Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Impact of ruptured cerebral aneurysm coiling and clipping on the incidence of cerebral vasospasm and clinical outcome.

BACKGROUND: This study assessed the impact of treatment modality of aneurysmal subarachnoid hemorrhage (aSAH) on the rate of vasospasm (VSP), mortality, and hospital length of stay (LOS) of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We analyzed patients with aSAH admitted between 1999 and 2005 undergoing either endovascular coiling (EC) or surgical clipping (SC) within 72 hours of onset. Clinical VSP was defined as neurological deficits unexplained by another etiology. Radiological VSP was defined based on transcranial Doppler (TCD) ultrasound, digital subtraction angiography (DSA), and CT criteria. Bivariate and logistic regression analysis was used to determine VSP predictors. RESULTS: Of 216 patients included, 98 (45%) underwent EC and 118 (55%) underwent SC. Clinical VSP was found in 26% of EC and 40% of SC patients (P < .03). TCD VSP, angiographic VSP, and CT infarctions were all significantly higher in the SC group. Mortality was similar in both groups however the LOS was longer in the SC patients (P= .03). Multivariate analysis showed that SC doubled the risk of clinical VSP (P < .03) and tripled the risk of composite VSP (P < .0006). CONCLUSIONS: Our study reveals that EC has a lower rate of VSP, shorter LOS, and comparable mortality to SC in aSAH.

Potential additional indicators for pacemaker requirement in isolated congenital atrioventricular block.

Low heart rate is the predominantly used indication for pacemaker intervention in patients with isolated congenital atrioventricular block (CAVB). The aim of this study was to compare the difference in heart rates recorded with ECG and Holter monitoring between paced (PM) and nonpaced (NPM) patients with isolated CAVB before pacemaker implantation to identify additional predictors for future PM need. Retrospective evaluation of atrial and ventricular rates (electrocardiography) and minimal and maximal (Holter) heart rates in 129 CAVB patients prior to PM implantation (n = 93) was performed, and results are expressed in V adjusted for age and sex. The average V score for the atrial rate was 0.51 (n = 50) in the PM group and 0.60 (n = 22) in the NPM group (not-significant). The average z score for the ventricular (average) rate was -0.91 (n = 83) in the PM group and -0.93 (n = 33) in the NPM group (not-significant). Minimal heart rate was -0.94 (n = 61) in the PM group and -0.86 (n = 25) in the NPM group (not significant). Maximal heart rate was -0.96 (n = 61) in the PM group and -0.95 (n = 26) in the NPM group (not significant). Initial recordings of the average heart rate and the minimal and maximal heart rate recorded during Holter monitoring do not seem to predict future pacemaker need in patients with CAVB. Studies with exercise stress tests are needed to confirm these findings.

Malignant peripheral nerve sheath tumor of the spine after radiation therapy for Hodgkin's lymphoma.

We report the development of a malignant peripheral nerve sheath tumor (MPNST) in 2 patients after irradiation for Hodgkin's lymphoma. Clinicians should be aware of this uncommon, but important fatal complication of radiation therapy. The first case is a 37-year-old man who was diagnosed with nodular sclerosing (NS) Hodgkin's lymphoma and underwent successful mantle radiation. He presented to our neurosurgery service with a left C6 radiculopathy 6 years later. The second case is a 30-year-old female diagnosed with NS Hodgkin's lymphoma. She did well with extensive radiotherapy until 5 years later when she developed severe right arm and chest pain secondary to recurrent lymphoma. After aggressive radio- and chemotherapy, she presented to the neurosurgery service with a right Horner's syndrome, right C6 radiculopathy, and weakness of her right triceps and wrist extensors. Both patients obtained magnetic resonance imaging revealing intradural extramedullary cervical nerve root associated mass lesions. Two years after radiation therapy for his Hodgkin's lymphoma, the first patient underwent a C6 laminectomy at an outside institution for resection of a benign neurofibroma. Four years later, he underwent a posterior C5-7 laminectomy with lateral mass plate fusion and partial excision of a recurrent mass diagnosed as a MPNST. The second patient underwent a C5-6 hemilaminectomy and partial resection of a tumor also pathologically consistent with MPNST. We present 2 case reports of patients who developed neurofibrosarcomatous tumors with malignant transformation after undergoing radiation therapy for Hodgkin's lymphoma. Despite prompt surgical resection, these tumors exhibited aggressive behavior. Numerous cases of soft tissue tumors have been described to arise in areas of prior radiation therapy; however, there have been rare reports of de novo MPNST after radiation therapy, especially in the setting of Hodgkin's lymphoma. Postirradiation MPNST should be considered in the differential diagnosis of a painful, enlarging mass in a previously irradiated area.

Predictors of outcome of myocarditis.

Heart failure from myocarditis may be transient or may progress to unremitting severe cardiac failure. This study was performed to determine the outcomes and prognostic features of pediatric patients with myocarditis. Patients with the diagnosis of myocarditis between 1990 and 2001 were identified through the coding system of Yale-New Haven Hospital. A total of 28 patients were included, with ages ranging from 1 day to 20 years. Before discharge, 11 patients developed unremitting severe cardiac failure. Of the remaining 17 patients, at the time of discharge 10 had normal systolic function and 7 had decreased systolic function. Unremitting cardiac failure developed in 9 of 14 patients (64%) with an ejection fraction < 30% and in only 2 of 14 (14%) of those with an ejection fraction > or = 30% on admission (p < 0.01). Furthermore, shortening fraction < 15%, left ventricular dilatation, and moderate to severe mitral regurgitation on admission as well as arrhythmia were significantly associated with development of unremitting severe cardiac failure. In this series of patients with myocarditis, by the time of discharge 39% of the patients had developed unremitting severe cardiac failure, 25% had depressed systolic function, and 36% had normal systolic function. Predictive factors at admission for poor outcome were ejection fraction < 30%, shortening fraction < 15%, left ventricular dilatation, and moderate to severe mitral regurgitation.

Ectopic cardiac calcification associated with hyperparathyroidism in a boy with hypophosphatemic rickets.

An adolescent with hypophosphatemic rickets developed cardiac calcifications in the absence of hypercalcemia or elevation of the phosphocalcic product (the product of the total serum calcium and phosphorus concentrations). Cardiac calcifications led to aortic and mitral valve dysfunction, myocardial calcification, and arrhythmia. Hyperparathyroidism probably played a significant role in the development of this complication, which emphasizes the necessity for intermittent assessment of parathyroid status in individuals receiving medical therapy for hypophosphatemic rickets.

Intractable epilepsy following radiosurgery for arteriovenous malformation.

Radiosurgery is often used to treat arteriovenous malformations (AVMs) located in deep brain locations. Most of these procedures are successful not only in obliterating the AVM but also in decreasing the frequency and severity of associated seizures. Although radiosurgery is occasionally associated with the development of easy-to-control seizures immediately postoperatively, there have been no reports of intractable epilepsy developing after radiosurgery. In this report, however, a case is presented in which a patient underwent gamma knife surgery (GKS) for an AVM, after which intractable epilepsy and mesial temporal sclerosis (MTS) gradually developed. A 37-year-old right-handed woman underwent GKS for a right mesial parietotemporooccipital AVM. One year later, the AVM had reduced in size, but the patient began to experience complex partial seizures (CPSs). These CPSs initially occurred at a frequency of one per month, but 6 months later they were occurring every other week. She also started having secondarily generalized tonic-clonic seizures (GTCSs) once per month. Over the next year the frequency of her seizures gradually increased to several CPSs per day and two to three GTCSs per week, despite treatment with various combinations of antiepileptic drugs. By this time her AVM had decreased to one half of its original size. Video-electroencephalography monitoring demonstrated that both the CPSs and GTCSs were arising from the right posterior quadrant. Magnetic resonance imaging revealed not only the presence of the right-sided AVM, but also right-sided MTS. The patient underwent surgical resection of the AVM and right temporal lobectomy. She has been free from seizure for longer than 1 year. Radiosurgery may be associated with intractable epilepsy and MTS.

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Lateralized seizure termination: relationship to outcome following anterior temporal lobectomy.

Determination of side of seizure onset is critical for a successful outcome following epilepsy surgery. Little is known about the significance of lateralized seizure termination. Sustained seizure activity contralateral to side of seizure onset, following termination of ictal activity ipsilateral to side of onset, may suggest the presence of an independent focus. Such activity, if present, should predict a poor outcome. We studied side of seizure termination in 13 patients undergoing monitoring with bitemporal depth electrodes and correlated this to outcome following anterior temporal lobectomy (ATL). Side of seizure onset was determined for all seizures during that evaluation. Based on side of final cessation of ictal activity, patients were classified as having ipsilateral final termination or simultaneous termination (Group 1; N=6) or contra-lateral or mixed final termination (Group 2; N=7). The Duke outcome classification system was used. At the end of 2 years follow-up, 6/6 patients in Group 1 and 3/7 patients in Group 2 were seizure free. We conclude that lateralized seizure termination during evaluation with depth electrodes may be useful in predicting outcome following ATL. Continued seizure activity contralateral to side of seizure onset (following termination of ictal activity ipsilateral to side of onset) predicts a poor outcome. This may indicate the presence of an independent seizure focus opposite to the side of surgery.

Three-dimensional computed tomographic cranial base measurements for improvement of surgical approaches to the petrous carotid artery and apex regions.

OBJECTIVE: The bony and vascular anatomic features in the region of the petrous apex can vary significantly. These variations affect the operative view obtained via extended subtemporal or anterior transpetrosal approaches to cranial base lesions for individual patients. The goal of this study was to evaluate three-dimensional computed tomography as a means of obtaining detailed preoperative anatomic information regarding bony and vascular landmarks and spatial relationships in the region of the petrous carotid artery and petrous apex. METHODS: We radiographically studied 15 patients (30 sides), using 0.8- to 1-mm-thick, reconstructed, computed tomographic images. Special attention was given to the course of the petrous carotid artery. RESULTS: The petrous carotid artery was located lateral to the trigeminal impression. The size of the petrous apex medial to the horizontal petrous carotid artery was observed to be variable. The width of bone from the trigeminal impression to the wall of the internal auditory canal averaged 9.6 mm (range, 5.2-16.1 mm). A variable amount of bone overlying the internal auditory canal (4.5 mm) was also present. Multiple other relationships among key landmarks were quantified. CONCLUSION: There is significant variability in the anatomic features of the petrous apex among patients. For each patient, detailed preoperative information regarding the amount of bone to be removed during a cranial base procedure can be obtained using three-dimensional computed tomography. This information may be critical for determination of the amount of extra exposure that can be achieved via an anterior petrosectomy for each patient.

Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.

Dilated cardiomyopathy in isolated congenital complete atrioventricular block: early and long-term risk in children.

OBJECTIVES: We sought to identify the risk factors predicting the development of dilated cardiomyopathy (DCM) in patients with isolated congenital complete atrioventricular block (CCAVB). BACKGROUND: Recently evidence has emerged that a subset of patients with CCAVB develop DCM. METHODS: This was a retrospective study of 149 patients with CCAVB who had heart size and left ventricular (LV) function assessed by echocardiography and chest radiography over a follow-up period of 10 +/- 7 years. RESULTS: Nine patients developed DCM at the age of 6.5 +/- 5 years. No definite cause could be identified. In these nine patients, CCAVB was diagnosed in eight at 23 +/- 2.3 weeks gestation and in one at birth. Maternal SSA/SSB antibodies were confirmed in seven of the nine patients. Pacemakers were implanted in eight patients in the first month and in one patient at five years of age. The initial left ventricular end-diastolic dimension (LVEDD) was in the 96th +/- 2.6 percentile and the cardiothoracic (CT) ratio was 64 +/- 3.8% in the nine patients who developed DCM, and differed significantly in patients with CCAVB (p < 0.005) who did not develop DCM. The LVEDD and CT ratio did not decrease in the patients with CCAVB and DCM, but decreased significantly in the patients with CCAVB without DCM (p < 0.001) once pacing was initiated. Two patients with DCM died within two months of diagnosis; one patient is neurologically compromised; two patients received a heart transplant; and four patients are listed for heart transplantation. CONCLUSIONS: Isolated CCAVB is associated with a long-term risk for the development of DCM. Risk factors may be SSA/SSB antibodies, increased heart size at initial evaluation and the absence of pacemaker-associated improvement.

Utility of three-dimensional computed tomographic angiography for assessment of relationships between the vertebrobasilar system and the cranial base.

OBJECTIVE: The optimal surgical exposure for basilar tip aneurysms is dictated by the relationship of the basilar bifurcation to the cranial base. This study was designed to evaluate three-dimensional computed tomographic angiography as a means of obtaining detailed anatomic information on the basilar artery and the surrounding cranial base in individual patients before surgery. METHODS: We studied 30 patients using three-dimensional computed tomographic angiographic reconstructions from 1-mm computed tomographic slices. Detailed anatomic measurements were performed to define the relationship between the basilar artery and the cranial base. Particular attention was paid to the height of the dorsum sellae and its relationship to the basilar bifurcation. RESULTS: The heights of the basilar apex and the vertebrobasilar junction, relative to the cranial base, were extremely variable. Considerable asymmetries in the heights of the left and right posterior clinoid processes were identified; in one case, this difference was more than 1 cm (mean difference in height, 0.9 mm; range, 0-10.3 mm). The heights of the posterior clinoid processes above the sellar floor ranged from 5.8 to 14.1 mm (mean height, 9.5 mm). We were able to determine the feasibility of the pterional/orbitozygomatic, middle fossa/ anterior petrosal, and presigmoid retrolabyrinthine approaches to an individual basilar bifurcation. We also estimated the amount of bone removal required and determined the operative distances via those approaches. CONCLUSION: Three-dimensional computed tomographic angiography is a useful tool for assessing critical anatomic relationships and represents an adjunct to conventional angiography in the planning of individualized, precisely tailored, cranial base approaches to the vertebrobasilar system.

Surgical approaches to pineal region tumors.

Direct surgical resection of pineal region tumors has become safer, more effective, and now plays an essential role in their management. Tissue diagnosis allows for the initiation of appropriate therapies and resection can be curative or improve the efficacy of adjuvant therapies. Several approaches have been reported. Based on our operative experience with 57 patients over a 20-year period, we conclude that the Infratentorial Supracerebellar and Parieto-Occipital Paramedian Transtentorial approaches provide excellent exposure while allowing minimally invasive, relatively low risk access to the majority of pineal region tumors. Indications, positioning, techniques, advantages, and disadvantages are discussed. A review of other approaches, pertinent historical remarks, and a discussion of the role of surgery in the contemporary management of pineal region tumors are presented.

Clinical Studies in Non-chromosome 4-Linked Facioscapulohumeral Muscular Dystrophy.

OBJECTIVES: To characterize clinically and molecularly a large, non-chromosome 4-linked facioscapulohumeral muscular dystrophy (FSHMD) family. METHODS: Neurological evaluations of affected (N = 55) and at-risk (N = 48) individuals were performed along with selected laboratory analyses, including creatine kinase testing, muscle biopsy, p13E-11 fragment analysis, and cytogenetic studies. Genetic analyses of the scapuloperoneal muscular dystrophy and scapuloperoneal muscular atrophy regions on chromosome 12 were performed using genetic markers flanking the intervals of interest and parametric LOD score analyses. RESULTS: Clinically, the FSHMD in individuals in this family is indistinguishable from that observed in chromosome 4-linked FSHMD. Fragment analysis with p13E-11 showed no small fragment segregating with the family and no evidence for 4:10 translocation or deletion of the p13E-11 binding site. Linkage analysis excluded the loci for autosomal-dominant scapuloperoneal muscular dystrophy and scapuloperoneal muscular atrophy. CONCLUSIONS: This family is clinically similar to patients with the chromosome 4-linked FSHMD. These data support our previous hypothesis of genetic heterogeneity within FSHMD.

Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats.

Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.