Dr Alison Tree
Honorary Faculty: Uro-oncology Clinical Trials
OrcID: 0000-0002-5033-424X
Phone: +44 20 8661 3271
Email: [email protected]
Also on: @alison_tree
Location: Sutton
OrcID: 0000-0002-5033-424X
Phone: +44 20 8661 3271
Email: [email protected]
Also on: @alison_tree
Location: SuttonBiography
Dr Alison Tree was appointed as a consultant clinical oncologist at The Royal Marsden NHS Foundation Trust in 2014, specialising in urological malignancies. Her MD thesis was on stereotactic body radiotherapy (SBRT) techniques for prostate and oligometastatic cancer.
Her current research interests focus on technical radiotherapy developments in prostate cancer, aiming to make radiotherapy more effective and reduce side effects. Dr Tree leads the Prostate Group in the International MR Linac consortium, which she now also chairs. She is lead GU editor for the International Journal of Radiation Oncology Biology and Physics.
She is currently leading trials in MR-guided prostate radiotherapy (the PRISM trial), boosting dominant intra-prostatic lesions (the DELINEATE trial) and ablating oligoprogressing metastases in advanced prostate cancer (the TRAP trial). Currently her group are recruiting to the HERMES trial which is testing whether prostate cancer can be cured in just 2 fractions and the DESTINATION trials, looking a novel ways to minimise side effects after radiotherapy. She is also involved in the PACE trials, and leads PACE C.
Dr Tree is a member of the Cancer Research UK Convergence Science Centre, which brings together leading researchers in engineering, physical sciences, life sciences and medicine to develop innovative ways to address challenges in cancer.
Types of Publications
Journal articles
The National Cancer Audit Collaborating Centre (NATCAN) was launched on Oct 1, 2022, and is delivering ten national cancer audits to assess and assure the quality of National Health Service (NHS) cancer care in England and Wales. These audits are a collaboration between clinical leaders, methodological experts, professional organisations, civil society, and policy makers to develop and implement performance measures across all NHS cancer care and inform quality improvement of the care pathway. The aims of NATCAN are to provide transparent and timely feedback to hospitals about their practices and outcomes of cancer care, identify opportunities for improvement of cancer care, and support hospitals to conduct quality-improvement initiatives. The key methods used to achieve these aims were use of routinely collected data that did not necessitate bespoke collection by health-care staff specifically for the audit; public reporting of outcomes of care at hospital and regional levels; assessment of determinants of variation in cancer care to target quality improvement; and a central governance structure to ensure that unsafe care or outlying performance were managed effectively and promptly. This Personal View provides comparisons between NATCAN and other international audit programmes, including how other countries could consider and incorporate components of NATCAN, alongside scope for future development.
<h4>Introduction</h4>Magnetic resonance image-guided adaptive radiotherapy (MRIgART) reduces uncertainties by correcting for day-to-day target and organ-at-risk deformation and motion. This is the first study to examine the dosimetric impact of MRIgART for ultrahypofractionated prostate cancer treatment, compared to standard-of-care image-guided non-adapted radiotherapy.<h4>Methods</h4>Twenty patients with localised prostate cancer, who received ultrahypofractionated MRIgART on the Unity MR linac (Elekta, Sweden) were retrospectively analysed. Online daily MRI was acquired for replanning (MRI<sub>session</sub>) and a second for position verification before treatment (MRI<sub>verification</sub>). To compare delivered dose with and without adaptation, three plans were generated offline per fraction; a session plan (reference plan adapted to MRI<sub>session</sub> anatomy), a verification plan (session plan recalculated on MRI<sub>verfication</sub> anatomy), and a non-adapted plan (reference plan recalculated on MRI<sub>verfication</sub> anatomy). Target and organ-at-risk doses were calculated, and dose difference evaluated.Secondary analysis, using deformable dose accumulation, estimated verification and non-adapted dose to primary target (CTVpsv) substructures; prostate, gross tumour volume (GTV) and proximal 1 cm of seminal vesicles (1cmSV). Impact of prostate, rectum and bladder volume changes on dose were evaluated.<h4>Results</h4>Median dose to 95 % of the CTVpsv was significantly higher with adaptation; 40.3, 40.0 and 38.2 Gy for session, verification, and non-adapted plans. Adaptation achieved a lower median urethra V42Gy dose but bladder V37Gy dose was lower when not adapting. Rectum V36Gy dose was similar for adapted and non-adapted plans.CTVpsv substructure dose difference was greatest for 1cmSV; 40.0 versus 37.5 Gy for verification/non-adapted plans. Adaptation achieved significantly higher prostate only, but not GTV doses. Prostate and rectal volume changes had a negative impact on non-adapted dose only.<h4>Conclusion</h4>MRIgART, offers significant dosimetric benefit for ultrahypofractionated prostate cancer compared to non-adapted strategies. Greatest benefit is expected for those with SV or high-risk of SV involvement, persistent rectal gas, prostate swelling and for the application of novel dose strategies including GTV dose escalation and non-involved prostate dose de-escalation.
<h4>Introduction</h4>Bladder and rectal preparation regimes for prostate cancer (PCa) radiotherapy (RT) can heighten anxiety before and during RT. Patient's perception of RT preparation is under-represented in the literature. To address this gap, patient's experience of preparation with respect to understanding, comfort, anxiety, effectiveness and impact on daily life was examined.<h4>Materials and methods</h4>A novel patient preparation survey was created and validated, it contained 12 original questions related to general, bladder and rectal preparation. Plus, the Patient Health Questionnaire 4 (PHQ4) and question 15 of the Expanded Prostate Cancer Index Composite (EPIC).Eligible patients were individuals referred for prostate or prostate bed +/- pelvic lymph node RT from March-May 2024. Surveys were issued immediately after the patient's planning scan, those completing the survey at this timepoint were asked to repeat it in their first and final weeks of RT.<h4>Results</h4>The survey was completed by 103/125 eligible patients at their planning scan, 47/103 in the first and 52/103 in the final week of RT. Perception of preparation was largely positive. For general and bladder preparation positive question response rate ranged from 55 to 98 % and negative from 0 to 26 %. Rectal preparation response rate was 59-100 % positive and 0-35 % negative. Difficulty maintaining a full bladder and using enemas was greatest at the end of RT.No significant difference in experience was found for participants using or not using enemas for preparation. Anxiety and depression (PHQ4) affected 12-13 % of respondents, and significantly more patients reported bowel toxicity (EPIC), in the last week of RT compared to earlier timepoints.<h4>Conclusion</h4>The authors conclude that the preparation needs of their patients are well met. However, a considerable number did find preparation difficult, disruptive and ineffective, more so at the end of treatment. Further qualitative analysis of patient's experience is needed to better understand why individuals experience varies.
<h4>Background and purpose</h4>Radiation damage to the neurovascular bundles (NVB) has been linked to erectile dysfunction after prostate cancer radiotherapy (PCa). NVB sparing using coplanar and non-coplanar automated treatment planning is presented here in two settings: (1) without compromising target coverage, (2) allowing target coverage compromise.<h4>Material and methods</h4>20 previously treated patients with localized PCa. Based on a MRI-CT match, the NVB were retrospectively delineated. All treatment plans (5 × 7.25 Gy) were automatically generated using Erasmus-iCycle (in-house automated treatment planning algorithm). Non-NVB sparing (non-NVBsparing) plans and NVB sparing plans in two settings were generated: (1) uncompromised NVB sparing (u-NVBsparing; maintaining target coverage) (2) and compromised NVB sparing (c-NVBsparing; allowing target underdosage). Coplanar and non-coplanar beam arrangements were compared. U-NVBsparing was compared to non-NVBsparing. C-NVBsparing plans were visualized in Pareto fronts. Statistical significance (p-value < 0.05) was determined by Wilcoxon signed-rank test.<h4>Results</h4>u-NVBsparing compared to non-NVBsparing plans showed statistically significant median reductions in NVB D0.1 cc (38.9 vs 42.6 Gy for coplanar; 38.9 vs 43.3 Gy for non-coplanar) and Dmean (25.6 vs 30.0 Gy for coplanar; 24.7 vs 30.2 Gy for noncoplanar). Further lowering NVB D0.1 cc in c-NVBsparing plans clearly correlated to lower target coverage. Non-coplanar c-NVBsparing plans maintained significantly higher target coverages for similar NVB D0.1 cc values, compared to coplanar plans.<h4>Conclusion</h4>NVB sparing without compromising target coverage is feasible. No clinically relevant benefit was found for non-coplanar compared to coplanar NVB sparing plans, although overall statistically superior. Further sparing of the NVB comes at the cost of target coverage, for which a Pareto front could be used as a tool in clinical practise.
Prostate cancer is the most common cancer in two thirds of the world, with an expected doubling in both incidence and mortality in the next two decades. No strong environmental associations exist for the development of prostate cancer; therefore, lifestyle measures are unlikely to mitigate this increasing burden. The last three decades have seen rapid developments in the diagnostic and therapeutic landscape of prostate cancer, including multiparametric magnetic resonance imaging, positron emission tomography, robotic surgery, image-guided hypofractionated and stereotactic radiotherapy, novel anti-androgens and radioligand therapies. Prostate cancer is unique in that not everyone with a diagnosis needs treatment, and active surveillance is the preferred option for some. This review discusses the contemporary management of all stages of prostate cancer in the light of these modern developments, enabling holistic individualization of treatment, and describes the promise of future research to further improve outcomes.
Prostate cancer is the most commonly diagnosed cancer in men worldwide. Radiotherapy is an integral component for the treatment of localized prostate cancer. Radiobiologically, prostate cancer is sensitive to an increased dose of radiotherapy delivered per fraction, called "hypofractionation", due to intrinsic differences in the rate of cancer cell growth and repair of DNA damage. Hypofractionation delivers planned treatment over fewer radiotherapy sessions compared to conventional fractionation and has been shown to be noninferior to conventional fractionation with an acceptable toxicity profile. Ultra-hypofractionation, often delivered via stereotactic body radiotherapy (SBRT), further reduces the number of treatments by using even larger doses per fraction and has shown promising results with high biochemical control rates and low rates of late toxicity. The adoption of hypofractionated and ultra-hypofractionated schedules improves resource utilization in radiation oncology without compromising patient safety or efficacy. Ongoing research continues to refine patient selection, fractionation schemes, and incorporates advanced imaging, precise treatment planning, and motion management techniques to help mitigate toxicity and optimize outcomes in localized intermediate and high-risk disease.
<h4>Purpose</h4>InPACT addresses the optimal management of locally advanced penile cancer, aiming to prospectively evaluate the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy. At trial inception, radiation therapy protocols for this rare cancer lacked consistency and standardization, necessitating multicenter, international collaboration to develop comprehensive radiation therapy planning, delivery, and quality assurance guidelines.<h4>Methods and materials</h4>InPACT has 2 main aims; to establish the efficacy of neoadjuvant chemotherapy or chemoradiotherapy in patients with macroscopically-involved inguinal nodes. Second, to compare prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields versus chemoradiation alone in patients whose inguinal node histology predicts a high risk of occult pelvic node involvement. The primary outcome measure for the trial is survival time. An international group was convened to achieve consensus on radiation therapy contouring, planning, dose, fractionation, and delivery for this rare cancer. These guidelines have been used throughout the conduct of the trial to date and form part of the radiation therapy quality assurance for each participating center.<h4>Results</h4>International consensus radiation therapy guidelines were established, encompassing risk status assessment and indications for each treatment region based on radiological and pathologic risk status of nodal basins. Guidance provides a nodal contouring atlas, addresses prepubic fat coverage, and specifies dose fractionation for both neoadjuvant and adjuvant settings, including recommendations for macroscopic disease. Trial recruitment is ongoing. Oncological and toxicity outcomes will be reported in due course.<h4>Conclusions</h4>The InPACT radiation therapy guidelines offer a step toward international consensus on contouring for inguino-pelvic radiation therapy in penile cancer.
<h4>Purpose</h4>To demonstrate the safety and feasibility of 2-fraction stereotactic body radiation therapy (SBRT) for prostate cancer.<h4>Methods and materials</h4>This single-center, noncomparative, phase 2/R-IDEAL 2b trial randomized 46 patients with intermediate/lower high-risk prostate cancer with visible gross tumor volume on multiparametric magnetic resonance imaging to receive 36.25 Gy in 5 fractions over 10 days or 24 Gy in 2 fractions with a gross tumor volume boost up to 27 Gy over 8 days. All treatment was delivered on a magnetic resonance linac with daily adaptive replanning. The primary endpoint was acute grade ≥2 (G2+) genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 5.0). Secondary endpoints include gastrointestinal (GI) toxicity and patient-reported outcomes.<h4>Results</h4>G2+ GU acute toxicity was observed in 6 of 22 patients (27.3%; 95% CI, 0.11-0.50) in the 2-fraction group and 7 of 24 patients (29.2%; 95% CI, 0.13-0.50) in the 5-fraction group. There were no grade 3 GU toxicities. G2+ urinary frequency rose from 4.5% (1 of 22) at week 2 to 13.6% (3 of 22) at week 4 in 2-fraction SBRT. G2+ urinary frequency peaked earlier in 5-fraction SBRT at 16.7% (4 of 24) in week 2, falling to 12.5% (3 of 24) at week 4. At 12 weeks, median Expanded Prostate Cancer Index Composite-26 urinary incontinence score was 85.5 (IQR, 75-100) for 2-fraction SBRT and 100 (IQR, 93.8-100) for 5-fraction SBRT. Urinary irritative-obstructive scores were higher at 12 weeks in the 2-fraction group (93.8; IQR, 87.5-100) than in the 5-fraction group (87.5; IQR, 81.3-93.8). Peak International Prostate Symptoms Score was lower in the 2-fraction group (8; IQR, 4-11) than in the 5-fraction group (13.5; IQR, 10-17). G2+ GI acute toxicity occurred in 3 of 24 (6.8%) after 5-fraction SBRT, but none after 2-fraction SBRT.<h4>Conclusions</h4>Acceptable acute GU toxicity was seen after 2-fraction SBRT. Acute GI toxicity was low. Randomized trials are warranted to explore late toxicity and biochemical control.
<h4>Objective</h4>To evaluate the area-based incidence of metastatic prostate cancer at diagnosis, reflecting the risk of late-stage diagnosis, and overall prostate cancer incidence, reflecting the risk of over-diagnosis, in a country without a formal screening programme.<h4>Methods and analysis</h4>National study of annual prostate cancer incidence between 2015 and 2019. Mixed-effects regression estimated area-based incidence, adjusted for age, ethnicity and socioeconomic deprivation. Linear regression assessed the association between metastatic and overall cancer incidence.<h4>Results</h4>National annual incidence of metastatic prostate cancer was 5.7 per 10 000 men and overall incidence was 43.9. Higher incidence of both metastatic and overall cancer were observed in areas with older populations and with more men with black ethnicity (both p<0.0001). Greater socioeconomic deprivation was linked to higher metastatic but lower overall cancer incidence (p<0.0001). Metastatic incidence varied across the country from 4.0 to 6.8, and prostate cancer overall from 37.9 to 50.1 per 10 000 men. Areas with higher metastatic cancer incidence had lower overall cancer incidence (p<0.0001).<h4>Conclusions</h4>There is significant geographic variation in metastatic prostate cancer incidence at diagnosis, with a higher incidence of metastatic cancer observed in areas with a lower overall prostate cancer incidence and in more socioeconomically deprived neighbourhoods, which likely contributes to poorer long-term outcomes. The findings highlight the need for a targeted, risk-based diagnostic approach as well as improved diagnostic facilities and referral pathways. Further research is needed to understand the factors driving this variation in order to reduce metastatic presentations and tackle inequalities in prostate cancer outcomes.
<h4>Background and objective</h4>International guidelines recommend treatment intensification combining docetaxel or androgen receptor pathway inhibitors with androgen deprivation therapy for metastatic hormone-sensitive prostate cancer (mHSPC). However, evidence suggests underuse in many high-income countries. This study evaluates the use of treatment intensification in the English National Health Service (NHS) and explores patient and hospital-level factors associated with variation.<h4>Methods</h4>All men diagnosed with mHSPC in England between January 2018 and December 2022 were identified through the national cancer registry. Treatment intensification within six months of diagnosis was assessed using hospital and systemic anti-cancer therapy data. Multilevel regression models explored associations between treatment intensification and sociodemographic factors including age, comorbidities, frailty, ethnicity, socioeconomic status, rurality, and year of diagnosis. Variation among the 47 specialist multidisciplinary teams (sMDTs), responsible for coordinating prostate cancer care in England, was also evaluated.<h4>Key findings and limitations</h4>Among 29,713 mHSPC patients, treatment intensification use was 39.0 %. Treatment intensification use decreased with age, comorbidities, frailty, socioeconomic deprivation, and among black patients (p always < 0.05). 59.8 % (n = 9184) of men aged 75 or younger had a record of treatment intensification, compared to only 16.8 % (n = 2404) of men older than 75. The use of treatment intensification across sMDTs ranged from 20.3 % to 53.7 %, with greater variation in older patients, particularly those older than 75.<h4>Conclusions and clinical implications</h4>There is potential underuse of treatment intensification for mHSPC patients, particularly among older, black, and socioeconomically deprived patients. Significant variation in practice exists between specialist prostate cancer teams (sMDTs) nationally, especially in older populations, indicating that many patients may not receive optimal care.
National cancer audits and registers have highlighted significant national and international variation in patient care and outcomes. Quality Improvement (QI) is mandated in radiation oncology but the interventions designed to support QI in this field remain poorly understood. This paper seeks to assess the types of QI interventions in radiation oncology, the QI evaluation design and their impact on process of care measures and patient-related outcomes. MEDLINE and EMBASE were searched systematically for studies of QI interventions in radiation oncology between 2000 and 2024. The studies needed to identify the quantitative or qualitative impact of the QI intervention on process of care measures or patient-related outcomes. Study results were summarised using narrative synthesis and appraised using the Quality Improvement Minimum Quality Criteria Set (QI-MQCS). 26 papers were included in the analysis. The majority of studies were conducted in the USA (n = 13) and in Europe (n = 7), with only two studies conducted at a national level. Ten studies covered all tumour types, with six specifically focusing on head and neck cancers, two each on prostate and nasopharyngeal cancers, and one study each examining lung, cervical, rectal, and breast cancers. The aspects of care evaluated most frequently were those relating to reducing waiting times or increasing utilisation of radiotherapy as per guidelines (n = 15), followed by those seeking to reduce radiotherapy contouring variability (n = 5) and those involving the management of symptoms during or after radiotherapy treatment (n = 6). Only 42 % of studies reported funding, with the most frequent funding source being national, government or federal (n = 6). All QI interventions across the 26 studies were successful as they resulted in an improvement in a process or patient-related outcome measure. The studies scored between 10 and 15 out of 16, according to the QI-MQCS criteria. Despite substantial investments in cancer research and development, there is a scarcity of information on how to enhance the quality of care in radiation oncology. While there are examples of national cancer audits and registers in a number of countries, much of the research in QI interventions is being conducted in the USA. This situation underscores the need for more comprehensive, well-funded studies and improved training for clinicians to conduct high-quality improvement activities and research. There should be a greater emphasis on the substantial gains that can be achieved by improving existing care in terms of access and outcomes, rather than solely focusing on innovation.
<h4>Purpose of review</h4>The introduction of PSMA-PET/CT scans is expected to increase the incidence of clinically lymph node-positive metastatic hormone-sensitive prostate cancer (mHSPC). The 8th AJCC-TNM classify disease with metastasis limited to pelvic nodes (cN1M0) and nonregional lymph nodes (M1a) as stage IV. To date, there is limited prospective evidence for management of this subgroup. Additionally, no specific recommendations currently exist for managing M1a as a distinct condition but as a part of CHAARTED low volume disease (LVD). Our review examines relevant results from phase III trials examining the management of clinically positive nodal disease over the last decade.<h4>Recent findings</h4>STAMPEDE is the only phase III trial that gave recent data about cN1M0 and isolated M1a management. Cohort sub-analysis of the control arm showed improved failure-free survival after local radiotherapy (RT) plus Androgen Deprivation Therapy (ADT), while metastasis-free survival benefit from Abiraterone Acetate with Prednisolone (AAP) addition was noted when compared to standard of care (SOC), awaiting the overall survival (OS) benefit result. The STAMPEDE H arm showed a marginal significance of M1a stratified OS after RT. Future trials, including PEARLS, ALADDIN and STAMPEDE2, are expected to offer more insights. Interventional Phase III trials directed to clinically node positive patients are still needed to aid deciding on the best management, and nodal metastasis number and size impact on prognosis.
<h4>Purpose</h4>Liver metastases are a significant clinical challenge in cancer management, often representing a stage of disease in which curative treatment is still possible. Stereotactic body radiation therapy (SBRT) has emerged as a promising modality for treating these metastases, offering a noninvasive approach with potential for high efficacy. This systematic review and meta-analysis provides a comprehensive analysis of the efficacy and safety of SBRT in treating liver metastases, and practice recommendations are provided.<h4>Methods and materials</h4>We performed a thorough literature review, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, and included 33 studies with a total of 3101 patients and 4437 liver metastases.<h4>Results</h4>The review revealed pooled local control rates at 1, 2, and 3 years of 85%, 75%, and 68% respectively, while overall survival rates were 79%, 54%, and 37%. Grade 3 and 4 side effects occurred in only 3% of patients. The review of the studies highlighted the importance of factors such as primary tumor histology, lesion characteristics, and radiation dose in predicting treatment outcomes.<h4>Conclusions</h4>This review supports the growing body of evidence that SBRT is an efficacious and safe treatment option for liver metastases. It underscores the need for careful patient selection and personalized treatment planning to optimize outcomes.
<h4>Purpose</h4>In prostate cancer patients, high radiation doses to the urethra have been associated with an increased risk of severe genitourinary toxicity following dose-escalated radiotherapy. Urethra-sparing techniques have emerged as a promising approach to reduce urinary toxicity. This international survey aims to evaluate current global practices in urethra-sparing and explore future directions for the implementation of this technique in external beam radiotherapy (EBRT) for prostate cancer.<h4>Methods and materials</h4>In April 2024, a survey consisting of 20 questions was distributed to 26 international radiation oncology experts in prostate cancer EBRT, with 23 experts participating. The survey focused on clinical scenarios which might take benefit from urethra-sparing, the definition of the urethra and urinary organs-at-risk, and urethral dose constraints.<h4>Results</h4>Magnetic resonance imaging with T2-weighted sequences is the preferred method for urethra contouring (83 % consensus). Based on the experts opinion, urethra-sparing should be considered for prostate cancer EBRT, regardless of pelvic irradiation, except in cases where the tumor is located within 2 mm of the urethra and/or transitional zone, or in T4 disease. Most experts would not apply specific dose constraints to the urethra for either conventional or moderate hypofractionation regimens. When delivering stereotactic body radiotherapy (SBRT), urethra-sparing with dose hotspot limitation (urethra steering) is recommended by 70 % of the experts, in particular when combined with focal boosting (91 %). Urethra dose-reduction is also the favored approach for salvage prostate reirradiation with SBRT (70 % agreement). Large variations exists regarding urethral dose constraints.<h4>Conclusions</h4>Urethra-sparing is a promising technique for the mitigation of urinary toxicity in prostate cancer patients undergoing EBRT, particularly recommended for ultra-hypofractionation and reirradiation with SBRT. The lack of consensus on specific urethral dose constraints and optimal sparing techniques underscores the need for further research to standardize practices in this field.
<h4>Background</h4>Trials comparing moderately hypofractionated radiotherapy (MHFRT) to conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs superiority) and MHFRT dose. We compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT.<h4>Methods</h4>This was an individual patient data meta-analysis that identified randomised phase 3 trials of CFRT versus MHFRT that had published individual patient-level data on efficacy and late toxicity. A systematic literature search using MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was initially conducted on Dec 15, 2023, and was re-conducted on Jan 8, 2025. Trials that did not publish efficacy data, did not publish late toxicity data, or did not use modern dose radiotherapy (≥70 Gy in 2 Gy equivalents) in the CFRT group were excluded. Individual patient data were provided to MARCAP by study investigators. Three separate meta-analyses were designed to compare efficacy (primary endpoint was progression-free survival), physician-scored late toxicity (co-primary endpoints were late grade 2 or higher genitourinary and late grade 2 or higher gastrointestinal toxic effects), and patient-reported outcomes (co-primary endpoints were clinically-significant decrements in patient-reported urinary or bowel quality of life) between patients receiving CFRT versus MHFRT.<h4>Findings</h4>We identified 1696 records for review. Seven phase 3 trials comparing MHFRT with CFRT were eligible for inclusion in our analysis. Individual patient data were obtained from these seven studies (3454 patients from three trials comparing CFRT with isodose MHFRT and 2426 patients from four trials comparing CFRT with dose-escalated MHFRT). At a median follow-up of 5·4 years (IQR 4·6-7·2) for isodose MHFRT and 7·1 years (5·7-8·4) for dose-escalated MHFRT, no differences in progression-free survival were detected (hazard ratio 0·92, 95% CI 0·81-1·05; p=0·21 and 0·94, 0·82-1·09; p=0·43 respectively). No increased odds of grade 2 or higher genitourinary toxic effects were identified for either isodose (odds ratio [OR] 1·16, 95 CI% 0·86-1·57; p=0·32) or dose-escalated MHFRT (1·20, 0·95-1·51; p=0·13). The odds of grade 2 or higher gastrointestinal toxic effects were significantly higher with dose-escalated (OR 1·48, 95% CI 1·14-1·92; p=0·0035) but not isodose MHFRT (1·30, 0·59-2·87; p=0·51). Isodose MHFRT was not found to show different odds of urinary quality-of-life decrement (OR 1·03, 95% CI 0·51-2·09; p=0·93) or bowel quality-of-life decrement (0·76, 0·40-1·43; p=0·39). Dose-escalated MHFRT was associated with greater odds of bowel quality-of-life decrement (OR 1·68, 95% CI 1·07-2·61; p=0·023), but no evidence of greater urinary quality-of-life decrement was found (1·57, 0·87-2·85; p=0·13).<h4>Interpretation</h4>Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel toxicity. Isodose regimens, eg, 60 Gy in 20 fractions, should be the standard MHFRT regimen for localised prostate cancer.<h4>Funding</h4>None.
<h4>Background</h4>While SBRT to NSBM has become common, particularly in the oligometastatic population, the approach to treating non-spine bone metastases (NSBM) with stereotactic body radiotherapy (SBRT) varies widely across institutions and clinical trial protocols. We present a comprehensive systematic review of the literatures to inform practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).<h4>Methods</h4>A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with at least 10 patients receiving SBRT for NSBM were identified and meta-analyses were completed to estimate pooled local control and overall survival rates. Published guidelines on NSBM SBRT were reviewed and consolidated.<h4>Results</h4>There were 25 studies included for qualitative analysis and 18 studies for quantitative analysis consisting of 13 retrospective studies, 2 non-randomized prospective studies, 1 randomized phase 2/3 trial, and a subgroup analysis of a phase I trial. The pooled local control rates at 1 and 2 years were 95 % (95 % CI: 89 %-98 %) and 94 % (95 % CI: 86 %-98 %), respectively. Pooled overall survival rates at 1 year and 2 years were 84 % (95 % CI: 73 %-91 %) and 81 % (95 % CI: 45 %-95 %), respectively. Consensus was reached on recommendations to inform treatment simulation, target delineation, dose fractionation, and anatomic site-specific recommendations.<h4>Conclusion</h4>We present ISRS-endorsed consensus recommendations to inform best practice of SBRT to NSBM, which we found to be efficacious and associated with low rates of adverse events.
<h4>Background</h4>The association between acute and late toxicity following prostate radiotherapy has not been well studied using data from multiple randomised clinical trials and fractionation schedules. We aimed to characterise the relationship between acute and late genitourinary and gastrointestinal toxicity among patients receiving conventionally fractionated or moderately hypofractionated prostate radiotherapy.<h4>Methods</h4>This was an individual patient data meta-analysis that identified randomised phase 3 trials of conventionally fractionated or moderately hypofractionated prostate radiotherapy in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium that had individual-level acute and late toxicity data available and were available before Dec 1, 2023. Trials without individual patient data were excluded. Data were provided to MARCAP by study investigators. The associations between acute (≤3 months after radiotherapy) and late (>3 months after radiotherapy) grade 2 or greater genitourinary and gastrointestinal toxicities were assessed using adjusted generalised linear mixed models (adjusted for age, androgen deprivation therapy status, type of radiotherapy, radiation dose, and radiation schedule). In the subset of trials that collected Expanded Prostate Cancer Index Composite quality of life (QOL) evaluations, the association between acute genitourinary and gastrointestinal toxicity and decrements at least twice the minimal clinically important difference (MCID) for urinary and bowel QOL were also evaluated.<h4>Findings</h4>Six of 26 available trials met all the eligibility criteria. 6593 patients were included (conventionally fractionated: n=4248; moderately hypofractionated: n=2345). Median follow-up was 72 months (IQR 61-94). Acute grade 2 or greater genitourinary toxicity was associated with both late grade 2 or greater genitourinary toxicity (odds ratio 2·20 [95% CI 1·88-2·57], p<0·0001) and decrement at least twice the MCID in urinary QOL (1·41 [1·17-1·68], p=0·0002). Acute grade 2 or greater gastrointestinal toxicity was associated with both late grade 2 or greater gastrointestinal toxicity (2·53 [2·07-3·08], p<0·0001) and decrement at least twice the MCID in bowel QOL (1·52 [1·26-1·83], p<0·0001).<h4>Interpretation</h4>Acute toxicity following prostate radiotherapy was statistically significantly associated with late toxicity and with decrement in patient-reported QOL metrics. These data support efforts to evaluate whether interventions that reduce acute toxicity ultimately reduce the risk of late toxicity.<h4>Funding</h4>National Institutes of Health and US Department of Defense.
<h4>Purpose</h4>Optimal management of oligoprogressive prostate cancer while on androgen receptor pathway inhibitors (ARPIs) is not known. The TRAP trial tests the role of stereotactic body radiation therapy (SBRT) in this setting. The objective of this phase 2 prospective, nonrandomized, single-arm trial was to determine if local control of oligoprogressive disease with SBRT can delay further progression by >4 months, postponing time to next therapy.<h4>Methods and materials</h4>Men with castration-resistant prostate cancer with ≤2 oligoprogressive sites developing on treatment with an ARPI, after initial response to therapy, were recruited. All patients were treated to a dose of 30 Gy in 5 fractions (alternate days) or 36 Gy in 6 fractions weekly (prostate only).<h4>Results</h4>Eighty-six men were recruited between October 2018 and February 2023. SBRT was delivered to 81 men. Mean age was 74 years. Most patients (67%) had 1 oligoprogressive disease lesion. Sites irradiated were bone (59%), lung (1%), lymph node (32%), and prostate (7%). Median follow-up was 22.9 months at the time of analysis. Fifty-five (68%) patients had progressed, 33 (41%) of patients progressed within 6 months of radiation therapy. Median progression-free survival (PFS) was 6.4 months (95% CI, 5.9-11.4). An estimated 39% (95% CI, 29-49) of patients have a prolonged PFS of > 12 months. Thirty-three (41%) of patients had started new treatment or died. Median time to either next treatment or death was 27.0 months (95% CI, 14.9-29.6). Median overall survival was 27.2 months (95% CI, 24.7-36.6). Four deaths occurred within 6 months of SBRT; none were related to radiation therapy treatment.<h4>Conclusions</h4>The TRAP trial has demonstrated a median PFS of 6.4 months after SBRT for oligoprogression of prostate cancer, meeting the primary endpoint. Further analysis of biomarker panel including circulating DNA and whole-body magnetic resonance imaging will promote better patient selection.
<h4>Purpose</h4>In the PACE-B study, a nonrandomized comparison of toxicity outcomes between stereotactic body radiation therapy (SBRT) platforms revealed fewer urinary side effects with CyberKnife (CK) compared with conventional linac (CL) SBRT. This analysis compares baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts in PACE-B, aiming to provide insight into possible reasons for differing toxicity outcomes between the platforms.<h4>Methods and materials</h4>Dosimetric parameters for the surrogate urethra (SU), contoured urethra, bladder, bladder trigone (BT), and rectum were extracted from available computed tomography planning scans of PACE-B SBRT patients. The SU and BT were retrospectively delineated. Dose levels analyzed included maximum point dose (Dmax), D2, D50, and D95, where D(n) represents the dose (Gy) to (n)% of the structure. Baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts were compared using Mann-Whitney U tests, t tests, and χ<sup>2</sup> tests.<h4>Results</h4>Of the 414 patients who received SBRT, 169 (41%) were treated with CK-SBRT and 245 (59%) with CL-SBRT, with dosimetric parameters available for 94% of patients (390/414). There was a nonstatistically significant trend toward more low-risk prostate cancer in the CK-SBRT cohort (12% vs 6% P = .02 [nonsignificant]). Margins were similar between platforms, except posteriorly, where CK-SBRT had smaller margins. CK-SBRT plans had significantly higher median SU Dmax (45.9 Gy vs 42.8 Gy, P < .0001), D2%, and D50% compared with CL-SBRT plans. Additionally, CK-SBRT plans had significantly higher median BT Dmax (43.4 Gy vs 41.6 Gy, P < .0001), D2%, and D95%, as well as higher median bladder Dmax, D50%, and D95%. CK-SBRT plans had lower median rectal D2% (35.5 Gy vs 36.0 Gy, P < .0001) but higher rectal D50% and D95%.<h4>Conclusions</h4>Although the CK-SBRT cohort showed lower urinary toxicity, the planned doses to urinary substructures were actually higher, likely due to heterogeneous dose planning. Factors like intrafraction tracking or other confounding variables may explain the differences in toxicity outcomes between the treatment platforms.
<h4>Background</h4>Moderately hypofractionated radiotherapy (MHRT) is a standard treatment for prostate cancer. Stereotactic body radiotherapy (SBRT) is also effective, and has been shown to be non-inferior to MHRT in a lower-risk group of patients who did not require hormone therapy (PACE-B), but randomised data on toxicity for higher-risk patients are lacking. We aimed to compare the early toxicity of MHRT and SBRT.<h4>Methods</h4>The randomised, open-label, phase 3, non-inferiority PACE-C trial, conducted at 53 hospitals across the UK, Republic of Ireland, and New Zealand, recruited men aged at least 18 years with intermediate-risk or high-risk histologically confirmed prostate adenocarcinoma (T1-T3a, Gleason 7-8, and prostate specific antigen 10-30 ng/mL) and with WHO performance status of 0-2. Participants were centrally randomly assigned (1:1; non-masked; permuted block size of four and six; stratified by centre and risk group) to MHRT (60 Gy; 20 daily fractions over 4 weeks) or SBRT (36·25 Gy; five daily or alternate day fractions; over 1-2 weeks) with an additional mandatory clinical target volume dose target of 40 Gy (no margin) to the prostate, and proximal 1 cm of seminal vesicles. 6 months of androgen deprivation therapy was planned and was started before commencement of radiotherapy. The primary outcome of PACE-C is freedom from biochemical or clinical failure, the data for which are not yet mature. The co-primary endpoints for this preplanned safety analysis were the percentages of Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicities at any point during or within 12 weeks of completion of radiotherapy (the early or acute period). Analyses are by treatment received, with participants included if they had one or more fractions of MHRT or SBRT, regardless of their allocated treatment. Late toxicity and efficacy data are awaited as the trial remains in follow-up. The study was prospectively registered with ClinicalTrials.gov, NCT01584258.<h4>Findings</h4>Between Nov 13, 2019, and June 24, 2022, 1208 participants were randomly assigned (601 to MHRT and 607 to SBRT). 608 patients received MHRT and 584 received SBRT, and thus were included in the study analysis. 1136 (95%) of 1192 patients were White, 20 (2%) were Black or Black British, 17 (1%) were Asian or Asian British, and seven (1%) were Chinese or other. During the early period (within 12 weeks of treatment), the co-primary endpoint of RTOG grade 2 or worse genitourinary toxicity was observed in 166 (27%) of 608 patients (95% CI 23·8 to 31·1) receiving MHRT and 162 (28%) of 582 patients (24·3 to 31·7) after SBRT (absolute difference 0·5%, 95% CI -4·7 to 5·7; p=0·89). For grade 2 or worse genitourinary Common Terminology Criteria for Adverse Events (CTCAE), 170 (28%) of 604 patients had events after MHRT and 195 (34%) of 581 patients had events after SBRT (p=0·050). Grade 3 CTCAE genitourinary toxicity was observed in three (<1%) patients receiving MHRT and three (1%) patients receiving SBRT. For grade 2 or worse gastrointestinal CTCAE, 60 (10%) of 604 patients had an event after MHRT and 96 (17%) of 581 patients had an event after SBRT (p=0·0011). Grade 3 CTCAE gastrointestinal toxicity was observed in three (<1%) patients receiving MHRT and four (1%) patients receiving SBRT. During the early period, the co-primary endpoint of RTOG grade 2 or worse gastrointestinal toxicity was observed in 69 (11%) of 608 patients (95% CI 9·0 to 14·2) receiving MHRT and 74 (13%) of 584 patients (10·2 to 15·8) receiving SBRT (absolute difference 1·4%, 95% CI -2·5 to 5·2; p=0·53). There were no treatment-related deaths.<h4>Interpretation</h4>Despite an accelerated treatment schedule and a larger treated volume than PACE-B, SBRT and MHRT had similar rates of early RTOG toxicity.<h4>Funding</h4>The Royal Marsden Cancer Charity.
This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates after stereotactic body radiation therapy (SBRT) for liver-confined hepatocellular carcinoma (HCC) and presents consensus guidelines regarding appropriate patient management. Using the Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published before October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases with the following search terms: ("stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "stereotactic ablative radiotherapy") AND ("hepatocellular carcinoma" OR "HCC"). An aggregated data meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, individual patient data analyses incorporating data from 6 institutions were conducted as their own subgroup analyses. Seventeen observational studies, comprising 1889 patients with HCC treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the aggregated data meta-analysis. The 3- and 5-year OS rates after SBRT were 57% (95% confidence interval [CI], 47%-66%) and 40% (95% CI, 29%-51%), respectively. The 3- and 5-year LC rates after SBRT were 84% (95% CI, 77%-90%) and 82% (95% CI, 74%-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the individual patient data analyses. Factors prognostic for improved OS were tumor size <3 cm, Eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. SBRT is an effective treatment modality for patients with HCC with mature follow-up. Clinical practice guidelines were developed on behalf of the International Stereotactic Radiosurgery Society (ISRS).
<h4>Purpose</h4>The FLAME trial provides strong evidence that MR-guided external beam radiation therapy (EBRT) focal boost for localized prostate cancer increases biochemical disease-free survival (bDFS) without increasing toxicity. Yet, there are many barriers to implementation of focal boost. Our objectives are to systemically review clinical outcomes for MR-guided EBRT focal boost and to consider approaches to increase implementation of this technique.<h4>Methods</h4>We conducted literature searches in four databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline. We included prospective phase II/III trials of patients with localized prostate cancer underdoing definitive EBRT with MR-guided focal boost. The outcomes of interest were bDFS and acute/late gastrointestinal and genitourinary toxicity.<h4>Results</h4>Seven studies were included. All studies had a median follow-up of greater than 4 years. There were heterogeneities in fractionation, treatment planning, and delivery. Studies demonstrated effectiveness, feasibility, and tolerability of focal boost. Based on the Phoenix criteria for biochemical recurrence, the reported 5-year biochemical recurrence-free survival rates ranged 69.7-100% across included studies. All studies reported good safety profiles. The reported ranges of acute/late grade 3 + gastrointestinal toxicities were 0%/1-10%. The reported ranges of acute/late grade 3 + genitourinary toxicities were 0-13%/0-5.6%.<h4>Conclusions</h4>There is strong evidence that it is possible to improve oncologic outcomes without substantially increasing toxicity through MR-guided focal boost, at least in the setting of a 35-fraction radiotherapy regimen. Barriers to clinical practice implementation are addressable through additional investigation and new technologies.
<h4>Background</h4>Centralising prostate cancer surgical and radiotherapy services, requires some patients to travel longer to access treatment, but its impact on actual treatment utilisation and outcomes is unknown.<h4>Methods</h4>Using national cancer registry records linked to administrative hospital data, we identified all patients with high risk and locally advanced prostate cancer diagnosed between 1 April 2019 and 31 March 2020 in the English National Health Service (n = 15,971). Estimated travel times from the patient residential areas to the nearest hospital providing surgery or radiotherapy were estimated for journeys by car and by public transport. Multivariable logistic regression was used to model relationships between travel time and receipt of care with adjustment for patient characteristics.<h4>Results</h4>10,693 (67%) men received radical surgery or radiotherapy (RT) within 12 months of diagnosis. Average travel time to the nearest hospital providing prostatectomy or RT was 23.2 min by private car and 58.2 min by public transport. We found no association between travel time, either by car or public transport and the likelihood of receiving curative treatment. Patients living in the most socially deprived areas, those aged over 70, those with two or more comorbidities, and those of black ethnic origin, were less likely to receive curative treatment (p& =& 0.001 for all associations).<h4>Conclusions</h4>The current configuration of national prostate cancer services is not associated with the likelihood of receiving curative treatment. Further increases in capacity will unlikely improve utilisation rates beyond addressing sociodemographic barriers.
<h4>Background</h4>The distances that patients have to travel can influence their access to cancer treatment. We investigated the determinants of travel time, separately for journeys by car and public transport, to centres providing radical surgery or radiotherapy for prostate cancer.<h4>Methods</h4>Using national cancer registry records linked to administrative hospital data, we identified patients who had radical surgery or radiotherapy for prostate cancer between January 2017 and December 2018 in the English National Health Service. Estimated travel times from the patients' residential area to the nearest specialist surgical or radiotherapy centre were estimated for journeys by car and by public transport.<h4>Results</h4>We included 13,186 men who had surgery and 26,581 who had radiotherapy. Estimated travel times by public transport (74.4 mins for surgery and 69.4 mins for radiotherapy) were more than twice as long as by car (33.4 mins and 29.1mins, respectively). Patients living in more socially deprived neighbourhoods in rural areas had the longest travel times to the nearest cancer treatment centres by car (62.0 mins for surgery and 52.1 mins for radiotherapy). Conversely patients living in more affluent neighbourhoods in urban conurbations had the shortest (18.7 mins for surgery and 17.9 mins for radiotherapy).<h4>Conclusion</h4>Travel times to cancer centres vary widely according to mode of transport, socioeconomic deprivation, and rurality. Policies changing the geographical configuration of cancer services should consider the impact on the expected travel times both by car and by public transport to avoid enhancing existing inequalities in access to treatment and patient outcomes.
Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.
Traditionally, external beam radiotherapy (EBRT) for localized prostate cancer (PCa) involved lengthy courses with low daily doses. However, advancements in radiation delivery and a better understanding of prostate radiobiology have enabled the development of shorter courses of EBRT. Ultrahypofractionated radiotherapy, administering doses greater than 5 Gy per fraction, is now considered a standard of care regimen for localized PCa, particularly for intermediate-risk disease. Stereotactic body radiotherapy (SBRT), a specific type of ultrahypofractionated radiotherapy employing advanced planning, imaging, and treatment technology to deliver in five or fewer fractions, is gaining prominence as a cost-effective, convenient, and safe alternative to longer radiotherapy courses. It is crucial to address practical considerations related to patient selection, fractionation scheme, target delineation, and planning objectives. This is especially important in challenging clinical situations where clear evidence for guidance may be lacking. The Radiosurgery Society endorses this case-based guide with the aim of providing a practical framework for delivering SBRT to the intact prostate, exemplified by two case studies. The article will explore common SBRT dose/fractionation schemes and dose constraints for organs-at-risk. Additionally, it will review existing evidence and expert opinions on topics such as SBRT dose escalation, the use of rectal spacers, the role of androgen deprivation therapy in the context of SBRT, SBRT in special patient populations (e.g., high-risk disease, large prostate, high baseline urinary symptom burdens, and inflammatory bowel disease), as well as new imaging-guidance techniques like Magnetic Resonance Imaging for SBRT delivery.
<h4>Background</h4>Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear.<h4>Methods</h4>RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.<h4>Findings</h4>Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths.<h4>Interpretation</h4>Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population.<h4>Funding</h4>Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
<h4>Background</h4>Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain.<h4>Methods</h4>RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047.<h4>Findings</h4>Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths.<h4>Interpretation</h4>Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy.<h4>Funding</h4>Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
<h4>Aims</h4>To assess toxicity and patient quality of life after stereotactic body radiotherapy (SBRT) to oligoprogressive disease (OPD) in patients with metastatic castrate-resistant prostate cancer (CRPC) on androgen receptor targeted agents (ARTA).<h4>Material and methods</h4>This phase II trial enrolled patients with metastatic CRPC with ≤ 2 oligoprogressive lesions in bone, lymph node, lung, or prostate. All patients were receiving systemic treatment with abiraterone or enzalutamide at the time of oligoprogression. All patients received SBRT to the OPD site(s) and continued the current ARTA. Patients received 30 Gy in 5 fractions (alternate days) to the OPD site. The primary endpoint of the trial is to assess if SBRT to OPD sites results in progression free survival of >6 months. The primary endpoint for this toxicity analysis is the rate of grade 3 or higher adverse events at any timepoint up to 6 months after SBRT. Secondary endpoints included comparing pre- and post-SBRT patient-related outcomes reported using visual analogue scale scores and EQ-5D health questionnaire.<h4>Results</h4>Forty enrolled patients had at least 6 months of follow-up at the time of analysis. Grade 3 or higher toxicity from any cause recorded using common terminology criteria for adverse events and radiation therapy oncology group was found in 8/40 (20%) of patients, but only 1/40 (2.5%) was deemed possibly related to SBRT. There was no significant difference in mean EQ5D visual analogue scale score from baseline to each timepoint after SBRT (p = 0.449).<h4>Conclusion</h4>In this prospective phase II clinical trial for OPD whilst on ARTA in the CRPC setting, we report low grade ≥ 3 toxicity after SBRT. There is no discernible change in patient-reported quality of life due to SBRT treatment. The final results of progression-free survival and toxicity of SBRT treatment will be reported once further follow-up is complete.
<h4>Purpose</h4>The urethra is a critical structure in prostate radiotherapy planning; however, it is impossible to visualise on CT. We developed a surrogate urethra model (SUM) for CT-only planning workflow and tested its geometric and dosimetric performance against the MRI-delineated urethra (MDU).<h4>Methods</h4>The SUM was compared against 34 different MDUs (within the treatment PTV) in patients treated with 36.25Gy (PTV)/40Gy (CTV) in 5 fractions as part of the PACE-B trial. To assess the surrogate's geometric performance, the Dice similarity coefficient (DSC), Hausdorff distance (HD), mean distance to agreement (MDTA) and the percentage of MDU outside the surrogate (UOS) were calculated. To evaluate the dosimetric performance, a paired <i>t</i>-test was used to calculate the mean of differences between the MDU and SUM for the D99, D98, D50, D2 and D1. The D(n) is the dose (Gy) to n% of the urethra.<h4>Results</h4>The median results showed low agreement on DSC (0.32; IQR 0.21-0.41), but low distance to agreement, as would be expected for a small structure (HD 8.4mm (IQR 7.1-10.1mm), MDTA 2.4mm (IQR, 2.2mm-3.2mm)). The UOS was 30% (IQR, 18-54%), indicating nearly a third of the urethra lay outside of the surrogate. However, when comparing urethral dose between the MDU and SUM, the mean of differences for D99, D98 and D95 were 0.12Gy (p=0.57), 0.09Gy (p=0.61), and 0.11Gy (p=0.46) respectively. The mean of differences between the D50, D2 and D1 were 0.08Gy (p=0.04), 0.09Gy (p=0.02) and 0.1Gy (p=0.01) respectively, indicating good dosimetric agreement between MDU and SUM.<h4>Conclusion</h4>While there were geometric differences between the MDU and SUM, there was no clinically significant difference between urethral dose-volume parameters. This surrogate model could be validated in a larger cohort and then used to estimate the urethral dose on CT planning scans in those without an MRI planning scan or urinary catheter.
<h4>Purpose</h4>External beam radiation therapy to the prostate is typically delivered after verification of prostatic position with image guidance. Prostate motion can occur during the delivery of each radiation treatment between the time of localization imaging and completion of treatment. The objective of this work is to review the literature on intrafraction motion (IFM) of the prostate during radiation therapy and offer clinical recommendations on management.<h4>Methods and materials</h4>A comprehensive literature review was conducted on prostate motion during prostate cancer radiation therapy. Information was organized around 3 key clinical questions, followed by an evidence-based recommendation.<h4>Results</h4>IFM of the prostate during radiation therapy is typically ≤3 mm and is unlikely to compromise prostate dosimetry to a clinically meaningful degree for men treated in a relatively short treatment duration with planning target volume (PTV) margins of ≥3 to 5 mm. IFM of 5 mm or more has been observed in up to ∼10% of treatment fractions, with limited dosimetric effect related to the infrequency of occurrence and longer fractionation of therapy. IFM can be monitored in continuous or discontinuous fashion with a variety of imaging platforms. Correction of IFM may have the greatest value when tighter PTV margins are desired (such as with stereotactic body radiation therapy or intraprostatic nodule boosting), ultrahypofractionated courses, or when treatment time exceeds several minutes.<h4>Conclusions</h4>This focused review summarizes literature and provides practical recommendations regarding IFM in the treatment of prostate cancer with external beam radiation therapy.
Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.
<h4>Purpose</h4>The use of magnetic resonance imaging (MRI) in radiotherapy planning is becoming more widespread, particularly with the emergence of MRI-guided radiotherapy systems. Existing guidelines for defining the prostate bed clinical target volume (CTV) show considerable heterogeneity. This study aimed to establish baseline interobserver variability (IOV) for prostate bed CTV contouring on MRI, develop international consensus guidelines, and evaluate its effect on IOV.<h4>Methods and materials</h4>Participants delineated the CTV on 3 MRI scans, obtained from the Elekta Unity MR-Linac, as per their normal practice. Radiation oncologist contours were visually examined for discrepancies, and interobserver comparisons were evaluated against simultaneous truth and performance level estimation (STAPLE) contours using overlap metrics (Dice similarity coefficient and Cohen's kappa), distance metrics (mean distance to agreement and Hausdorff distance), and volume measurements. A literature review of postradical prostatectomy local recurrence patterns was performed and presented alongside IOV results to the participants. Consensus guidelines were collectively constructed, and IOV assessment was repeated using these guidelines.<h4>Results</h4>Sixteen radiation oncologists' contours were included in the final analysis. Visual evaluation demonstrated significant differences in the superior, inferior, and anterior borders. Baseline IOV assessment indicated moderate agreement for the overlap metrics while volume and distance metrics demonstrated greater variability. Consensus for optimal prostate bed CTV boundaries was established during a virtual meeting. After guideline development, a decrease in IOV was observed. The maximum volume ratio decreased from 4.7 to 3.1 and volume coefficient of variation reduced from 40% to 34%. The mean Dice similarity coefficient rose from 0.72 to 0.75 and the mean distance to agreement decreased from 3.63 to 2.95 mm.<h4>Conclusions</h4>Interobserver variability in prostate bed contouring exists among international genitourinary experts, although this is lower than previously reported. Consensus guidelines for MRI-based prostate bed contouring have been developed, and this has resulted in an improvement in contouring concordance. However, IOV persists and strategies such as an education program, development of a contouring atlas, and further refinement of the guidelines may lead to additional improvements.
<h4>Background and purpose</h4>MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac.<h4>Materials and methods</h4>Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires.<h4>Results</h4>Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months.<h4>Conclusion</h4>This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.
<h4>Background</h4>Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily.<h4>Methods</h4>The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015.<h4>Results</h4>A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively.<h4>Conclusion</h4>Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option.
<h4>Background</h4>Whether stereotactic body radiotherapy (SBRT) is noninferior to conventionally or moderately hypofractionated regimens with respect to biochemical or clinical failure in patients with localized prostate cancer is unclear.<h4>Methods</h4>We conducted a phase 3, international, open-label, randomized, controlled trial. Men with stage T1 or T2 prostate cancer, a Gleason score of 3+4 or less, and a prostate-specific antigen (PSA) level of no more than 20 ng per milliliter were randomly assigned (in a 1:1 ratio) to receive SBRT (36.25 Gy in 5 fractions over a period of 1 or 2 weeks) or control radiotherapy (78 Gy in 39 fractions over a period of 7.5 weeks or 62 Gy in 20 fractions over a period of 4 weeks). Androgen-deprivation therapy was not permitted. The primary end point was freedom from biochemical or clinical failure, with a critical hazard ratio for noninferiority of 1.45. The analysis was performed in the intention-to-treat population.<h4>Results</h4>A total of 874 patients underwent randomization at 38 centers (433 patients in the SBRT group and 441 in the control radiotherapy group) between August 2012 and January 2018. The median age of the patients was 69.8 years, and the median PSA level was 8.0 ng per milliliter; the National Comprehensive Cancer Network risk category was low for 8.4% of the patients and intermediate for 91.6%. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% (95% confidence interval [CI], 93.3 to 97.4) in the SBRT group and 94.6% (95% CI, 91.9 to 96.4) in the control radiotherapy group (unadjusted hazard ratio for biochemical or clinical failure, 0.73; 90% CI, 0.48 to 1.12; P = 0.004 for noninferiority), which indicated the noninferiority of SBRT. At 5 years, the cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects was 26.9% (95% CI, 22.8 to 31.5) with SBRT and 18.3% (95% CI, 14.8 to 22.5) with control radiotherapy (P<0.001), and the cumulative incidence of late RTOG grade 2 or higher gastrointestinal toxic effects was 10.7% (95% CI, 8.1 to 14.2) and 10.2% (95% CI, 7.7 to 13.5), respectively (P = 0.94).<h4>Conclusions</h4>Five-fraction SBRT was noninferior to control radiotherapy with respect to biochemical or clinical failure and may be an efficacious treatment option for patients with low-to-intermediate-risk localized prostate cancer as defined in this trial. (Funded by Accuray and others; PACE-B ClinicalTrials.gov number, NCT01584258.).
<h4>Background and objective</h4>Randomised data on patient-reported outcomes (PROs) for stereotactic body radiotherapy (SBRT) and prostatectomy in localised prostate cancer are lacking. PACE-A compared patient-reported health-related quality of life after SBRT with that after prostatectomy.<h4>Methods</h4>PACE is a phase 3 open-label, randomised controlled trial. PACE-A randomised men with low- to intermediate-risk localised prostate cancer to SBRT or prostatectomy (1:1). Androgen deprivation therapy (ADT) was not permitted. The coprimary outcomes were the Expanded Prostate Index Composite (EPIC-26) number of absorbent urinary pads required daily and bowel domain score at 2 yr. The secondary endpoints were clinician-reported toxicity, sexual functioning, and other PROs.<h4>Key findings and limitations</h4>In total, 123 men were randomised (60 undergoing prostatectomy and 63 SBRT) from August 2012 to February 2022. The median follow-up time was 60.7 mo. The median age was 65.5 yr and the median prostate-specific antigen (PSA) value 7.9 ng/ml; 92% had National Comprehensive Cancer Network (NCCN) intermediate-risk disease. Fifty participants received prostatectomy and 60 received SBRT. At 2 yr, 16/32 (50%) prostatectomy and three of 46 (6.5%) SBRT participants used one or more urinary pads daily (p < 0.001; 15 and two, respectively, used one pad daily); the estimated difference was 43% (95% confidence interval [CI]: 25%, 62%). At 2 yr, bowel scores were better for prostatectomy (median [interquartile range] 100 [100-100]) than for SBRT (87.5 [79.2-100]; p < 0.001), with an estimated mean difference of 8.9 between these (95% CI: 4.2, 13.7); sexual scores were worse for prostatectomy (18 [13.8-40.3]) than for SBRT (62.5 [32.0-87.5]). The limitations were slow recruitment and incomplete 2-yr PRO response rates.<h4>Conclusions and clinical implications</h4>SBRT was associated with less patient-reported urinary incontinence and sexual dysfunction, and slightly more bowel bother than prostatectomy. These randomised data should inform treatment decision-making for patients with localised, intermediate-risk prostate cancer.
<h4>Background and objective</h4>Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes.<h4>Methods</h4>We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment.<h4>Key findings and limitations</h4>A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data.<h4>Conclusions and clinical implications</h4>This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics.
<h4>Importance</h4>In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.<h4>Objective</h4>To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).<h4>Design, setting, and participants</h4>This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023.<h4>Exposure</h4>All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care.<h4>Main outcomes and measures</h4>Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery.<h4>Results</h4>In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects.<h4>Conclusions and relevance</h4>In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.
HERMES is a phase II trial of MRI-guided daily-adaptive radiotherapy (MRIgART) randomising men with localised prostate cancer to either 2-fractions of SBRT with a boost to the tumour or 5-fraction SBRT. In the context of this highly innovative regime the dose delivered must be carefully considered. The first ten patients recruited to HERMES were analysed in order to establish the dose received by the targets and organs at risk (OARS) in the context of intrafraction motion. A regression analysis was performed to measure how the volume of air within the rectum might further impact rectal dose secondary to the electron return effect (ERE). One hundred percent of CTV target objectives were achieved on the MRI taken prior to beam-on-time. The post-delivery MRI showed that high-dose CTV coverage was achieved in 90% of sub-fractions (each fraction is delivered in two sub-fractions) in the 2-fraction cohort and in 88% of fractions the 5-fraction cohort. Rectal D1 cm<sup>3</sup> was the most exceeded constraint; three patients exceeded the D1 cm<sup>3</sup> < 20.8 Gy in the 2-fraction cohort and one patient exceeded the D1 cm<sup>3</sup> < 36 Gy in the 5-fraction cohort. The volume of rectal gas within 1 cm of the prostate was directly proportional to the increase in rectal D1 cm<sup>3</sup>, with a strong (R = 0.69) and very strong (R = 0.90) correlation in the 2-fraction and 5-fraction cohort respectively. Dose delivery specified in HERMES is feasible, although for some patients delivered doses to both target and OARs may vary from those planned.
<h4>Introduction</h4>We aimed to establish if stereotactic body radiotherapy to the prostate can be delivered safely using reduced clinical target volume (CTV) to planning target volume (PTV) margins on the 1.5T MR-Linac (MRL) (Elekta, Stockholm, Sweden), in the absence of gating.<h4>Methods</h4>Cine images taken in 3 orthogonal planes during the delivery of prostate SBRT with 36.25 Gray (Gy) in 5 fractions on the MRL were analysed. Using the data from 20 patients, the percentage of radiotherapy (RT) delivery time where the prostate position moved beyond 1, 2, 3, 4 and 5 mm in the left-right (LR), superior-inferior (SI), anterior-posterior (AP) and any direction was calculated.<h4>Results</h4>The prostate moved less than 3 mm in any direction for 90% of the monitoring period in 95% of patients. On a per-fraction basis, 93% of fractions displayed motion in all directions within 3 mm for 90% of the fraction delivery time. Recurring motion patterns were observed showing that the prostate moved with shallow drift (most common), transient excursions and persistent excursions during treatment.<h4>Conclusion</h4>A 3 mm CTV-PTV margin is safe to use for the treatment of 5 fraction prostate SBRT on the MRL, without gating. In the context of gating this work suggests that treatment time will not be extensively lengthened when an appropriate gating window is applied.
<h4>Purpose</h4>Ultrahypofractionated radiation therapy (UHRT) is an effective treatment for localized prostate cancer with an acceptable toxicity profile; boosting the visible intraprostatic tumor has been shown to improve biochemical disease-free survival with no significant effect on genitourinary (GU) and gastrointestinal (GI) toxicity.<h4>Methods and materials</h4>HERMES is a single-center noncomparative randomized phase 2 trial in men with intermediate or lower high risk prostate cancer. Patients were allocated (1:1) to 36.25 Gy in 5 fractions over 2 weeks or 24 Gy in 2 fractions over 8 days with an integrated boost to the magnetic resonance imaging (MRI) visible tumor of 27 Gy in 2 fractions. A minimization algorithm with a random element with risk group as a balancing factor was used for participant randomization. Treatment was delivered on the Unity MR-Linac (Elekta AB) with daily online adaption. The primary endpoint was acute GU Common Terminology Criteria for Adverse Events version 5.0 toxicity with the aim of excluding a doubling of the rate of acute grade 2+ GU toxicity seen in PACE. Analysis was by treatment received and included all participants who received at least 1 fraction of study treatment. This interim analysis was prespecified (stage 1 of a 2-stage Simon design) for when 10 participants in each treatment group had completed the acute toxicity monitoring period (12 weeks after radiation therapy).<h4>Results</h4>Acute grade 2 GU toxicity was reported in 1 (10%) patient in the 5-fraction group and 2 (20%) patients in the 2-fraction group. No grade 3+ GU toxicities were reported.<h4>Conclusions</h4>At this interim analysis, the rate of GU toxicity in the 2-fraction and 5-fraction treatment groups was found to be below the prespecified threshold (5/10 grade 2+) and continuation of the study to complete recruitment of 23 participants per group was recommended.
The advent of MRI guided radiotherapy (MRIgRT) offers enormous promise in the treatment of prostate cancer. The MR-linac offers men the opportunity to receive daily MR imaging to guide and influence their radiotherapy treatment. This review focuses on the advantages that MRIgRT potentially offers as well as any potential disadvantages to MRIgRT that may have been recognized thus far. Ongoing clinical trials evaluating this novel treatment platform for the treatment of prostate cancer are also discussed.
<h4>Purpose</h4>Dose-escalated radiation therapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiation therapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease while limiting toxicity. This study evaluated the toxicity and quality of life (QoL) with CyberKnife-based SBRT and simultaneous integrated boost in localized prostate cancer.<h4>Methods and materials</h4>Eligible participants included newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least 1 of the following: Gleason ≥4+3, magnetic resonance imaging(MRI)-defined T3a N0, prostate-specific antigen ≥20) with up to 2 MRI-identified DILs. Participants received 36.25 Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5 Gy as allowed by organ-at-risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2+ genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using Radiation Therapy Oncology Group scoring, biochemical parameters, International Prostate Symptom Score, International Index of Erectile Function 5, and EQ-5D QoL outcomes were assessed.<h4>Results</h4>Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43 Gy. Cumulative acute grade 2+ genitourinary and gastrointestinal toxicity were 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. International Prostate Symptom Score and urinary QoL scores recovered to baseline by 6 months. Patient-reported outcomes showed no significant change in EQ-5D QoL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date.<h4>Conclusions</h4>CyberKnife SBRT-delivered dose of 36.25 Gy to the prostate with a simultaneous integrated boost up to 47.5 Gy is well tolerated. Acute and late genitourinary and gastrointestinal toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.
<b>Background/Objectives:</b> Advancements in radiotherapy technology now enable the delivery of ablative doses to targets in the upper urinary tract, including primary renal cell carcinoma (RCC) or upper tract urothelial carcinomas (UTUC), and secondary involvement by other histologies. Magnetic resonance imaging-guided linear accelerators (MR-Linacs) have shown promise to further improve the precision and adaptability of stereotactic body radiotherapy (SBRT). <b>Methods:</b> This single-institution retrospective study analyzed 34 patients (31 with upper urinary tract non-metastatic primaries [RCC or UTUC] and 3 with metastases of non-genitourinary histology) who received SBRT from August 2020 through September 2024 using a 1.5 Tesla MR-Linac system. Treatment plans were adjusted by using [online settings] for "adapt-to-position" (ATP) and "adapt-to-shape" (ATS) strategies for anatomic changes that developed during treatment; compression belts were used for motion management. <b>Results:</b> The median duration of treatment was 56 min overall and was significantly shorter using the adapt-to-position (ATP) (median 54 min, range 38-97 min) in comparison with adapt-to-shape (ATS) option (median 80, range 53-235 min). Most patients (77%) experienced self-resolving grade 1-2 acute radiation-induced toxicity; none had grade ≥ 3. Three participants (9%) experienced late grade 1-2 toxicity, potentially attributable to SBRT, with one (3%) experiencing grade 3. <b>Conclusions:</b> We conclude that MR-Linac-based SBRT, supported by online plan adaptation, is a feasible, safe, and highly precise treatment modality for the definitive management of select upper urinary tract lesions.
<h4>Background and purpose</h4>The implementation of MRI-guided online adaptive radiotherapy has facilitated the extension of therapeutic radiographers' roles to include contouring, thus releasing the clinician from attending daily treatment. Following undergoing a specifically designed training programme, an online interobserver variability study was performed.<h4>Materials and methods</h4>117 images from six patients treated on a MR Linac were contoured online by either radiographer or clinician and the same images contoured offline by the alternate profession. Dice similarity coefficient (DSC), mean distance to agreement (MDA), Hausdorff distance (HD) and volume metrics were used to analyse contours. Additionally, the online radiographer contours and optimised plans (n = 59) were analysed using the offline clinician defined contours. After clinical implementation of radiographer contouring, target volume comparison and dose analysis was performed on 20 contours from five patients.<h4>Results</h4>Comparison of the radiographers' and clinicians' contours resulted in a median (range) DSC of 0.92 (0.86 - 0.99), median (range) MDA of 0.98 mm (0.2-1.7) and median (range) HD of 6.3 mm (2.5-11.5) for all 117 fractions. There was no significant difference in volume size between the two groups. Of the 59 plans created with radiographer online contours and overlaid with clinicians' offline contours, 39 met mandatory dose constraints and 12 were acceptable because 95 % of the high dose PTV was covered by 95 % dose, or the high dose PTV was within 3 % of online plan. A clinician blindly reviewed the eight remaining fractions and, using trial quality assurance metrics, deemed all to be acceptable. Following clinical implementation of radiographer contouring, the median (range) DSC of CTV was 0.93 (0.88-1.0), median (range) MDA was 0.8 mm (0.04-1.18) and HD was 5.15 mm (2.09-8.54) respectively. Of the 20 plans created using radiographer online contours overlaid with clinicians' offline contours, 18 met the dosimetric success criteria, the remaining 2 were deemed acceptable by a clinician.<h4>Conclusion</h4>Radiographer and clinician prostate and seminal vesicle contours on MRI for an online adaptive workflow are comparable and produce clinically acceptable plans. Radiographer contouring for prostate treatment on a MR-linac can be effectively introduced with appropriate training and evaluation. A DSC threshold for target structures could be implemented to streamline future training.
The implementation of MRI-guided online adaptive radiotherapy has enabled extension of therapeutic radiographers' roles to include contouring. An offline interobserver variability study compared five radiographers' and five clinicians' contours on 10 MRIs acquired on a MR-Linac from 10 patients. All contours were compared to a "gold standard" created from an average of clinicians' contours. The median (range) DSC of radiographers' and clinicians' contours compared to the "gold standard" was 0.91 (0.86-0.96), and 0.93 (0.88-0.97) respectively illustrating non-inferiority of the radiographers' contours to the clinicians. There was no significant difference in HD, MDA or volume size between the groups.
<h4>Objective</h4>To assess the impact of centralization of prostate cancer surgery and radiotherapy services on the choice of prostate cancer treatment.<h4>Patients and methods</h4>This national population-based study used linked cancer registry data and administrative hospital-level data for all 16 621 patients who were diagnosed between 1 January 2017 and 31 December 2018 with intermediate-risk prostate cancer and who underwent radical prostatectomy (RP) or radical radiation therapy (RT) in the English National Health Service (NHS). Travel times by car to treating centres were estimated using a geographic information system. We used logistic regression to assess the impact of the relative proximity of alternative treatment options on the type of treatment received, with adjustment for patient characteristics.<h4>Results</h4>Of the 78 NHS hospitals that provide RT or RP for prostate cancer, 41% provide both, 36% provide RT and 23% provide RP. Compared to patients who had both treatment options available at their nearest centre where overall 57% of patients received RT and 43% RP, patients were less likely to receive RT if their nearest centre offered RP only and the extra travel time to a hospital providing RT was >15 min (52% of patients received RT and 48% RP%, odds ratio [OR] 0.70 (0.58-0.85); P < 0.001). Conversely, patients were more likely to receive RT if their nearest centre offered RT and the extra travel time to a hospital providing RP was >15 min (63% of patients received RT and 37% RP, OR 1.23 (1.08-1.40); P < 0.001). There was a negligible impact on the type of treatment received if centres providing alternative treatment options were ≤15-min travel time from each other.<h4>Conclusion</h4>The relative proximity of prostate cancer treatment options to a patient's residence is an independent predictor for the type of radical treatment received. Centralization policies for prostate cancer should not focus on one treatment modality but should consider all treatments to avoid a negative impact on treatment choice.
<h4>Purpose</h4>A scoping literature review was conducted to identify gastrointestinal (GI) factors most likely to influence prostate motion during radiotherapy. We proffer that patient specific measurement of these GI factors could predict motion uncertainty during radiotherapy, facilitating personalised care by optimising treatment technique e.g., daily adaption or via bespoke patient pre-habilitation and preparation.<h4>Methods</h4>The scoping review was undertaken as per JBI guidelines. Searches were conducted across four databases: Ovid Medline®, EMBASE, CINAHL and EBSCO discovery. Articles written in English from 2010-present were included. Those pertaining to paediatrics, biological women exclusively, infectious and post-treatment GI morbidity and diet were excluded.Common GI factors impacting men were identified and related symptoms, incidence and measurement tools examined. Prevalence among persons with prostate cancer was explored and suitable assessment tools discussed.<h4>Results</h4>A preliminary search identified four prominent GI-factors: mental health, co-morbidity and medication, physical activity, and pelvic floor disorder. The scoping search found 3644 articles; 1646 were removed as duplicates. A further 1249 were excluded after title and abstract screening, 162 remained subsequent to full text review: 42 mental health, 53 co-morbidity and medication, 39 physical activity and 28 pelvic floor disorder.Six GI factors prevalent in the prostate cancer population and estimated most likely to influence prostate motion were identified: depression, anxiety, diabetes, obesity, low physical activity, and pelvic floor disorder. Reliable, quick, and easy to use tools are available to quantify these factors.<h4>Conclusion</h4>A comprehensive GI factor assessment package suitable to implement into the radiotherapy clinic has been created. Unveiling these GI factors upfront will guide improved personalisation of radiotherapy.
<h4>Introduction</h4>Distended rectums on pre-radiotherapy scans are historically associated with poorer outcomes in patients treated with two-dimensional IGRT. Subsequently, strict rectal tolerances and preparation regimes were implemented. Contemporary IGRT, daily online registration to the prostate, corrects interfraction motion but intrafraction motion remains. We re-examine the need for rectal management strategies when using contemporary IGRT by quantifying rectal volume and its effect on intrafraction motion.<h4>Materials and methods</h4>Pre and during radiotherapy rectal volumes and intrafraction motion were retrospectively calculated for 20 patients treated in 5-fractions and 20 treated in 20-fractions. Small (rectal volume at planning-CT ≤ median), and large (volume > median) subgroups were formed, and rectal volume between timepoints and subgroups compared. Rectal volume and intrafraction motion correlation was examined using Spearman's rho. Intrafraction motion difference between small and large subgroups and between fractions with rectal volume < or ≥ 90 cm<sup>3</sup> were assessed.<h4>Results</h4>Median rectal volume was 74 cm<sup>3</sup>, 64 cm<sup>3</sup> and 65 cm<sup>3</sup> on diagnostic-MRI, planning-CT and treatment imaging respectively (ns). No significant correlation was found between patient's rectal volume at planning-CT and median intrafraction motion, nor treatment rectal volume and intrafraction motion for individual fractions. No significant difference in intrafraction motion between small and large subgroups presented and for fractions where rectal volume breached 90 cm<sup>3</sup>, motion during that fraction was not significantly greater.<h4>Conclusion</h4>Larger rectal volumes before radiotherapy and during treatment did not cause greater intrafraction motion. Findings support the relaxation of strict rectal diameter tolerances and do not support the need for rectal preparation when delivering contemporary IGRT to the prostate.
<h4>Background</h4>T<sub>2</sub> <sup>*</sup> mapping can characterize tumor hypoxia, which may be associated with resistance to therapy. Acquiring T<sub>2</sub> <sup>*</sup> maps during MR-guided radiotherapy could inform treatment adaptation by, for example, escalating the dose to resistant sub-volumes.<h4>Purpose</h4>The purpose of this work is to demonstrate the feasibility of the accelerated T<sub>2</sub> <sup>*</sup> mapping technique using model-based image reconstruction with integrated trajectory auto-correction (TrACR) for MR-guided radiotherapy on an MR-Linear accelerator (MR-Linac).<h4>Materials and methods</h4>The proposed method was validated in a numerical phantom, where two T<sub>2</sub> <sup>*</sup> mapping approaches (sequential and joint) were compared for different noise levels (0,0.1,0.5,1) and gradient delays ([1, -1] and [1, -2] in units of dwell time for x- and y-axis, respectively). Fully sampled k-space was retrospectively undersampled using two different undersampling patterns. Root mean square errors (RMSEs) were calculated between reconstructed T<sub>2</sub> <sup>*</sup> maps and ground truth. In vivo data was acquired twice weekly in one prostate and one head and neck cancer patient undergoing treatment on a 1.5 T MR-Linac. Data were retrospectively undersampled and T<sub>2</sub> <sup>*</sup> maps reconstructed, with and without trajectory corrections were compared.<h4>Results</h4>Numerical simulations demonstrated that, for all noise levels, T<sub>2</sub> <sup>*</sup> maps reconstructed with a joint approach demonstrated less error compared to an uncorrected and sequential approach. For a noise level of 0.1, uniform undersampling and gradient delay [1, -1] (in units of dwell time for x- and y-axis, respectively), RMSEs for sequential and joint approaches were 13.01 and 9.32 ms, respectively, which reduced to 10.92 and 5.89 ms for a gradient delay of [1, 2]. Similarly, for alternate undersampling and gradient delay [1, -1], RMSEs for sequential and joint approaches were 9.80 and 8.90 ms, respectively, which reduced to 9.10 and 5.40 ms for gradient delay [1, 2]. For in vivo data, T<sub>2</sub> <sup>*</sup> maps reconstructed with our proposed approach resulted in less artifacts and improved visual appearance compared to the uncorrected approach. For both prostate and head and neck cancer patients, T<sub>2</sub> <sup>*</sup> maps reconstructed from different treatment fractions showed changes within the planning target volume (PTV).<h4>Conclusion</h4>Using the proposed approach, a retrospective data-driven gradient delay correction can be performed, which is particularly relevant for hybrid devices, where full information on the machine configuration is not available for image reconstruction. T<sub>2</sub> <sup>*</sup> maps were acquired in under 5 min and can be integrated into MR-guided radiotherapy treatment workflows, which minimizes patient burden and leaves time for additional imaging for online adaptive radiotherapy on an MR-Linac.
<h4>Background and purpose</h4>The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it.<h4>Materials and methods</h4>Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm<sup>2</sup>, region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CV<sub>D</sub>) and calculation methods (CV<sub>C</sub>). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group.<h4>Results</h4>The median (range) CV<sub>D</sub> and CV<sub>C</sub> were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CV<sub>C</sub> to 0.04 (0.01-0.16). CV<sub>D</sub> was comparable between ROI types.<h4>Conclusion</h4>Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations.
<h4>Aims</h4>The introduction of on-line magnetic resonance image-guided radiotherapy (MRIgRT) has led to an improvement in the therapeutic workflow of radiotherapy treatments thanks to the better visualization of therapy volumes assured by the higher soft tissue contrast. Magnetic Resonance contrast agents (MRCA) could improve the target delineation in on-line MRIgRT planning as well as reduce inter-observer variability and enable innovative treatment optimization protocols. The aim of this survey is to investigate the utilization of MRCA among centres that clinically implemented on-line MRIgRT technology.<h4>Methods</h4>In September 2021, we conducted an online survey consisting of a sixteen-question questionnaire that was distributed to the all the hospitals around the world equipped with MR Linacs. The questionnaire was developed by two Italian 0.35 T and 1.5 T MR-Linac centres and was validated by four other collaborating centres, using a Delphi consensus methodology.<h4>Results</h4>The survey was distributed to 52 centres and 43 centres completed it (82.7%). Among these centres, 23 institutions (53.5%) used the 0.35T MR-Linac system, while the remaining 20 (46.5%) used the 1.5T MR-Linac system.According to results obtained, 25 (58%) of the centres implemented the use of MRCA for on-line MRIgRT. Gadoxetate (Eovist®; Primovist®) was reported to be the most used MRCA (80%) and liver the most common site of application (58%). Over 70% of responders agreed/strongly agreed to the need for international guidelines.<h4>Conclusions</h4>The use of MRCA in clinical practice presents several pitfalls and future research will be necessary to understand the actual advantage derived from the use of MRCA in clinical practice, their toxicity profiles and better define the need of formulating guidelines for standardising the use of MRCA in MRIgRT workflow.
<h4>Purpose</h4>Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction.<h4>Methods and materials</h4>Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2<sub>α/β= 3 Gy</sub>) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions.<h4>Results</h4>The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P = .21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P = .07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P = .05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P = .27-.98).<h4>Conclusions</h4>We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care.
<h4>Purpose</h4>Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial.<h4>Methods and materials</h4>The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test.<h4>Results</h4>The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/β = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/β = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/β = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but α/β ratio estimates remained stable.<h4>Conclusions</h4>Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/β ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/β ratio assumptions of 3 to 5 Gy.
<h4>Background</h4>Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.<h4>Methods</h4>In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.<h4>Results</h4>A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.<h4>Conclusions</h4>In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).
<h4>Purpose</h4>Evidence of a volume-outcome association in cancer surgery has shaped the centralization of cancer services; however, it is unknown whether a similar association exists for radiation therapy. The objective of this study was to determine the association between radiation therapy treatment volume and patient outcomes.<h4>Methods and materials</h4>This systematic review and meta-analysis included studies that compared outcomes of patients who underwent definitive radiation therapy at high-volume radiation therapy facilities (HVRFs) versus low-volume facilities (LVRFs). The systematic review used Ovid MEDLINE and Embase. For the meta-analysis, a random effects model was used. Absolute effects and hazard ratios (HRs) were used to compare patient outcomes.<h4>Results</h4>The search identified 20 studies assessing the association between radiation therapy volume and patient outcomes. Seven of the studies looked at head and neck cancers (HNCs). The remaining studies covered cervical (4), prostate (4), bladder (3), lung (2), anal (2), esophageal (1), brain (2), liver (1), and pancreatic cancer (1). The meta-analysis demonstrated that HVRFs were associated with a lower chance of death compared with LVRFs (pooled HR, 0.90; 95% CI, 0.87- 0.94). HNCs had the strongest evidence of a volume-outcome association for both nasopharyngeal cancer (pooled HR, 0.74; 95% CI, 0.62-0.89) and nonnasopharyngeal HNC subsites (pooled HR, 0.80; 95% CI, 0.75-0.84), followed by prostate cancer (pooled HR, 0.92; 95% CI, 0.86-0.98). The remaining cancer types showed weak evidence of an association. The results also demonstrate that some centers defined as HVRFs are undertaking very few procedures per annum (<5 radiation therapy cases per year).<h4>Conclusions</h4>An association between radiation therapy treatment volume and patient outcomes exists for most cancer types. Centralization of radiation therapy services should be considered for cancer types with the strongest volume-outcome association, but the effect on equitable access to services needs to be explicitly considered.
<h4>Purpose</h4>The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT).<h4>Materials and methods</h4>Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality.<h4>Results</h4>Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (<i>P</i> interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; <i>P</i> < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; <i>P</i> = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; <i>P</i> < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; <i>P</i> = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; <i>P</i> = .0009) with concurrent/adjuvant ADT.<h4>Conclusion</h4>ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.
<h4>Objectives</h4>To measure the magnitude of intra-fraction prostate motion (IFPM) during stereotactic radiotherapy (SBRT) delivered without intra-fraction tracking.To assess if current margins adequately cover IFPM.To derive margins using new guidelines.<h4>Methods</h4>IFPM was determined in 20 patients receiving 36.25 Gy in 5 fractions using 97 pairs of pre- and post-treatment cone beam CT (CBCT) scans. Correlation of time between CBCT acquisitions and motion was determined. The magnitude of IFPM was compared to current margins (6 mm isotropic, 3 mm posterior). Margins were calculated using IFPM alone and updated guidelines.<h4>Results</h4>The averaged 3D root mean square IFPM was 2.5 mm (4.2 mm). Independent prostate motion was predominantly posterior (70%) and inferior (63%). There was weak correlation between posterior (ρ = 0.38) and inferior (ρ = 0.36) IFPM and time. IFPM greater than current margins occurred in 8 of 97 fractions, six in the posterior direction. Margins were ≤3.5 mm using IFPM alone and ≤3.3 mm Left 3.5 mm Right, 7.0 mm inferior, 3.7 mm superior, 4.4 mm anterior and 3.3 mm posterior using new guidelines, compensating for motion in 92% of fractions.<h4>Conclusions</h4>Our current SBRT margins account for 92% of IFPM, predominantly posterior and inferior. Although updated guidelines suggest an increase in margins inferiorly, any increase must be balanced against the possibility of increased toxicity, particularly if biochemical control and side-effects are favourable with current practice.<h4>Advances in knowledge</h4>The difference between current clinical margins and those determined using updated guidance is demonstrated. The implications must be considered against clinical outcomes.
<h4>Background</h4>Radium-223 is a bone-seeking, ɑ-emitting radionuclide used to treat men with bone metastases from castration-resistant prostate cancer. Sclerotic bone lesions cannot be evaluated using Response Evaluation Criteria in Solid Tumors. Therefore, imaging response biomarkers are needed.<h4>Methods</h4>We conducted a phase 2 randomized trial to assess disease response to radium-223. Men with metastatic castration-resistant prostate cancer and bone metastases were randomly allocated to 55 or 88 kBq/kg radium-223 every 4 weeks for 6 cycles. Whole-body diffusion-weighted magnetic resonance imaging (DWI) was performed at baseline, at cycles 2 and 4, and after treatment. The primary endpoint was defined as a 30% increase in global median apparent diffusion coefficient.<h4>Results</h4>Disease response on DWI was seen in 14 of 36 evaluable patients (39%; 95% confidence interval = 23% to 56%), with marked interpatient and intrapatient heterogeneity of response. There was an association between prostate-specific antigen response and MRI response (odds ratio = 18.5, 95% confidence interval = 1.32 to 258, P = .013). Mean administered activity of radium-223 per cycle was not associated with global MRI response (P = .216) but was associated with DWI response using a 5-target-lesion evaluation (P = .007). In 26 of 36 (72%) patients, new bone metastases, not present at baseline, were seen on DWI scans during radium-223 treatment.<h4>Conclusions</h4>DWI is useful for assessment of disease response in bone. Response to radium-223 is heterogeneous, both between patients and between different metastases in the same patient. New bone metastases appear during radium-223 treatment.The REASURE trial is registered under ISRCTN17805587.
<h4>Purpose</h4>The CHHiP trial assessed moderately hypofractionated radiation therapy in localized prostate cancer. We utilized longitudinal prostate-specific antigen (PSA) measurements collected over time to evaluate and characterize patient prognosis.<h4>Methods and materials</h4>We developed a clinical dynamic prediction joint model to predict the risk of biochemical or clinical recurrence. Modeling included repeated PSA values and adjusted for baseline prognostic risk factors of age, tumor characteristics, and treatment received. We included 3071 trial participants for model development using a mixed-effect submodel for the longitudinal PSAs and a time-to-event hazard submodel for predicting recurrence of prostate cancer. We evaluated how baseline prognostic factor subgroups affected the nonlinear PSA levels over time and quantified the association of PSA on time to recurrence. We assessed bootstrapped optimism-adjusted predictive performance on calibration and discrimination. Additionally, we performed comparative dynamic predictions on patients with contrasting prognostic factors and investigated PSA thresholds over landmark times to correlate with prognosis.<h4>Results</h4>Patients who developed recurrence had generally higher baseline and overall PSA values during follow-up and had an exponentially rising PSA in the 2 years before recurrence. Additionally, most baseline risk factors were significant in the mixed-effect and relative-risk submodels. PSA value and rate of change were predictive of recurrence. Predictive performance of the model was good across different prediction times over an 8-year period, with an overall mean area under the curve of 0.70, mean Brier score of 0.10, and mean integrated calibration index of 0.048; these were further improved for predictions after 5 years of accrued longitudinal posttreatment PSA assessments. PSA thresholds <0.23 ng/mL after 3 years were indicative of a minimal risk of recurrence by 8 years.<h4>Conclusions</h4>We successfully developed a joint statistical model to predict prostate cancer recurrence, evaluating prognostic factors and longitudinal PSA. We showed dynamically updated PSA information can improve prognostication, which can be used to guide follow-up and treatment management options.
Several studies have demonstrated the association between acute and late radiotherapy toxicity in prostate cancer using older radiotherapy techniques. However, whether this association is present with newer techniques such as stereotactic body radiotherapy (SBRT), remains unclear. We use univariable and multivariable logistic regression to analyse the association between grade 2 or worse acute gastrointestinal (GI) and genitourinary (GU) toxicities with equivalent late toxicities in patients treated with SBRT and conventional or moderately fractionated radiotherapy (CRT) within the PACE-B study. 842 patients were included in this analysis. Common Terminology Criteria for Adverse Events (CTCAE) was the primary clinician reported outcome measure used in this analysis. In univariable analysis, experiencing a grade 2+ acute GU toxicity was significantly associated with developing a grade 2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), <i>p</i> < 0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), <i>p</i> < 0.0001). This association remained significant in multivariable analysis. In univariable analysis, experiencing a grade 2+ acute GI toxicity was also associated with developing a grade 2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), <i>p</i> < 0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), <i>p</i> < 0.0001). This association also remained significant in multivariable analysis. Grade 2+ baseline GU symptoms were also associated with grade 2+ late urinary toxicity in both univariable and multivariable analysis. Overall, acute toxicity is an important predictor variable for late GU/GI toxicity after localised prostate radiotherapy using SBRT and CRT. Future work should test whether optimising symptoms pre-treatment and early intervention in those with significant acute toxicities could mitigate the development late of toxicity.
<h4>Aims</h4>Stereotactic body radiotherapy (SBRT) is increasingly used to treat sacral metastases. We analysed our centre's local relapse rates and patterns of failure after sacral SBRT and assessed whether using the consensus contouring recommendation (CCR) may have prevented local relapse.<h4>Materials and methods</h4>We conducted a single-centre retrospective review of patients treated with sacral SBRT between February 2012 and December 2021. The cumulative incidence of local relapse, patterns of failure and overall survival were determined. Two investigators reviewed planning computed tomography scans and imaging at relapse to determine if local relapse was potentially preventable with a larger CCR-derived radiotherapy field.<h4>Results</h4>In total, 34 patients received sacral SBRT, with doses ranging from 24 to 40 Gy over three to five fractions. The most frequently used schedule was 30 Gy in three fractions. Common primaries treated included prostate (n = 16), breast (n = 6), lung (n = 3) and renal (n = 3) cancers. The median follow-up was 20 months (interquartile range 13-55 months). The cumulative incidence of local relapse (4/34) was 2.9% (95% confidence interval 0.2-13.2), 6.3% (95% confidence interval 1.1-18.5) and 16.8% (95% confidence interval 4.7-35.4) at 6 months, 1 year and 2 years, respectively. The patterns of failure were local-only (1/34), local and distant (3/34) and distant relapse (10/34). The overall survival was 96.7% (95% confidence interval 90.5-100) and 90.6% (95% confidence interval 78.6-100) at 1 and 2 years, respectively. For prostate/breast primaries, the cumulative incidence of local relapse was 4.5% (95% confidence interval 0.3-19.4), 4.5% (95% confidence interval 0.3-19.4) and 12.5% (95% confidence interval 1.7-34.8) at 6 months, 1 and 2 years, respectively. Twenty-nine cases (85.3%) deviated from the CCR. Sacral relapse was potentially preventable if the CCR was used in one patient (2.9% of the whole cohort and 25% of the relapsed cohort).<h4>Discussion</h4>We have shown excellent local control rates with sacral SBRT, which was largely planned with a margin expansion approach.
<h4>Purpose</h4>The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.<h4>Materials and methods</h4>Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the <i>R</i><sup>2</sup>). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.<h4>Results</h4>Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The <i>R</i><sup>2</sup> values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.<h4>Conclusion</h4>BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa.
<h4>Purpose</h4>Magnetic resonance (MR)-guided radiation therapy (MRgRT) is a new technique for treatment of localized prostate cancer (PCa). We report the 12-month outcomes for the first PCa patients treated within an international consortium (the MOMENTUM study) on a 1.5T MR-Linac system with ultrahypofractionated radiation therapy.<h4>Methods and materials</h4>Patients treated with 5 × 7.25 Gy were identified. Prostate specific antigen-level, physician-reported toxicity (Common Terminology Criteria for Adverse Events [CTCAE]), and patient-reported outcomes (Quality of Life Questionnaire PR25 and Quality of Life Questionnaire C30 questionnaires) were recorded at baseline and at 3, 6, and 12 months of follow-up (FU). Pairwise comparative statistics were conducted to compare outcomes between baseline and FU.<h4>Results</h4>The study included 425 patients with localized PCa (11.4% low, 82.0% intermediate, and 6.6% high-risk), and 365, 313, and 186 patients reached 3-, 6-, and 12-months FU, respectively. Median prostate specific antigen level declined significantly to 1.2 ng/mL and 0.1 ng/mL at 12 months FU for the nonandrogen deprivation therapy (ADT) and ADT group, respectively. The peak of genitourinary and gastrointestinal CTCAE toxicity was reported at 3 months FU, with 18.7% and 1.7% grade ≥2, respectively. The QLQ-PR25 questionnaire outcomes showed significant deterioration in urinary domain score at all FU moments, from 8.3 (interquartile range [IQR], 4.1-16.6) at baseline to 12.4 (IQR, 8.3-24.8; P = .005) at 3 months, 12.4 (IQR, 8.3-20.8; P = .018;) at 6 months, and 12.4 (IQR, 8.3-20.8; P = .001) at 12 months. For the non-ADT group, physician- and patient-reported erectile function worsened significantly between baseline and 12 months FU.<h4>Conclusions</h4>Ultrahypofractionated MR-guided radiation therapy for localized PCa using a 1.5T MR-Linac is effective and safe. The peak of CTCAE genitourinary and gastrointestinal toxicity was reported at 3 months FU. Furthermore, for patients without ADT, a significant increase in CTCAE erectile dysfunction was reported at 12 months FU. These data are useful for educating patients on expected outcomes and informing study design of future comparative-effectiveness studies.
<h4>Purpose</h4>Our purpose was to report 5-year efficacy and toxicity of intraprostatic lesion boosting using standard and hypofractionated radiation therapy.<h4>Methods and materials</h4>DELINEATE (ISRCTN 04483921) is a single center phase 2 multicohort study including standardly fractionated (cohort A: 74 Gy/37F to prostate and seminal vesicles [PSV]; cohort C 74 Gy/37F to PSV plus 60 Gy/37F to pelvic lymph nodes) and moderately hypofractionated (cohort B: 60 Gy/20F to PSV) prostate intensity-modulated radiation therapy patients with National Comprehensive Cancer Network intermediate/high-risk disease. Patients received an integrated boost of 82 Gy (cohorts A and C) or 67 Gy (cohort B) to multiparametric magnetic resonance imaging identified lesion(s). Primary endpoint was late Radiation Therapy Oncology Group (RTOG) gastrointestinal (GI) toxicity at 1 year. Secondary endpoints were acute and late toxicity (clinician and patient reported) and freedom from biochemical/clinical failure at 5 years.<h4>Results</h4>Two hundred and sixty-five men were recruited and 256 were treated (55 cohort A, 153 cohort B, and 48 cohort C). Median follow-up for each cohort was >5 years. Cumulative late RTOG grade 2+ GI toxicity at 1 year was 3.6% (95% confidence interval [CI], 0.9%-13.8%) (cohort A), 7.2% (95% CI, 4%-12.6%) (cohort B), and 8.4% (95% CI, 3.2%-20.8%) (cohort C). Cumulative late RTOG grade 2+ GI toxicity to 5 years was 12.8% (95% CI, 6.3%-25.1%) (cohort A), 14.6% (95% CI, 9.9%-21.4%) (cohort B), and 20.7% (95% CI, 11.2%-36.2%) (cohort C). Cumulative RTOG grade 2+ genitourinary toxicity to 5 years was 12.9% (95% CI, 6.4%-25.2%) (cohort A), 18.2% (95% CI, 12.8%-25.4%) (cohort B), and 18.2% (95% CI, 9.5%-33.2%) (cohort C). Five-year freedom from biochemical/clinical failure was 98.2% (95% CI, 87.8%-99.7%) (cohort A), 96.7% (95% CI, 91.3%- 98.8%) (cohort B), and 95.1% (95% CI, 81.6-98.7%) (cohort C).<h4>Conclusions</h4>The DELINEATE trial has shown safety, tolerability, and feasibility of focal boosting in 20 or 37 fractions. Efficacy results indicate a low chance of prostate cancer recurrence 5 years after radiation therapy. Evidence from ongoing phase 3 randomized trials is awaited.
<h4>Background</h4>Stereotactic body radiotherapy (SBRT) is an effective and safe modality for early-stage lung cancer and lung metastases. However, tumors in an ultra-central location pose unique safety considerations. We performed a systematic review and meta-analysis to summarize the current safety and efficacy data and provide practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).<h4>Methods</h4>We performed a systematic review using PubMed and EMBASE databases of patients with ultra-central lung tumors treated with SBRT. Studies reporting local control (LC) and/or toxicity were included. Studies with <5 treated lesions, non-English language, re-irradiation, nodal tumors, or mixed outcomes in which ultra-central tumors could not be discerned were excluded. Random-effects meta-analysis was performed for studies reporting relevant endpoints. Meta-regression was conducted to determine the effect of various covariates on the primary outcomes.<h4>Results</h4>602 unique studies were identified of which 27 (one prospective observational, the remainder retrospective) were included, representing 1183 treated targets. All studies defined ultra-central as the planning target volume (PTV) overlapping the proximal bronchial tree (PBT). The most common dose fractionations were 50 Gy/5, 60 Gy/8, and 60 Gy/12 fractions. The pooled 1- and 2-year LC estimates were 92 % and 89 %, respectively. Meta-regression identified biological effective dose (BED10) as a significant predictor of 1-year LC. A total of 109 grade 3-4 toxicity events, with a pooled incidence of 6 %, were reported, most commonly pneumonitis. There were 73 treatment related deaths, with a pooled incidence of 4 %, with the most common being hemoptysis. Anticoagulation, interstitial lung disease, endobronchial tumor, and concomitant targeted therapies were observed risk factors for fatal toxicity events.<h4>Conclusion</h4>SBRT for ultra-central lung tumors results in acceptable rates of local control, albeit with risks of severe toxicity. Caution should be taken for appropriate patient selection, consideration of concomitant therapies, and radiotherapy plan design.
<h4>Background</h4>In a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer-without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians' perceived barriers toward its implementation.<h4>Methods</h4>We invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media.<h4>Results</h4>263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%).<h4>Conclusions</h4>Two years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.
<h4>Aims</h4>Prostate morphological changes during external beam radiotherapy are poorly understood. Excellent soft-tissue visualisation offered by magnetic resonance image-guided radiotherapy (MRIgRT) provides an opportunity to better understand such changes. The aim of this study was to quantify prostate volume and dimension changes occurring during extreme and moderately hypofractionated schedules.<h4>Materials and methods</h4>Forty prostate cancer patients treated on the Unity 1.5 Tesla magnetic resonance linear accelerator (MRL) were retrospectively reviewed. The cohort comprised patients treated with 36.25 Gy in five fractions (n = 20) and 60 Gy in 20 fractions (n = 20). The volume of the delineated prostates on reference planning computed tomography (fused with MRI) and daily T2-weighted 2-min session images acquired on Unity were charted. Forty planning computed tomography and 500 MRL prostate volumes were evaluated. The mean absolute and relative change in prostate volume during radiotherapy was compared using a paired t-test (P value <0.01 considered significant to control for multiple comparisons). The maximum dimension of the delineated prostate was measured in three isocentric planes.<h4>Results</h4>Significant prostate volume changes, relative to MRL imaging fraction 1 (MRL#1), were seen at all time points for the five-fraction group. The peak mean relative volume increase was 21% (P < 0.001), occurring at MRL#3 and MRL#4 after 14.5 and 21.75 Gy, respectively. Prostate expansion was greatest in the superior-inferior direction; the peak mean maximal extension was 5.9 mm. The maximal extension in the left-right and anterior-posterior directions measured 1.1 and 2.2 mm, respectively. For the 20-fraction group, prostate volume increased relative to MRL#1, for all treatment time points. The mean relative volume increase was 11% (P < 0.001) at MRL#5 after 12 Gy, it then fluctuated between 8 and 13%. From MRL#5 to MRL#20, the volume increase was significant (P < 0.01) for 12 of 16 time points calculated. The peak mean maximal extension in the superior-inferior direction was 3.1 mm. The maximal extension in the left-right and anterior-posterior directions measured 1.7 and 3.7 mm, respectively.<h4>Conclusion</h4>Significant prostate volume and dimension changes occur during extreme and moderately hypofractionated radiotherapy. The extent of change was greater during extreme hypofractionation. MRIgRT offers the opportunity to reveal, quantify and correct for this deformation.
The pattern of metastases in prostate cancer (PC) is evolving. Increased use of imaging, newer imaging techniques with higher sensitivity for disease detection and patients receiving multiple lines of novel therapies with increased life expectancy are likely to be contributory. Awareness of metastatic disease patterns improves early diagnosis, accurate staging, and initiation of appropriate therapy, and can inform prognostic information and anticipate potential disease complications. The aim of this review is to document the spectrum of metastases in PC including emerging and unusual patterns, and to highlight the role of novel imaging including prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET) and whole-body magnetic resonance imaging (WB-MRI) to improve diagnostic and response assessment accuracy.
The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.
Prostate cancer is the most frequent genitourinary tumor worldwide. Maintaining an optimum bone health throughout the natural course of prostate cancer is an important aspect in the management of this disease, particularly in this at risk population of older and frail patients who experience bone loss related to androgen-deprivation therapy (ADT) and/or patients who develop bone metastases. The number of treatment options for advanced prostate cancer that combine ADT with docetaxel, new hormonal agents and/or radiotherapy has increased substantially in recent years. Bisphosphonates and other bone targeted agents such as denosumab have shown an improvement in bone mineral density and are suited for patients with treatment-related osteoporosis and/or bone metastases with an increased risk of skeletal-related events (SREs). In this context, the aim of this review is to analyse key aspects of bone health and therapies that can prevent the occurrence of SREs throughout the clinical course of prostate cancer, and how to combine them with new available treatments in this setting.
<h4>Introduction</h4>Prostate cancer is a common malignancy for which radiation therapy (RT) provides an excellent management option with high rates of control and low toxicity. Historically RT has been given with CT based image guidance. Recently, magnetic resonance (MR) imaging capabilities have been successfully integrated with RT delivery platforms, presenting an appealing, yet complex, expensive, and time-consuming method of adapting and guiding RT. The precise benefits of MR guidance for localized prostate cancer are unclear. We sought to summarize optimal strategies to test the benefits of MR guidance specifically in localized prostate cancer.<h4>Methods</h4>A group of radiation oncologists, physicists, and statisticians were identified to collectively address this topic. Participants had a history of treating prostate cancer patients with the two commercially available MRI-guided RT devices. Participants also had a clinical focus on randomized trials in localized prostate cancer. The goal was to review both ongoing trials and present a conceptual focus on MRI-guided RT specifically in the definitive treatment of prostate cancer, along with developing and proposing novel trials for future consideration. Trial hypotheses, endpoints, and areas for improvement in localized prostate cancer that specifically leverage MR guided technology are presented.<h4>Results</h4>Multiple prospective trials were found that explored the potential of adaptive MRI-guided radiotherapy in the definitive treatment of prostate cancer. Different primary areas of improvement that MR guidance may offer in prostate cancer were summarized. Eight clinical trial design strategies are presented that summarize options for clinical trials testing the potential benefits of MRI-guided RT.<h4>Conclusions</h4>The number and scope of trials evaluating MRI-guided RT for localized prostate cancer is limited. Yet multiple promising opportunities to test this technology and potentially improve outcomes for men with prostate cancer undergoing definitive RT exist. Attention, in the form of multi-institutional randomized trials, is needed.
Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.
MRI can help to categorize tissues as malignant or non-malignant both anatomically and functionally, with a high level of spatial and temporal resolution. This non-invasive imaging modality has been integrated with radiotherapy in devices that can differentially target the most aggressive and resistant regions of tumours. The past decade has seen the clinical deployment of treatment devices that combine imaging with targeted irradiation, making the aspiration of integrated MRI-guided radiotherapy (MRIgRT) a reality. The two main clinical drivers for the adoption of MRIgRT are the ability to image anatomical changes that occur before and during treatment in order to adapt the treatment approach, and to image and target the biological features of each tumour. Using motion management and biological targeting, the radiation dose delivered to the tumour can be adjusted during treatment to improve the probability of tumour control, while simultaneously reducing the radiation delivered to non-malignant tissues, thereby reducing the risk of treatment-related toxicities. The benefits of this approach are expected to increase survival and quality of life. In this Review, we describe the current state of MRIgRT, and the opportunities and challenges of this new radiotherapy approach.
Magnetic resonance imaging (MRI)-guided radiotherapy allows for online adaptation of the radiation plan on the basis of anatomical and functional changes during treatment. MRI-guided radiotherapy holds significant promise for broadening the therapeutic window for multiple urological cancers.
<h4>Purpose</h4>Online adaptive radiation therapy (ART) allows real-time plan generation and delivery to account for daily anatomic changes. Owing to the time-intensive nature of this process, physicians frequently cover adaptive treatments for patients whose original treatment plan was prescribed by another provider. There is currently no published guidance on the contents of physician sign-outs, or adaptive guidelines, to ensure the safe and consistent delivery of adaptive treatments.<h4>Methods and materials</h4>A group of radiation oncologists, each with at least 3 years of experience prescribing and covering online adaptive radiation treatments, formed a working group to identify the critical components of adaptive guidelines. The members of the working group collectively were experienced with the 3 commercially available real-time ART platforms. Key components of the adaptive guidelines necessary to preserve the prescribed treatment intent were identified.<h4>Results</h4>Eleven radiation oncologists from 9 cancer centers, with a range of 3 to 6 years ART experience, formed the adaptive guidelines working group. Three categories of information that are essential for safely delivering an online ART approach were identified: recontouring instructions (including anatomic considerations for specific cases), defining replanning rules, and establishing motion management guidelines.<h4>Conclusions</h4>When physician coverage is needed for ART, clear communication is critical for treatment to be delivered according to the original intent of the prescription. The proposed ART recommendations that include physician sign-out for this highly technical treatment process can be especially beneficial in improving communication across potentially multiple transitions of care.
<h4>Background</h4>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.<h4>Objective</h4>To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT.<h4>Design, setting, and participants</h4>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.<h4>Outcome measurements and statistical analyses</h4>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).<h4>Results and limitations</h4>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.<h4>Conclusions</h4>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.<h4>Patient summary</h4>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.
A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate.
<h4>Context</h4>The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear.<h4>Objective</h4>To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT.<h4>Evidence acquisition</h4>A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states.<h4>Evidence synthesis</h4>The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups.<h4>Conclusions</h4>Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis.<h4>Patient summary</h4>Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.
PEARLS is a multi-stage randomised controlled trial for prostate cancer patients with pelvic and/or para-aortic PSMA-avid lymph node disease at presentation. The aim of the trial is to determine whether extending the radiotherapy field to cover the para-aortic lymph nodes (up to L1/L2 vertebral interspace) can improve outcomes for this patient group.
<h4>Aims</h4>Oligoprogression is poorly defined in current literature. Little is known about the natural history and significance of oligoprogression in patients with hormone-resistant prostate cancer on abiraterone or enzalutamide treatment [termed androgen receptor-targeted therapy (ARTT)]. The aim of this study was to determine the prevalence of oligoprogression, describe the characteristics of oligoprogression in a cohort of patients from a single center, and identify the number of patients potentially treatable with stereotactic body radiotherapy (SBRT).<h4>Methods</h4>Castration-resistant prostate cancer (CRPC) patients who radiologically progressed while on ARTT were included. Patients with oligoprogressive disease (OPD) (≤3 lesions) on any imaging were identified in a retrospective analysis of electronic patient records. Kaplan-Meier method and log-rank test were used to calculate progression-free and overall survival.<h4>Results</h4>A total of 102 patients with metastatic CRPC on ARTT were included. Thirty (29%) patients presented with oligoprogression (46 lesions in total); 21 (21% of total) patients had lesions suitable for SBRT. The majority of lesions were in the bone (21, 46%) or lymph nodes (15, 33%). Patients with oligoprogression while on ARTT had a significantly better prostate-specific antigen (PSA) response on commencing ARTT as compared to patients who later developed polyprogression. However, PSA doubling time immediately prior to progression did not predict OPD. Median progression-free survival to oligoprogression versus polyprogression was 16.8 vs. 11.7 months. Time to further progression after oligoprogression was 13.6 months in those treated with radiotherapy (RT) for oligoprogression vs. 5.7 months in those treated with the continuation of ARTT alone.<h4>Conclusions</h4>In this study, nearly a third of patients on ARTT for CRPC were found to have OPD. OPD patients had a better PSA response on ART and a longer duration on ARTT before developing OPD as compared to those developing polyprogressive disease (Poly-PD). The majority of patients (70%) with OPD had lesions suitable for SBRT treatment. Prospective randomized control trials are needed to establish if there is a survival benefit of SBRT in oligoprogressive prostate cancer and to determine predictive indicators.
Androgen deprivation therapy (ADT) is an integral component in the management of prostate cancer across multiple disease states. Traditionally, luteinizing hormone-releasing hormone (LHRH) agonists constituted the backbone of ADT. However, gonadotropin-releasing hormone receptor hormone (GnRH) antagonists also are available, which offer faster testosterone suppression and reduced likelihood of ADT-related adverse effects compared with LHRH agonists, including the potential for fewer ADT-associated major cardiac events. Until recently, all forms of LHRH agonists and GnRH antagonist formulations were of parenteral administration. However, recently relugolix gained Food and Drug Administration approval as the first oral GnRH antagonist. Relugolix achieves faster and more complete testosterone suppression compared with an LHRH agonist. This translates to more rapid prostate-specific antigen response compared with LHRH agonists. After discontinuation of relugolix, testosterone recovers faster than after GnRH agonists or injectable GnRH antagonist therapy. Overall, these factors provide opportunities for more precisely defined ADT duration when combined with radiation therapy. The rapid onset and offset of testosterone suppression with relugolix may require physicians to rethink the mechanism and goals of ADT when prescribing. As an oral formulation, relugolix enables patients to avoid pain and injection site reactions, limit extra office visits for injections, and achieve a shorter duration of experiencing the side effects of castrate testosterone levels. This convenience and tolerability may enhance physicians' willingness to prescribe ADT and patients' feeling of control during their ADT course, but the potential advantages are accompanied by the risks of patients choosing to discontinue therapy to escape side effects of ADT. This article focuses on different aspects of what is known and unknown regarding the optimal use of ADT and radiation therapy, and how relugolix, due to its properties, fit into our current treatment paradigms for localized prostate cancer.
The implementation of adaptive radiotherapy for prostate cancer compensates for inter-fraction motion, at the penalty of increased time in room. The subsequent increase in bladder filling may impact dosimetry, which we have investigated on ten patients treated on the MR-linac. Patients drank water before treatment, to achieve a bladder volume of 200-300 cm<sup>3</sup>. Bladder and bowel were re-outlined offline on 140 images and plans recalculated. All mandatory bladder dose constraints and 99.1% of bowel constraints were achieved at time of treatment, despite varying bladder volumes and varying adherence to original bladder filling guidance.
<h4>Background</h4>The prostate demonstrates inter- and intra- fractional changes and thus adaptive radiotherapy would be required to ensure optimal coverage. Daily adaptive radiotherapy for MRI-guided radiotherapy can be both time and resource intensive when structure delineation is completed manually. Contours can be auto-generated on the MR-Linac via a deformable image registration (DIR) based mapping process from the reference image. This study evaluates the performance of automatically generated target structure contours against manually delineated contours by radiation oncologists for prostate radiotherapy on the Elekta Unity MR-Linac.<h4>Methods</h4>Plans were generated from prostate contours propagated by DIR and rigid image registration (RIR) for forty fractions from ten patients. A two-dose level SIB (simultaneous integrated boost) IMRT plan is used to treat localised prostate cancer; 6000 cGy to the prostate and 4860 cGy to the seminal vesicles. The dose coverage of the PTV 6000 and PTV 4860 created from the manually drawn target structures was evaluated with each plan. If the dose objectives were met, the plan was considered successful in covering the gold standard (clinician-delineated) volume.<h4>Results</h4>The mandatory PTV 6000 dose objective (D98% > 5580 cGy) was met in 81 % of DIR plans and 45 % of RIR plans. The SV were mapped by DIR only and for all the plans, the PTV 4860 dose objective met the optimal target (D98% > 4617 cGy). The plans created by RIR led to under-coverage of the clinician-delineated prostate, predominantly at the apex or the bladder-prostate interface.<h4>Conclusion</h4>Plans created from DIR propagation of prostate contours outperform those created from RIR propagation. In approximately 1 in 5 DIR plans, dosimetric coverage of the gold standard PTV was not clinically acceptable. Thus, at our institution, we use a combination of DIR propagation of contours alongside manual editing of contours where deemed necessary for online treatments.
Advances in radiotherapy technology have increased precision of treatment delivery and in some tumour types, improved cure rates and decreased side effects. A new generation of radiotherapy machines, hybrids of an MRI scanner and a linear accelerator, has the potential to further transform the practice of radiation therapy in some cancers. Facilitating superior image quality and the ability to change the dose distribution online on a daily basis (termed "daily adaptive replanning"), MRI-guided radiotherapy machines allow for new possibilities including increasing dose, for hard to treat cancers, and more selective sparing of healthy tissues, where toxicity reduction is the key priority.These machines have already been used to treat most types of cancer, although experience is still in its infancy. This review summarises the potential and current evidence for MRI-guided radiotherapy, with a predominant focus on prostate cancer. Current advantages and disadvantages are discussed including a realistic appraisal of the likely potential to improve patient outcomes. In addition, horizon scanning for near-term possibilities for research and development will hopefully delineate the potential role for this technology over the next decade.
<h4>Purpose</h4>CHHiP is a randomized trial evaluating moderately hypofractionated radiation therapy for treatment of localized prostate cancer. Of all participants, 97% of them had concurrent short-course hormone therapy (HT), either luteinizing hormone-releasing hormone analog (LHRHa) or 150 mg of bicalutamide daily. This exploratory analysis compares efficacy and side effects in a nonrandomized comparison.<h4>Methods and materials</h4>In our study, 2700 patients received LHRHa and 403 received bicalutamide. The primary endpoint was biochemical/clinical failure. Groups were compared with Cox regression adjusted for various prognostic factors and stratified by radiation therapy dose. A key secondary endpoint was erectile dysfunction (ED) assessed by clinicians (using scores from Late Effects on Normal Tissues: Subjective/Objective/Management [LENT-SOM] subjective erectile function for vaginal penetration) and patients (single items within the University of California-Los Angeles Prostate Cancer Index [UCLA PCI] and Expanded Prostate Cancer Index Composite [EPIC]-50 questionnaires) at 2 years and compared between HT regimens by χ<sup>2</sup> trend test.<h4>Results</h4>Bicalutamide patients were significantly younger (median 67 vs 69 years LHRHa). Median follow-up was 9.3 years. There was no difference in biochemical or clinical failure with an adjusted hazard ratio or 0.97 (95% confidence interval, 0.77-1.23; P = .8). At 2 years, grade ≥2 LENT-SOM ED was reported in significantly more LHRHa patients (313 out of 590; 53%) versus bicalutamide (17 out of 68; 25%) (P < .0001). There were no differences in ED seen with UCLA-PCI and EPIC-50 questionnaires.<h4>Conclusions</h4>In this nonrandomized comparison, there was no evidence of a difference in efficacy according to type of HT received. Bicalutamide preserved clinician assessed (LENT-SOM) erectile function at 2 years but patient-reported outcomes were similar between groups.
<h4>Background</h4>Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT.<h4>Methods</h4>PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258.<h4>Findings</h4>We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe.<h4>Interpretation</h4>In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited.<h4>Funding</h4>Accuray.
<h4>Background and purpose</h4>Oligometastatic prostate cancer is a new and emerging treatment field with only few prospective randomized studies published so far. Despite the lack of strong level I evidence, metastasis-directed therapies (MDT) are widely used in clinical practice, mainly based on retrospective and small phase 2 studies and with a large difference across centers. Pending results of ongoing prospective randomized trials, there is a clear need for more consistent treatment indications and radiotherapy practices.<h4>Material and methods</h4>A European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee consisting of radiation oncologists' experts in prostate cancer was asked to answer a dedicated questionnaire, including 41 questions on the main controversial issues with regard to oligometastatic prostate cancer.<h4>Results</h4>The panel achieved consensus on patient selection and routine use of prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging as preferred staging and restaging imaging. MDT strategies are recommended in the de novo oligometastatic, oligorecurrent and oligoprogressive disease setting for nodal, bone and visceral metastases. Radiation therapy doses, volumes and techniques were discussed and commented.<h4>Conclusion</h4>These recommendations have the purpose of providing standardization and consensus to optimize the radiotherapy treatment of oligometastatic prostate cancer until mature results of randomized trials are available.
<h4>Objective</h4>To present the long-term adjuvant radiotherapy outcomes of patients with pN3 squamous cell carcinoma of the penis (SCCp) treated at two UK centres.<h4>Patients and methods</h4>We conducted a retrospective audit of all pN3 SCCp patients, deemed suitable for adjuvant therapy by a specialist multidisciplinary team at St George's and Leeds Hospitals, who received adjuvant radiotherapy. Primary outcomes were recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Secondary outcomes were time to adjuvant treatment, frequency of in-field recurrence, site and side of recurrence, and dose and schedule of radiotherapy.<h4>Results</h4>A total of 146 patients were included: 121 completed radiotherapy, 4 did not complete radiotherapy and 21 did not start it. The median (interquartile range [IQR]) age was 59 (54-70)years. The 5-year RFS was 51%, CSS was 51% and OS was 44%. Adjuvant radiotherapy was started at a median (IQR) of 75 (48-106) days. A dose of 45 Gy in 20 fractions was most commonly used. Of the 125 patients who started adjuvant treatment, 55 relapsed. Of these relapses, 30 occurred in an inguinal or pelvic nodal station and 26 of the 30 were in a radiation field. Relapses in 18 of the 55 cases were in visceral sites only and seven were in both nodal (non-irradiated sites) and visceral sites. Doses of <50 Gy were used more commonly before 2013 and higher doses (>50 Gy) were more commonly used after 2013.<h4>Conclusions</h4>Application of a standard radiotherapy protocol within a centralized supra-network setting has achieved survival outcomes that would appear better than those previously documented for either radiotherapy or chemotherapy in a cohort with solely pN3 disease. The addition of adjuvant chemotherapy may improve these outcomes further. These data suggest that adjuvant radiotherapy has a role to play in the management of men with pN3 SCCp.
<h4>Introduction</h4>The role of the Urology Specialist Therapeutic Radiographer (USTR) was introduced to support a busy NHS uro-oncology practice. Key objectives were to improve patient preparedness for and experience of radiotherapy, focussed on prostate cancer. Pre-radiotherapy information seminars were developed, and on-treatment patient review managed by the USTRs. To evaluate the revamped patient pathway and direct further improvements, a patient experience survey was designed.<h4>Methods</h4>An 18-point patient questionnaire was produced. The questionnaire captured patient experience and preparedness; pre, during and at completion of treatment. The patient population comprised men receiving radiotherapy for primary prostate cancer within one UK Trust.<h4>Results</h4>Two-hundred and fifty-one responses were received. Seventy-three percent of patients felt completely prepared for radiotherapy, higher in those who attended a seminar (77%) compared to those who did not (61%). Eighty-nine and eighty-six percent of respondents were completely satisfied with verbal and written information received prior to commencing radiotherapy respectively. Seventy-three percent of responders would have found additional resources helpful. With respect to on-treatment clinics; eighty-five percent were seen on time or within 20 minutes, eighty-three percent felt fully involved in decisions regarding their care and ninety-one percent reported complete satisfaction with the knowledge of the health care professional reviewing them. The follow-up process was completely understood by eighty-eight percent and overall patient experience rated excellent by eighty-five percent of responders.<h4>Conclusion</h4>The revamped pathway implemented by USTRs has achieved high levels of satisfaction at all stages of the prostate patient's radiotherapy. By diversifying the format of information giving, the USTRs hope to further meet the information needs of patients.<h4>Implications for practice</h4>Validation of a prostate cancer radiotherapy pathway which employs USTRs and utilises a patient preparation seminar. This model could support the introduction of Specialist Therapeutic Radiographers in other Trusts and treatment sites.
<h4>Purpose</h4>Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.<h4>Methods and materials</h4>The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models.<h4>Results</h4>Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy.<h4>Conclusions</h4>We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy.
Online magnetic resonance-guided radiotherapy (oMRgRT) represents one of the most innovative applications of current image-guided radiation therapy (IGRT). The revolutionary concept of oMRgRT systems is the ability to acquire MR images for adaptive treatment planning and also online imaging during treatment delivery. The daily adaptive planning strategies allow to improve targeting accuracy while avoiding critical structures. This ESTRO-ACROP recommendation aims to provide an overview of available systems and guidance for best practice in the implementation phase of hybrid MR-linac systems. Unlike the implementation of other radiotherapy techniques, oMRgRT adds the MR environment to the daily practice of radiotherapy, which might be a new experience for many centers. New issues and challenges that need to be thoroughly explored before starting clinical treatments will be highlighted.
<h4>Purpose</h4>High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium.<h4>Methods and materials</h4>Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment).<h4>Results</h4>A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed.<h4>Conclusions</h4>In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging.
<h4>Background and purpose</h4>Transperineal ultrasound (TPUS) is used clinically for directly assessing prostate motion. Factors affecting accuracy and precision in TPUS motion estimation must be assessed to realise its full potential.<h4>Methods and materials</h4>Patients were imaged using volumetric TPUS during the Clarity-Pro trial (NCT02388308). Prostate motion was measured online at patient set-up and offline by experienced observers. Cone beam CT with markers was used as a comparator and observer performance was also quantified. The influence of different clinical factors was examined to establish specific recommendations towards efficacious ultrasound guided radiotherapy.<h4>Results</h4>From 330 fractions in 22 patients, offline observer random errors were 1.5 mm, 1.3 mm, 1.9 mm (left-right, superior-inferior, anteroposterior respectively). Errors increased in fractions exhibiting poor image quality to 3.3 mm, 3.3 mm and 6.8 mm. Poor image quality was associated with inconsistent probe placement, large anatomical changes and unfavourable imaging conditions within the patient. Online matching exhibited increased observer errors of: 3.2 mm, 2.9 mm and 4.7 mm. Four patients exhibited large systematic residual errors, of which three had poor quality images. Patient habitus showed no correlation with observer error, residual error, or image quality.<h4>Conclusions</h4>TPUS offers the unique potential to directly assess inter- and intra-fraction motion on conventional linacs. Inconsistent image quality, inexperienced operators and the pressures of the clinical environment may degrade precision and accuracy. Experienced operators are essential and cross-centre standards for training and QA should be established that build upon current guidance. Greater use of automation technologies may further minimise uncertainties.
<h4>Purpose</h4>In 2009, the Radiation Therapy Oncology Group (RTOG) genitourinary members published a consensus atlas for contouring prostate pelvic nodal clinical target volumes (CTVs). Data have emerged further informing nodal recurrence patterns. The objective of this study is to provide an updated prostate pelvic nodal consensus atlas.<h4>Methods and materials</h4>A literature review was performed abstracting data on nodal recurrence patterns. Data were presented to a panel of international experts, including radiation oncologists, radiologists, and urologists. After data review, participants contoured nodal CTVs on 3 cases: postoperative, intact node positive, and intact node negative. Radiation oncologist contours were analyzed qualitatively using count maps, which provided a visual assessment of controversial regions, and quantitatively analyzed using Sorensen-Dice similarity coefficients and Hausdorff distances compared with the 2009 RTOG atlas. Diagnostic radiologists generated a reference table outlining considerations for determining clinical node positivity.<h4>Results</h4>Eighteen radiation oncologists' contours (54 CTVs) were included. Two urologists' volumes were examined in a separate analysis. The mean CTV for the postoperative case was 302 cm<sup>3</sup>, intact node positive case was 409 cm<sup>3</sup>, and intact node negative case was 342 cm<sup>3</sup>. Compared with the original RTOG consensus, the mean Sorensen-Dice similarity coefficient for the postoperative case was 0.63 (standard deviation [SD] 0.13), the intact node positive case was 0.68 (SD 0.13), and the intact node negative case was 0.66 (SD 0.18). The mean Hausdorff distance (in cm) for the postoperative case was 0.24 (SD 0.13), the intact node positive case was 0.23 (SD 0.09), and intact node negative case was 0.33 (SD 0.24). Four regions of CTV controversy were identified, and consensus for each of these areas was reached.<h4>Conclusions</h4>Discordance with the 2009 RTOG consensus atlas was seen in a group of experienced NRG Oncology and international genitourinary radiation oncologists. To address areas of variability and account for new data, an updated NRG Oncology consensus contour atlas was developed.
<h4>Background</h4>Radium-223 is a bone-seeking, alpha-emitting radionuclide used in metastatic castration-resistant prostate cancer (mCRPC). Radium-223 increases the risk of fracture when used in combination with abiraterone and prednisolone. The risk of fracture in men receiving radium-223 monotherapy is unclear.<h4>Patients and methods</h4>This was a prospective, multicenter phase II study of radium-223 in 36 men with mCRPC and a reference cohort (n = 36) matched for fracture risk and not treated with radium-223. Bone fractures were assessed using whole-body magnetic resonance imaging. The primary outcome was risk of new fractures.<h4>Results</h4>Thirty-six patients were treated with up to six 4-week cycles of radium-223. With a median follow-up of 16.3 months, 74 new fractures were identified in 20 patients. Freedom from fracture was 56% (95% confidence interval, 35.3-71.6) at 12 months. On multivariate analysis, prior corticosteroid use was associated with risk of fracture. In the reference cohort (n = 36), 16 new fractures were identified in 12 patients over a median follow-up of 24 months. Across both cohorts, 67% of all fractures occurred at uninvolved bone.<h4>Conclusions</h4>Men with mCRPC, and particularly those treated with radium-223, are at risk of fracture. They should receive a bone health agent to reduce the risk of fragility fractures.
<h4>Background and purpose</h4>Between 30% and 47% of patients treated with definitive radiotherapy (RT) for prostate cancer are at risk of intraprostatic recurrence during follow-up. Re-irradiation with stereotactic body RT (SBRT) is emerging as a feasible and safe therapeutic option. However, no consensus or guidelines exist on this topic. The purpose of this ESTRO ACROP project is to investigate expert opinion on salvage SBRT for intraprostatic relapse after RT.<h4>Materials and methods</h4>A 40-item questionnaire on salvage SBRT was prepared by an internal committee and reviewed by a panel of leading radiation oncologists plus a urologist expert in prostate cancer. Following the procedure of a Delphi consensus, 3 rounds of questionnaires were sent to selected experts on prostate re-irradiation.<h4>Results</h4>Among the 33 contacted experts, 18 (54.5%) agreed to participate. At the end of the final round, participants were able to find consensus on 14 out of 40 questions (35% overall) and major agreement on 13 questions (32.5% overall). Specifically, the consensus was reached regarding some selection criteria (no age limit, ECOG 0-1, satisfactory urinary flow), diagnostic procedures (exclusion of metastatic disease, SBRT target defined on the MRI) and therapeutic approach (no need for concomitant ADT, consideration of the first RT dose, validity of Phoenix criteria for salvage SBRT failure).<h4>Conclusion</h4>While awaiting the results of ongoing studies, our ESTRO ACROP Delphi consensus may serve as a practical guidance for salvage SBRT. Future research should address the existing disagreements on this promising approach.
<h4>Purpose</h4>Daily quantitative MR imaging during radiotherapy of cancer patients has become feasible with MRI systems integrated with linear accelerators (MR-linacs). Quantitative images could be used for treatment response monitoring. With intravoxel incoherent motion (IVIM) MRI, it is possible to acquire perfusion information without the use of contrast agents. In this multicenter study, daily IVIM measurements were performed in prostate cancer patients to identify changes that potentially reflect response to treatment.<h4>Materials and methods</h4>Forty-three patients were included, treated with 20 fractions of 3 Gy on a 1.5 T MR-linac. IVIM measurements were performed on each treatment day. The diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were calculated based on the median signal intensities in the non-cancerous prostate and the tumor. Repeatability coefficients (RCs) were determined based on the first two treatment fractions. Separate linear mixed-effects models were constructed for the three IVIM parameters.<h4>Results</h4>In total, 726 fractions were analyzed. Pre-treatment average values, measured on the first fraction before irradiation, were 1.46 × 10<sup>-3</sup> mm<sup>2</sup>/s, 0.086, and 28.7 × 10<sup>-3</sup> mm<sup>2</sup>/s in the non-cancerous prostate and 1.19 × 10<sup>-3</sup> mm<sup>2</sup>/s, 0.088, and 28.9 × 10<sup>-3</sup> mm<sup>2</sup>/s in the tumor, for D, f, and D*, respectively. The repeatability coefficients for D, f, and D* in the non-cancerous prostate were 0.09 × 10<sup>-3</sup> mm<sup>2</sup>/s, 0.05, and 15.3 × 10<sup>-3</sup> mm<sup>2</sup>/s. In the tumor, these values were 0.44 × 10<sup>-3</sup> mm<sup>2</sup>/s, 0.16, and 76.4 × 10<sup>-3</sup> mm<sup>2</sup>/s. The mixed effects analysis showed an increase in D of the tumors over the course of treatment, while remaining stable in the non-cancerous prostate. The f and D* increased in both the non-cancerous prostate and tumor.<h4>Conclusions</h4>It is feasible to perform daily IVIM measurements on an MR-linac system. Although the repeatability coefficients were high, changes in IVIM perfusion parameters were measured on a group level, indicating that IVIM has potential for measuring treatment response.
The drive towards hypofractionated prostate radiotherapy is motivated by a low alpha/beta ratio for prostate cancer (1 to 3 Gy) compared to surrounding organs at risk, implying an improved therapeutic ratio with increasing dose per fraction. Early evidence from studies of ultrahypofractionated (UHF) prostate HDR brachytherapy has shown good tolerability in terms of normal tissue toxicities and clinical outcomes similar to conventional fractionation schedules. MR-guided stereotactic body radiotherapy (SBRT) with online plan adaptation and real-time tumour imaging may enable UHF doses to be delivered to the prostate safely, without the invasiveness of brachytherapy. The feasibility of UHF prostate treatment planning for the Unity MR-Linac (MRL, Elekta AB, Stockholm) was investigated for target prescriptions and planning constraints derived from the HDR brachytherapy and SBRT literature. Monaco 5.40 (Elekta) was used to generate MRL step-and-shoot IMRT plans for three dose fractionation protocols (5, 2 and 1 fractions), for ten randomly selected previously treated prostate cancer patients. Of the ten plans per UHF scheme, all clinical goals were met in all cases for 5 fractions, and in six cases for both 2 and 1 fraction schemes. PTV D95% was compromised by up to 6.4% and 3.9% of the associated target dose for 2 and 1 fraction plans respectively. There were two cases of PTV D95% compromise greater than a 5% dose decrease for the 2 fraction plans. The study suggests feasibility of the UHF treatment planning approaches if combined with real-time motion mitigation strategies.
There has been growing interest in oligometastatic prostate cancer (OMPC) with a mounting body of evidence to suggest that it is a distinct disease state, both biologically and prognostically, when compared to polymetastatic prostate cancer. Three subgroups have been recognised; de novo synchronous, metachronous/oligorecurrent and oligoprogressive disease. The belief that patients with OMPC can be treated more aggressively to improve survival is transforming patient care. Identifying these patients poses the first challenge, and we explore the imaging modalities currently utilised and those that are promising. For patients with de novo synchronous OMPC, both early systemic treatment in addition to androgen deprivation therapy (ADT) and radiotherapy to the prostate increase overall survival (OS), and both are increasingly being integrated into routine clinical practice. Metastasis-directed therapy (MDT) has predominantly been delivered using stereotactic body radiotherapy (SBRT) in prostate cancer and studies have shown SBRT is well-tolerated, provides excellent local control and can be used to delay ADT in the metachronous setting. We discuss the current management strategies in OMPC, review the evidence supporting the use of SBRT and outline ongoing trials.
The MR-Linac (MRL) provides a novel treatment modality that enables online adaptive treatments, but also creates new challenges for patient positioning in a laser-free environment. The accuracy and duration of prostate patient set-up on the MRL using two different methods for patient alignment was determined to establish standard of practice on the MRL. Differences in set-up accuracy were significant in the longitudinal direction and are accounted for in online plan adaption. Both methods recorded similar set-up times. The vendor recommended alignment method involves less manipulation of the patient and will be adopted as the standard positioning method for prostate and other pelvic patients on the MRL in future.
<b>Purpose:</b> MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. <b>Methods and Results:</b> In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). <b>Conclusion:</b> The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.
<h4>Introduction</h4>MR-guided adapted radiotherapy (MRgART) using a high field MR-linac has recently become available. We report the estimated delivered fractional dose of the first five prostate cancer patients treated at our centre using MRgART and compare this to C-Arm linac daily Image Guided Radiotherapy (IGRT).<h4>Methods</h4>Patients were treated using adapted treatment plans shaped to their daily anatomy. The treatments were recalculated on an MR image acquired immediately prior to treatment delivery in order to estimate the delivered fractional dose. C-arm linac non-adapted VMAT treatment plans were recalculated on the same MR images to estimate the fractional dose that would have been delivered using conventional radiotherapy techniques using a daily IGRT protocol.<h4>Results</h4>95% and 93% of mandatory target coverage objectives and organ at risk dose constraints were achieved by MRgART and C-arm linac delivered dose estimates, respectively. Both delivery techniques were estimated to have achieved 98% of mandatory Organ At Risk (OAR) dose constraints whereas for the target clinical goals, 86% and 80% were achieved by MRgART and C-arm linac delivered dose estimates.<h4>Conclusions</h4>Prostate MRgART can be delivered using the a high field MR-linac. Radiotherapy performed on a C-arm linac offers a good solution for prostate cancer patients who present with favourable anatomy at the time of reference imaging and demonstrate stable anatomy throughout the course of their treatment. For patients with critical OARs abutting target volumes on their reference image we have demonstrated the potential for a target dose coverage improvement for MRgART compared to C-arm linac treatment.
<h4>Background and purpose</h4>Daily image guidance is standard care for prostate radiotherapy. Innovations which improve the accuracy and efficiency of ultrasound guidance are needed, particularly with respect to reducing interobserver variation. This study explores automation tools for this purpose, demonstrated on the Elekta Clarity Autoscan®. The study was conducted as part of the Clarity-Pro trial (NCT02388308).<h4>Materials and methods</h4>Ultrasound scan volumes were collected from 32 patients. Prostate matches were performed using two proposed workflows and the results compared with Clarity's proprietary software. Gold standard matches derived from manually localised landmarks provided a reference. The two workflows incorporated a custom 3D image registration algorithm, which was benchmarked against a third-party application (Elastix).<h4>Results</h4>Significant reductions in match errors were reported from both workflows compared to standard protocol. Median (IQR) absolute errors in the left-right, anteroposterior and craniocaudal axes were lowest for the Manually Initiated workflow: 0.7(1.0) mm, 0.7(0.9) mm, 0.6(0.9) mm compared to 1.0(1.7) mm, 0.9(1.4) mm, 0.9(1.2) mm for Clarity. Median interobserver variation was ≪0.01 mm in all axes for both workflows compared to 2.2 mm, 1.7 mm, 1.5 mm for Clarity in left-right, anteroposterior and craniocaudal axes. Mean matching times was also reduced to 43 s from 152 s for Clarity. Inexperienced users of the proposed workflows attained better match precision than experienced users on Clarity.<h4>Conclusion</h4>Automated image registration with effective input and verification steps should increase the efficacy of interfraction ultrasound guidance compared to the current commercially available tools.
BACKGROUND AND PURPOSE:Anatomical changes during external beam radiotherapy prevent the accurate delivery of the intended dose distribution. Resolving the delivered dose, which is currently unknown, is crucial to link radiotherapy doses to clinical outcomes and ultimately improve the standard of care. MATERIAL AND METHODS:In this study, we present a dose reconstruction workflow based on data routinely acquired during MR-guided radiotherapy. It employs 3D MR images, 2D cine MR images and treatment machine log files to calculate the delivered dose taking intrafractional motion into account. The developed pipeline was used to measure anatomical changes and assess their dosimetric impact in 89 prostate radiotherapy fractions delivered with a 1.5 T MR-linac at our institute. RESULTS:Over the course of radiation delivery, the CTV shifted 0.6 mm ± 2.1 mm posteriorly and 1.3 mm ± 1.5 mm inferiorly. When extrapolating the dose changes in each case to 20 fractions, the mean clinical target volume D98% and clinical target volume D50% dose-volume metrics decreased by 1.1 Gy ± 1.6 Gy and 0.1 Gy ± 0.2 Gy, respectively. Bladder D3% did not change (0.0 Gy ± 1.2 Gy), while rectum D3% decreased by 1.0 Gy ± 2.0 Gy. Although anatomical changes and their dosimetric impact were small in the majority of cases, large intrafractional motion caused the delivered dose to substantially deviate from the intended plan in some fractions. CONCLUSIONS:The presented end-to-end workflow is able to reliably, non-invasively and automatically reconstruct the delivered prostate radiotherapy dose by processing MR-linac treatment log files and online MR images. In the future, we envision this workflow to be adapted to other cancer sites and ultimately to enter widespread clinical use.
<h4>Purpose</h4>To report a planned analysis of the efficacy and toxicity of dose escalation to the intraprostatic dominant nodule identified on multiparametric magnetic resonance imaging using standard and hypofractionated external beam radiation therapy.<h4>Methods and materials</h4>DELINEATE is a single centre prospective phase 2 multicohort study including standard (cohort A: 74 Gy in 37 fractions) and moderately hypofractionated (cohort B: 60 Gy in 20 fractions) prostate image guided intensity modulated radiation therapy in patients with National Comprehensive Cancer Network intermediate- and high-risk disease. Patients received an integrated boost of 82 Gy (cohort A) and 67 Gy (cohort B) to lesions visible on multiparametric magnetic resonance imaging. Fifty-five patients were treated in cohort A, and 158 patients were treated in cohort B; the first 50 sequentially treated patients in cohort B were included in this planned analysis. The primary endpoint was late Radiation Therapy Oncology Group rectal toxicity at 1 year. Secondary endpoints included acute and late toxicity measured with clinician- and patient-reported outcomes at other time points and biochemical relapse-free survival for cohort A. Median follow-up was 74.5 months for cohort A and 52.0 months for cohort B.<h4>Results</h4>In cohorts A and B, 27% and 40% of patients, respectively, were classified as having National Comprehensive Cancer Network high-risk disease. The cumulative 1-year incidence of Radiation Therapy Oncology Group grade 2 or worse rectal and urinary toxicity was 3.6% and 0% in cohort A and 8% and 10% in cohort B, respectively. There was no reported late grade 3 rectal toxicity in either cohort. Within cohort A, 4 of 55 (7%) patients had biochemical relapse.<h4>Conclusions</h4>Delivery of a simultaneous integrated boost to intraprostatic dominant nodules is feasible in prostate radiation therapy using standard and moderately hypofractionated regimens, with rectal and genitourinary toxicity comparable to contemporary series without an intraprostatic boost.
<h4>Introduction</h4>Dose escalation to dominant intraprostatic lesions (DILs) is a novel method to increase the therapeutic ratio in localised prostate cancer. The Stereotactic Prostate Augmented Radiotherapy with Cyberknife (SPARC) trial was designed to determine the feasibility of a focal boost defined with multiparametric magnetic resonance imaging (mpMRI) using stereotactic ablative body radiotherapy (SABR).<h4>Materials and methods</h4>Patients were included with newly diagnosed intermediate to high risk prostate cancer with at least one of: Gleason score 4 + 3, stage T3a, or PSA > 20 ng/ml. Visible disease on mpMRI was mandatory and up to 2 separate nodules were allowed. All patients received androgen deprivation. Patients received 36.25 Gy in 5 fractions using CyberKnife® and the DIL received a simultaneous boost to a maximum of 47.5 Gy, as allowed by OAR constraints. Genitourinary (GU) and gastrointestinal (GI) toxicity was reported using the RTOG scoring criteria. International Index of Erectile Function (IIEF) and EQ-5D global health scores were regularly captured.<h4>Results</h4>An interim safety analysis was performed on the first 8 patients, recruited between July 2013 and December 2015. Median follow up was 56 months (range 50-74). Median D95 values for the prostate PTV and boost volume were 36.55 Gy (range 35.87-36.99) and 46.62 Gy (range 44.85-48.25) respectively. Of the dose constraints, 10/80 were not achieved but all were minor dose variations. Grade 2+ acute GU and GI toxicities were 37.5% respectively while grade 2+ late GU and GI toxicities were 12.5% and 0% respectively. IIEF and quality of life scores recovered over time and all patients remain in biochemical remission.<h4>Conclusion</h4>The first patients have been successfully treated with prostate SABR and focal boost on the SPARC trial, with excellent adherence to the planning protocol. Toxicity and efficacy results are promising and further recruitment is underway.
<h4>Purpose</h4>Red cell distribution width (RDW) measures red cells' size variability. Metastatic penile cancer displays poor chemotherapy response. As no validated prognostic predictor exists, we investigated whether RDW correlates independently with survival outcomes in metastatic penile cancer treated by chemotherapy.<h4>Methods</h4>Electronic chemotherapy files of patients with metastatic penile cancer (M1 or N3) from a large academic supra-regional centre were retrospectively analysed between 2005 and 2018. Patients were stratified into RDW > 13.9% and < 13.9%, as per published data on RDW in renal cell carcinoma. Survival time was calculated from the date of chemotherapy initiation until the date of death.<h4>Results</h4>58 patients were analysed. The RDW-high group (n = 31) had a poorer survival than the RDW-low group (n = 27). Median overall survival (mOS) in all patients was 19.0 months (95% CI 13.1-24.9). mOS for RDW-high was 15.0 months (95% CI 10.1-19.9) and 37.0 months (95% CI 32.3-43.1) for RDW-low. Kaplan-Meier curves showed a clear disparity in survival (log rank p = 0.025). Cox proportional hazard ratio for death, corrected for T-stage, grade, age and deprivation score was 0.43 (p = 0.04). Sub-analysis of the M1 patients showed mOS in RDW-high of 17 m (95% CI 11.6-22.4) vs. NR; HR for death of 0.42. N3 patients' mOS in RDW-high cohort was 30 months (95% CI 4.5-55.9) vs. 13 months (95% CI 1.8-24.2) in RDW-low; HR for death was 0.30.<h4>Conclusion</h4>RDW correlates independently with survival outcomes in metastatic penile cancer and may act as a potential predictor of survival outcomes for patients with metastatic penile cancer receiving chemotherapy.
<h4>Purpose of review</h4>This review summarizes the prospective clinical evidence regarding local therapy in metastatic prostate cancer.<h4>Recent findings</h4>The phase 3 STAMPEDE trial showed that prostate radiotherapy confers a survival benefit for newly diagnosed patients with low volume metastatic hormone-sensitive prostate cancer (HSPC). No survival benefit was noted for those with high volume disease. A subsequent meta-analysis combining the data of the STAMPEDE trial with that of the HORRAD trial corroborated these findings. The phase 2 randomized STOMP trial investigated local treatment of metastases in patients with oligometastatic HSPC, and showed an improvement in hormone therapy-free survival. Local prostate radiotherapy should be offered to patients with newly diagnosed low volume metastatic HSPC. Early clinical evidence suggests that local treatment to metastatic disease might be beneficial for patients with oligometastatic HSPC, but larger trials are awaited.
•PIVOTALboost evaluates benefits/toxicity of pelvic node RT and focal boost dose escalation.•Unfavourable intermediate/high risk and bulky local disease are most likely to benefit.•Functional MRI imaging is used to select patients for different types of dose escalation.•HDR brachytherapy or focal dose escalation with IMRT are used as options.•Training and support is provided to reduce variations of contouring and radiotherapy planning.•The trial is recruiting patients in 38 radiotherapy centres through the UK.
External beam radiotherapy remains the primary treatment modality for localized prostate cancer. The radiobiology of prostate carcinoma lends itself to hypofractionation, with recent studies showing good outcomes with shorter treatment schedules. However, the ability to accurately deliver hypofractionated treatment is limited by current image-guided techniques. Magnetic resonance imaging is the main diagnostic tool for localized prostate cancer and its use in the therapeutic setting offers anatomical information to improve organ delineation. MR-guided radiotherapy, with daily re-planning, has shown early promise in the accurate delivery of radiotherapy. In this article, we discuss the shortcomings of current image-guidance strategies and the potential benefits and limitations of MR-guided treatment for prostate cancer. We also recount present experiences of MR-linac workflow and the opportunities afforded by this technology.
Evidence is accumulating for seven and less fractions in localised prostate cancer, including one large randomised trial. However, there is much more evidence yet to come and changing practice in advance of this may be premature. We review the reasons to persist with moderate hypofractionation for prostate cancer radiotherapy, until the results of further phase III studies are known.
<h4>Purpose</h4>During a global pandemic, the benefit of routine visits and treatment of patients with cancer must be weighed against the risks to patients, staff, and society. Prostate cancer is one of the most common cancers radiation oncology departments treat, and efficient resource utilization is essential in the setting of a pandemic. Herein, we aim to establish recommendations and a framework by which to evaluate prostate radiation therapy management decisions.<h4>Methods and materials</h4>Radiation oncologists from the United States and the United Kingdom rapidly conducted a systematic review and agreed upon recommendations to safely manage patients with prostate cancer during the COVID-19 pandemic. A RADS framework was created: remote visits, and avoidance, deferment, and shortening of radiation therapy was applied to determine appropriate approaches.<h4>Results</h4>Recommendations were provided by the National Comprehensive Cancer Network risk group regarding clinical node-positive, postprostatectomy, oligometastatic, and low-volume M1 disease. Across all prostate cancer stages, telemedicine consultations and return visits were recommended when resources/staff available. Delays in consultations and return visits of between 1 and 6 months were deemed safe based on stage of disease. Treatment can be avoided or delayed until safe for very low, low, and favorable intermediate-risk disease. Unfavorable intermediate-risk, high-risk, clinical node-positive, recurrence postsurgery, oligometastatic, and low-volume M1 disease can receive neoadjuvant hormone therapy for 4 to 6 months as necessary. Ultrahypofractionation is preferred for localized, oligometastatic, and low-volume M1, and moderate hypofractionation is preferred for postprostatectomy and clinical node positive disease. Salvage is preferred to adjuvant radiation.<h4>Conclusions</h4>Resources can be reduced for all identified stages of prostate cancer. The RADS (remote visits, and avoidance, deferment, and shortening of radiation therapy) framework can be applied to other disease sites to help with decision making in a global pandemic.
<h4>Purpose</h4>During a global pandemic, the benefit of routine visits and treatment of patients with cancer must be weighed against the risks to patients, staff, and society. Prostate cancer is one of the most common cancers radiation oncology departments treat, and efficient resource utilization is essential in the setting of a pandemic. Herein, we aim to establish recommendations and a framework by which to evaluate prostate radiation therapy management decisions.<h4>Methods and materials</h4>Radiation oncologists from the United States and the United Kingdom rapidly conducted a systematic review and agreed upon recommendations to safely manage patients with prostate cancer during the COVID-19 pandemic. A RADS framework was created: remote visits, and avoidance, deferment, and shortening of radiation therapy was applied to determine appropriate approaches.<h4>Results</h4>Recommendations were provided by the National Comprehensive Cancer Network risk group regarding clinical node-positive, postprostatectomy, oligometastatic, and low-volume M1 disease. Across all prostate cancer stages, telemedicine consultations and return visits were recommended when resources/staff available. Delays in consultations and return visits of between 1 and 6 months were deemed safe based on stage of disease. Treatment can be avoided or delayed until safe for very low, low, and favorable intermediate-risk disease. Unfavorable intermediate-risk, high-risk, clinical node-positive, recurrence postsurgery, oligometastatic, and low-volume M1 disease can receive neoadjuvant hormone therapy for 4 to 6 months as necessary. Ultrahypofractionation is preferred for localized, oligometastatic, and low-volume M1, and moderate hypofractionation is preferred for postprostatectomy and clinical node positive disease. Salvage is preferred to adjuvant radiation.<h4>Conclusions</h4>Resources can be reduced for all identified stages of prostate cancer. The RADS (remote visits, and avoidance, deferment, and shortening of radiation therapy) framework can be applied to other disease sites to help with decision making in a global pandemic.
<h4>Purpose</h4>With the availability of ultra-sensitive PSA assays, early biochemical relapse (eBCR) of prostate cancer is increasingly being detected at values much lower than the conventional threshold of 0.2 ng/ml. Accurate localisation of disease in this setting may allow treatment modification and improved outcomes, especially in patients with pelvis-confined or extra-pelvic oligometastasis (defined as up to three pelvic nodal or distant sites). We aimed to measure the detection rate of [68]Ga-PSMA-HBNED-CC (PSMA)-PET/CT and its influence on patient management in eBCR of prostate cancer following radical prostatectomy (RP).<h4>Methods</h4>We retrospectively identified 28 patients who underwent PSMA-PET/CT for post-RP eBCR (PSA < 0.5 ng/ml) at our tertiary care cancer centre. Two nuclear medicine physicians independently recorded the sites of PSMA-PET/CT positivity. Multidisciplinary meeting records were accessed to determine changes in management decisions following PSMA-PET/CT scans.<h4>Results</h4>The mean age of patients was 65.6 years (range: 50-76.2 years); median PSA was 0.22 ng/ml (interquartile range: 0.15 ng/ml to 0.34 ng/ml). Thirteen patients (46.4%) had received radiotherapy in the past. PSMA-PET/CT was positive in 17 patients (60.7%). Only one patient had polymetastasis (> 3 sites); the remainder either had prostatectomy bed recurrence (n = 2), pelvic oligometastasis (n = 10), or extra-pelvic oligometastasis (n = 4). PSMA-PET/CT resulted in management change in 12 patients (42.8%), involving stereotactic body radiotherapy (n = 6), salvage radiotherapy (n = 4), and systemic treatment (n = 2).<h4>Conclusions</h4>Our findings show that PSMA-PET/CT has a high detection rate in the eBCR setting following RP, with a large proportion of patients found to have fewer than three lesions. PSMA-PET/CT may be of value in patients with early PSA failure, and impact on the choice of potentially curative salvage treatments.
<h4>Background and purpose</h4>Prostate bed radiotherapy is a standard treatment after radical prostatectomy. Recent evidence suggests that, for patients with a PSA > 0.34 ng/ml, the radiotherapy treatment volume should include not only the prostate bed but also the pelvic lymph nodes. We describe the patterns of failure after prostate bed radiotherapy, focussing on the proportion of patients with radiologically confirmed pelvic nodal failure only, in the absence of distant disease.<h4>Materials and methods</h4>Patients included were men receiving prostate bed radiotherapy at the Royal Marsden Hospital between 1997 and 2013. The key outcome of interest was the pattern of radiologic failure after prostate bed radiotherapy. Baseline characteristics of patients experiencing pelvic nodal failure without distant disease were compared versus all other relapse patterns. Comparisons were by Chi-square test, with multiple testing adjusted p < 0.005 significant.<h4>Results</h4>140 of 322 patients developed biochemical failure after salvage RT. Radiologic failure occurred in 89 patients. 35 of the 89 patients (39%) with radiologic failure had pelvic nodal failure without distant disease, with no significant differences in baseline characteristics when compared to all other patients. The rate of pelvic nodal failure was the same for patients with PSA above or below 0.34 ng/ml (16/149, 95% CI = 6-17% vs 19/171, 95% CI = 7-17%).<h4>Conclusions</h4>Pelvic lymph node disease, without more distant disease, is a common site of failure in men receiving radiotherapy to the prostate bed, including those with PSA < 0.34 ng/ml. This observation informs the case for including the pelvic lymph nodes in the radiotherapy treatment volume.
<h4>Background</h4>Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.<h4>Methods</h4>PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.<h4>Findings</h4>Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred.<h4>Interpretation</h4>Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.<h4>Funding</h4>Accuray and National Institute of Health Research.
<h4>Background</h4>Stereotactic body radiotherapy (SBRT) and elective nodal radiotherapy (ENRT) are being investigated as metastasis-directed treatments in oligorecurrent prostate cancer (PC); however, comparative data are still lacking.<h4>Objective</h4>To compare outcome and toxicity between both treatments. Primary endpoint was metastasis-free survival, adjusted for selected variables (aMFS).<h4>Design, setting, and participants</h4>This was a multi-institutional, retrospective analysis of 506 (SBRT: 309, ENRT: 197) patients with hormone-sensitive nodal oligorecurrent PC (five or fewer lymph nodes (LNs; N1/M1a), treated between 2004 and 2017. Median follow-up was 36 mo (interquartile range 23-56).<h4>Intervention</h4>SBRT was defined as a minimum of 5 Gy per fraction to each lesion with a maximum of 10 fractions. ENRT was defined as a minimum dose of 45 Gy in up to 25 fractions to the elective nodes, with or without a simultaneous boost to the suspicious node(s). The choice of radiotherapy (RT) was at the discretion of the treating physician, with treatments being unbalanced over the centers.<h4>Outcome measurements and statistical analysis</h4>In total, 506 patients from 15 different treatment centers were included. Primary treatment was radical prostatectomy, RT, or their combination. Nodal recurrences were detected by positron emission tomography/computer tomography (97%) or conventional imaging (3%). Descriptive statistics was used to summarize patient characteristics.<h4>Results and limitations</h4>ENRT was associated with fewer nodal recurrences compared with SBRT (p < 0.001). In a multivariable analysis, patients with one LN at recurrence had longer aMFS after ENRT (hazard ratio: 0.50, 95% confidence interval 0.30-0.85, p = 0.009). Late toxicity was higher after ENRT compared with that after SBRT (16% vs. 5%, p < 0.01). Limitations include higher use of hormone therapy in the ENRT cohort and nonstandardized follow-up.<h4>Conclusions</h4>ENRT reduces the number of nodal recurrences as compared with SBRT, however at higher toxicity. Our findings hypothesize that ENRT should be preferred to SBRT in the treatment of nodal oligorecurrences. This hypothesis needs to be evaluated in a randomized trial.<h4>Patient summary</h4>This study investigated the difference between stereotactic and elective nodal radiotherapy in treating limited nodal metastatic prostate cancer. Nodal relapse was less frequent following elective nodal radiotherapy than following stereotactic body radiotherapy, and thus elective nodal radiotherapy might be the preferred treatment.
We have developed a method to determine intrafraction motion of the prostate through automatic fiducial marker (FM) tracking on 3D cine-magnetic resonance (MR) images with high spatial and temporal resolution. Twenty-nine patients undergoing prostate stereotactic body radiotherapy (SBRT), with four implanted cylindrical gold FMs, had cine-MR imaging sessions after each of five weekly fractions. Each cine-MR examination consisted of 55 sequentially obtained 3D datasets ('dynamics'), acquired over a 11 s period, covering a total of 10 min. FM locations in the first dynamic were manually identified by a clinician, FM centers in subsequent dynamics were automatically determined. Center of mass (COM) translations and rotations were determined by calculating the rigid transformations between the FM template of the first and subsequent dynamics. The algorithm was applied to 7315 dynamics over 133 scans of 29 patients and the obtained results were validated by comparing the COM locations recorded by the clinician at the halfway-dynamic (after 5 min) and end dynamic (after 10 min). The mean COM translations at 10 min were X: 0.0 [Formula: see text] 0.8 mm, Y: 1.0 [Formula: see text] 1.9 mm and Z: 0.9 [Formula: see text] 2.0 mm. The mean rotation results at 10 min were X: 0.1 [Formula: see text] 3.9°, Y: 0.0 [Formula: see text] 1.3° and Z: 0.1 [Formula: see text] 1.2°. The tracking success rate was 97.7% with a mean 3D COM error of 1.1 mm. We have developed a robust, fast and accurate FM tracking algorithm for cine-MR data, which allows for continuous monitoring of prostate motion during MR-guided radiotherapy (MRgRT). These results will be used to validate automatic prostate tracking based on soft-tissue contrast.
<h4>Purpose of review</h4>Systemic therapy for patients with hormone-sensitive oligometastatic prostate cancer is non-curative and associated with toxicities. Meanwhile, this population presents unique clinical opportunities to improve outcomes, including the demonstrated benefits of radiotherapy to the primary tumor or oligometastatic sites.<h4>Recent findings</h4>Recently published randomized studies have demonstrated benefits with the addition of radiotherapy to the primary disease or metastatic lesions in patients with synchronous or metachronous disease. The introduction of novel PET imaging has improved the sensitivity and specificity for detecting metastatic disease and provides an opportunity to better select patients who will benefit from local therapy. The data presented in this review supports revisiting practice guidelines for patients with hormone-sensitive metastatic prostate cancer, particularly in relation to the role of radiotherapy to the primary tumor and sites of oligometastatic disease. Future trials will aim to further establish the role of metastasis-directed therapies in metachronous, synchronous, and castrate-resistant disease.
External beam radiotherapy for prostate cancer is an optimal treatment choice for men with localised prostate cancer and is associated with long term disease control in most patients. Image-guided prostate radiotherapy is standard of care, however, current techniques can include invasive procedures with imaging of poor soft tissue resolution, thus limiting accuracy. MRI is the imaging of choice for local prostate cancer staging and in radiotherapy planning has been shown to reduce target volume and reduce inter-observer prostate contouring variability. The ultimate aim would be to have a MR-only workflow for prostate radiotherapy. Within this article, we discuss these opportunities and challenges, relevant due to the increasing availability of MR-guided radiotherapy. Prospective multi-centre studies are underway to determine the feasibility of MR-guided prostate radiotherapy and daily adaptive replanning. In parallel, development and adaptation of the existing radiotherapy multidisciplinary workforce is essential to enable an efficient and effective MR-guided radiotherapy workflow. This technology potentially provides us with the anatomical and biological information to further improve outcomes for our patients.
<h4>Purpose</h4>There are sparse data describing outcomes of bone-only oligometastatic prostate cancer in comparison with lymph node disease treated with stereotactic body radiotherapy (SBRT). The primary aim of this study was to report progression-free survival (PFS) data for patients with bone-only disease. Influence of hormone sensitivity and androgen deprivation therapy use was also assessed.<h4>Methods</h4>This is a single-centre retrospective cohort study. Hormone-sensitive and castrate-resistant patients with oligometastatic (≤ 3) bone-only prostate cancer treated with SBRT were included. Data were collected using electronic records. Kaplan-Meier survivor function, log rank test, as well as Cox regression were used to calculate PFS and overall survival.<h4>Results</h4>In total, 51 patients with 64 bone metastases treated with SBRT were included. Nine patients were castrate resistant and 42 patient's hormone sensitive at the time of SBRT. Median follow-up was 23 months. Median PFS was 24 months in hormone-sensitive patients and 3 months in castrate-resistant patients. No patients experienced grade 3 or 4 toxicities. There were three in-field recurrences.<h4>Conclusions</h4>In this study, patients with bone oligometastatic disease showed potential benefit from SBRT with a median PFS of 11 months. Hormone-sensitive patients showed the greatest benefit, with results similar to that published for oligometastatic pelvic nodal disease treated with SBRT. Prospective randomised control trials are needed to determine the survival benefit of SBRT in oligometastatic bone-only prostate cancer and to determine prognostic indicators.
Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. In the era of well-tolerated targeted treatments, resistance inevitably occurs and overcoming this is a challenge. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance. Stereotactic body radiotherapy is now frequently used in treating oligometastatic disease using ablative doses with minimally invasive techniques and acceptable toxicity. We discuss the current retrospective clinical evidence base supporting the use of local ablative therapy for oligoprogression in metastatic patients on targeted treatments within multiple tumour sites. As there is currently a lack of published prospective data available, the best management for these patients remains unclear. We discuss current trials in recruitment and the potential advancements in treating this group of patients with stereotactic radiotherapy.
<h4>Objective:</h4>With increasing incorporation of MRI in radiotherapy, we investigate two MRI sequences for prostate delineation in radiographer-led image guidance.<h4>Methods:</h4>Five therapeutic radiographers contoured the prostate individually on CT, T<sub>2</sub> weighted (T<sub>2</sub>W) and T<sub>2</sub>* weighted (T<sub>2</sub>*W) imaging for 10 patients. Contours were analysed with Monaco ADMIRE (research v. 2.0) to assess interobserver variability and accuracy by comparison with a gold standard clinician contour. Observers recorded time taken for contouring and scored image quality and confidence in contouring.<h4>Results:</h4>There is good agreement when comparing radiographer contours to the gold-standard for all three imaging types with Dice similarity co-efficient 0.91-0.94, Cohen's κ 0.85-0.91, Hausdorff distance 4.6-7.6 mm and mean distance between contours 0.9-1.2 mm. In addition, there is good concordance between radiographers across all imaging modalities. Both T<sub>2</sub>W and T<sub>2</sub>*W MRI show reduced interobserver variability and improved accuracy compared to CT, this was statistically significant for T<sub>2</sub>*W imaging compared to CT across all four comparison metrics. Comparing MRI sequences reveals significantly reduced interobserver variability and significantly improved accuracy on T<sub>2</sub>*W compared to T<sub>2</sub>W MRI for DSC and Cohen's κ. Both MRI sequences scored significantly higher compared to CT for image quality and confidence in contouring, particularly T<sub>2</sub>*W. This was also reflected in the shorter time for contouring, measuring 15.4, 9.6 and 9.8 min for CT, T<sub>2</sub>W and T<sub>2</sub>*W MRI respectively. Conclusion: Therapeutic radiographer prostate contours are more accurate, show less interobserver variability and are more confidently and quickly outlined on MRI compared to CT, particularly using T<sub>2</sub>*W MRI. Advances in knowledge: Our work is relevant for MRI sequence choice and development of the roles of the interprofessional team in the advancement of MRI-guided radiotherapy.
<h4>Background and purpose</h4>Intraprostatic fiducial markers (FM) improve the accuracy of radiotherapy (RT) delivery. Here we assess geometric integrity and contouring consistency using a T2*-weighted (T2*W) sequence alone, which allows visualization of the FM.<h4>Material and methods</h4>Ten patients scanned within the Prostate Advances in Comparative Evidence (PACE) trial (NCT01584258) had prostate images acquired with computed tomography (CT) and Magnetic Resonance (MR) Imaging: T2-weighted (T2W) and T2*W sequences. The prostate was contoured independently on each imaging dataset by three clinicians. Interobserver variability was assessed using comparison indices with Monaco ADMIRE (research version 2.0, Elekta AB) and examined for statistical differences between imaging sets. CT and MR images of two test objects were acquired to assess geometric distortion and accuracy of marker positioning. The first was a linear test object comprising straight tubes in three orthogonal directions, the second was a smaller test object with markers suspended in gel.<h4>Results</h4>Interobserver variability for prostate contouring was lower for both T2W and T2*W compared to CT, this was statistically significant when comparing CT and T2*W images. All markers are visible in T2*W images with 29/30 correctly identified, only 3/30 are visible in T2W images. Assessment of geometric distortion revealed in-plane displacements were under 0.375 mm in MRI, and through plane displacements could not be detected. The signal loss in the MR images is symmetric in relation to the true marker position shown in CT images.<h4>Conclusion</h4>Prostate T2*W images are geometrically accurate, and yield consistent prostate contours. This single sequence can be used to identify FM and for prostate delineation in a mixed MR-CT workflow.
<h4>Introduction</h4>In the United Kingdom fiducial marker IGRT is the second most common verification method employed in radical prostate radiotherapy yet little evidence exists to support centres introducing or developing this practice. We developed a survey to elicit current fiducial marker practices adopted in the UK, to recommend standardisation of practice.<h4>Methods</h4>A 16 question survey was distributed across UK Radiotherapy centres via promotion at the British Uro-Oncology Group Conference, 2016. Included were questions relating to workforce planning, patient preparation, insertion procedure and verification methods. The survey was open from September 2016 to January 2017.<h4>Results</h4>Results from 15 centres routinely inserting fiducial markers for prostate IGRT are presented. Eleven professional groups insert fiducial markers across the UK. Fourteen centres insert fiducial markers trans-rectally; one trans-perineally. Centres adopting a trans-rectal approach administer prophylactic ciprofloxacin as a single agent or combined with gentamicin or metronidazole; poor agreement between regimes presented. One centre has introduced targeted antibiotic prophylaxis. Five brands of fiducial markers are utilised nationally. Fourteen centres standardly insert three single fiducial markers, two common configurations emerged. Coupled fiducial markers are routinely implanted by one centre. All centres delay at least one week between fiducial marker insertion and planning CT; seven centres wait two weeks. The most common fiducial verification method is two-dimensional, paired kilo Voltage imaging.<h4>Conclusion</h4>Variation in fiducial marker practice across the UK is considerable. Standardisation is required to support centres and healthcare professionals developing this service. Seven recommendations, to unify practice, have been proposed based on survey results and literature.
<h4>Purpose</h4>Our purpose was to perform an in vivo validation of ultrasound imaging for intrafraction motion estimation using the Elekta Clarity Autoscan system during prostate radiation therapy. The study was conducted as part of the Clarity-Pro trial (NCT02388308).<h4>Methods and materials</h4>Initial locations of intraprostatic fiducial markers were identified from cone beam computed tomography scans. Marker positions were translated according to Clarity intrafraction 3-dimensional prostate motion estimates. The updated locations were projected onto the 2-dimensional electronic portal imager plane. These Clarity-based estimates were compared with the actual portal-imaged 2-dimensional marker positions. Images from 16 patients encompassing 80 fractions were analyzed. To investigate the influence of intraprostatic markers and image quality on ultrasound motion estimation, 3 observers rated image quality, and the marker visibility on ultrasound images was assessed.<h4>Results</h4>The median difference between Clarity-defined intrafraction marker locations and portal-imaged marker locations was 0.6 mm (with 95% limit of agreement at 2.5 mm). Markers were identified on ultrasound in only 3 of a possible 240 instances. No linear relationship between image quality and Clarity motion estimation confidence was identified. The difference between Clarity-based motion estimates and electronic portal-imaged marker location was also independent of image quality. Clarity estimation confidence was degraded in a single fraction owing to poor probe placement.<h4>Conclusions</h4>The accuracy of Clarity intrafraction prostate motion estimation is comparable with that of other motion-monitoring systems in radiation therapy. The effect of fiducial markers in the study was deemed negligible as they were rarely visible on ultrasound images compared with intrinsic anatomic features. Clarity motion estimation confidence was robust to variations in image quality and the number of ultrasound-imaged anatomic features; however, it was degraded as a result of poor probe placement.
Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.
<h4>Aims</h4>There are limited data on dosimetric correlates of toxicity in stereotactic body radiotherapy (SBRT) for prostate cancer. We aimed to identify potential relationships between dose and toxicity using conventional dose-volume histograms (DVHs) and dose-surface maps (DSMs).<h4>Materials and methods</h4>Urinary bladder trigone and rectum DSMs were produced for a single-institution service evaluation cohort of 50 patients receiving SBRT for localised prostate cancer, together with conventional DVHs for bladder and rectum. Patients had been prospectively recruited to this cohort and treated according to a pre-defined protocol to a dose of 36.25 Gy in five fractions. Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) toxicity data were recorded prospectively. Logistic regression was used to identify dosimetric predictors of acute IPSS+10 (rise of 10 points or more above baseline) and grade 2+ RTOG toxicity.<h4>Results</h4>On univariate analysis, trigone area receiving 40 Gy and trigone D<sub>max</sub> were associated with IPSS+10 (odds ratio 1.06 [1.02-1.11], P = 0.007 and odds ratio 1.54 [1.06-2.25], P = 0.024, respectively). These two variables were highly correlated. In a multivariate model, including all baseline variables, trigone D<sub>max</sub> remained associated with IPSS+10 (odds ratio 1.91 [1.13-3.22], P = 0.016). These findings were not significant with Holm-Bonferroni correction for multiple testing (corrected P value threshold 0.006). No associations were seen between rectal toxicity and DVH or DSM parameters.<h4>Conclusions</h4>Our study suggests a potential relationship between high doses to the urinary bladder trigone and patient-reported urinary toxicity in prostate SBRT, and is consistent with previous studies in conventionally fractionated radiotherapy, justifying further evaluation in larger cohorts.
<b>Background:</b> Magnetic resonance (MR)-fusion contouring is the standard of care in prostate stereotactic body radiotherapy (SBRT) for target volume localisation. However, the planning computerised tomography (CT) scan continues to be used for dose calculation and treatment planning and verification. Discrepancies between the planning MR and CT scans may negate the benefits of MR-fusion contouring and it adds a significant resource burden. We aimed to determine whether CT-only contouring resulted in a dosimetric detriment compared with MR-fusion contouring in prostate SBRT planning. <b>Methods:</b> We retrospectively compared target volumes and SBRT plans for 20 patients treated clinically with MR-fusion contouring (standard of care) with those produced by re-contouring using CT data only. Dose was 36.25 Gy in 5 fractions. CT-only contouring was done on two occasions blind to MR data and reviewed by a separate observer. Primary outcome was the difference in rectal volume receiving 36 Gy or above. <b>Results:</b> Absolute target volumes were similar: 63.5 cc (SD ± 27.9) versus 63.2 (SD ± 26.5), Dice coefficient 0.86 (SD ± 0.04). Mean difference in apex superior-inferior position was 1.1 (SD ± 3.5; CI: −0.4–2.6). Small dosimetric differences in favour of CT-only contours were seen, with the mean rectal V36 Gy 0.3 cc (95% CI: 0.1–0.5) lower for CT-only contouring. <b>Conclusions:</b> Prostate SBRT can be successfully planned without MR-fusion contouring. Consideration can be given to omitting MR-fusion from the prostate SBRT workflow, provided reference to diagnostic MR imaging is available. Development of MR-only work flow is a key research priority to gain access to the anatomical fidelity of MR imaging.
Prostate cancer is the most common non-cutaneous cancer in males. There are a number of options for patients with localized early stage disease, including active surveillance for low-risk disease, surgery, brachytherapy, and external beam radiotherapy. Increasingly, external beam radiotherapy, in the form of dose-escalated and moderately hypofractionated regimens, is being utilized in prostate cancer, with randomized evidence to support their use. Stereotactic body radiotherapy, which is a form of extreme hypofractionation, delivered with high precision and conformality typically over 1 to 5 fractions, offers a more contemporary approach with several advantages including being non-invasive, cost-effective, convenient for patients, and potentially improving patient access. In fact, one study has estimated that if half of the patients currently eligible for conventional fractionated radiotherapy in the United States were treated instead with stereotactic body radiotherapy, this would result in a total cost savings of US$250 million per year. There is also a strong radiobiological rationale to support its use, with prostate cancer believed to have a low α/β ratio and therefore being preferentially sensitive to larger fraction sizes. To date, there are no published randomized trials reporting on the comparative efficacy of stereotactic body radiotherapy compared to alternative treatment modalities, although multiple randomized trials are currently accruing. Yet, early results from the randomized phase III study of HYPOfractionated RadioTherapy of intermediate risk localized Prostate Cancer (HYPO-RT-PC) trial, as well as multiple single-arm phase I/II trials, indicate low rates of late adverse effects with this approach. In patients with low- to intermediate-risk disease, excellent biochemical relapse-free survival outcomes have been reported, albeit with relatively short median follow-up times. These promising early results, coupled with the enormous potential cost savings and implications for resource availability, suggest that stereotactic body radiotherapy will take center stage in the treatment of prostate cancer in the years to come.
Radiation therapy to the prostate involves increasingly sophisticated delivery techniques and changing fractionation schedules. With a low estimated α/β ratio, a larger dose per fraction would be beneficial, with moderate fractionation schedules rapidly becoming a standard of care. The integration of a magnetic resonance imaging (MRI) scanner and linear accelerator allows for accurate soft tissue tracking with the capacity to replan for the anatomy of the day. Extreme hypofractionation schedules become a possibility using the potentially automated steps of autosegmentation, MRI-only workflow, and real-time adaptive planning. The present report reviews the steps involved in hypofractionated adaptive MRI-guided prostate radiation therapy and addresses the challenges for implementation.
There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.
PURPOSE OF REVIEW: It is now accepted that prostate cancer has a low alpha/beta ratio, establishing a strong basis for hypofractionation of prostate radiotherapy. This review focuses on the rationale for hypofractionation and presents the evidence base for establishing moderate hypofractionation for localised disease as the new standard of care. The emerging evidence for extreme hypofractionation in managing localized and oligometastatic prostate cancer is reviewed. RECENT FINDINGS: The 5-year efficacy and toxicity outcomes from four phase III studies have been published within the last 12 months. These studies randomizing over 6000 patients to conventional fractionation (1.8-2.0 Gy per fraction) or moderate hypofractionation (3.0-3.4 Gy per fraction). They demonstrate hypofractionation to be non-inferior to conventional fractionation. Moderate hypofractionation for localized prostate cancer is safe and effective. There is a growing body of evidence in support of extreme hypofractionation for localized prostate cancer. Extreme hypofractionation may have a role in managing prostate oligometastases, but further studies are needed.
<h4>Background</h4>The optimal management of the primary tumor in metastatic at diagnosis (M1) prostate cancer (PCa) patients is not yet established. We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) hypothesizing that this could improve outcome through better local disease control and the induction of an antitumor immune response (abscopal effect).<h4>Patients and methods</h4>M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden between June 2003 and December 2013 were identified. LRT was defined as either surgery, radiotherapy (RT) or transurethral prostatectomy (TURP) administered to the primary tumor at any time point from diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models.<h4>Results</h4>Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point during their disease course; 72 patients received LRT (56.9% TURP, 52.7% RT). None of the patients were treated with prostatectomy. LRT was more frequently performed in patients with low volume disease (35.4% vs. 16.2%; P < .001), lower prostate-specific antigen (PSA) level at diagnosis (median PSA: 75 vs. 184 ng/mL; P = .005) and local symptoms (34.2% vs. 4.8%; P < .001). LRT was associated in UV and MV analysis with longer OS (62.1 vs. 55.8 months; hazard ratio [HR], 0.74; P = .044), which remained significant for RT (69.4 vs. 55.1 months; HR, 0.54; P = .002) but not for TURP. RT was associated with better OS independent of disease volume at diagnosis.<h4>Conclusion</h4>These data support the conduct of randomized phase III trials to evaluate the benefit of local control in patients with M1 disease at diagnosis.
<h4>Background and purpose</h4>Delivering selected parts of volumetric modulated arc therapy (VMAT) plans using step-and-shoot intensity modulated radiotherapy (IMRT) beams has the potential to increase plan quality by allowing specific aperture positioning. This study investigates the quality of treatment plans and the accuracy of in vivo portal dosimetry in such a hybrid approach for the case of prostate radiotherapy.<h4>Material and methods</h4>Conformal and limited-modulation VMAT plans were produced, together with five hybrid IMRT/VMAT plans, in which 0%, 25%, 50%, 75% or 100% of the segments were sequenced for IMRT, while the remainder were sequenced for VMAT. Integrated portal images were predicted for the plans. The plans were then delivered as a single hybrid beam using an Elekta Synergy accelerator with Agility head to a water-equivalent phantom and treatment time, isocentric dose and portal images were measured.<h4>Results</h4>Increasing the IMRT percentage improves dose uniformity to the planning target volume (p<0.01 for 50% IMRT or more), substantially reduces the volume of rectum irradiated to 65Gy (p=0.02 for 25% IMRT) and increases the monitor units (p<0.001). Delivery time also increases substantially. All plans show accurate delivery of dose and reliable prediction of portal images.<h4>Conclusions</h4>Hybrid IMRT/VMAT can be efficiently planned and delivered as a single beam sequence. Beyond 25% IMRT, the delivery time becomes unacceptably long, with increased risk of intrafraction motion, but 25% IMRT is an attractive compromise. Integrated portal images can be used to perform in vivo dosimetry for this technique.
Dose escalated radiotherapy improves outcomes for men with prostate cancer. A plateau for benefit from dose escalation using EBRT may not have been reached for some patients with higher risk disease. The use of increasingly conformal techniques, such as step and shoot IMRT or more recently VMAT, has allowed treatment intensification to be achieved whilst minimising associated increases in toxicity to surrounding normal structures. To support further safe dose escalation, the uncertainties in the treatment target position will need be minimised using optimal planning and image-guided radiotherapy (IGRT). In particular the increasing usage of profoundly hypo-fractionated stereotactic therapy is predicated on the ability to confidently direct treatment precisely to the intended target for the duration of each treatment. This article reviews published studies on the influences of varies types of motion on daily prostate position and how these may be mitigated to improve IGRT in future. In particular the role that MRI has played in the generation of data is discussed and the potential role of the MR-Linac in next-generation IGRT is discussed.
<h4>Unlabelled</h4>The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials.<h4>Patient summary</h4>This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.
<h4>Aims</h4>To report the relapse pattern of stereotactic body radiotherapy (SBRT) for oligorecurrent nodal prostate cancer (PCa).<h4>Materials and methods</h4>PCa patients with ≤3 lymph nodes (N1/M1a) at the time of recurrence were treated with SBRT. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a biological effective dose of at least 80 Gy to all metastatic sites. Distant progression-free survival was defined as the time interval between the first day of SBRT and appearance of new metastatic lesions, outside the high-dose region. Relapses after SBRT were recorded and compared with the initially treated site. Secondary end points were local control, time to palliative androgen deprivation therapy and toxicity scored using the Common Terminology Criteria for Adverse Events v4.0.<h4>Results</h4>Overall, 89 metastases were treated in 72 patients. The median distant progression-free survival was 21 months (95% confidence interval 16-25 months) with 88% of patients having ≤3 metastases at the time of progression. The median time from first SBRT to the start of palliative androgen deprivation therapy was 44 months (95% confidence interval 17-70 months). Most relapses (68%) occurred in nodal regions. Relapses after pelvic nodal SBRT (n = 36) were located in the pelvis (n = 14), retroperitoneum (n = 1), pelvis and retroperitoneum (n = 8) or in non-nodal regions (n = 13). Relapses after SBRT for extrapelvic nodes (n = 5) were located in the pelvis (n = 1) or the pelvis and retroperitoneum (n = 4). Late grade 1 and 2 toxicity was observed in 17% (n = 12) and 4% of patients (n = 3).<h4>Conclusion</h4>SBRT for oligometastatic PCa nodal recurrences is safe. Most subsequent relapses are again nodal and oligometastatic.
Dose escalation to the prostate improves tumor control but at the expense of increased rectal toxicity. Modern imaging can be used to detect the most common site of recurrence, the intraprostatic lesion (IPL), which has led to the concept of focusing dose escalation to the IPL in order to improve the therapeutic ratio. Imaging must be able to detect lesions with adequate sensitivity and specificity to accurately delineate the IPL. This information must be carefully integrated into the radiotherapy planning process to ensure the dose is targeted to the IPL. This review will consider the role and challenges of multiparametric MRI and PET computed tomography in delineating a tumor boost to be delivered by external beam radiotherapy.
<h4>Aims</h4>To retrospectively review the toxicity and early outcome data from patients who have received stereotactic body radiotherapy (SBRT) for extracranial oligometastases at a single UK institution.<h4>Materials and methods</h4>Eligible patients had ≤3 extracranial metastases and performance status ≤2. Prior systemic therapy and radical treatment of oligometastastic relapse with any standard treatment modality was permitted. Patients with synchronous metastatic disease were excluded unless they had evidence of controlled primary disease after radical therapy. Follow-up consisted of clinical examination, biochemical and radiological assessments in accordance with standard clinical care. Progression events were defined using RECIST. Toxicity was evaluated using CTCAE v4.0. Local control, progression-free survival (PFS), freedom from widespread distant metastasis (defined as disease not amenable to further radical salvage therapy) and overall survival were calculated.<h4>Results</h4>Between July 2011 and April 2014, 73 patients with 87 metastases received SBRT (range 1-3 per patient). The median follow-up was 14.5 months (range 0-26.4). The median PFS was 14.5 months (1 year PFS 57%, 2 year 28%); 1 year overall survival 96%, 2 year 79.8%; 2 year local control 88%. At 2 years, 46% of patients were free from widespread distant metastases. No ≥ grade 3 acute or late toxicity was observed.<h4>Conclusion</h4>At this time point, observed toxicity is minimal with excellent local control rates. This promising treatment paradigm requires further investigation in the context of a randomised controlled trial to establish if the addition of SBRT to standard care improves survival outcomes.
The use of stereotactic body radiotherapy (SBRT) for localised prostate cancer is now supported by a substantial body of non-randomised data, with medium-term outcomes consistent with current standard radiotherapy. The ability to deliver profoundly hypofractionated treatment, combined with the relatively low α/β ratio of prostate cancer, may result in a more favourable therapeutic ratio, presenting an opportunity for isotoxic dose escalation. Furthermore, as treatment can be given in five attendances, SBRT has the potential both to reduce costs and improve patient quality of life. However, in a treatment landscape with many competing options of broadly similar efficacy, randomised trials are essential to define the relative benefits of this approach. SBRT also has an emerging application in oligometastatic prostate cancer, with promising early outcomes for delaying disease progression and deferring the need for androgen deprivation therapy.
<h4>Aims</h4>The α/β ratio for prostate cancer is thought to be low and less than for the rectum, which is usually the dose-limiting organ. Hypofractionated radiotherapy should therefore improve the therapeutic ratio, increasing cure rates with less toxicity. A number of models for predicting biochemical relapse-free survival have been developed from large series of patients treated with conventional and moderately hypofractionated radiotherapy. The purpose of this study was to test these models when significant numbers of patients treated with profoundly hypofractionated radiotherapy were included.<h4>Materials and methods</h4>A systematic review of the literature with regard to hypofractionated radiotherapy for prostate cancer was conducted, focussing on data recently presented on prostate stereotactic body radiotherapy. For the work described here, we have taken published biochemical control rates for a range of moderately and profoundly fractionated schedules and plotted these together with a range of radiobiological models, which are described.<h4>Results</h4>The data reviewed show consistency between the various radiobiological model predictions and the currently observed data.<h4>Conclusion</h4>Current radiobiological models provide accurate predictions of biochemical relapse-free survival, even when profoundly hypofractionated patients are included in the analysis.
<h4>Aims</h4>Stereotactic body radiotherapy (SBRT) combines image-guided radiotherapy with hypofractionation, both of which will probably result in improvements in patient outcomes in prostate cancer. Most clinical experience with this technique resides in North America. Here we present the first UK cohort to receive SBRT for prostate cancer.<h4>Materials and methods</h4>Fifty-one prostate cancer patients (10 low risk, 35 intermediate risk and 6 high risk) were treated with 36.25 Gy in five fractions over 1-2 weeks and gold seed image guidance. All patients had toxicity International Prostate Symptom score (IPSS) and Radiation Therapy Oncology Group recorded prospectively and prostate-specific antigen was measured 3-6 monthly during follow-up.<h4>Results</h4>The median IPSS was 6, 11, 8 and 5 at baseline, 1-3 weeks, 4-6 weeks and 7-12 weeks after treatment. Radiation Therapy Oncology Group genitourinary and gastrointestinal toxicity of grade 2 was seen in 22% and 14%, respectively, at 1-3 weeks after treatment; no patient had grade 3+ toxicity at this time point, although two patients had grade 3 urinary frequency recorded during treatment. The median follow-up for the 42 patients who did not receive androgen deprivation was 14.5 months. Prostate-specific antigen at 13-18 months after treatment was 1.3 ng/ml.<h4>Conclusion</h4>Prostate SBRT is a promising treatment for organ-confined prostate cancer and is currently being investigated in a UK-led phase III trial.
<h4>Background</h4>The delivery of a simultaneous integrated boost to the intra-prostatic tumour nodule may improve local control. The ability to deliver such treatments with hypofractionated SBRT was attempted using RapidArc (Varian Medical systems, Palo Alto, CA) and Multiplan (Accuray inc, Sunnyvale, CA).<h4>Materials and methods</h4>15 patients with dominant prostate nodules had RapidArc and Multiplan plans created using a 5 mm isotropic margin, except 3 mm posteriorly, aiming to deliver 47.5 Gy in 5 fractions to the boost whilst treating the whole prostate to 36.25 Gy in 5 fractions. An additional RapidArc plan was created using an 8 mm isotropic margin, except 5 mm posteriorly, to account for lack of intrafraction tracking.<h4>Results</h4>Both RapidArc and Multiplan can produce clinically acceptable boost plans to a dose of 47.5 Gy in 5 fractions. The mean rectal doses were lower for RapidArc plans (D50 13.2 Gy vs 15.5 Gy) but the number of missed constraints was the same for both planning methods (11/75). When the margin was increased to 8 mm/5 mm for the RapidArc plans to account for intrafraction motion, 37/75 constraints were missed.<h4>Conclusions</h4>RapidArc and Multiplan can produce clinically acceptable simultaneous integrated boost plans, but the mean rectal D50 and D20 with RapidArc are lower. If the margins are increased to account for intrafraction motion, the RapidArc plans exceed at least one dose constraint in 13/15 cases. Delivering a simultaneous boost with hypofractionation appears feasible, but requires small margins needing intrafraction motion tracking.
The evidence supporting dose escalation for localised prostate cancer is widely accepted, but in tandem with improvements in biochemical control, dose escalation increases side-effects. In a scenario where most patients achieve control of their cancer, quality of life concerns predominate. Here we examine the biological ways in which an effective dose can be escalated without an unacceptable increase in toxicity. Possible avenues include exploiting the unusual radiobiology of prostate cancer by hypofractionation, the use of image guidance, adaptive planning and prostate motion management. We await with anticipation the results of large randomised trials of hypofractionation, moderate and profound, to establish whether we can further improve the balance between cure and quality of life.
The management of metastatic solid tumours has historically focused on systemic treatment given with palliative intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity-modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites. Many non-randomised studies have shown that SBRT for oligometastases is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 2-5 year progression-free survival of about 20%. Although complete cure might be possible in a few patients with oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also postpone the need for further treatment. We review published work showing that SBRT offers durable local control and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential.
<h4>Aims</h4>Primary brain tumours in adults are rare, with high-grade gliomas (HGG) being the most common and most aggressive type. The clinical management of rare tumours such as HGG can be heterogeneous across different cancer centres. The aim of this survey was to determine current UK practice in the primary management of HGG, particularly in light of the improved outcomes reported recently.<h4>Materials and methods</h4>In February 2009, a questionnaire was sent to 71 consultant clinical oncologists in the UK who were reported to have a neuro-oncology practice. Questions focussed on the radiotherapeutic management of HGG.<h4>Results</h4>In total, 46/71 (65%) completed questionnaires were returned; 31/46 (67%) routinely used magnetic resonance imaging/computed tomography fusion for radiotherapy planning; 34/36 (94%) routinely prescribed 60Gy in 30 fractions in a single phase; 7/36 (19%) would consider 54-55Gy in 30 fractions in selected clinical scenarios; 42/46 (91%) defined the planning target volume (PTV) as the gross tumour volume (GTV)+2-3cm margin and 42/46 (91%) outlined at least one 'organ at risk' (OAR). Accepted tolerance doses varied considerably, e.g. retina range: 30-54Gy. Sixty-four per cent of clinicians (27/42) compromise the PTV and 30% (14/42) the GTV in order to keep OARs within preset tolerances. Nearly one-third (14/42) involve the patient in this decision-making process, e.g. weighing up the risk of late toxicity with the risks of reducing the dose to the PTV.<h4>Conclusion</h4>The results of this survey show areas of strong agreement as well as areas of variation in clinical practice of aspects of treatment planning for HGG between UK neuro-oncologists.
<h4>Introduction</h4>The prognosis from non-small cell lung cancer remains poor, even in those patients suitable for radical radiotherapy. The ability of radiotherapy to achieve local control is hampered by the sensitivity of normal structures to irradiation at the high tumour doses needed. This study aimed to look at the potential gain in tumour control probability from dose escalation facilitated by moderate deep inspiration breath-hold.<h4>Method</h4>The data from 28 patients, recruited into two separate studies were used. These patients underwent planning with and without the use of moderate deep inspiration breath-hold with an active breathing control (ABC) device. Whilst maintaining the mean lung dose (MLD) at the level of the conventional plan, the ABC plan dose was theoretically escalated to a maximum of 84 Gy, constrained by usual normal tissue tolerances. Calculations were performed using data for both lungs and for the ipsilateral lung only. Resulting local progression-free survival at 30 months was calculated using a standard logistic model.<h4>Results</h4>The prescription dose could be escalated from 64 Gy to a mean of 73.7+/-6.5 Gy without margin reduction, which represents a statistically significant increase in tumour control probability from 0.15+/-0.01 to 0.29+/-0.11 (p<0.0001). The results were not statistically different whether both lungs or just the ipsilateral lung was used for calculations.<h4>Conclusion</h4>A near-doubling of tumour control probability is possible with modest dose escalation, which can be achieved with no extra increase in lung dose if deep inspiration breath-hold techniques are used.