Table 2.

Challenges in glioma response criteria and proposed solutions.

Challenge	Macdonald criterion for progression	Concerns	Proposals
Size	“50% increase in size”	Suggests size is equivalent to cross-sectional area Highly irregular tumors are the norm Poor reproducibility Cystic components might affect measurement Presence of multiple lesions might affect measurement 50% threshold is arbitrary	Use volume of enhancing tissue after standard dose of gadolinium on MRI as a marker instead of overall size6,18 Do not include cysts11,12,17,18 Sum all enhancing intra-axial tumor voxels, contiguous or not6,12,18 Define basis for change. We use nadir as basis for PD, baseline as basis for PR5,17 Define minimum size a priori on the basis of imaging technique. We use 500 μl as the smallest amount for volumetric approaches (approximately the volume of a sphere 10 mm in diameter) when 1 mm × 1 mm × 1 mm three-dimensional MRI data of good quality are available Define what the 50% change in size means. We propose 50% change in volume, not 50% change in area. This approach is more sensitive: patients who are failing treatment will be declared sooner; patients who are succeeding on treatment will also be declared sooner7,11,32
Steroid dosing	“Escalating steroid doses…in the absence of significant CT worsening…are included in the stable category.”	Might not be able to determine progression on the basis of steroid increase Affected by number of days that a steroid dose has remained stable	CR or PR not possible if steroid dose is increasing4 MRI assessment requires at least 3 days of stable steroid dosing, preferably 7 days.4,5,11 PD not called due to steroids alone, but only by radiographic or clinical criteria4 PD not determined due to steroids alone, but only by radiographic or clinical criteria4
Neurological status	Unequivocal neurological deterioration	Scales are not ideal Changes might not be due to the tumor	Define prospectively the degree of change required to make a determination of progression. One option is a drop in Karnofsky Performance Score to below 50 or a decrease of more than two levels6
Distinction between a tumor border and a new lesion	“…new areas of tumor”	Satellite lesions are common in glioma	Determine the distance within which a second focus of enhancement is considered part of parent lesion. We arbitrarily define a distance of within 50 mm in the same hemisphere or along the corpus callosum as not a new lesion Contralateral hemisphere lesions (e.g. on opposite side of falx) are immediately considered new lesions12
Degree of enhancement	No comment	Antiangiogenic therapy clearly affects the degree of enhancement Enhancement is not binary	Identify a threshold for enhancement before study initiation. We propose any enhancement visible to the interpreter12 Include secondary effects, such as mass effect or surrounding edema (see comment on multimodal imaging below)
Tumor mimics or pseudoprogression	“Investigator [must] carefully exclude… pseudoprogression.”	Numerous concerns; maintain as much control as possible over variables	Use precontrast MRI as well as post-contrast MRI4 Continue to attempt to maintain control over variables (Box 1)4 Include all enhancing intra-axial tissue as part of the tumor until or unless consensus criteria are developed for distinguishing tumor from pseudoprogression
Multimodal imaging	No comment	All imaging modalities need to support the same conclusion	Maintain vigilant awareness of the possibility that all modalities need to supply the same conclusion Include changes T2-weighted or FLAIR images as secondary end point Use only MRI with and without gadolinium unless patient unable to undergo MRI Use standard dosing of gadolinium contrast agent and standardize and record timing of scan after dosing4 Consider mechanistic imaging whenever possible5

Abbreviations: CR, complete response; FLAIR, fluid-attenuated inversion recovery; PD, progressive disease; PR, partial response.