A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: luteinising hormone-releasing hormone agonists versus transdermal oestradiol

Background Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. Objective To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Design, setting, and participants Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. Interventions LHRHa as per local practice, OP (FemSeven 100 μg/24 h patches). Outcome measurements and statistical analysis The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. Results and limitations A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001). Conclusions Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial

Real world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer

Objectives: To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone-naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial. Subjects/patients and Methods: Patients in the West of Scotland Cancer Network (WoSCAN) with newly diagnosed mPC were identified from the regional multidisciplinary team (MDT) meetings and their treatment details were collected from electronic patient records. The rate of febrile neutropenia, hospitalisations, time to progression and overall survival were compared between those patients who received docetaxel and androgen deprivation therapy (ADT), or ADT alone using survival analysis. Results: Out of 270 eligible patients, 103 received docetaxel (38.1%). 35 patients (34%) were hospitalised and there were 17 episodes of febrile neutropenia (16.5%). Two patients (1.9%) died within 30 days of chemotherapy. Patients who received ADT alone had an increased risk of progression (HR 2.03, 95% CI (1.27, 3.25), log-rank test, p= 0.002) and had an increased risk of death (HR 5.88, 95% CI 2.52, 13.72, log-rank p=0.001) compared to the docetaxel group. The risk of febrile neutropenia was nine times greater if chemotherapy was started within three weeks of ADT initiation (95% CI (1.22,77.72) p= 0.032). Conclusion: Docetaxel chemotherapy in hormone-naïve mPC has significant toxicities, but has a similar effect on time to progression and overall survival as seen in randomised trials. Chemotherapy should be started 3 weeks or more after androgen deprivation

Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.

BACKGROUND: We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial. METHODS: FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FINDINGS: Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were -0·3% (-1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and -0·7% (-1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy. INTERPRETATION: 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. FUNDING: National Institute for Health Research Health Technology Assessment Programme

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme

Background Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. Methods PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 μg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. Findings Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4–7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80–1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86–1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). Interpretation Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. Funding Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London

Board-certified specialty training program in radiation oncology in a war-torn country: Challenges, solutions and outcomes.

BackgroundResidency programs leading to board certification are important for safe and competent Radiation Oncology (RO) practice. In some developing nations, there is a gap in this field. This work addresses the experience that was accomplished to establish such a program in Iraq despite all the challenges that faces a country under war.MethodsDescriptive report of challenges faced in a developing country that is still reeling from war, the steps taken to overcome these challenges and outcomes after graduation of two classes.ResultsAfter over 18 months of prerequisite technical and logistical preparations, a group of local and external faculty members were invited to establish the required syllabus of a structured RO residency program in Iraq. It is comprised of a total of 100 post-graduate academic credits over a 48-months period after clinical internship. First year evaluations included regular practical assessments; seven in-house papers covering RO, cancer and radiation biology, medical physics, radiological anatomy and diagnostic oncology, tumor pathology, onco-pharmacology, and medical statistics, research methodology, and cancer epidemiology, followed by a comprehensive examination. Subsequent evaluations were on an annual bases with enrollment in the American College of Radiology In-Training examination in RO. Final assessment included logbook and skills' reviews, graduation thesis or peer-review publication, two-papers' written examination, and an exit practical examination.ConclusionsGiven the political, economic and social difficulties in post-war Iraq, it was a major challenge to establish a residency program in RO. Despite the significant difficulties, the first residency program leading to board certification in RO was successfully started in Iraq. The new specialists will help in addressing the shortage of radiation oncologists in the country

Board-certified specialty training program in radiation oncology in a war-torn country: Challenges, solutions and outcomes.

Background: Residency programs leading to board certification are important for safe and competent Radiation Oncology (RO) practice. In some developing nations, there is a gap in this field. This work addresses the experience that was accomplished to establish such a program in Iraq despite all the challenges that faces a country under war. Methods: Descriptive report of challenges faced in a developing country that is still reeling from war, the steps taken to overcome these challenges and outcomes after graduation of two classes. Results: After over 18 months of prerequisite technical and logistical preparations, a group of local and external faculty members were invited to establish the required syllabus of a structured RO residency program in Iraq. It is comprised of a total of 100 post-graduate academic credits over a 48-months period after clinical internship. First year evaluations included regular practical assessments; seven in-house papers covering RO, cancer and radiation biology, medical physics, radiological anatomy and diagnostic oncology, tumor pathology, onco-pharmacology, and medical statistics, research methodology, and cancer epidemiology, followed by a comprehensive examination. Subsequent evaluations were on an annual bases with enrollment in the American College of Radiology In-Training examination in RO. Final assessment included logbook and skills\u27 reviews, graduation thesis or peer-review publication, two-papers\u27 written examination, and an exit practical examination. Conclusions: Given the political, economic and social difficulties in post-war Iraq, it was a major challenge to establish a residency program in RO. Despite the significant difficulties, the first residency program leading to board certification in RO was successfully started in Iraq. The new specialists will help in addressing the shortage of radiation oncologists in the country

Board-certified specialty training program in radiation oncology in a war-torn country: Challenges, solutions and outcomes

Background: Residency programs leading to board certification are important for safe and competent Radiation Oncology (RO) practice. In some developing nations, there is a gap in this field. This work addresses the experience that was accomplished to establish such a program in Iraq despite all the challenges that faces a country under war. Methods: Descriptive report of challenges faced in a developing country that is still reeling from war, the steps taken to overcome these challenges and outcomes after graduation of two classes. Results: After over 18 months of prerequisite technical and logistical preparations, a group of local and external faculty members were invited to establish the required syllabus of a structured RO residency program in Iraq. It is comprised of a total of 100 post-graduate academic credits over a 48-months period after clinical internship. First year evaluations included regular practical assessments; seven in-house papers covering RO, cancer and radiation biology, medical physics, radiological anatomy and diagnostic oncology, tumor pathology, onco-pharmacology, and medical statistics, research methodology, and cancer epidemiology, followed by a comprehensive examination. Subsequent evaluations were on an annual bases with enrollment in the American College of Radiology In-Training examination in RO. Final assessment included logbook and skills\u27 reviews, graduation thesis or peer-review publication, two-papers\u27 written examination, and an exit practical examination. Conclusions: Given the political, economic and social difficulties in post-war Iraq, it was a major challenge to establish a residency program in RO. Despite the significant difficulties, the first residency program leading to board certification in RO was successfully started in Iraq. The new specialists will help in addressing the shortage of radiation oncologists in the country