Standardizing Tumor Assessment Criteria

Oncology clinical trials routinely rely on tumor assessments using medical imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) to demonstrate the efficacy of cancer therapies. While these technologies have greatly enhanced the development of oncology drugs, they also present trial sponsors and the scientific community with a number of challenges. One of the complexities surrounds the application of published accepted assessment criteria for imaging reviews in oncology trials.

(Photography: Ghislain & Marie David de Lossy, Getty Images)

Among the most utilized assessment criteria in oncology clinical trials are Response Evaluation Criteria in Solid Tumors (RECIST),¹ World Health Organization (WHO),² and the International Working Group Response Criteria for Non-Hodgkin's Lymphomas.³ While these guidelines have greatly improved the level of consistency and harmonization for the assessment of medical images, they don't often address the rigor needed for standardized assessments. Even the most widely utilized accepted oncology assessment criteria require additional clarifications in order to provide a more objective and harmonized tumor response assessment that is tailored to the needs of the given oncology indication and clinical trial.

Clarified assessment criteria

The rate of change in both imaging technology and cancer therapies is a major factor behind the need to refine and clarify published assessment guidelines. Although current assessment criteria incorporate many of the existing imaging modalities, the constant improvements in imaging technology make it challenging for any published guideline to reflect the most recent developments, or to take into account the growing availability of certain technologies such as positron emission tomography (PET).

Furthermore, the biopharmaceutical industry is continually developing novel treatments that target cancers in unique ways. For instance, there is an increasing trend within the industry to develop cytostatic compounds where tumor shrinkage as an outcome is unexpected or compounds that promote an immune response where tumor shrinkage may be delayed and preceded by interval tumor growth. These new approaches often require variations and flexibility in developing imaging assessment criteria to detect and measure disease responses in different and sensitive ways.

Even when the guidelines are as up-to-date as possible for a particular indication or investigational setting, they are often not detailed enough to cover all the variables that arise when studying a specific oncology therapy. Current assessment criteria are not applicable for every indication in the same way.

For example, RECIST is a common accepted criteria for solid tumors, and an ovarian cancer trial, melanoma trial, and prostate cancer trial may all use RECIST. However, there will be some differences in how RECIST is applied to each of these indications. The ovarian cancer study may utilize tumor markers to assess response, while the melanoma study may include measurements of skin lesions. Similarly, a prostate cancer trial may include patients with only nonmeasurable disease as part of the study population. In short, the published assessment criteria should not be considered as definitive but rather as a foundation upon which to build and refine.

By further clarifying assessment criteria, the consistency, reliability, and usability of the imaging assessments may be enhanced. The optimal application of the assessment criteria ensures a more consistent and robust imaging review process that validates the treatment response and outcome of a trial.

Key considerations for clarification

When evaluating the assessment criteria for implementation in a clinical trial, numerous factors must be taken into consideration, including: the applicability of the assessment criteria and specific imaging review challenges associated with a given cancer indication; recent studies that may have shed new light on a particular indication, mode of treatment or imaging technology; current accepted practices by regulatory authorities, such as the FDA and EMEA; and the specific imaging equipment used at the various trial sites. This will ensure that objective, comprehensive, and sensitive assessment criteria are in place for optimal reviewing consistency and reliable results.

Several of the medical and technological considerations related to oncology trials and medical imaging that should be addressed when clarifying the assessment criteria to support objective and harmonized reviews include but are not limited to the following recommendations (the examples provided are hypothetical for a Non-Hodgkin's Lymphoma trial):

• Developing clear definitions of measurable and nonmeasurable disease: For example, should nodules in solid organs qualify as measurable disease, and if so, under what circumstances?

• Establishing and defining the number and categories of selectable measurable lesions: For example, should measurable nodal disease and measurable organ nodules be distinct categories?

• Determining which modalities are to be used to identify and assess measurable lesions: For example, can physical exams be used to identify and assess measurable nodal disease?

• Anticipating changes in modality for tumor assessments during the trial and defining rules for assessment of those cases, if applicable: For example, can measurable nodes continue to be measured if there is a change from CT to MRI halfway through the study, and if so, under what conditions?

• Creating clear response assessments for nonmeasurable disease: For example, should progressive disease of nonmeasurable nodal disease be based on a visual estimation of a percent size increase from nadir?

• Defining minimum requirements for new lesions: For example, should new organ nodules be of a certain size to be considered new lesions?

These factors and others must be considered when developing an objective and comprehensive review process that provides credible, dependable, and uniform results that will withstand scrutiny by regulators or the scientific community (Table 1 provides further considerations for clarifying assessment criteria). Hence, a careful analysis of how a given criteria will apply to a particular oncology indication and clinical trial is a critical element to trial success.

Table 1. Considerations when clarifying assessment criteria for oncology trials.

Meeting the challenge

The benefits of imaging technologies in the development and clinical testing of oncology therapies are well established. MRI, CT, and other imaging modalities can provide faster results in determining the efficacy of novel cancer treatments. At the same time, the rapid development and growing complexity of imaging technologies, the increasing development of compounds with unique mechanisms of action, and the unique features of specific tumor cell types create significant challenges concerning image variability and accurate assessment of imaging data to determine disease response in patients.

While published assessment guidelines have brought much needed standardization to the process of analyzing medical images in oncology studies, it is vitally important to go beyond these basic guidelines when establishing criteria for tumor assessments. Modifying the guidelines to fit the specifics of each trial and indication and defining the review process as precisely as possible can greatly reduce the variability and increase the reliability of the data from advanced imaging technologies. The result may be faster development and approval of new therapies for serious diseases—an outcome that benefits everyone.

Sandra Chica,* MD, is medical director of oncology and Kelie Luby, MS, MTPW, is senior medical writer at Perceptive Informatics, 200 West Street, Waltham, MA 02451, email: Sandra.Chica@perceptive.com

*To whom all correspondence should be addressed.References

1. P. Therasse, S.G. Arbuck, E.A. Eisenhauer et al., "New Guidelines to Evaluate the Response to Treatment in Solid Tumors," Journal of the National Cancer Institute, 92, 205-216 (2000).

2. World Health Organization, WHO Handbook for Reporting Results of Cancer Treatment, Offset Publication No. 48 (Geneva, 1979).

3. B.D. Cheson, S.J. Horning, B. Coiffier et al., "IWC: Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas," Journal of Clinical Oncology, 17, 1244-1253 (1999).