Chemo-radiotherapy for malignant brain tumors

I) Malignant gliomas: Randomized clinical trials conducted in the USA showed that radiotherapy plus chemotherapy with nitrosoureas offered a long-term survival advantage to patients younger than 60 years old with malignant gliomas. Combination chemotherapy, such as procarbazine/CCNU/vincristine (PCV) must be tested further, and intra-arterial chemotherapy with nitrosoureas offered no survival advantage. Combination chemotherapy with PCV showed efficacy for patients with anaplastic oligodendroglioma and anaplastic oligoastrocytoma. II) Medulloblastoma: The addition of chemotherapy to radiotherapy improved the survival of patients with poor risk medulloblastoma, and may reduce the required craniospinal radiation dose in patients with good risk medulloblastoma. III) Primary CNS lymphoma (PCNSL): Combination of chemotherapy with high-dose MTX and radiotherapy improved survival of patients with PCNSL; however, the neurotoxicity produced by this treatment modality is a serious problem in older patients. IV) Intracranial germ cell tumors: The addition of chemotherapy to radiotherapy may produce long term survival with good quality of life in patients with germinoma. Neoadjuvant therapy consisting of chemotherapy and radiotherapy followed by complete surgical excision improved survival of patients with intracranial nongerminomatous germ cell tumors.     

Clinical trial of 5'-DFUR against various malignant tumors

5'-DFUR was administered orally to 18 patients with various malignant tumors at a daily dose of 800-1200 mg to evaluate its clinical efficacy and side effects. Out of 17 evaluable cases, PR was observed in one larynx cancer case and three breast cancer cases, with an efficacy rate of 23.5%. Side effects was observed in only one case. These were digestive symptoms which were alleviated by reduction of the dosage. No other severe side effect was observed. These results suggest that 5'-DFUR has potential as a useful oral anticancer agent.     

Clinical trial of CPT-11 and VM-26/VP-16 for patients with recurrent malignant brain tumors

CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m²) followed 24 h later by VM-26 (125 mg/m²). VP-16 (125 mg/m²) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m². Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3–31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.     

Phase II trial of merbarone in patients with malignant brain tumors

The standard treatment for patients with primary malignant glioma includes surgical resection, radiotherapy, and nitrosourea. Despite this multimodality approach, adults with newly diagnosed glioblastoma multiforme (GBM) and high-grade astrocytoma have a median survival duration of 50 weeks and 150 weeks respectively. Chemotherapy has had a limited impact on the survival of these patients. Merbarone (5-phenylcarboxamide-2-thiobarbituric acid) is a nonsedating derivative of barbituric acid that crosses the blood brain barrier. Antitumor activity of merbarone has been described against L1210, B16 melanoma cell line and the M5076 sarcoma cells in phase I studies. Merbarone inhibits DNA synthesis and tumor growth by inducing single strand breaks in DNA. It also inhibits RNA and protein synthesis. We evaluated merbarone in a phase II trial in patients (pts) with recurrent or refractory GBM (7 pts) and high grade anaplastic astrocytoma (7 pts). Fourteen patients (nine males, five females) were treated with merbarone at a dose of 1000 mg per m² per day by continuous intravenous infusion for 5 days every 3 weeks. Every patient received at least two cycles of treatment No complete or partial responses were observed, although one patient had stable disease lasting 20 weeks. Our conclusion is that merbarone is ineffective against GBM and high-grade anaplastic astrocytoma at the dose and schedule in which it was administered in this trial.     

MCNU delivery into malignant brain tumor and normal brain tissue by intravenous or intraarterial infusion

In 13 Fischer 344 rats transplanted intracerebrally with 9 L gliosarcoma, 13 normal Fischer 344 rats and 4 clinical cases of malignant glioma, a new water-soluble nitrosourea (MCNU) was given and the concentration was measured in blood, tumor tissues, normal brains around the tumors and normal hemispheres by intravenous or intraarterial infusion of MCNU. At 5 min. after administration of MCNU 20 mg/kg (4-5 mg/body) in 9 L gliosarcoma bearing Fischer rats, mean MCNU concentration in the blood was not different between 20 micrograms/ml intravenous and 23 micrograms/ml intraarterial administrations whereas that in the tumor tissues by intracarotid infusion of MCNU was 40 +/- 14.4 micrograms/g which was about two times as much as 22.9 +/- 8.13 micrograms/g by intravenous infusion of MCNU. Mean MCNU concentration of normal brains around tumor tissues was 2.49 micrograms/g in intravenous and 8.95 micrograms/g in intracarotid infusion. MCNU concentration of tumor tissues in 4 cases of malignant gliomas was higher by intracarotid administration than by intravenous administration compared to that in the blood. Maximum tumor/blood ratio of MCNU was 1.94 in intracarotid administration for the malignant glioma. It is suggested that intraarterial administration was more useful than intravenous infusion as an administration route for malignant brain tumors.     

Therapeutic anti-angiogenesis for malignant brain tumors.

Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials.     

Results of interstitial brachytherapy for malignant brain tumors

We evaluated the efficacy of brachytherapy in patients with malignant brain tumors and assessed the factors associated with longer disease control after treatment. From June 1989 to October 1995, 73 patients were treated with stereotactic brachytherapy with temporary placement of iodine-125 implants. The median age was 52 (range 9-79). Median KPS was 80. There were 48 patients with a glioblastoma multiforme, 13 with an anaplastic astrocytoma, and 12 with other tumors. Of the 67 evaluable patients, 20 underwent brachytherapy as part of the therapy for a newly diagnosed tumor (17 were glioblastomas) and 46 had brachytherapy at the time of progression (28 were glioblastomas). Median survival time for all patients undergoing brachytherapy from diagnosis was 70.3 weeks. Median survival from implant was 39.3 weeks. For patients with an anaplastic astrocytoma, median survival from diagnosis and implant was 158.1 and 36.9 weeks respectively. For patients with a glioblastoma multiforme, median survival from diagnosis and implant was 62.9 and 37.1 weeks respectively. Eleven patients (16%) developed radiation necrosis. Nine patients (13%) developed other complications. Age and histologic diagnosis were significant predictors of survival from diagnosis. Age and KPS were independent predictors of time to failure after implant. Certain characteristics, specifically younger age (<55), and a higher KPS (相似文献   

Sensitivity of human malignant intracranial tumors against MCNU in vitro in comparison to ACNU and BCNU

Summary An in vitro chemosensitivity test was carried out in 50 specimen of human malignant intracranial tumors. Aim of the study was to evaluate the proportion of sensitivity against MCNU (Ranomustine) in comparison to ACNU and BCNU. 47 tests were evaluable. Mean viability of the specimen was 83.3 ± 18.7%, mean plating efficiency was 0.068 ± 0.051%. 9/47 settings revealed sensitivity against MCNU in vitro (ACNU: 10/47; BCNU: 16/46). There was no advantage of MCNU concerning age or sex of the patients. Brain metastases seemed to be slightly more frequent sensitive against MCNU than primary brain tumors. Cross resistance between ACNU, BCNU and MCNU was rather high. The results of this in vitro series do not encourage a clinical trial of MCNU as an alternative to the commonly used nitrosoureas.Behring Werke, D-3550 Marburg/Lahn, FRG     

Boron neutron capture therapy for malignant brain tumors

Journal of Neuro-Oncology - Multidisciplinary studies for glial tumors has produced an enormous amount of information including imaging, histology, and a large cohort of molecular data (i.e....     

Resent advances in chemotherapy for malignant brain tumors

Most malignant brain tumors are resistant to the chemotherapeutic agents because of the existence of several mechanisms or substances such as the blood-brain barrier, genes and proteins. Recently many studies have been started to overcome the chemoresistance. Especially recent advances in the field of molecular biology have contributed to examination of the chemosensitivities of tumor cells. Trials for the individualization of the treatment, so-called Taylor-made therapy, is one of these challenges. Loss of chromosome 1 p and 19 q is considered to be closely related to chemosensitivity in anaplastic oligodendrogliomas. This is one of the breakthroughs in the field of chemotherapy for malignant brain tumors. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme which reduces the cytocidal effect of nitrosourea. In order to overcome the chemoresistance, drugs except nitrosourea or some drugs which reduce the MGMT activity are used for tumors expressing MGMT. New technology targeting growth factor receptor such as EGFR or VEGFR is also applied to cancer chemotherapy. On the other hand, multi-institutional cooperative studies have been started to obtain evidence in cancer treatment. Phase II study for a small number of patients is not sufficient to demonstrate the efficacy of the treatment and to establish the standard therapy. Multi-institutional randomized controlled study by JCOG Brain Tumor Study Group is the first trial for the treatment of malignant astrocytomas under well-established quality control and quality assurance systems. It can be a model of clinical trials for malignant brain tumors in Japan.     

Chemosensitivity of malignant human brain tumors

Tumor cell proliferation and morphological changes in tumor cells under the influence of different cytostatic agents were measured in an in vitro assay to determine chemosensitivity of human malignant brain tumors. Aliquots of 2 to 5 x 10(4) cells of a tumor cell suspension (prepared from biopsy specimen by mechanical and enzymatic disintegration) were incubated for 72 hr in the presence of different cytostatic agents. After another nine days of incubation in fresh medium, cell proliferation was calculated by incorporation of 14C-leucine and 3H-uridine and measurement in a liquid scintillation counter. Morphological changes in tumor cells were evaluated in Labtek tissue culture slides cultured under identical conditions. All drugs were tested in pharmacologically achievable concentrations. In vitro BCNU-sensitivity of 7/17 patients correlated with a postoperative recurrence free interval of 15.1 months, in vitro BCNU-resistance of 10/17 patients correlated with a postoperative recurrence free interval of 6.38 months (p less than 0.001). Tumors of lower grades of malignancy (astrocytoma III, malignant ependymoma, medulloblastoma) in our series have a statistically significant higher median BCNU-sensitivity (63.5%, p less than 0.05) and are sensitive to more drugs (3.6 drugs, median out of six selected drugs, p less than 0.01) than tumors of higher grades of malignancy (astrocytoma IV, glioblastoma multiforme; 29.54% BCNU-sensitivity, 1.4 effective drugs). In our series differences of BCNU-tumor sensitivity and number of effective drugs were not statistically significant if related to age and sex of tumor bearing patients. We think this assay provides the opportunity to test a large number of drugs in a very short period of time. Results may indicate alternative drug regimen for those patients resistant to conventional chemotherapy.     

New development of surgical treatment for malignant brain tumors

The most important prognosticator for malignant brain tumor patients is the degree of tumor removal. On the other hand, surgical removal should not induce aggravation of the patient performance status. In accordance with the result, surgical planning for glioma should be carefully considered. However, there is no standard guide for preoperative planning to date. However, there is no standard guide for preoperative planning to the present. We attempted to divide gliomas into 5 stages according to the difficulty of the surgery and analyzed the relation between the removal rate and each stage. The results demonstrated that the stage is correlated with the removal rate. This staging might contribute to standardization of glioma surgery. For surgical planning of tumors around the motor area, fiber tractography and magnetoencephalography should be very useful. As an intraoperative examination, monitoring of motor evoked potential is necessary to resect tumors around the motor area. For resection of tumors around the speech area, functional brain mapping under awake surgery is the most reliable method. In addition to these techniques for safe surgery, neuro-navigation and chemical navigation using 5-aminolevulinic acid are used to achieve of the maximum removal rate. Finally, development of preoperative examinations, microsurgical technique, and intraoperative monitoring enabled us to do safer and move sure surgery.     

Radiation-inducible caspase-8 gene therapy for malignant brain tumors

PURPOSE: Patients with malignant gliomas have a poor prognosis. To explore a novel and more effective approach for the treatment of patients with malignant gliomas, we designed a strategy that combines caspase-8 (CSP8) gene therapy and radiation treatment (RT). In addition, the specificity of the combined therapy was investigated to decrease the unpleasant effects experienced by the surrounding normal tissue. METHODS AND MATERIALS: We constructed the plasmid pEGR-green fluorescence protein that included the radiation-inducible early growth response gene-1 (Egr-1) promoter and evaluated its characteristics. The pEGR-CSP8 was constructed and included the Egr-1 promoter and CSP8 complementary DNA. Assays that evaluated the apoptosis inducibility and cytotoxicity caused by CSP8 gene therapy combined with RT were performed using U251 and U87 glioma cells. The pEGR-CSP8 was transfected into the subcutaneous U251 glioma cells of nude mice by means of in vivo electroporation. The in vivo effects of CSP8 gene therapy combined with RT were evaluated. RESULTS: The Egr-1 promoter yielded a better response with fractionated RT than with single-dose RT. In the assay of apoptosis inducibility and cytotoxicity, pEGR-CSP8 showed response for RT. The pEGR-CSP8 combined with RT is capable of inducing cell death effectively. In mice treated with pEGR-CSP8 and RT, apoptotic cells were detected in pathologic sections, and a significant difference was observed in tumor volumes. CONCLUSIONS: Our results indicate that radiation-inducible gene therapy may have great potential because this can be spatially or temporally controlled by exogenous RT and is safe and specific.     

Interstitial hyperthermia of malignant brain tumors by implant heating system: Clinical experience

Summary An implant heating system using a ferromagnetic implant with low Curie temperature has been developed for treating human brain tumors. Safe and repeated hyperthermia was possible over periods averaging ten weeks in 23 out of 25 patients with malignant brain tumors without development of major side effects.Evaluation of the effects of this new treatment is still preliminary. Overall response rate was 34.8%. However, five of thirteen cases of malignant glioma and two of five cases of brain metastasis were responded well to interstitial hyperthermia given with or without irradiation. Pathological findings common to the treated tumors were circumscribed, ellipsoid shape of coagulation necrosis around the implant. Degeneration of tumor cells, hemorrhage, vascular stasis and thrombosis were found adjacent to the necrosis.In the future, a combination of interstitial hyperthermia with brachytherapy and chemotherapy may offer improved local control of brain tumor.     

Thermoradiotherapy of recurrent malignant brain tumors.

In an attempt to improve local control and survival over those achieved with brain implant alone, a Phase I/II study of interstitial thermoradiotherapy was undertaken for recurrent malignant gliomas and recurrent solitary brain metastases. Between June 1987 and September 1990, 49 tumors in 48 patients were treated with thermoradiotherapy, including 26 glioblastoma multiforme (GM), 16 anaplastic astrocytomas (AA), 4 adenocarcinomas, and 3 melanomas. Patient age ranged from 18 to 71 years and Karnofsky Performance Status from 40 to 90. Stereotactically implanted catheters were used for both hyperthermia and brachytherapy. Hyperthermia was administered immediately before and after brachytherapy, heating as much of the tumor as possible to 42.5 degrees C for 30 min using helical coil microwave antennas. High-activity iodine-125 sources delivered tumor doses of 32.6 to 63.3 Gy. Complications included reversible neurologic changes in 13 patients, 9 seizures, 4 infections, 1 deep venous thrombosis with pulmonary embolus, and 1 scalp burn. Eighteen patients underwent reoperation for tumor and/or necrosis. Follow-up ranged from 9 to 166+ weeks. The median follow-up for living patients with GM and AA was 37 weeks and 92 weeks, respectively. Actuarial median survival was 47 weeks for patients with GM. For patients with AA, actuarial survival was 65% at 18 months and median survival has not yet been reached. Multivariate analysis showed a strong correlation between freedom from local tumor progression and "T90" temperature or minimum tumor temperature. Interstitial brain thermoradiotherapy is now being evaluated in a randomized Phase II trial for previously untreated GM.