patients demonstrated such variation in CTV that an offline adaptive plan was used for treatment after the first five CBCT. Comparing the offline adaptive plan with the conventional plan, the CTV coverage improved from a minimum of 60.1 to 94.7% in subsequent weekly CBCT. Using the CBCT data, modelling an online adaptive protocol showed that coverage of the CTV by the 95% prescribed dose line by small, medium and large adaptive plans were 34.9, 67.4 and 90.7% of occasions, respectively. More normal tissue was irradiated using a conventional CTV to planning target volume margin (1.5 cm) compared to an online adaptive process (0.5 cm). An offline adaptive strategy improves dose coverage in certain patients to the CTV and results in a higher conformity index compared to conventional planning. Further research in online adaptive radiation therapy for bladder cancer is indicated.

Inter-observer variability of clinical target volume delineation for bladder cancer using CT and cone beam CT.

To compare the image quality of cone beam CT (CBCT) with that of planning CT (pCT) scan, and quantify inter-observer differences in therapeutic indices based on these scans prior to the introduction of an adaptive radiation therapy protocol for bladder cancer. Four consecutive patients were selected with muscle invasive bladder cancer receiving radical dose radiation therapy. Four radiation oncologists specializing in genitourinary malignancies contoured the clinical target volume (CTV) and rectum on both a pCT and a randomly chosen CBCT of the same patient. A conformity index (CI) for CTV and the rectum was determined for both pCT and CBCT. The maximal lateral, anterior, posterior, cranial and caudal extensions of the CTV for both CT and CBCT were determined for each observer. Variation in volumes of both the CTV and rectum for both pCT and were also compared using Varian Eclipse planning software (Varian Medical Systems, Palo Alto, CA, USA). Using pCT the mean CI for the CTV was 0.79; using CBCT the mean CI for the CTV was 0.75. For the rectum, the mean CI for using CT was 0.80 and for CBCT was 0.74. Greatest variation on CBCT CTV contours was seen in the supero-inferior direction with variation up to 2.1 cm between different radiation oncologists. With the variation in CI for pCT and CBCT of the CTV and rectum (0.04 and 0.06 respectively), CBCT is not significantly inferior to the pCT in terms of inter-observer contouring variability.

Implementation of daily image-guided radiation therapy using an in-room CT scanner for prostate cancer isocentre localization.

The Tattersall's Cancer Centre has been performing image-guided radiation therapy (IGRT) using an in-room CT on rails since 2003 to verify accurate patient setup position (relative to bony anatomy) immediately prior to treatment delivery for prostate cancer patients. While the concept of online correction for bony anatomy is well established, the use of an in-room CT scanner also enables the collection and offline analysis of soft tissue volumetric data. Although initially IGRT was implemented under a research protocol, in-room CT verification has continued to be used to measure and correct for patient setup variations for all patients undergoing intensity modulated radiation therapy (IMRT) treatments. The present paper outlines the protocol that was used to implement IGRT using an in-room CT scanner at the Tattersall's Cancer Centre. Online corrections that minimize patient setup uncertainties allow confidence in delivering dose escalation as well as decreasing the margins required around the target volume. With improvements in auto-contouring tools, IGRT will also have the ability to measure and correct for variations in target and critical structure positioning online, rather than the current offline methods utilized.

Thermoluminescence dosimetry for in-vivo verification of high dose rate brachytherapy for prostate cancer.

It was the aim of the study to verify dose delivered in urethra and rectum during High Dose Rate brachytherapy boost (HDRBB) of prostate cancer patients. During the first fraction of HDRBB measurement catheters were placed in the urethra and rectum of prostate cancer patients. These contained LiF:Mg,Ti Thermoluminescence Dosimetry (TLD) rods of 1 mm diameter, with up to 11 detectors positioned every 16 mm separated by radio-opaque markers. A Lorentzian peak function was used to fit the data. Measurements from 50 patients were evaluated and measured doses were compared with predictions from the treatment planning system (Plato Vs 13.5 to 14.1). Prospective urinary and rectal toxicity scores were collected following treatment. In more than 90% of cases, the Lorentzian peak function provided a good fit to both experimental and planning urethral data (r2 > 0.9). In general there was good agreement between measured and predicted doses with the average difference between measured and planned maximum dose being 0.1 Gy. No significant association between dose and any clinical endpoints was observed in 43 patients available for clinical evaluation. An average inferior shift of 2 mm between the plan and the measurement performed approximately 1 hour after the planning CT scan was found for the dose distribution in the cohort of patients for the urethra measurements. Rectal measurements proved to be more difficult to interpret as there is more variability of TLD position between planning and treatment. TLD in-vivo measurements are easily performed in urethra and rectum during HDR brachytherapy of prostate patients. They verify the delivery and provide information about the dose delivered to critical structures. The latter may be of particular interest if higher doses are to be given per fraction such as in HDR monotherapy.

Australian and New Zealand three-dimensional conformal radiation therapy consensus guidelines for prostate cancer.

Three-dimensional conformal radiation therapy (3DCRT) has been shown to reduce normal tissue toxicity and allow dose escalation in the curative treatment of prostate cancer. The Faculty of Radiation Oncology Genito-Urinary Group initiated a consensus process to generate evidence-based guidelines for the safe and effective implementation of 3DCRT. All radiation oncology departments in Australia and New Zealand were invited to complete a survey of their prostate practice and to send representatives to a consensus workshop. After a review of the evidence, key issues were identified and debated. If agreement was not reached, working parties were formed to make recommendations. Draft guidelines were circulated to workshop participants for approval prior to publication. Where possible, evidence-based recommendations have been made with regard to patient selection, risk stratification, simulation, planning, treatment delivery and toxicity reporting. This is the first time a group of radiation therapists, physicists and oncologists representing professional radiotherapy practice across Australia and New Zealand have worked together to develop best-practice guidelines. These guidelines should serve as a baseline for prospective clinical trials, outcome research and quality assurance.

Three-dimensional conformal radiotherapy in the treatment of prostate cancer in Australia and New Zealand: Report on a survey of radiotherapy centres and the proceedings of a consensus workshop.

There is an increasing use of 3-D conformal radiotherapy (3DCRT) in the radiotherapeutic management of prostate cancer. The Faculty of Radiation Oncology Genito-Urinary Group carried out a survey of Australian and New Zealand radiotherapy centres in the preparation of a consensus workshop. Of the 19 centres that were represented, there were 24 radiation oncologists, 16 radiation therapists and 12 medical physicists. The survey collected demographic information and data on the practices undertaken at those centres when delivering curative radiotherapy in the treatment of prostate cancer. There was much variation in the delivery of treatment in the areas of patient set-up, contouring of target volumes and organs of interest during computer planning, the techniques and the dose constraints used in these techniques, the use of adjuvant androgen deprivation therapy and the quality assurance processes used in monitoring effects of treatment. This variability reflects the range of data in the published literature. Emerging trends of practices were also identified. This is a first report on a multi-disciplinary approach to the development of guidelines in 3DCRT of prostate cancer.

Clinical prioritisation for curative radiotherapy: a local waiting list initiative.

AIMS: Waiting time for radiotherapy is a major problem in radiation oncology practice. The aim of this paper is to present the experience of the Peter MacCallum Cancer Centre in trialling a number of strategies to reduce patient waiting times. MATERIALS AND METHODS: All patients starting megavoltage radiotherapy with curative intent in three separate 1-week blocks had their waiting times recorded. The cohorts were each 8 weeks apart and were before (September), during (November) and after (January) the introduction of a priority points system. RESULTS: Median waiting time was 35 days in September, 42 days in November and 31 days in January. The number of extremely long waits (>90 days) decreased to 1 by January. Significantly more patients were pre-booked for treatment in January (27/51) compared with September (17/65; P = 0.003) and November (12/65; P < 0.001). Pre-booked patients had shorter waiting times compared with patients who was not pre-booked (P < 0.0001). Difficulties at one particular treating location contributed to the longer median waiting times in November. Although there had no significant difference in waiting time in non-breast unit patients between the three cohorts, there was a decrease in waiting times in breast unit patients, especially between November and January (P = 0.0008). There was no significant increase in delay to starting treatment in other treating units, resulting in more equitable access across all units. CONCLUSIONS: A combination of encouraging pre-booking and the introduction of a priority points system has led to a decrease in waiting times, especially among breast unit patients.