Glioblastoma, specifically IDH-wildtype glioblastoma (World Health Organization grade 4), presents a significant clinical challenge. Despite standard treatment protocols, including surgery, radiation, and chemotherapy, the median overall survival remains less than 18 months. This aggressive tumor biology necessitates a comprehensive understanding of treatment strategies and accurate response assessment for optimal patient management.
The successful management of IDH-wildtype glioblastoma hinges on differentiating true tumor progression from treatment-related effects such as pseudoprogression (PsP), radiation necrosis, and pseudoresponse (PsR). This distinction is critical for informed decision-making regarding treatment regimens and prognosis. Clinical symptoms alone are often insufficient for accurate differentiation, highlighting the crucial role of imaging in post-treatment evaluation.
Treatment Pathways for IDH-Wildtype Glioblastoma
The initial standard treatment involves maximal safe surgical resection, followed by concurrent radiotherapy and chemotherapy with temozolomide. Adjuvant temozolomide cycles (6-12) are typically administered to patients under 70 years of age with good general and neurological condition. Patients presenting with unfavorable prognostic factors may undergo hypofractionated radiation therapy (RT) or chemotherapy alone according to their O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.
Treatment at recurrence is individualized based on prior therapies, age, Karnofsky Performance Status (KPS), MGMT promoter methylation status, and the specific patterns of disease progression. Re-resection can improve survival if maximal safe resection is achieved with minimal residual tumor. The efficacy of re-irradiation is debatable. Temozolomide rechallenge and lomustine are also potential options for alkylating chemotherapy. Bevacizumab, an antiangiogenic agent, can prolong progression-free survival (PFS) but has not demonstrated an overall survival (OS) benefit in recurrent tumors. Immunotherapy, including vaccination therapy, oncolytic viral therapy, and immune checkpoint inhibitors, is an emerging treatment modality, but its survival benefit remains under investigation. An overview of the clinical pathway for newly diagnosed and recurrent IDH-wildtype glioblastoma, combined with the timeline and imaging period, is summarized in Figure 1.
alt: Clinical pathway for IDH-wildtype glioblastoma showing treatment options and imaging timeline.
The Importance of Context and Communication
Radiologists play a critical role in differentiating tumor progression from treatment-related changes. It’s crucial to emphasize that accurate interpretation relies not only on current imaging findings but also on a comprehensive understanding of the clinical context. This includes the incidence, timing, and risk factors associated with various treatment-related changes. Reviewing preoperative, immediate postoperative, and serial follow-up images, as well as the surgical notes, RT charts, and treatment timelines, is essential for a thorough assessment. Active communication among radiologists, neurosurgeons, neurologists, radiation oncologists, and pathologists is vital, particularly in complex cases.
Understanding the Blood-Brain Barrier
The blood-brain barrier (BBB) protects brain tissue by restricting the passage of contrast agents. Contrast enhancement on MRI reflects the breakdown of the BBB. Neoangiogenesis, a hallmark of glioblastoma, is a primary cause of contrast enhancement. However, cytotoxic therapies and immunotherapies can also disrupt the BBB, leading to inflammation and contrast enhancement, making it difficult to distinguish from tumor recurrence. Conversely, antiangiogenic therapies like bevacizumab can restore the BBB, reducing contrast enhancement even in the presence of tumor growth, resulting in pseudoresponse (PsR).
Recommended Imaging Protocols
Standard MRI protocols for glioma assessment in clinical trials should incorporate:
- 3D pre- and post-contrast T1-weighted imaging (T1)
- 2D post-contrast T2-weighted (T2) and pre-contrast fluid-attenuation inversion recovery (FLAIR) imaging
- 2D diffusion-weighted imaging (DWI)
Perfusion imaging techniques like dynamic susceptibility contrast imaging or arterial spin labeling are recommended to gain greater insights into the underlying tumor physiology for baseline and follow-up scans. While advanced imaging methods, such as MR spectroscopy (MRS), offer insights into tumor metabolism, a lack of standardization prevents their widespread use. Post-contrast FLAIR imaging may be beneficial for detecting leptomeningeal metastases (LM) at recurrence. Amino acid PET is approved in Europe for differentiating treatment-related changes from tumor recurrence, but not in the U.S.
RANO 2.0 Criteria
The Response Assessment in Neuro-Oncology (RANO) criteria were developed to standardize response assessments for gliomas in clinical trials. RANO 2.0 provides a unified set of response criteria for all gliomas, replacing previous RANO-HGG and RANO-LGG criteria.
Key aspects of RANO 2.0 include:
- Baseline Imaging: The first post-radiotherapy (post-RT) MRI (21–35 days after RT completion) is used as the baseline in newly diagnosed patients. Pre-treatment (pre-Tx) scan (≤14 days before the start of treatment) should be used as the baseline in recurrent patients.
- Confirmation of Progression: Repeat MRI is mandatory within 12 weeks after radiotherapy completion to distinguish PsP from tumor progression. Progression can be confidently diagnosed without follow-up imaging only if it occurs outside the radiation field or is pathologically confirmed.
- Contrast Enhancement: For IDH-wildtype glioblastomas with contrast enhancement, non-enhancing tumor will no longer be evaluated, except when assessing the response to antiangiogenic agents. For uncommon IDH-wildtype glioblastomas without contrast enhancement, T2/FLAIR should be performed.
While RANO 2.0 offers a standardized framework for clinical trials, its application in routine clinical practice is limited by the exclusion of advanced imaging modalities. Therefore, clinical context and advanced imaging findings should be prioritized over strict adherence to RANO 2.0 for accurate diagnosis in individual patients.
Post-Treatment Imaging Findings: A Detailed Overview
Several post-treatment imaging findings can mimic tumor progression, necessitating careful differentiation. These include pseudoprogression (PsP) after RT, radiation necrosis, pseudoresponse (PsR), and PsP after immunotherapy. An overview of post-treatment imaging findings, combined with the timeline and imaging period with a checklist for interpretation is presented in Figure 2.
alt: Post-treatment imaging findings timeline: PsP, radiation necrosis, PsR, and PsP after immunotherapy.
Pseudoprogression After Radiotherapy
PsP after radiotherapy is defined as the enlargement or new appearance of contrast enhancement within the radiation field, mimicking tumor progression, but resolving spontaneously on follow-up imaging without treatment modification. It’s crucial to differentiate PsP from true tumor progression, as misdiagnosis can lead to premature termination of effective treatment.
Clinical Presentation
PsP occurs in 30-40% of patients within 12-24 weeks of completing radiotherapy. The RANO 2.0 criteria define the PsP time period within 12 weeks of completing radiotherapy, although it may be seen up to 24 weeks. Neurological status may or may not be associated with PsP. PsP typically resolves spontaneously without further intervention.
Risk Factors
MGMT promoter methylation, a predictive biomarker for temozolomide treatment and a strong prognostic marker, is also a significant risk factor for PsP. Patients with MGMT promoter methylation are more likely to develop PsP.
Pathophysiology and Histopathology
PsP is thought to represent edema and increased vascular permeability resulting from radiotherapy-induced tumor and endothelial cell death. Transient interruption of myelin synthesis and temozolomide-induced DNA damage can also contribute. There are currently no specific histopathological criteria for diagnosing PsP or radiation necrosis. The final diagnosis relies on the pathologist’s judgment and may show interobserver variability. In post-treatment diagnosis of PsP, radiologists cannot simply pass on the burden of accurate diagnosis to the pathology department, and radiological impressions should be actively communicated with clinicians and pathologists.
Imaging
Conventional imaging has limited value in differentiating PsP from tumor recurrence. While certain features like callosal involvement or subependymal spread are reportedly associated with tumor recurrence, these can also occur in PsP.
Advanced imaging modalities can provide more useful information:
- Diffusion-weighted imaging (DWI): PsP typically shows a higher apparent diffusion coefficient (ADC) value compared to tumor recurrence.
- Perfusion imaging: PsP typically shows a lower relative cerebral blood volume (rCBV) than tumor recurrence.
- MR Spectroscopy (MRS): Higher NAA and Cr values, and lower Cho values, leading to lower Cho/NAA and Cho/Cr ratios, are observed in PsP compared to tumor recurrence.
- Amide Proton Transfer (APT) Imaging: Lower APT signals are observed in PsP compared to tumor recurrence.
- Amino Acid PET: Less tracer uptake is observed in PsP compared to tumor recurrence.
Consider comparing ADC and rCBV values to initial preoperative imaging for more accurate differentiation, noting that recurrent tumors usually maintain similar ADC and rCBV trends as the original tumor. See Figures 3, 4, and 5 for representative imaging examples. Table 1 summarizes the clinical and imaging differences between PsP after radiotherapy and tumor progression and recurrence.
alt: MRI scans showing pseudoprogression after radiotherapy in a glioblastoma patient with MGMT promoter methylation.
alt: MRI showing early tumor progression outside the radiation therapy field in a glioblastoma patient.
alt: MRI showing early tumor progression inside the radiation therapy field in a glioblastoma patient.
alt: Table summarizing clinical and imaging differences between pseudoprogression and tumor progression/recurrence.
Radiation Necrosis
Radiation necrosis must be accurately diagnosed to prevent inappropriate termination of effective treatment. It manifests as a gradually enlarging contrast-enhanced lesion on follow-up imaging, often mimicking tumor recurrence.
Clinical Presentation
Radiation necrosis typically occurs 9-12 months after treatment, or even years later, with an incidence of up to 25%. Clinical presentation mirrors tumor progression with neurological decline. Unlike PsP, radiation necrosis can persist longer with a worse prognosis. Treatment involves corticosteroids for cerebral edema and surgical decompression for severe mass effects. Bevacizumab has demonstrated efficacy in improving neurological symptoms.
Risk Factors
Re-irradiation, especially at high doses and large treatment volumes, increases the risk of radiation necrosis.
Pathophysiology and Histopathology
Radiation necrosis involves more severe tissue reactions than PsP. Radiation-induced vascular damage leads to endothelial cell damage, vascular hyalinization, cellular swelling, and necrosis. White matter damage and upregulated vascular endothelial growth factor (VEGF) expression also contribute. Histologically, it is characterized by coagulative necrosis with gemistocytic astrocytes. There are currently no specific guidelines for the histopathological characterization of radiation necrosis. Pathological differentiation from tumor recurrence is not always easy.
Imaging
In conventional imaging, radiation necrosis typically occurs in the white matter within the radiation field. Internal enhancement patterns like “Swiss cheese” or “soap bubble” patterns are more typical. However, evaluation of these patterns can be subjective and inaccurate.
Advanced imaging findings include:
- DWI: Higher ADC values compared to tumor recurrence.
- Perfusion imaging: Lower rCBV than tumor recurrence. Centrally restricted diffusion may be present.
- MRS: Relatively higher NAA values and lower Cho values, leading to lower Cho/NAA and Cho/Cr ratios. Elevated lipid-lactate peaks may also suggest radiation necrosis.
- APT Imaging: Lower APT signals are observed in radiation necrosis than in tumor recurrence.
- Amino Acid PET: Less tracer uptake than tumor recurrence, although false-positive uptake can occur after re-irradiation.
Figure 6 shows a representative case of pathologically confirmed radiation necrosis. Table 2 summarizes the clinical and imaging differences between radiation necrosis and tumor recurrence or progression.
alt: MRI showing radiation necrosis with central diffusion restriction.
alt: Table summarizing clinical and imaging differences between radiation necrosis and tumor recurrence/progression.
Pseudoresponse in Antiangiogenic Therapy
PsR occurs during bevacizumab treatment. It is characterized by a decrease in contrast enhancement without a true antitumor effect. The lesion remains stable or has progressed on T2/FLAIR images. Understanding PsR is important for correctly interpreting post-treatment imaging results during bevacizumab treatment.
Clinical Presentation
PsR is usually observed shortly after the initiation of bevacizumab treatment. Neurological symptoms may improve due to reduced vasogenic edema and mass effect. Approximately 30% of patients undergoing bevacizumab treatment may show PsR.
Pathophysiology and Histopathology
By targeting VEGF, bevacizumab reduces tumor vascularity and normalizes tumor vasculature. It also reduces tumor-associated edema and tissue hypoxia. Angiogenesis blockade may lead to “vessel co-option” where the glioblastoma utilizes mature vasculature in normal tissue. The histopathology of PsR is not well described.
Imaging
PsR shows a rapid decrease in contrast-enhancing tumor and peritumoral edema. Non-enhancing tumor remains stable or increases in size. Careful examination of T2/FLAIR is needed to delineate the extent of non-enhancing tumors. Figure 7 shows a representative case of PsR tumor progression.
alt: MRI showing pseudoresponse after bevacizumab treatment with non-enhancing tumor progression.
Pseudoprogression During Immunotherapy
During immunotherapy, PsP may manifest as enlarged or newly developed contrast-enhancing lesions with increased perilesional edema, decreasing in size during follow-up without further treatment. The timeframe for PsP during immunotherapy is longer than for PsP after radiotherapy.
Clinical Presentation
The timeframe for PsP during immunotherapy is several months longer than for PsP after radiotherapy and remains to be defined. Patients may present with worsening neurological symptoms.
Pathophysiology and Histopathology
Intratumoral immune cell infiltrates are associated with geographic necrosis and vascular wall hyalinization. Increased cellularity can be observed due to reactive astrocytosis.
Imaging
Little information is available regarding the differentiation of PsP during immunotherapy from tumor progression using imaging in IDH-wildtype glioblastoma. Future research should involve a multicenter study with a comprehensive evaluation of both MRI and PET imaging parameters.
Tumor Recurrence/Progression
Accurate diagnosis of tumor recurrence/progression is crucial for treatment decisions. The median OS after the first recurrence is approximately 9 months. The pattern of recurrence can be classified as local, distant, or mixed (illustrated in Fig. 8). Local recurrence is adjacent to the resection cavity or within the radiation field. Distant recurrence is distant from the resection cavity or beyond the radiation field. Leptomeningeal metastases (LM) can also occur.
alt: Schematic illustrations of local, distal, and mixed tumor recurrence patterns.
Imaging characteristics include:
- Contrast-enhancing tumor with necrosis, low ADC, and high rCBV values.
- Non-enhancing tumor recurrence may be observed, especially after bevacizumab treatment.
- MRS: Higher Cho and lower NAA and Cr values.
- APT Imaging: High APT signals.
- Amino Acid PET: Increased tracker uptake.
Ventricular enlargement can suggest LM. Post-contrast FLAIR increases the sensitivity for LM diagnosis. Figure 9 shows representative cases of tumor recurrence/progression with mixed recurrence (local recurrence with LM) and distant recurrence. Figure 10 shows a representative case of tumor recurrence manifesting as a solitary LM.
alt: MRI showing mixed and distal tumor recurrence/progression patterns.
alt: MRI showing tumor recurrence/progression manifesting as isolated leptomeningeal metastases.
Conclusion
Post-treatment imaging interpretation in IDH-wildtype glioblastoma requires a thorough understanding of imaging findings and clinical context. Radiologists are integral to the multidisciplinary neuro-oncology team, and accurate differentiation of true tumor progression from treatment-related changes is essential. Effective communication among neurosurgeons, neurologists, radiation oncologists, and pathologists will enhance understanding and advance the fight against IDH-wildtype glioblastoma.
