Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: The Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer. METHODS: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events. ETHICS AND DISSEMINATION: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets. TRIAL REGISTRATION NUMBER: NCT02603341

Bias in Estimating the Causal Hazard Ratio When Using Two-Stage Instrumental Variable Methods

Two-stage instrumental variable methods are commonly used to estimate the causal effects of treatments on survival in the presence of measured and unmeasured confounding. Two-stage residual inclusion (2SRI) has been the method of choice over two-stage predictor substitution (2SPS) in clinical studies. We directly compare the bias in the causal hazard ratio estimated by these two methods. Under a principal stratification framework, we derive a closed-form solution for asymptotic bias of the causal hazard ratio among compliers for both the 2SPS and 2SRI methods when survival time follows the Weibull distribution with random censoring. When there is no unmeasured confounding and no always takers, our analytic results show that 2SRI is generally asymptotically unbiased, but 2SPS is not. However, when there is substantial unmeasured confounding, 2SPS performs better than 2SRI with respect to bias under certain scenarios. We use extensive simulation studies to confirm the analytic results from our closed-form solutions. We apply these two methods to prostate cancer treatment data from Surveillance, Epidemiology and End Results-Medicare and compare these 2SRI and 2SPS estimates with results from two published randomized trials

Comparative Analysis of 5-Year Clinical Outcomes and Patterns of Failure of Proton Beam Therapy Versus Intensity Modulated Radiation therapy for Prostate Cancer in the Postoperative Setting

Purpose: Although proton beam therapy (PBT) is a rapidly expanding modality to treat prostate cancer compared with intensity modulated radiation therapy (IMRT), data comparing disease control outcomes and patterns of failure in the postprostatectomy setting remain substantially limited. Methods and Materials: All patients who underwent postoperative IMRT or PBT to the prostate bed only at a single institution were included (2009-2017). Endpoints included biochemical failure (BF; using institutional and recent cooperative group trial definitions), local failure (LF), regional failure (RF), distant failure (DF), and all-cause mortality. A case-matched cohort analysis was performed using 3-to-1 nearest-neighbor matching; multivariable Cox proportional hazards modeling (MVA) estimated hazard ratios for disease-related outcomes by treatment modality. Results: Of 295 men, 260 were matched (n = 65 PBT, 195 IMRT); after matching, only age at diagnosis (P .05). RT modality was not significantly associated with BF on MVA using institutional or cooperative group definitions (all P > .05), nor with LF (P = .82), RF (P = .11), DF (P = .36), or all-cause mortality (P = .69). Patterns of failure were qualitatively similar between cohorts (DF: bone, retroperitoneal nodes, lung). Conclusions: In this single institution, case-matched analysis, PBT yielded similar long-term disease-related outcomes and patterns of failure to IMRT in the postprostatectomy setting. (C) 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved

Long-term Clinical Outcomes in Favorable Risk Prostate Cancer Patients Receiving Proton Beam Therapy

PURPOSE: Long-term data regarding the disease control outcomes of proton beam therapy (PBT) for patients with favorable risk intact prostate cancer (PC) are limited. Herein, we report our institution's long-term disease control outcomes in PC patients with clinically localized disease who received PBT as primary treatment. METHODS: One hundred sixty-six favorable risk PC patients who received definitive PBT to the prostate gland at our institution from 2010 to 2012 were retrospectively assessed. The outcomes studied were biochemical failure-free survival (BFFS), biochemical failure, local failure, regional failure, distant failure, PC-specific survival, and overall survival. Patterns of failure were also analyzed. Multivariate Cox proportional hazards modeling was used to estimate independent predictors of BFFS. RESULTS: The median length of follow-up was 8.3 years (range, 1.2–10.5 years). The majority of patients had low-risk disease (58%, n = 96), with a median age of 64 years at the onset of treatment. Of 166 treated men, 13 (7.8%), 8 (4.8%), 2 (1.2%) patient(s) experienced biochemical failure, local failure, regional failure, respectively. Regional failure was seen in an obturator lymph node in 1 patient and the external iliac lymph nodes in the other. None of the patients experienced distant failure. There were 5 (3.0%) deaths, none of which were due to PC. The 5- and 8-year BFFS rate were 97% and 92%, respectively. None of the clinical disease characteristics or treatment-related factors assessed were associated with BFFS on multivariate Cox proportional hazards modeling (all P > .05). CONCLUSION: Disease control rates reported in our assessment of PBT were similar to those reported in previous clinically localized intact PC analyses, which used intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, or radical prostatectomy as definitive therapy. In addition, BFFS rates were similar, if not improved, to previous PBT studies

Comparative toxicity outcomes of proton-beam therapy versus intensity-modulated radiotherapy for prostate cancer in the postoperative setting

Background Despite increasing utilization of proton-beam therapy (PBT) in the postprostatectomy setting, no data exist regarding toxicity outcomes relative to intensity-modulated radiotherapy (IMRT). The authors compared acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes in patients with prostate cancer (PC) who received treatment with postprostatectomy IMRT versus PBT. Methods With institutional review board approval, patients with PC who received adjuvant or salvage IMRT or PBT (70.2 gray with an endorectal balloon) after prostatectomy from 2009 through 2017 were reviewed. Factors including combined IMRT and PBT and/or concurrent malignancies prompted exclusion. A case-matched cohort analysis was performed using nearest-neighbor 3-to-1 matching by age and GU/GI disorder history. Logistic and Cox regressions were used to identify univariate and multivariate associations between toxicities and cohort/dosimetric characteristics. Toxicity-free survival (TFS) was assessed using the Kaplan-Meier method. Results Three hundred seven men (mean +/- SD age, 59.7 +/- 6.3 years; IMRT, n = 237; PBT, n = 70) were identified, generating 70 matched pairs. The median follow-up was 48.6 and 46.1 months for the IMRT and PBT groups, respectively. Although PBT was superior at reducing low-range (volumes receiving 10% to 40% of the dose, respectively) bladder and rectal doses (all P = .05). Five-year grade >= 2 GU and grade >= 1 GI TFS was 61.1% and 73.7% for IMRT, respectively, and 70.7% and 75.3% for PBT, respectively; and 5-year grade >= 3 GU and GI TFS was >95% for both groups (all P >= .05). Conclusions Postprostatectomy PBT minimized low-range bladder and rectal doses relative to IMRT; however, treatment modality was not associated with clinician-reported GU/GI toxicities. Future prospective investigation and ongoing follow-up will determine whether dosimetric differences between IMRT and PBT confer clinically meaningful differences in long-term outcomes

Topological Interference Management With Transmitter Cooperation

Interference networks with no channel state information at the transmitter except for the knowledge of the connectivity graph have been recently studied under the topological interference management framework. In this paper, we consider a similar problem with topological knowledge but in a distributed broadcast channel setting, i.e., a network where transmitter cooperation is enabled. We show that the topological information can also be exploited in this case to strictly improve the degrees of freedom (DoF) as long as the network is not fully connected, which is a reasonable assumption in practice. Achievability schemes from graph theoretic and interference alignment perspectives are proposed. Together with outer bounds built upon generator sequence, the concept of compound channel settings, and the relation to index coding, we characterize the symmetric DoF for the so-called regular networks with constant number of interfering links, and identify the sufficient and/or necessary conditions for the arbitrary network topologies to achieve a certain amount of symmetric DoF

Creating research-ready partnerships: The initial development of seven implementation laboratories to advance cancer control

BACKGROUND: In 2019-2020, with National Cancer Institute funding, seven implementation laboratory (I-Lab) partnerships between scientists and stakeholders in \u27real-world\u27 settings working to implement evidence-based interventions were developed within the Implementation Science Centers in Cancer Control (ISC3) consortium. This paper describes and compares approaches to the initial development of seven I-Labs in order to gain an understanding of the development of research partnerships representing various implementation science designs. METHODS: In April-June 2021, members of the ISC3 Implementation Laboratories workgroup interviewed research teams involved in I-Lab development in each center. This cross-sectional study used semi-structured interviews and case-study-based methods to collect and analyze data about I-Lab designs and activities. Interview notes were analyzed to identify a set of comparable domains across sites. These domains served as the framework for seven case descriptions summarizing design decisions and partnership elements across sites. RESULTS: Domains identified from interviews as comparable across sites included engagement of community and clinical I-Lab members in research activities, data sources, engagement methods, dissemination strategies, and health equity. The I-Labs use a variety of research partnership designs to support engagement including participatory research, community-engaged research, and learning health systems of embedded research. Regarding data, I-Labs in which members use common electronic health records (EHRs) leverage these both as a data source and a digital implementation strategy. I-Labs without a shared EHR among partners also leverage other sources for research or surveillance, most commonly qualitative data, surveys, and public health data systems. All seven I-Labs use advisory boards or partnership meetings to engage with members; six use stakeholder interviews and regular communications. Most (70%) tools or methods used to engage I-Lab members such as advisory groups, coalitions, or regular communications, were pre-existing. Think tanks, which two I-Labs developed, represented novel engagement approaches. To disseminate research results, all centers developed web-based products, and most (n = 6) use publications, learning collaboratives, and community forums. Important variations emerged in approaches to health equity, ranging from partnering with members serving historically marginalized populations to the development of novel methods. CONCLUSIONS: The development of the ISC3 implementation laboratories, which represented a variety of research partnership designs, offers the opportunity to advance understanding of how researchers developed and built partnerships to effectively engage stakeholders throughout the cancer control research lifecycle. In future years, we will be able to share lessons learned for the development and sustainment of implementation laboratories