Abstract
Background
Patients with IDH-mutant low-grade glioma (LGG) can achieve many years of survival with radiation (RT) and chemotherapy. There is a risk of overtreatment and negative treatment side effects if these patients are unnecessarily retreated due to perceived tumor progression in the absence of true tumor regrowth. A better understanding of volumetric postradiation FLAIR changes will help with the clinical interpretation of disease progression/treatment effect and will help guide management decisions. We conducted this research to characterize the changes in MRI FLAIR hyperintensity that occur in LGG patients following RT, to better understand the radiation-treatment effects or “pseudoprogression” that occurs in the absence of true tumor regrowth.
Methods
Serial MRI scans of patients with LGG were reviewed, including pre-RT and for 2.5 years post-RT. Segmentation for volumetric analysis was performed with manual supervision using ITK-SNAP (open-source segmentation software). Descriptive statistics are reported.
Results
Sixteen patients with histologic grade 2 gliomas were included. 159 MRI scans were segmented using ITK-SNAP (median 9.5 MRIs/patient). Nine of 16 MRIs showed decreasing FLAIR volume immediately post-RT, while 7/16 showed increasing FLAIR volume. After the initial post-RT MRI, 12/16 patients had MRIs with an increase in FLAIR volume sometime during the first year. The FLAIR volume stabilized or decreased a median of 18.4 months and a mean of 15.0 months post-RT.
Conclusions
FLAIR hyperintensity changes on MRI are highly variable in the first 1.5 years post-RT in low-grade glioma, but after 1.5 years, FLAIR volumes stabilize and decrease, likely indicating the inflection point where post-RT pseudoprogression stabilizes.
Keywords: low-grade glioma, neuroradiology, pseudo-progression, radiotherapy
Key Points.
- This paper explores variable FLAIR changes post-RT in glioma, which stabilize after 1.5 years.
- This timeline can guide expectations on what to expect for pseudoprogression in low-grade glioma.
Importance of the Study.
Brain radiation therapy induces long-term changes in the radiation field, which can appear on MRI for years following. Studies have begun to attempt to distinguish postradiation pseudoprogression from true tumor regrowth. However, there is limited data investigating and characterizing pseudoprogression in patients with low-grade gliomas. Our study characterizes the volumetric changes in MRI FLAIR hyperintensity that occur in low-grade glioma patients following radiation therapy in the absence of true tumor regrowth. In conjunction with a small number of recent studies investigating this phenomenon, it adds to our understanding of the postradiation changes that can be expected in patients with low-grade-mutant glioma. A greater understanding of these changes promises to improve patient care by avoiding unnecessary and deleterious retreatment with aggressive therapy in the absence of true tumor regrowth.
When treated appropriately, patients with IDH-mutant glioma can often achieve many years of survival. Data from the CoDEL1 (NCT00887146) and CATNON2 (NCT00626990) studies have demonstrated that patients with IDH-mutant tumors respond more favorably to multimodal therapy, combining radiation and chemotherapy than to single-modality treatment.1,2 Radiation therapy (RT) has the potential to cause long-term changes within and adjacent to the radiation field, which can be symptomatic.3,4 These postradiation sequelae, observable on MRI, occur along a spectrum, ranging from radiation-induced reactive changes—commonly referred to as “pseudoprogression” or “pseudo-progressive disease (psPD)”—to more severe radiation necrosis, with late changes occurring up to several years following radiation.5,6 While the onset, duration, and timing of pseudoprogression have been well described for glioblastoma, there is less information for low-grade or IDH-mutant glioma.
Currently, conventional MRI is insufficiently reliable in distinguishing between pseudoprogression and early tumor progression in glioma patients.7 On T2 FLAIR images, the recurrence of IDH-mutant gliomas is often characterized by hyperintense signals.8,9 However, an increase in hyperintense signal can also occur due to disruptions in the vessel permeability of the blood–brain barrier.8,9 Radiation therapy, whether administered with or without chemotherapy, can disrupt the capillaries comprising the blood–brain barrier, making these changes appear nearly identical to tumor progression on MRI.9,10
Some functional imaging modalities, such as DWI, perfusion imaging, MR spectroscopy, and PET/SPECT, show promise in distinguishing tumor recurrence from non-neoplastic radiation effects. However, these modalities have limitations in mixed lesions (part-neoplastic and part treatment-related), are less widely available, and incur higher costs for patients and health systems.11
Significant therapeutic implications arise from the difficulty in distinguishing pseudoprogression from the progressive infiltrative tumor. Premature re-treatment in the absence of true tumor growth could subject patients to unnecessary surgery, chemotherapy, and additional radiation. It is especially important to be cautious about re-treating low-grade glioma IDH-mutant patients because, in the absence of poor prognostic genetic mutations (ie CDKN2A/B deletions), tumor regrowth on this timeline (1.5 years following radiation) is relatively unlikely.12 Though early recurrence and true progression of grade 2 IDH-mutant gliomas are rare, it is important to understand the evolution of radiation-related treatment effects on MRI, so that pseudoprogression can be distinguished from true progression. The purpose of this study is to quantify the volumetric changes observed on T2/FLAIR imaging following radiochemotherapy for grade 2 gliomas.
Materials and Methods
In this IRB-approved retrospective study, patients with low-grade glioma were identified from a multsidisciplinary neuro-oncology tumor board list including sequential patients with a diagnosis of low-grade IDH-mutant glioma, prior treatment with radiation therapy for their tumors, and their inclusion in the multidisciplinary tumor board (due to imaging changes observed following radiation therapy). Patients were excluded if they did not have pre and postradiation MRI available in our PACS system. The IRB approved a waiver of informed consent for this minimal-risk study. Serial MRI scans of these patients were reviewed, including preradiation therapy (RT) scans and scans administered at regular intervals for 2.5 years post-RT. ITK-SNAP, an open-source software used to segment structures in 3D biomedical images, was utilized to quantify the volumetric changes of hyperintensity over time. An automated segmenting program within ITK-SNAP was trained by the investigators to classify areas of each MRI as “white matter changes” or normal parenchyma. Progressive disease status was determined utilizing the 2010 RANO criteria for disease progression in low-grade glioma, as greater than a 25% increase in volume on T2/FLAIR or new lesion present, not attributable to other causes.13 Areas of hyperintensity were considered pseudoprogression (PsPD) if the increases in hyperintensity disappeared or remained stable for at least a year without new therapy.9,14 After the automated segmentation, each MRI segmentation was manually edited as needed to ensure that only the pseudoprogressive portions of the MRIs were included as measurements constituting “volume changes,” and that areas outside the radiation field were excluded. Measurements were reported in cubic millimeters, these values were calculated by ITK-SNAP based on the spatial resolution (voxel dimensions) of the underlying images.
Once all measurements were obtained for all patients, descriptive statistics were used to perform a comparative analysis of changes over time among the subjects. Overall survival (OS) was calculated from the onset of radiation therapy to the date of death, and progression-free survival (PFS) was calculated from the onset of radiation therapy to the start of true progression or death.
Results
Sixteen patients with histologic grade 2 gliomas were selected from previous tumor board lists to be included in this retrospective analysis. Four of these patients were diagnosed with astrocytoma, twelve with oligodendroglioma, and 15 out of 16 of these had confirmed IDH mutations. The time from histologic diagnosis to radiation therapy ranged from 2.2 to 235 months, with a median of 2.9 months. Table 1 provides the clinical characteristics of these patients, as well as OS, PFS, and details regarding radiation therapy doses.
Table 1.
Patient Demographics, Tumor Characteristics, and FLAIR Hyperintensity Changes Over Time
| Age (@ RT) | Tumor type | Radiation Dose (cGy) | Alive? | Hyperintensity vol @ RT (mm3) | Time: Dx to end of RT (mo.) | Time: RT to stability/decrease FLAIR changes | Progression free survival (mo.) | OS from time of RT (mo.) |
|---|---|---|---|---|---|---|---|---|
| 66 | O | 4005 | Yes | 9.33 × 104 | 307.2 | N/A | 9.1 | 16.6 |
| 30 | A | 5400 | Yes | 1.24 × 104 | 2.5 | 20.35 | 42.7 | 42.7 |
| 45 | A | 6000 | Yes | 5.881 × 103 | 2.1 | 25.7 | 43.8 | 43.8 |
| 61 | O | 5400 | Yes | 1.95 × 104 | 65 | 17.6 | 67.8 | 67.8 |
| 54 | O | 6000 | No | 4.31 × 104 | 108.2 | N/A | 16 | 21 |
| 75 | O | 5040 | Yes | 1.02 × 105 | 79 | N/A | 36.3 | 36.3 |
| 26 | A | 6000 | Yes | 5.54 × 104 | 2.6 | 2 | 109.7 | 163.2 |
| 39 | O | 5400 | Yes | 5.04 × 103 | 2.3 | N/A | 45.2 | 45.2 |
| 36 | O | 5400 | Yes | 2.99 × 104 | 2.7 | 11.9 | 73.3 | 73.3 |
| 56 | O | 5400 | Yes | 2.87 × 104 | 3.5 | 16.9 | 39.4 | 39.4 |
| 24 | A | 5400 | Yes | 3.35 × 104 | 6.9 | 5.1 | 23.4 | 23.4 |
| 35 | O | 6000 | Yes | 2.26 × 104 | 129.3 | 20.3 | 67.6 | 67.6 |
| 55 | O | 5040 | Yes | 1.85 × 104 | 232 | 18.4 | 27.6 | 27.6 |
| 56 | O | 5400 | No | 2.22 × 104 | 103.9 | 15.3 | 54.2 | 54.2 |
| 51 | O | 5400 | Yes | 9.07 × 103 | 104 | 7.323 | 58.8 | 66.5 |
| 49 | O | 5040 | Yes | 5.79 × 103 | 2.6 | 19.6 | 62.7 | 62.7 |
A total of 159 MRI scans were segmented using ITK-SNAP. Each patient had scans reviewed up to 2.5 years following radiation therapy (RT), with a median of 9.5 scans per patient, (range of 4–13 scans). The mean pre-RT tumor volume was 31.6 cm3 (standard deviation 29 cm3, range 5–100 cm3). Nine of 16 MRIs showed a decreasing FLAIR volume immediately following RT, while 7 out of 16 showed an increasing FLAIR volume of hyperintensity. After the initial post-RT MRI, 12 out of 16 patients had MRIs showing an increase in FLAIR volume that was consistent with pseudoprogression sometime within the first year. After this initial year, the FLAIR volume stabilized or decreased at a median of 18.4 months and a mean of 15.0 months following radiation treatment, regardless of whether the volume of hyperintensity had increased or decreased during the first year. Figure 1 provides an example of the pseudoprogression seen over the course of 1 year in a patient with IDH-mutant oligodendroglioma. Figure 2 demonstrates the trends in the change of FLAIR hyperintensity volume over time. These volume changes are described further in Table 2, which quantifies the average volume change observed between MRIs, as well as the maximum volume change from baseline observed, and the corresponding percentage change in size from baseline.
Figure 1.
Development of pseudoprogression over the course of 1 year in a patient with frontal oligodendroglioma.
Figure 2.
Graphical representation of FLAIR hyperintensity change over time for all patients.
Table 2.
Average FLAIR Hyperintensity Changes (From Sequential MRIs) and Maximum Volume Change for Each Patient. Described Both in Volume (mm3) and as a Percentage of Change, Which Indicates the Magnitude of Volume Change Relative to the Total Volume of Enhancement on the Previous MRI (Column 3) or Baseline MRI (Column 4)
| Patient | Baseline (@RT) hyperintensity vol (mm^3) | Avg. vol. change from previous MRI (mm3); (% change) | Max. vol. change from baseline (mm3); (% change) |
|---|---|---|---|
| 1 | 9.33 × 104 | 1.06 × 104 (11.3) | 6.00 × 104 (64.3) |
| 2 | 1.24 × 104 | 6.94 × 102 (5.6) | 4.98 × 103 (40.2) |
| 3 | 5.88 × 103 | 3.47 × 103 (59.0) | 3.07 × 104 (522.0) |
| 4 | 1.95 × 104 | 2.44 × 103 (12.5) | 8.41 × 103 (43.1) |
| 5 | 4.31 × 104 | 9.12 × 103 (21.2) | 1.82 × 104 (42.2) |
| 6 | 1.02 × 105 | 1.74 × 104 (17.1) | 2.60 × 104 (25.5) |
| 7 | 5.54 × 104 | 8.55 × 103 (15.4) | 2.87 × 104 (51.8) |
| 8 | 5.04 × 103 | 8.40 × 102 (16.7) | 5.04 × 103 (100.0) |
| 9 | 2.99 × 104 | 3.29 × 103 (11.0) | 6.28 × 103 (21) |
| 10 | 2.87 × 104 | 4.88 × 103 (17.0) | 3.13 × 104 (109.1) |
| 11 | 3.35 × 104 | 3.32 × 103 (9.9) | 1.37 × 104 (40.9) |
| 12 | 2.26 × 104 | 2.18 × 103 (9.65) | 7.13 × 103 (31.6) |
| 13 | 1.85 × 104 | 4.47 × 103 (24.2) | 1.64 × 104 (88.7) |
| 14 | 2.22 × 104 | 4.65 × 103 (21.0) | 1.76 × 104 (79.3) |
| 15 | 9.07 × 103 | 2.84 × 103 (31.3) | 1.30 × 104 (143.3) |
| 16 | 5.79 × 103 | 9.23 × 102 (15.9) | 2.26 × 103 (39.0) |
During the 2.5-year study period, median progression-free survival and median overall survival were not reached, with 14 out of 16 patients alive, and 12 out of 16 progression-free.
Out of the 4 patients (patients 1, 5, 7, and 14 in Tables 1 and 2) who did progress, one of them (patient 1) progressed with a persistent increase in hyperintensity volume on T2 FLAIR MRI. This may suggest that the increase in hyperintensity volume either transitioned from pseudoprogression to true progression or that it may have only ever been a true progressive disease. The other 3 patients who eventually progressed did so after our study observation period had ended. Patient 5 never exhibited PsPD during our monitoring (though they were only monitored until 5.4 months due to limited MRI data), then progressed at 16 months. Patient 14 had a transient increase in hyperintensity volume from 16 to 22 months, but then a decrease again following that, and progressed at 58.8 months. Patient 7 did exhibit pseudoprogression that peaked at 15.2 months and then began to decrease/stabilize. They then progressed at 109.7 months.
Discussion
Radiation therapy has long been known to induce long-term changes in the radiation field, and these changes can appear on MRI for years following.3–6 However, MRI alone is not a reliable method for distinguishing between true tumor regrowth and postradiation pseudoprogression. Although this phenomenon has been studied in patients with high-grade gliomas, there is less data regarding PsPD in patients with low-grade gliomas, and to our knowledge, a definitive timeline for when these changes can be expected in this population has not been established. Distinguishing between these groups is important due to differing tumor characteristics and the lower doses of radiation used to treat patients with low-grade gliomas.
In this retrospective study, we reviewed serial MRI scans of patients with IDH-mutant gliomas for 2.5 years following radiation therapy to determine the frequency of pseudoprogressive changes on MRI and the volumetric extent of the radiation effects. We investigated the timing and trends of these changes to better understand what providers can expect to see when reviewing imaging studies of their patients with low-grade gliomas. Patients with grade 2 gliomas in this study displayed variable changes in FLAIR hyperintensity measurements during the first year following radiation treatment were variable. Though 75% of them experienced an increase in FLAIR volume at least one-time point during this first-year period, an overall average increase in hyperintensity across patients (from baseline to 1 year) was not statistically significant. Among the patients who exhibited early increases in hyperintensity volume (prior to 1 year), 11 out of 12 did not experience true progression during or following the study. This suggests that such early imaging changes may not indicate true progression in a majority of cases.
On average, after 1.5 years, FLAIR volumes stabilized and decreased, likely indicating the inflection point where post-RT pseudoprogression stabilized in the patients in our study. It is important to note that though there were some significant increases in the size of hyperintensity overall, many interval changes were relatively subtle. As shown in Table 2, the average change in volume from MRI to MRI often represented a small percentage of the total hyperintensity volume, and these volume changes are spread through the entire 3D image, making it potentially hard to perceive when looking at individual MRI images.
There is a growing body of literature investigating this issue. However, much of the existing literature regarding pseudoprogression focuses primarily on patients with high-grade glioma. A small number of studies have specifically examined pseudoprogression following radiation therapy in low-grade gliomas.7,9,12,14–20 One of these studies was focused on children, most of whom had pilocytic astrocytomas.16 Another included patients with grade 3 glioma.12 One of the retrospective analyses that specifically investigated pseudoprogressive disease in low-grade glioma found pseudoprogression in around 20% of their initial cohort of IDH-mutant gliomas, which comprised only 13 patients. After analyzing the pseudoprogression observed in these patients, it was estimated that pseudoprogression began after a wide range of 3–78 months, and lasted a median of 6 months, with a range of 2–26 months.9 An evaluation of frequency and duration of pseudoprogression in 136 pediatric LGG patients found PsPD to have occurred in 39.7% of patients, with onset at a median of 6.3 months following radiation therapy and persistence for a median of 7.2 months.14 A more recent study of patients with IDH-mutated grade 2 glioma monitored for pseudoprogression in 106 patients, and identified PsPD in 23% of patients.17 Due to the long observational period, it was able to stratify the time at which pseudoprogression occurred, observing PsPD at only 13% after the first year, 22% at 5 years, and 28% at 10 years.17 The study of PsPD is also expanding to characterize its appearance across various therapeutic approaches, investigating rates of PsPD in proton versus photon therapy,18,19 and in radiotherapy alone versus radiotherapy combined with temozolomide.20
A limitation of our study is that though we were able to characterize trends in T2/FLAIR changes over time, these changes may represent a complex interplay between treatment effect, disease progression, and residual tumor. We do not have histopathological confirmation corresponding to the post-treatment MRI scans to characterize the exact etiology of these changes. Another limitation is the time period over which the study was conducted, as it limits the observation of PsPD to 2.5 years following radiation therapy, and as evidenced by a study in a similar cohort of patients, some patients who were not considered to have pseudoprogression in our study may go on to develop it at a later date.17 In addition, longer-term follow-up would help to determine any clinical significance of any prior pseudoprogressive changes observed.
Due to the relative paucity of data in this cohort of low-grade glioma patients, and the heterogeneity of the existing data, additional prospective studies with a larger sample size and longer-term follow-up are needed to better characterize the prevalence and time course of pseudoprogression in this patient cohort. If this trend continues in future studies, it may suggest a timeframe at which providers can expect to stop seeing increases in hyperintensity on MRI in the absence of true tumor regrowth. This could provide a roadmap to patients and providers, indicating an expanded timeline for pseudoprogression in IDH-mutant low-grade glioma relative to what has been described in glioblastoma. An exact timeline has not yet been established; in the present study there seemed to be an inflection point in PsPD at around 1.5 years after radiation, while some studies have found earlier stabilization of PsPD and others have shown PsPD continuing at later time points. However, a growing body of evidence characterizing increases in PsPD does indicate that some increase in hyperintensity on MRI may be expected and does not necessitate further treatment for assumed tumor regrowth. Understanding the postradiation changes that can be expected in patients with low-grade-mutant glioma can help providers avoid unnecessary re-treatment, thereby significantly reducing symptom burden and improving quality of life for patients and establishing a post-treatment baseline from which true progressive disease may be measured.
Contributor Information
Isabella Sutherland, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Adam Ulano, Department of Radiology, University of Vermont Medical Center, Burlington, VT, USA; Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Alissa A Thomas, Department of Neurological Sciences, University of Vermont Medical Center, Burlington, VT, USA; Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Funding
Institutional funding was provided via a grant (040311 COM-SumStu Sutherland-Thomas) from the UVM Cancer Center. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement. The authors have no relevant financial or nonfinancial interests to disclose.
Author contributions
All authors contributed to the preparation of the manuscript. The project was developed, designed, and implemented by A.A.T., I.S., and A.U.. The first draft of this manuscript was written by I.S., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Data availability
De-identified data will be made available upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
De-identified data will be made available upon reasonable request.