Jeffrey S. Weinberg

Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure

OBJECT The authors report data concerning the safety, effectiveness, and patterns of failure obtained in a Phase I/II study of stereotactic body radiotherapy (SBRT) for spinal metastatic tumors. METHODS Sixty-three cancer patients underwent near-simultaneous computed tomography-guided SBRT. Spinal magnetic resonance imaging was conducted at baseline and at each follow-up visit. The National Cancer Institute Common Toxicity Criteria 2.0 assessments were used to evaluate toxicity. RESULTS The median tumor volume of 74 spinal metastatic lesions was 37.4 cm3 (range 1.6-358 cm3). No neuropathy or myelopathy was observed during a median follow-up period of 21.3 months (range 0.9-49.6 months). The actuarial 1-year tumor progression-free incidence was 84% for all tumors. Pattern-of-failure analysis showed two primary mechanisms of failure: 1) recurrence in the bone adjacent to the site of previous treatment, and 2) recurrence in the epidural space adjacent to the spinal cord. Grade 3 or 4 toxicities were limited to acute Grade 3 nausea, vomiting, and diarrhea (one case); Grade 3 dysphagia and trismus (one case); and Grade 3 noncardiac chest pain (one case). There was no subacute or late Grade 3 or 4 toxicity. CONCLUSIONS Analysis of the data obtained in the present study supports the safety and effectiveness of SBRT in cases of spinal metastatic cancer. The authors consider it prudent to routinely treat the pedicles and posterior elements using a wide bone margin posterior to the diseased vertebrae because of the possible direct extension into these structures. For patients without a history of radiotherapy, more liberal spinal cord dose constraints than those used in this study could be applied to help reduce failures in the epidural space.

Correlations between magnetic resonance spectroscopy and image-guided histopathology, with special attention to radiation necrosis.

OBJECTIVE The differentiation of tumor recurrence from radiation necrosis in patients with malignant gliomas who have been treated previously remains a challenge. Magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography cannot provide definitive histopathological insight. Multivoxel proton magnetic resonance spectroscopic imaging (1H MRSI) may be reliable in guiding the clinical management of untreated patients; however, its value in managing previously treated patients remains unclear. METHODS Twenty-seven patients who had been treated previously with surgery, radiotherapy, and chemotherapy and reoperated for clinical and/or radiographic signs that caused suspicion for recurrent disease were studied. Tissues were categorized into four groups: spectroscopically normal, pure tumor, mixed tumor and radiation necrosis, and pure radiation necrosis. Spectral data for choline (Cho), lipid-lactate (Lip-Lac), N-acetylaspartate, and creatine (Cr) were analyzed as Cho/normal Cr (nCr), Lip-Lac/Cho, Lip-Lac/nCr, N-acetylaspartate/Cho, N-acetylaspartate/nCr, and Cho/normal Cho (nCho). Stereotactic biopsies were obtained within 48 hours of 1H MRSI and were directly correlated digitally with 1H MRSI data. Logistic regression analysis was performed on the basis of data obtained from 99 1H MRSI observations to determine whether the 1H MRSI ratios varied according to tissue category. RESULTS 1H MRSI ratios were found to distinguish pure tumor from pure necrosis. The odds of a biopsy’s being pure tumor and having either a Cho/nCr value greater than 1.79 or a Lip-Lac/Cho value less than 0.75 are seven times the odds of that biopsy’s being pure necrosis (odds ratio, 7.00;P = 0.0136). The odds of a biopsy’s being pure necrosis and having either a Cho/nCr value less than 0.89 or a Cho/nCho value less than 0.66 are six times the odds of that biopsy’s being pure tumor (odds ratio, 5.71;P = 0.0329). The odds of a biopsy’s being pure necrosis and having either a Lip-Lac/Cho value greater than 1.36 or a Lip-Lac/nCr value greater than 2.84 are more than five times the odds of the biopsy’s being pure tumor (odds ratio, 5.25;P = 0.0322). In addition, although only marginally significant, Lip-Lac/Cho and Lip-Lac/nCr ratios distinguish pure tumor from pure necrosis. No values suggested that mixed specimens could be distinguished in a statistically significant way from either pure tumor or pure necrosis. CONCLUSION The data that we gathered suggest that metabolite ratios derived on the basis of 1H MRSI spectral patterns do allow reliable differential diagnostic statements to be made when the tissues are composed of either pure tumor or pure necrosis, but the spectral patterns are less definitive when tissues composed of varying degrees of mixed tumor and necrosis are examined.

Associations among Magnetic Resonance Spectroscopy, Apparent Diffusion Coefficients, and Image-guided Histopathology with Special Attention to Radiation Necrosis

OBJECTIVE:In patients with malignant glioma previously treated with surgery, radiation, and chemotherapy, clinical and radiographic signs of recurrent disease often require differentiation between radiation necrosis and recurrent tumor. Published work suggests that although magnetic resonance spectroscopy (MRS) can reliably differentiate pure tumor, pure necrosis, and spectroscopically normal tissues, it may not be particularly helpful because most patients have mixed histological findings comprised of necrosis and tumor. To improve our clinical ability to discriminate among these histological entities, we have analyzed MRS in conjunction with apparent diffusion coefficient (ADC) sequences derived from magnetic resonance imaging. METHODS:In 18 patients, spectroscopic and diffusion-weighted images were obtained before surgery for suspected recurrent neoplastic disease. Spectral data for pure tumor, pure necrosis, and mixed tumor and necrosis were derived from 65 spectroscopic observations in patients with previously treated gliomas (n = 16) and metastatic tumors (n = 2). Spectral data for choline (Cho), N-acetylaspartate (NAA), creatine (Cr), and lipid-lactate were analyzed separately and in conjunction with ADCs in all patients (15 observations of pure tumor, 33 observations of pure necrosis, and 13 observations of mixed tumor and necrosis). Histological specimens were obtained stereotactically at the time of surgery (<48 h after image acquisition) for recurrent disease and digitally co-registered with MRS data. RESULTS:ADC values for pure tumor, pure necrosis, and mixed tumor and necrosis were 1.30, 1.60, and 1.42, respectively. Cho/NAA less than 0.20, NAA/normal Cr greater than 1.56, and NAA/Cho greater than 1.32 increase the odds that a tissue biopsy will be pure necrosis versus mixed tumor and necrosis. Although various values of all MRS ratios analyzed may provide positive correlations for histopathological differentiation of tissue between that of pure tumor and that of pure necrosis, the addition of ADC values to only NAA/Cho and NAA/normal Cr increases the odds of correct differentiation between pure tumor and pure necrosis. The addition of ADC values does not provide additional information beyond that of MRS in distinguishing specimens of mixed tumor and necrosis from either pure tumor or pure necrosis. CONCLUSION:It has been demonstrated that MRS ratio analysis may allow for the clinical discrimination between specimens of pure tumor and pure necrosis, and the addition of ADC data into this analysis may enhance this specific differentiation. However, although a trend toward correlation between ADC values and the various histopathological features was noted, the direct addition of ADC data does not seem to allow further discrimination, beyond that provided by MRS, among specimens of mixed tumor and necrosis and either pure tumor or pure necrosis.

Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: An emerging paradigm for achieving true stereotaxy

PURPOSE To report treatment setup data from an emerging technique using near-simultaneous computed tomography (CT) image-guided stereotactic radiotherapy for the treatment of spinal and paraspinal tumors. METHODS AND MATERIALS A targeting system that integrates a CT-on-rails scanner with a linear accelerator (LINAC) was evaluated in the lead-in portion of a Phase I/II protocol for treating patients with paraspinal metastases. Patients were immobilized in supine position by a moldable body cushion vacuum wrapped with a plastic fixation sheet. Planning CT and immediately repeated CT were performed on the LINAC/CT-on-rails unit to assess respiratory-related vertebral body motion. Coplanar intensity-modulated radiotherapy (IMRT) using 7-9 beams was used to deliver 30 Gy in five fractions to the target volume, while limiting the spinal cord dose to <10 Gy. Pretreatment CT scans were fused with the planning CT scans to determine the correct target isocenter by accounting for any translational and roll (axial) rotational discrepancies from the planning CT. (Corrections caused by yaw and pitch rotations have not yet been implemented.) The reproducibility of the treatment isocenter as compared with the planned isocenter was measured with digitally reconstructed radiographs (DRRs), portal film imaging, and immediate post-treatment verification CT scans. Phantom measurements were taken for dose verification for each IMRT plan. RESULTS Based on a total of 36 CT scans (3 for planning, 3 for respiration study, 15 pretreatment, and 15 post-treatment) from 3 patients, no respiration-associated vertebral body motion was seen. A comparison of the corrected daily anterior-posterior (AP) and lateral (LAT) digital portal images with the planning AP and LAT DRRs confirmed that the isocenter setup accuracy for the 15 treatments was within 1 mm of the planning isocenter. The results from the immediate post-treatment CT scans reconfirmed the findings from the portal images and verified the absence of spinal movement during the treatment. The ion-chamber measurement for the high-dose region was within 2% of the planning dose for three patient treatment plans. Film dose measurement in an IMRT quality assurance phantom demonstrated good agreement from 90% to 30% isodose lines between the planned and measured results. CONCLUSION Preliminary experience suggests that the near-simultaneous CT image-guided verification technique can be used as a new platform technology for extracranial applications of stereotactic radiotherapy and radiosurgery to spinal and paraspinal tumors.

Volumetric Assessment of Glioma Removal by Intraoperative High-field Magnetic Resonance Imaging

OBJECTIVE:To investigate the contribution of high-field intraoperative magnetic resonance imaging (iMRI) for further reduction of tumor volume in glioma surgery. METHODS:From April 2002 to June 2003, 182 neurosurgical procedures were performed with a 1.5-T magnetic resonance system. Among patients who underwent these procedures, 47 patients with gliomas (14 with World Health Organization Grade I or II glioma, and 33 with World Health Organization Grade III or IV glioma) who underwent craniotomy were investigated retrospectively. Completeness of tumor resection and volumetric analysis were assessed with intraoperative imaging data. RESULTS:Surgical procedures were influenced by iMRI in 36.2% of operations, and surgery was continued to remove residual tumor. Additional further resection significantly reduced the percentage of final tumor volume compared with first iMRI scan (6.9% ± 10.3% versus 21.4% ± 13.8%; P < 0.001). Percentages of final tumor volume also were significantly reduced in both low-grade (10.3% ± 11.5% versus 25.8% ± 16.3%; P < 0.05) and high-grade gliomas (5.4% ± 9.9% versus 19.5% ± 13.0%; P < 0.001). Complete resection was achieved finally in 36.2% of all patients (low-grade, 57.1%; high-grade, 27.3%). Among the 17 patients in whom complete tumor resection was achieved, 7 complete resections (41.2%) were attributable to further tumor removal after iMRI. We did not encounter unexpected events attributable to high-field iMRI, and standard neurosurgical equipment could be used safely. CONCLUSION:Despite extended resections, introduction of high-field iMRI in conjunction with functional navigation did not translate into an increased risk of postoperative deficits. The use of high-field iMRI increased radicality in glioma surgery without additional morbidity.

IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

BACKGROUND IDH1 gene mutations identify gliomas with a distinct molecular evolutionary origin. We sought to determine the impact of surgical resection on survival after controlling for IDH1 status in malignant astrocytomas-World Health Organization grade III anaplastic astrocytomas and grade IV glioblastoma. METHODS Clinical parameters including volumetric assessment of preoperative and postoperative MRI were recorded prospectively on 335 malignant astrocytoma patients: n = 128 anaplastic astrocytomas and n = 207 glioblastoma. IDH1 status was assessed by sequencing and immunohistochemistry. RESULTS IDH1 mutation was independently associated with complete resection of enhancing disease (93% complete resections among mutants vs 67% among wild-type, P < .001), indicating IDH1 mutant gliomas were more amenable to resection. The impact of residual tumor on survival differed between IDH1 wild-type and mutant tumors. Complete resection of enhancing disease among IDH1 wild-type tumors was associated with a median survival of 19.6 months versus 10.7 months for incomplete resection; however, no survival benefit was observed in association with further resection of nonenhancing disease (minimization of total tumor volume). In contrast, IDH1 mutants displayed an additional survival benefit associated with maximal resection of total tumor volume (median survival 9.75 y for >5 cc residual vs not reached for <5 cc, P = .025). CONCLUSIONS The survival benefit associated with surgical resection differs based on IDH1 genotype in malignant astrocytic gliomas. Therapeutic benefit from maximal surgical resection, including both enhancing and nonenhancing tumor, may contribute to the better prognosis observed in the IDH1 mutant subgroup. Thus, individualized surgical strategies for malignant astrocytoma may be considered based on IDH1 status.

Spinal cord ependymoma: Radical surgical resection and outcome

OBJECTIVE Several authors have noted increased neurological deficits and worsening dysesthesia in the postoperative period in patients with spinal cord ependymoma. We describe the neurological progression and pain evolution of these patients over the 1-year period after surgery. In addition, our favored method of en bloc tumor resection is illustrated, and the rate of complications, recurrence, and survival in this group of patients is addressed. METHODS We operated on 26 patients (12 male and 14 female) with low-grade spinal cord ependymomas between 1975 and 2001. The median age at diagnosis was 42 years. Tumors extended into the cervical cord in 13 patients, the thoracic cord in 7 patients, and the conus medullaris in 6 patients. Eleven patients had previous surgery and/or radiation therapy. RESULTS We achieved a gross total resection in 88% of patients, whereas 8% had a subtotal resection and 4% had a biopsy. Only 1 patient developed a recurrence over a mean follow-up period of 31 months. CONCLUSION We conclude that radical surgical resection of spinal cord ependymomas can be safely achieved in the majority of patients. A trend toward neurological improvement from a postoperative deficit can be expected between 1 and 3 months after surgery and continues up to 1 year. Postoperative dysesthesias begin to improve within 1 month of surgery and are significantly better by 1 year after surgery. The best predictor of outcome is the preoperative neurological status.

Impact of intraoperative high-field magnetic resonance imaging guidance on glioma surgery: a prospective volumetric analysis.

OBJECTIVETo determine the impact of intraoperative magnetic resonance imaging (iMRI) on the decision to proceed with additional glioma resection during surgery and to maximize extent of resection (EOR). METHODSPatients who underwent craniotomy for glioma resection with high-field iMRI guidance were prospectively evaluated between September 2006 and August 2007. Volumetric analysis and EOR were assessed with iMRI, using postcontrast T1-weighted images for tumors showing contrast enhancement and T2-weighted images for nonenhancing tumors. RESULTSForty-six patients underwent resection using iMRI guidance, with iMRI being used to evaluate the EOR in 44 patients and for reregistration in 2 patients. Surgery was terminated after iMRI in 23 patients (52%) because gross total resection was achieved or because of residual tumor infiltration in an eloquent brain region. Twenty-one patients (47%) underwent additional resection of residual tumor after iMRI. For enhancing gliomas, the median EOR increased significantly from 84% (range, 59%–97%) to 99% (range, 85%–100%) with additional tumor removal after iMRI (P < 0.001). For nonenhancing gliomas, the median EOR increased (from 63% to 80%) with additional tumor removal after iMRI, but not significantly, owing to the small sample size (7 patients). Overall, the EOR increased from 76% (range, 35%–97%) to 96% (range, 48%–100%) (P < 0.001). Gross total resection was achieved after additional tumor removal after iMRI in 15 of 21 patients (71%). Overall, 29 patients (65%) experienced gross total resection, and in 15 (52%), this was achieved with the contribution of iMRI. CONCLUSIONHigh-field iMRI is a safe and reliable technique, and its use optimizes the extent of glioma resection.

Awake craniotomy for brain tumors near eloquent cortex: Correlation of intraoperative cortical mapping with neurological outcomes in 309 consecutive patients

OBJECTIVEIntraoperative localization of cortical areas for motor and language function has been advocated to minimize postoperative neurological deficits. We report herein the results of a retrospective study of cortical mapping and subsequent clinical outcomes in a large series of patients. METHODSPatients with intracerebral tumors near and/or within eloquent cortices (n = 309) were clinically evaluated before surgery, immediately after, and 1 month and 3 months after surgery. Craniotomy was tailored to encompass tumor plus adjacent areas presumed to contain eloquent cortex. Intraoperative cortical stimulation for language, motor, and/or sensory function was performed in all patients to safely maximize surgical resection. RESULTSA gross total resection (≥95%) was obtained in 64%, and a resection of 85% or more was obtained in 77% of the procedures. Eloquent areas were identified in 65% of cases, and in that group, worsened neurological deficits were observed in 21% of patients, whereas only 9% with negative mapping sustained such deficits (P < 0.01). Intraoperative neurological deficits occurred in 64 patients (21%); of these, 25 (39%) experienced worsened neurological outcome at 1 month, whereas only 27 of 245 patients (11%) without intraoperative changes had such outcomes (P < 0.001). At 1 month, 83% overall showed improved or stable neurological status, whereas 17% had new or worse deficits; however, at 3 months, 7% of patients had a persistent neurological deficit. Extent of resection less than 95% also predicted worsening of neurological status (P < 0.025). CONCLUSIONNegative mapping of eloquent areas provides a safe margin for surgical resection with a low incidence of neurological deficits. However, identification of eloquent areas not only failed to eliminate but rather increased the risk of postoperative deficits, likely indicating close proximity of functional cortex to tumor.

Brain Metastases in Patients with Ovarian Carcinoma: Prognostic Factors and Outcome

Between January 1975 and April 2001, 8,225 patients with ovarian cancer were seen at The University of Texas M. D. Anderson Cancer Center. Brain metastases developed in 72 of these patients (0.9%). The medical records of these patients were reviewed to assess the incidence of these metastases and their correlates of survival, as well as to describe the various treatment modalities used against them and their respective outcomes. The mean age of patients at the time of brain metastasis diagnosis was 53.7 years. The median interval between the diagnosis of the primary cancer and brain metastasis was 1.84 years. Neurological deficit, headache, and seizure were the most common symptoms. The brain was the only site of metastasis in 43% of patients. Multiple metastases were seen in 65% of them, although this may be a slight underestimate, as brain metastases in 17% of patients were evaluated prior to the magnetic resonance imaging era. The median survival time after the diagnosis of brain metastases was 6.27 months (95% CI, 4.48–8.06 months). The combination of surgical resection and whole-brain radiation therapy (WBRT) resulted in a longer survival time (median, 23.07 months) than did WBRT alone (median, 5.33 months) or surgery alone (median, 6.90 months) (p < 0.01 in both instances, multivariate Cox proportional hazards model analysis). The prognosis for patients with brain metastases from ovarian cancer appears to be poor. The existence of systemic dissemination at the time of brain metastasis was associated with a worse survival trend. The only significant predictor of survival in our series was the treatment modality. In particular, the resection of brain metastasis from ovarian cancer followed by WBRT appeared to be superior to resection alone or WBRT alone.