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
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
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.