As with other solid tumors, the assessment of overall radiographic response (ORR) has been an important end point for HGG clinical trials, especially those that use cytotoxic chemotherapy. Reduction in tumor size may correlate with symptomatic improvement and longer survival and therefore may provide a surrogate for clinical benefit. Twenty years ago, Macdonald et al3
proposed criteria for ORR in patients with supratentorial HGG based on 2-dimensional measurement of contrast enhancement partly resulting from imaging-based responses of oligodendrogliomas to chemotherapy.4
Similar to the brain tumor response criteria proposed by Levin et al,5
Macdonald and colleauges' criteria integrated clinical status into the definitions of both response and progression, as well as corticosteroid use, into the definition of response. The latter was based on the observation that corticosteroid use can substantially decrease tumor contrast enhancement on both CT6
and MRI scans.7
Macdonald and colleagues' criteria have subsequently remained the adopted, de facto standard for response assessment in HGG clinical trials. Although a number of studies suggest that 1-dimensional tumor measurements using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria8
may be equally effective, these criteria have not been widely adopted for patients with brain tumor9,10
Volumetric imaging may potentially be more accurate but is currently neither widely available nor standardized.11,12
Finally, change in tumor size as a continuous variable has been advocated as a measure of activity,13
but this approach also requires validation for patients with HGG.
The use of ORR as a primary end point has several advantages. ORR is a direct measure of therapeutic effect and is not affected by disease natural history, which may affect duration-based end points. It can also be determined relatively rapidly. In addition, there are extensive historical ORR data for a variety of salvage therapies, including cytotoxic chemotherapy14,15
and bevacizumab-based regimens,16,17
that can serve as comparators to the activity of planned study therapies. Furthermore, ORR is not affected by subsequent salvage therapies. For these reasons, some have argued that ORR is the only reliable end point for single-arm studies. Finally, regulatory agencies such as the US Food and Drug Administration (FDA) continue to place emphasis on ORR as an end point.18
In fact, durable ORR was the primary criterion cited by the FDA in their recent accelerated approval of bevacizumab for recurrent GBM.
However, the utility of ORR as a primary end point has potential limitations. First, the ability of ORR to consistently predict meaningful clinical benefit is variable.10–12,19
One possible explanation is that extravasation of contrast material across leaky intratumoral blood vessels, the surrogate used to determine tumor burden and thus ORR, can be influenced by several factors, including use of corticosteroids, inflammation, seizures, surgery, ischemia, and radiation effect on tumor, normal brain, and vascular permeability.20–22
Variations in radiological techniques can also influence contrast uptake.11
Furthermore, numeric cutoffs to define ORR were originally derived from the World Health Organization's solid tumor criteria, which may or may not be valid for CNS tumors. Importantly, ORR does not credit prolonged disease stabilization. Many new therapies, including targeted molecular agents, are predominantly cytostatic and are likely to produce stable disease rather than tumor regression. Furthermore, most classical cytotoxic agents do not yield significant ORR rates, yet they may show efficacy in terms of progression-free survival (PFS) or overall survical (OS) when given to patients with newly diagnosed conditions (eg, temozolomide). Such tumor control generally represents meaningful clinical benefit among patients with HGG. For cytostatic agents, other end points such as PFS at 6 months (PFS-6), may better reflect antitumor activity. Finally, radiographic assessment can be challenging because of difficulties in measuring irregularly shaped tumors, interobserver variability, lack of guidelines for assessment of multifocal disease, and the inability to measure nonenhancing tumor.11
A strategy to offset some of these issues is the use of blinded central imaging review to reduce bias and subjectivity in tumor measurement, thereby improving reliability. However, centralized review may not be practical for many phase II studies and may neglect clinical deterioration.
The utility of ORR based on contrast assessment is further limited by 2 clinically relevant scenarios, particularly in the current era. Although it has been noted after radiotherapy alone,23
an increase in contrast enhancement and edema, with or without accompanying neurologic findings, referred to as pseudoprogression, has been reported in up to 30% of patients with newly diagnosed HGG following completion of temozolomide chemoradiotherapy.24–26
In addition, pseudoprogression has been observed with other therapies, including biodegradable chemotherapy polymers,27
immunotoxins administered by convection-enhanced delivery,28
viral gene therapy,29
focal irradiation with brachytherapy or stereotactic radiosurgery,30
Although the underlying mechanism is not fully understood, these changes are felt to reflect increased permeability and/or vascular damage. Unfortunately, no currently available imaging modality reliably distinguishes pseudoprogression from true progression with sufficient sensitivity and specificity for routine use. In such situations, progression can only be reliably defined if it occurs at a distant site, is confirmed histopathologically, or worsens on sequential imaging.
Paradoxically, the second scenario limiting current radiographic assessment is the phenomenon of pseudoresponse. Pseudoresponse refers to improved contrast enhancement due to diminished vascular permeability that does not necessarily reflect a true underlying anti-tumor effect. For example, rapid and marked improvement in contrast enhancement has been noted less than 1-2 days after antivascular endothelial growth factor (VEGF) therapy.32
In other cases, despite improved enhancement, progressive, infiltrative nonenhancing tumor as assessed by FLAIR/T2 sequences has been noted.33
The recently announced RANO criteria34
build on the foundation established by the criteria of Levin et al5
and Macdonald et al1
and were developed to address the radiographic findings associated with pseudoprogression and pseudoresponse. In addition, pending experience and evaluation of the RANO criteria, concerns remain regarding the interpretation of ORR as an end point for trials investigating therapeutic approaches that are associated with either pseudoprogression or pseudoresponse. Future studies that include an evaluation of the potential correlation of ORR, preferably using the RANO criteria, with OS, will be particularly helpful to better define the value of ORR as an end point in the modern era.