AIM: To investigate changes on magnetic resonance imaging (MRI) which occur with intracavitary Gliadel wafer placement in patients with glioblastoma multiforme (GBM).

METHODS: This retrospective Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board, with a waiver of informed consent. A total of eight patients aged 29-67 years with GBM underwent Gliadel wafer placement. T2-weighted/FLAIR images and post-contrast T1-weighted images both before and after wafer placement were retrospectively reviewed in consensus to determine changes in the following parameters: appearance of the pericavitary tissue, pattern of tumor recurrence or progression and appearance of the Gliadel wafer itself.

RESULTS: Five out of the eight patients had a progressive increase in enhancement and pericavitary T2/ FLAIR hyperintensity within the first 2 mo and a subsequent decrease in these MRI findings. None of these patients had tumor recurrence within the first 6 mo. Three out of the eight patients demonstrated a progressive increase in enhancement and pericavitary T2 hyperintensity, which continued after the first 6 mo, and were subsequently diagnosed with true tumor progression. There was no increase in distant/nonlocal tumor recurrence. The Gliadel wafer appearance changed over time.

CONCLUSION: Pseudoprogression is common after intracavitary Gliadel wafer placement and thus care should be taken before diagnosing tumor progression or recurrence within the first 2 mo.

Despite vast efforts in drug development, only limited advancements in malignant glioma therapy have been achieved[1]. Various new chemotherapeutic agents for glioblastoma multiforme (GBM) treatment, including but not limited to alkylating agents, tyrosine kinase inhibitors, and angiogenesis inhibitors, have yielded only minor benefits in patient survival[1] and the standard of care remains surgery, radiation, and concurrent chemotherapy with the alkylating agent temozolomide (TMZ)[2]. For most patients, the prognosis remains dismal with a median overall survival of 14.6 mo[2].

Thus, in addition to standard oral and intravenous chemotherapy, other routes of drug delivery are being explored. One example is the placement of chemotherapeutic wafers in the tumor resection cavity, called Gliadel wafers[3] (Eisai Co. Ltd., Tokyo, Japan). Gliadel wafers are composed of a biodegradable polymer wafer impregnated with 3.85% carmustine [1,3-Bis(2-Chloroethyl)-1-Nitroso-urea, BCNU]. BCNU is a chemotherapeutic agent which alkylates reactive sites on nucleoproteins and interferes with DNA synthesis and repair[4]. In 1996, Gliadel wafers became the first new treatment to be FDA-approved for malignant glioma, specifically recurrent GBM, since the introduction of systemic chemotherapy. It was the first and currently remains the only interstitial chemotherapeutic drug approved for malignant glioma[5]. Subsequently, in 2003, it was approved for primary therapy for GBM as well. During the surgical procedure, right after tumor resection or debulking, up to 8 wafers are deposited along the wall of the resection cavity (Figure 1). The implanted wafers are left in situ, providing a controlled release of BCNU over a period of 2 to 3 wk[6].

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Intracavitary Gliadel wafer placement. This image, taken at time of Gliadel wafer placement in the operating room, demonstrates the lining of wafers (white round structures) along the wall of the resection cavity site.

However, the introduction of different chemotherapies invariably results in new and different imaging findings both in the peritumoral and pericavitary regions. These pericavitary parenchymal changes can mimic tumor recurrence and progression, referred to as pseudoprogression. Therefore, knowledge of these changes on MR imaging is of utmost importance for proper identification and accurate interpretation. The radiologist (1) must be aware of appearance of the wafers on imaging and, once correctly identified, be able to (2) contextually analyze the associated pericavitary parenchymal changes on the images and provide the appropriate interpretation of those changes.

Despite multiple randomized clinical trials demonstrating a clinical efficacy in both primary[7,8] and recurrent[9] GBM, little has been published regarding the radiological findings of these wafers. Although multiple non-radiological studies have briefly touched on the parenchymal changes and complications seen after intracavitary placement of Gliadel wafers[9-11], to date, no published radiological study exists describing the peritumoral or pericavitary imaging findings. Only two dedicated radiology articles have been published describing the imaging appearance of carmustine wafers itself[12] and a second one additionally describing the pattern of recurrence and evolutionary changes in the surgical bed without particular focus on the pericavitary region[13]. The fact that Gliadel wafers can cause pseudoprogression, mimicking true tumor recurrence or progression, is clinically significant. The phenomenon of pseudoprogression is a well-known treatment-related response known to occur most commonly with concurrent radiation and TMZ administration[14]. However, this has not been described to occur with Gliadel wafers.

Therefore, the purpose of this article is to describe the parenchymal changes seen post- intracavitary Gliadel wafer placement and to provide potential ways to help differentiate Gliadel wafer pseudoprogression changes from true tumor progression. We will also illustrate the appearance of the Gliadel wafer itself on imaging modalities and describe patterns of tumor recurrence and progression.

This retrospective Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board, with a waiver of informed consent.

Our results demonstrate that the placement of Gliadel wafers into the resection cavity may result in a tissue reaction that may mimic tumor progression on MRI, a phenomenon referred to as pseudoprogression. This is evidenced radiologically as an increase in pericavitary enhancement and T2WI/FLAIR hyperintensity within the first 2 mo after wafer deposition and subsequent decrease of these MRI findings. Previous studies have briefly described parenchymal changes on Gliadel wafer placement[9,10]; however, these studies have not established a time point when these changes are most common or expected and when pseudoprogression is unlikely based on timing and ancillary advanced MR techniques such as MR perfusion imaging. Our results demonstrate that continued increase in enhancement after the 2 mo period should be considered as probable tumor progression rather than post Gliadel wafer changes; and, MR perfusion imaging can be helpful to further characterize and differentiate between these entities. It is essential in both clinical practice and clinical trials that radiographic time-to-progression be interpreted cautiously in this setting. The timing of pseudoprogression with Gliadel wafers is concordant with the new Response Assessment in Neurooncology (RANO) criteria which states the progression cannot be diagnosed within the first 3 mo after concurrent chemoradiation therapy unless it is outside the radiation field or there is pathological confirmation of progressive disease[17]. Our results are concordant with the latter definition of pseudoprogression standardized in the RANO criteria for brain tumors. Intracavitary Gliadel wafers can cause pseudoprogression; therefore, recognition is paramount to avoid misdiagnosis of recurrent tumor resulting in an unnecessary second surgery or change in the patient’s chemotherapeutic regimen based on the assumption that this reflects treatment failure. On the other hand, it is important to recognize that when these MRI changes increase or persist beyond 2 mo, these imaging findings are unlikely to represent post-Gliadel wafer changes; and advanced MR techniques can be employed to further characterize and help differentiate recurrent tumor from post-treatment changes.

This study also confirms that there is no increase in nonlocal tumor recurrence. Presumably, given that Gliadel wafers work locally on the pericavitary infiltrated tissue, one can hypothesize that the consequence of local control of disease might be an increase in distant/nonlocal (a distance of 1.5 cm or more from the primary tumor) recurrence of tumor[16]. Our results showed that 29% of Gliadel wafer patients had nonlocal tumor recurrence. Similar findings also resulted from the Giese et al[16] study which demonstrated no statistical difference in the pattern of recurrence between the Gliadel and placebo group; in this study, nonlocal recurrence occurred in 30% of patients in the Gliadel group vs 28% in the placebo group[16].

In our study, the differing patterns of Gliadel wafer appearance depend on their in situ time and are concordant with the literature[12]. In the acute phase (less than 7 d), the wafers appear hypointense on both T1WI and T2WI images. This appearance reflects their hydrophobic composition[12]. In the subacute phase (1 wk to 3 mo), the wafers become more proteinaceous and thus demonstrate hyperintensity on T1WI and hypointensity on T2WI[12]. After 3 mo, the wafers for the most part have completely degraded and thus cannot be seen on imaging. Awareness in local chemotherapy options such as Gliadel wafer placement available for GBM treatment as well as the ability to, independently from medical records, identify these on MRI can help a radiologist to entertain the possibility that an increase in enhancement and T2WI/FLAIR hyperintensity within the first 2 mo post Gliadel wafer deposition might be due to pseudoprogression rather than true tumor recurrence or progression.

This pilot study is the first study dedicated to fully describing the phenomenon of pseudoprogression and the post-treatment changes that occur with Gliadel wafer deposition. This increases the awareness of the radiologist not to potentially misdiagnose these post-treatment changes as true tumor recurrence or progression. However, a prospective study with a larger patient population is needed to confirm our preliminary results and to more precisely determine a time point where post-treatment changes vs tumor progression unmistakably diverge. Furthermore, unlike a retrospective study which might have potential biases regarding imaging times and particular sequences, a prospective study in which standardized imaging protocols and sequences are done can address these limitations and will be helpful to evaluate the role of the MR perfusion and diffusion in diagnosing pseudoprogression. This is expected to lead to a more accurate diagnosis early on during treatment.

In conclusion, pseudoprogression is common after intracavitary placement of Gliadel wafers and should not be automatically interpreted as tumor progression or recurrence within the first 2 mo.