Pseudoprogression: Relevance With Respect to Treatment of High-Grade Gliomas

Abstract

The post-treatment imaging assessment of high-grade gliomas remains challenging notwithstanding the increased utilization of advanced MRI and PET imaging. Several post-treatment imaging entities are recognized including: late-delayed radiation injury, including radionecrosis mimicking tumor progression; early-delayed (within 6 months of temozolomide-based chemoradiation) post-treatment radiographic changes, herein referred to as pseudoprogression (the subject of this review); early post-treatment changes following local glioma therapy (i.e. biodegradable BCNU wafer implantation or stereotactic radiotherapy); and pseudoresponse, seen following treatment with angiogenic inhibition based therapy such as bevacizumab. A literature review searched specifically for "pseudoprogression" within the last 5 years (2005-2010). Approximately 24 recent papers were identified and reviewed in detail. Eight small population-based studies demonstrate 26-58% (median 49%) of glioblastoma patients treated with chemoradiotherapy manifest early disease progression at first post-radiotherapy imaging. Patients with early radiographic disease progression continued on planned therapy, and a median of 38% (range 28-66%) showed radiographic improvement or stabilization and were defined retrospectively as manifesting pseudoprogression. In conclusion, pseudoprogression is a frequent early post-treatment imaging change that at present is not easily differentiated from tumor progression by anatomic or physiologic brain imaging. Consequently, an operational definition of pseudoprogression has been adopted by the Response Assessment in Neuro-Oncology Working Group wherein either the index (i.e. target) lesion stabilizes or diminishes in size on continued post-radiation (temozolomide) therapy as determined by follow-up radiologic imaging.

Single dose bevacizumab as treatment for symptomatic, corticosteroid-refractory pseudoprogression after chemoradiation therapy for newly diagnosed glioblastoma: A case report

“…Pseudoprogression is best diagnosed through serial MRIs because no established method of imaging is yet capable of providing a definitive diagnosis of true tumor progression versus enhancement changes due to other reasons [2][3][4][5][6][7]. Increased contrast enhancement and peritumoral edema that decrease with time are characteristic of pseudoprogression whereas such changes are stable with bona fide tumor progression.…”

“…After completion of concurrent RT and TMZ (most commonly within the first 3 months after completing treatment, but with a range in occurrence from the first few weeks to 6 months post-treatment), patients with high-grade brain tumors can present with an increase in contrast-enhancing lesion size, followed often by subsequent improvement or stabilization without further treatment [2][3][4][5][6][7]. This subacute treatment-related reaction can occur with or without clinical deterioration, but pseudoprogression is clinically asymptomatic in most patients [13].…”

“…It may represent at least in part an active inflammatory response against the tumor, and some studies have found an association between the incidence of pseudoprogression and increased survival [2][3][4][5][6][7]9].…”

“…The differentiation of a recurrent/progressive tumor from radiation injury is often a clinical dilemma, given that pseudoprogression may influence decisions to continue adjuvant chemotherapy rather than changing to a second-line therapy for recurrent disease [2][3][4][5][6][7]17]. If a post-chemoradiotherapy follow-up MRI examination demonstrates complete or partial response or stable disease (i.e., smaller or stable tumor enhancement), maintenance of chemotherapy is typically continued.…”

“…The increased gadolinium contrast enhancement on magnetic resonance imaging (MRI) can be misinterpreted as tumor recurrence or radiation necrosis (RN). Radiation therapy with concurrent TMZ chemotherapy followed by adjuvant TMZ is associated with the occurrence of pseudoprogression in up to 38% (28% to 66%) of cases [7]. The incidence of pseudoprogression appears to be higher in malignant gliomas with O6-Methylguanine-DNA-mehtyltransferase (MGMT) gene promoter methylation, which is associated with improved treatment outcomes [8].…”