The development of radiologic criteria for the assessment of response to treatment in high-grade gliomas (HGGs) has evolved considerably over the past few decades since the original response criteria based on computed tomography imaging. Accuracy and objectivity in the assessment of response to treatment of HGGs is necessary for altering treatment regimens, establishing accurate provider communication, and improving the quality of clinical trials. Future studies assessing emerging advanced neuroimaging techniques will facilitate the development of even more accurate evidence-based radiologic response criteria.
High-grade glioma (HGG) is the most common form of primary brain tumor in adults. The World Health Organization (WHO) classification for central nervous system gliomas includes 2 grades that constitute HGG: anaplastic astrocytoma (WHO grade 3) and glioblastoma multiforme (WHO grade 4). The evaluation of response to treatment for patients with these tumors is of high clinical value in several respects. First, a patient’s response to a particular treatment must be able to be analyzed objectively and easily communicated among practitioners. If one particular treatment fails to produce favorable results, an alternative treatment strategy can be pursued. Also, an objective scale must be available for clinical trials of new treatments. Traditional end points for the assessment of efficacy in clinical trials are progression-free survival (PFS), radiographic response rate (RRR), and overall survival (OS). Unlike OS, PFS and RRR depend on reproducible and accurate imaging measurements to analyze tumor progression.
The development and refinement of specific radiographic response criteria have spanned several decades and several imaging modalities, and have evolved considerably over the past 3 decades. Contrast-enhanced computed tomography (CT) scans were initially used to analyze tumor progression. Criteria that had been developed for CT imaging were expanded to include T1-weighted magnetic resonance imaging (MRI) with gadolinium contrast. Both methods detect disruption of the blood-brain barrier by evaluating areas of tumor enhancement. Newer response criteria, including the recently published Response Assessment in Neuro-Oncology (RANO) criteria, attempt to address limitations of prior response criteria and use fluid-attenuated inversion recovery (FLAIR) and T2-weighted MRI combined with T1-weighted MRI with gadolinium contrast to evaluate tumor size. Further study of advanced MR techniques, such as perfusion/permeability imaging and diffusion-weighted imaging, and functional assessment of tumors with MR spectroscopy (MRS) and positron emission tomography (PET) scanning, will likely allow for more accurate response criteria to be developed in the future. In this review, various schemes that have been developed and implemented to determine response to treatment and recurrence of HGG, and the status of current and emerging neuroimaging modalities used to make these assessments, are reviewed.
Development of criteria for determining response
Starting in the 1970s, several investigators have attempted to create practical criteria for assessing tumor response to treatment based on combinations of neuroimaging studies, patient clinical status, and relative interventions, such as corticosteroid administration. Although the basic principles of each of these schemes have remained more or less consistent with regard to determining treatment response versus tumor progression, the neuroimaging modalities used to make these determinations and specific criteria have evolved considerably. Starting with the Levin criteria in the late 1970s to the most recent implementation of the RANO criteria in 2010, the various criteria for assessing tumor response to multimodality treatment regimens are discussed in the following sections.
Levin Criteria (1977)
An early attempt to classify response to treatment of HGGs was published by Levin and colleagues in 1977. The grading scheme they developed incorporated 4 separate modalities, including the neurologic examination, a radionuclide brain scan, an electroencephalogram, and a CT scan. Each was individually analyzed and any change from baseline was graded on a scale from +3 (“markedly better”) to –3 (“markedly worse”). The CT scan was analyzed specifically for interval changes in tumor size, central lucency, degree of edema, degree of contrast enhancement, and size of the ventricular system. The corticosteroid dosages required by the patient at the time of grading were also accounted for as part of the assessment. This system represents one of the earliest published attempts at characterizing response to treatment of HGGs with the use of CT imaging.
WHO Oncology Response Criteria (1979)
In 1979, WHO developed criteria for grading response to therapy that was not specific for HGG, but applicable to all types of cancer. Assessment of tumor size was based on 2-dimensional analysis of the tumor. The product of the 2 largest cross-sectional diameters of a specific enhancing lesion seen on CT scan was used as the primary measure of tumor size.
The criteria proposed by WHO identified 4 response categories. Complete response (CR) was characterized by complete disappearance of the lesion on subsequent CT scans. Partial response (PR) was characterized by a greater than 50% reduction in tumor size. Progressive disease (PD) indicated that tumor size had increased by more than 25% on repeat imaging. Stable disease (SD) was characterized by a reduction in size of less than 50% or an increase in size of less than 25%. Macdonald and colleagues would be the first group to apply these categories of progression to brain tumors specifically.
Macdonald Criteria (1990)
In 1990, Macdonald and colleagues published a new set of criteria demonstrating that the WHO criteria of 1979 could be applied directly to brain tumors, specifically HGGs. Like the WHO criteria, the Macdonald criteria used the maximal cross-sectional enhancing diameters of a specific lesion on CT scan as the primary tumor measure. In addition to radiographic response, Macdonald and colleagues incorporated the clinical assessment of the patient and the current corticosteroid dose into the response grading scheme.
The categories of response in the Macdonald criteria are similar to the WHO Oncology Response criteria with regard to changes in tumor size. CR was defined as complete disappearance of tumor, with the additional requirements of no corticosteroids and stable or improved neurologic examination. PR was characterized by greater than 50% reduction in tumor size along with no new lesions, stable or reduced corticosteroid requirements, and stable or improved neurologic examination. PD was defined as any of the following: greater than 25% enlargement of tumor size, a new lesion, or clinical deterioration. SD was defined as a stable clinical examination that did not qualify as CR, PD, or PR.
Over the next several years, the Macdonald criteria would be met with some criticism. Because of reliance on 2-dimensional assessment of tumor size, irregularly shaped tumors are difficult to assess and may therefore result in a high degree of interobserver variability. The criteria also provide little guidance for measuring tumors within or adjacent to cystic cavities or surgical cavities, and for multifocal tumors. Another limitation of the Macdonald criteria is that the primary tumor measurement relies only on enhancing portions of the tumor, so nonenhancing portions are not taken into consideration. Furthermore, the degree of contrast enhancement can be very nonspecific. Factors that may influence enhancement include corticosteroid dosages, the amount of contrast used during the scan, postsurgical changes, treatment-related inflammation, seizure activity, ischemia, subacute radiation effects and radiation necrosis, and antiangiogenic agents.
The Macdonald criteria have since been adapted to include MRI with gadolinium contrast, under the same assumption that breakdown of the blood-brain barrier and disrupted vascular architecture will also manifest as contrast enhancement. Because corticosteroids can influence the amount of contrast enhancement, Macdonald and colleagues proposed that patients be kept on stable doses of corticosteroids when assessing for response. When new doses of corticosteroids were required, Macdonald and colleagues originally proposed waiting 2 weeks for reassessment; however, new evidence suggests that 5 days are likely sufficient. The Macdonald criteria were the most widely used method of assessing response until the RANO criteria were published in 2010.
Response Evaluation Criteria in Solid Tumors (2000, 2009)
The Response Evaluation Criteria in Solid Tumors (RECIST) were introduced in 2000, and then revised in 2009 for the evaluation of systemic cancers. In contrast to the WHO Oncology Response criteria, the RECIST criteria are based on the longest unidirectional single diameter in the axial plane. When multiple lesions are present, the diameters are summed to provide the primary tumor size measurement. As part of the RECIST criteria, the categories of response also differed from WHO criteria in that PR was defined as a greater than 30% decrease in the sums of maximal diameters of tumors, PD was characterized by a greater than 20% increase in the sums of diameters of tumors, and SD was defined as a lesion not classified as PD or PR.
The revised RECIST guidelines defined a minimum of 2 and a maximum of 5 lesions to be counted in cases of multiple lesions. Also, pathologic lymph nodes were incorporated into the assessment. To prevent overcalling progression, the revised RECIST guidelines also suggest a 5-mm absolute minimum increase requirement to diagnose PD. Several studies have suggested that the RECIST criteria have good concordance with both 2-dimensional measurements (Macdonald criteria) and volumetric measurements when determining response in both adult and pediatric high-grade gliomas.
Development of the current standard criteria (RANO criteria)
Limitations of the Macdonald Criteria
Multimodality therapy for HGGs has evolved dramatically since the publication of the Macdonald criteria. Standard first-line therapy for high-grade gliomas currently involves maximal tumor resection followed by radiotherapy and concurrent and adjuvant temozolomide. Therapy with antiangiogenic agents, such as bevacizumab and cediranib, or additional chemotherapy regimens, is reserved for patients demonstrating recurrence or tumor progression following first-line therapy. Recently observed effects of these current treatment modalities, namely pseudoprogression and pseudoresponse, have presented new challenges to the practicality of the Macdonald criteria in determining response to treatment.
Pseudoprogression
Pseudoprogression refers to the phenomenon whereby an increase in contrast enhancement does not accurately reflect actual tumor progression, and is thought to occur as a result of increased vascular permeability in tumors primarily following treatment with radiation and temozolomide. Several studies have reported that 20% to 30% of patients treated with radiation and temozolomide develop pseudoprogression on the first postradiation MRI, and that pseudoprogression is most likely to occur 4 to 12 weeks after completion of radiation therapy. Pseudoprogression will eventually resolve on subsequent MRI. To be considered pseudoprogression, the new region of enhancement must be within the radiation field. Of note, this phenomenon occurs more often in patients with methylated MGMT-promoter tumors.
The clinical significance of pseudoprogression may be profound. Nontumoral enhancement mistaken for PD may result in premature discontinuation of adjuvant therapy that is actually effective. Also, pseudoprogression may have implications for response reporting in clinical trials, especially in trails using PFS and RRR as primary end points.
To evaluate tumor progression in these patients, FLAIR and T2-weighted sequences can be obtained on MRI. Progressive increases in nonenhancing FLAIR and T2-weighted signals reflect actual tumor progression. An increase in these signals must be differentiated from other potential causes, including the effects of radiation, decreased corticosteroids, demyelination, ischemia, infection, seizures, and postoperative changes. Changes in FLAIR and T2-weighted imaging that suggest infiltrating tumor include mass effect, infiltration of the cortical ribbon, and an involvement of an area outside the radiation field. In addition, newer imaging modalities, such as MR perfusion and permeability imaging, can more easily distinguish between real progression and pseudoprogression.
Pseudoresponse
Pseudoresponse refers to a decrease in contrast uptake that does not reflect actual tumor regression. This phenomenon occurs most commonly in patients treated with antiangiogenic therapies, such as bevacizumab (an anti–vascular endothelial growth factor [VEGF] monoclonal antibody) and cedirinib (an anti-VEGF receptor monoclonal antibody), and can be seen as early as 1 to 2 days after initiation of antiangiogenic therapy. Pseudoresponse is thought to be the result of normalization of vessel permeability and not a true antitumor response. Also, increasing evidence suggests that anti-VEGF therapies increase blood vessel co-option by tumor cells. Co-opted vessels are believed to be less permeable and therefore less visible on contrast-enhanced MRI.
RANO Group Criteria
The RANO group was an international effort to develop new standardized response criteria for clinical trials in brain tumors and response to therapy in individual patients with brain tumors. In 2010, the RANO group published response criteria based on the Macdonald criteria but expanded these to define more-specific methods of measurement. The RANO criteria set more-specific guidelines for exact measurement of tumor size, and made significant changes to address the limitations of the Macdonald criteria ( Tables 1 and 2 ).
| Response | Criteria |
|---|---|
| Complete response | Requires all of the following: complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on physiologic replacement doses only); and stable or improved clinically. Note: Patients with nonmeasurable disease only cannot have a complete response; the best response possible is stable disease |
| Partial response | Requires all of the following: ≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan; and stable or improved clinically. Note: Patients with nonmeasurable disease only cannot have a partial response; the best response possible is stable disease |
| Stable disease | Requires all of the following: does not qualify for complete response, partial response, or progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan. In the event that the corticosteroid dose was increased for new symptoms and signs without confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows that this increase in corticosteroids was required because of disease progression, the last scan considered to show stable disease will be the scan obtained when the corticosteroid dose was equivalent to the baseline dose |
| Progression | Defined by any of the following: ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids a ; significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy a not caused by comorbid events (eg, radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor (eg, seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, and so on) or changes in corticosteroid dose; failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease |
a Stable doses of corticosteroids include patients not on corticosteroids.
| Criterion | CR | PR | SD | PD |
|---|---|---|---|---|
| T1 gadolinium-enhancing disease | None | ≥50% ↓ | < 50% ↓ but <25% ↑ | ≥25% ↑ a |
| T2/FLAIR | Stable or ↓ | Stable or ↓ | Stable or↓ | ↑ a |
| New lesion | None | None | None | Present a |
| Corticosteroids | None | Stable or ↓ | Stable or ↓ | NA b |
| Clinical status | Stable or ↑ | Stable or ↑ | Stable or ↑ | ↓ a |
| Requirement for response | All | All | All | Any a |
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