Laterality of Radiation Therapy in Breast Cancer is Not Associated With Increased Risk of Coronary Artery Disease in the Contemporary Era.

Purpose: External beam radiation therapy (EBRT) is a critical component of breast cancer (BC) therapy. Given the improvement in technology in the contemporary era, we hypothesized that there is no difference in the development of or worsening of existing coronary artery disease (CAD) in patients with BC receiving left versus right-sided radiation. Methods and Materials: For the meta-analysis portion of our study, we searched PubMed, Web of Science, and Scopus and included studies from January 1999 to September 2022. CAD was identified using a homogenous metric across multiple studies included. We computed the risk ratio (RR) for included studies using a random effects model. For the institutional cohort portion of our study, we selected high cardiovascular-risk patients who received diagnoses of BC between 2010 and 2022 if they met our inclusion criteria. We performed a Cox proportional hazards model with stepwise adjustment. Results: A pooled random effects model with 9 studies showed that patients with left-sided BC receiving EBRT had a 10% increased risk of CAD when compared with patients with right-sided BC receiving EBRT (RR, 1.10; 95% CI, 1.02-1.18; P = .01). However, subgroup analysis of 6 studies that included patients diagnosed after 1980 did not show a significant difference in CAD based on BC laterality (RR, 1.07; 95% CI, 0.95-1.20; P = .27). For the institutional cohort portion of the study, we found that patients with left-sided BC who received EBRT did not have a significantly higher risk of CAD when compared with their right-sided counterparts (hazard ratios [HR], 0.73; 95% CI, 0.34-1.54; P = .402). Conclusions: Our study suggests a historical trend of increased CAD in BC patients receiving left-sided EBRT. Data from patients diagnosed after 2010 in our institutional cohort did not show a significant difference, emphasizing that modern EBRT regimens are safe, and laterality of BC does not affect CAD outcomes in the short term after a BC diagnosis.

NCCN Guidelines® Insights: Rectal Cancer, Version 3.2024.

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Vaccination of Adults With Cancer: ASCO Guideline.

PURPOSE: To guide the vaccination of adults with solid tumors or hematologic malignancies. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and nonrandomized studies on the efficacy and safety of vaccines used by adults with cancer or their household contacts. This review builds on a 2013 guideline by the Infectious Disease Society of America. PubMed and the Cochrane Library were searched from January 1, 2013, to February 16, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: A total of 102 publications were included in the systematic review: 24 systematic reviews, 14 RCTs, and 64 nonrandomized studies. The largest body of evidence addressed COVID-19 vaccines. RECOMMENDATIONS: The goal of vaccination is to limit the severity of infection and prevent infection where feasible. Optimizing vaccination status should be considered a key element in the care of patients with cancer. This approach includes the documentation of vaccination status at the time of the first patient visit; timely provision of recommended vaccines; and appropriate revaccination after hematopoietic stem-cell transplantation, chimeric antigen receptor T-cell therapy, or B-cell-depleting therapy. Active interaction and coordination among healthcare providers, including primary care practitioners, pharmacists, and nursing team members, are needed. Vaccination of household contacts will enhance protection for patients with cancer. Some vaccination and revaccination plans for patients with cancer may be affected by the underlying immune status and the anticancer therapy received. As a result, vaccine strategies may differ from the vaccine recommendations for the general healthy adult population vaccine.Additional information is available at www.asco.org/supportive-care-guidelines.

Consideration of Metastasis-Directed Therapy for Patients With Metastatic Colorectal Cancer: Expert Survey and Systematic Review.

BACKGROUND: A survey of medical oncologists (MOs), radiation oncologists (ROs), and surgical oncologists (SOs) who are experts in the management of patients with metastatic colorectal cancer (mCRC) was conducted to identify factors used to consider metastasis-directed therapy (MDT). MATERIALS AND METHODS: An online survey to assess clinical factors when weighing MDT in patients with mCRC was developed based on systematic review of the literature and integrated with clinical vignettes. Supporting evidence from the systematic review was included to aid in answering questions. RESULTS: Among 75 experts on mCRC invited, 47 (response rate 62.7%) chose to participate including 16 MOs, 16 ROs, and 15 SOs. Most experts would not consider MDT in patients with 3 lesions in both the liver and lung regardless of distribution or timing of metastatic disease diagnosis (6 vs. 36 months after definitive treatment). Similarly, for patients with retroperitoneal lymph node and lung and liver involvement, most experts would not offer MDT regardless of timing of metastatic disease diagnosis. In general, SOs were willing to consider MDT in patients with more advanced disease, ROs were more willing to offer treatment regardless of metastatic site location, and MOs were the least likely to consider MDT. CONCLUSIONS: Among experts caring for patients with mCRC, significant variation was noted among MOs, ROs, and SOs in the distribution and volume of metastatic disease for which MDT would be considered. This variability highlights differing opinions on management of these patients and underscores the need for well-designed prospective randomized trials to characterize the risks and potential benefits of MDT.

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

PURPOSE: Peposertib-an orally administered DNA-dependent protein kinase inhibitor-has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer. PATIENTS AND METHODS: Patients were treated for 5 to 5.5 weeks with 50- to 250-mg peposertib once daily, capecitabine 825 mg/m2 twice daily, and radiotherapy (RT), 5 days per week. Following clinical restaging (8 weeks after CRT completion), patients with clinical complete response (cCR) could opt for surveillance. Total mesorectal excision was recommended upon incomplete response (IR). RESULTS: Nineteen patients were treated with peposertib at doses of 50 mg (n = 1), 100 mg, 150 mg, and 250 mg (n = 6 each). Dose-limiting toxicities occurred in one out of five (100 mg), one out of six (150 mg), and three out of six (250 mg) evaluable patients. Peposertib ≤150 mg once daily was tolerable in combination with CRT. After 8 weeks of treatment with peposertib and CRT, the cCR was 15.8% (n = 3). Among the three patients with cCR, two underwent surgery and had residual tumors. Among the 16 patients with IR, seven underwent surgery and had residual tumors; five of the remaining nine patients opted for consolidative chemotherapy. The combined cCR/pathologic complete response (pCR) rate was 5.3% (n = 1, 100 mg cohort). CONCLUSIONS: Peposertib did not improve complete response rates at tolerable dose levels. The study was closed without declaring the MTD/RP2D.

Incident Atrial Fibrillation and Survival Outcomes in Esophageal Cancer following Radiotherapy.

PURPOSE: Radiation therapy (RT) associates with long-term cardiotoxicity. In preclinical models, RT exposure induces early cardiotoxic arrhythmias including atrial fibrillation (AF). Yet, whether this occurs in patients is unknown. METHODS AND MATERIALS: Leveraging a large cohort of consecutive patients with esophageal cancer treated with thoracic RT from 2007 to 2019, we assessed incidence and outcomes of incident AF. Secondary outcomes included major adverse cardiovascular events (MACE), defined as AF, heart failure, ventricular arrhythmias, and sudden death, by cardiac RT dose. We also assessed the relationship between AF development and progression-free and overall survival. Observed incident AF rates were compared with Framingham predicted rates, and absolute excess risks were estimated. Multivariate regression was used to define the relationship between clinical and RT measures, and outcomes. Differences in outcomes, by AF status, were also evaluated via 30-day landmark analysis. Furthermore, we assessed the effect of cardiac substructure RT dose (eg, left atrium, LA) on the risk of post RT-related outcomes. RESULTS: Overall, from 238 RT treated patients with esophageal cancer, 21.4% developed incident AF, and 33% developed MACE with the majority (84%) of events occurring ≤2 years of RT initiation (median time to AF, 4.1 months). Cumulative incidence of AF and MACE at 1 year was 19.5%, and 25.7%, respectively; translating into an observed incident AF rate of 824 per 10,000 person-years, compared with the Framingham predicted rate of 92 (relative risk, 8.96; P < .001, absolute excess risk 732). Increasing LA dose strongly associated with incident AF (P = .001); and those with AF saw worse disease progression (hazard ratio, 1.54; P = .03). In multivariate models, outside of traditional cancer-related factors, increasing RT dose to the LA remained associated with worse overall survival. CONCLUSIONS: Among patients with esophageal cancer, radiation therapy increases AF risk, and associates with worse long-term outcomes.

Long-term Clinical Outcomes of Yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma: A 5-Year Institutional Experience.

RATIONALE AND OBJECTIVES: To examine the clinical outcomes of yttrium-90 (Y90) transarterial radioembolization (TARE) for primary hepatocellular carcinoma (HCC) through the evaluation of a 5-year institutional experience. MATERIALS AND METHODS: This retrospective study evaluated 88 consecutive patients with primary HCC receiving Y90 TARE treatment at an academic medical center from 2017 to 2021. Disease distribution was bilobar in 60.2% of patients with an average lesion diameter of 5.0 ± 3.4 cm and Barcelona Clinic Liver Cancer stage B or C in 77% of the participants. Clinical outcomes were elucidated by examination of complications, liver function tests, biochemical response, and radiographic response. Objective response ratio (ORR) and progression-free survival (PFS) were also calculated. RESULTS: The mean administered Y90 radiation dose was 127.8 ± 20.2 Gy. No significant complications or LFT elevations occurred post-therapy. Of the 73.9% of patients with α-fetoprotein-producing tumors, 67.8% experienced a complete or partial biochemical response 1 month post-treatment. The ORR was 83.3% on 6-month imaging and PFS was 9.6 ± 8.5 months. Functional outcomes (Eastern Cooperative Oncology Group) were maintained or improved in 79.6% and 76.1% of patients by 6 months and 1 year post-treatment, respectively. The mean survival was 14.7 ± 12.1 months. At 6 months post-treatment, 77.3% of patients were downstaged to or maintained Milan criteria, which was sustained for 74.4% and 70.0% of patients 1 year and 2 years after treatment, respectively. CONCLUSION: Y90-TARE is a safe and effective therapy for primary HCC. Enduring outcomes further act as a realistic bridge to liver transplantation, with a majority of patients maintaining Milan criteria and preserving their functional status long term.

Treatment Patterns and Outcomes for Patients with Ampullary Carcinoma Who Do Not Undergo Surgery.

Surgical resection is the standard of care for ampullary adenocarcinoma (AC). Many patients are ineligible due to comorbidities/advanced disease. Evidence for the optimal non-operative management of localized AC is lacking. We hypothesize that patients treated with chemotherapy (CT) and definitive radiation (DRT) will have superior survival (OS) compared to those treated with CT alone. We performed a retrospective review of the National Cancer Database from 2004 to 2017 to identify patients with non-metastatic AC and no surgical intervention. Patients were categorized as having received no treatment, palliative radiotherapy (PRT) alone, CT alone, CT + PRT, DRT alone, or CT + DRT. We utilized Kaplan-Meier analysis to determine OS and the log-rank test to compare survival curves. Among 2176 patients, treatment groups were: No treatment (71.2%), PRT alone (1.9%), CT alone (13.1%), CT + PRT (1.6%), DRT alone (2.4%), and CT + DRT (9.7%). One-year OS varied by treatment group, ranging from 35.1% (PRT alone) to 59.4% (CT + DRT). The one-year OS in a matched cohort was not significantly different between CT alone and CT + DRT (HR 0.87, 95% CI 0.69-1.10, p = 0.87). Most patients with non-metastatic AC not treated with surgery do not receive any treatment. There is no difference in one-year OS between those undergoing CT alone and CT + DRT.

Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

Intraoperative Radiation Therapy for Gastrointestinal Malignancies.

Despite improvements in definitive therapy, many patients with gastrointestinal malignancies experience local recurrences or have unresectable disease making subsequent management often challenging and morbid. Although higher doses of radiation may offer improved local control, the ability for dose escalation of external beam radiation therapy is often limited by adjacent radiosensitive structures. Intraoperative radiation therapy allows for additional radiotherapy to be delivered directly to the tumor or areas at highest risk for local recurrence while minimizing toxicity to adjacent structures, offering potentially improved outcomes for patients with unresectable disease or those with a high risk of local recurrence.

Oligometastatic Colorectal Cancer: A Review of Definitions and Patient Selection for Local Therapies.

PURPOSE: Nearly one-third of patients diagnosed with colorectal cancer (CRC) will ultimately develop metastatic disease. While a small percentage of patients can be considered for curative resection, more patients have limited disease that can be considered for local therapy. Challenges remain in defining oligometastatic CRC as well as developing treatment strategies guided by high level evidence. METHODS: In this review, we present the challenges in defining oligometastatic CRC and summarize the current literature on treatment and outcomes of local therapy in patients with metastatic CRC. RESULTS: For patients with liver- and/or lung-confined CRC metastases, surgical resection is the standard of care given the potential for long-term progression-free and overall survival. For patients with liver- or lung-confined disease not amenable to surgical resection, non-surgical local therapies, such as thermal ablation, hepatic arterial infusion pump (HAIP), or stereotactic body radiation therapy (SBRT), should be considered. For patients with more advanced disease, such as lymph node or bony metastases, the role of metastasis-directed therapy is controversial. Emerging data suggests that SBRT to ablate all metastases can improve progression-free and overall survival. CONCLUSION: Multidisciplinary management is critical for patients with metastatic CRC due to the complexity of their cases and the nuanced patient, tumor, biological, and anatomical factors that must be weighed when considering local therapy. High-quality prospective randomized data in CRC are needed to further clarify the role of local ablative therapy in patients with unresectable oligometastatic CRC with ongoing studies including the RESOLUTE trial (ACTRN12621001198819) and the upcoming NCTN ERASur trial (NCT05673148).

Alliance for Clinical Trials in Oncology (Alliance) trial A022101/NRG-GI009: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

Background: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Local Therapies in Advanced Colorectal Cancer.

Curative intent surgical resection of colorectal metastases to the liver and lungs in eligible patients results in improved disease control and prolonged overall survival with the potential for cure in a subset of patients. Additional ablative and local therapies for use in the liver, lungs, and other body sites have been developed with emerging data on the utility and toxicity of these treatments. Future studies should focus on identification of appropriate candidates for treatment and determining the optimal modality and timing of treatment accounting for both patient and disease factors.

Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies.

BACKGROUND: Chest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in numerous studies including the landmark Darby study published in 2013 demonstrating a linear increase in cardiac mortality with increasing mean heart radiation dose. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown. METHODS: We queried clincaltrials.gov to identify phase II/III trials in lung, esophageal, lymphoma, mesothelioma, thymoma, or breast cancer from 1/1/2006-2/1/2021 enrolling greater than 100 patients wherein chest RT was delivered in at least one treatment arm. The primary endpoint was the rate of inclusion of cardiotoxicity as a specific primary or secondary endpoint in the pre- (enrollment started prior to 1/1/2014) versus post-Darby era using the Chi-square test (p<0.05 considered significant). We also analyzed clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint using logistic regression analysis. RESULTS: In total, 1,822 trials were identified, of which 256 merited inclusion. 32% were for esophageal, 31% lung, 28% breast, and 7% lymphoma/thymoma/mesothelioma cancers, respectively. 5% (N=13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no difference in the inclusion of cardiotoxicity endpoints in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P=0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, p=0.17) and breast cancer (5.7% vs. 10.8%, p=0.43) studies, though these increases remained statistically non-significant. We found no clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint. CONCLUSIONS: Among prospective trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.

Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. METHODS AND MATERIALS: From 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs). RESULTS: The 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting. CONCLUSION: In contemporary chest RT-based clinical trials, reported CVD rates were lower than expected population rates.