Panel Creates ‘Single Language’ for Grading Delayed Effects

ST. PETERSBURG, Florida—New cancer regimens are sometimes a double-edged sword, offering better survival but also delayed toxicity affecting quality of life. At the Late Effects of Normal Tissues (LENT) IV workshop, an international, multidisciplinary panel tackled the Herculean task of defining, grading, and reporting chronic toxicity. The workshop included representatives from more than 10 countries, including two European organizations.

"It’s not a clear-cut issue like survival—we’re trying to quantitate about 500 different toxicity endpoints in a uniform way," said conference moderator Andy Trotti, MD, associate professor and director of clinical research in radiation oncology, H. Lee Moffitt Cancer Center at the University of South Florida, Tampa. "The delayed effects of cancer treatment are usually far less visible than acute effects, less appreciated even by experienced professionals, and often much harder to measure."

Delayed effects of chemotherapy, radiation therapy, and surgery include chronic fatigue, musculoskeletal atrophy and fibrosis, pain syndromes, limited mobility and exercise intolerance, dry mouth and dental disease, chronic edema, impaired cognitive and sexual functions, chronic intestinal dysfunction, and increased risk of heart disease and stroke.

Reporting and analyzing complications like these has, in the past, often suffered from a hit-or-miss approach: culling random observations hastily scrawled in charts or relying on complaints from patients, who are often reluctant to trouble harried providers.

Over the years, different cooperative oncology groups have developed their own toxicity scales. These groups include the Radiation Therapy Oncology Group (RTOG) and at least four others. However, lack of uniformity among the different scales hinders comparability and interpretation of results.

"Through the hard work of the participants of this workshop, one day in the near future, all of these organizations should be able to speak in a single toxicity language, utilizing a common platform, a common library of definitions, terminology, and severity scaling guided by standardized data collection and reporting techniques," Dr. Trotti said.

His team is comprised of 90 investigators, including surgeons, radiation oncologists, medical oncologists, nurses, research associates, biologists, statisticians, and other specialists; 12 National Cancer Institute (NCI) representatives; and 25 industry sponsors.

The workshop aimed to incorporate recent developments in toxicity grading into the NCI Common Toxicity Criteria (CTC v 2.0) system, which in 1998 became the international standard. However, even this system lacks criteria for many surgical effects and for delayed toxicity.

"The principal goal of this workshop is to address these gaps in the CTC, eventually producing a true multimodality system, covering the survivorship of the patient," Dr. Trotti said.

Dimitrios Colevas MD, chair of the NCI’s CTC Development Team, commented: "This is one of several efforts we are supporting, including pediatric and surgical working groups that are interested in improving and completing the CTC. We hope to integrate the work of these various groups into CTC version 3.0, to be disseminated in 2003, after review by the cooperative groups and other agencies."

At the conference, 11 individual site committees, like the gastrointestinal group chaired by radiation oncologist Ross Abrams, MD, of Johns Hopkins University, confronted toxicity issues unique to their disease site. "Trying to change established criteria, even if they are not adequate, is difficult because each organization and modality has its own culture and view of things," Dr. Abrams said. "However, we took a fully interdisciplinary approach, and we found that we aren’t as far apart as we thought."

Three previous LENT conferences over the past decade have developed the SOMA late effects grading system. It has been tested by many institutions, but never widely adopted for clinical trials. "Actually, the SOMA system was ahead of its time," Dr Trotti said. "It was very comprehensive, which also made it cumbersome. We hope to diminish the burden of data collection through the power of informatics. We will be incorporating the best parts of SOMA into the new CTC."

Although targeted cancer therapies theoretically avoid damaging normal tissue, most of these agents will be combined with traditional therapy, giving rise to potential new toxicities demanding increased, not decreased, application of criteria like those developed by the workshop. Corey Langer, MD, of Fox Chase Cancer Center, commented: "Recently, an NCI trial of an angiogenesis inhibitor was halted when severe thromboembolic events were noted when it was combined with other agents. This is something we couldn’t predict from animal studies or single agent use in humans."

Dr. Trotti noted that the pharmaceutical industry has taken an interest in developing agents that reduce toxicity. "Their attendance at and support of this workshop show that they realize we need standardized toxicity endpoints for the evaluation of new drugs that can modulate tissue injury," he said.

Overall, Dr. Trotti called the workshop very productive. "We not only created new late effects criteria for the NCI but also developed tools for data collection that should make the process more efficient, standardized, and complete," he said. "In addition, we will publish more than 25 papers from the proceedings. This workshop should help to move this field forward toward a long-term goal of reducing and preventing toxicity."