Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy

Image-guided radiotherapy (IGRT) increases the accuracy of treatment delivery through daily target localisation. We report on toxicity symptoms experienced during radiotherapy treatment, with and without IGRT in prostate cancer patients treated radically

NaF PET/CT for response assessment of prostate cancer bone metastases treated with single fraction stereotactic ablative body radiotherapy

Introduction: In prostate cancer patients, imaging of bone metastases is enhanced through the use of sodium fluoride positron emission tomography (18F-NaF PET/CT). This imaging technique shows areas of enhanced osteoblastic activity and blood flow. In this work, 18F-NaF PET/CT was investigated for response assessment to single fraction stereotactic ablative body radiotherapy (SABR) to bone metastases in prostate cancer patients. Methods: Patients with bone metastases in a prospective trial treated with single fraction SABR received a 18F-NaF PET/CT scan prior to and 6 months post-SABR. The SUVmax in the tumour was determined and the difference between before and after SABR determined. The change in uptake in the non-tumour bone was also measured as a function of the received SABR dose. Results: Reduction in SUVmax was observed in 29 of 33 lesions 6 months after SABR (mean absolute decrease in SUVmax 17.7, 95% CI 25.8 to - 9.4, p = 0.0001). Of the three lesions with increased SUVmax post-SABR, two were from the same patient and located in the vertebral column. Both were determined to be local progression in addition to one fracture. The third lesion (in a rib) was shown to be controlled locally but suffered from a fracture at 24 months. Progression adjacent to the treated volume was observed in two patients. The non-tumour bone irradiated showed increased loss in uptake with increasing dose, with a median loss in uptake of 23.3% for bone receiving 24 Gy. Conclusion: 18F-NaF PET/CT for response assessment of bone metastases to single fraction SABR indicates high rates of reduction of osteoblastic activity in the tumour and non-tumour bone receiving high doses. The occurrence of marginal recurrence indicates use of larger clinical target volumes may be warranted in treatment of bone metastases. Trial registration: POPSTAR, \u27Pilot Study of patients with Oligometastases from Prostate cancer treated with STereotactic Ablative Radiotherapy\u27, Universal Trial Number U1111-1140-7563, Registered 17th April 2013

Patterns of the use of advanced radiation therapy techniques for the management of bone metastases and the associated factors in Victoria.

INTRODUCTION: To describe the pattern of the use of advanced radiation therapy (RT) techniques, including intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic body RT (SBRT) for the management of bone metastases (BM), and the associated factors in Victoria. METHODS: We used a population-based cohort of patients from the state-wide Victorian Radiotherapy Minimum Data Set (VRMDS) who received RT for BM between 2012 and 2017. The primary outcome was proportion of RT courses using advanced RT techniques. The Cochran-Armitage test for trend was used to evaluate temporal trend in advanced RT use. Multinomial logistic regression was used to identify factors associated with advanced RT use. RESULTS: A total of 18,158 courses of RT were delivered to 10,956 patients-16,626 (91.6%) courses were 3D conformal RT, 857 (4.7%) IMRT/VMAT and 675 (3.7%) SBRT. There was a sharp increase in IMRT/VMAT use from <1% in 2012-2015, to 10.1% in 2016 and 16.3% in 2017 (P-trend < 0.001). Increase in SBRT use was more gradual, from 1.2% in 2012 to 4.8% in 2016 and 5.5% in 2017 for SBRT (P-trend<0.001). In multivariate analyses, year of RT was the strongest predictor of IMRT/VMAT use (OR = 41; 95%CI = 25-67; P < 0.001, comparing 2012-2013 and 2016-2017). Primary tumour type (prostate cancer) was the strongest predictor of SBRT use (OR = 6.07; 95% CI = 4.19-8.80; P < 0.001). CONCLUSION: Overall, there was increasing trend in the use of advanced RT techniques for BM in Victoria, with a distinct pattern for IMRT/VMAT compared with SBRT - SBRT uptake was more gradual while IMRT/VMAT uptake was abrupt, occurring contemporaneously with Medicare Benefit Scheme funding changes in 2016

Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial

Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule. RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART. A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy. Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts

Image guided and adaptive radiotherapy for muscle invasive bladder cancer

© 2014 Dr. Farshad ForoudiPublications included in thesis:Foroudi, F., Haworth, A., Pangehel, A., Wong, J., Roxby, P., Duchesne, G., et al. (2009). Inter-observer variability of clinical target volume delineation for bladder cancer using CT and cone beam CT. Journal of Medical Imaging & Radiation Oncology, 53, 100-106. DOI: 10.1111/j.1754-9485.2009.02044.xForoudi, F., Wong, J., Haworth, A., Baille, A., McAlpine, J., Rolfo, A., et al. (2009). Offline adaptive radiotherapy for bladder cancer using cone beam computed tomography. Journal of Medical Imaging & Radiation Oncology, 53, 226-233. 10.1111/j.1754-9485.2009.02066.xForoudi, F., Wong, J., Kron, T., Roxby, P., Haworth, A., Bailey, A., et al. (2010). Development and evaluation of a training program for therapeutic radiographers as a basis for online adaptive radiation therapy for bladder carcinoma. Radiography, 16(1), 14-20. DOI: 10.1016/j.radi.2009.09.002Foroudi, F., Wong, J., Kron, T., Rolfo, A., Haworth, A., Roxby, P., et al. (2011). Online adaptive radiotherapy for muscle invasive bladder cancer: results of a pilot study. International Journal of Radiation Oncology Biology Physics, 81(3), 765-771. DOI: 10.1016/j.ijrobp.2010.06.061Foroudi, F., Wilson, L., Bressel, M., Haworth, A., Hornby, C., Pham, D., et al. (2012). A dosimetric comparison of 3D conformal vs intensity modulated vs volumetric arc radiation therapy for muscle invasive bladder cancer. Radiation Oncology, 7:111. DOI: 10.1186/1748-717X-7-111Foroudi, F., Pham, D., Bressel, M., Wong, J., Rolfo, A., Roxby, P., et al. (2012). Bladder cancer radiotherapy margins: a comparison of daily alignment using skin or bone or soft tissue. Clinical Oncology, 24(10), 673-681. DOI: 10.1016/j.clon.2012.06.012Foroudi, F., Pham, D., Bressel, M., Tongs, D., Rolfo, A., Styles, C., et al. (2013). The utility of e-Learning to support training for a multi-centre bladder online adaptive radiotherapy trial (TROG 10.01 BOLART). Radiotherapy Oncology, 109(1), 165-169. DOI: 10.1016/j.radonc.2012.10.019Foroudi, F., Pham, D., Bressel, M., Gill, S., & Kron, T. (2012). Intra-fraction bladder motion in radiotherapy estimated from pretreatment and posttreatment volumetric imaging. International Journal of Radiation Oncology Biology Physics, 86(1), 77-82. DOI: 10.1016/j.ijrobp.2012.11.035Foroudi, F., Pham, D., Bressel, M., Hardcastle, N., Gill, S., & Kron, T. (2014). Comparison of margins, integral dose and interfraction target coverage with image guided radiotherapy (IGRT) compared to non-image guided radiotherapy for bladder cancer. Clinical Oncology, 26(8), 497-505. DOI: 10.1016/j.clon.2014.03.007Foroudi, F., Pham, D., Rolfo, A., Bresse,l M., Tang, C. I., Tan, A., et al. (2014).The outcome of a multicentre feasibility study of online adaptive radiotherapy for muscle invasive bladder cancer TROG 10.01 BOLART. Radiotherapy and Oncology, 111(2), 316-320. DOI: 10.1016/j.radonc.2014.02.015Introduction: Bladder cancer is one of the ten most frequent cancers in Australia. It is also the only common cancer for which survival has decreased over the last twenty years. The two curative treatment options for muscle invasive bladder cancer are radical surgery requiring removal of the bladder, or radical radiotherapy (alone or in combination with chemotherapy). Radical radiotherapy allows many patients to keep their natural bladder. As a dynamic soft tissue organ, the bladder size, shape and position vary with bladder and rectal filling, requiring traditional radiotherapy fields to have large margins around the target. With conventional radiation treatment such large margins increase the risk of normal tissue side effects and yet there still remains the risk of missing the bladder cancer on some treatment fractions. Methods: I have developed an innovative technique with a new device, cone beam computed tomography to match radiation fields and volume on a daily basis to the bladder position and size. This technique reduced the margin of the radiation fields required around the bladder. I have led a number of training programs and their evaluation to teach radiation therapists to conduct such treatments. In addition to the development work, I have conducted a prospective pilot study in 27 participants, of this adaptive radiotherapy technique. Following further refinement I led the multi-centre clinical trial that established the technique as standard of care in a number of institutions. Results: I found that cone beam computer tomography was of sufficient quality to be used to match radiation fields to the bladder on a daily basis. I determined that such daily matching prior to treatment was better than an ‘offline” process where an average radiation treatment plan was created after several radiation treatments. I found in our pilot study that adaptive radiation treatment decreased surrounding normal tissue irradiation. Separate studies showed that both workshop and e-Learning based radiation therapist training increased confidence and decreased variation from the gold standard (radiation oncologist results). I conducted a number of studies examining appropriate margins for bladder cancer radiation treatment with different imaging techniques. Through a multi-centre feasibility study of 54 participants, I introduced the image guided adaptive radiotherapy technique into a number of Australia centres, and demonstrated that, while technically possible, the margin around the bladder in this protocol was too small. Conclusions: Image guided and adaptive radiotherapy is possible in many radiation therapy departments with likely benefits for patients in terms of cancer control and reduced normal tissue side effects. Through my work the technique has been established as standard of care in a number of Australian and New Zealand centres. However such radiotherapy techniques can continue to be optimised. Future phase III studies are required to conclusively prove their benefit

Large institutional variations in use of androgen deprivation therapy with definitive radiotherapy in a population-based cohort of men with intermediate- and high-risk prostate cancer

OBJECTIVE: To evaluate the pattern of use of androgen deprivation therapy (ADT) with definitive radiotherapy (RT) in men with prostate cancer (PCa) in a population-based study in Australia. PATIENTS AND METHODS: This is a prospective cohort of men with intermediate- and high-risk PCa, captured in the population-based Prostate Cancer Outcome Registry Victoria, who were treated with definitive prostate RT between January 2010 and December 2015. The primary outcome of interest was ADT utilization. Chi-squared test for trend was used to evaluate the temporal trend in the use of ADT over the study period. Multivariate logistic regressions were used to evaluate the effects of patient-, tumour- and treatment-related factors, and treatment institutions (public/ private and metropolitan/ regional) on the likelihood of ADT utilization. RESULTS: A total of 1806 men were included in the study, 199 of whom (11%) had favourable National Comprehensive Cancer Network (NCCN) intermediate-risk disease (i.e. only one intermediate-risk feature, primary Gleason grade 3, and <50% biopsy core involved), 687 (38%) had unfavourable NCCN intermediate-risk disease, and 920 (51%) had high-risk disease. Of the 1806 men, 1155 (64%) received ADT with RT. Men with NCCN high-risk PCa (84%) were more likely to have ADT than men with favourable NCCN intermediate-risk (32%) and unfavourable NCCN intermediate-risk (46%) PCa (P < 0.001). Men treated in public institutions (66%, vs 47% in private institutions; P < 0.001) and regional centres (78%, vs 59% in metropolitan institutions; P < 0.001) were more likely to receive ADT. There was a trend towards an increase in ADT utilization from 50% in 2010 to 64% in 2015 (P < 0.001). In multivariate analyses (adjusting for age, tumour-related factors, year of treatment and use of brachytherapy boost), treatment institution (public and regional) remained independently associated with increased likelihood of ADT utilization. Men with intermediate-risk PCa treated in regional and public institutions were 2.7 times (95% confidence interval [CI] 1.9-3.9; P < 0.001) and 2.8 times (95% CI 1.4-5.3; P = 0.002), more likely to receive ADT with RT, respectively, while men with high-risk PCa treated in regional and public institutions were 3.1 times (95% CI 1.7-5.7; P < 0.001) and 3.0 times (95% CI 1.7-5.4; P < 0.001), more likely to receive ADT with RT, respectively. CONCLUSION: This is the largest Australasian contemporary series reporting on the pattern of use of ADT with definitive prostate RT. While there was an increasing trend towards use of ADT over time, ADT still appeared to be underutilized in certain groups of patients who may benefit from ADT, with approximately one in five men with high-risk and one in two with unfavourable intermediate-risk PCa not receiving ADT with RT. There was notable variation in the use of ADT between public vs private and metropolitan vs regional institutions

Androgen deprivation therapy use with post-prostatectomy radiotherapy in the Prostate Cancer Outcomes Registry Victoria

INTRODUCTION: The aim of this study is to evaluate the use of androgen deprivation therapy (ADT) with post-prostatectomy radiotherapy (PPRT) in a population-based cohort of Australian men. METHODS: This is a prospective cohort of men with localised prostate cancer captured in the Prostate Cancer Outcomes Registry Victoria (PCOR-Vic), who received PPRT between January 2010 and December 2015. The primary outcome was ADT use with PPRT. Multivariate logistic regressions were used to identify patient, tumour and institutional factors influencing ADT use. RESULTS: 485 men were included in this study - 115 (24%) had pT2 disease, 231 (48%) pT3a, 134 (28%) pT3b and 5 (1%) pT4. Eighteen (4%) men had ISUP grade 1 disease, 139 (29%) ISUP grade 2, 170 (35%) ISUP grade 3 and 158 (33%) ISUP grade 4/5, while 267 (64%) men had positive surgical margins. Median time from prostatectomy to PPRT was 8.1 months (IQR = 5.3-13.9). Sixty-six (14%) patients had ADT with PPRT. In multivariate analyses, men who had increased age (OR = 1.06; 95% CI = 1.01-1.11), seminal vesicle involvement (OR = 3.81; 95% CI = 1.63-8.91) and underwent treatment in regional centres (OR = 2.17; 95% CI = 1.08-4.33) were more likely to have ADT with PPRT. CONCLUSION: We reported that 14% of men treated with PPRT received ADT in a population-based cohort of Australian men, which was less than half of the proportion of ADT use with PPRT in the US. It will be of interest to evaluate the uptake of ADT with PPRT in the coming years following recent publications of level 1 evidence confirming overall survival benefits of ADT with PPRT

Introduction of online adaptive radiotherapy for bladder cancer through a multicentre clinical trial (Trans-Tasman Radiation Oncology Group 10.01): Lessons learned

Online adaptive radiotherapy for bladder cancer is a novel radiotherapy technique that was found feasible in a pilot study at a single academic institution. In September 2010 this technique was opened as a multicenter study through the Trans-Tasman Radiation Oncology Group (TROG 10.01 bladder online adaptive radiotherapy treatment). Twelve centers across Australia and New-Zealand registered interest into the trial. A multidisciplinary team of radiation oncologists, radiation therapists and medical physicists represented the trial credentialing and technical support team. To provide timely activation and proper implementation of the adaptive technique the following key areas were addressed at each site: Staff education/training; Practical image guided radiotherapy assessment; provision of help desk and feedback. The trial credentialing process involved face-to-face training and technical problem solving via full day site visits. A dedicated "help-desk" team was developed to provide support for the clinical trial. 26% of the workload occurred at the credentialing period while the remaining 74% came post-center activation. The workload was made up of the following key areas; protocol clarification (36%), technical problems (46%) while staff training was less than 10%. Clinical trial credentialing is important to minimizing trial deviations. It should not only focus on site activation quality assurance but also provide ongoing education and technical support