NRG-GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer.

PURPOSE: This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer. METHODS: This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28-day cycles until progression or unacceptable toxicity. The primary end point was progression-free survival in the intention-to-treat population. Homologous repair deficiency was explored using the BROCA-GO sequencing panel. RESULTS: A total of 120 patients were enrolled and all were included in the intention-to-treat analysis. Median age was 66 (range, 41-86) years and 47 (39.2%) had serous histology. Median progression-free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91-2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43-1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA-GO panel results were not associated with response. CONCLUSION: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.

A Pragmatic Cluster-Randomized Trial of a Standing Order Entry Intervention for Colony-Stimulating Factor Use Among Patients at Intermediate Risk for Febrile Neutropenia.

PURPOSE: Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens. METHODS: TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to SOE of automated PP-CSF orders for high FN risk regimens and alerts against PP-CSF use for low-risk regimens versus usual care. A secondary 1:1 randomization assigned 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for intermediate-risk regimens. Clinicians were allowed to over-ride the SOE. Patients with breast, colorectal, or non-small-cell lung cancer were enrolled. Mixed-effect logistic regression models were used to test differences between randomized sites. RESULTS: Between January 2016 and April 2020, 846 eligible patients receiving intermediate-risk regimens were registered to either SOE to prescribe (12 sites: n = 542) or an alert to not prescribe PP-CSF (12 sites: n = 304). Rates of PP-CSF use were higher among sites randomized to SOE (37.1% v 9.9%, odds ratio, 5.91; 95% CI, 1.77 to 19.70; P = .0038). Rates of FN were low and identical between arms (3.7% v 3.7%). CONCLUSION: Although implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving first-line intermediate-risk regimens, FN rates were low and did not differ between arms. Although this guideline-informed SOE influenced prescribing, the results suggest that neither SOE nor PP-CSF provides sufficient benefit to justify their use for all patients receiving first-line intermediate-risk regimens.

Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing: A Cluster Randomized Clinical Trial.

Importance: Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines. Objective: To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia. Design, Setting, and Participants: This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021. Interventions: Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. Main Outcomes and Measures: The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic. Results: A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups. Conclusions and Relevance: In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing. Trial Registration: ClinicalTrials.gov Identifier: NCT02728596.

Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation.

BACKGROUND: Cellular rejection after cardiac transplantation is treatable with timely diagnosis. Because noninvasive methods for diagnosis are limited, surveillance endomyocardial biopsies are routinely performed in the first year after transplantation. The aim of this study was to test whether myocardial strain and strain rate as assessed by speckle-tracking echocardiography would be a sensitive noninvasive method for the detection of asymptomatic rejection. METHODS: Surveillance biopsies and echocardiograms obtained in the first year after transplantation were retrospectively reviewed, and patients with asymptomatic biopsy-proven cellular rejection were identified, as well as control transplantation patients without rejection or cardiac complications. Circumferential and longitudinal strain and strain rate were measured using Velocity Vector Imaging software from echocardiograms performed at three time points for patients with rejection-baseline (no rejection), rejection, and resolution (of rejection)-and three time points for control patients-baseline (within the first month after transplantation), 6 months, and 12 months after transplantation. RESULTS: Speckle-tracking strain and strain rate measurements were obtained from 30 patients with asymptomatic biopsy-proven rejection and 14 control transplantation patients. There were no significant differences in circumferential and longitudinal strain or strain rate between the baseline, rejection, and resolution studies. Furthermore, there were no significant differences in strain and strain rate in control transplantation patients during the first year after transplantation or compared with patients with rejection. CONCLUSIONS: Speckle-tracking analysis was unable to detect changes on serial studies from patients with asymptomatic rejection and thus cannot replace biopsy. Other noninvasive methods for the diagnosis of cellular-mediated rejection are needed.

Clinical value of stress-only Tc-99m SPECT imaging: importance of attenuation correction.

BACKGROUND: In selected patients, stress-only SPECT imaging has been proposed as an alternative to rest-stress SPECT imaging to improve laboratory efficiency and reduce radiation exposure. The impact of attenuation correction (AC) upon interpretation, post-test patient management and cardiac risk stratification in relation to stress-only imaging is not well understood. OBJECTIVES: The purpose of this study was to determine the clinical value for laboratory throughput and predicting outcomes of normal and abnormal stress-only SPECT imaging with AC in a consecutive series of clinically referred patients. METHODS: A retrospective analysis of 1,383 consecutive patients who were scheduled for stress-only SPECT imaging for symptom assessment of suspected myocardial ischemia was performed. All images had been interpreted and categorized using the standard 17-segment model without AC followed by AC. Follow-up data for 2.1 ± 1.3 years after SPECT imaging for the occurrence of cardiac events (non-fatal MI, cardiac death, and cardiac revascularization) previously collected by routine methods were reviewed. RESULTS: Non-AC SPECT image interpretation revealed that 58% (802/1383) of patients had abnormal stress images. AC image interpretation of the abnormal non-AC images re-classified 83% (666/802) of these as normal. Among patients with abnormal stress images after AC (136/1383), 63% (86/136) returned for additional rest scans, while the remaining 37% (50/136) were clinically managed without further rest images. The incidence of cardiac death or non-fatal MI was very low in patients with normal stress-only scans (0.7%). CONCLUSION: A strategy of stress-only imaging with AC in symptomatic patients is an efficient method which appropriately identifies at risk and low-risk patients yielding a low percentage requiring rest imaging. Clinical decisions can be made based on abnormal stress-only imaging without further rest imaging if clinically appropriate.