Nitrosourea-based Chemotherapy Research Articles

Prognostic significance of loss of O6-methylguanine-DNA methyltransferase expression in supratentorial diffuse low-grade astrocytoma

BackgroundO6-Methylguanine-DNA methyltransferase is a DNA repair protein. Epigenetic silencing of MGMT function by its promoter hypermethylation is considered to contribute to carcinogenesis. If loss of function in MGMT is related to tumor progression, the immunohistochemical method may predict the malignant change of gliomas. MethodWe investigated the expression of MGMT by immunohistochemical method in 28 supratentorial hemispheric diffuse astrocytomas. The prognostic significance of MGMT expression, proliferation index (MIB-1), and various clinical factors was evaluated. ResultsThere were 19 MGMT-positive and 9 MGMT-negative astrocytomas. Their rates of malignant transformation at 5 years were 12.3% and 51.4%, respectively. The difference was significant in the univariate (P = .004) and multivariate analyses (P = .044). Age, sex, extent of surgery, MIB-1 value, and radiation therapy at initial treatment did not correlate with the malignant progression. The 10-year overall survival rates were 71.8% and 58.3% in the patients with MGMT-positive and MGMT-negative tumors, respectively, and were not significantly different between these 2 groups (P = .079). Two long-term survivors with MGMT-negative tumor responded well to nitrosourea-based chemotherapy and lived more than 8 years after malignant transformation. The patients' age (P = .0047) and the degree of surgical removal (P = .0082) affected the overall survival in the univariate analysis. In the multivariate analysis, none of these factors reached significance. ConclusionAlthough the status of MGMT did not affect the overall survival, immunohistochemical evaluation of MGMT expression may be a good marker for tumor progression.

Treatment of gliomatosis cerebri with temozolomide: A retrospective study of the AINO (Italian Association for Neuro- Oncology)

2033 Background: The optimal management for patients with primary gliomatosis cerebri is unknown, and some recent studies suggest that temozolomide could be useful as an upfront treatment. Methods: Between 1999 and 2005, 46 patients with biopsy proven gliomatosis cerebri were treated with temozolomide either upfront or at progression after prior radiotherapy/chemotherapy. Histological diagnoses were as follows: glioblastoma in 3 patients, malignant glioma in 8, anaplastic astrocytoma in 8, gemistocytic astrocytoma in 2, astrocytoma in 13, anaplastic oligodendroglioma in 1, anaplastic oligoastrocytoma in 1, oligoastrocytoma in 1, oligodendroglioma in 4, glial proliferation consistent with GC in 5. Median age was 49 years (range 14–70), with 20 males and 26 females and a median KPS at diagnosis of 80 (range 50–90). Twenty-three out of 46 (50%) pre-treatment MRI demonstrated some degree of contrast enhancement. Twenty-three of 46 patients were treated upfront, while 23 had received prior radiation therapy or nitrosourea-based chemotherapy. All patients received temozolomide 200 mg/m2 die for 5 days every 4 weeks until progression or unacceptable toxicity. Response was evaluated, according to Macdonald criteria, on T1-weighted with Gadolinium and FLAIR images. Results: Two patients (4%) showed a CR of the contrast enhancing area, 2 patients (4%) a PR, 5 (11%) a minor response, 18 (39%) a SD and 19 (42%) a PD. Overall response rate (CR + PR + “minor response”) was 19%, while a clinical benefit was observed in 13/46 patients (28%). Median TTP was 9 months (range 1–27), and median survival 14 months (range 3–123). PFS at 6 months was 57%, at 12 months 35%. Oligodendroglial tumours showed a 38% response rate and a TTP of 11 months. Response rate was higher among patients treated at progression compared to those treated upfront (13% versus 26%). Grade III-IV haematological toxicity was mild. Conclusions: Temozolomide has some activity in primary GC (19% response rate), and is well tolerated. A significant neurological improvement can be observed in patients with either response or stable disease on MRI. To improve the efficacy of temozolomide in the upfront setting (in order to delay a large field RT), a phase II study with a dose-dense regimen is ongoing. No significant financial relationships to disclose.

Detrimental Effects of Tumor Progression on Cognitive Function of Patients With High-Grade Glioma

There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

Syndrome de Turcot confirmé par biologie moléculaire

Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer. We report a case of a 45-year-old woman who underwent in 1995 neuro-oncological treatment for an anaplastic astrocytoma (grade III according to the World Health Organization classification). Treatment included complete surgery, radiotherapy, a first-line nitrosourea-based chemotherapy regimen and a second-line platinium salt-based regimen. It was then noted that the patient's brother had colorectal cancer. A genetic study detected a germ-line mutation on the hMSH2 gene specific of HNPCC syndrome (Human Non Polyposis Colorectal Cancer). Colonoscopy was normal. Eight years after the diagnosis, the patient developed a gliomatosis cerebri and died. Relevant personal and familial history can provide the clue to the diagnosis of Turcot's syndrome. Molecular diagnosis may contribute to appropriate care of affected patients.

Recent developments in the use of chemotherapy in brain tumours

Several recent studies have further clarified the role of chemotherapy in newly diagnosed anaplastic glioma. For newly diagnosed glioblastoma, combined daily radiotherapy with daily temozolomide followed by six cycles of adjuvant temozolomide improves overall survival. This benefit is especially observed in patients with a methylated promotor of the MGMT gene which encodes an alkyltransferase; this observation however, needs confirmation. Although oligodendroglial tumours are sensitive to chemotherapy, classical adjuvant nitrosourea-based chemotherapy does not improve overall survival in newly diagnosed anaplastic oligodendroglioma, even in the subset of 1p/19q loss tumours. It may increase progression-free survival however, and further studies must show if combined modality treatment with daily chemotherapy during radiotherapy increases survival. Trials exploring the role of chemotherapy in low-grade glioma are ongoing. No standard chemotherapy is currently available for highly anaplastic glioma failing first-line temozolomide-based therapy.

Phase I/II study (UKT-03) of CCNU/temozolomide chemotherapy in addition to radiotherapy as first-line therapy for glioblastoma: Status report

1566 Background: Primary chemotherapy with single agent temozolomide or nitrosourea-based chemotherapy in addition to radiotherapy prolongs survival in patients with glioblastoma. Previous studies ...

Nitrosourea-based chemotherapy in optic pathway glioma with progressive visual loss

Purpose: To report two patients with progressive optic pathway gliomas who had reversible visual loss after treatment with nitrosourea-based chemotherapy. Design: Retrospective case series. Results: Two patients with optic pathway gliomas and progressive visual field loss were treated with nitrosourea-based chemotherapy consisting of 6-thioguanine, procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (TPCV). Both patients experienced dramatic and sustained visual improvement after treatment. Conclusion: Patients with progressive optic pathway gliomas may benefit from initial therapy with nitrosourea-based chemotherapy.This treatment might delay or avoid the need for radiation therapy and its associated side effects, especially in younger aged children.

314 Partial brain irradiation (PBI) or whole brain irradiation (WBI), the justified solution

Glioblastoma (GBM) is the most malignant among astrocytic tumours and is associated with a poor prognosis. Age, performance status, mini-mental status examination score, methylation status of methylguanine methyltransferase promoter and extent of surgery constitute the main prognostic factors. Surgery aimed to complete resection should be the first therapeutic modality in the management of glioblastoma. However, complete resection is virtually impossible due to infiltrative nature of this disease and relapse is almost inevitable. Postoperative concomitant chemo-radiation is the standard treatment and consists of 60 Gy of external-beam radiotherapy (to be delivered to a target volume including a 2–3 cm ring of tissue surrounding the perimeter of the contrast enhancing lesion on pre-operative CT/MRI scans) plus temozolomide (TMZ) administered concomitantly (75 mg/m2 daily) and after radiotherapy (150–200 mg/m2, for 5 days every 4 weeks). At time of recurrence/progression, a nitrosourea-based chemotherapy constitutes a reasonable option, as well as a temozolomide re-challenge for patients without progression during prior temozolomide treatment.

Intra-arterial cisplatin plus oral etoposide for the treatment of recurrent malignant glioma: a phase II study.

Twenty-five adults with recurrent malignant glioma were enrolled into a phase II clinical study. All patients had undergone surgical resection and had failed radiotherapy and first-line treatment with nitrosourea-based chemotherapy; five had failed second-line chemotherapy. Our objective was to test the efficacy of combining intra-arterially (i.a.) infused cisplatin and oral etoposide. Using conventional angiographic technique to access anterior/posterior cerebral circulation, cisplatin 60 mg/m2 was administered by i.a. infusion on day 1 of treatment. Oral etoposide 50 mg/m2/day was given days 1-21, with a 7 day rest interval between courses. Response to treatment was evaluated in 20 patients. Two patients with anaplastic astrocytoma had partial responses (PR) and six patients experienced stable disease (SD) for an overall response rate (PR +/- SD) of 40%. The median time to disease progression (MTP) following treatment for the responder subgroup was 18 weeks. The median survival time from treatment (MST) for the responders (n = 8) and non-responders (n = 12) was 56.5 weeks and 11 weeks, respectively. Combined i.a. cisplatin and oral etoposide was well-tolerated, but produced an objective response in only a minority of patients. Those considered responders (PR + SD) experienced significant survival advantage when compared to the non-responders. Nonetheless, i.a. delivery of chemotherapy is an expensive and technologically burdensome treatment for most patients to access, requiring proximity to a major center with neuro-oncological and neuroradiological clinical services. This is of special concern for patients suffering recurrent disease with progressive neurological symptoms at a time in their course when quality of life must be safeguarded and palliation of symptoms should be the therapeutic goal. Despite the efforts of previous investigators to use this combination of agents to treat recurrent malignant glioma, we cannot recommend the use of i.a. chemotherapy for salvage treatment of this disease.

Effective chemotherapy for advanced CNS embryonal tumors in adults.

Embryonal tumors of the CNS include, among others, medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors (PNETs). Almost all data on the treatment of embryonal CNS tumors are derived from the pediatric population, since these tumors are uncommon in adulthood. The purpose of this study was to examine the rate and duration of response to chemotherapy of advanced embryonal CNS tumors in adults. We retrospectively studied all adult (> 18 years of age) patients with advanced embryonal tumors of the CNS who received chemotherapy at our institution between 1976 and 1994. Seventeen consecutive patients were treated with regimens that contained either nitrosourea or cisplatin or both sequentially, with no patients having received the combination of nitrosourea and cisplatin concurrently. In patients who received cisplatin-based chemotherapy, responses were observed in 84.5% (26% complete response [CR] rate), 10.5% remained stable, and 5% progressed. The median time to progression was 18 months for patients who had a CR, 6 months for those with partial response (PR), and 10 months for stable patients. Among patients who received nitrosourea-based chemotherapy, PR was observed in 27%, 36.5% remained stable, and 36.5% progress. The median time to progression was 6 months for patients who had a PR and 6.5 months for stable patients. In adults with advanced embryonal CNS tumors, conventional-dose intravenous cisplatin-based chemotherapy regimens are able to produce responses in the majority of the patients (84.5%), even as second- or third-line regimens. Nitrosourea-based regimens less frequently produce responses (27%).

Chemotherapy response criteria in malignant glioma.

No one has ever proven a relationship between the extent of response to chemotherapy in malignant glioma and time to progression or survival. We studied the predictive value of "imaging response" following two courses of nitrosourea-based chemotherapy in 136 patients with recurrent astrocytoma/malignant glioma. We performed image analysis by blinded side-to-side comparison of sequential studies, and categorized response into: partial response (PR) (>50% reduction), minor response (MR) (25-50% reduction), stable disease (SD) (<25% change), progressive disease (PD) (>25% increase). Patients with PR, MR, and SD did not differ with respect to time to progression (TTP) (p > 0.2) or survival (p > 0.2). Median TTP was 27 weeks for SD, 43 weeks for MR, and 30 weeks for PR. Patients with PD had a significantly reduced survival (p < 0.001). Median survival was 21 weeks for PD, 53 weeks for SD, 63 weeks for MR, and 48 weeks for PR. The lack of relationship between response and TTP may be due to early relapses in patients with response, a cytostatic benefit of chemotherapy in some patients who do not have an objective response, or a relatively favorable natural history in some tumors that do not respond to chemotherapy. Our data do not support the validity of current response grading, assessed after two courses of chemotherapy. Further research and validation of response criteria is necessary.

Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.

The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O6-benzylguanine (O6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.e.) in athymic rats. Whereas i.a. O6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.e. activity 8 h after administration, intraperitoneal (i.p.) O6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O6BG (10 mg/kg) and i.a. O6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21. P = 0.001). O6BG i.a. or i.p. (days 22 and 23, P = 0.001), BCNU i.v. (37.5 mg/kg, day 29, P = 0.001), and O6BG i.p. (10 mg/kg), plus BCNU i.v. (6.25 mg/kg, day 37, P < 0.001). Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

Hypofractionated stereotactic radiotherapy in the management of recurrent glioma

Purpose : This study aimed to assess the efficacy and toxicity of hypofractionated stereotactic radiotherapy (SRT) in the management of patients with recurring glioma. Methods and Materials : From January 1989 to July 1994, 36 patients with glioma were treated at the time of recurrence. Twenty-nine had recurrent high-grade astrocytoma, 3 high-grade oligodendroglioma, 1 high-grade ependymoma, and 3 pilocytic astrocytoma. Hypofractionated stereotactic radiotherapy was given using either three noncoplanar arcs or four to six noncoplanar fixed beams at 5 Gy/fraction, to doses ranging from 20 to 50 Gy initially on a dose escalation program. Two patients received 20 Gy, 8 received 30 Gy, 10 received 35 Gy, 10 received 40 Gy, 5 received 45 Gy, 5 received 45 Gy, and 1 received 50 Gy, treating 5 days/week. Results : The median survival of 29 patients with recurrent high-grade astrocytoma was 11 months from the time of SRT. This compared to a median survival of 7 months for a cohort matched for age, performance status, and initial histologic grade who received nitrosourea-based chemotherapy at recurrence ( p < 0.05). Initial low-grade astrocytoma histology was the only favorable prognostic factor for survival on univariate analysis. Three patients with recurrent oligodendroglioma remain alive 11, 23, and 34 months after SRT. Three children treated for recurrent pilocytic astrocytoma remain alive 14, 41, and 55 months following SR. Presumed radiation damage, defined as reversible steroid-dependent toxicity, was observed in 13 patients (36%) and required reoperation in 2 (6%). A total dose of >40 Gy was a major predictor of radiation damage ( p < 0.005). Conclusion : Hypofractionated SRT is a noninvasive, well-tolerated, outpatient-based method of delivering palliative, high-dose-, focal irradiation.

Combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas.

To determine the efficacy of the combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea for patients with recurrent malignant gliomas after failure of either previous radiotherapy alone or previous radiotherapy plus nitrosourea-based chemotherapy. Seventy-seven patients with recurrent malignant gliomas were studied. 6-Thioguanine was administered for 4 days before lomustine, and procarbazine was administered for 1 day before and 2 days after lomustine to potentiate lomustine's antitumor effect. Hydroxyurea was initiated 1 day before lomustine and continued for a total of 3 days. Thirty patients with glioblastomas and 47 patients with anaplastic gliomas were eligible for evaluation. In the glioblastoma group, 2 of 30 patients had a partial response and 8 of 30 patients had stable disease. This group of patients who responded and had stable disease included 6 of 10 patients who had not undergone previous chemotherapy but only 4 of 20 who had undergone previous chemotherapy. The overall median time to disease progression for the glioblastoma group was 9 weeks. In the anaplastic glioma group, 11 of 47 patients had a partial response and 25 of 47 had stable disease, including 23 of 30 without previous chemotherapy and 13 of 17 who had undergone previous chemotherapy. The median time to disease progression for the whole anaplastic glioma group was 24 weeks; however, the time to disease progression was 50 weeks for responding patients who had not undergone previous chemotherapy and 25 weeks for those who had undergone previous chemotherapy. Our results indicate that chemotherapy with a combination of 6-thioguanine, procarbazine, lomustine, and hydroxyurea is active for patients with recurrent anaplastic gliomas and glioblastomas not previously treated with nitrosourea-based chemotherapy but is inactive for patients with glioblastomas previously treated with chemotherapy.

Pre-radiation chemotherapy for malignant glioma in adults.

To review our experience with pre-radiation chemotherapy for malignant glioma. Consecutive adults with newly diagnosed glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic mixed glioma with a Karnofsky Performance Score of 60 or greater were treated with one cycle of procarbazine, lomustine and vincristine or lomustine alone, prior to radiation. Computed tomographic scans were obtained soon after surgery, eight weeks later, after radiation, and at regular intervals thereafter. The effects of chemotherapy and subsequent radiation and durations of tumor control and survival were assessed in this single arm, single center, prospective trial. Thirty-seven patients started chemotherapy, 36 were rescanned eight weeks after diagnosis. Five patients (16%) responded to the first cycle of chemotherapy, three had glioblastoma and two anaplastic oligodendroglioma. Seven (19%) progressed during the first cycle, 6 had glioblastoma; with the addition of radiation one progressive case responded, three stabilized, and three continued to progress. Median times to progression and median durations of survival were 26 weeks and 60 weeks for the entire group, 24 weeks and 44 weeks for glioblastoma, and greater than 104 weeks for anaplastic astrocytoma. Most patients with glioblastoma do not respond to one cycle of nitrosourea-based chemotherapy given prior to radiation, but patients with anaplastic oligodendroglioma sometimes do. Patients with anaplastic astrocytoma may not respond to one cycle of chemotherapy, but often respond to subsequent radiation. Judging by survival results, radiation can be delayed eight weeks without appearing to compromise patient outcome. Pre-radiation chemotherapy with newer agents can be evaluated more fully in the future knowing that brief delays in radiation are unlikely to yield substantially inferior results.

Treatment of high-risk medulloblastoma and other primitive neuroectodermal tumors with reduced dose craniospinal radiation therapy and multi-agent nitrosourea-based chemotherapy.

To investigate toxicity, and progression-free survival (PFS) of children and adults with newly diagnosed medulloblastoma, pineoblastoma, and other primitive neuroectodermal tumors (PNET) with a combined modality regimen of radiation therapy and adjuvant nitrosourea-based chemotherapy. Between 1984 and 1992, 34 evaluable patients with newly diagnosed tumors were treated with chemotherapy and radiotherapy according to a single-arm phase II study. One cycle of chemotherapy was given prior to and for 6 cycles following craniospinal radiotherapy (CSA). Procarbazine, 6-thioguanine, and dibromodulcitol were given before lomustine (CCNU) to enhance CCNU-induced tumor cell kill and to reduce alkyltransferase repair of ethylated DNA. Vincristine was given 1 and 3 weeks after CCNU to kill cells that began to cycle after the challenge of the first four drugs. Chemotherapy was given in the outpatient setting. CSA radiation was planned to deliver a dose of 54 Gy to the primary tumor site and 24 Gy to the rest of the neuroaxis. Additional radiation was given to bulky disease outside the primary site if present. Hydroxyurea was used during radiotherapy as a radiosensitizer. Patients treated included 27 with medulloblastoma, 5 with pineoblastoma, and 2 with supratentorial PNET. All but 3 medulloblastoma cases were considered high risk either because of bulky residual disease remaining after surgery and/or metastatic disease detected during staging. For the 34 patients, 24 have progressed, 20 have died. Overall estimated PFS was 55% at 3 years and 35% at 5 years. The 5-year survival estimate is 56%. One patient had inadequate staging to determine M stage. Of the remaining 33 patients, there were 19 patients who had metastatic disease at diagnosis (M1 or higher stage) who had a 3- and 5-year PFS of 42 and 21% respectively and 5-year survival of 42%. There were 14 patients who had negative staging (M0 stage) who had a 3- and 5-year PFS of 69 and 52% respectively and 5-year survival of 71%. Of the 27 patients with medulloblastoma, 15 had M1 or higher stage. These 15 patients had a 5-year PFS and overall survival of only 20 and 40% respectively. Medulloblastoma patients with M0 staging had a 5-year PFS and overall survival of 52 and 73% respectively. Overall toxicity was primarily due to mild hematological toxicity and related to the use of the chemotherapy. The results using this therapy in high-risk groups of patients does not offer any improvement over results reported in other recent studies. The reason for these results may be due to the lowered craniospinal radiation dose.

Age influences chemotherapy response in astrocytomas.

In patients with cerebral astrocytomas treated with nitrosourea-based chemotherapy, to determine whether age is predictive of response, time to progression, survival, or rate of complications. Retrospective analysis of neuroimaging studies and clinical data. University hospital with a busy neuro-oncology service. One hundred forty-eight patients with pathologically confirmed malignant astrocytomas or recurrent astrocytomas. Partial response occurred in 39% of patients aged < 40 years, in 17% of those aged 40 to 59, and in only 5% of those aged > or = 60 (p < 0.001). Median time to progression after chemotherapy was 23 weeks in patients aged < 60 and 6 weeks in patients aged > or = 60 (p < 0.001). Median survival after chemotherapy was 43 weeks in patients aged < 60 but only 24 weeks in patients aged > or = 60 (p < 0.001). Differences between age groups in response rate, time to progression, and survival persisted with adjustment for tumor grade. The risk of myelosuppressive complications requiring hospitalization was significantly related to age (p = 0.03); such complications occurred in 35% of patients aged > or = 60 and 16% of patients under 60 years. Age is strongly predictive of the likelihood of a response to chemotherapy, time to progression, survival, and risk of myelosuppressive complications. Patients aged > or = 60 have a lower change of benefit and an increased risk of myelosuppressive complications from chemotherapy for astrocytomas compared with younger patients.

O6-methylguanine-DNA methyltransferase in tumors and cells of the oligodendrocyte lineage.

Oligodendrogliomas respond to nitrosourea-based chemotherapy and are induced in rats following transplacental exposure to ethylnitrosourea, observations suggesting that neoplastic and normal cells of the oligodendrocyte lineage are "sensitive" to nitrosoureas. Nitrosoureas alkylate DNA at O6-guanine with repair mediated by O6-methylguanine-DNA methyltransferase (MGMT). The cytotoxic and carcinogenic properties of the nitrosoureas appear related to MGMT activity. To explore why oligodendrogliomas respond to chemotherapy, we measured MGMT activity in five chemosensitive human oligodendrogliomas and in rat oligodendrocyte lineage cells. We also measured MGMT activity in rat astrocytes and compared the cytotoxic effects of carmustine (BCNU) on oligodendrocyte lineage cells and astrocytes. Low levels of MGMT activity were found in five of five human oligodendrogliomas. Cultures of neonatal rat glia enriched for oligodendrocyte lineage cells also had low levels of MGMT activity, approximately one-third that found in astrocytes (p < 0.02), and oligodendrocyte lineage cells were more sensitive to BCNU than astrocytes. Low MGMT activity may contribute to the chemosensitivity of some human oligodendrogliomas and rat oligodendrocyte lineage cells also have low levels. If drug resistance mechanisms in tumors reflect the biochemical properties of their cells of origin, then normal glia may serve as a laboratory substitute for human glioma.

Survival in patients with recurrent glioma as a measure of treatment efficacy: Prognostic factors following nitrosourea chemotherapy

The assessment of efficacy of treatment in patients with recurrent glioma is notoriously difficult, and survival is the most objective endpoint. Between 1970 and 1992, a cohort of 211 patients with recurrent glioma received nitrosourea-based chemotherapy at the time of disease progression. The median survival from the start of chemotherapy was 7 months, with 30% 1-year and 10% 2-year survival probabilities. One-year survival was 22% in 147 patients with recurrent high-grade astrocytoma, 41% in 37 patients with low-grade astrocytoma and 45% in 24 patients with oligodendroglioma. Age, histological grade and Karnofsky performance status (KPS) at recurrence were independent prognostic factors for survival on multivariate analysis. Based on patients' age, tumour grade and KPS, it was possible to define three distinct prognostic groups with 1-year survival probabilities of 60, 21 and 17% ( P < 0.005). Response to chemotherapy was difficult to assess but correlated with prognostic subgroup, with highest response rate (46%) in the most favourable group and lowest (13%) in the poor prognostic group. In patients with recurrent glioma, patient and tumour parameters are the major determinants of outcome which are identical to prognostic factors at the time of primary diagnosis. They can be used to provide prognostic information for the individual patient, and to stratify patients particularly in trials assessing the efficacy of novel treatments.

Recurrent brainstem gliomas treated with oral VP-16.

12 patients: (7 males and 5 females) with recurrent brainstem gliomas were treated with the oral topoisomerase inhibitor VP-16 (Etoposide). Patients ranged in age from 3 to 49 years with a median age of 7 years. All patients had been previously treated with radiation therapy (conventional fractionation: 4; hyperfractionation: 8) and 5 had received prior nitrosourea-based chemotherapy at time of tumor recurrence. Tumor recurrence was documented by radiographic tumor enlargement utilizing brain MRI with gadolinium enhancement (12) and clinical neurologic deterioration (9). Two patients underwent biopsy pathologically documenting tumor recurrence. Each cycle of therapy consisted of 21 days of VP-16 (50 mg/m2/day) followed by a 14 day rest followed by an additional 21 days of VP-16 (50 mg/m2 day). Complete blood counts were followed bi-weekly and a neurologic examination and brain MRI scan with contrast were performed prior to initiation of each cycle of therapy. Treatment related complications included: partial alopecia (5); diarrhea (5); weight loss (4); neutropenia (2); and thrombocytopenia (4). No patient required transfusion or antibiotic treatment of neutropenic fever. There were no treatment related deaths. 12 patients were evaluable of whom 6 demonstrated a radiographic response (1 complete; 3 partial; 2 stable disease) with a median duration of response of 8 months. In summary; oral VP-16 is a well tolerated and relatively non-toxic chemotherapeutic agent with apparent activity in this small cohort of patients with recurrent brainstem gliomas.