Combination chemotherapy with carmustine and cisplatin before,during, and after radiotherapy for adult malignant gliomas

Summary Twenty-two patients, aged 16 to 67, who had malignant gliomas after surgical resection were treated with carmustine and cisplatin intravenous infusion before, during, and after radiotherapy. All patients had subtotal or total resection, or biopsy as the initial procedure. Twenty-one patients who had at least 2 cycles of chemotherapy and finished the whole course of radiotherapy were considered to be evaluable for responses. Among them, 5 had glioblastoma multiforme, 16 had anaplastic astrocytoma. The median time to tumor progression was 35 weeks (range 12–130 weeks) and median survival time was 66 weeks (range 10–156 weeks). Early progression occurred more frequently in patients with biopsy only and subtotal resection, and in patients with glioblastoma than in those with anaplastic astrocytoma. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients, and with ototoxicity in 1 patient, nephrotoxicity in 2 patients. Combination of carmustine and cisplatin with cranial irradiation for malignant gliomas is moderately toxic and appears to offer no obvious survival advantage compared with radiation therapy plus BCNU alone.     

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.     

External irradiation followed by an interstitial high activity iodine-125 implant "boost" in the initial treatment of malignant gliomas: NCOG study 6G-82-2.

Between January 1982 and January 1990, 107 patients with unifocal, circumscribed malignant gliomas participated in a non-randomized trial testing brachytherapy in their initial treatment. Focal external irradiation (6000 cGy) was combined with an implant of high-activity iodine-125 (5000-6000 cGy) and six courses of procarbazine, lomustine, and vincristine. Of the 101 evaluable patients, 63 received implants. Of these, 29 had non-glioblastoma anaplastic gliomas, and 34 had glioblastoma multiforme. The other 38 did not receive implants, in most cases because radiation therapy failed to reduce the size of the tumor. The median survival was 165 weeks for all evaluable patients with non-glioblastoma anaplastic gliomas, 157 weeks for those with implants, 67 weeks for all evaluable glioblastoma patients, and 88 weeks for those with implants. Of the glioblastoma patients with implants, nine were alive after 2 years, and three were alive after 3 years. In each of the groups, nearly half the patients underwent reoperation for clinical deterioration, increasing steroid dependency, and increasing mass effect at the implantation site after 46.1 weeks (median) for glioblastoma multiforme and 41.3 weeks for non-glioblastoma patients. Karnofsky Performance Scores showed only a small decline in performance after brachytherapy. Patients receiving implants for non-glioblastoma anaplastic gliomas had a mean Karnofsky Performance Score of 91% (range 90-100%) after 1 month and 78% (range 60-100%) 30 months after brachytherapy. Those treated for glioblastoma multiforme had a mean Karnofsky Performance Score of 86% (range 60-100%) at 1 month and 75% (range 60-100%) at 24 months. The quality of life of treated patients appears to be satisfactory. On the basis of comparisons with previous studies, we conclude that a brachytherapy "boost" after external irradiation may be valuable for some patients with glioblastoma multiforme but not for those with non-glioblastoma anaplastic gliomas.     

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.     

Topotecan treatment of adults with primary malignant glioma. The Brain Tumor Center at Duke

BACKGROUND: Topotecan activity was evaluated for the treatment of malignant glioma. METHODS: Sixty-three patients with newly diagnosed (n = 25) or recurrent (n = 38) malignant glioma were treated with topotecan [AU: Please verify all dosages here and throughout text.]at a dose of 2.6 mg/m2 over a 72-hour period weekly. Recurrent tumors included glioblastoma multiforme (GBM) (n = 28) and anaplastic astrocytoma (AA) (n = 10). Newly diagnosed tumors included GBM (n = 14), AA (n = 8), and anaplastic oligodendroglioma (n = 3). RESULTS: Partial responses were observed in 2 of 14 evaluable patients with newly diagnosed GBM, 1 of 8 patients with newly diagnosed AA, 3 of 10 patients with recurrent AA, and none of 28 patients with recurrent GBM. Four patients with recurrent AA and 7 patients with recurrent GBM demonstrated stable disease (range, 8-52 weeks; median, 21 weeks). Toxicity was limited to infrequent National Cancer Institute Common Toxicity Criteria Grade 3 myelosuppression. CONCLUSIONS: These results suggest that topotecan has modest activity against malignant glioma and continued evaluation of its effectiveness may be warranted when alternative schedules or combination regimens are used.     

Supratentorial malignant glioma: an analysis of radiation therapy in 178 cases

To analyze treatment results of supratentorial malignant gliomas in the megavoltage era, all the histologic specimens were reviewed and glioblastoma multiforme (GBM) was distinguished from anaplastic astrocytoma (AA) by the presence of necrosis. Among those who had completed radiotherapy and who had been followed for at least one year, 135 GBM and 43 AA patients were found. The median survival time (MST) after operation was 12 months for GBM and 18 months for AA. The 5-year survival rate was 0.9% for GBM and 18% for AA. The size of radiation field had little influence on survival time; MST was 12 months for GBM patients treated with a local field covering tumor plus less than 2 cm margin, 12 months for those treated with a generous field (2 cm or more margin), and 13 months for those treated to whole brain. Also for AA, whole brain radiation did not prolong survival. Initial relapse of GBM and AA developed within the irradiated volume in 86% of the cases treated with a generous field. Whole brain radiation seemed useless for the treatment of malignant gliomas. Survival time appeared to be dose-dependent; MST was 10, 13, and 16 months for GBM patients who received 45-57, 57-63, and 63-72 Gy, respectively. Extensive surgical resection was associated with a better prognosis in GBM. AA patients 60 years old or older had a poorer prognosis than younger patients, but age was not a significant prognostic factor for GBM. Chemotherapy appeared to prolong survival slightly without improving long-term survival.(ABSTRACT TRUNCATED AT 250 WORDS)     

Results of conventional radiotherapy in malignant gliomas:

Results of radiotherapy for 164 supratentorial malignant gliomas were analyzed based on recent histological subclassification into glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Patients with AA had a better prognosis than those with GBM. The 5-year survival rate was 1% for GBM and 16% for AA. The size of radiation field did not influence survival significantly, and whole brain radiation appeared of no benefit. Survival time prolonged with an increase of radiation dose between 45 Gy and 72 Gy. The optimal radiotherapy for the disease is discussed.     

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.     

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.     

选择性化疗方案治疗恶性胶质瘤的疗效和生存情况分析

背景与目的：O^6-甲基鸟嘌呤-DNA甲基转移酶（O^6-methylguanine-DNA methyhransferase,MGMT）表达与胶质瘤患者的化疗耐药相关。本研究总结MGMT高表达和低表达恶性胶质瘤患者的化疗方案、近期疗效和生存情况．分析选择性化疗是否对MGMT高表达患者有益。方法：自2000年8月至2006年1月,中山大学肿瘤防治中心神经肿瘤科收治的经手术后病理确诊的成人恶性脑胶质瘤患者57例．所有病例化疗前均有可评价病灶。化疗前用免疫组化方法检测肿瘤组织MGMT表达情况．对MGMT高表达者．尽量避免使用亚硝脲类或替莫唑胺单药化疗,采用不含亚硝脲类或替莫唑胺方案,或由替莫唑胺（temozolomide,TMZ）和顺铂组成联合化疗方案;或亚硝脲类药物、替莫唑胺分别与其他细胞毒药物组成联合化疗方案（VM-26、DDP、CBP、IFO、VP16）;对MGMT低表达者,不限制亚硝脲类药物或替莫唑胺的应用。结果：35例患者MGMT高表达,22例MGMT低表达,MGMT低表达组的客观有效率（objective response,OR）和疾病控制率（response rate,RR）高于MGMT高表达组（40．9％：22．9％和72．7％：60.0%．但差异无统计学意义（P〉0．05）。57例中位随访时间11．7个月（0．7～53．4）。MGMT低表达组和高表达组中位无疾病进展时间（Drogressive-free survival,PFS）分别是8．5个月（95％CI 4．8—19．3）和6．7（95％CI 3．7—9．3）,中位生存时间（overail survival,OS）分别是20．3（95％CI 14．3～）和16．105％CI 11．1～26．2）,中位PFS和0S在MGMT低表达组和高表达组差异无统计学意义（P〉0．05）。结论：在化疗前检测恶性胶质瘤MGMT表达情况,对MGMT高表达患者选用有助于克服耐药的化疗方案进行选择性化疗。可使MGMT高表达患者的近期疗效（客观有效率和疾病控制率）和生存时间（无疾病进展生存和总生存）达到MGMT低表达患者水平。     

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.     

VP-16, vincristine and procarbazine with radiation therapy for treatment of malignant brain tumors

Summary Twelve patients aged 34 to 65 with malignant gliomas were treated with VP-16, Procarbazine, Vincristine and concurrent radiation therapy. There were 9 patients with glioblastoma multiforme and 3 with anaplastic astrocytoma. All patients had a subtotal resection or biopsy as the initial procedure.Six patients (1 anaplastic astrocytoma) have developed progressive disease. Mean time to tumor progression was 46 weeks. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients. These data compare favorably to data obtained from similiar patients treated with radiation therapy and BCNU.     

Radiation therapy with uneven fractionation for malignant gliomas

From 1989 to 1995, we administered a combination of large and small fraction doses (UFX, uneven fractionation) for patients with malignant gliomas. In this study, we compared the treatment outcomes of radiation therapy by uneven fractionation to that of historical control which was treated with radiation therapy by conventional fractionation (CFX). The pathologic classification was anaplastic astrocytoma (AA) in 120 and glioblastoma multiforme (GBM) in 64 patients. Of the 184 patients, 89 patients received a conventional fractionation schedule (CFX) of radiation (2 Gy/fraction, 5 times/week; total, 60 Gy/6 weeks). The other 95 patients received an uneven fractionation schedule (UFX) of radiation (5 Gy on Monday, 1 Gy from Tuesday through Friday; total, 63 Gy/7 weeks). The one-, two-, and five-year survival rates of the AA patients were 74%, 55%, and 30%, respectively. The five-year survival rates of AA patients who received CFX and UFX schedule of radiation were 24% and 38%, respectively. In the GBM patients, the five-year survival rates were 12% in patients who received CFX and 11% in patients who received UFX. UFX seemed to be more effective than CFX for treating AA patients. In multivariate analysis using the Cox regression analysis, which included various patients and treatment characteristics, age, histology and extent of surgery were the significant prognostic factors. In conclusion, UFX is an promising fractionation method for AA patients but not for GBM patients.     

Intravenous BCNU and AZQ in patients with recurrent malignant gliomas

Twenty-four patients with recurrent malignant glioma were treated with intravenous BCNU (80 mg/m²/day × 3 days) alternating with AZQ (8 mg/m²/day × 5 days) every 6–8 weeks. Twenty patients received two or more courses of chemotherapy, ten anaplastic astrocytomas (AA), eight glioblastomas (GBM), and two malignant oligodendrogliomas (Oligo). All had prior surgery and irradiation; one had prior chemotherapy. Median age was 37.5 years. The median Zubrod performance status (PS) was 1. Three patients (15%) achieved response status, and 7 (35%) had stable disease with median times to tumor progression (MTP) of 56 wks and 35 wks. MTP for patients with progression was 11 weeks. No GBM was responsive to chemotherapy and none of the ten patients with stable or responsive disease were older than fifty years. Dose limiting toxicity was consisted of thrombocytopenia and leukopenia. Young patients with recurrent AA and good PS appear more likely to respond to alternating BCNU/AZQ chemotherapy. The overall response rate (response plus stable) of 50% was comparable to that of BCNU alone and the hematologic toxicity was cumulative.     

Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas

Background To reduce this complication and to enhance the radiation effect to hypoxic cells of high-grade gliomas, the authors performed noninvasive fractionated stereotactic radiotherapy (FSRT) using a Gamma unit combined with hyperbaric oxygen (HBO) therapy for the treatment of recurrent disease. Patients and methods Twenty-five consecutive patients who had previously received radiotherapy with chemotherapy for recurrent high-grade gliomas, including 14 patients with anaplastic astrocytoma (AA) and 11 with glioblastoma multiforme (GBM), underwent Gamma FSRT immediately after HBO therapy (2.5 atmospheres absolute for 60 min). The Gamma FSRT was repeatedly performed using a relocatable head cast. Median tumor volume was 8.7 cc (range, 1.7–159.3 cc), and the median total radiation dose was 22 Gy (range, 18–27 Gy) to the tumor margin in 8 fractions. Results Actuarial median survival time after FSRT was 19 months for patients with AA and 11 months for patients with GBM, which was significantly different (P = 0.012, log-rank test). Two patients underwent subsequent second FSRT for regional or remote recurrence. Seven patients (28%) underwent subsequent craniotomies and resections at a mean of 8.4 months after FSRT treatment, and 4 of them had radiation effects without viable cells and remained alive for 50–78 months. Conclusion Gamma FSRT after HBO therapy appears to confer a survival benefit for patients with recurrent high-grade gliomas and warrants further investigation.     

Radiotherapy plus concurrent and adjuvant procarbazine, lomustine, and vincristine chemotherapy for patients with malignant glioma

We analyzed the clinical efficacy and toxicity of concurrent therapy as a first line modality for malignant glioma patients. From 1998 to 2004, 39 patients, 22 with glioblastoma (GM), nine with anaplastic astrocytoma (AA), 7 with anaplastic oligodendroglioma (AO) and 1 with anaplastic oligodendro-astrocytoma (AOA) were enrolled in this study. The median age was 46.2 years (range 8-67). Both external involved field radiotherapy and chemotherapy, composed of CCNU (75-110 mg/m(2)), procarbazine (60 mg/m(2)) and vincristine (1.4 mg/m(2)), were started simultaneously two weeks after surgery. The median progression-free survival time for the GM, AA, and AO patients was 6, 26, and 31 months, respectively. The median survival of the patients with GM and AA was 27 and 41 months. The two-year survival rate of the GM and AA patients was 50.4 and 66.7%, respectively. Grade III/IV hematological toxicity was reduced from 25.6 to 13% after reduction of the dose of CCNU (75 mg/m(2)). Radiation necrosis was confirmed by pathologic examination in four patients (10.3%). The median interval from the completion of radiotherapy to the diagnosis of necrosis was 19 weeks. Modified concurrent chemoradiotherapy may be a feasible option for treating malignant glioma with acceptable toxicity.     

Combined Intra-Arterial Chemotherapy and Irradiation of Malignant Gliomas

Seventy-nine patients with malignant gliomas (19 anaplastic astrocytomas and 60 glioblastoma multiforme) received 4 cycles of infra-ophthalmic carotid injection of 160 mg carmustine, 2mg vincristine IV and procarbazine orally SO mg 3 times daily for 1 week, followed by whole-brain irradiation, with a midpoint dose of 54 Gy/6 weeks. Response, judged by CT-scan, was seen in 31 out of 57 evaluable patients with a median survival of 30 months and 40% survival at 3 years. In all patients who responded to the treatment, a tumour regression was seen on CT-scan after chemotherapy before irradiation. In the 26 patients with progressive disease under chemotherapy, the median survival was 5 months. None of the patients who had progressive disease during chemotherapy had benefit from irradiation. The most important prognostic factors were good pretreatment performance status, glucocorticoid dependency and age. Few serious side-effects of the angiographic procedure were seen. Leukoencephalopathy was not observed in this study.     

Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas

BACKGROUND: The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS: This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS: For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS: Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.     

Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy

PURPOSE: To report the results of a Phase I/II clinical trial for patients with malignant gliomas, treated with combined X-ray radiotherapy (XRT), chemotherapy, and carbon ion radiotherapy (CRT). METHODS AND MATERIALS: Between October 1994 and February 2002, 48 patients with histologically confirmed malignant gliomas (16 anaplastic astrocytoma (AA) and 32 glioblastoma multiforme (GBM) were enrolled in a Phase I/II clinical study. The treatment involved the application of 50 Gy/25 fractions/5 weeks of XRT, followed by CRT at 8 fractions/2 weeks. Nimustine hydrochloride (ACNU) were administered at a dose of 100 mg/m(2) concurrently in weeks 1, 4, or 5 of XRT. The carbon ion dose was increased from 16.8 to 24.8 Gray equivalent (GyE) in 10% incremental steps (16.8, 18.4, 20.0, 22.4, and 24.8 GyE, respectively). RESULTS: There was no Grade 3 or higher acute reaction in the brain. The late reactions included four cases of Grade 2 brain morbidity and four cases of Grade 2 brain reaction among 48 cases. The median survival time (MST) of AA patients was 35 months and that of GBM patients 17 months (p = 0.0035). The median progression-free survival and MST of GBM showed 4 and 7 months for the low-dose group, 7 and 19 months for the middle-dose group, and 14 and 26 months for the high-dose group. CONCLUSION: The results of combined therapy using XRT, ACNU chemotherapy, and CRT showed the potential efficacy of CRT for malignant gliomas in terms of the improved survival rate in those patients who received higher carbon doses.     

"Instant-mix" whole brain photon with neutron boost radiotherapy for malignant gliomas

From July 1985 through March 1987, 44 consecutive patients with supratentorial, nonmetastatic anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with whole brain photon irradiation with concomitant neutron boost at the University of Chicago. All patients had biopsy proven disease and surgery ranged from biopsy to total gross excision. Whole brain photon radiation was given at 1.5 Gy per fraction, 5 days weekly for a total dose of 45 Gy in 6 weeks. Neutron boost radiation was prescribed to a target minimum dose that included the pre-surgical CT tumor volume plus 1 cm margin. Neutrons were administered 5-20 minutes prior to photon radiation twice weekly and a total dose of 5.2 Gyn gamma was administered over 6 weeks. Median follow-up was 36 months. The median survival was 40.3 months for anaplastic astrocytoma (10 patients) and 11 months for glioblastoma multiforme (34 patients) and 12 months for the overall group. Variables that predicted longer median survival included histology (AA vs. GBM), age (less than or equal to 39 years vs. older), and extent of surgery (total gross or partial excision vs. biopsy) whereas tumor size and Karnofsky performance status did not have a significant influence. The median survival of the anaplastic astrocytoma group was better than expected compared to the RTOG 80-07 study (a dose-finding study of similar design to this study) and historical data. Reasons for this are discussed.