Cancer Clinical Trials Systematically Underreport Thromboembolic Risks, Researchers Warn

Researchers have identified widespread inconsistent and potentially inaccurate reporting of venous and arterial thrombotic events in cancer (search)Search disease clinical trials, raising serious concerns about patient safety and informed consent. According to a commentary published in the Journal of Clinical Oncology, this systematic underreporting prevents clinicians from accurately assessing thromboembolic risks and implementing appropriate prophylactic measures.

"Mandatory and uniform reporting of all [venous and arterial thromboembolism (search)Search disease events] in cancer (search)Search disease trials is needed to ethically guide both the initial risk assessment and informed patient consenting of drug-associated [venous and arterial thromboembolism] in cancer-directed therapy," stressed the study authors, led by corresponding author David C. Calverley, MD, from the Section of Hematology/Oncology at Portland VA Medical CenterView company profile in Oregon.

Significant Discrepancies Between Trials and Real-World Data

The magnitude of the reporting problem becomes clear when comparing clinical trial data with real-world evidence. A real-world analysis of venous thromboembolism (search)Search disease in patients with cancer (search)Search disease receiving chemotherapy found that 13.5% of patients experienced venous thromboembolism 12 months after starting chemotherapy, with ranges varying from 9.8% to 21.3% depending on cancer location.

However, clinical trials consistently report much lower rates. In one striking example, a clinical trial of chemotherapy schedules in patients with advanced colorectal cancer (search)Search disease reported only a 1% rate of venous thromboembolism (search)Search disease among participants. Yet detailed chart review revealed that at least 10.2% of study participants actually had venous thromboembolic events, making it the most common grade 3/4 adverse event in the study.

Similarly, a systematic review of randomized clinical trials in pancreatic cancer (search)Search disease patients found reported rates of venous thromboembolism (search)Search disease were significantly lower among 13 trials focused on chemotherapy efficacy compared to nine trials focused on thromboprophylaxis efficacy (5.9% vs 16.5%; P < .001). The thromboprophylaxis studies more closely matched real-world incidence rates.

Multiple Factors Contributing to Underreporting

Calverley and colleagues identified several factors contributing to these reporting discrepancies:

• The Common Terminology Criteria for Adverse Events poorly categorizes thromboembolic events
• Lack of formal criteria or biomarkers for assessing whether thromboembolic events are treatment-related
• Asymptomatic venous thromboembolisms often go unreported despite their clinical significance
• Trials ending too early to capture delayed events
• Patient discontinuation concerns when thromboembolism events are reported
• Limited awareness of the clinical significance of certain thromboembolic events
• Drug company proprietary data restrictions

The researchers noted that "physicians vary their approach regarding [venous thromboembolism (search)Search disease] attribution to the anticancer therapy under investigation. Some providers report all [venous thromboembolism] events, whereas others fail to report [venous thromboembolism] or [arterial thromboembolism (search)Search disease] events based on subjective drug attribution judgments."

Emerging Therapies Show Concerning Patterns

The reporting problems are particularly pronounced with newer cancer (search)Search disease therapies. Reports of thromboembolic events were especially uncommon in early phase III randomized clinical trials that led to immune checkpoint inhibitor approvals. However, subsequent analysis of 18 real-world studies showed a cumulative incidence of 5% to 8% for venous thromboembolism (search)Search disease at 6 months and more than 10% at 1 year among patients receiving immune checkpoint inhibitors (search)Search drug.

Real-world rates for arterial thromboembolic events with immune checkpoint inhibitors (search)Search drug ranged from 1% to 5% at 12 months compared with 1.1% at 3 years among randomized controlled trials, with several trials not reporting any arterial thromboembolic event rates. One study even suggested a possible delayed temporal effect, showing a 41% risk of arterial thromboembolism (search)Search disease at 1 year and a 97% risk at 4 years.

For vascular endothelial growth factor (search)Search target-targeted tyrosine kinase inhibitors, clinical trials showed an arterial thromboembolic incidence rate of 1.4%, while real-world data revealed a rate of 3.99% when patients with cardiovascular history and risk factors were included.

Clinical Significance and Prevention Opportunities

Thromboembolism represents a major clinical concern, having been identified as a top non-cancer (search)Search disease-related cause of mortality among cancer patients receiving outpatient chemotherapy, tied with infections. Cardiovascular adverse events, often caused by venous and arterial thromboembolism (search)Search disease, are also significant drivers of non-cancer-related morbidity in cancer patients.

Importantly, thromboembolic events can be prevented with appropriate prophylaxis. A large randomized controlled trial of primary prophylaxis with rivaroxabanView drug details at 10 mg once daily in ambulatory cancer (search)Search disease patients initiating systemic therapy demonstrated a 60% reduction in the composite risk of venous thromboembolism (search)Search disease or venous thromboembolic-related death versus placebo. The treatment also reduced arterial and visceral thromboembolic events by 38% compared with placebo.

Comprehensive Reform Recommendations

To address these critical issues, Calverley and colleagues proposed eight key recommendations:

• Incorporate International Society on Thrombosis and Haemostasis (ISTH) criteria for reporting thromboembolic events in phase III trials
• Report all thromboembolic events consistently, without causal bias
• Document serious and nonserious events separately
• Include venous and arterial thromboembolisms as prespecified secondary endpoints
• Extend trial follow-ups to match treatment duration
• Harmonize definitions of serious versus nonserious thromboembolic events
• Include descriptors of location and extent of thromboembolic events
• Add thromboembolic event reporting to CONSORT Harms reporting metrics required for all randomized clinical trials

Expert Perspective on Risk Management

Alok Khorana, MD, Professor of Medicine at Cleveland ClinicView company profile Lerner College of Medicine and Director of the Gastrointestinal Malignancies Program, emphasized that thromboembolic risks should not derail drug development but rather be properly managed.

"Venous and arterial thromboembolism (search)Search disease are well-known complications of both cancer (search)Search disease and treatments for cancer," Khorana explained. "An elevated risk of thromboembolism should therefore not be viewed as an event that could derail drug development but rather as a complication whose risk can be mitigated with appropriate information."

He stressed that "assigning causality should not be the priority, rather mandatory reporting of events will allow a better understanding of the risk and whether it is elevated with a specific drug or not."

Call for Systemic Change

The authors concluded that accurate reporting is essential for optimal patient care. "Care in a multidisciplinary setting (ie, primary care, preventive cardiology, and thrombosis specialists) is paramount to providing the best available care to this growing patient population but is reliant on the accuracy of data available to inform practice and change," they stated.

The researchers believe their recommendations would provide ethical guidance for risk assessments and practical guidance for timely administration of prophylactic treatments, ultimately improving patient outcomes and quality of life through better risk mitigation strategies.