Isolated diffusion restriction precedes the development of enhancing tumor in a subset of patients with glioblastoma.

BACKGROUND AND PURPOSE: Most response criteria for patients with glioblastoma rely on increases in the contrast enhancing abnormality to determine tumor progression. Our aim was to determine retrospectively in patients with glioblastoma whether diffusion restriction can predict the development of new enhancing mass lesions. MATERIALS AND METHODS: We reviewed the brain MR imaging scans (including DWI and ADC maps) of 208 patients with glioblastoma. Patients with restricted diffusion in or adjacent to the tumor were identified, with further analysis only performed on those patients with low-ADC lesions without enhancement. These patients were followed to determine if new concordant enhancement developed at the site of the low-ADC lesion. A Wilcoxon signed rank test, competing risk analysis, and Kaplan-Meier curves were used to compare the mean drop in ADC values, assess enhancement-free survival, and determine overall survival, respectively. RESULTS: In 67 of the 208 patients (32.2%), visibly detectable restricted diffusion was seen during treatment. The study cohort was formed by the 27 patients with low-ADC lesions and no corresponding enhancement. Twenty-three (85.2%) patients developed gadolinium-enhancing tumor at the site of restricted diffusion a median of 3.0 months later (95% CI, 2.6-4.1 months). The mean decrease in ADC was 22.9% from baseline (P < .001). The 3-month enhancement-free survival probability was 0.481 (95% CI, 0.288-0.675). The 12-month overall survival probability was 0.521 (95% CI, 0.345-0.788). Restricted diffusion predicted enhancement regardless of antiangiogenic therapy with bevacizumab. CONCLUSIONS: In a subset of patients with glioblastoma, development of a new focus of restricted diffusion during treatment may precede the development of new enhancing tumor.

Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma.

BACKGROUND: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. METHODS: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease. RESULTS: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. CONCLUSIONS: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control.

Use of MR spectroscopy and functional imaging in the treatment planning of gliomas.

Routine anatomical imaging with CT and MRI does not reliably indicate the true extent or the most malignant areas of gliomas and cannot identify the functionally critical parts of the brain. The aim of the study was to see if the use of MR spectroscopic imaging (MRSI) along with functional MRI (fMRI) can better define both the target and the critical structures to be avoided to improve radiation delivery in gliomas. 12 patients with gliomas underwent multivoxel MRS and functional imaging using GE processing software. The choline to creatine ratio (Cho:Cr), which represents the degree of abnormality for each individual voxel on MRSI, was derived, converted into a grayscale grading system, fused to the MRI images and then transferred to the planning CT images. An intensity-modulated radiation therapy (IMRT) plan was developed using the dose constraints based on both the anatomical and the functionally critical regions. Cho:Cr consistently identified the gross tumour volume (GTV) within the microscopic disease (clinical target volume, CTV) and allowed dose painting using IMRT. No correlation between MRSI based Cho:Cr > or =2 and MR defined CTV nor their location was noted. However, MRSI defined Cho:Cr > or =3 was smaller by 40% compared with post-contrast T1 weighted MRI defined GTV volumes. fMRI helped in optimizing the orientation of the beams. In conclusion, both MRSI and fMRI provide additional information to conventional imaging that may guide dose painting in treatment planning of gliomas. A Phase I IMRT dose intensification trial in gliomas using this information is planned.

Internal auditory canal involvement of acoustic neuromas: surgical correlates to magnetic resonance imaging findings.

OBJECTIVE: Factors that play a role in the selection of surgical approach for acoustic neuromas include patient health and age, size of tumor, hearing status, and location of tumor in the internal auditory canal (IAC) and the cerebellopontine angle. Deep extension into the IAC makes hearing preservation extremely difficult when a retrosigmoid craniotomy is used, and the best approach is a middle fossa subtemporal route. Modern gadolinium-enhanced magnetic resonance imaging (MRI) can be inaccurate in identifying the presence of tumor laterally in the IAC. This may affect the selection of a surgical approach. STUDY DESIGN: This study was a retrospective case review. SETTING: Patients were accrued from a tertiary referral otologic practice. PATIENTS: From 1997 through 2000, the authors identified six patients who had undergone acoustic neuroma surgery, had adequate imaging and intraoperative data, and demonstrated a lack of correlation between MRI and intraoperative findings of the lateral IAC. INTERVENTION: The interventions were preoperative MRI of the IAC and surgical resection of an acoustic neuroma. MAIN OUTCOME MEASURE: Comparison of MRI and intraoperative findings of the lateral IAC were the main outcome measures. RESULTS: Six patients demonstrated a lack of correlation between MRI and intraoperative findings of the lateral IAC. CONCLUSIONS: Gadolinium-enhanced T1-weighted MRI findings of the depth of penetration into the lateral aspect of the IAC do not always correlate with intraoperative findings and thus may have implications in the selection of surgical approaches to acoustic neuromas.

Posterior petrous face meningiomas.

OBJECTIVE: To define the clinical presentation, treatment options, and outcomes for a subset of meningiomas of the posterior fossa skull base that arise from the posterior petrous face between the region of the porus acousticus and the sigmoid sinus. STUDY DESIGN AND SETTING: A retrospective chart review from a large skull base surgery practice at a tertiary care institution. RESULTS: This cohort of patients presented with minimal symptoms, yet large tumors, averaging 3.8 cms and causing significant cerebellar compression. Retrosigmoid craniotomies afforded excellent exposure. CONCLUSION AND SIGNIFICANCE: Patients with large tumors emanating from the posterior fossa aspect of the temporal bone should be evaluated on the basis of their site of origin. Patients with tumors emanating from the anterior or ventral portion of the temporal bone have greater symptoms and greater operative complications than those emanating from the posterior petrous face, between the porus acousticus and sigmoid sinus.

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme.

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.

Endoscopic biopsy for tumors of the third ventricle.

Twelve patients underwent endoscopic biopsy of a tumor involving the third ventricle. Nine patients had no significant medical history while 3 had a history of cancer. Unique characteristics of each case dictated the optimal surgical technique. Endoscopic tumor biopsy was combined with additional procedures in 9 cases; shunt insertion (3), shunt insertion with endoscopic septostomy (5), and transcallosal craniotomy (1). Diagnosis was established in 11 patients (92%); 6 primary brain tumors, 3 metastatic central nervous system tumors, 1 metastatic systemic cancer, and 1 region of post-treatment gliosis. One case was aborted due to poor visualization. Therapy was directly influenced by endoscopic biopsy in 11/12 cases (92%) and craniotomy for tumor resection was avoided in 10/12 patients (83%). Of the 5 patients who underwent endoscopic septostomy, 4 required no subsequent procedures for hydrocephalus. There were no complications, and hospital stay averaged 1.78 days for patients who underwent successful endoscopic biopsy. Tumors of the third ventricle are amenable to endoscopic biopsy with excellent diagnostic yield and low morbidity. The procedure must be tailored depending upon the tumor location within the third ventricle, the degree of ventriculomegaly, and the need to perform a septostomy. Singularly or combined with other endoscopic procedures, patients can be spared multiple and more invasive surgical procedures.

An integrated functional magnetic resonance imaging procedure for preoperative mapping of cortical areas associated with tactile, motor, language, and visual functions.

OBJECTIVE: To evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions. METHODS: Sensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6). RESULTS: For healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke's area, and 93% for the putative Broca's area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke's area, and 77% for the putative Broca's area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results. CONCLUSION: This integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

Ommaya reservoirs for the treatment of leptomeningeal metastases.

OBJECTIVE: Ommaya reservoirs are frequently used to deliver intraventricular chemotherapy in cancer patients with leptomeningeal metastases. We review techniques of catheter placement and complication avoidance. METHODS: Between January 1995 and June 1998, Ommaya reservoirs were placed in 107 patients for the treatment or prophylaxis of leptomeningeal metastases at the Memorial Sloan-Kettering Cancer Center. Patients with slit ventricles (total, 25) underwent preoperative pneumoencephalography for ventricular dilation. Intraoperative fluoroscopic guidance was used in 77 patients to confirm the catheter tip position at the foramen of Monro. Other intraoperative aids included endoscopy in 21 patients, ultrasound in 7, and stereotaxy in 6. No aids were used in 3 patients, more than one aid was used in 9, and the technique could not be determined retrospectively in 3. RESULTS: The median survival of patients treated for leptomeningeal metastases was 9 months (Kaplan-Meier method). Eight patients developed hydrocephalus requiring conversion of the Ommaya reservoir to a ventriculoperitoneal shunt and precluding delivery of chemotherapeutic agents. An additional 11 patients referred for Ommaya reservoir placement demonstrated elevated intracranial pressure requiring an initial ventriculoperitoneal shunt. Complications of Ommaya reservoir placement occurred in 10 patients (9.3%) and included two infections, five catheter malpositions, and three intracranial hemorrhages. Two deaths occurred secondary to intracranial hemorrhage: one after postoperative anticoagulation for a mechanical heart valve, and one attributed to treatment-related thrombocytopenia. Nine patients (8.4%) had treatment-related imaging abnormalities; seven were asymptomatic and two developed symptomatic leukoencephalopathy. CONCLUSION: Complications associated with Ommaya reservoirs can be minimized by intraoperative confirmation of the catheter position with fluoroscopic guidance and/or endoscopy. We recommend postoperative computed tomographic scans before initiation of intraventricular chemotherapy. Patients with elevated intracranial pressure may require shunting procedures in lieu of Ommaya reservoir placement.

Intergeneric poliovirus recombinants for the treatment of malignant glioma.

Poliovirus neuropathogenicity depends on sequences within the 5' nontranslated region of the virus. Exchange of the poliovirus internal ribosomal entry site with its counterpart from human rhinovirus type 2 resulted in attenuation of neurovirulence in primates. Despite deficient virus propagation in cells of neuronal origin, nonpathogenic polio recombinants retain excellent growth characteristics in cell lines derived from glial neoplasms. Susceptibility of malignant glioma cells to poliovirus may be mediated by expression of a poliovirus receptor, CD155, in glial neoplasms. Intergeneric polio recombinants with heterologous internal ribosomal entry site elements unfolded strong oncolytic potential against experimentally induced gliomas in athymic mice. Our observations suggest that highly attenuated poliovirus recombinants may have applicability as biotherapeutic antineoplastic agents.

Radiosurgery for malignant meningioma: results in 22 patients.

OBJECT: The initial treatment of malignant meningiomas in the past has included surgical removal followed by fractionated external-beam radiotherapy. Radiosurgery has been added to the options for treatment of primary or recurrent tumors over the last 10 years. The authors report their results of using gamma knife radiosurgery (GKS) to treat 22 patients over an 8-year period. METHODS: Twenty-two patients who underwent GKS for malignant meningioma between December 1991 and May 1999 were evaluated. Three patients were treated with GKS as a boost to radiotherapy and 19 for recurrence following radiotherapy. Outcome factors including patient survival, freedom from progression, and complications were analyzed. In addition, in the recurrent group, variables such as patient age, sex, tumor location, target volume, margin dose, and maximum dose were also analyzed. Univariate and multivariate analyses were performed. Overall 5-year survival and progression-free survival estimates were 40% and 26%, respectively. Age (p < or = 0.003) and tumor volume (p < or = 0.05) were significant predictors of time to progression and survival in both univariate and multivariate analyses. Five patients (23%) developed radiation necrosis. Significant relationships between complications and treatment variables or patient characteristics could not be established. CONCLUSIONS: Tumor control following GKS is greater in patients with smaller-sized tumors (< 8 cm3) and in younger patients. Gamma knife radiosurgery can be performed to treat malignant meningioma with acceptable toxicity. The efficacy of GKS relative to other therapies for recurrent malignant meningioma as well as the value of GKS as a boost to radiotherapy will require further evaluation.

Radiosurgery for brain metastases: is whole brain radiotherapy necessary?

PURPOSE: Because whole brain radiotherapy (WBRT) may cause dementia in long-term survivors, selected patients with brain metastases may benefit from initial treatment with radiosurgery (RS) alone reserving WBRT for salvage as needed. We reviewed results of RS +/- WBRT in patients with newly diagnosed brain metastasis to provide background for a prospective trial. METHODS AND MATERIALS: Patients with single or multiple brain metastases managed initially with RS alone vs. RS + WBRT (62 vs. 43 patients) from 1991 through February 1997 were retrospectively reviewed. The use of upfront WBRT depended on physician preference and referral patterns. Survival, freedom from progression (FFP) endpoints, and brain control allowing for successful salvage therapy were measured from the date of diagnosis of brain metastases. Actuarial curves were estimated using the Kaplan-Meier method. Analyses to adjust for known prognostic factors were performed using the Cox proportional hazards model (CPHM) stratified by primary site. RESULTS: Survival and local FFP were the same for RS alone vs. RS + WBRT (median survival 11.3 vs. 11.1 months and 1-year local FFP by patient 71% vs. 79%, respectively). Brain FFP (scoring new metastases and/or local failure) was significantly worse for RS alone vs. RS + WBRT (28% vs. 69% at 1 year; CPHM adjustedp = 0.03 and hazard ratio = 0.476). However, brain control allowing for successful salvage of a first failure was not significantly different for RS alone vs. RS + WBRT (62% vs. 73% at 1 year; CPHM adjusted p = 0.56). CONCLUSIONS: The omission of WBRT in the initial management of patients treated with RS for up to 4 brain metastases does not appear to compromise survival or intracranial control allowing for salvage therapy as indicated. A randomized trial of RS vs. RS + WBRT is needed to assess survival, quality of life, and cost in good-prognosis patients with newly diagnosed brain metastases.

Concordance between functional magnetic resonance imaging and intraoperative language mapping.

Although the correspondence between functional-magnetic resonance imaging (fMRI) representations of the sensorimotor cortex and intraoperative electrophysiology (including somatosensory evoked potential, SSEP, recordings and direct cortical stimulation) has been reported, a similar correspondence between fMRI and intraoperative localization of the language-sensitive cortex is not as well established. The aim of the present study was to evaluate the concordance between fMRI and intraoperative electrophysiology with respect to the localization of the language-sensitive and sensorimotor cortices. We present the results of 21 patients who underwent language and sensorimotor mapping by fMRI and intraoperative electrophysiology including SSEP recordings (n = 21), direct cortical stimulation of motor cortex (n = 15) and direct cortical stimulation of Broca's and Wernicke's area (n = 5). When responses were obtained with both methods, localization of function concurred in all cases. These observations suggest that fMRI represents a reliable preoperative tool for the identification of language-sensitive areas.

Survival and functional status after resection of recurrent glioblastoma multiforme.

OBJECTIVE: To determine the selection factors for and results of second resections performed to treat recurrent glioblastoma multiforme (GM), we studied 301 patients with GM who were treated from the time of diagnosis using two prospective clinical protocols. METHODS: The patients were prospectively followed from the time of diagnosis, using clinical and radiographic criteria after maximal surgical resection and external beam radiotherapy with or without adjuvant chemotherapy. Resection of recurrent GM was performed at the recommendation of the treating clinicians. The results of the second resections were retrospectively reviewed and analyzed using multivariate logistic regression, Kaplan-Meier-Turnbull survival analysis, Cox regression, and propensity score stratification. RESULTS: Forty-six patients underwent second resections during the study period. The actuarial rate of the second resections was 15% of the patients 1 year after diagnosis and 31% 2 years after diagnosis. Younger age (P = 0.01) and more extensive initial resection (P = 0.02), but not Karnofsky Performance Scale (KPS) score at the time of diagnosis or recurrence, predicted a higher chance of selection for reoperation after initial tumor recurrence. Twenty-eight percent of the patients had improved KPS scores after undergoing reoperation, 49% were stable, and 23% had declines in KPS scores of 10 to 30 points. There was no operative mortality. After reoperation, 85% of the patients received chemotherapy, 11% received brachytherapy or underwent stereotactic radiosurgery, and 17% underwent third resections. The median survival period after reoperation was 36 weeks. Higher preoperative KPS scores predicted longer survival periods after reoperation (P = 0.03). Age and interval since diagnosis were not significant prognostic factors. The median high-quality survival period (KPS score, > or =70) was 18 weeks. The median survival period after first tumor progression was 23 weeks for 130 patients treated using the same protocols who did not undergo reoperations. Patients who did undergo reoperations experienced clinically and statistically significantly longer survival periods. However, this was determined to be partially because of selection bias. CONCLUSION: Survival after resection of recurrent GM remains poor despite advances in imaging, operative technique, and adjuvant therapies. High-quality survival after resection of recurrence to treat GM seems to have increased significantly since an earlier report from our institution.