Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Cost-effectiveness of hypofractionated versus conventional radiotherapy in patients with intermediate-risk prostate cancer: An ancillary study of the PROstate fractionated irradiation trial - PROFIT.

PURPOSE: To evaluate the cost-effectiveness of moderate Hypofractionated Radiotherapy (H-RT) compared to Conventional Radiotherapy (C-RT) for intermediate-risk prostate caner (PCa). METHODS: A prospective randomized clinical trial including 222 patients from six French cancer centers was conducted as an ancillary study of the international PROstate Fractionated Irradiation Trial (PROFIT). We carried-out a cost-effectiveness analysis (CEA) from the payer's perspective, with a time horizon of 48 months. Patients assigned to the H-RT arm received 6000 cGy in 20 fractions over 4 weeks, or 7800 cGy in 39 fractions over 7 to 8 weeks in the C-RT arm. Patients completed quality of life (QoL) questionnaire: Expanded Prostate Cancer Index Composite (EPIC) at baseline, 24 and 48 months, which were mapped to obtain a EuroQol five-dimensional questionnaire (EQ-5D) equivalent to generate Quality Adjusted Life Years (QALY). We assessed differences in QALYs and costs between the two arms with Generalized Linear Models (GLMs). Costs, estimated in euro (€) 2020, were combined with QALYs to estimate the Incremental Cost-effectiveness ratio (ICER) with non-parametric bootstrap. RESULTS: Total costs per patien were lower in the H-RT arm compared to the C-RT arm €3,062 (95 % CI: 2,368 to 3,754) versus €4,285 (95 % CI: 3,355 to 5,215), (p < 0.05). QALY were marginally higher in the H-RT arm, however this difference was not significant: 0.044 (95 % CI: - 0.016 to 0.099). CONCLUSIONS: Treating localized prostate cancer with moderate H-RT could reduce national health insurance spending. Adopting such a treatment with an updated reimbursement tariff would result in improving resource allocation in RT management.

Marine heat wave and multiple stressors tip bull kelp forest to sea urchin barrens.

Extreme climatic events have recently impacted marine ecosystems around the world, including foundation species such as corals and kelps. Here, we describe the rapid climate-driven catastrophic shift in 2014 from a previously robust kelp forest to unproductive large scale urchin barrens in northern California. Bull kelp canopy was reduced by >90% along more than 350 km of coastline. Twenty years of kelp ecosystem surveys reveal the timing and magnitude of events, including mass mortalities of sea stars (2013-), intense ocean warming (2014-2017), and sea urchin barrens (2015-). Multiple stressors led to the unprecedented and long-lasting decline of the kelp forest. Kelp deforestation triggered mass (80%) abalone mortality (2017) resulting in the closure in 2018 of the recreational abalone fishery worth an estimated $44 M and the collapse of the north coast commercial red sea urchin fishery (2015-) worth $3 M. Key questions remain such as the relative roles of ocean warming and sea star disease in the massive purple sea urchin population increase. Science and policy will need to partner to better understand drivers, build climate-resilient fisheries and kelp forest recovery strategies in order to restore essential kelp forest ecosystem services.

Stereotactic Ablative Radiotherapy Versus Low Dose Rate Brachytherapy or External Beam Radiotherapy: Propensity Score Matched Analyses of Canadian Data.

AIMS: To compare biochemical failure-free survival (BFFS) and overall survival for prostate cancer treated with stereotactic ablative radiotherapy (SABR), low dose rate (LDR) brachytherapy or external beam radiotherapy (EBRT) using a large Canadian multi-institutional database. MATERIALS AND METHODS: Patients with low risk localised prostate cancer treated with SABR, LDR or EBRT and no androgen deprivation therapy were selected. Propensity score matching was used to create two sets of matched cohorts with LDR and EBRT serving as control groups. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to compare differences in BFFS and overall survival between treatment groups. RESULTS: The pre-matched cohort contained 602 patients; the median follow-up was >5.0 years. There were no significant differences in BFFS before or after matching for SABR versus LDR but the prostate-specific antigen (PSA) nadir was lower after LDR. For the SABR versus EBRT, SABR had a BFFS trend before matching (P = 0.08), which became significant after matching (P < 0.001). CONCLUSIONS: Using the Genitourinary Radiation Oncologists of Canada Prostate Cancer Risk Stratification database, low risk prostate cancer patients receiving SABR had similar BFFS compared with patients receiving LDR but better BFFS than EBRT patients. Further comparative studies of efficacy, quality of life and economic outcomes using a broader risk of patients are warranted.

[Hypofractionated radiotherapy in prostate cancer]. / Hypofractionnement à visée curative dans le cancer de la prostate.

Radiotherapy plays a central role in the management of localized prostate cancer, but the total duration of treatment of nearly 2 months poses not only problems of fatigue related to repetitive transports, especially for older patients, but also increases the overall cost of treatment including linear accelerators occupancy and patient transportation. To address this problem, various teams have developed hypofractionated radiotherapy protocols seeking to maintain the same efficacy and toxicity while reducing the total duration of treatment. These hypofractionated protocols require recent techniques such as image-guided radiation therapy (IGRT) and intensity-modulated radiation therapy (IMRT). Single centre series have validated the feasibility of "light" hypofractionation schemes at doses per fraction less than 6 Gy Similarly, different teams have shown the possibility of stereotactic irradiation for delivering "severe" hypofractionation schemes at doses greater than 6 Gy per fraction. Whatever the dose per fraction, the current clinical data support the conclusion that hypofractionated radiotherapy does not increase mid-term toxicity and could even improve biochemical control. Studies with the objective of demonstrating non-inferiority are expected to definitively validate the role of hypofractionated irradiation in the treatment of prostate cancer.

Results from a multicenter prostate IMRT dosimetry intercomparison for an OCOG-TROG clinical trial.

PURPOSE: A multi-institution dosimetry intercomparison has been undertaken of prostate intensity modulated radiation therapy (IMRT) delivery. The dosimetry intercomparison was incorporated into the quality assurance for site credentialing for the Trans-Tasman Radiation Oncology Group Prostate Fractionated Irradiation Trial 08.01 clinical trial. METHODS: An anthropomorphic pelvic phantom with realistic anatomy was used along with multiplanar dosimetry tools for the assessment. Nineteen centers across Australia and New Zealand participated in the study. RESULTS: In comparing planned versus measured dose to the target at the isocenter within the phantom, all centers were able to achieve a total delivered dose within 3% of planned dose. In multiplanar analysis with radiochromic film using the gamma analysis method to compare delivered and planned dose, pass rates for a 5%/3 mm criterion were better than 90% for a coronal slice through the isocenter. Pass rates for an off-axis coronal slice were also better than 90% except for one instance with 84% pass rate. CONCLUSIONS: Strengths of the dosimetry assessment procedure included the true anthropomorphic nature of the phantom used, the involvement of an expert from the reference center in carrying out the assessment at every site, and the ability of the assessment to detect and resolve dosimetry discrepancies.

Locally advanced prostate cancer: current controversies and optimisation opportunities.

Prostate cancer is the most common malignancy in men worldwide. The rate of patients presenting with locally advanced prostate cancer has declined in recent decades, mainly due to prostate-specific antigen screening, but the management of these patients still remains controversial. Current literature suggests that the standard of care for these patients is a combination approach with radiation therapy and androgen deprivation therapy. However, there remain many unresolved issues, including the role of dose-escalated radiation therapy, the additional benefit of surgery and the role of systemic therapy, both standard chemotherapeutic agents and novel agents. Furthermore, in the era of personalised medicine, additional research is needed to evaluate the role of biomarkers to better predict the risk of local and systemic relapse in this population.

Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response.

BACKGROUND: High plasma osteopontin (OPN) has been linked to tumour hypoxia, metastasis, and poor prognosis. This study aims to assess whether plasma osteopontin was a biomarker of increasing progression within prostate cancer (PCa) prognostic groups and whether it reflected treatment response to local and systemic therapies. METHODS: Baseline OPN was determined in men with localised (n=199), locally recurrent (n=9) and castrate-resistant, metastatic PCa (CRPC-MET; n=37). Receiver-operating curves (ROC) were generated to describe the accuracy of OPN for distinguishing between localised risk groups or localised vs metastatic disease. We also measured OPN pre- and posttreatment, following radical prostatectomy, external beam radiotherapy (EBRT), androgen deprivation (AD) or taxane-based chemotherapy. RESULTS: The CRPC-MET patients had increased baseline values (mean 219; 56-513 ng ml(-1); P<0.0001) compared with the localised, non-metastatic group (mean 72; 12-438 ng ml(-1)). The area under the ROC to differentiate localised vs metastatic disease was improved when OPN was added to prostate-specific antigen (PSA) (0.943-0.969). Osteopontin neither distinguished high-risk PCa from other localised PCa nor correlated with serum PSA at baseline. Osteopontin levels reduced in low-risk patients after radical prostatectomy (P=0.005) and in CRPC-MET patients after chemotherapy (P=0.027), but not after EBRT or AD. CONCLUSION: Plasma OPN is as good as PSA at predicting treatment response in CRPC-MET patients after chemotherapy. Our data do not support the use of plasma OPN as a biomarker of increasing tumour burden within localised PCa.

Topotecan and cyclophosphamide in adults with relapsed sarcoma.

UNLABELLED: Background. The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing's sarcoma (EWS). We sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Patients and Methods. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75 mg/m(2)/day (days 1-5) and C = cyclophosphamide at 250 mg/m(2)/day (days 1-5) every 21 days. Results. Fifteen patients, median age 31 years (range 17.5-56) had nonpleomorphic rhabdomyosarcoma (RMS, n = 6), EWS, n = 5, synovial sarcoma (SS, n = 2) leiomyosarcoma (LMS, n = 1), and desmoplastic small round cell tumour (DSRCT, n = 1). Median time to progression was 2.5 months (range 1.6-13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. CONCLUSION: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients.

Clinical features, treatment, and outcome in 102 adult and pediatric patients with localized high-grade synovial sarcoma.

Background. There remains controversy on the routine use of chemotherapy in localized SS. Methods. The records of 87 adult (AP) and 15 pediatric (PP) patients with localized SS diagnosed between 1986 and 2007 at 2 centres in Toronto were reviewed. Results. Median age for AP and PP was 37.6 (range 15-76) and 14 (range 0.4-18) years, respectively. 65 (64%) patients had large tumours (>5 cm). All patients underwent en bloc surgical resection resulting in 94 (92.2%) negative and 8 (7.8%) microscopically positive surgical margins. 72 (82.8%) AP and 8 (53%) PP received radiotherapy. Chemotherapy was administered to 12 (13.8%) AP and 13 (87%) PP. 10 AP and 5 PP were evaluable for response to neoadjuvant chemotherapy, with response rate of 10% and 40%, respectively. 5-year EFS and OS was 69.3 ± 4.8% and 80.3 ± 4.3%, respectively, and was similar for AP and PP, In patients with tumors >5 cm, in whom chemotherapy might be considered most appropriate, relapse occurred in 9/19 (47%) with chemotherapy, compared to 17/46 (37%) In those without. Conclusions. Patients with localized SS have a good chance of cure with surgery and RT. Evidence for a well-defined role of chemotherapy to improve survival In localized SS remains elusive.

Development of a dosimetry inter-comparison for IMRT as part of site credentialing for a TROG multi-centre clinical trial for prostate cancer.

A methodology has been developed for a dosimetry inter-comparison of intensity modulated radiation therapy (IMRT) delivery in Australasia. The inter-comparison is part of site credentialing for those sites participating in the prostate fractionated irradiation trial (PROFIT) for intermediate-risk prostate patients developed by the Ontario Clinical Oncology Group and coordinated in Australasia by the Trans Tasman Radiation Oncology Group. Features of the dosimetry inter-comparison design included the use of a dedicated pelvic anthropomorphic phantom, the use of a single CT data set of the phantom including contours and the use of radiochromic film as a dosimeter. Action levels for agreement between measured dose and treatment planning system dose have been proposed based on measurement uncertainty and international experience. A trial run of the dosimetry procedure at the reference centre gave results within the predefined action levels.

Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: a clinical initiative.

The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.

Radiation therapy in prostate cancer: a risk-adapted strategy.

External-beam radiotherapy and brachytherapy, widely utilized as curative treatment modalities for prostate cancer, have undergone significant clinical and technological advances in recent decades. Contemporary radiotherapy treatment algorithms use pretreatment prognostic factors to stratify patients into low-, intermediate-, and high-risk groups that correlate with both pathologic stage of disease and risk of recurrence after treatment. The use of risk groups and additional prognostic factors guide selection of the optimal treatment modalities for individual patients. Here, the roles of external-beam radiotherapy, brachytherapy, and neoadjuvant or adjuvant androgen deprivation therapy are discussed in that context. Additional prognostic factors for recurrence in the post-prostatectomy setting and the role of adjuvant and salvage radiation therapy are also reviewed. The risk-adaptive approach in radiotherapy for prostate cancer aims to optimize cancer control outcomes while minimizing the morbidity of treatment.

Inter-observer variability of prostate delineation on cone beam computerised tomography images.

AIM: To determine the inter-observer variability of defining the prostate gland on cone beam computerised tomography images for the purposes of image-guided radiotherapy. MATERIALS AND METHODS: Five genitourinary oncologists contoured the prostate gland on five cone beam computerised tomography datasets. The variations in prostate boundary delineation and consequent isocentre placement between observers were measured. Variations in volume and centre of mass were calculated. The variation in boundary definition was determined with finite element modelling. RESULTS: The average standard deviation for centre of mass displacements was small, measuring 0.7, 1.8 and 2.8mm in the left-right, anterior-posterior and superior-inferior directions, respectively. The standard deviation for volume determination was 8.93 cm(3) with large variability (3.98-19.00 cm(3)). The mean difference between the computerised tomography-derived volume and the mean cone beam-derived volume was 16% (range 0-23.7%). The mean standard deviations for left-right, anterior-posterior and superior-inferior boundary displacements were, respectively, 1.8, 2.1 and 3.6 mm. The maximum deviation seen was 9.7 mm in the superior direction. CONCLUSION: Expert observers had difficulty agreeing upon the location of the prostate peri-prostatic interface on the images provided. The effect on the centre of mass determination was small, and inter-observer variability for prostate detection on cone beam computerised tomography images is not prohibitive to the use of soft tissue guidance protocols. Potential exists for significant systematic matching errors, and points to the need for rigorous therapist image recognition training and development of guidance protocols before clinical implementation of soft tissue cone beam image guidance.

Defining the optimal treatment strategy for localized prostate cancer patients: a survey of ongoing studies at the National Cancer Institute of Canada Clinical Trials Group.

The designation "clinically localized prostate cancer" comprises a group of biologically heterogeneous tumours with different growth rates and risks of relapse. Because prostate cancer is primarily a disease of older men, treatment selection must take into account the prognosis of the tumour, patient age, comorbidities, side effects of treatment, and patient preferences. Clinical trials must identify the various prognostic groups and test the appropriate treatment strategies within these subgroups.

A two isocenter IMRT technique with a controlled junction dose for long volume targets.

Most IMRT techniques have been designed to treat targets smaller than the field size of conventional linac accelerators. In order to overcome the field size restrictions in applying IMRT, we developed a two isocenter IMRT technique to treat long volume targets. The technique exploits an extended dose gradient throughout a junction region of 4-6 cm to minimize the impact of field match errors on a junction dose and manipulates the inverse planning and IMRT segments to fill in the dose gradient and achieve dose uniformity. Techniques for abutting both conventional fields with IMRT ('Static + IMRT') and IMRT fields ('IMRT + IMRT') using two separate isocenters have been developed. Five long volume sarcoma cases have been planned in Pinnacle (Philips, Madison, USA) using Elekta Synergy and Varian 2100EX linacs; two of the cases were clinically treated with this technique. Advantages were demonstrated with well-controlled junction target uniformity and tolerance to setup uncertainties. The junction target dose heterogeneity was controlled at a level of +/-5%; for 3 mm setup errors at the field edges, the junction target dose changed less than 5% and the dose sparing to organs at risk (OARs) was maintained. Film measurements confirmed the treatment planning results.

Intra-prostatic fiducial markers and concurrent androgen deprivation.

AIMS: To document the case of a man with adenocarcinoma of the prostate treated with external beam radiotherapy and concurrent androgen deprivation. MATERIALS AND METHODS: The man, who received 79.8 Gy in 42 fractions of radiotherapy over 8.5 weeks using three intra-prostatic gold fiducial markers for on-line set-up correction, started an anti-androgen 2.5 weeks before radiotherapy, on the day of his planning computed tomography, and a gonadotropin-releasing hormone agonist on his first day of radiotherapy. RESULTS: In the sixth week of radiotherapy, the distance between the fiducial markers had diminished: superior to posterior-mid (from 19 to 11 mm), posterior-mid to inferior (from 19 to 15 mm), and superior to inferior (from 31 to 22 mm), so the patient was rescanned. Between the two planning computed tomographies, the prostate volume had decreased from 44.3 to 28.3 cm3 (-36%). Had the planned radiotherapy been delivered to the anatomy of the rescan, the dose to the rectal wall would have exceeded the planned dose-volume histogram constraints. However, with the patient set up to the fiducial markers, the dose-volume histogram constraints for the rectal wall and bladder wall were met throughout the course of radiotherapy. CONCLUSION: Involution of the prostate owing to concurrent androgen deprivation may cause in-migration of implanted fiducial markers and excessive dose to the rectal wall. With concurrent androgen deprivation, daily on-line set-up correction to fiducial markers can aid in safe dose escalation.