Gene therapy for malignant gliomas

Malignant gliomas are attractive targets for gene therapy because of their relatively well-localized distribution. Several new strategies have been devised that target different aspects of glioma biology. Gene transfer can be used to synthesize chemotherapy drugs that block DNA synthesis within these highly mitotic tumors. New genes can be introduced that restore the functions of mutated tumor suppressor genes or block the molecular pathways needed for tumor angiogenesis. Alternatively, the immune response to these tumors can be augmented by the local production of cytokines. Finally, viruses themselves can be used as tumoricidal agents by designing viruses that selectively replicate and destroy tumor cells. The advantages and limitations of these approaches are discussed in the context of their possible application to the treatment of these highly lethal malignancies.     

Prognostic factors in malignant gliomas

The most important prognostic factor in malignant gliomas is histopathological diagnosis of the tumor. The survival of patients with anaplastic astrocytoma is much longer than that of patients with glioblastoma. The median survival of the former has been improved up to almost 4 years by the recent progress of multidisciplinary treatment, whereas that of the latter has still remained in less than 1.5 years. Other important factors proved to be associated with survival of patients with malignant gliomas are the age of patients, Karnofsky performance status on admission, surgery, radiotherapy and chemotherapy. There is substantial evidence suggesting an association between younger patient age and longer survival in adults with supratentorial anaplastic astrocytoma as well as glioblastoma. It is also consistent with evidence that the patients with better performance status on admission live longer after treatment. Gross total resection of supratentorial anaplastic astrocytoma is directly associated with longer and better survival when compared to subtotal or partial resection. For glioblastoma, however, gross total resection has not been proved to have a significant survival advantage over subtotal or partial removal. Radiotherapy has been proved to be associated with longer survival of patients with supratentorial anaplastic astrocytoma and glioblastoma. Chemotherapy has not proved effective in prolonging the survival of patients with glioblastoma. Multidrug chemotherapy with CCNU, procarbazine and vincristine has proved to have significant survival advantage over BCNU alone, suggesting chemotherapy is also a prognostic factor in patients with anaplastic astrocytoma.     

Stereotactic radiosurgery for recurrent malignant gliomas

PURPOSE: To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS: We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS: The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION: Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.     

Chemotherapy and immunotherapy in adult malignant gliomas

This review summarizes papers published during 1991 and 1992. The poor results obtained in the postneurosurgical treatment of gliomas led researchers to pursue attempts to try to overcome glioma cell resistance. The intra-arterial route was explored in several phase II studies with new drugs and even immunoconjugates; rates of response between 30% to 60% were obtained. New drugs (fotemustine, eflornithine, and estramustine) or combined protocols planned to circumvent chemoresistance were tested and showed some efficiency with moderate toxicity, enlarging the number of drugs available against malignant gliomas. On the contrary, two retrospective analyses warned about the risk of reduction of median time to survival due to adjuvant chemotherapy in anaplastic astrocytomas; this finding, if confirmed, would suggest to defer chemotherapy at the time of recurrence in this type of glial tumor. Immunobiologic therapies as immunomodifiers, immunoconjugates, or cytotoxic lymphocyte-activated killer cells and tumor-infiltrating lymphocytes were tested and allowed some responses to be obtained. In young children, chemotherapy regimens were found to be efficient in malignant plexus choroid carcinomas and low-grade gliomas, allowing radiation therapy to be deferred. Many studies were methodologically unsatisfactory because of uncertain pathology grouping, noncompliance to initial protocols, or too small populations of patients.     

Treatment of malignant gliomas: a new approach

The etiology of seizures associated with cocaine use is unclear. Because cocaine seizures are relatively uncommon, they should be diagnosed by exclusion and a neurological workup to rule out central nervous system (CNS) catastrophe should be made. This report describes the clinical findings, treatment, and blood cocaine and metabolite concentrations in a patient who, on two separate occasions, had seizures associated with crack cocaine ingestion. Approximately 1 hour after the ingestion incidents, the patient had multiple, generalized seizures that abated spontaneously. His workup for CNS bleeding, infection, and trauma was negative. Cocaine concentrations on the first incident peaked at 2.48 mg/L and on the second incident peaked at 3.9 mg/L. Other clinical findings included tachycardia, hypertension, diaphoresis, and disorientation. Blood cocaine and metabolite analysis revealed extremely high concentrations. Other than the incident of seizures and transient cardiovascular aberrations, these high concentrations were tolerated by the patient without further sequelae. A review of cocaine-induced seizures and treatment is included.     

Role of surgery in the treatment of malignant gliomas

The mucicrin stimulating the hexosamine gastrointestinal secretion and extracted form porcine duodenum, was concentrated in the zone 7 using sephadex G 100. The molecular weight of 4000-5000 corresponds to this zone. An opposite activity was detected in zone 3. The factor from digestive mucous origin being able to diminish the hexosamine gastric secretion and not influencing the arterial pressure was called mucimitigin. The molecular weight of about 35000 corresponds to this factor.     

Cardiac malignant pheochromocytoma with bone metastases

A patient with malignant cardiac pheochromocytoma with bone metastases is described. The primary tumor was located between the pulmonary trunk and the left atrium, while metastatic lesions were found in the iliac bones. Treatments with antihypertensive agents, alpha-methylparatyrosine, and combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine partially improved the patient's symptoms, catecholamine levels, and the metastatic lesion of the iliac bones. However, the primary tumor in the heart progressively increased in size and the patient died of disseminated intravascular coagulation and other various complications about 4 years after the diagnosis of the disease.     

Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid

Malignant gliomas account for more than 60% of all primary brain tumors in adults. Adjuvant chemotherapy in addition to radical surgery and radiation therapy has provided only a modest increase in survival. Retinoic acid has been shown to have growth-inhibitory activity against glioma cells in culture. This provides the rationale for a Phase II study using 13-cis-retinoic acid (CRA) in patients with recurrent malignant brain tumors. The objective of this study was to determine the clinical activity of CRA in patients with a histologically proven diagnosis of malignant brain tumor and documented progressive or recurrent disease after radiation and chemotherapy. Fifty patients with documented recurrent disease were treated with CRA as a single agent p.o. at a dose of 60-100 mg/m2 per day. Three weeks of treatment were followed by 1 week of rest. Of the 43 patients who received more than 4 weeks of therapy, 3 (7%) achieved partial response, 7 (16%) achieved minor response, 13 (30%) remained stable, and 20 (47%) had disease progression. The median time from onset of treatment to disease progression for the whole group of 43 patients was 16 weeks (19 weeks for glioblastomas and 11 weeks for anaplastic glioma), whereas that for the 23 patients with partial response and minor response and who remained stable was 66 weeks, and that for the 20 patients with progressive disease was only 8 weeks. The median survival time for glioblastoma was 58 weeks, and 34 weeks for anaplastic astrocytoma. Toxicity was mainly dermatological, with dry skin and cheilitis. These preliminary results suggest that 13-cis-retinoic acid is active against malignant gliomas and is very well tolerated.     

Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.     

Contrast-enhanced MR "magnetization transfer technique". Improved tumor contrast, delineation and visibility of intracranial malignant gliomas and metastases in radiosurgical treatment planning

AIMS: To improve tumor conspicuity and delineation on contrast-enhanced T1-weighted MR images with and without magnetization transfer (MT) contrast as a strategy to improve the macroscopic boost volume definition in the planning process of radiosurgery in patients with high grade gliomas or metastatic brain lesions. PATIENTS AND METHODS: Thirty-two patients (mean age 47 years) with histologically proven or suspected high grade glioma (n = 12) or metastatic brain lesions (n = 20) were prospectively examined by MR imaging. After the administration of gadolinium dimeglumine (0.1 mmol/kg body weight) the lesions were imaged with a T1-weighted MT-fast low angle shot (FLASH) pulse sequence and with a conventional T1-weighted SE sequence without MT saturation. RESULTS: The mean CNR of enhancing lesions on T1-weighted MT-FLASH was 15 +/- 5 compared to 11 +/- 4 on SE images, representing a significant (p < .01) improvement. The mean tumor diameter of malignant gliomas was significantly (p < .01) larger measured on T1-weighted MT-FLASH images compared to those obtained from T1-weighted SE images and were comparable for metastatic lesions. Lesion conspicuity and delineation were improved in 50% of patients with high grade gliomas and in 35% of patients with brain metastases. Lesion conspicuity was markedly improved in the posterior fossa. Additional contrast enhancing lesions were detected in 10% of patients with metastases on MT-FLASH images. CONCLUSIONS: It is concluded that contrast-enhanced MT-FLASH images may improve lesion detection and delineation in the planning process of radiosurgery in patients with intracranial high grade gliomas or metastases or even alter the treatment approach.     

Effect of brain edema on the recurrence pattern of malignant gliomas

PURPOSE: To assess the influence of initial preoperative brain edema in malignant gliomas on regrowth patterns. SUBJECTS AND METHODS: 79 patients with histologically verified supratentorial malignant glioma were prospectively studied by magnetic resonance imaging (MRI) before and every 2-3 months after surgery. The median follow-up time was 11 months. We correlated the configuration of the initial vasogenic edema on T2-weighted images with tumor regrowth patterns on contrast-enhanced T1-weighted images. RESULTS: 35/47 tumor regrowths (75%) imitated the initial edema configuration, while 11/47 occurred within the initial tumor bed; in one case tumor recurrence was multilocal. CONCLUSION: In glioblastoma, tumor regrowth patterns correlate positively with the configuration of the initial vasogenic brain edema. The initial, "presurgical" peritumoral edema should thus be considered when planning further treatment.     

Principles of treatment of malignant gliomas in adults: an overview

The cornerstone of conventional treatments of malignant gliomas in adults has been surgical debulking, radiation therapy and chemotherapy. Almost always a combination of these treatments is used. With these conventional treatments the outcome, as measured by survival and quality of life, has remained universally dismal. Novel treatments, which are at different stages of laboratory and clinical trials, may offer a ray of hope for treatment of malignant gliomas. Development of these methods are directly related to the discoveries, over the past two decades, of cellular and molecular mechanisms involved in the genesis of brain tumors. Understanding of the mechanisms of tumor genesis may open new avenues of effective treatments for this devastating cancer.     

Supratentorial malignant gliomas in childhood: a single institution perspective

BACKGROUND: A retrospective study evaluated the clinical characteristics, prognostic factors, and outcome of patients with newly diagnosed supratentorial malignant gliomas treated with preirradiation chemotherapy. METHODS: Of 41 patients with supratentorial malignant gliomas accrued between 1984-1994, all had neuroimaging documentation of the extent of resection and 37 had complete neuraxis staging prior to treatment; 80% were treated with one of a variety of neoadjuvant chemotherapy regimens. RESULTS: Thirteen patients had anaplastic astrocytoma (AA), 25 had glioblastoma multiforme (GBM), and 3 had anaplastic oligodendroglioma. Gross total resection (GTR) was performed in 10 patients, subtotal resection (STR) in 22 patients, and biopsy (Bx) alone in 9 patients. For the entire group the 3-year overall and progression free survivals were 35 +/- 8% and 18 +/- 6%, respectively. Tumor recurrence was dominantly local. However, 9 patients with initially local disease failed at a distant neuraxis site, giving a 26 +/- 7% actuarial risk of dissemination at 3 years. The only significant prognostic factor was extent of tumor resection: patients who underwent GTR survived longer than those who underwent STR or Bx (P = 0.004). Histology (GBM vs. AA), age, and the use of enhanced local dose radiation therapy (brachytherapy or stereotactic irradiation) did not affect survival. CONCLUSIONS: Neoadjuvant chemotherapy was not associated with a survival rate significantly different from that observed in adjuvant chemotherapy studies. Systematic neuraxis staging at diagnosis and recurrence revealed a rate of neuraxis dissemination as a component of recurrence that was higher than previously reported; the utility of craniospinal irradiation in preventing isolated dissemination remains uncertain.     

Correlation between dynamic MRI and outcome in patients with malignant gliomas

We assessed the correlation between dynamic MRI results and clinical outcomes in patients with malignant gliomas. Rapid serial MRIs were obtained after bolus injection of gadolinium that resulted in an initial fast uptake followed by a slow uptake of contrast. The maximum rate of uptake and delayed rate of uptake were correlated with survival and prognostic covariates such as age and histology. In 121 subjects, higher maximum uptake rates, 3.6 signal intensity units per second or greater, were associated with shorter survival (p = 0.0066). The correlation of delayed rate of uptake with survival was less significant. After adjusting for age, histology, and Karnofsky performance score, the maximum rate of uptake remained more significantly correlated with survival than the delayed rate of uptake. Thirty-one patients had surgery within 1 month of dynamic MRI, and those with glioblastoma multiforme or anaplastic gliomas had higher maximum rates of uptake than those with pure necrosis or mixed tumor and necrosis (p = 0.022). No correlation between delayed rate of uptake and histology was seen in this group of patients. Our results suggest that the maximum rate of uptake in dynamic MRI can be a prognostic measure for patients with malignant gliomas. Further prospective study is needed to assess the utility of this technique for evaluating brain tumors.     

Radiotherapy after hyperbaric oxygenation for malignant gliomas: a pilot study

The results of radiotherapy combined with hyperbaric oxygen in 9 patients with malignant glioma were compared with those of radiotherapy without hyperbaric O2 in 12 patients. This is the first report of a pilot study of irradiation immediately after exposure to hyperbaric O2 in humans. All patients receiving this treatment showed more than 50% regression of the tumor, and in 4 of them, the tumors disappeared completely. Only 4 out of 12 patients without hyperbaric O2 showed decreases in tumor size, and all 12 patients died within 36 months. So far, this new regimen seems to be a useful form of radiotherapy for malignant gliomas.     

Bilateral isolated metastases of malignant melanoma to the cerebellopontine angle

PURPOSE: Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, not the time to Cmax (Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to Cmax (Tmax) instead of Cmax. METHODS: We have previously redirected attention to Tmax as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts Tmax easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for Tmax treatment differences. Three separate BE studies are then analyzed by both methods. RESULTS: By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended" analysis of BE studies. First, Cmax, a continuous variable peak-height or extent measure has usurped Tmax's function and performs erratically as a substitute measure for the rate of absorption. Second, Tmax, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, Cmax), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired alpha level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.     

Effect of adjuvant iridium-192 brachytherapy on the survival of patients with malignant gliomas

The effect of iridium-192 brachytherapy (BRTX) on the survival of patients with malignant gliomas was evaluated in 83 patients with malignant gliomas (42 astrocytoma grade III, 41 glioblastoma multiforme) over a period of 8.5 years. Fifty patients (Group 1) received only standard external beam radiotherapy (EBRT) (mean dose 51.5 +/- 12.4 Gy in 2.0 Gy fractions), and 33 patients (Group 2) received EBRT (mean dose 51.0 +/- 10.8 Gy) combined with BRTX (mean dose 50.2 +/- 13.2 Gy, dose rate of 0.3-0.4 Gy/hr). The median survival periods for patients in Groups 1 and 2 were 12.2 and 23.7 months, respectively (p = 0.0145). The median survival for 17 patients in Group 2 with glioblastoma multiforme was 21.9 months. Using BRTX as an adjuvant to EBRT appeared to confer survival benefits compared to only EBRT (p = 0.0284). Univariate and multivariate analysis identified the variables of histological diagnosis, location, Karnofsky performance status, and BRTX as relevant risk factors for survival time (p < 0.05 for each factor). Among these factors, BRTX was the most important for prolonging survival (p = 0.0015). Adjuvant iridium-192 BRTX and conventional EBRT appears to greatly improve the survival time of patients with malignant gliomas compared to only EBRT and may be the treatment of choice in selected patients with tumors located in deep-seated or eloquent areas.