Mrs Allison Steigler

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%).

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups. Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3¿4 months to 6¿9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4¿6 months to 18¿36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855. Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0¿15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77¿0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78¿0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83¿1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group. Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended. Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.

Purpose: Recent voxel-based studies have shown that the dose to specific rectal and urethro-vesical subregions is predictive of toxicities after prostate cancer intensity modulated radiation therapy. The objective of this study was to validate the discriminatory power of these subregions with respect to the whole organs in a large independent population. Methods and Materials: The validation cohort consisted of 450 patients from the TROG03.04-RADAR trial treated with 3-dimensional conformal radiation therapy at 66 to 74 Gy. Previous voxel-based analyses identified an inferoanterior rectal subregion as predictive of rectal bleeding and 5 subregions in the urethra and the posterior and superior part of the bladder as predictive of urinary incontinence, dysuria, retention, and hematuria. In the validation cohort, these subregions were segmented in each patient's anatomy. Dose-volume histograms (DVHs) of the whole organs and the 6 subregions were compared bin-wise between patients with and without toxicities. The discriminatory power of DVHs for grade =2 toxicity endpoints was assessed using the area under the receiver operating characteristic curve (AUC). Results: Subregion DVHs were significantly different between patients with and without toxicities for late rectal bleeding (V44-V74), acute urinary incontinence (V68-V72), late dysuria (V56-V68), and late retention (V14-V64). The dose to the rectal subregion and the whole rectum were equally predictive of rectal bleeding (V68; AUC = 0.61). The doses to 3 out of the 5 urethro-vesical subregions were found to be more predictive than the dose to the whole bladder: in the urethra for acute incontinence (V71 AUC = 0.69 vs V71 AUC = 0.66), in the posterior part of the bladder for late dysuria (V65 AUC = 0.66 vs V68 AUC = 0.59), and late retention (V39 AUC = 0.74 vs no significant AUC). Conclusions: Three subregions located in the urethra and the bladder were successfully validated as more predictive of urinary toxicity than the whole bladder for urinary incontinence, retention, and dysuria. Sparing the posterior part of the bladder in particular in treatment planning may reduce the risk of late urinary retention.

Aims: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10¿years outcome data from the TROG 03.04 RADAR trial. Methods: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10¿years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. Results: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10¿years follow-up interval of the study (log-rank test P¿<¿0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05¿1.92, P¿=¿0.021). Conclusions: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

Purpose: Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP). Methods and Materials: Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets. Results: Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients. Conclusions: Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients.

Purpose: To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer. Methods and Materials: Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS ± 18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group. Results: A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P =.002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P =.76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P <.0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups. Conclusions: Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial.

Prostate cancer progression has been shown to be dependent on the development of autonomic nerves into the tumour microenvironment. Sympathetic nerves activate adrenergic neurosignalling that is necessary in early stages of tumour progression and for initiating an angiogenic switch, whereas parasympathetic nerves activate cholinergic neurosignalling resulting in tumour dissemination and metastasis. The innervation of prostate cancer seems to be initiated by neurotrophic growth factors, such as the precursor to nerve growth factor secreted by tumour cells, and the contribution of brain-derived neural progenitor cells has also been reported. Current experimental, epidemiological and clinical evidence shows the stimulatory effect of tumour innervation and neurosignalling in prostate cancer. Using nerves and neurosignalling could have value in the management of prostate cancer by predicting aggressive disease, treating localized disease through denervation and relieving cancer-associated pain in bone metastases.

Background: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. Methods: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was =7 and baseline prostate-specific antigen [PSA] concentration was =10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. Findings: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9¿11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3¿16·0) for 6AS+RT versus 9·7% (7·3¿12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3¿7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50¿0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7¿13·7) with zoledronic acid vs 11·7% (9·2¿14·1) without, representing an absolute difference o...

Background and purpose: To evaluate the impact of treatment planning and delivery factors on treatment outcome as measured by post-treatment disease progression. Materials and methods: Accruing 813 external beam radiotherapy participants during 2003¿2007, the RADAR trial collected a comprehensive range of clinical treatment factor data for each participant. Both the Fine and Gray competing risks modelling and the Kaplan¿Meier (KM) analysis were undertaken to determine the impact of these factors on local-composite progression (LCP), with 709 participants available for analysis. Results: Participants with treatments involving 7 or more beams experienced significantly higher incidence of LCP, with a sub-hazard ratio (relative to 3-beam participants) of 3.056 (CI: 1.446¿6.458, p < 0.0034). Participants treated with a more rigorous dose calculation algorithm also displayed significantly higher incidence of LCP, with a sub-hazard ratio of 1.686 (CI: 1.334¿2.132, p < 0.0001). The KM analysis resulted in the same groups showing a higher incidence of LCP, with log-rank test results of p = 0.0005 and p = 0.0008 respectively. Conclusions: The RADAR dataset has enabled a successful secondary analysis in which the impact of technical modifications has been assessed, challenging several established hypotheses. Increasingly precise treatments should be complemented with increasing accuracy to avoid potential geometric miss.

Introduction: Quality assurance methods are incorporated into multicentre radiotherapy clinical trials for ensuring consistent application of trial protocol and quantifying treatment uncertainties. The study's purpose was to determine whether post-treatment disease progression is associated with measures of the quality of radiotherapy treatment. Methods: The TROG 03.04 RADAR trial tested the impact of androgen deprivation on prostate cancer patients receiving dose-escalated external beam radiation therapy. The trial incorporated a plan-review process and Level III dosimetric intercomparison at each centre, from which variables suggestive of treatment quality were collected. Kaplan¿Meier statistics and Fine and Gray competing risk modelling were employed to test for associations between quality-related variables and the participant outcome local composite progression. Results: Increased ¿dose-difference¿ at the prostatic apex and at the anterior rectal wall, between planned and measured dose, was associated with reduced progression. Participants whose treatment plans included clinical target volume (CTV) to planning target volume (PTV) margins exceeding protocol requirements also experienced reduced progression. Other quality-related variables, including total accrual from participating centres, measures of target coverage and other variations from protocol, were not significantly associated with progression. Conclusions: This analysis has revealed the association of several treatment quality factors with disease progression. Increased dose and dose margin coverage in the prostate region can reduce disease progression. Extensive and rigorous monitoring has helped to maximise treatment quality, reducing the incidence of quality-indicator outliers, and thus reduce the chance of observing significant associations with progression rates.

Repeated surveys of prostate cancer (PCa) patients indicate that their prevalence of depression is well above that for their non-PCa peers. Although standard first-line treatments for depression are only about 35% effective, some recent comments have suggested that a focus upon the possible correlates (factors that aggravate or mediate depression) might help improve treatment efficacy. To investigate this issue, 144 10 year PCa survivors were asked about the frequency of urinary incontinence, a common side effect of some PCa treatments. The 53 patients who suffered urinary incontinence had significantly higher depression scores on the Zung Self-rating Depression Scale than those patients who did not report urinary incontinence. Using mediation analysis, patients' psychological resilience (PR) significantly mediated the depressive effects of urinary incontinence, but those effects were confined to just one of the five components of PR¿a sense of control over the things that happen to oneself. Implications for treatment models of psychosocial oncology support for PCa survivors are discussed.

Background It remains unclear whether eradication of oligometastases by stereotactic body radiation therapy or other means will result in cure or prolongation of survival in some cases, or merely provide palliation. We address this issue with prospectively collected progression and treatment data from the TROG 03.04 RADAR randomised controlled trial for men with locally advanced prostate cancer (PC). Methods Three Fine and Gray competing risk survival models with time-dependent covariates were used to determine whether metastatic progression status at first diagnosis of bony metastases, i.e. number of bony sites involved and presence of prior or simultaneous other sites of progression, impacts on prostate cancer-specific mortality (PCSM) when adjusted for baseline prognostic factors and allocated primary treatment. Results Between 2003 and 2014, 176 of the 1071 subjects developed bone metastases, 152 developed other sites of progression and 91 died of PC. All subjects received secondary treatment using androgen suppression but none received extirpative treatments. The three models found evidence: 1 ¿ of a clear prognostic gradient according to number of bony metastatic sites; 2 ¿ that other sites of progression contributed to PCSM to a lesser extent than bone progression; and 3 ¿ that further bony metastatic progression in men with up to 3 bony metastases had a major impact on PCSM. Conclusion Randomised trials are essential to determine the value of extirpative treatment for oligometastatic bony metastases due to PC.

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.

Objective To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. Patients and Methods Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. Results Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. Conclusion In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates. © 2013 The Authors. BJU International © 2013 BJU International.