Imaging Glioblastoma Posttreatment: Progression, Pseudoprogression, Pseudoresponse, Radiation Necrosis

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Key points

  • Various assessment guidelines for tumor progression, primarily designed for the purpose of phase 2 clinical trials, have been used over the course of the past several decades, with changes over time reflecting evolution in the approach to treatment and technological advances in imaging.

  • Radiation necrosis and pseudoprogression are often thought of as 2 opposite extremes on the spectrum of radiation-induced injury, and imaging features may mimic disease progression.

  • Pseudoresponse occurs in the

Progression

Various assessment guidelines for tumor progression, primarily designed for the purpose of phase 2 clinical trials, have been used over the course of the past several decades. Changes over time reflect evolution in the approach to treatment and technological advances in imaging.

The Levin criteria was a numerical grading system introduced in 1977, and imaging features important to diagnosis included size of tumor, central lucency, degree of contrast enhancement, surrounding edema, and ventricle

Definition of pseudoprogression

Pseudoprogression is defined as radiographic evidence of disease progression, typically within 3 to 6 months posttreatment, followed by spontaneous resolution or improvement without additional treatment.16, 17 Pseudoprogression may be accompanied by symptoms in 21% to 34% of patients with high-grade gliomas, but may be asymptomatic in patients with low-grade gliomas, particularly in the adult population.18 The pathophysiology of pseudoprogression is distinct from radiation necrosis, and likely

Factors associated with pseudoprogression

Factors associated with pseudoprogression include cancer genotype and radiation dose. MGMT methylation is associated with increased probability of pseudoprogression and better outcomes.27, 28, 29 For instance, in a group of 157 patients with glioblastoma multiforme, IDH1 mutation, and MGMT methylation predicted a high probability of pseudoprogression, as well as improved overall survival.30 The incidence of pseudoprogression in patients with MGMT methylated tumor genetics was shown to be 91%

Differentiating pseudoprogression from true progression

Immediate postsurgical imaging should take place within 48 hours postoperatively, in order to avoid postprocedural confounders such as enhancement associated with subacute ischemia.38 Subsequent follow-up imaging typically takes place after completion of chemoradiation, usually over the course of 6 weeks.

On conventional imaging, enhancement pattern and signal intensity on T2-weighted images are important factors in diagnosing tumor recurrence. Several studies have identified specific

Perfusion-Weighted Imaging

Three methods are used for PWI, 2 of which rely on the injection of an extrinsic contrast medium (dynamic susceptibility contrast [DSC] and dynamic contrast enhancement [DCE]), and 1 that uses blood as an intrinsic contrast medium (arterial spin labeling [ASL]). In a recent survey conducted by the American Society of Neuroradiology, 151 of 195 institutions endorsed offering perfusion MR imaging and 87% included perfusion as part of the standard brain tumor protocol, with percentage increase to

Diffusion-Weighted Imaging

DWI is an MR imaging technique sensitive to the molecular motion of water through the addition of 2 identical diffusion gradients, one on each side of a 180° refocusing pulse89; increased cellularity in the setting of high-grade glioma confers high microscopic tissue organization, and is detected as reduced diffusion.77 Apparent diffusion coefficient (ADC), a measure of water diffusivity, has therefore been used in the differentiation of tumor progression from pseudoprogression.66, 89, 90, 91,

Pseudoprogression in immunotherapy

In the setting of immunotherapy, increase in size of a treated lesion may reflect a localized inflammatory response induced by immunotherapy and apparent new, enhancing lesions may represent immune response in previously infiltrative, nonenhancing disease. Delayed response and/or a “flare phenomenon” may occur,132, 133 and a number of studies have been performed to explore the associated perfusion134, 135 and diffusion135, 136 changes. Application of MRS to treatment response in immunotherapy

Pseudoresponse

Whereas pseudoprogression typically occurs in the setting of administration of radiation and an alkylating agent, pseudoresponse occurs in the setting of antiangiogenic therapy. Glioblastoma is a highly vascular tumor that depends on angiogenesis for growth, with upregulation of several proangiogenic factors, including VEGF, hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor, angiopoietins, and IL-8,139 resulting in disorganized vasculature with abnormalities in

Radiation necrosis

Radiation necrosis and pseudoprogression are often thought of as 2 opposite extremes along the spectrum of radiation-induced injury. The terms are often interchanged, and several studies examining progression versus “treatment-related change” refer to pseudoprogression and radiation necrosis as a single collective entity.49, 54, 152, 153, 154 However, pseudoprogression and radiation necrosis are, in fact, distinct in timing, pathomechanism, histopathology, and prognosis. Pseudoprogression

Summary

Treatment response assessment in glioblastoma is important to management decisions and legitimacy of clinical trials. The RANO criteria are the most widely used guidelines in glioma response, but new enhancement seen within the radiation field during the first 12 weeks after treatment is difficult to definitively classify as true progression. Several patterns of enhancement and T2 signal are suggestive of pseudoprogression and radiation necrosis; ultimately, a multimodality approach including

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  • Cited by (56)

    • Radiomics for pseudoprogression prediction in high grade gliomas: added value of MR contrast agent

      2022, Heliyon
      Citation Excerpt :

      Figure 1 shows an example of true progression and Figure 2 an example of pseudoprogression. Pseudoprogression usually occurs within 3–6 months after completion of multimodal therapy [11] and is defined as a progression of findings on MRI images without clinical correlation, which then regresses over the course of therapy without any changes of therapeutic management [12]. Pseudoprogression appears as contrast-enhancing lesions on T1-weighted images and features an increase in signal intensity on FLAIR images surrounding the resection cavity [13, 14].

    View all citing articles on Scopus

    Disclosure Statement: The authors have no conflicts of interest to disclose.

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