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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. [ABSTRACT FROM AUTHOR]

Background The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. Methods We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS ± 18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Results Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP ( p < 0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. Conclusion RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: In the TROG 96.01 trial 6month neo-adjuvant androgen suppression (NAS) and radiotherapy (RT) for locally advanced prostate cancer prevented distant progressions (DPs) when compared to RT alone, but 3months did not. We ask why? Methods: Between 1996 and 2000, 802 men with T2-4 N0 M0 prostate cancers received RT alone (0month NAS) to 66Gy, 3months or 6months NAS before RT. Interval hazards and cumulative incidences of DP were compared using competing risks methodology. Results: In the first 4 follow-up years 39, 40 and 26 DPs were diagnosed in subjects treated with 0, 3 and 6month NAS, respectively. Compared with 0month, significant reductions in PSA doubling time in subjects with DP occurred following 3month NAS (p =0.01), but a significant reduction (p =0.01) and a near significant delay in DPs (p =0.06) occurred after 6month NAS. Subsequently 25, 20 and 11 DPs occurred in the three trial arms. After early secondary therapy for PSA or local progression 34, 19 and 12 DPs were diagnosed after median delays of almost 4years. Conclusions: The data are consistent with the failure of 3month NAS to prevent the progression of sub-clinical metastatic deposits already present before treatment. [Copyright &y& Elsevier]

Abstract: Background and purpose: To identify contributing factors to delayed rectal and urinary symptoms in a randomised trial comparing different durations of maximal androgen deprivation (MAD), given prior to radiotherapy, for locally advanced prostate cancer. Patients and methods: Between 1996 and 2000, 818 patients with stages T2b,c, 3 and 4 prostate cancer were entered into a trial comparing 0, 3 and 6 months of MAD prior to and during radiotherapy. Their delayed normal tissue effects were recorded by their treating doctors using standardised scales and by the patients using a self-assessment questionnaire regularly. Time to occurrence and prevalence data were analysed. Results: Rectal and urinary symptom levels were observed to vary markedly over time in at least 80% of patients, with some indicating lasting resolution of symptoms. Prevalence rates were found to be substantially lower than actuarial probability rates. Baseline symptom levels and greatest acute symptom levels were both very powerful predictors. Obstructive lower urinary tract symptoms were noted to improve during the first 4 years after radiotherapy in approximately 60% of cases in each treatment arm. However, the treatment arm itself was not shown to influence these improvements in other univariate or multivariate analyses. MAD was shown to reduce both time to occurrence and prevalence of delayed proctopathic symptoms, but this effect was confirmed statistically in the 3 month treatment arm only. Multivariate models indicated that higher levels of haemoglobin prior to any treatment may in some way protect against delayed proctopathic symptoms. Conclusions: Prevalence data provide more clinically meaningful estimates of risk of delayed effects in normal tissues where assessment relies substantially on reported symptom levels. In these tissues consideration of the impact of baseline symptom levels and pathologies, and greatest acute symptom levels in analyses of delayed effects appears mandatory. Obstructive lower urinary symptoms improve over several years in the majority of patients treated for locally advanced prostate cancer by radiotherapy. Future research could address whether rectal toxicity is affected by initial haemoglobin levels and declines in it due to MAD. [Copyright &y& Elsevier]

• Voxel-wise analysis correlated rectal toxicities with dose in the pelvic anatomy. • Grade ≥2 bleeding correlated with high doses to a small rectal volume. • This confirmed the serial response of the rectum with respect to rectal bleeding. • Grade ≥2 tenesmus correlated with low-intermediate doses to the perirectal fat space. • This demonstrated the parallel response of the PRFS with respect to tenesmus. This study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. Planned dose distributions for up to 657 patients of the Trans Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar computed tomography dataset. Voxel-based multiple comparison permutation dose difference testing, Cox regression modelling and LASSO feature selection were used to identify regions where dose-increase was associated with grade ≥2 rectal bleeding (RB) or tenesmus, according to the LENT/SOMA scale. This was externally validated by registering dose distributions from the RT01 (n = 388) and CHHiP (n = 241) trials onto the same exemplar and repeating the tests on each of these data sets, and on all three datasets combined. Voxel-based Cox regression and permutation dose difference testing revealed regions where increased dose was correlated with gastrointestinal toxicity. Grade ≥2 RB was associated with posteriorly extended lateral beams that manifested high doses (>55 Gy) in a small rectal volume adjacent to the clinical target volume. A correlation was found between grade ≥2 tenesmus and increased low-intermediate dose (∼25 Gy) at the posterior beam region, including the posterior rectum and perirectal fat space (PRFS). The serial response of the rectum with respect to RB has been demonstrated in patients with posteriorly extended lateral beams. Similarly, the parallel response of the PRFS with respect to tenesmus has been demonstrated in patients treated with the posterior beam. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Temporal distributions in PSA levels following therapeutic intervention for prostate cancer are known to contain characteristics prognostic of disease progression. An algorithm was developed for extracting such characteristics, specifically in the context of previous observations following radiotherapy. Material and methods: Segmented regression methods were investigated for characterising the ‘signatures’ in log(PSA) descent patterns between intervention and nadir. Results: The segmented regression method can automatically identify and parameterise features in a PSA distribution including failure points and doubling time patterns following nadir. The method has previously been applied to the analysis of descent patterns on a large clinical data series (Radiother Oncol 2009;90:382–8). Batch-processing of data using the method for all patients in a clinical trial would establish population parameter values and ranges. Subsequent application to an individual patient’s PSA data would determine which resulting prognostic group they fall into. Conclusions: As more complete and higher-resolution PSA progression datasets become available, techniques such as presented here will allow flexible definition of the characteristics being examined and rapid extraction of parameters for correlation with clinical progression data. [Copyright &y& Elsevier]

Abstract: Background: We sought to determine whether inter-patient variations in pattern of PSA changes after radiation exist and, if so, are they prognostically significant. Methods: In the Trans-Tasman Radiation Oncology Group (TROG) 96.01 randomized controlled trial, patients with T2b,c,3,4 N0 prostate cancer (PC) were randomised to 0, 3 or 6months maximal androgen deprivation prior to 66Gy to the prostate and seminal vesicles (XRT). Patterns of anatomical site of failure were one of the trial endpoints. Serial serum PSA’s were mandated at all follow-up visits. Pattern recognition software was developed to characterize PSA response “signatures” (PRS) after therapy in individual patients. Results: By 2000, 270 eligible patients were randomised to radiation alone. Individual patient PSA values were observed to descend after radiation according to one of two characteristic “signatures”: single exponential (PRS Type 1), non-exponential (PRS Type 2). Compared to PRS Type 1, men with PRS Type 2 (50% of the group) had lower PSA nadir (nPSA) levels (p <.0001), longer doubling times on relapse (p =.006) and significantly lower rates of local (hazard ratio [HR]: 0.47, 95% confidence interval [0.30–0.75], p =.0014) and distant failure (HR: 0.25[0.13–0.46], p <.0001), death due to PC (HR: 0.20[0.10–0.42], p <.0001) and death due to any cause (HR: 0.37 [0.23–0.60], p <.0001). PRS retained its powerful prognostic significance in Cox models that incorporated all key pre-treatment covariates and nPSA. Conclusions: PRS reflect the presence of tumor phenotypes that vary substantially in their clinical behavior and response to XRT. Molecular characterization is now necessary. [Copyright &y& Elsevier]

Abstract: Purpose: We sought to categorize longitudinal radiation-induced rectal toxicity data obtained from men participating in a randomised controlled trial for locally advanced prostate cancer. Materials and methods: Data from self-assessed questionnaires of rectal symptoms and clinician recorded remedial interventions were collected during the TROG 96.01 trial. In this trial, volunteers were randomised to radiation with or without neoadjuvant androgen deprivation. Characterization of longitudinal variations in symptom intensity was achieved using prevalence data. An integrated visualization and clustering approach based on memetic algorithms was used to define the compositions of symptom clusters occurring before, during and after radiation. The utility of the CTC grading system as a means of identifying specific injury profiles was evaluated using concordance analyses. Results: Seven well-defined clusters of rectal symptoms were present prior to treatment, 25 were seen immediately following radiation and 7 at years 1, 2 and 3 following radiation. CTC grading did not concord with the degree of rectal ‘distress’ and ‘problems’ at all time points. Concordance was not improved by adding urgency to the CTC scale. Conclusions: The CTC scale has serious shortcomings. A powerful new technique for non-hierarchical clustering may contribute to the categorization of rectal toxicity data for genomic profiling studies and detailed patho-physiological studies. [Copyright &y& Elsevier]