For the first time since 1998, the National Cancer Institute has issued revisions to the Common Toxicity Criteria (CTC), descriptive terminology used for reporting adverse events associated with cancer therapy. The third edition of the revamped and renamed guidelines, the Common Terminology Criteria for Adverse Events (CTCAE v3.0), incorporates new categories and offers a uniform method of grading all adverse events without regard to timing or cause of the events.
"The main benefit of the CTCAE v3.0 is standardization," said A. Dimitrios Colevas, M.D., a senior investigator at the investigational drug branch of NCIs Cancer Therapy Evaluation Program (CTEP) and chair of the CTC Development Team there. "With this tool, researchers can assess the relative incidence and severity of adverse events associated with any oncology trial worldwide in a much more comprehensive fashion."
The revised title of the terminology comes from the understanding that the cause of an adverse event may be unrelated to treatment. "For example, if someone develops pneumonia while they are receiving a new drug, or getting radiation or having surgery, that pneumonia may be caused by the intervention, by the underlying disease, or by something other than the treatment," Colevas said. "The term toxicity seems to assign blame to the therapy."
The CTCAE, like its predecessors, is considered the standard dictionary for researchers for reporting adverse events in clinical trials of cancer treatments. It is also useful for compiling study summaries of adverse effects and for writing scientific articles and reports for regulatory agencies.
The impetus for the latest revisions came from four different areas of oncology treatment and research, said Ann Setser, a nurse consultant in the office of the associate medical director of NCIs CTEP. For many years, pediatric oncologists have noted that the prior versions of the CTC did not adequately capture adverse events related to growth and development and other long-term secondary effects of treatments for children with cancer. In addition, radiation oncologists had developed separate elaborate adverse events evaluation criteria for late radiation effects. Surgical oncologists found that the second version of the CTC, developed primarily as a tool for grading chemotherapy trial adverse events, did not capture or grade adequately events associated with surgical interventions. Lastly, the medical oncology research community realized the need to edit some adverse events and to add new ones.
"Historically, there have not been well-defined standard criteria for late or chronic effects," Setser said. "Because of increasing cancer survivorship and the general higher scrutiny that results from research, the radiation and surgical oncologists felt it was important to have standardized late effects."
This new version of the CTCAE includes 28 categories and more than 900 adverse events, whereas the earlier version had 24 categories and 300 adverse events. Setser noted that "about 35 criteria in the new version are type, site, organ, or structure-specific, providing surgical and radiation oncologists precise anatomic sites to describe adverse events."
The four new categories of adverse events are death, growth and development, surgical intra-operative injury, and vascular. For many physicians unfamiliar with the implications of assigning standard CTC adverse event terms associated with interventions, there will be a need for education to dispel the notion that an adverse event represents a therapeutic wrongdoing or avoidable toxicity, Setser said.
Most people with cancer have chemotherapy or radiation treatment, yet little is known about long-term and late secondary effects, especially among adults. "There are 9.6 million cancer survivors in the United States alone, with 14% of them surviving more than 20 years," said Noreen Aziz, M.D., Ph.D., program director in the Office of Cancer Survivorship of NCI. "While the risk of recurrence may go down over time, the risk for late effects increases. So it is important to try to examine these late effects and to try to grade them in terms of severity, especially among survivors of adult cancer."
Aziz, a member of the CTC Development Steering Committee who participated in the meetings at which CTCAE v3.0 was drafted, added that "this instrument has the potential to facilitate standardized reporting of adverse events and the comparison [among] trials and [among] institutions. Thus, it should impact positively the quality of care for cancer survivors."
Experts in other disease specialties are looking to the updated CTCAE as a model. Richard Hafner, M.D., a medical officer in the Division of AIDS at the National Institute for Allergy and Infectious Diseases, said his group is in the process of "updating and harmonizing one common table for division-wide use, instead of the four or five currently being used." It is expected that the new table for grading the severity of adverse experiences for AIDS will be ready for online use within the next year.
Initial steps are also under way to standardize a common vocabulary for adverse events of imaging by the American College of Radiology Imaging Network (ACRIN), an NCI-sponsored clinical trials cooperative group. "This would be the first step to creating a working CTCAE vocabulary for use in imaging clinical trials across the world," said Barbara Galen, the acting chief of the Diagnostic Imaging Branch of the Cancer Imaging Program. "So this could be something very exciting for us to accomplish."
An informatics tool is being developed to further simplify use of the third version of the CTCAE. The tool will be a Web-based application that will allow easy coordination with a protocol, Setser said. "With this application, investigators will be able to find adverse effects easily, grade them electronically, and then plug the information into their own databases." Setser has begun an education initiative at the NCI cooperative group meetings and will conduct training workshops for all groups before the end of the year.
More information is available from the CTEP homepage at http://ctep.info.nih.gov/.
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