Table 1.

Contrast enhancement on CT or MRI as a surrogate of disease in malignant glioma*

Biomarker	Incremental Context of Use			Incremental Evidentiary Standards for Regulatory Qualification
				Risk-Benefit		Evidentiary Standards
	Purpose	Drug Development Circumstance	Decision/Action	Benefit	Risk
Prognosis
Initial/Residual Contrast- Enhancing Tumor Size (with or without digital image subtraction)	Prognosis (pretreatment)	Risk stratification (homogenize risk) enables drug development and use in more clearly defined patient groups (risk stratification)	Establish as “required/ necessary” test/ measurement	Reduced bias associated with large and small enhancing lesions, which tend to have dramatically different prognoses, independent of therapy. Better enable drug development by homogenizing risk.	Not accounting for enhancing tumor size prior to therapy may result in premature “failure” of new therapies due to risk bias associated with initial tumor size. Larger sample sizes needed to observe a treatment effect for a drug in the phase III setting.	Surgical studies demonstrating contrast- enhancing tumor contains the highest tumor cell density and proliferation rate, along with other histologic measures of malignancy.16,18,20–31 Prospective single and/or multicenter data associating initial enhancing tumor size or residual enhancing tumor size after resection with time to event outcome (TTP, PFS, objective response rate, OS).32–77,79–91,129,191–194 Prospective phase I–III trials associating initial tumor size, residual enhancing tumor size, or extent of resection with time to event outcome (TTP, PFS, objective response rate, OS).61,92–99,166

*Descriptions of the context of use (prognosis), how it will be used in drug development (risk stratification), balance of potential benefits and risks, as well as the evidentiary standards available to support use of contrast enhancement as a surrogate of disease in malignant glioma, per recommendations by the FDA and NIH.