Persistent Diffusion-Restricted Lesions in Bevacizumab-Treated Malignant Gliomas Are Associated with Improved Survival Compared with Matched Controls

Patient Selection

This retrospective study was granted a waiver of informed consent by our institutional review board, and all data collection was performed in compliance with Health Insurance Portability and Accountability Act regulations. Prospectively, 24 patients with malignant glioma who developed regions of well-demarcated high signal intensity on diffusion-weighted imaging that also corresponded to regions of reduced ADC values on surveillance imaging were identified by the senior author. Patients were screened for the diagnosis of malignant glioma (WHO grades III and IV), treatment with bevacizumab between January 2007 through August 2011, and a well-circumscribed lesion with restricted diffusion near the original tumor site that persisted for at least 2 months. Patients were required to be older than 18 years of age; have a history of surgical resection, temozolomide administration, and external beam radiation therapy; and have a baseline KPS ≥70 at diagnosis. Additional inclusion criteria were accurate reporting of recurrence status, absence of intracranial hemorrhage, and absence of clinical findings or observations of acute or subacute ischemia. Twenty cases were included in the study. As a control cohort, 60 patients with malignant glioma lacking conspicuous diffusion signal abnormality (both the well-circumscribed discrete lesions described above as well as any speckled diffuse pattern of diffusion restriction that can be seen in bevacizumab-treated patients) were collected from our neuro-oncology data base. Controls were matched by sex, age, treatment (bevacizumab), tumor grade, and tumor histology at the time of bevacizumab treatment.

MR Diffusion Image Acquisition and Postprocessing Image Analysis

Patients were imaged on either a 1.5T or 3T clinical MR imaging system, with 50% of patients undergoing all studies on a 1.5T system and 50% of patients undergoing ≤2 studies on a 3T scanner and the rest of the studies on a 1.5T scanner (Avanto or Sonata, Siemens, Erlangen, Germany; HDx or LX, GE Healthcare, Milwaukee, Wisconsin) or a 3T scanner (Verio or Trio; Siemens). Anatomic sequences were collected according to standard clinical protocols and included axial precontrast T1-weighted, T2-weighted fast spin-echo, and FLAIR T2-weighted images and Gd-DTPA–enhanced (Magnevist; Berlex, Wayne, New Jersey; 0.1 mmol/kg) axial T1-weighted images acquired after contrast injection. DWI was collected before contrast administration with TE/TR = 90–100/8000–10,000 ms, NEX = 1, section thickness = 3–5 mm with 0- to 1-mm intersection distance, matrix size = 128 × 128 (reconstructed images were zero-padded and interpolated to 256 × 256), and FOV = 24 cm by using a twice-refocused spin-echo–EPI preparation.¹⁶ ADC images were calculated from acquired DWIs with b = 1000 s/mm² and b = 0 s/mm² images.

Five patients had dynamic susceptibility perfusion imaging, performed following a preload dose (0.025 mmol/kg) of gadolinium contrast agent to diminish contrast leakage effects, followed by administration of a 3- to 5-mL/s bolus of Gd-DTPA at a dose of 10–20 mL (0.075 mmol/kg) followed by a 20-mL flush of isotonic saline by using a power injector. Parameters used included the following: TE ranging from 23 to 50 ms, TR ranging from 1250 to 1400 ms, flip angles ranging from 30° to 35°, 40–90 repetitions (temporal time points), section thickness ranging from 4 to 7 mm with intersection gap ranging from 0 to 1.5 mm, number of sections ranging from 6 to 20, and matrix size ranging from 80 × 96 to 128 × 128. Postprocessing data analysis was performed to determine standardized rCBV by using previously published methods¹⁷ and commercially available software (IB Neuro v2.0; Imaging Biometrics, Elm Grove, Wisconsin).

¹⁸F-FDOPA PET images were obtained for 7 patients as previously described.¹⁸ A high-resolution full-ring ECAT HR or ECAT HR+ PET scanner (CTI-Siemens, Knoxville, Tennessee) was used to acquire images, which contained either 47 contiguous transaxial sections with a section thickness of 3.4 mm (with the ECAT HR) or 63 contiguous transaxial sections with a section thickness of 2.4 mm (axial FOV of 15 cm with the ECAT HR+). After an intravenous injection of 3.5 mCi of ¹⁸F-FDOPA, images were acquired immediately with 30-minute emission and 5-minute transmission scans.

Manual regions of interest contouring DWI-hyperintense lesions were obtained by a single observer and verified by 2 independent observers. Mean ADC within the region of interest and volume of the region of interest were extracted on each follow-up time point by using the Analysis of Functional NeuroImages software package (http://afni.nimh.nih.gov/afni). A single 2-mm-diameter circular region of interest was used to sample within the region of diffusion abnormality, and the minimum mean ADC value was recorded for all scan dates for each patient. For advanced imaging studies, color-coded rCBV perfusion maps, and ¹⁸F-FDOPA PET scans were registered and compared with a b = 1000 s/mm² DWI obtained within 2 weeks of rCBV or ¹⁸F-FDOPA PET image acquisition.

Statistical Analysis

An unpaired Student t test was used to compare the mean ADC values across tumor grades. Linear regression was performed to define the trends in change in mean ADC values with time, and nonlinear regression was performed to define trends in the change in lesion volume with time. The comparison of the change in mean ADC with time and the change in the volume of restricted diffusion with time with survival outcomes was analyzed by using Kaplan-Meier analysis with a logrank test and Cox hazard models. Survival analysis comparing outcomes including TTP and TTS and OS from the initial diagnosis was performed to compare patients with controls.