Search

Purpose/objective(s) Men with localized prostate cancer have many options for initial definitive treatment. In 2015, Cancer Care Ontario Quality Based Procedures (QBP) recommended that men undergoing radical prostatectomy (RP) in Ontario be seen by a radiation oncologist (RO) or discussed at a multidisciplinary case conference (MCC) prior to surgery. An a-priori target rate of 76% was set by QBP, but to our knowledge, has not been reported upon to date. Our objective was to use population-based data to explore factors associated with not receiving RO consult/MCC prior to RP. Materials/methods Men with localized prostate cancer diagnosed and treated in Ontario, Canada with RP between 2007 and 2017 were identified using administrative data from the Institute for Clinical Evaluative Sciences. Physician billing data was utilized to identify patients who received RO consult/MCC prior to RP. Trends were evaluated using the Cochran-Armitage test. Multivariable logistic regression was used to identify patient and provider factors predictive of RO/MCC prior to RP. Results 31,467 men with localized prostate cancer underwent RP between 2007 and 2017. Prior to RP, 29.3% of men were seen by RO, 1.0% underwent MCC, and 1.6% had both. RO consult/MCC prior to RP increased from 18.0% in 2007 to 47.8% in 2017 (P Conclusion Despite increasing rates of utilization, a large proportion of men are not seen by RO or MCC prior to RP in Ontario, Canada. While the largest factors predicting RO consult/MCC discussion appear to be geographic and which urologist performs the RP, these factors are closely intertwined. In addition, these factors may be related to RO availability and radiation system capacity, which would need to be addressed to meet patient demand should QBP consultation rates be mandated to reduce disparities in pre-RP consultation practices.

Purpose/Objective(s) The standard treatment for metastatic prostate cancer is systemic therapy. This prospective phase I/II study assessed the utility of SBRT to all tumor sites plus intermittent androgen deprivation therapy (ADT) in patients with hormone sensitive oligometastatic prostate cancer. Endpoints included incidence of SBRT induced late toxicities and clinical outcomes including cumulative incidences of developing biochemical progression, new metastases, restarting ADT, castration resistant prostate cancer (CRPC), and overall survival (OS). Materials/Methods Synchronous and metachronous metastatic disease presentations were eligible if there were ≤ 5 metastases, with ≤ 3 metastases in any one organ system. Conventional scans (CT/bonescan +/- MRI) were used to stage patients at baseline, although novel PET imaging was optional. SBRT was delivered to all sites of disease, including the prostate if not previously treated. SBRT dose was site dependent but was generally 30-35 Gy in 5 fractions for lymph nodes and non-spine bone lesions, 24-28 Gy in 2 fractions for spine, and 35 Gy in 5 fractions to the prostate. ADT was started prior to or immediately after SBRT and was continued for 1 year before moving to an intermittent approach. ADT was to be restarted when the PSA reached ≥ 10 ng/mL or earlier if clinically indicated (development of new metastases or rapidly rising PSA). Toxicity (CTCAE v4.0) and PSA measurements were collected every 4 months during follow-up. Conventional scans were performed at a minimum of once per year, but more frequent imaging was allowed at the discretion of the physician. Time zero was start of ADT or SBRT, whichever was earlier. Results 92 patients with 158 metastases were accrued with a median age of 74 years. Median follow-up time was 37 months. Median baseline PSA was 8.5 ng/mL (range 0.78 – 179.8). 39 (42%) patients had Gleason score of 8-10. 32 (35%) patients had synchronous disease presentation. 14 (15%) patients were staged with PET imaging. 5 (5%) patients developed late grade 3 GU toxicity and 6 (7%) patients developed a late SBRT induced bone fracture. There were no grade 4/5 toxicities. Median PSA nadir was 0.02 ng/mL. 50% of patients reached a PSA nadir of ≤ 0.02 ng/mL, while 92% of patients reached a PSA nadir of Conclusion The incidence of grade ≥ 3 toxicity was low when combining SBRT with intermittent ADT for hormone sensitive oligometastatic prostate cancer. With > 3 years of median follow-up, outcomes are promising compared to historical results of using ADT alone, particularly with regards to the development of CRPC. Further work will be done to identify potential predictors of clinical outcomes.

PURPOSE/OBJECTIVE(S) There is a lack of early predictive measures of outcome for patients with intermediate-risk prostate cancer (PCa) treated with stereotactic body radiotherapy (SBRT). We aim to explore 4-year PSA response rate (4yPSARR) as an early predictive measure. MATERIALS/METHODS Individual patient data from 6 institutions for patients with intermediate-risk PCa treated with SBRT between 2006 and 2016 with a 4-year (42-54 months) PSA available were analyzed. Cumulative incidences of biochemical failure and metastasis were calculated using Nelson-Aalen estimates and overall survival was calculated using the Kaplan-Meier method. Biochemical failure-free survival was analyzed according to 4yPSARR with groups dichotomized based on PSA < 0.4 ng/mL or ≥ 0.4 ng/mL and compared using the log-rank test. Multivariable competing risk analysis was performed to predict for biochemical failure and development of metastasis. RESULTS Six-hundred thirty-seven patients were included, including 424 (67%) with favorable and 213 (33%) with unfavorable intermediate-risk disease. Median follow-up was 6.2 years (IQR 4.9-7.9). The cumulative incidence of biochemical failure and metastasis, and overall survival at 6 years was 7%, 0.6% and 97%, respectively. The cumulative incidence of biochemical failure at 6 years if 4yPSARR < 0.4ng/mL was 1.7%, compared to 27% if 4yPSARR ≥ 0.4 ng/mL (P < 0.0001). On multivariable competing risk analysis, 4yPSARR was a statistically significant predictor of biochemical failure-free survival (sHR 15.3, 95% CI 7.5-31.3, P < 0.001) and metastasis-free survival (sHR 31.2, 95% CI 3.1-311.6, P = 0.003). CONCLUSION 4yPSARR is an encouraging early predictor of outcome in patients with intermediate-risk PCa treated with SBRT. Validation in prospective trials is warranted.

Purpose/Objective(s) Adjuvant radiation plays a significant role in reducing locoregional recurrences in uterine cancers. Standard treatment consists of daily radiation for 5 weeks which can be challenging for patients and the healthcare system, especially during the COVID pandemic. Hypofractionated radiotherapy has been evaluated and established in other pelvic malignancies. This study aims to evaluate the acute urinary and bowel toxicities, and patient reported outcomes following stereotactic hypofractionated adjuvant radiation for endometrial cancer. Materials/Methods This is a prospective phase I/II trial in which patients with endometrial cancer planned for adjuvant radiation received 30 Gy in 5 fractions, every other day or once weekly. Treatment was delivered at two centers with volumetric arc radiation therapy with a body-vacuum immobilization, bowel enema and 3D image-guidance. Toxicity assessment, outcomes and patient reported quality of life (QOL, EORTC core QLQ-C30 and endometrial EN24) were collected at baseline, fractions (F) 3 and 5, and at regular follow-up intervals. Higher scores represent better global QOL/health status or worse symptoms (scale 0 – 100). Changes in QOL over time were investigated with linear mixed-effects models. A P-value threshold of 0.05 was used for statistical significance. A change in QOL score of ≥ 10 points was considered clinically significant. Results The median age of the 41 enrolled patients is 66 (range: 51 – 88). Histologies included 29 endometrioid adenocarcinoma, 8 serous/clear cell, 1 carcinosarcoma, and 3 dedifferentiated. Thirty patients had stage 1 disease while 3 had stage 2 and 8 stage 3. Seven patients received sequential chemotherapy and 3 had additional vault brachytherapy. Median follow-up is 9 months, with worst toxicity (GI or GU) of grade 1 and 2 in 63% and 24% respectively. No patients have experienced a grade 3 or higher toxicity. Patient-reported diarrhea and gastrointestinal domain scores were statistically significantly worse than baseline at F5 (mean paired difference = 27.2; 8.7, P Conclusion Stereotactic hypofractionated radiation for uterine cancers is feasible and well-tolerated with short-term follow-up. Longer follow-up and future randomized studies are needed to further evaluate this treatment.

PURPOSE/OBJECTIVE(S) Stereotactic body radiation therapy (SBRT) has emerged as a promising modality for the treatment of prostate cancer (PCa) and involves the delivery of ablative doses of radiation to the prostate. The patterns of failure at the time of biochemical recurrence (BCR) after SBRT remain unknown. The purpose of this study is to explore the development of distant metastasis (DM) following the diagnosis of BCR. MATERIALS/METHODS We queried a multi-institutional database of 2,430 patients who were prospectively treated with SBRT on single institution phase II trials or registries to identify patients who developed a BCR by the Phoenix criteria or by initiation of salvage therapy for PSA rise at a lower threshold. Patterns of distant failure were obtained for patients who had BCR, including presence and sites of DM. Multivariable analysis (MVA) using logistic regression was used to evaluate the association between multiple clinicopathologic and treatment variables and DM. RESULTS 150 patients with BCR were identified (6.2% of total). Of these, 19% presented with low-risk, 42% with intermediate-risk, and 39% with high-risk disease. The median PSA at BCR was 4.56, median time to BCR was 36 months, and median follow-up after BCR was 15.5 months. Sixty-seven patients (44.7%) had DM identified at or after the time of BCR. Among those with DM, 13 had M1a disease, 50 had M1b disease, 3 had M1c disease, and 1 had an unknown distribution of disease. Time to BCR was significantly shorter in patients with DM compared to those who did not have DM (28.1 vs. 41.4 months, P = 0.002) and initial PSA (iPSA) was significantly greater (11.0 vs. 8.0, P = 0.03). On MVA, Gleason Grade Group (GG) 4 (vs. GG 1, OR 3.76, P = 0.047) and higher SBRT dose (36.25 Gy vs. 35 Gy: OR 4.03, P = 0.02; 40 Gy vs. 35 Gy: OR 3.73, P = 0.03) were significantly associated with DM. CONCLUSION A substantial proportion of patients with BCR after SBRT for localized PCa ultimately develop DM, particularly those with higher iPSA and shorter time to BCR. The association with SBRT dose is likely reflective of the use of higher doses in more modern cohorts with higher-risk disease, while the association with GG likely reflects the more aggressive biology of these tumors at presentation. Further research into patterns of failure after SBRT is needed, especially in the context of more sensitive nuclear imaging. Early predictors of treatment failure are needed to facilitate timely treatment intensification.

PURPOSE/OBJECTIVE(S) Little is known about optimal dose constraints when high dose rate (HDR) brachytherapy is used as monotherapy for prostate cancer. Most dose constraints for HDR monotherapy were extrapolated from predictors of toxicity when HDR brachytherapy was combined with external beam radiotherapy as a boost. We sought to determine clinical and dosimetric predictors of toxicity and health related quality of life (HRQOL) in men treated with HDR brachytherapy as monotherapy. MATERIALS/METHODS Eligible patients were treated with single fraction HDR brachytherapy as monotherapy on two prospective clinical trials at a single institution. Patients in the first trial (HDR-mono) received a single fraction of 19 Gy without a dominant intraprostatic lesion (DIL) boost, and patients from the second trial (MARS) received 19 Gy in a single fraction with an MRI-guided DIL boost to ≥ 23 Gy. ADT was not used. Univariable and multivariable logistic regression was used to evaluate clinical (age, IPSS score, prostate volume, alpha blocker use at baseline, and receipt of a DIL boost) and dosimetric (prostate V100, V150, V200, D90, Urethral Dmax and D10, and Rectal Dmax and V80) predictors of CTCAE v4 acute/late toxicity and HRQOL changes measured with expanded prostate index composite (EPIC). Three classifications of late minimally clinically important changes (MCICs) were evaluated: small (> 0.5 standard deviation [SD]), moderate (> 1.0 SD) and severe (> 2.0 SD) declines compared to baseline. RESULTS 147 patients were included (87 from HDR-mono, 60 from MARS). Median follow-up was 62.8 months. Only increasing prostate size predicted acute GU toxicity ≥ grade 2 (OR 1.05, 95% CI 1.01-1.09, P = 0.021). On multivariable regression, predictors of late GU toxicity ≥ grade 2 were not receiving a DIL boost (OR 3.78, 95% CI 1.88-7.83, P < 0.001) and higher baseline IPSS score (OR 1.89, 95% CI 1.89-3.18, P = 0.015). Rectal and urethral dose constraints were not associated with late GU/GI toxicity ≥ grade 2. Contrary to our hypothesis, small (OR 0.91, 95% CI 0.81-0.98, P = 0.032) and moderate (OR 0.91, 95% CI 0.80-0.98, P = 0.037) urinary MCICs were less frequent in those with higher urethral Dmax. No impact of urethra D10 on urinary MCICs was seen. Rectal Dmax and V80 did not predict bowel MCIC changes at any threshold. CONCLUSION We were unable to identify dose constraints that were predictive of late toxicity or relevant HRQOL changes in single fraction HDR brachytherapy. This suggests dose parameters used in these trials were safe, and that minor variability in plan dosimetry likely has little clinical significance. While increasing urethral Dmax paradoxically predicted for less frequent urinary MCICs, we do not believe this finding is clinically relevant. Further research exploring optimal dose constraints to be used in HDR brachytherapy as monotherapy for prostate cancer is warranted.

Purpose/Objective(s) Since the seminal Phoenix definition (nadir PSA+2) of biochemical failure (BCF) was published in 2006, increasingly more patients with low- and intermediate-risk prostate cancer (PCa) are being treated with stereotactic body radiation therapy (SBRT). Since SBRT leads to lower nadir PSA (nPSA) compared to conventionally fractionated RT, we investigated if an earlier nPSA+threshold can be used as an alternative definition of BCF. Materials/Methods PSA kinetics from 9 institutions were retrospectively analyzed for patients with localized PCa treated definitively with SBRT alone from 2003 to 2018. Patients received 35 to 40 Gy in 5 fractions, 38 Gy in 4 fractions or 26 Gy in 2 fractions (EQD23 Gy = 70-95 Gy) per institutional standards. Cox multivariable regression model was used to determine the adjusted association of relative change in PSA kinetics with biochemical relapse-free survival (BRFS) and association of BCF with time to nadir+2. Results A total of 2061 patients were included. Median follow-up was 71.9 months (interquartile range [IQR], 41.2-96.0). BCF occurred in 140 (6.8%) of patients. Median nPSA was 0.16 ng/mL, median time to nPSA was 48 months. Sensitivity of Phoenix definition for BCF was 93%, compared to 96%, 100%, and 100% for nPSA+1.5, nPSA+1.0 and nPSA+0.5, respectively. False positive rate of Phoenix definition was 30%, compared to 41%, 58%, and 71% for nPSA+1.5, nPSA+1.0 and nPSA+0.5, respectively. In patients who developed BCF, lead time gained from an earlier nPSA+threshold definition compared to Phoenix definition was 6 (IQR 0-15.3), 0 (IQR 0-11.3), 0 (IQR 0-0) months for nPSA+0.5, nPSA+1.0 and nPSA+1.5, respectively. Relative change in PSA between 6 months and 18 months after treatment was significantly associated with BRFS (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.28-2.34, P 18 months. In patients who had BCF, 27 (19.3%) reached nPSA+2 in ≤18 months, and 113 (80.7%) in > 18 months. Median time to nPSA+2 was significantly longer in patients with BCF (41 vs. 12 months, P Conclusion A lower nadir-based threshold provides minimal increase in sensitivity at the cost of a higher false positive rate and does not provide a clinically relevant lead time benefit for a pending BCF in patients with low- to intermediate-risk PCa undergoing SBRT. A rate-of-change based metric in the first 18 months post-SBRT is significantly associated with BRFS. Patients who have an early PSA bounce after SBRT rarely develop a true BCF and true BCF tends to happen later (> 18 months). Phoenix definition remains a valuable tool in the SBRT era. BCF should not be prematurely called which runs the risk of high rates of false positivity.

PURPOSE/OBJECTIVE(S) To report on the long-term results of patients with localized high risk prostate cancer treated with elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost along with adjuvant androgen deprivation therapy (ADT). MATERIALS/METHODS This was a prospective single-institution single-arm phase II study. Patients with high-risk prostate cancer (any of cT3 disease, PSA > 20 ng/mL, or Gleason score 8-10) were eligible. Patients underwent radiotherapy to a dose of 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous image-guided (matched to prostatic fiducial markers) IMRT boost of 22.5 Gy to the prostate for a total of 67.5 Gy in 25 fractions (2.7 Gy per fraction) over 5 weeks. Patients were to receive ADT for 2-3 years. Endpoints included biochemical failure (Phoenix definition), distant radiographic failure, and overall survival. Univariate and multivariable analyses were performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0 for 5 years. RESULTS Two hundred thirty patients (median age 71 years) were enrolled from 2004-2010. Median follow-up was 11.2 years (IQR 8.1-12.9). 67% of patients had Gleason score ≥ 8, 44% had PSA > 20 ng/mL, and 27% had cT3 disease. Median ADT duration was 30 months (IQR 21-33). Median PSA nadir was 0.02 ng/mL (IQR 0.02-0.02). Cumulative incidence of testosterone recovery (> 1.7 nmol/L) was 47.6% and 77.5% at 5 and 10 years, respectively. Cumulative incidence of biochemical failure was 15% and 33.4% at 5 and 10 years, respectively. At 10 years, the cumulative incidence of distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir > 0.05 ng/mL was predictive of biochemical failure (HR 6.8, 95% CI 4-11.8, P 0.1 ng/mL (HR 5.2, 95% 2.2-12, P = 0.0001) and ADT use 24 months) (HR 2.3, 95% CI 1.3-3.9, P = 0.004) were predictive of worse survival. The 5-year cumulative incidence of any late grade ≥ 3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively. CONCLUSION This was a large prospective study evaluating EPNI and a simultaneous hypofractionated prostate boost over 5 weeks combined with 2-3 years of ADT for localized high risk prostate cancer with very mature follow-up. Ten-year biochemical control and overall survival rates were favorable. Lower PSA nadir predicted for higher biochemical control, less distant failure, and longer overall survival. ADT duration of ≤ 12 months was associated with decreased overall survival.

Purpose/Objective(s) Salvage therapies for localized radiorecurrent prostate cancer often carry significant short- and long-term morbidity. Focal salvage high dose rate (HDR) brachytherapy is an appealing treatment technique which delivers an ablative dose of radiotherapy to the portion of the prostate containing recurrent disease; however, limited prospective data is available. We sought to explore the toxicities, health related quality of life and efficacy of focal salvage HDR brachytherapy after previous definitive radiotherapy. Materials/Methods Patients with locally recurrent prostate cancer after previous external beam radiotherapy (EBRT) and/or brachytherapy were enrolled on a prospective clinical trial. Patients received MRI-guided, ultrasound-based focal HDR brachytherapy delivered over two fractions of 13.5 Gy delivered 1-2 weeks apart. Adjuvant androgen deprivation therapy (ADT) was not used. Toxicity was measured using CTCAE v4. Posttreatment response was evaluated using MRI 1-2 years after salvage. Biochemical failure was defined as PSA nadir + 2ng/mL. Results Thirty patients were treated between November 2012 and September 2019. Median follow-up was 35 months (range: 13 – 92 months). Fifteen patients were initially treated with EBRT, 3 with low dose rate (LDR) brachytherapy monotherapy, 1 with EBRT and LDR brachytherapy boost, 2 with EBRT and HDR brachytherapy boost, and 9 with HDR brachytherapy as monotherapy (all 19 Gy in a single fraction). Median clinical target volume (CTV) at time of salvage was 5.22 mL (range: 2.18 – 15.71 mL), corresponding to a median of 20.0% of the prostate volume (range: 8.8% – 39.2%). Median PSA at salvage was 4.46 ng/mL (range: 0.99 – 11.63 ng/mL). The median CTV V100 was 96.5% (range: 90.5% – 99.5%), and median CTV D90 was 15.1 Gy per fraction (range: 13.6 – 18.1 Gy). Seventeen patients experienced subsequent biochemical failure, and 9 have received ADT and/or further local salvage. No patients have died from prostate cancer. Median time to biochemical failure was 41.5 months, and median time to ADT/salvage therapy was 70.6 months. The three-year biochemical failure-free event rate was 61.8% (95% CI 44.0 – 86.6%), and three-year ADT/salvage therapy-free event rate was 86.0% (95% CI 74.1 – 99.8%). No acute grade ≥ 3 GU/GI toxicity was observed. One late grade 3 GU toxicity event occurred, cystitis at 42 months post treatment, which did not persist on follow-up. No late grade ≥ 3 GI toxicity was seen. Of the 28 patients who had a post-treatment MRI, 26 had evidence of a local treatment response. Conclusion In our updated results, we found focal salvage HDR brachytherapy is well tolerated with a favorable side effect profile and 3-year biochemical control rates in line with other salvage therapies for radiorecurrent prostate cancer. While early MRI response at the treated site is common, this does not preclude subsequent biochemical failure.

PURPOSE/OBJECTIVE(S) Multiparametric magnetic resonance imaging (mpMRI) is increasingly being used in high dose rate (HDR) brachytherapy treatment planning. Its enhanced soft tissue contrast over conventional computed tomography increases the ability to identify the dominant intraprostatic lesion (DIL) and enables focal boosting using HDR brachytherapy. This can have important implications for adjacent organs at risk. We therefore investigated the acute and late toxicities reported within our institutional experience with this approach. MATERIALS/METHODS We compiled 4 cohorts of prostate cancer patients treated with mpMRI dose painted HDR brachytherapy (either as a boost or as monotherapy on clinical trial) between December 2014 and October 2018. Salvage brachytherapy was excluded. Three of the cohorts were from prospective clinical trials (MARS, HDR monotherapy and SPARE). For the MR-HDR boost cohort, pertinent demographic, clinical and dosimetric information were extracted from patients' medical records. Descriptive statistics were used to summarize baseline data. Toxicities experienced were coded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The Nelson-Aalen estimator method using 95% confidence intervals was used to assess the cumulative incidence of biochemical failure (BCF; using the Phoenix Failure definition) and the cumulative incidences of grade 2 or higher toxicity. RESULTS 144 patients with a mean age (65.6 ± 6.7 years), follow-up (55.7 ± 15.0 months) and baseline PSA (9.7 ± 8.3 ng/mL), with predominantly cT2a (32.6%) and Gleason 7 (3+4; 62.0%) disease, were included in the final analysis. Fifteen patients treated with MR-HDR boost were followed elsewhere so no toxicity data were available at time of analysis. All risk groups were represented: low (10.4%), favorable (27.8%) and unfavorable intermediate (36.8%), and high (25.0%). 25/137 (18%) experienced BCF with cumulative incidence rates of 20.6% at 5-years. A total of 41/129 (32%) patients experienced any grade 2+ GU (1 G3) and 7/129 patients (5.4%) experienced any grade 2+ GI (0 G3) toxicity. The cumulative incidence rates at 5-years were 33.2% for GU and 5.7% for GI, respectively. Neither BCF or toxicity (GU or GI) was significantly different between treatment groups. CONCLUSION Dose escalation to the DIL using mp-MRI dose painted HDR brachytherapy appears to be feasible, safe and well-tolerated. Further follow-up and investigation are warranted to determine whether MR-HDR improves outcomes compared to standard non-MR-HDR brachytherapy.

PURPOSE/OBJECTIVE(S) The role of elective nodal irradiation (ENI) in localized prostate cancer (PCa) is controversial. With the increasing use of SBRT to the prostate, data is needed regarding the safety and efficacy of ENI using ultra-hypofractionated radiation (UHRT). MATERIALS/METHODS Between 2013 and 2020, 4 prospective clinical trials of intermediate or high-risk PCa receiving dose-escalated RT to the prostate (via either HDR brachytherapy or SBRT boost) and ENI using UHRT (25Gy in 5 weekly fractions) were conducted. Primary endpoints included acute genitourinary and gastrointestinal toxicities (CTCAE v3.0/4.0), and secondary endpoints included late genitourinary and gastrointestinal toxicities and biochemical failure (Phoenix definition). RESULTS One hundred sixty-five patients were enrolled, of whom 98 (59%) had high risk disease. ADT was used in 141 (85%). Median follow-up was 38 months (IQR 10-63). The worst acute genitourinary and gastrointestinal toxicities respectively were 48% and 7.5% for grade 2, and 2.7% and 0% for grade 3. Cumulative incidence of late grade 2+ genitourinary and gastrointestinal toxicities at 36 months were 58% and 11.3% and for late grade 3+ toxicities were 1% and 0%, respectively. No grade 4+ acute or late toxicities were observed. The 3-year biochemical recurrence-free survival was 98%. CONCLUSION ENI using UHRT is associated with low incidence of grade 3+ toxicity, while grade 1-2 acute genitourinary and gastrointestinal toxicity is common. Randomized phase 3 trials are needed.

Background Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however,>30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR¼3.21 (1.35–7.67); P¼0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR¼2.71 (1.11–6.63); P¼0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR¼3.23 (1.22–8.59); P¼0.019] whilst CAPRA itself was not significant [HR¼1.88, (0.52–6.77); P¼0.332]. A high concordance [100% (61.5–100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Aims Since 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC. Materials and methods Searches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC. Results Twenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival. Conclusion Docetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.

Aims To determine intra-fraction displacement of the prostate during extreme hypofractionated radiotherapy using pre- and post-treatment orthogonal images with three implanted gold seed fiducial markers. Materials and methods In total, 265 image pairs were obtained from 53 patients who underwent extreme hypofractionated radiotherapy to a dose of 35 Gy in five fractions on standard linear accelerators. Position verification was obtained with orthogonal X-rays before and after treatment and were used to determine intra-fraction prostate displacement. Results The mean intra-fraction prostate displacements were −0.03 ± 0.61 mm (one standard deviation), 0.21 ± 1.50 mm and −0.86 ± 1.73 mm in the left–right, superior–inferior and anterior–posterior directions, respectively. The mean intra-fraction displacement during the first two fractions was moderately correlated with the displacement in the remaining three fractions, with correlation coefficients of 0.63 (95% confidence interval 0.43–0.77) and 0.47 (95% confidence interval 0.22–0.65) in the superior–inferior and anterior–posterior directions, respectively. There was no significant correlation in the left–right direction with a coefficient of –0.04 (95% confidence interval −0.31–0.23). Conclusions The mean intra-fraction prostate displacement during a course of extreme hypofractionated radiotherapy is small. A strategy using the first two fractions to predict future displacements >5 mm warrants further validation.

Aims We hypothesised that accelerated fractionated radiotherapy may provide a good palliative approach for dysphagia relief in patients with incurable oesophageal cancer, significantly reducing the overall duration of treatment, while providing symptom response with an acceptable toxicity profile. A phase I/II accelerated fractionation study was conducted to evaluate the efficacy and toxicity of this approach. Materials and methods Patients with incurable oesophageal cancer, symptomatic with dysphagia, Eastern Cooperative Oncology Group performance status≤3, without fistula or oesophageal stent in situ , were eligible. Treatment consisted of 40Gy in 20 fractions, twice a day (2Gy per fraction, ≥6h apart), 5 days a week, over 2 weeks. Results Of the 39 evaluable patients, the dysphagia response rate was 69% (27/39) with a median response duration of 5.5 months. The median time to response was 4 weeks. Twenty-eight per cent (11/39) of patients had transient worsening in their dysphagia scores. Acute toxicity (weeks 1–8) occurred in 41% (16/39) of patients. An improvement in global quality of life by week 8 was seen in 42% of patients. There were no late neurological sequelae. The median overall survival was 8 (range 1.7–58+) months. Conclusion The ideal palliative regimen should be relatively short, with minimal toxicity, while offering a favourable response profile. Accelerated fractionation fulfils these criteria and is a suitable treatment alternative for the palliation of dysphagia, especially if the goal is to deliver a higher total biological dose within a shorter (2 week) period of time.

Design: Population-based cohort study. Background: Malignant spinal cord compression (MSCC) has long been recognized as an important complication of cancer, but its incidence is unknown. Objectives: To describe the incidence, the management, and the outcome of MSCC in the cancer population of the Canadian province of Ontario. Methods: Episodes of MSCC, and treatments used for each episode, were identified by linking electronic hospital separation records and cancer centre records to Ontario’s population-based cancer registry. The cumulative frequency of MSCC in the last 5 years of life was described in the 121 435 patients who died of cancer in Ontario between 1990 and 1995. Survival after the first episode of MSCC, and duration of hospitalization with MSCC, was described. Results: The cumulative probability of experiencing at least one episode of MSCC in the 5 years preceding death from cancer was 2.5% overall, and ranged from 0.2% in cancer of the pancreas to 7.9% in myeloma. Overall, 60.2% of first episodes of MSCC were treated with primary radiotherapy, and 16.1% with surgerypostoperative radiotherapy, while in the remaining 23.7%, there was no record of radiotherapy or surgery. Overall, the median survival following the first episode of MSCC was 2.9 months. The diagnosis of MSCC was associated with a doubling of the time spent in hospital in the last year of life. Conclusion: MSCC is a fairly common occurrence among patients dying of cancer. There is a 40-fold variation in the cumulative incidence of MSCC among different types of cancer. Loblaw, D. A. et al. (2003). Clinical Oncology 15, 211–217 2003 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.

were male (78%) and underwent maximal transurethral resection of bladder tumor prior to RT (90%). Thirty-seven patients (67%) received concurrent chemotherapy; all but 2 of these patients received platinumbased regimens. Most patients (85%) received bladder and pelvic nodal radiation. Thirty-four patients (62%) were treated with intensity modulated RT (IMRT). The median dose to the bladder tumor was 6480 cGy (range 5000-7250 cGy), 1.8 to 2.15 Gy per day, and median dose to the pelvic lymph nodes was 4500 cGy (range 3960-5000 cGy). There were 19 bladder failures (12 biopsy-proven muscle-invasive and 7 superficial/in situ recurrences). Local control at 1 and 2 years was 78% and 69%, respectively. Patient age

Intensity-modulated radiotherapy (IMRT) is the delivery of radiation to the patient via fields that have non-uniform radiation fluence. IMRT allows concave dose distributions and dose gradients with narrower margins than those possible using conventional methods [1,2]. IMRT is ideal for irradiating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting [2]. This can provide increased tumour control through allowing safer dose escalation and/or can reduce normal tissue complications through organ at risk sparing. The technique has been driven by sophisticated, computer-based inverse planning programs and computed tomography-based planning capabilities [3]. IMRT began in the Karolinska Institute in Stockholm in 1982 [4]. The first clinical IMRT in theworld by any techniquewas performed at Baylor College of Medicine, Houston, Texas, USA in March 1994 [5]. Since 2000, IMRT use has exploded, particularly for the treatment of localised prostate cancer and head and neck cancer. Goldin and colleagues [6] presented a Surveillance, Epidemiology and End-Results analysis of the use of IMRT for prostate cancer at the American Society of Therapeutic Radiology and Oncology Annual Scientific Meeting in 2011. They reported that, of patients treated with external radiation, IMRT use rose from 0.2% in 2000 to 97% in 2008 for the primary treatment of prostate cancer (and 0 to 82% in the postoperative setting). In this special issue, a compendium of systematic reviews of the literature on the benefits of IMRT is presented, as well as a practice guideline based on each review. Carried out by a renowned guideline group, Cancer Care Ontario, the authors have painstakingly combed the modern literature (up to 2009). What little they found was surprising, given how avidly IMRT has been adopted in North America. For all

The discovery of androgen deprivation therapy (ADT) has been one of the most important advances in the treatment of prostate cancer. Here, the indications for the use of ADT are reviewed, together with the data supporting each indication. The settings for ADT use include cytoreduction; combined ADT and radiotherapy; pathologic node-positive disease; and recurrent, metastatic, or progressive prostate cancer.

Aims Most men with low-risk localised prostate cancer prefer treatments with high control rates and minimal disruption to their lives. Hypofractionating external radiation treatments can theoretically maintain high bioequivalent tumour doses, decrease treatment visits and decrease acute and late toxicities. The aim of this study was to assess the toxicity and feasibility of a hypofractionated accelerated regimen for these patients. Materials and methods The present study was a phase I/II study in which patients with T1–2b, Gleason ≤6 and prostate-specific antigen (PSA) ≤10ng/ml prostate cancer received 35Gy in five fractions, once a week over 29 days. Treatment was delivered with intensity-modulated radiotherapy on standard linear accelerators, with daily image guidance using gold seed fiducials, and a 4mm clinical target volume to planning target volume margin. Results As of January 2008, the target accrual of 30 patients had been reached and all had completed treatment and at least 6 months of follow-up. Dose–volume histogram objectives were achievable in all patients. Treatment was very well tolerated with no grade 3 or 4 genitourinary toxicity, gastrointestinal toxicity nor fatigue observed (95% confidence interval 0–12%). As a group, compared with baseline, the following additional grade 2 toxicities were observed: 13% genitourinary, 7% gastrointestinal and 10% fatigue. At 6 months all scores had returned to or improved over baseline. The median PSA before treatment was 6.0ng/ml. At 6 months, the median PSA was 1.8ng/ml and 75% had a PSA ≤3.0ng/ml. Conclusions This novel technique using standard linear accelerators seems feasible and is well tolerated. Further follow-up will be carried out to document late toxicity and efficacy.

Aims To determine the cerebrospinal fluid concentrations and the functional and pain outcomes after a single intravenous infusion of erythropoietin at the start of a standard radiotherapy and steroid protocol. Materials and methods Ten paraparetic patients with malignant extradural spinal cord compression who were eligible for radiotherapy, lumbar puncture and intravenous epoetin alpha were enrolled. The patients received epoetin alpha 1500IU/kg intravenously over 30min followed by a standardised dexamethasone and radiotherapy protocol. A lumbar puncture and venipuncture were carried out 24–30h after the epoetin alpha infusion. The patients were followed closely at defined intervals. Results Erythropoietin was detectable in the cerebrospinal fluid in all eight patients sampled (median 92.5mIU/ml, range 17.8–214.0mIU/ml). Before treatment, eight patients were non-ambulatory and two patients were ambulatory with assistance. After treatment, eight (80%, 95% confidence interval [CI] 44–97%) improved at least one functional class and recovered or maintained ambulation. Five of seven patients (71%; 95% CI 29–96%) with objective sensory deficits and one of seven (14%; 95% CI 0–58%) catheter-dependent patients recovered. Overall, 78% (95% CI 40–97%) had a pain response. Conclusions After an intravenous infusion of epoetin alpha, radiotherapy and steroids, high concentrations of erythropoietin were detectable in the cerebrospinal fluid. Patients with malignant extradural spinal cord compression showed encouraging improvements in neurological function and pain.

Over the last few years, the management of prostate cancer has undergone many changes and due to substantial developments in the understanding of prostate cancer biology, functional imaging, technological radiotherapy and new systemic agents. There is an ever-growing spectrum of treatment strategies aimed at improving patient selection, treatment outcomes and disease evaluation. This special issue will explore some of these exciting and emerging new management schemes to understand the rationale and their methodology, evaluate the current data underpinning the basis of its development and future directions. The topics selected for this special issue on prostate cancer range from functional imaging to the use of new targeted therapies in the setting of non-metastatic prostate cancer. This issue begins with the use of functional and molecular imaging from Turkbey et al. [1]. Standard magnetic resonance imaging (MRI) sequences have been the recognised gold standard for pelvic imaging, particularly for appropriate T staging in prostate cancer. The development of MRI sequences such as diffusion-weighted MRI, dynamic contrast-enhanced MRI and MRI spectroscopy has provided greater assessment and functionality. Used together with standard MRI sequences, this multi-parametric MRI combination can greatly improve both the identification and the staging of prostate cancer to enable better patient selection for strategies that include focal therapy, dose escalation with simultaneous integrated boosting for the whole gland or treatment of the dominant intra-prostatic nodule, as well as the evaluation of treatment responses. The availability of higher strength MRI imagers and multi-channel phased array surface coils may provide equivalent imaging to endorectal coil probes and can have advantages for both patient comfort and image co-registration when used for radiotherapy treatment planning. In addition, there are many new positron emission tomography (PET) tracers that have been shown to provide greater sensitivity and specificity compared with the fluorine-18 labelled glucose analogue (FDG-PET) for prostate cancer imaging. These PET tracers include 11 C-acetate and 11 C-choline or 11 F-choline with newer tracers that target the amino acid transport, such as 11 C-methionine and 11 F-FACBC (synthetic L-leucine amino-acid analogue). These scans may provide useful information in recurrent local disease or the detection of early nodal involvement. There is renewed interest in the prostate-specific membrane antigen as an imaging biomarker. The opportunities that these new functional and molecular imaging modalities can offer are many, but there must be appropriate and careful clinical correlation in