Supratentorial Malignant Gliomas Research Articles

Management of patients aged ≫60 years with malignant glioma: good clinical status and radiotherapy determine outcome

Many clinical trials have shown that the most important prognostic variable in patients with malignant glioma is advanced age. However, can some patients aged >60 years still have relatively good outcomes with conventional surgical and radiotherapeutic treatment? A previous audit of practice (1983-89) suggested that functional status was an impor tant prognostic variable in the elderly. We have reviewed a fur ther cohort (1989-96) to evaluate changes in practice and outcomes given advances in neuroimaging, neurosurger y and radiotherapy.The major findings in this series of 80 patients aged over 60 years with a histological diagnosis of supratentorial malignant glioma were: (i) There was a relationship between management undertaken and clinical status of the patients ( p < 0.01), i.e. patients in good grade generally had tumour debulking and radiotherapy, whilst those in poor grade generally had only biopsy. (ii) There was a significant increase in sur vival of patients in the second period who received surgical debulking and post-operative radiotherapy (from a median of 23 to 41 weeks ( p < 0.05). (iii) It is likely that case selection accounted for much of this improvement since there was a direct relationship between median survival time and good clinical grade using the WHO performance scale. (iv) A shorter radiotherapy course (30Gy in six fractions) was as efficacious as a conventional course (60Gy in 30 fractions), and those patients having radiotherapy survived significantly longer than those not having this treatment ( p = 0.001). This study has again demonstrated the importance of preoperative clinical grade and radiotherapy treatment in deter mining outcomes in patients >60 years. To put these data in a societal context a recent prospective multicentre audit of patients with malignant glioma in Scotland, and another audit from our unit, showed that between 24 and 65% of patients aged >60 years, with a CT diagnosis of malignant glioma do not undergo either surger y or radiotherapy. Advanced age per se should not be a bar to inter ventional treatment in patients aged >60 years with suspected malignant glioma.

Radiotherapy combined with nimustine hydrochloride and etoposide for malignant gliomas: results of a pilot study.

The aim of this study was to examine the effectiveness of radio-chemotherapy using nimustine hydrochloride (ACNU) and etoposide (VP-16) for malignant gliomas. From 1985 through 1998, 33 consecutive patients with supratentorial malignant gliomas were treated by a single protocol. The mean age was 45.8 years (range 12-76 years). The median Karnofsky performance score was 80 (range 60-100). There were 14 anaplastic astrocytomas (AA) and 19 glioblastomas (GBM). Following surgery, 60 Gy of radiotherapy combined with an adjuvant chemotherapy using ACNU (80 mg/m(2) i.v. days 1 and 36) and etoposide (80 mg/m(2) i.v. days 2, 3, 37 and 38) was administered. On completion of the initial radio-chemotherapy, a single cycle of the same chemotherapy was repeated every 6-8 weeks until tumor progression or for 2 years at the maximum. All 33 patients tolerated treatment. We observed complete response in five cases (15%), partial response in nine (27%), no change in 11 (33%) and progressive disease in eight (24%). The response rate (>50% reduction) was therefore 42.4%. Median progression-free survival (PFS) for all 33 patients was 8.4 months: 7.8 months for GBMs and 13.5 months for AAs. There was no significant difference in PFS between GBM and AA patients (p = 0.14). The median survival time of all 33 patients was 21.1 months: 16.2 months for GBMs and 49.9 months for AAs. The difference in survival between AA and GBM was statistically significant (p = 0.0019). Myelosuppression appeared in 11 patients: grade 2 hematological toxicity in 10 cases (30%) and grade 3 in one case (3%). We did not observe any gastrointestinal toxicity. Multivariate analysis showed that age and initial histological grade had independent prognostic significance. RT with ACNU and etoposide are feasible and well tolerated and the treatment results were comparable to the best results reported in the literature.

Evaluation of early response to SU101 target-based therapy in patients with recurrent supratentorial malignant gliomas using FDG PET and Gd-DTPA MRI.

Changes in [18F]-2-fluoro-2-deoxyglucose (FDG) uptake and gadopentetate dimeglumine (Gd-DTPA) enhancement before and after the first course of treatment with a cytostatic agent SU101 (N-[(4-trifluoromethyl)-phenyl]-5-methylisoxazole-4-carboxamide, SUGEN) were assessed using positron emission tomography (PET) and magnetic resonance imaging (MRI) in a pilot study of 8 patients with recurrent supratentorial malignant gliomas. The localization and the volume of Gd-DTPA enhancement and FDG hypermetabolism were analyzed. PET and MRI studies were performed one week before and 7.6+/-3.7 weeks after administration of SU101. The ratios of mean tumor activity to mean contralateral white matter and ipsilateral cerebellar activity were calculated for tumor regions, and SUV values corrected to the subjects' body surface area and glucose level (SUVbsa*glu) were calculated for nontumor regions. Five patients had a substantial increase of tumor volume on both PET and MRI during the first course of SU101. PET and MRI showed roughly equivalent volume changes. Large tumor volume increases were associated with a short time to clinical progression. The metabolic change in the tumor following the first course of SU101 varied from patient to patient, ranging from a 31% reduction to a 43% increase in FDG uptake ratio. Changes in FDG uptake were not predictive of time to progression or survival. In 2 patients with marked clinical deterioration and rapid tumor growth, there were differences in localization of Gd-DTPA enhancement and FDG hypermetabolism suggesting that hypermetabolism beyond the area of contrast enhancement may be of value in predicting rapid progression of high-grade glioma. SU101 did not induce any appreciable changes in SUVbsa*glu for non-tumor brain in 6 of 8 patients.

Frontal lobe dysfunction in patients with non-frontal malignant gliomas: a monoaminergic dysregulation?

Previous investigations concerned with the neuropsychological function of patients with intracerebral supratentorial malignant gliomas has revealed the frequent occurrence of signs suggestive of an inhibitory frontal lobe dysfunction regardless of the intracerebral localization of the tumor and before the diagnosis was known to either the investigator or the patient. Upon closer analysis, the frontal lobe dysfunction has been verified by the demonstration of reduced blood flow in frontal areas in these patients. Since many of the findings can be related to a dysfunction of dopaminergic neurotransmission, we hypothesize that abnormal astrocytes interfere with the metabolism, transport and release of various neurotransmitters of which dopamine may be the one responsible for the most striking neuropsychological abnormalities in patients with malignant gliomas.

Postoperative radiotherapy for supratentorial malignant gliomas.

From January 1988 to December 1996, sixty-five patients with histologically confirmed supratentorial malignant gliomas were treated with postoperative radiation therapy in our department. They were subjected to this analysis according to different clinical and pathologic parameters. The overall 1-year, 2-year survival rate was 57% and 23%, respectively. With univariate analysis, age, postoperative Karnofsky performance status, duration of symptoms, multiplicity of lesions and the extent of surgery were identified as significant prognostic factors. With multivariate analysis, postoperative Karnofsky performance status and the extent of surgery continued to show independent prognostic significance on overall survival.

Hypofractionated Stereotactic Radiotherapy for Malignant Glioma: A Phase I/II Study

In order to shorten treatment time for patients with newly diagnosed supratentorial malignant glioma, a phase I study of LINAC-based hypofractionated stereotactic radiotherapy (SRT) was initiated in September 1991. Nineteen adult patients entered the study. They were treated with 23 MV photons using a single-isocenter arc technique. Six patients received 5 × 5 Gy, 11 received 5 × 6 Gy, and 2 received 5 × 7 Gy over 1 week. Treatment plans were normalized to 100% at the isocenter. Target volume encompassed the tumor with a margin of 1.5–2 cm and was surrounded by the 80% isodose. Five patients had anaplastic astrocytoma and 14 had glioblastoma multiforme. Median tumor volume before SRT was 20.4 cm3. A matching group of 19 patients who received conventionally fractionated radiotherapy (CFRT) was selected in order to compare time to progression and survival. CFRT was applied with daily fractions of 2 Gy up to 60 Gy in 6 weeks. No chemotherapy was given. Seven of 19 patients developed acute grade III or IV toxicity (RTOG central nervous system toxicity criteria) and had to be treated with high-dose steroids and/or mannitol within 8 weeks after SRT (1 of 6 after 5 × 5 Gy, 5 of 11 after 5 × 6 Gy, and 1 of 2 after 5 × 7 Gy). In contrast, only 2 patients had signs of late toxicity. No radionecrosis was observed. Median time to progression was 5 months, median survival 7 months (CFRT: 7 and 11 months, p>0.1). One-year survival rate was 32% versus 37%. However, it was 0% after 5 × 5 Gy, but 40% after 5 × 6 or 7 Gy (p = 0.06). In conclusion, toxicity of SRT with 5 × 6 or 7 Gy was not acceptable. The 5 × 5 Gy regimen was tolerable, but not effective with regard to time to progression and overall survival.

Radical surgery and reoperation in supratentorial malignant glial tumors.

The treatment modalities for gliomas are still questioning and searching. We reviewed the effect of the extent of surgical resection and reoperation on the length and quality of survival in 152 consecutive patients who underwent operation for supratentorial gliomas at GATA Neurosurgery clinic between 1985 to 1995. Seventy-two patients (50%) had glioblastoma multiforme (GBM), and 48 patients (33%) had anaplastic astrocytoma (AA). Gross total resection was achieved in 70 cases (49%), subtotal resection was performed in 60 cases (42%), and biopsy was carried out in 14 cases (9%). Thirty-two patients were reoperated for recurrency and the median interval between the first operation and reoperation was 9.5 months in glioblastoma multiforme, and 11.7 months in anaplastic astrocytoma. The resection groups were compared for age, sex, preoperative and postoperative Karnofsky rating, tumor location, postoperative radiation therapy, and chemotherapy, and survival according to multivariate analysis. Preoperative Karnofsky rating and surgical resection type were the most important factors related to survival after operation or reoperation. The gross total resection group lived longer than the subtotal resection group by life table analysis. Median survival of GBM was 76 weeks in gross total resection group, and 33 months in AA group with total resection (p < 0.001). Preoperative Karnofsky scores had a statistically significant effect on the quality of life and survival after operation and reoperation in all cases (p = 0.005). Radical surgery and reoperation also improve quality and length of life in selective malignant supratentorial gliomas.

Effect of brain edema on the recurrence pattern of malignant gliomas

To assess the influence of initial preoperative brain edema in malignant gliomas on regrowth patterns. 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. 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. 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.

Clinical results of unconventional fractionation radiotherapy in central nervous system tumors.

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.

Hypofractionated stereotactic radiotherapy for malignant glioma—a pase I/II study

In order to shorten treatment time for patients with newly diagnosed supratentorial malignant glioma, a phase I study of LINAC-based hypofractionated stereotactic radiotherapy (SRT) was initiated in September 1991. Nineteen adult patients entered the study. They were treated with 23 MV photons using a single-isocenter arc technique. Six patients received 5 × 5 Gy, 11 received 5 × 6 Gy, and 2 received 5 × 7 Gy over 1 week. Treatment plans were normalized to 100% at the isocenter. Target volume encompassed the tumor with a margin of 1.5–2 cm and was surrounded by the 80% isodose. Five patients had anaplastic astrocytoma and 14 had glioblastoma multiforme. Median tumor volume before SRT was 20.4 cm3. A matching group of 19 patients who received conventionally fractionated radiotherapy (CFRT) was selected in order to compare time to progression and survival. CFRT was applied with daily fractions of 2 Gy up to 60 Gy in 6 weeks. No chemotherapy was given. Seven of 19 patients developed acute grade III or IV toxicity (RTOG central nervous system toxicity criteria) and had to be treated with high-dose steroids and/or mannitol within 8 weeks after SRT (1 of 6 after 5 × 5 Gy, 5 of 11 after 5 × 6 Gy, and 1 of 2 after 5 × 7 Gy). In contrast, only 2 patients had signs of late toxicity. No radionecrosis was observed. Median time to progression was 5 months, median survival 7 months (CFRT: 7 and 11 months, p>0.1). One-year survival rate was 32% versus 37%. However, it was 0% after 5 × 5 Gy, but 40% after 5 × 6 or 7 Gy (p = 0.06). In conclusion, toxicity of SRT with 5 × 6 or 7 Gy was not acceptable. The 5 × 5 Gy regimen was tolerable, but not effective with regard to time to progression and overall survival.

Neuropathology of pediatric brain tumors

Pediatric central nervous system neoplasms include a spectrum of both glial and nonglial tumors that differ significantly in location and biological behavior from those of adults. Brain tumors in infants and children most often arise from central neuroepithelial tissue, whereas a significant number of adult tumors arise from central nervous system coverings (e.g., meningioma), adjacent tissue (e.g., pituitary adenoma), or metastases. Most adult brain tumors are supratentorial malignant gliomas, whereas the most common malignant pediatric brain tumor is the cerebellar primitive neuroectodermal tumor (medulloblastoma). This article reviews neuropathological characteristics of the more common pediatric brain tumors. Entities, such as the brainstem glioma, and less common neoplasms like the desmoplastic infantile ganglioglioma and the central nervous system atypical teratoid/rhabdoid tumor are reviewed because they occur almost exclusively in children. Known cytogenetic and molecular characteristics of childhood brain tumors are also reviewed.

Supratentorial malignant gliomas in childhood: a single institution perspective.

A retrospective study evaluated the clinical characteristics, prognostic factors, and outcome of patients with newly diagnosed supratentorial malignant gliomas treated with preirradiation chemotherapy. 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. 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. 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.

Multivariate analysis of prognostic factors in 106 patients with malignant glioma.

The aim of this study was to evaluate the outcome and prognostic factors influencing survival in 106 patients with supratentorial malignant gliomas treated with radiotherapy. The study group included 84 patients treated by surgery and post-operative radiotherapy and 22 patients treated by postbiopsy irradiation. Radiotherapy was delivered to the tumour area with a 2 cm margin, the aimed curative dose was 60 Gy in 6-7 weeks. The 60-month overall survival (Kaplan-Meier) was 20%. Following a univariate analysis, younger age (P < 0.001), longer duration of symptoms (P = 0.009), good performance status after radiotherapy (P < 0.001), other than grade 4 histology (P < 0.001) and higher radiation dose (P < 0.001) were associated with better overall survival rates. Multivariate analysis found that age, symptom duration, histology, extent of symptoms and radiation dose were independent prognostic factors influencing survival. In conclusion, conventional radiotherapy of supratentorial malignant gliomas results in survival that is comparable to results from clinical experiments with different fractionation schedules and radiation with chemotherapy or radiosensitisers. To improve the results, new approaches are needed, especially for patients with the poorest prognosis after standard treatment.

Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas: Radiation therapy oncology group study 83‐02

Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas: Radiation therapy oncology group study 83‐02

The expanding role of chemotherapy for pediatric supratentorial malignant gliomas.

Supratentorial malignant gliomas are among the most difficult tumors to treat in children. With a combination of surgery and irradiation, the median survival for children with malignant gliomas is only 9 months. Even among survivors, irradiation causes long-lasting neurological impairment, especially in young children. These disappointing results have stimulated interest in adjuvant chemotherapy as a more effective treatment for pediatric gliomas. In 1976, the first pediatric randomized trial of adjuvant chemotherapy incorporated CCNU, vincristine and prednisone. The addition of these agents to standard irradiation and surgery enhanced the 5-year survival rate from 18% to 43%. Other trials with multiple drug regimens, now considered to be suboptimal in dosing, have not further enhanced disease-free survival. Current trials of high-dose chemotherapy combined with autologous bone marrow rescue for children with recurrent malignant gliomas have produced some durable survivors, but long-term benefits for children with newly diagnosed malignant gliomas are yet to be realized.

Malignant gliomas in children.

Childhood supratentorial malignant gliomas, though less common than those in adults, are responsible for disproportionately high morbidity and mortality rates. Important advances have been made in our ability to diagnose these tumors by noninvasive neuroimaging techniques. In addition, progress has been made in our ability to correlate pathology and biological features with clinical outcomes to provide prognostic information. Neuroimaging and tissue prognostic factors now have important roles which directly affect clinical management. While surgery and radiation therapy are critical components of the treatment of childhood supratentorial gliomas, the role of chemotherapy is less clear. Significant responses have been demonstrated for chemotherapy regimens in infants with malignant gliomas and high-dose chemotherapy and ABMR regimens also produce encouraging response rates. The results of current clinical trials will help us determine if these response rates will translate into prolonged patient survival and allow us to identify subgroups of childhood malignant glioma patients that may benefit from adjuvant chemotherapy.

258 A phase III multi-institutional randomised trial of lonidamine (L) and post-operative radiotherapy (RT) in supratentorial malignant glioma

Lonidamine, an indazole carboxylic acid derivative, was reported in Phase II/III trials to have efficacy as radiopotentiator in malignant glioma. Between October 1990 and August 1994, 191 pts. with supratentorial malignant glioma were randomly allocated to treatment with RT or RT + L, following surgical resection. Prior to randomisation patients were stratified according to age. One patient was ineligible and excluded from the study (not malignant glioma). Patients (pts) in arm A (98 pts) received RT alone (50 Gy whole bram plus 14 Gy coned-down boost to the tumour volume, 2 Gy/day for 5 days a week), those in arm B (92 pts) received RT + L (150 mg 3 times daily for 1 year starting from 3 days before irradiation). The groups were comparable in median age, performance status, TNM classes, sex, residual tumour size after surgery and histologic grade. Median follow up was 49 weeks. Intention to treat analysis failed to demonstrate significance difference in the survival rates and shapes of the survival curves between the two treatment arms. Cumulative survival at 12 and 24 months calculated by the Kaplan Meier method were 50% ± 5% and 13.4% ± 4% for arm A, 49% ± 5% and 13.4% ± 4% for arm B. (P> 0.4). The Cox proportional hazards model confirmed the prognostic variables of age ( P P P

The Course of Seizure Disorders in Patients With Malignant Gliomas

To describe the morbidity associated with seizures and the efficacy of anticonvulsant therapy in adult patients with malignant gliomas (MGs). A retrospective review of charts was performed to determine the occurrence of seizures at diagnosis, the frequency and character of subsequent seizures, and the use and toxic side effects of anticonvulsants. Sixty-five consecutive adult patients with supratentorial MGs who were examined in the neurooncology clinic at a university medical center were studied. The diagnosis was glioblastoma in 47 of the patients, and it was anaplastic astrocytoma in 18 patients. The mean age of the patients was 49.5 years. The median Karnofsky status score was 80. The median survival was 18 months. Twenty-nine patients presented with seizures, and 21 of these had subsequent (eg, "recurrent") seizures while they were receiving anticonvulsant therapy. Ten of 36 patients who were free of seizures at diagnosis experienced seizures after diagnosis (eg, "late onset") while they were being treated with anticonvulsants, including five patients who had single seizures. Long-term seizure frequency in excess of one per month was observed in 13 patients. Ten patients had episodes of partial motor status epilepticus. Most recurrent and late-onset seizures occurred despite therapeutic anticonvulsant levels, and without evidence of tumor progression. Rash associated with anticonvulsants was observed in 26% of the patients. Other clinically important toxic side effects were observed in 14% of the patients who were receiving long-term anticonvulsant therapy. Seizures contributed substantially to the neurologic morbidity of MGs in at least 25% of these patients. The occurrence of seizures at diagnosis was a strong predictor of subsequent seizures, and in many patients, seizures proved to be refractory to standard anticonvulsant therapy. Long-term anticonvulsant toxic side effects are relatively common in patients with MGs. The use of long-term seizure prophylaxis for patients with MGs who are free of seizures at presentation is not clearly beneficial and should be studied in a prospective trial.

Prognostic implications of the extent of surgical resection in patients with intracranial malignant gliomas.

The goal of treating patients with malignant gliomas by intracranial surgery has been to remove as much tumor as possible without causing new neurologic deficits. However, it is still debatable whether the degree of surgical resection correlates with survival times of patients with supratentorial gliomas. One hundred and one patients with supratentorial malignant gliomas who underwent either a gross total resection, a subtotal resection, and/or a partial resection were examined. A correlation between their length of survival and the degree of surgical resection was determined. The survival rates of patients who underwent total resections were significantly higher than those of patients who underwent subtotal or partial resections (P < 0.01). However, there was no significant difference in the survival rates between the subtotal and partial resection groups. These results also were confirmed by independent variables, such as age, location of the tumors, and histologic subtypes, with the exceptions of temporal gliomas and those younger than 60 years. The favorable prognosis of patients with malignant gliomas depends upon the total resection of these tumors. These findings should be of help in designing preoperative surgical intervention strategies.

Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas

High grade malignant gliomas are among the most radioresistant human tumors and total doses up to 80 Gy are inadequate to achieve long-term local control in most of the patients. Hypoxia has been demonstrated in primary brain tumors and may be one of the reasons for their radioresistance. In experimental models carbogen breathing and nicotinamide have been shown to act against hypoxia by different mechanisms and both modalities were tested in 16 patients with supratentorial malignant gliomas in combination with a conventional radiotherapy scheme (50 Gy in 25 daily fractions). The present study was performed to determine the feasibility and toxicity of conventional radiotherapy combined with carbogen breathing and nicotinamide. The unexpectedly high incidence of acute liver toxicity, the possible increase of subacute and late CNS toxicity, and the absence of a higher effectivity led us to reconsider this new treatment modality for patients with malignant gliomas.