Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

BCNU-DBD (Dibromodulcitol) chemotherapy of recurrent supratentorial anaplastic astrocytomas and glioblastomas.

Our aim was to investigate the effect of BCNU and DBD combined chemotherapy in patients with recurrent malignant gliomas. Forty-six patients were treated with combined chemotherapy. Out of 26 patients with anaplastic astrocytomas 11 were originally low-grade where no postoperative radiotherapy was applied. Fifteen patients with anaplastic astrocytoma responded well to the chemotherapy and 9 survived longer than one year. Median survival time was 14 months. Complete response of recurrent glioblastoma did not occur and only 4 patients survived longer than one year. Median survival time was 7 months. Ratio of patients with response and stable disease was 70 and 55 %, respectively. BCNU and DBD combination proved to be an effective combination for recurrent malignant gliomas. It was remarkable that patients' survival with primary or secondary lower grade astrocytoma were significantly longer than that in patients with glioblastomas. Treatment of lower grade tumors, even at their malignant recurrences is promising.

Preoperative history and postoperative survival of supratentorial low-grade astrocytomas.

The preoperative history and postoperative course of histologically verified 348 low-grade and 383 anaplastic astrocytomas have been reviewed. In 71.2 and 48.0% of patients epilepsy was the initial symptom of a suspected astrocytoma, and the history was longer than 3 years in 28.1 and 19.5% of cases, respectively. Before the advent of CT, angiography was performed because of a suspected tumour 2-9 years before surgery in 34 cases. The second angiography years later demonstrated the tumour which in 18 cases at surgery proved to be low-grade astrocytoma or anaplastic astrocytoma in 16 cases. During the last 10 years CT or MRI demonstrated a low-density lesion in 21 patients years before surgery. Operation was postponed for different reasons. Ten tumours appeared at 'delayed' surgery as low-grade, but 11 as anaplastic astrocytoma. In the same period 29 further patients were operated on after a history of seizures, longer than 3 years. Histology showed anaplastic astrocytoma in 10 cases also. Malignant transformation occurred nearly in half of the patients during the observation period. This strongly suggests that dedifferentiation is a spontaneous process, an intrinsic feature of astrocytomas and does not depend on any kind of external stimulus. Another 51 patients' surgery was performed following a shorter (1-24 months) history of epilepsy. The 5-year survival rate was 44 and 39.5% Median survival times (53.5 and 51 months) did not show a significant difference between the two groups, but the total survival, including second survivals after reoperation displayed a significant difference (57.5 vs 67.5 months) in favour of patients with a shorter history of seizures. These experiences confirm the difficulties in decision of the time of surgery. Considering the frequent malignant transformation among patients with a long history of seizures, followed by a relatively shorter survival, it may be supposed that an early radical removal in suitable cases might prevent the late dedifferentiation and recurrence.

Apoptosis and p53 expression in human gliomas.

Twenty-five human gliomas of different histological grade and type were studied for p53 expression by immunohistochemistry and for apoptosis using ApopTag method. p53 expression (percentage of positive cells) was highest in anaplastic astrocytomas, followed by low grade astrocytomas and surprisingly in glioblastomas. Granular cytoplasmic p53 positivity appeared in 4/5 low grade oligodendroglioma and in 2/5 low grade mixed oligoastrocytomas. The means of apoptosis index in the different tumor types ranged between 0.8 and 11.5 with the highest values in anaplastic astrocytoma and glioblastomas. Although the number of cases per group were relatively low and the individual vales showed differences it seems that p53 expression is related to the biological aggressiveness of gliomas. It is also suggested that high level of apoptosis in malignant glioma could represent a p53 independent pathway.

Histologically confirmed changes on CT of reoperated low-grade astrocytomas.

During a 15-year period 37 patients with primary low-grade astrocytoma have been operated upon twice in our institute. CT and histological data at the time of the first and second operations were compared. The majority of primary astrocytomas showed as a low-density area without contrast enhancement; minimal, mainly marginal enhancement was present in six cases. At reoperation 10 tumours were histologically unchanged; the corresponding CT studies displayed a nonenhancing lesion, although insignificant contrast uptake could be seen in three cases. There were 18 tumours which had transformed into anaplastic astrocytoma: CT before repeat surgery showed more or less marked enhancement. In all nine cases which progressed into glioblastoma multiforme strong contrast enhancement was seen on CT at the time of recurrence. Although the grade of contrast uptake varied, the appearance of or increase in enhancement was a sign of some degree of anaplastic change, particularly convincing in cases of dedifferentiated glioblastoma multiforme.

Re-operations of supratentorial anaplastic astrocytomas.

Results of re-operations of 99 adult patients with recurrent supratentorial lobar glioblastomas (60 patients) and anaplastic astrocytomas (39 patients) have been reviewed. In all cases both surgical interventions were performed at the same institute. Age of patients with glioblastoma varied between 19 and 64 and with anaplastic astrocytoma between 21 and 68 years, with a mean value of 48 and 36 years, respectively. The median interval between the first and second operations was 47 weeks for patients with glioblastoma and 83 weeks with anaplastic astrocytoma. The mortality rate of the re-operations was 3%. Following re-operation radio- and/or chemotherapy was applied in most of the cases. Median survival time after re-operation was 18.5 weeks in patients with glioblastoma and 55 weeks with anaplastic astrocytoma. Survival curves were calculated according to Kaplan-Meier method and for statistical evaluation the generalized Wilcoxon test and multiple linear regression method were used. Histologically lower grade tumour at the first operation and longer interval between the two operations proved to influence positively and dedifferentiation of the primary tumour negatively the survival time.

[Diagnostic and therapeutic possibilities in adult malignant gliomas]. / Felnóttkori malignus gliomák diagnosztikai és terápiás lehetóségei.

Despite of the recent advances in diagnostic and therapeutic techniques the outcome of patients with malignant gliomas remains poor. The most widely used classifications and management of supratentorial gliomas are reviewed focusing on the chemotherapeutic possibilities. More accurate diagnosis and new therapeutic approaches will be available with the results of immunological studies. With the help of genetical experiments the development and malignant transformation of the gliomas will come to light. The gene therapy seems to be promising even in case of malignant glioma.

Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas. EORTC Brain Tumor Group.

OBJECTIVE: We tested adjuvant chemotherapy combining dibromodulcitol (DBD) and bischloroethylnitrosourea (BCNU) given postoperatively to adults with newly diagnosed supratentorial malignant gliomas. METHODS: We enrolled 269 patients, 255 of whom were eligible. After surgery, we treated all patients with radiation therapy, using a median dose of 60 Gy given in 30 fractions. After randomization, patients in the chemotherapy group also received (1) six weekly courses, administered during irradiation, of DBD 700 mg/m2 and (2) one to nine (median, four) courses, administered during the first year following radiation therapy, of DBD 1,000 mg/m2 on day 1 and BCNU 150 mg/m2 on day 2, with the course being repeated every 6 weeks. RESULTS: Patients treated with radiation therapy along with DBD plus BCNU (group 2) had significantly longer survival time (p = 0.044) and time to progression (p = 0.003) than did those treated with radiation therapy alone (group 1). The median survival time was 13.0 months for group 2 and 10.4 months for group 1; the median time to progression was 8.1 months for group 2 and 6.7 months for group 1. The percentage of patients alive at 18 and 24 months was 34% and 21% in group 2 compared with 21% and 12% in group 1. CONCLUSION: DBD plus BCNU is an effective adjuvant therapy for malignant glioma.

Characterization of human gliomas by a monoclonal antibody both on tissue culture and paraffin-embedded sections.

A monoclonal antibody designated OITIC3-11 was produced against GFAP positive human glioblastoma multiforme tumour cells. The specificity of the monoclonal antibody was tested on different types of human brain tumours and on normal adult brain both on tissue cultures and paraffin-embedded sections. The OITIC3-11 monoclonal antibody reacted with 16 of 18 malignant and 1 of 6 benign gliomas but did not react with meningioma, pituitary adenoma, metastatic brain tumours and normal adult brain tissue.

Chronic extradural haematoma--report of 33 cases.

During 35 years (1955-1989) 236 extradural haematomas were operated on in the National Institute of Neurosurgery, Budapest. 33 of them were operated on after the 4th day following trauma. These cases were termed as chronic ones. There was no mortality and only two patients had permanent neurological signs. The much more favourable outcome of the chronic extradural haematoma could be explained with the slow development of the haematoma. It is remarkable that the trauma itself was not recognised in several cases.

Combined treatment of anaplastic astrocytoma (grade 3-4) with diacetyl-dianhydro-galactitol (DADAG).

Autoradiographic studies of labeled diacetyldianhydro-galactitol (DADAG) with tumor bearing animals revealed that the CNS accumulates high amounts of DADAG-derived radioactivity and the elimination from the brain seems to be relatively slow. This observation and the activity of DADAG against murine ependymoblastoma classified the drug as a promising agent for the treatment of malignant brain tumors. In a series of 30 evaluable consecutive patients who were operated on for anaplastic astrocytomas, DADAG has been applied during and subsequent to postoperative radiotherapy. No severe toxicity occurred. Survivals were compared with a group of patients who got irradiation alone. Statistical analysis did not show significantly better survivals in the DADAG treated group: median value was 46.5 weeks, p = 0.232.

The distribution of bromine content of dibromodulcitol in the central nervous system of patients with malignant gliomas.

The bromine content of human gliomas and white matter was determined by neutron activation analysis (NAA) following p.o. administration of a single dose of 400-500 mg/m2 dibromodulcitol (DBD). In another group of patients with brain gliomas, the bromine content was measured subsequent to application of a single dose of 334 mg/m2 of sodium bromide (equivalent dose regarding the bromine content of DBD). The bromine content of these two groups was compared to the values found in a third control group of untreated patients. The amount of bromine after DBD application was three to four times higher than in the untreated samples and the average accumulation ratio of 1.8 +/- 0.4 proved to be nearly identical both in tumour and white matter. The bromine values after NaBr treatment showed a different pattern of distribution. The accumulation was higher in the tumour tissue than in the normal white matter. These findings demonstrate that the pharmacokinetic properties of DBD- and NaBr-derived bromine are different, suggesting that the increase of bromine after DBD administration could be due to covalently bound bromine in DBD.

Primary spinal intramedullary malignant lymphoma. A case report.

A rare case of primary malignant intramedullary lymphoma, localized in the cervical part of the spinal cord, is presented. The onset of clinical symptoms was associated with herpes zoster infection. Surgery led to the histological diagnosis. The clinical investigations excluded the presence of lymphoma in other sites in the central nervous system and in the extraneural organs. Postoperative irradiation and chemotherapy effected relict of neurological symptoms.

Contribution to the problem of giant cell astrocytomas.

Histological, immunocytochemical, and biological features of 38 giant cell gliomas were investigated. The invasion of these tumors and its giant cells by histiocytes, lymphocytes, plasma cells, and especially by eosinophilic granulocytes is viewed as an immune response, which may explain a favorable clinical course. Fifty-three percent of the patients were younger than 45 years at the time of surgery. The average postoperative survival of 27.4 months was clearly longer than in glioblastoma. These biological features suggest a differentiation from glioblastoma multiforme. The classification of this entity as "monstrocellular astrocytoma" is proposed.

Dibromodulcitol-based combined postoperative chemotherapy of malignant astrocytomas and glioblastomas.

Continuing our earlier studies with dibromodulcitol (DBD), in a series of 38 evaluable consecutive patients who were operated on for malignant supratentorial gliomas, radiotherapy with smaller daily but higher total doses of DBD has been started 3-5 weeks after surgery. This was followed alternately by a combination chemotherapy of CCNU and DBD or CCNU and Procarbazine. No severe myelotoxicity occurred. Survivals were compared with a group of patients who got irradiation alone. Statistical analysis showed a significantly better survival in the presently treated group: median survival was 55 weeks, p = 0.02. These values were very similar to those groups which were treated by intermittent DBD schedule during irradiation. This study seems to confirm our previous suggestion that the concurrent use of DBD during irradiation might be an important factor in improving survival times.

Supratentorial lobar pilocytic astrocytomas: report of 45 operated cases, including 9 recurrences.

45 cases with supratentorial, lobar--mainly temporo-parietal--pilocytic astrocytoma are analysed. The mostly highly vascularized tumours frequently present with histologically different tissue components. Formation of cysts of various size was found in 67%. The tumour usually ran a benign clinical course with a comparatively low incidence of recurrence. Malignant transformation of recurrent tumours was not observed. Radiotherapy of conventional dosage did not prove to have any influence on survival, neither post-operatively nor after re-operation. Transformation of persisting pluripotential cells of the subependymal periventricular plate after migration to the surface of the brain is being discussed as the origin of this variant of pilocytic astrocytoma.

The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour.

The uptake of [3H]-dibromodulcitol ( [3H]-DBD) into glioblastomas, white matter and cerebrospinal fluid was studied in 10 patients. Single-tissue samples were taken from different subjects at 4, 15 and 24 hr after [3H]-DBD administration. The level of 3H-compounds in the central nervous system was similar after a single (400 mg/m2), or 3 smaller daily oral doses of 150-180 mg/m2 of [3H]-DBD. The distribution of radioactivity was uniform in the tumour, white matter and muscle. Between 3 and 15 hr after administration of DBD the concentration of radioactivity did not change significantly and was between 5 and 13 micrograms of DBD/g tissue wet wt. At the same time the level in the cerebrospinal fluid (CSF) remained between 1 and 4 micrograms/ml. Meanwhile, the average concentration of radioactivity in the plasma fell from 11 to 3 micrograms/ml. The elimination half-life of the labelled compounds from the tissues was about 1 day as judged from the limited number of non-serial data obtained 4 and 24 hr after the last dose of repeated drug administration.

Combined radiotherapy and chemotherapy with dibromodulcitol and CCNU in the postoperative treatment of malignant gliomas.

Within 4 weeks after definitive surgery, 91 patients with supratentorial glioblastomas and malignant astrocytomas were randomized to one of three treatment arms: Group 1 received radiotherapy alone; Group 2 received dibromodulcitol (DBD) during radiotherapy, and treatment was then continued with DBD; and Group 3 received DBD during radiotherapy, followed by combination chemotherapy of CCNU and DBD. No severe myelotoxicity occurred, but combined treatment with CCNU and DBD occasionally caused a transient myelosuppression. Statistical analysis of 84 evaluable patients showed a significantly longer survival period in those who received chemotherapy during and after irradiation. Median survival times in the three groups were 40, 57, and 60 weeks, respectively; the corresponding p value for Groups 2 and 3 was 0.025 and 0.0015. The ratio of patients surviving over 18 and 24 months was highest in Group 3. This study suggests that the administration of DBD during irradiation might have been the main factor in improving survival times.

Supratentorial lobar ependymomas: reports on the grading and survival periods in 80 cases, including 46 recurrences.

We report 80 supratentorial lobar ependymomas, including 46 recurrences. All underwent operation. In the total collection 34.5% survived for more than 5 years. The behaviour of children and adults was nearly identical. Based on a histological grading into three steps of malignancy (E1, E2, E3), the ependymomas in low grade 1 showed a 5 years' survival time of 41.5%. Compared to a 28.5% survival in group E2 at the same time. Results in group E3, which histologically resembled malignant glioma or glioblastoma, are not relevant because of the small number of cases. More than 50% of the E1 recurrences showed transformation to E2. No transformation into a lower grade of malignancy has been observed.

[Simultaneous occurrence of pituitary adenoma and thyrogenic hyperthyroidism]. / Gleichzeitiges Auftreten eines Adenoms der Hypophyse und einer thyreogenen Hyperthyreose.

Subtotal tumour removal had been performed in a 34-year-old female patient for an extensive intra- and suprasellar expansive process. The considerably increased prolactin level did not decrease postoperatively, but normalised only after a three months bromocriptine treatment. The primary hyperthyroidism has been recovering after administering methimazolum. In a second case was reported on a 65-year-old female patient, suffering from rachitic dwarfism, stenosis of the aortic valve and tumour of the hypophysis, causing acromegaly, whose diabetes mellitus of contrainsular type could have been hardly balanced with insulin of a 128-unit-dose daily, and whose hyperthyroidism was due to an autonomous adenoma of the thyroid gland, first I-131 treatment was administered and she got into an euthyroid state. Six weeks following the removal of the acidophilic adenoma of the hypophysis administration of insulin could have been ceased, and the results of her growth hormone became normal. The clinical picture partly corresponds with Troell-Junet's syndrome.