Philip H. Gutin

Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarrazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

Data from Northern California Oncology Group protocol 6G61, which was closed in February 1983, were reanalyzed in December 1988. The protocol called for a randomized trial that compared the effects of following 60 Gy radiation/oral hydroxyurea treatment with either carmustine (BCNU) or the combination of procarbazine, lomustine (CCNU), and vincristine (PCV) for two histologic strata: glioblastoma multiforme and other anaplastic gliomas. PCV produced longer survival and time to tumor progression than BCNU for both histologic groups, although the difference was statistically significant only for the anaplastic gliomas. With PCV treatment, time to progression and survival doubled for anaplastic glioma patients in the 50th and 25th percentiles.

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.

Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

PURPOSE Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas. METHODS AND MATERIALS After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab. RESULTS Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%. DISCUSSION Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality

PURPOSE NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Radiation therapy in the treatment of partially resected meningiomas

To address the question of whether radiation therapy is beneficial in the management of partially resected meningiomas, we reviewed the records of all patients admitted to the University of California, San Francisco, between 1968 and 1978 who had a diagnosis of intracranial meningioma. The patients were divided into three groups: 51 patients had gross total resection and did not receive radiation therapy, 30 patients had subtotal resection and no radiation therapy, and 54 patients had subtotal resection followed by radiation therapy. The subtotal resection groups were similar in average age, male:female ratio, and tumor location, which allowed a valid comparison of the effects of irradiation. The recurrence rate in the total resection group was 4% (2 of 51 patients). Among patients in the subtotal resection groups, 60% of nonirradiated patients had a recurrence, compared with only 32% of the irradiated patients. The median time to recurrence was significantly longer in the irradiated group than in the nonirradiated group (125 vs. 66 months, P less than 0.05). There was no complication related to irradiation. These results provide convincing evidence that radiation therapy is beneficial in the treatment of partially resected meningiomas.

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Genetic Clues to Meningioma Meningiomas are the most common primary brain tumors in adults. Located within the layer of tissue covering the brain, these tumors are usually slow-growing and benign but can cause serious neurological complications. About half of these tumors have mutations in the neurofibromin 2 gene (NF2). To identify other genes that contribute to meningioma pathogenesis, Clark et al. (p. 1077, published online 24 January) performed genome sequence analysis on 300 tumors. Meningiomas fell into two general classes: benign tumors located at the skull base—which tend to harbor mutations in the TRAF7, KLF4, AKT1, and SMO genes—and higher-grade tumors located in the cerebral and cerebellar hemispheres harbor mutations in NF2. The mutational profiles of meningiomas, a common type of brain tumor, correlate with their anatomical location and clinical status. We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

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.

An Integrated Functional Magnetic Resonance Imaging Procedure for Preoperative Mapping of Cortical Areas Associated with Tactile, Motor, Language, and Visual Functions

OBJECTIVETo 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. METHODSSensitivity 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). RESULTSFor 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. CONCLUSIONThis 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.

Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group

PURPOSE Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG). PATIENTS AND METHODS Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion. RESULTS A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years. CONCLUSION CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.

Radiation injury to the nervous system

Part 1 Response of normal tissue to ionizing radiation: cellular and molecular targets in normal tissue radiation injury biochemical response of normal tissues to ionizing radiation early and late effects of radiation on normal tissues influence of fractionation on normal tissue tolerance influence of dose rate on normal tissue tolerance. Part 2 Tolerance of the nervous system to ionizing radiation - experimental results: central nervous system radiation injury in small and large animal models experimental central nervous system injury from fast neutrons and from implanted isotopes the pathology of central nervous system radiation injury. Part 3 Tolerance of the nervous system to ionzing radiation - clinical experience: diagnostic imaging of central nervous system radiation injury tolerance of the brain and spinal cord to conventional irradiation factors affecting radiation injury after interstitial brachytherapy for brain tumors treatment of radiation necrosis of the brain tolerance of the visual apparatus to conventional therapeutic irradiation radiation and the hypothalamic-pituitary axis changes in intellect associated with cranial radiation therapy injury to the central nervous system after high LET radiation drug/radiation interactions and central nervous system injury radiation injury to peripheral and cranial nerves. Part 4 Tolerance of the nervous system to ionizing radiation - related issues: the effects of heat on the nervous system prospects for radioprotection of the nervous system radiation-induced tumors of the nervous system.