The purpose of this Special Communication is to summarize guidelines and recommendations stemming from an expert panel convened by the National Institutes of Health, National Center for Medical ...Rehabilitation Research (NCMRR) for a workshop entitled The Future of Medical Rehabilitation Clinical Trials, held September 29-30, 2016, at the NCMRR offices in Bethesda, Maryland. The ultimate goal of both the workshop and this summary is to offer guidance on clinical trials design and operations to the medical rehabilitation research community, with the intent of maximizing the effect of future trials.
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Background: Stereotactic MR-guided adaptive radiotherapy (SMART) brings several advancements including enhanced soft tissue definition, adaptation of individual fractions based on daily anatomy, ...real time tracking of prostate coupled with beam gating that prevents treatment delivery if the prostate is outside the treatment boundary and negating the need for invasive fiducial markers. Here we evaluate treatment response and acute and intermediate patient adverse events amongst prostate cancer patients who underwent SMART. Methods: A total of 197 patients with localised prostate cancer were treated with SMART. Patients were assessed for eligibility against robust institutional criteria. SMART consisted of MR- and computed tomography (CT) simulation scan, inverse intensity-modulated radiotherapy (IMRT) treatment planning and daily plan re-optimization prior to treatment delivery with editing CTVs (as per daily variation) and OAR recontouring within the first 3 cm outside the PTV. Prescription dose was 36.25 Gy in 5 fractions delivered on alternate days. Patients who completed a baseline 12 item PRO-CTC AE, before treatment, were subsequently followed up with the same graded questionnaire at set time points. Results: Median follow up was 12 months (inter quartile range 6 – 36). Patients included low (6%), intermediate (86%) and high risk (8%). Median pre-treatment PSA was 7.09 ng/ml (interquartile range IQR 1 – 133.2). At first follow up at 6 months, median drop in PSA was 97.09 % from base line (range 27.7– 99.9 %, SD 15.04). At second follow up at 12 months, median change in PSA was 96.92% (range 5.88– 233.3%, SD 12.41). At 24 months median PSA was 0.28 ng/ml (IQR 0.03 -3.26) with a median drop from baseline of 95.98%. ADT was used in 88% of patients and median duration of ADT was 6 months (IQR 3-30). 69 patients, who completed baseline and subsequent PRO CTC AE questionnaires in different time frames were included in analysis. More than 80% of men reported no change from baseline urinary toxicity during follow up apart from urinary urgency. Regarding GI toxicities, new ≥ frequent/severe patient reported adverse events were diarrhoea (9%), constipation (3%) and pain on opening bowels (6%) in the first 3 months but were all absent after 33 months. No patient reported frequent GI bleeding. No grade ≥4 toxicity was seen. Conclusions: SMART shows low acute and intermediate toxicities and excellent short-term outcomes.
La presente investigación se desarrolla en el marco del proyecto CAI+D (en curso) «Tradiciones selectivas: trazo(a)s presentes y emergentes de la migración italiana y francófona de la ciudad de Santa ...Fe» (FHUC-UNL) y tiene por objeto un primer acercamiento a la figura del escritor santafesino Edgardo Pesante como «intelectual», atendiendo a la complejidad que dicho concepto condensa. Para ello se trabajará sobre tres aristas: sus facetas como escritor, gestor de políticas de promoción cultural (específicamente literarias) y crítico. Esta aproximación, si bien se aclara primitiva, resulta de interés para pensar no sólo los lindes o puntos de contacto con otros agentes culturales de la provincia de Santa Fe, sino también la importancia que su figura de intelectual constituye para la región (cuestión que ya vislumbramos en estudios previos con el análisis de caso de Domingo Buonocore).
Renal cell cancer (RCC) has traditionally been considered radioresistant. Because of this, conventional radiotherapy (RT) has been predominantly relegated to the palliation of symptomatic metastatic ...disease. The implementation of stereotactic ablative radiotherapy (SABR) has made it possible to deliver higher ablative doses safely, shifting the renal radioresistance paradigm. SABR has increasingly been adopted into the multidisciplinary framework for the treatment of locally recurrent, oligoprogressive, and oligometastatic disease. Furthermore, there is growing evidence of SABR as a non-invasive definitive therapy in patients with primary RCC who are medically inoperable or who decline surgery, unsuited to invasive ablation (surgery or percutaneous techniques), or at high-risk of requiring post-operative dialysis. Encouraging outcomes have even been reported in cases of solitary kidney or pre-existing chronic disease (poor eGFR), with a high likelihood of preserving renal function. A review of clinical evidence supporting the use of ablative radiotherapy (SABR) in primary, recurrent, and metastatic RCC has been conducted. Given the potential immunogenic effect of the high RT doses, we also explore emerging opportunities to combine SABR with systemic treatments. In addition, we explore future directions and ongoing clinical trials in the evolving landscape of this disease.
Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or ...metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices.
A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints.
Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2;
= .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5;
< .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0;
= .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6;
< .001).
Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.
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Background: Studies have shown an improvement in overall survival (OS) and symptom control in metastatic castration-resistant prostate cancer (mCRPC) with Radium-223 treatment. ...However, there is little information about predicting outcomes using either PSA or Alkaline Phosphatase (ALP) response or comparing bone only disease to bone and lymph node (LN) involvement. Methods: 335 patients receiving Radium 223 at 6 UK centres between March 2014 and June 2020 were included. The primary endpoint was overall survival, secondary endpoints were toxicity, symptomatic benefit and skeletal-related events(SRE) Results: The median age was 75, with 71% having bone only metastases and 29% also having lymph node involvement. Those with PSA response (30%) had a statistically significant improvement in OS, compared to non-responders (18.2 vs 13.8 months, p = 0.026). They also showed highest rate of imaging response/stable disease (54% vs 34%). ALP response was seen in 82%. This did not translate to significantly improved OS, but did correlate with better symptomatic benefit (40% vs 29%). Those with bone only disease showed a survival benefit compared to those with LN involvement (19.4 vs 11.4 months, p = 0.046). Other than anaemia (23.5%), Grade 2 or above toxicities were uncommon including thrombocytopenia and neutropenia(5.5 and 6.2% respectively ) . 14% patients required at-least one blood transfusion. SRE were seen in 24% overall, but lower of in PSA responders(18%). Conclusions: Real life multicentre data suggests that PSA response and bone only disease could be predictors for better survival following Radium-223, whereas ALP response correlates better with symptomatic benefit.
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Background: Immunotherapy is an ineffective approach in molecularly unselected mCRPC, and improving patient selection for targeted treatment in this setting is an unmet medical need. We evaluated ...the antitumour activity of pembrolizumab in a subset of molecularly selected mCRPC with putative phenotypes associated with immunotherapy sensitivity. Methods: PERSEUS1 (NCT03506997) is a multicentre, open-label, single arm, phase II trial in patients suffering from mCRPC progressive on at least one approved treatment for mCRPC, and who had at least one of the following molecular profiles: mismatch repair deficiency (MMRd); bi-allelic CDK12 loss; high microsatellite instability with either MMRd, a high CD3 count, or high mutational load (HIMUT); HIMUT with high CD3 or a deleterious mutation in a DNA repair gene; or DNA repair defects with high CD3. Patients were treated with pembrolizumab 200mg intravenously every 3 weeks until progression, unacceptable toxicity, or 2 years. The primary endpoint was composite response rate by 24-weeks based on either: iRECIST, circulating tumour cell (CTC) count conversion from ≥5 to <5/7.5ml, or PSA decline ≥50%. The trial used a two-stage Simon Minimax design; H
a
=40%, H
0
=20%. We report stage 1, with target n=24 participants and >5 responses required to warrant progression to stage 2. Progression-free survival (PFS), overall survival (OS) and safety using CTCAE v4.0 were secondary endpoints. Results: From Nov-2018 to May-2023, 25 participants were enrolled, with 24 reaching response-evaluability. Median follow-up was 28.4 months. Median age of evaluable patients was 69 years, and patients had received 1-4 previous lines of treatment. Participants received a median of 6 cycles of pembrolizumab (range 2–13). Seven out of 24 patients (29.2%) had a composite response by 24 weeks (95% CI 12.6%-51.1%). Responses according to iRECIST, CTC and PSA criteria were 3/24 (12.5%), 3/24 (12.5%) and 4/24 (16.7%) respectively. Median PFS was 4.2 months (95% CI 3.0–8.3). Median OS was 14.5 months (95% CI 9.9–18.4). Of the 3 radiological responses, 2 patients were MMRd, including one with complete metabolic response (iRECIST partial response (PR); 49 months, ongoing) and another with PR (8.3 months PFS). Eight patients (33.3%) experienced grade 3-4 toxicity. This led to discontinuation in two patients: one (patient with complete metabolic response) with immunotherapy-induced colitis, and another with immune-related myocarditis and pneumonitis. Conclusions: Pembrolizumab showed prolonged antitumour activity against a subset of molecularly selected mCRPC. Although the analysis met the pre-specified threshold of composite response criteria, due to slow accrual and modest clinical relevance in most responders, it was decided not to continue to stage 2 of the trial. Clinical trial information: NCT03506997 .
To compare survival of patients who received LDR prostate brachytherapy relative to that of peers in the general population of England, UK.
Net survival was estimated for 2472 cases treated between ...2002 and 2016 using population-based analysis guidelines. Life tables adjusted for social deprivation in England from the Office for National Statistics were used to match patients by affluence based on their postcode.
The median (range) age at time of brachytherapy was 66 (55-84) years, 84% resided in Southeast England, 51% under an index of deprivation quintile 5 (most affluent), 55% were clinical stage T1 and the remainder T2. Death from any cause occurred in 270 patients at a median (range) of 7 (1-17) years postimplant. Five and 10-year estimates (95% CI) of overall survival were 96% (95-97) and 90% (89-92), and net survival 103% (102-104) and 109% (107-110) respectively. The net survival remained above 100% in all age-at-treatment and clinical stage groups.
Net survival above 100% indicates patients survive longer than the matched general population. The study shows for the first time the net survival of patients treated with a radical therapy for localized prostate cancer in England. The impact of treatment choice on the long-term net survival advantage requires further investigation.
Objectives
To assess the long‐term treatment efficacy of low‐dose‐rate (LDR) brachytherapy for the treatment of localized prostate cancer.
Patients and Methods
Cause‐of‐death annotation in our ...prospective database was supplemented with death certificate information obtained via an internal audit of patients treated from 1999 to 2017 with LDR prostate brachytherapy as monotherapy or as combination with androgen deprivation therapy and/or external beam radiotherapy. Overall and disease‐specific survival were the primary outcomes, estimated with Kaplan–Meier and competing risks multi‐state models. Clinical variables influencing mortality were assessed with Cox proportional hazards regression in a sub‐analysis of men to assess the predictive value of prostate‐specific antigen (PSA) level at 48 months post implant.
Results
The audit process began in October 2017 and culminated in June 2020 with a curated series of 2936 patients. All‐cause and prostate cancer‐specific death prevalence were 11% and 2.9%, respectively. The median (range) follow‐up time was 10 (3–21) years and the median (range) time to death from any cause was 9 (3–21) years. At 15 years post implant the overall and prostate cancer‐specific survival probability were 81% and 95%, respectively. The 15‐year cumulative incidence rates of death not due and due to prostate cancer were 14% and 5%, respectively. A greater risk of death due to prostate cancer was conferred by increasing age at therapy (hazard ratio HR 1.1, P < 0.001), advanced clinical stages relative to T1a‐T2a (HR 1.9, P = 0.048 for T2b; HR 2.7, P = 0.023 for T2c‐T3b) and a 48‐month PSA level >1.0 ng/mL (HR 6.8, P < 0.001).
Conclusion
This study constitutes the largest retrospective analyses of long‐term mortality outcomes from prospectively collected prostate brachytherapy data and confirms the excellent treatment efficacy of LDR prostate brachytherapy for localized prostate cancer. T2 clinical stage subdivisions and 48‐month PSA level >1.0 ng/mL appear to be strong indicators of prostate cancer‐related survival.
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