CCL2/CCR2 Expression in Locally Advanced Prostate Cancer and Patient Long-Term Outcome: 10-Year Results from the TROG 03.04 RADAR Trial.

This study investigated the prognostic value of the chemokine C-C motif ligand 2 (CCL2) and its receptor C-C motif chemokine receptor 2 (CCR2) expression in locally advanced prostate cancer treated with radiotherapy and androgen deprivation using the 10-year outcome data from the TROG 03.04 RADAR clinical trial. CCL2 and CCR2 protein expression in prostate cancer biopsies at the time of diagnosis were quantified by immunohistochemistry and digital quantification. CCR2 protein expression was detected in prostate cancer cells and was associated with prostate-specific antigen serum concentration (p = 0.045). However, neither CCL2 nor CCR2 tissue expression could predict prostate cancer progression, or other clinicopathological parameters including perineural invasion and patient outcome. In serum samples, CCL2 concentration at the time of diagnosis, as assayed by enzyme-linked immunosorbent assay, was significantly higher in patients with prostate cancer compared with benign prostatic hyperplasia (median difference 0.22 ng/mL, 95% CI, 0.17-0.30) (p < 0.0001) and normal controls (median difference 0.13 ng/mL, 95% CI, 0.13-0.17) (p < 0.0001). However, circulating CCL2 was not statistically significant as a predictor of disease progression and patient outcome. In conclusion, this study shows that although CCL2 and CCR2 are expressed in prostate cancer, with an increased level of CCL2 in the serum, neither CCL2 nor CCR2 expression has a clinical prognostic value in locally advanced prostate cancer.

Validation of prediction models for radiation-induced late rectal bleeding: Evidence from a large pooled population of prostate cancer patients.

PURPOSE: To validate published models for the risk estimate of grade ≥ 1 (G1+), grade ≥ 2 (G2+) and grade = 3 (G3) late rectal bleeding (LRB) after radical radiotherapy for prostate cancer in a large pooled population from three prospective trials. MATERIALS AND METHODS: The external validation population included patients from Europe, and Oceanian centres enrolled between 2003 and 2014. Patients received 3DCRT or IMRT at doses between 66-80 Gy. IMRT was administered with conventional or hypofractionated schemes (2.35-2.65 Gy/fr). LRB was prospectively scored using patient-reported questionnaires (LENT/SOMA scale) with a 3-year follow-up. All Normal Tissue Complication Probability (NTCP) models published until 2021 based on the Equivalent Uniform Dose (EUD) from the rectal Dose Volume Histogram (DVH) were considered for validation. Model performance in validation was evaluated through calibration and discrimination. RESULTS: Sixteen NTCP models were tested on data from 1633 patients. G1+ LRB was scored in 465 patients (28.5%), G2+ in 255 patients (15.6%) and G3 in 112 patients (6.8%). The best performances for G2+ and G3 LRB highlighted the importance of the medium-high doses to the rectum (volume parameters n = 0.24 and n = 0.18, respectively). Good performance was seen for models of severe LRB. Moreover, a multivariate model with two clinical factors found the best calibration slope. CONCLUSION: Five published NTCP models developed on non-contemporary cohorts were able to predict a relative increase in the toxicity response in a more recent validation population. Compared to QUANTEC findings, dosimetric results pointed toward mid-high doses of rectal DVH. The external validation cohort confirmed abdominal surgery and cardiovascular diseases as risk factors.

High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.

BACKGROUND: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown. OBJECTIVE: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT. DESIGN, SETTING, AND PARTICIPANTS: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS). RESULTS AND LIMITATIONS: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes. CONCLUSIONS: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT. PATIENT SUMMARY: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis.

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.

Tumor innervation and clinical outcome in pancreatic cancer.

Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77-4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue (p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19-0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.

Increased Dose to Organs in Urinary Tract Associates With Measures of Genitourinary Toxicity in Pooled Voxel-Based Analysis of 3 Randomized Phase III Trials.

Purpose: Dose information from organ sub-regions has been shown to be more predictive of genitourinary toxicity than whole organ dose volume histogram information. This study aimed to identify anatomically-localized regions where 3D dose is associated with genitourinary toxicities in healthy tissues throughout the pelvic anatomy. Methods and Materials: Dose distributions for up to 656 patients of the Trans-Tasman Radiation Oncology Group 03.04 RADAR trial were deformably registered onto a single exemplar CT dataset. Voxel- based multiple comparison permutation dose difference testing, Cox regression modeling and LASSO feature selection were used to identify regions where 3D dose-increase was associated with late grade ≥ 2 genitourinary dysuria, incontinence and frequency, and late grade ≥ 1 haematuria. This was externally validated by registering dose distributions from the RT01 (up to n = 388) and CHHiP (up to n = 247) trials onto the same exemplar and repeating the voxel-based tests on each of these data sets. All three datasets were then combined, and the tests repeated. Results: Voxel-based Cox regression and multiple comparison permutation dose difference testing revealed regions where increased dose was correlated with genitourinary toxicity. Increased dose in the vicinity of the membranous and spongy urethra was associated with dysuria for all datasets. Haematuria was similarly correlated with increased dose at the membranous and spongy urethra, for the RADAR, CHHiP, and combined datasets. Some evidence was found for the association between incontinence and increased dose at the internal and external urethral sphincter for RADAR and the internal sphincter alone for the combined dataset. Incontinence was also strongly correlated with dose from posterior oblique beams. Patients with fields extending inferiorly and posteriorly to the CTV, adjacent to the membranous and spongy urethra, were found to experience increased frequency. Conclusions: Anatomically-localized dose-toxicity relationships were determined for late genitourinary symptoms in the urethra and urinary sphincters. Low-intermediate doses to the extraprostatic urethra were associated with risk of late dysuria and haematuria, while dose to the urinary sphincters was associated with incontinence.

Relationships between rectal and perirectal doses and rectal bleeding or tenesmus in pooled voxel-based analysis of 3 randomised phase III trials.

BACKGROUND AND PURPOSE: This study aimed to identify anatomically-localised regions where planned radiotherapy dose is associated with gastrointestinal toxicities in healthy tissues throughout the pelvic anatomy. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials.

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.

External Validation of a Predictive Model of Urethral Strictures for Prostate Patients Treated With HDR Brachytherapy Boost.

Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor. Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman-Kutcher-Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/ß = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it. Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present. Conclusions: Lyman-Kutcher-Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.

Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial.

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.

Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04 RADAR Trial.

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.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

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 of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study. INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

Body composition, fatigue and exercise in patients with prostate cancer undergoing androgen-deprivation therapy.

OBJECTIVES: To investigate the association between lean mass (LM) and fat mass (FM) with fatigue and vitality before and after exercise in patients with prostate cancer already undergoing androgen-deprivation therapy (ADT). SUBJECTS AND METHODS: Cross-sectional associations between LM and FM with fatigue and/or vitality measures were examined in 229 patients (aged 43-90 years). Prospective analysis was undertaken in 129 patients who underwent a supervised 3-6 months exercise programme (predominantly resistance + aerobic). Whole body and appendicular LM, and total and trunk FM were assessed by dual X-ray absorptiometry. Fatigue was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-30) and vitality using the Short Form-36. RESULTS: Based on the EORTC QLQ-30, 19% of patients had clinically relevant fatigue. There was no association between LM and fatigue; however, total (P = 0.013), trunk (P = 0.015) and percentage (P = 0.008) FM were higher in fatigued than not fatigued patients, with total and trunk FM 5.0 and 2.6 kg higher, respectively. For quartiles of vitality, a similar pattern emerged for FM with those in the lowest quartile of vitality having the highest FM values (P = 0.014-0.034). In contrast, following supervised exercise, change in fatigue and vitality were associated with change in total LM (r = -0.182, P = 0.042 and r = 0.309, P = 0.001, respectively) but not FM. Patients fatigued at baseline but not fatigued following the exercise programme gained a median (interquartile range) of 2.1 (0.7-3.2) kg LM. CONCLUSION: In patients with prostate cancer treated with ADT, body composition is associated with fatigue, with higher total and trunk FM in those with clinically relevant fatigue. However, following exercise those no longer fatigued had an accompanying substantial increase in LM. Modifying body composition, both LM and FM, in patients with prostate cancer may favourably alter cancer-related fatigue levels and should be a target of exercise medicine in this population.

Association between measures of treatment quality and disease progression in prostate cancer radiotherapy: An exploratory analysis from the TROG 03.04 RADAR trial.

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.

Proteins Annexin A2 and PSA in Prostate Cancer Biopsies Do Not Predict Biochemical Failure.

BACKGROUND/AIM: We previously reported the use of mass spectrometry and western blotting to identify proteins from tumour regions of formalin-fixed paraffin-embedded biopsies from 16 men who presented with apparently localized prostate cancer, and found that annexin A2 (ANXA2) appeared to be a better predictor of subsequent biochemical failure than prostate-specific antigen (PSA). MATERIALS AND METHODS: In this follow-up study, ANXA2 and PSA were measured using western blotting of proteins extracted from biopsies from 37 men from a subsequent prostate cancer trial. RESULTS: No significant differences in ANXA2 and PSA levels were observed between men with and without biochemical failure. The statistical effect sizes were small, d=0.116 for ANXA2, and 0.266 for PSA. CONCLUSION: ANXA2 and PSA proteins measured from biopsy tumour regions are unlikely to be good biomarkers for prediction of the clinical outcome of prostate cancer presenting with apparently localized disease.

Spatial features of dose-surface maps from deformably-registered plans correlate with late gastrointestinal complications.

This study investigates the associations between spatial distribution of dose to the rectal surface and observed gastrointestinal toxicities after deformably registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate brachytherapy (HDRBT) prostate cancer treatment. The study contains data for 118 patients where the HDRBT CT was deformably-registered to the EBRT CT. The EBRT and registered HDRBT TG43 dose distributions in a reference 2 Gy/fraction were 3D-summed. Rectum dose-surface maps (DSMs) were obtained by virtually unfolding the rectum surface slice-by-slice. Associations with late peak gastrointestinal toxicities were investigated using voxel-wise DSM analysis as well as parameterised spatial patterns. The latter were obtained by thresholding DSMs from 1-80 Gy (increment = 1) and extracting inferior-superior extent, left-right extent, area, perimeter, compactness, circularity and ellipse fit parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate features with toxicities. Rectal bleeding, stool frequency, diarrhoea and urgency/tenesmus were associated with greater lateral and/or longitudinal spread of the high doses near the anterior rectal surface. Rectal bleeding and stool frequency were also influenced by greater low-intermediate doses to the most inferior 20% of the rectum and greater low-intermediate-high doses to 40-80% of the rectum length respectively. Greater low-intermediate doses to the superior 20% and inferior 20% of the rectum length were associated with anorectal pain and urgency/tenesmus respectively. Diarrhoea, completeness of evacuation and proctitis were also related to greater low doses to the posterior side of the rectum. Spatial features for the intermediate-high dose regions such as area, perimeter, compactness, circularity, ellipse eccentricity and confinement to ellipse fits were strongly associated with toxicities other than anorectal pain. Consequently, toxicity is related to the shape of isodoses as well as dose coverage. The findings indicate spatial constraints on doses to certain sections of the rectum may be important for reducing toxicities and optimising dose.

Psychological resilience aspects that mediate the depressive effects of urinary incontinence in prostate cancer survivors 10 years after treatment with radiation and hormone ablation.

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.

Accumulation of rectum dose-volume metrics for prostate external beam radiotherapy combined with brachytherapy: Evaluating deformably registered dose distribution addition using parameter-based addition.

INTRODUCTION: To investigate the accuracy of deriving dose-volume histogram (DVH) parameters from deformably registered data by comparing values with the simple addition of DVHs from each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR-BT) brachytherapy prostate treatment. METHODS: Eighty-two patients received EBRT in 23 fractions of 2 Gy and HDR-BT TG43 in three fractions of 6.5 Gy. The HDR-BT CT was deformably registered to the EBRT CT. The rectum D0.1cc , D1cc , D2cc and D10cc were calculated in two ways. (i) Parameter-adding: the EBRT DVH parameters (or the EBRT prescription dose) were added to the unregistered HDR-BT DVH parameters. (ii) Distribution-adding: the parameters were extracted after the EBRT doses were 3D-summed with the registered HDR-BT doses. Resulting differences between the parameters were investigated. RESULTS: The D0.1cc , D1cc and D2cc from parameter-adding were 21.3% (P < 0.001), 6.3% (P < 0.001) and 3.5% (P < 0.001) smaller than those from distribution-adding. The D10cc was 2.2% (P = 0.015) larger for distribution-adding. CONCLUSION: Distribution-adding was confounded by unsystematic inter/intra-observer rectum-contouring errors and registration accuracy near the anterior rectal wall. Consequently, clinical use of distribution-adding to assess rectal doses requires careful contour and registration evaluation.

Modeling Urinary Dysfunction After External Beam Radiation Therapy of the Prostate Using Bladder Dose-Surface Maps: Evidence of Spatially Variable Response of the Bladder Surface.

PURPOSE: We assessed the association of the spatial distribution of dose to the bladder surface, described using dose-surface maps, with the risk of urinary dysfunction. METHODS AND MATERIALS: The bladder dose-surface maps of 754 participants from the TROG 03.04-RADAR trial were generated from the volumetric data by virtually cutting the bladder at the sagittal slice, intersecting the bladder center-of-mass through to the bladder posterior and projecting the dose information on a 2-dimensional plane. Pixelwise dose comparisons were performed between patients with and without symptoms (dysuria, hematuria, incontinence, and an International Prostate Symptom Score increase of ≥10 [ΔIPSS10]). The results with and without permutation-based multiple-comparison adjustments are reported. The pixelwise multivariate analysis findings (peak-event model for dysuria, hematuria, and ΔIPSS10; event-count model for incontinence), with adjustments for clinical factors, are also reported. RESULTS: The associations of the spatially specific dose measures to urinary dysfunction were dependent on the presence of specific symptoms. The doses received by the anteroinferior and, to lesser extent, posterosuperior surface of the bladder had the strongest relationship with the incidence of dysuria, hematuria, and ΔIPSS10, both with and without adjustment for clinical factors. For the doses to the posteroinferior region corresponding to the area of the trigone, the only symptom with significance was incontinence. CONCLUSIONS: A spatially variable response of the bladder surface to the dose was found for symptoms of urinary dysfunction. Limiting the dose extending anteriorly might help reduce the risk of urinary dysfunction.