Better Radiation Toxicity Standards Needed in Both Clinical Trials and Practice

TAMPA, Florida—Standards for reporting toxicity related to radiotherapy are at least 5 years behind those developed for chemotherapy and need to be improved before the field can advance, according to Andy Trotti, MD. "There is a need for a common late effects grading system and a need for reporting standards," Dr. Trotti said. He is program leader and director of clinical trials, Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Barriers to progress in this area have included "doctor denial" of toxicity in general and a lack of reporting standards, according to Dr. Trotti. "Morbidity monitors are lacking in the routine clinical practice of radiation therapy and quality assurance; this area is not included in cancer outcomes; and there are no accepted reporting requirements," he said. "Lack of infrastructure and funding for toxicity research is also a part of the problem."

There are, however, several forces promoting standardized grading of toxicity. As listed by Dr. Trotti these include:

• clinical trials requirements;

• advocacy groups;

• government regulators;

• outcomes research;

• information technology;

• toxicity intervention studies;

• third parties such as insurance companies and HMOs;

• the need to define clinically "acceptable" risk;

• the need for quality assurance in routine practice; and

• growing concern over medical errors.

Measuring Toxicity

"Toxicity criteria are crucial to the evaluation of radiation protectors and toxicity modifiers," Dr. Trotti said. "Measuring toxicity is more complex than measuring clinical efficacy and may involve more than 300 kinds of toxic effects," he continued. "We need valid and reliable scoring criteria that are widely applied so data can be compared between trials."

The process of data collection also needs attention. "How do we make sure we have reasonably complete and accurate toxicity data in clinical trials or in routine practice? There are no standard tools to help us elicit toxicity information from the patient," Dr. Trotti said.

Standardized systems for reporting radiation toxicity data are also needed. Dr. Trotti said that there are few standards for how to report data consistently between trials, which makes comparing toxicity of different trials difficult.

Current Criteria

Criteria for reporting acute radiation-related toxicity include the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) and criteria developed by the Radiation Therapy Oncology Group (RTOG).

The original 1984 RTOG criteria for acute radiation toxicity included 14 organ systems. This rather heterogenous system includes consideration not only of toxicity symptoms but also of pain management and dietary requirements.

"In 1997, the NCI coordinated a comprehensive process to revise the toxicity criteria. This included participation by NCI, the FDA, the cooperative groups, international cooperative groups, and industry," Dr. Trotti explained.

"The RTOG was asked to revise and incorporate the acute radiation toxicity criteria into the CTC. This helped to produce CTC Version 2, which was disseminated on the NCI web site but has never been published by the NCI. It is attached to most clinical trials, especially NCI-sponsored trials, and it is widely used in industry-sponsored trials. CTC V 2.0 is now the most widely accepted standard. That has made it easier to compare data between trials. The RTOG has published an explanation of how the revised criteria change the process of scoring radiotherapy toxicity," he continued. CTC V 2.0 was developed as a dynamic, web-based reference document that is expected to evolve as needs change and advances in toxicity grading occur.

Common Late-Effects Criteria Needed

"Criteria for scoring late effects are not nearly as well developed as those for acute effects," Dr. Trotti said. "We need the same kind of comprehensive, commonly accepted scale in the late effects area," he continued. "The lack of ability to compare late effects between trials is hindering the development of radiation protectors and toxicity modifiers. Investigators and industry have been frustrated by the lack of a common system and more objective endpoints."

Dr. Trotti also said that a commonly accepted system for comparing late radiation effects that could be used in routine clinical practice would also help physicians appreciate how much toxicity they are producing in their patients and see the need for toxicity modifiers.

Radiation therapy experts are currently proposing to revisit the current time-related defintion of late effects. "Late effects are now arbitrarily defined as starting 90 days after the beginning of radiation therapy," Dr. Trotti said. "This definition may no longer be useful as we move into accelerated fractionation schemes and regimens that involve concurrent chemotherapy, where it may often take 8 to 10 weeks after treatment is over for acute effects like mucositis to resolve," Dr. Trotti said. "This causes a confusing overlap between acute and late toxicity definitions. Maybe we should do away with the concept of late toxicity and just score each toxicity as we see it. These issues will need further discussion."