The landscape of cancer treatment is constantly evolving, with clinical trials playing a pivotal role in developing new therapies. A crucial aspect of these trials is the accurate and specific reporting of adverse events (AEs). This process is not only a regulatory requirement but also a vital tool for protecting patients and determining the true effects of new cancer treatments.
In the realm of clinical trials, the National Cancer Institute (NCI) has set the gold standard for assessing and reporting AEs. Since the inception of the NCI Common Toxicity Criteria (CTC) in 1982, the Cancer Therapy Evaluation Program (CTEP) has been at the forefront of this effort. The most recent iteration, the Common Terminology Criteria for Adverse Events (CTCAE) v6.0 was released in 2026, reflecting the ongoing advancements in cancer treatment and patient care.
The significance of adverse event reporting
Adverse event reporting is a cornerstone of clinical trials, ensuring that any untoward medical occurrences associated with a drug or intervention are documented and evaluated. An AE can manifest as any unfavorable and unintended sign, symptom, or disease, whether or not it is directly related to the treatment. These events can range from mild and asymptomatic to severe and life-threatening.
The documentation of AEs serves multiple purposes. It helps clinicians capture any deleterious effects from the drug or intervention, documents the severity of the event, and assists in assigning attribution. The Principal Investigator is ultimately responsible for all elements of an AE report, ensuring that the information is accurate and complete.
Grading the severity of adverse events
The severity of AEs is graded using a standardized system to ensure consistency and clarity in reporting. The CTCAE provides detailed definitions and grades for AEs, allowing clinicians to accurately characterize the severity of an event. This grading system uses specific terminology, such as semi-colons to indicate ‘or’ within the description of a grade and em dashes to denote grades not applicable to the AE.
When grading AEs, clinicians must document signs, symptoms, and objective measures that characterize the severity of the event. They should attempt to use descriptive terms found in the CTCAE definitions and grades to assist with grading. It is important to note that a participant need not exhibit all elements of a grade description to be designated that grade. When a participant exhibits elements of multiple grades, the highest grade is to be assigned.
Assigning attribution to adverse events
The documentation of AEs does not necessarily imply causality to the drug or intervention. The clinical team must assign attribution of the event, determining whether it is related to the drug, the intervention, or something else. Causes of AEs can include protocol treatment, pre-existing conditions, concomitant medications, or other factors.
Attribution standards include categories such as unrelated, unlikely, possible, probable, and definite. Designating an event as treatment-related (or not) can be done by the treating clinician at the time of clinical evaluation. Investigators may also make these designations later, during aggregate data review and reporting.
Reporting novel adverse events
As cancer treatments continue to evolve, so do the potential adverse events associated with them. The CTCAE is regularly updated to reflect these advancements and to describe any deleterious event a patient may experience. However, there may be instances where a novel, yet-to-be-defined adverse event occurs.
In such cases, the NCI allows the submitter to report the appropriate verbatim term via the ‘Other, Specify’ mechanism. This mechanism should only be used when a suitable CTCAE term cannot be found. Overuse of the ‘other, specify’ mechanism may lead to a report being flagged or rejected. Investigators will be required to correct and resubmit reports if NCI staff identify a suitable CTCAE term.
To use the ‘Other, Specify’ mechanism, the clinical team must identify the most appropriate CTCAE System Organ Class (SOC) to classify the event, name the adverse event explicitly and briefly, and grade the event from Grade 1 to Grade 5 according to the descriptions provided.
