Growth rate of non-operated meningiomas.

INTRODUCTION: Meningiomas are dural-based brain tumors that are typically histologically benign. Some meningiomas grow slowly or seemingly not at all with planimetric measurement. Volumetric measurement may be more accurate because tumors may grow in different directions than the planimetric axes. METHODS: Twenty-one patients (with 22 tumors) had serial MRI brain scans available for review. We reviewed the charts and measured tumor dimensions on the MRI scans. Relative growth rates were calculated for volume and maximum initial diameter using published formulas. Patient demographics, tumor location, and special radiologic characteristics (calcification, T2 hypointensity, dural tail, mass effect, and midline shift) were compared to the volumetric growth rate. RESULTS: Patients included 17 females and 4 males; age at diagnosis 36 to 74 years (mean 61). Follow-up was 2.08 to 10.83 years (mean 3.64). Most tumors were located in the convexity (27.27 %), sphenoid wing (27.27 %), or cerebellopontine angle (13.04 %). Two meningiomas (9.09 %) demonstrated no growth. The mean relative volumetric growth rate was 5.82 %/year, and planimetric was 2.00 %/year (difference 3.82 %/year, p-value < 0.0001). Convexity location had near significant association with slower relative volumetric growth. There were no significant associations between other tumor locations, age, gender, or radiologic characteristics and volumetric growth. CONCLUSIONS: The mean volumetric growth rate was significantly greater than the planimetric growth rate, suggesting that volumetric measurement conveys more information and is superior in assessing tumor growth. This information could have clinical value in determining the frequency of follow-up imaging and the urgency of surgical intervention.

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Neoadjuvant procarbazine, CCNU, and vincristine for anaplastic and aggressive oligodendroglioma.

The authors reviewed the results of neoadjuvant (preradiation) procarbazine, CCNU, and vincristine chemotherapy for anaplastic oligodendrogliomas because, increasingly, chemotherapy is prescribed before radiation for oligodendroglial neoplasms. The data indicate that 70% of patients respond to neoadjuvant chemotherapy, whereas 30% require early radiation because they either have chemoresistant tumors or experience unacceptable chemotoxicity.

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

Meningiomas: the decision not to operate.

In a consecutive series of 100 patients diagnosed with meningiomas, we advised 12 patients not to have surgery, and followed them from 3.3 to 12.8 years (mean, 8.8 years). The two determinants of this decision were either absence of related neurologic symptoms or signs and concern about high operative risk of neurologic impairment. Serial imaging studies showed meningioma growth in only one of the 12 unoperated patients and only one had convincing progression of neurologic impairment.

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group.

Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.

External beam radiotherapy: hard facts and painful realities.

In comparison to whole brain radiotherapy, local field radiotherapy in a consecutive series of 100 patients with malignant astrocytoma resulted in remarkably less toxicity. Survivorship is not different; the advantage is limited to the 7% long term survivors (defined as living 100% or more beyond median) since toxicity from brain radiation does not occur until a year or more after treatment.

A new head holder for reducing axial movement and repositioning errors during physiological CT imaging.

OBJECTIVE: We designed a new head holder for immobilization and repositioning in dynamic CT studies of the brain. MATERIALS AND METHODS: A customized thermoplastic face mask and foam head rest were made to restrict movement of the head in all directions, but particularly out of the axial plane (z-movement). RESULTS: This design provided a rigid, detailed mold of the face and back of the head that minimized motion during lengthy CT studies and enabled accurate repositioning of the head for follow-up studies. Markers applied directly to the skin were used to quantify z-movement. CONCLUSION: When tested on 12 subjects, immobilization was limited to < 2.0 mm under worst-case conditions when the subject was asked to attempt forced movements. Repositioning was accurate to < 1.5 mm when the subject was removed from the head holder and then placed back into it.

Relative absence of neuropsychological deficit in patients with low grade astrocytomas.

Given the current accuracy and precision of modern brain imaging technology, there is presumed to be little utility in neuropsychological assessment procedures in patients with brain tumors. The primary exposure of many clinical neuropsychologists to patients with brain tumors is during their training, in the form of didactic classroom activities, such as reviewing the brain tumor cases of early investigators in the field. Historically, these brain tumors were the more aggressive and destructive tumors, such as grade III and IV astrocytomas, that could be identified with pre CT and pre MRI technology. With current imaging technology, low grade tumors that might previously have gone undiagnosed for years can be detected and patients followed over time. This series of cases represents documentation of the very unique neuropsychological status of patients with relatively slow growing, infiltrative brain tumors classified as grade II astrocytomas. The potential relevance of neuropsychological assessment for such cases is discussed.

Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma.

PURPOSE: We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy. Its purpose was to compare the efficacy of AZQ with that of BCNU, the standard agent for brain tumor chemotherapy. PATIENTS AND METHODS: Randomization between the two regimens occurred 8 weeks after completion of radiotherapy. A total of 251 patients were randomized to receive either AZQ or BCNU, and there were no significant differences between the two treatment arms in any of the known prognostic variables, including age, histologic grade, and Karnofsky performance status (KPS). RESULTS: There was no significant difference in either time to tumor progression or survival between the two treatment arms. Age and histology were strong predictors of outcome, whereas KPS had relatively less effect. Three groups of patients with distinctly different outcomes could be identified: (1) older age (45+) and glioblastoma/gliosarcoma (GBM/GS) patients had a median survival of 37 weeks after randomization; (2) patients with either older age or GBM/GS had a median survival of 61 weeks; and (3) younger age (< 45) and non-GBM/GS (usually anaplastic astrocytoma) patients had a median survival of 147 weeks. Toxicity was primarily hematologic, although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU. Patients randomized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction (P = .011 and .016, respectively). CONCLUSION: There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study, although AZQ was somewhat better tolerated.

Phase I study of BCNU and intravenous 6-mercaptopurine in patients with anaplastic gliomas.

On the basis of response rates of up to 50%, BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] is the primary drug used in the chemotherapy of anaplastic gliomas. Preclinical data obtained in several experimental systems show that the cytotoxicity of chloroethylnitrosoureas can be increased by the concomitant use of thiopurines. In this phase I trial, patients with anaplastic gliomas received standard-dose BCNU (200 mg/m2 x 1) in combination with escalating doses of intravenous 6-mercaptopurine (200, 350, 500, and 750 mg/m2 daily x 3), with BCNU being given on day 3 to maximize the effect of the drugs on cellular DNA. No increase in hematologic toxicity was demonstrated as the dose of 6-mercaptopurine was increased. Responses and stabilization of disease were observed in several patients. Due to the safety of and the evidence of activity found for this regimen in the present trial, 750 mg/m2 6-mercaptopurine has been incorporated into subsequent studies.

Influence of the type of surgery on the histologic diagnosis in patients with anaplastic gliomas.

Stereotactic biopsy of CNS tumors provides a small amount of tissue for pathologic diagnosis. This potentially leads to inaccurate grading of gliomas because of their histologic heterogeneity. We compared histologic diagnoses in a consecutive series of 329 patients with newly diagnosed anaplastic gliomas whose diagnoses were established by either stereotactic biopsy or open resection. Of 262 patients undergoing resection, 214 (82%) had glioblastomas and 48 (18%) had anaplastic astrocytomas (AAs). Of 67 patients undergoing stereotactic biopsy, 33 (49%) had glioblastomas and 34 (51%) had AAs. This difference suggests that some AAs diagnosed by stereotactic biopsy are actually glioblastomas and has important implications for the design and interpretation of clinical trials.

Quantitative measurements of capillary transport in human brain tumors by computed tomography.

The rate at which water-soluble chemotherapeutic drugs enter brain tumors can be extremely variable. The ability to measure or predict the rate of drug entry may have an important role in treatment. We have developed a method that uses information from contrast-enhanced computed tomographic scans to measure quantitatively the rate of transcapillary transport of iodinated compounds in brain tumors. In a group of 10 patients with brain tumors, we obtained serial measurements of tissue (Am) and arterial plasma (Cp) iodine concentration from timed computed tomographic scans done over 30 minutes, after intravenous infusion of meglumine iothalamate (Conray-60). These measurements were analyzed with a two-compartment pharmacokinetic model and nonlinear least-squares regression methods to obtain K1, a blood-to-tissue transfer constant; k2, a tissue-to-blood rate constant; and Vp, tissue plasma vascular volume. Images of K1, k2, and Vp were reconstructed after calculating these values for each 0.8 x 0.8 x 5-mm volume element of the original data. Mean whole tumor K1 values varied from 2.0 mu 1 gm-1 min-1 in a thalamic astrocytoma to 33.9 mu 1 gm-1 min-1 in a glioblastoma multiforme. The value of k2 varied from 0.034 to 0.108 min-1, and Vp varied from 2.4 to 7.9 ml 100 gm-1. In tumor-free brain, the K1 of meglumine iothalamate was 2.9 mu 1 gm-1 min-1; k2 was 0.058 min-1; and Vp was 2.1 ml 100 gm-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.

Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.

Effects of treatment on long-term survivors with malignant astrocytomas.

We reviewed the records of 160 consecutive patients with glioblastoma and anaplastic astrocytoma to evaluate the long-term consequences of radiation therapy and chemotherapy. We defined long-term survivors as those patients with glioblastoma or anaplastic astrocytoma who lived at least 100% longer than median survival of historical controls, for example, 2 years for patients with glioblastoma and 4 years for patients with anaplastic astrocytoma. There were 9 (5.6%) long-term survivors. Three (30%) became demented and died without evidence of tumor recurrence. One, after survival of 10 years, died of tumor recurrence. Of the remaining survivors, 2 (22%) have significantly impaired short-term memory function and other neurological deficits such as gait apraxia. Three (30%) can function independently. It is likely but cannot be proved that it is radiotherapy and not chemotherapy that is the causal factor of this dismal therapeutic outcome. Our study suggests restraint in the use of radiotherapy for patients with brain tumors that have more favorable prognoses than glioblastomas and anaplastic astrocytomas, such as low-grade astrocytomas and oligodendrogliomas.

Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma.

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.

Reoperation for malignant astrocytoma.

We evaluated 15 consecutive patients with malignant astrocytomas who were reoperated for functional status and survival. Their Karnovsky Performance Status (KPS) was not changed by surgery. None suffered perioperative death, wound infection, or complications. Patients with glioblastoma maintained KPS unchanged for a mean of 13 weeks (median, 10 weeks); with anaplastic astrocytoma, mean, 37.2 weeks (median, 24 weeks). Life spans were approximately twice that of non-reoperated historical controls. Reoperation for patients with recurrent malignant astrocytoma should be seriously considered when a gross total re-resection can be the goal in a patient whose tumor is in an accessible brain region.