Single blind randomized Phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial

Background: The treatment results of external beam radiotherapy for intermediate and high risk prostate cancer patients are insufficient with five-year biochemical relapse rates of approximately 35%. Several randomized trials have shown that dose escalation to the entire prostate improves biochemical disease free survival. However, further dose escalation to the whole gland is limited due to an unacceptable high risk of acute and late toxicity. Moreover, local recurrences often originate at the location of the macroscopic tumor, so boosting the radiation dose at the macroscopic tumor within the prostate might increase local control. A reduction of distant metastases and improved survival can be expected by reducing local failure. The aim of this study is to investigate the benefit of an ablative microboost to the macroscopic tumor within the prostate in patients treated with external beam radiotherapy for prostate cancer.Methods/Design: The FLAME-trial (Focal Lesion Ablative Microboost in prostatE cancer) is a single blind randomized controlled phase III trial. We aim to include 566 patients (283 per treatment arm) with intermediate or high risk adenocarcinoma of the prostate who are scheduled for external beam radiotherapy using fiducial markers for position verification. With this number of patients, the expected increase in five-year freedom from biochemical failure rate of 10% can be detected with a power of 80%. Patients allocated to the standard arm receive a dose of 77 Gy in 35 fractions to the entire prostate and patients in the experimental arm receive 77 Gy to the entire prostate and an additional integrated microboost to the macroscopic tumor of 95 Gy in 35 fractions. The secondary outcome measures include treatment-related toxicity, quality of life and disease-specific survival. Furthermore, by localizing the recurrent tumors within the prostate during follow-up and correlating this with the delivered dose, we can obtain accurate dose-effect information for both the macroscopic tumor and subclinical disease in prostate cancer. The rationale, study design and the first 50 patients included are described.Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Post-Traumatic Stress in Head and Neck Cancer Survivors and their Partners

The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.The publisher's agreement states that: Author(s) retain the right to make an AAM (Author's Accepted Manuscript )of their Article available for public release on any of the following 12 months after first publication ("Embargo Period"): their employer's internal website; their institutional and/or funder repositories. AAMs may also be deposited in such repositories immediately on acceptance, provided that they are not made publicly available until after the Embargo Period. An acknowledgement in the following form should be included, together with a link to the published version on the publisher's website: “This is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: http://dx.doi.org/[insert DOI]”.Purpose: Head and neck cancer (HNC) diagnosis and treatment are distressing and have immediate detrimental impacts on functioning and quality of life (QoL). Nevertheless, little is known about long-term psychosocial effects. The aim of this study was to determine the prevalence and correlates of clinical post-traumatic stress disorder (PTSD) and subclinical post-traumatic stress symptoms (PTSS) in HNC patients surviving more than 2 years since treatment and in their partners. Methods: HNC survivors identified from the cancer registry of a London hospital and their partners completed measures of PTSS, depression and anxiety, fear of cancer recurrence, social support, appearance concerns and health-related QoL. Data regarding their clinical and demographic characteristics were also collected. Correlations, as well as linear and logistic regression coefficients, were calculated to estimate associations with PTSS scores. Results: In this analysis of 93 HNC survivors, at a mean of 6 years (SD = 4) after treatment, 33.4% reported PTSS and 11.8% met the criteria for post-traumatic stress disorder (PTSD). Fear of cancer recurrence was independently associated with PTSS (p  .05). Conclusions: This is the first examination of post-traumatic stress in survivors of HNC and shows that high levels of cancer-related PTSS exist for many years after diagnosis in both patients and their partners.Doctoral Scholarship from Saving Faces—The Facial Surgery Research Foundation

Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258