New place of the chemotherapy in gliomas

During these last 25 years, despite numerous phases III studies, standard of treatment in glioblastoma multiforme (GBM) consisted of surgery and post-operative radiotherapy, while benefit of chemotherapy was a matter of debate. A phase III study, conducted by EORTC and NCI Canada and involving 573 patients, concluded clearly to the benefit of adding temozolomide during and after radiotherapy as adjuvant treatment. Using this schedule, median survival increase from 12,1 to 14,6 months, and 2 year survival rate from 8 to 26%. In the same time, for anaplastic oligodendroglioma (AO) the phase III study conducted by Cairncross, that compared radiotherapy to a schedule that deliver a chemotherapy with PCV followed by radiotherapy, failed to determine a significant benefit on overall survival, despite the particular chemosensitivity of theses tumors. Moreover, these two studies did underlined impact of biological markers (methylation of the promoter of O6 methylguanine DNA transferase (MGMT) gene for GBM and chromosomes 1p and 19q deletion for AO), that may become decisional markers in the future. We review here the new place of chemotherapy in the adjuvant treatment of GBM and anaplastic gliomas, as well as the impact of these pivotal studies on second lines therapies, and future clinical research.     

Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: A retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy.

PURPOSE: To determine any differences in outcome for patients with anaplastic astrocytoma (AA) treated with adjuvant carmustine (BCNU) versus procarbazine, lomustine, and vincristine (PCV) chemotherapy. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) database was reviewed for patients with newly diagnosed AA treated according to protocols that included either BCNU or PCV adjuvant chemotherapy. All patients were treated with radiation therapy. The outcome analysis included overall survival, taking into account patient age, extent of resection, Karnofsky performance status (KPS), and treatment group (BCNU v PCV). Stratified and nonstratified Cox proportional hazards models were used, as well as an analysis using matched cases between the groups. RESULTS: A total of 257 patients were treated with BCNU according to RTOG protocols 70-18, 83-02, and 90-06; 175 patients were treated with PCV according to RTOG protocol 94-04. All pretreatment characteristics except KPS were well balanced by treatment group; 61% of the BCNU group had a KPS of 90 to 100 compared with 73% of the PCV group (P =.0075). No statistically significant difference in survival was observed in any age group or by KPS or extent of surgery. The stratified analysis also showed no trends for improved survival by treatment group (P =. 40). The Cox model identified only age, KPS, and extent of surgery as important variables influencing survival, not treatment group. Matching cases between groups using age, KPS, and surgery resulted in 133 matched pairs. No difference in survival was observed (P =. 41). In a Cox model in which each matched pair is a strata, there was no difference between groups (P =.20). CONCLUSION: Using this retrospective analysis, there does not seem to be any survival benefit to PCV chemotherapy. Future phase III studies for patients with AA may need to consider whether BCNU or PCV is used in the control arm.     

High-grade gliomas in patients with prior systemic malignancies

BACKGROUND: The current study was conducted to characterize the impact of a prior malignancy on the diagnosis, treatment, and outcome of high-grade glioma. METHODS: A retrospective study of 21 patients with a histologic diagnosis of glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO) after a prior diagnosis of solid tumor or hematologic malignancy was conducted. Glioma histology (GBM vs. AA/AO), patient age ( 60 years), and extent of resection (biopsy vs. subtotal vs. complete) were evaluated for their prognostic influence. RESULTS: Of the 21 patients studied, 17 had GBM, 3 had AA, and 1 patient had high-grade AO. There were 25 systemic carcinomas diagnosed in 21 patients (18 solid tumors including breast carcinoma, prostate carcinoma, and melanoma and 7 hematologic malignancies). The glioma occurred within a previous radiation field in only three patients, two of whom had solid tumors and one of whom had a childhood hematologic malignancy. Surgical resection was the initial treatment for the brain tumor in 17 patients, and the majority of patients received radiation therapy and adjuvant chemotherapy. Four patients who initially were misdiagnosed as having brain metastases received whole brain radiation therapy as their initial treatment, thereby compromising optimal care. The overall median survival for all the patients in the current study was 14 months (range, 1-44 months) from the time of brain tumor diagnosis. The extent of resection was found to be the only prognostic variable that was associated with survival (P = 0.03). CONCLUSIONS: Secondary glioma may occur in patients as a consequence of therapy for a prior malignancy, but most often represents a sporadic event. The outcome and recommended treatment are identical to those for patients with primary gliomas. Accurate diagnosis is essential; neuroimaging often is suggestive of a primary brain tumor and should initiate surgical intervention so that histopathology can be obtained early and appropriate treatment instituted.     

Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

Data from Northern California Oncology Group protocol 6G61, which was closed in February 1983, were reanalyzed in December 1988. The protocol called for a randomized trial that compared the effects of following 60 Gy radiation/oral hydroxyurea treatment with either carmustine (BCNU) or the combination of procarbazine, lomustine (CCNU), and vincristine (PCV) for two histologic strata: glioblastoma multiforme and other anaplastic gliomas. PCV produced longer survival and time to tumor progression than BCNU for both histologic groups, although the difference was statistically significant only for the anaplastic gliomas. With PCV treatment, time to progression and survival doubled for anaplastic glioma patients in the 50th and 25th percentiles.     

Radiation Therapy and Hydroxyurea Followed by the Combination of 6-Thioguanine and BCNU for the Treatment of Primary Malignant Brain Tumors

Purpose: This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU.Methods and Materials: Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m² every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m²/dose of 6TG, with escalation to a maximum dose of 100 mg/m²/dose. The primary study end points were time to tumor progression and survival.Results: A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m²) or lower dose of 6TG was not statistically significant in this model.Conclusions: This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.     

Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.     

Chemoradiation for anaplastic oligodendrogliomas: clinical outcomes and prognostic value of molecular markers

Combination of procarbazine, lomustine and vincristine (PCV) with radiation therapy (RT) has been associated with longer survival in patients with anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA), especially in those with chromosome 1p/19q codeletion. We report a multicenter retrospective study of 84 consecutive adult patients with AO and AOA treated with RT plus concomitant and adjuvant temozolomide (TMZ) between February 2004 and January 2011. Correlations between chromosome 1p/19q codeletion, isocitrate dehydrogenase1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. For all 84 patients the median overall survival (OS) and progression-free survival rates were 55.6 and 45.2 months, respectively. Grade 3 or 4 hematological toxicity occurred in 17 % of patients. Chromosome 1p/19q codeletion was detected in 57 %, IDH1 mutation in 63 %, and MGMT promoter methylation in 74 % of evaluable patients. In multivariate analysis the presence of chromosome 1p/19q codeletion was associated with significant survival benefit (median OS 34 months in noncodeleted tumors and not reached in codeleted tumors; HR 0.16, 95 % CI 0.03–0.45; P = 0.005). IDH1 mutation was also of prognostic significance for longer survival (P = 0.001; HR 0.20, 95 % 0.06–0.41), whereas MGMT promoter methylation was only of borderline significance. The study indicates that RT with concomitant and adjuvant TMZ is a relatively safe treatment associated with longer survival in patients with 1p/19q codeleted and IDH1 mutated tumors. Results from ongoing randomized studies will be essential to clarify if RT plus TMZ may provide survival as good as or better than RT combined with PCV for patients with AO and AOA.     

A retrospective study of the safety of BCNU wafers with concurrent temozolomide and radiotherapy and adjuvant temozolomide for newly diagnosed glioblastoma patients

Despite aggressive therapy, most patients with glioblastoma multiforme (GBM) die within 2 years of diagnosis. The efficacy and safety of carmustine (BCNU) wafers followed by radiotherapy have been demonstrated in patients with malignant glioma. However, there is a reluctance to recommend them for newly diagnosed GBM patients due to the potential toxicity of BCNU wafers combined with temozolomide (TMZ) chemotherapy and radiotherapy. The purpose of this study was to assess the safety of BCNU wafers implanted at initial surgery, followed by concurrent TMZ and radiotherapy, and then adjuvant TMZ for the treatment of newly diagnosed GBM. We conducted a retrospective analysis of clinic and hospital records of 21 newly diagnosed GBM patients who received multimodal therapy at Florida Hospital Cancer Institute from January 2003 to December 2005. Three of 21 patients had grade 3 toxicities (two with cerebritis, one with psychosis). Grade 4 toxicities were not observed. Median overall survival was 17 months, median progression-free survival was 8.5 months, and 2-year survival was 39%. Multimodal treatment with surgery, BCNU wafers, radiotherapy, and TMZ did not result in a notable increase in significant toxicities. Survival outcomes were comparable to those in other studies in which patients were treated with concurrent TMZ and radiotherapy followed by adjuvant TMZ. Thus, the implantation of BCNU wafers prior to TMZ and radiotherapy appears safe in newly diagnosed GBM patients.     

Concomitant Chemoradiotherapy, Neutron Boost, and Adjuvant Chemotherapy for Anaplastic Astrocytoma and Glioblastoma Multiforme

The survival rate for patients with malignant gliomas is poor. We describe the results of a prospective study using concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for patients with malignant gliomas. Forty-two patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with postoperative photon radiation 45 Gy/25 fraction (fxs) with concomitant continuous intravenous infusion of 5-fluorouracil at 300 mg/m²/day × 5 days and hydroxyurea 0.5 g orally every 12 hr for 6 days for 5 consecutive weeks, followed by a neutron boost of 450 N cGy/6 fxs delivered twice weekly. Adjuvant chemotherapy with procarbazine, CCNU, and vincristine (PCV) was given up to 1 year or until tumor progression. Thirty-four patients (81%) had GBM and 8 patients (19%) had AA. Sixteen patients (38%) were ineligible for the neutron boost because of large tumors or poor performance status and instead received a photon boost with concomitant chemotherapy for a total dose of 60-65 Gy to the tumor. The overall median survival is 68 weeks at a median follow-up of 203 weeks (range 166-302 weeks for the 11 patients remaining alive); 7/8 patients with AA are alive, 2 of these with progressive disease. For AA the median survival is not reached at a median follow-up of 203 weeks (range 166-302 weeks for the 7 patients alive with AA). Time to tumor progression for the 1 dead patient with AA was 35 weeks and the other 2 patients failed at 171 weeks and 179 weeks following treatment. The median survival for the 34 patients with GBM was 62 weeks; 4/34 patients with GBM are alive at 285, 238, 216, and 206 weeks. Multivariate survival analysis in the 34 patients with GBM revealed age and Karnofsky performance status as important prognostic factors. Extent of surgery and neutrons did not affect survival. Concomitant chemoradiotherapy was well tolerated by all patients. The only toxicities observed were mucositis × grade II in 3 patients (7%) and mild myelosuppression in 1 patient (2.4%). Adjuvant PCV was well tolerated. Continuous concomitant chemoradiotherapy was well tolerated by all patients with acceptable side effects. The survival rate for the patients with GBM suggests no significant impact on the prognosis for these patients. Patients with AA did well; however, the patient numbers are small.     

Advantage of post-radiotherapy chemotherapy with CCNU, procarbazine, and vincristine (mPCV) over chemotherapy with VM-26 and CCNU for malignant gliomas.

Between 1981 and 1987, 133 patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were treated with surgery and post-operative radiotherapy. 36 AA and 31 GBM patients were treated with adjuvant chemotherapy consisting of CCNU 100 mg/m2 day 1, procarbazine 60 mg/m2 days 1-14, and vincristine 1.4 mg/m2 (max. 2 mg) days 1 and 8, every 6 weeks which we called a "modified PCV" (mPCV) regimen. 37 AA and 29 GBM patients were treated with adjuvant chemotherapy consisting of VM-26 75 mg/m2 days 1 and 2, and CCNU 60 mg/m2 days 3 and 4, every 6 weeks. Prognostic covariates such as patient's age, Karnofsky performance status score and the extent of surgery were balanced between the two treatment groups. The time to tumor progression and survival time for both regimens show that mPCV produces a two-fold increase in these factors at the 50th and 25th percentile for AA patients, but not for GBM patients, although there are more long-term GBM survivors with mPCV than with the VM-26 + CCNU regimen.     

Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy.

PURPOSE: Most primary oligodendrogliomas and mixed gliomas (oligoastrocytoma) respond to treatment with procarbazine, lomustine, and vincristine (PCV), with response rates of approximately 80%. However, limited data on second-line treatments are available in patients with recurrent tumors. A novel second-generation alkylating agent, temozolomide, has recently demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme and anaplastic astrocytoma. This study describes the effects of temozolomide in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic mixed oligoastrocytoma (AOA). PATIENTS AND METHODS: Forty-eight patients with histologically confirmed AO or AOA who had received previous PCV chemotherapy were treated with temozolomide (150 to 200 mg/m2/d for 5 days per 28-day cycle). The primary end point was objective response. Secondary end points included progression-free survival (PFS), time to progression, overall survival (OS), safety, and tolerability. RESULTS: Eight patients (16.7%) experienced a complete response, 13 patients (27.1%) experienced a partial response (objective response rate, 43.8%), and 19 patients (39.6%) experienced stable disease. For the entire treatment group, median PFS was 6.7 months and median OS was 10 months. For objective responders, median PFS was 13.1 months and median OS was 16 months. For complete responders, PFS was more than 11. 8 months and OS was more than 26 months. Response correlated with improved survival. Temozolomide was safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia. CONCLUSION: Temozolomide is safe and effective in the treatment of recurrent AO and AOA.     

Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas.

PURPOSE: In the current study, we sought to determine whether the addition of DFMO (alpha-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. PATIENTS AND METHODS: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m(2) p.o. q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) follow-ups were nominally at the end of each 6- or 8-week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematological and other adverse effects were at 2-week intervals. RESULTS: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1% anaplastic astrocytoma (AA), 3.5% anaplastic oligoastrocytoma (AOA), 14% anaplastic oligodendroglioma (AO), and 4.4% other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3% AA; (b) 7% AOA; (c) 21.1% AO; and (d) 2.6% malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. CONCLUSIONS: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.     

Comparative analysis of temozolomide (TMZ) versus 1,3-bis (2-chloroethyl)-1 nitrosourea (BCNU) in newly diagnosed glioblastoma multiforme (GBM) patients

PURPOSE: Although TMZ replaced BCNU as the standard initial chemotherapy in the treatment of GBM, no studies have been reported comparing BCNU with TMZ. We therefore did a retrospective analysis comparing these agents as initial therapy in GBM. PATIENTS AND METHODS: Eighty-one patients with GBM in our institution received both radiation and chemotherapy as initial treatment after surgery or biopsy; 49 receiving BCNU and 32 TMZ. These were analyzed for overall survival (OS) and progression-free survival (PFS) versus the type of chemotherapy used. The influence of salvage therapy on the outcome was investigated also. RESULTS: Median OS was superior in the TMZ versus the BCNU group (15.9 vs. 11.5 months) and the curves were judged to be significantly different by the log-rank test; P < 0.02. However, PFS was not significantly different between the two groups. Bevacizumab plus irinotecan (BI) was used as salvage therapy in one-third of the TMZ patients but in none of the BCNU patients. When patients receiving BI were omitted from the TMZ group the OS curve overlapped that of BCNU patients. CONCLUSION: These data suggest that the superior OS of the TMZ-treated GBM patients was not due to better tumor control by TMZ but was possibly related to the newer salvage therapy that was available to them.     

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.     

Temozolomide for malignant primary spinal cord glioma: an experience of six cases and a literature review

Malignant primary spinal cord gliomas (PSCGs) are rare, and the optimal treatment for these lesions remains controversial. We report herein treatment outcomes of six malignant PSCGs managed with temozolomide (TMZ)-based multidisciplinary treatment. TMZ was administered concomitantly with fractionated radiotherapy for two newly diagnosed primary spinal cord glioblastoma multiforme (GBM), followed by adjuvant chemotherapy with TMZ. For one anaplastic astrocytoma (AA) and one anaplastic ependymoma (AEPN), TMZ was given as adjuvant therapy at first recurrence. One malignantly transformed ependymoma (EPN) and one malignantly transformed diffuse astrocytoma (DA) were treated with TMZ after radiotherapy at second recurrence. Two patients with newly diagnosed GBM died, 12 and 16 months, respectively, after being treated with TMZ, during and after radiation therapy. One patient with AA and one with malignantly transformed EPN showed good response to salvage therapy with TMZ and had stable disease 21 and 20 months, respectively, after TMZ treatment. One patient with recurrent AEPN and one with malignantly transformed DA died from uncontrolled progression of the lesions despite TMZ chemotherapy. Three patients developed grade 1 or 2 neutropenia, anemia, and infection. Nonhematologic toxicities occurred in all patients; however, they were below grade 3 in severity. TMZ treatment may have a positive effect on control of malignant PSCGs and survival for some patients. Specifically, treatment with TMZ during and after radiation therapy might provide survival benefit to patients with primary spinal cord GBM. A multicenter cooperative investigation for a large-scale study on malignant PSCGs may be required.     

Interstitial brachytherapy for newly diagnosed patients with malignant gliomas: the UCSF experience.

Although interstitial brachytherapy appears to be effective in treating recurrent malignant gliomas, it has been studied less extensively in patients with newly diagnosed tumors. To examine the effect of this treatment when used at the time of primary diagnosis, we retrospectively reviewed the records of 88 patients who received temporary interstitial implants of 125I for newly diagnosed malignant gliomas. This brachytherapy was preceded by a course of external radiation therapy and followed, in some cases, by chemotherapy. The median duration of survival after the beginning of external radiation therapy was 87 weeks in patients with glioblastoma multiforme and 160 weeks in those with anaplastic gliomas. In 46% of patients with glioblastoma multiforme and 56% of those with anaplastic gliomas, a second operation was necessary to remove symptomatic radiation necrosis, recurrent tumor, or both. Our results support the conclusion that interstitial brachytherapy used at the primary diagnosis lengthens survival in selected patients with glioblastoma multiforme. However, the toxicity is significant in terms of the need for surgical resection of symptomatic necrosis. In patients with anaplastic gliomas, the toxicity associated with the treatment probably outweighs its advantages.     

Treatment of malignant gliomas with surgery,intraarterial chemotherapy with ACNU and radiation therapy

Summary Forty-five patients with malignant gliomas were treated after aggressive surgical resection with alternating intravenous carmustine and cisplatin both during and after radiation therapy. Thirty-three patients were considered evaluable for responses, 17 had glioblastoma multiforme (GBM),14 had anaplastic astrocytoma (AA) and 2 had anaplastic oligodendroglioma (AO). The median age of the evaluable patients was 47 years. The median time to tumor progression was 34.5 weeks, and the median survival for the entire group was 76 weeks. Early progression occurred more frequently in patients with glioblastoma than in those with AA or AO. Seventeen patients (55%) were alive at 18 months (6 GBM, 9 AA, 2 AO). Toxicity was mainly hematologic, otic and tolerable. The results suggest that further trial is warranted to assess the efficacy of alternating carmustine and cisplatin in conjunction with radiation therapy postoperatively in patients with malignant gliomas.     

Clinicopathological study of oligodendroglial tumors: the effectiveness of interferon β, ACNU/MCNU, and radiation (IAR/IMR) for anaplastic tumors

The retrospective clinicopathological characteristics of oligodendroglial tumors were investigated in patients who underwent surgery, radiotherapy, and/or chemotherapy. Regarding oligodendroglioma and oligoastrocytoma without malignancy, patients who had undergone radiation therapy at a total dose of 40–50 Gy had relatively long postoperative survival. Of these 15 patients, 6 showed signs of recurrence, and after additional treatment, 5 patients are still alive. On the other hand, regarding anaplastic oligodendroglial tumors, patients with anaplastic oligoastrocytoma responded well to combination chemotherapy with interferon β, nitrosourea derivatives (ACNU/MCNU), and radiation therapy (referred to as IAR/IMR) and survived longer than patients with anaplastic oligodendroglioma. In conclusion, patients with oligodendroglial tumors could survive longer by treatment involving surgery and radiotherapy. As for malignancy, cases of anaplastic oligoastrocytoma could be effectively treated by adjuvant therapy using IAR/IMR after surgery, but in case of anaplastic oligodendroglioma, the response to IAR/IMR was not good, and another strategy of treatment should be recommended.     

MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma

Hypermethylation of the O⁶-methylguanine-DNA-methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation. To address this issue, we assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM.     

Radical proposal for the treatment of malignant astrocytoma.

The traditional treatment for anaplastic astrocytoma (AAF) and glioblastoma multiforme (GBM) leads to local relapse. The recurring element is assumed to be previously radioresistant, reorganizing hypoxic cells that require up to three times the traditional photon irradiation dose for inactivation. We are proposing to coagulate the original lesion with high-dose precision brachytherapy, immediately followed by resection to save the patient from secondary effects of the necrotic region. The treatment then continues with adjuvant external beam radiation therapy to the local surrounding brain and concomitant chemotherapy. The approach inverts the traditional regimen. It has the virtue of being precise, avoiding secondary effects of the necrotic tumor, and satisfying accepted radiobiological principles.