Phase II study of thalidomide and radiation in children with newly diagnosed brain stem gliomas and glioblastoma multiforme

A phase II study was conducted to assess the efficacy of administering daily thalidomide concomitantly with radiation and continuing for up to 1 year following radiation in children with brain stem gliomas (BSG) or glioblastoma multiforme (GBM). Secondary objectives were to obtain preliminary evidence of biologic activity of thalidomide and to evaluate toxicities from chronic administration of thalidomide in this population. Thirteen patients (2–14 years old) with newly diagnosed BSG (12 patients) or GBM (one patient) were enrolled between July 1999 and June 2000. All patients received focal radiotherapy to a total dose of 5,580 cGy. Thalidomide was administered once daily beginning on the first day of radiation and continued for 12 months or until the patient came off study. The starting dose was 12 mg/kg (rounded down to the nearest 50 mg) and was increased by 20% weekly, if tolerated, to 24 mg/kg or 1,000 mg (whichever was lower). Advanced imaging techniques and urine and serum analysis for anti-angiogenic markers were performed in some patients in an attempt to correlate changes with clinical effect of therapy. No patients completed the planned 12 months of thalidomide therapy and all have since died of disease progression. The median duration of therapy was 5 months (range 2–11 months). Nine patients came off study for progressive disease (PD), three patients due to toxicity and one patient withdrew consent. Several patients on this study required more extended courses of high dose steroids than would have been otherwise expected for this population due to significant peritumoral edema and necrosis. No consistent pattern emerged from the biologic correlative studies from 11 patients. However, advanced imaging with techniques such as MR spectroscopy, MR perfusion and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were helpful in distinguishing growing tumor from treatment effect and necrosis in some patients. The median time to progression (TTP) was 5 months (range 2–11 months) and the median time to death (TTD) was 9 months (range 5–17 months). In this small patient sample adding thalidomide to radiation did not improve TTP or TTD from historical controls, however, toxicity appeared to be increased.     

A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy

Temozolomide is a novel second-generation oral alkylating agent with demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). A multicenter phase II trial was conducted to determine the efficacy and safety of temozolomide before radiotherapy in patients with newly diagnosed GBM and AA. Fifty-seven patients (51 adult, 6 pediatric) with newly diagnosed supratentorial GBM or AA were treated with temozolomide (200 mg/m ( 2 ) per day for 5 consecutive days every 28 days) for a maximum of 4 cycles. All patients were then treated with external beam radiotherapy. Twenty-two patients (39%) achieved objective response, including 6 (11%) with complete response (CR) and 16 (28%) with partial response (PR). Additionally, 18 (32%) patients had stable disease (SD). Of 21 patients (18 adult, 3 pediatric) with AA, 2 (10%) achieved CR, 5 (24%) achieved PR, and 8 (38%) had SD. Among adult patients with AA, the median progression-free and overall survival rates were 7.6 and 23.5 months, respectively. Among 36 patients (33 adult, 3 pediatric) with GBM, 4 (11%) had CR, 11 (31%) had PR, and 10 (28%) had SD. The median progression-free and overall survival rates among adult patients with GBM were 3.9 and 13.2 months, respectively. Temozolomide was safe and well tolerated in adult and pediatric patients. Grades 3 and 4 adverse events were reported in 16 (28%) and 7 (12%) patients, respectively. Temozolomide was safe and effective in treating newly diagnosed GBM and AA before radiotherapy. This pre-irradiation treatment approach appears promising, but will require additional evaluation in comparative studies.     

A Phase I study of concurrent RMP-7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

BACKGROUND: Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. METHODS: RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3-12 yrs). RESULTS: One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. CONCLUSIONS: The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors.     

A phase II study of gefitinib and irradiation in children with newly diagnosed brainstem gliomas: a report from the Pediatric Brain Tumor Consortium

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m(2)/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patients were withdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9 ±5.6 % and 9.3 ±4%, respectively. Overall survival rates were 56.4 ±7.6% and 19.6 ±5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progression-free survivors with ≥36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents.     

Response to a phase II study of concomitant-to-sequential use of etoposide and radiation therapy in newly diagnosed malignant gliomas

We evaluated the antitumor efficacy of and patient tolerance to a phase II study of concomitant-to-sequential use of etoposide and radiotherapy for newly diagnosed malignant gliomas. Fifty-two supratentorial malignant glioma patients were enrolled in this phase II study between May 1995 and May 1998. Standard cranial irradiation and six courses of etoposide (100 mg/m2 - xdays 1-3) were administered. The first course of etoposide was given on days 1 to 3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. Fifty-one patients were assessable for toxicity, response, and survival. A complete surgical resection was only noted for 17 patients. Six patients had a confirmed complete response, and eight patients displayed a partial response. Six patients progressed within the first 3 months of starting treatment. The rate of objective response for assessable patients with residual tumor was 41.1%. Hematologic toxicity was mild; grade 3 or 4 neutropenia was noted in five patients, without sepsis. The overall median survival time (MST) was 12.5 months, and the mean survival of this population was 14.9 months. These results suggest a certain efficacy of this regimen testing a concomitant-to-sequential use of etoposide and radiotherapy for newly diagnosed malignant gliomas, and that continued evaluation of this combination is warranted, especially because this treatment is also well tolerated.     

A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma

PURPOSE: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). METHODS AND MATERIALS: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. RESULTS: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.     

A phase I dose-escalation study of fractionated stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant gliomas

PURPOSE: To determine the maximum tolerated dose (MTD) of fractionated stereotactic radiosurgery (SRS) with gefitinib in patients with recurrent malignant gliomas. METHODS AND MATERIALS: A Phase I clinical trial was performed. Eligible patients had pathologically proved recurrent anaplastic astrocytoma or glioblastoma. Patients started gefitinib (250 mg/day) 7 days before SRS and continued for 1 year or until disease progression. SRS was delivered in three fractions over 3 days. The planning target volume (PTV) was the T1-weighted MRI postcontrast enhancing lesion+2 mm. The first cohort received an SRS dose of 18 Gy, and subsequent cohorts received higher doses up to the maximum dose of 36 Gy. Dose-limiting toxicity (DLT) was any Grade 3 toxicity. The MTD was exceeded if 2 of 6 patients in a cohort experienced DLT. RESULTS: Characteristics of the 15 patients enrolled were: 9 men, 6 women; median age, 47 years (range, 23-65 years); 11 glioblastoma, 4 AA; median prior RT dose, 60 Gy (range, 54-61.2 Gy); median interval since RT, 12 months (range, 3-57 months); median PTV, 41 cc (range, 12-151 cc). Median follow-up time was 7 months (range, 2-28 months). Median time on gefitinib was 5 months (range, 2-12 months). No patient experienced a DLT, and the SRS dose was escalated from 18 to 36 Gy. Grade 1-2 gefitinib-related dermatitis and diarrhea were common (10 and 7 patients, respectively). CONCLUSION: Fractionated SRS to a dose of 36 Gy in three fractions is well tolerated with gefitinib at daily dose of 250 mg. Further studies of SRS and novel molecular targeted agents are warranted in this challenging clinical setting.     

Phase I trial of capecitabine rapidly disintegrating tablets and concomitant radiation therapy in children with newly diagnosed brainstem gliomas and high-grade gliomas

Background

We conducted a phase I study to estimate the maximum tolerated dose and describe the dose-limiting toxicities and pharmacokinetics of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy to children with newly diagnosed brainstem or high-grade gliomas.

Methods

Children 3–21 y with newly diagnosed intrinsic brainstem or high-grade gliomas were eligible for enrollment. The starting dose was 500 mg/m², given twice daily, with subsequent cohorts enrolled at 650 mg/m² and 850 mg/m² using a 3 + 3 phase I design. Children received capecitabine at the assigned dose daily for 9 wks starting from the first day of radiation therapy (RT). Following a 2-wk break, patients received 3 courses of capecitabine 1250 mg/m² twice daily for 14 days followed by a 7-day rest. Pharmacokinetic sampling was performed in consenting patients. Six additional patients with intrinsic brainstem gliomas were enrolled at the maximum tolerated dose to further characterize the pharmacokinetic and toxicity profiles.

Results

Twenty-four patients were enrolled. Twenty were fully assessable for toxicity. Dose-limiting toxicities were palmar plantar erythroderma (grades 2 and 3) and elevation of alanine aminotransferase (grades 2 and 3). Systemic exposure to capecitabine and metabolites was similar to or slightly lower than predicted based on adult data.

Conclusions

Capecitabine with concurrent RT was generally well tolerated. The recommended phase II capecitabine dose when given with concurrent RT is 650 mg/m², administered twice daily. A phase II study to evaluate the efficacy of this regimen in children with intrinsic brainstem gliomas is in progress (PBTC-030).     

Treatment of newly diagnosed diffuse brain stem gliomas in children: in search of the holy grail

Diffuse brain stem glioma is the most devastating of pediatric malignancies. Virtually all children with this disease die within 1–2 years of diagnosis. After three decades of exhaustive research, the key to controlling this malignancy still eludes us. Attempts to improve survival using radiation, chemotherapy and biologic agents have yet to culminate in meaningful advances. Recent advances in molecular biology have led to the development of more targeted therapies, which are now being introduced in clinical trials for children with brain stem glioma. As our understanding of the biology of this disease improves, so too will our ability to target it more effectively. Real strides in improving the lives of children with brain stem glioma may finally be within our grasp.     

Treatment of newly diagnosed diffuse brain stem gliomas in children: in search of the holy grail

Diffuse brain stem glioma is the most devastating of pediatric malignancies. Virtually all children with this disease die within 1-2 years of diagnosis. After three decades of exhaustive research, the key to controlling this malignancy still eludes us. Attempts to improve survival using radiation, chemotherapy and biologic agents have yet to culminate in meaningful advances. Recent advances in molecular biology have led to the development of more targeted therapies, which are now being introduced in clinical trials for children with brain stem glioma. As our understanding of the biology of this disease improves, so too will our ability to target it more effectively. Real strides in improving the lives of children with brain stem glioma may finally be within our grasp.     

A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood

A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.     

Phase II trial of tipifarnib and radiation in children with newly diagnosed diffuse intrinsic pontine gliomas

We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily (125 mg/m(2)/dose) during RT; after RT, it was taken at 200 mg/m(2) twice daily for 21 days, in 28-day cycles. Initial and follow-up neuroimaging was centrally reviewed. Forty eligible patients (median age, 5.5 years; range, 3.3-16.5 years) had a median progression-free survival of 6.8 months (range, 0.2-18.6 months) and median overall survival of 8.3 months (range, 0.2-18.6 months). Kaplan-Meier estimates (± standard error) of 1-year progression-free and overall survival were 12.9% ±4.9% and 34.3% ±7.4%, respectively. A single patient remained on tipifarnib without progression at the completion of the study, two years after initiation of treatment. Seven patients were without disease progression for at least six months, three of whom remained controlled for more than a year. The most frequent toxicity was grade 3 lymphopenia. We documented a single instance of "pseudoprogression" by neuroimaging review. We found no discordance among 3 approaches to defining disease progression: as interpreted by treating institutions (based on clinical status and/or imaging) and by central review (using bi-dimensional tumor "area" versus volumetric measurements). For children with diffuse BSGs, tipifarnib administered with irradiation offered no clinical advantage over historical controls. Biopsies and molecular analyses of pediatric BSGs are vital for identification of new agents and for rational use of targeted agents.     

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

Journal of Neuro-Oncology - Cyclin-dependent kinase-retinoblastoma (CDK-RB) pathway is dysregulated in some diffuse intrinsic pontine gliomas (DIPG). We evaluated safety, feasibility, and early...     

RTOG 0211:a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients

PURPOSE: To determine the safety and efficacy of gefitinib,an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor,in combination with radiation for newly diagnosed glioblastoma(GBM) patients.METHODS AND MATERIALS: Between March 21,2002,and May 3,2004,Radiation Therapy Oncology Group(RTOG) 0211 enrolled 31 and 147GBM patients in the phase 1 and 2 arms,respectively.Treatment consisted of daily oral gefinitnib started at the time of conventional cranial radiation therapy(RT) and continued post RT for 18 months or until progression.Tissue microarrays from 68 cases were analyzed for EGFR expression.RESULTS: The maximum tolerated dose(MTD) of gefitinib was determined to be 500 mg in patients on non-enzyme-inducing anticonvulsant drugs(non-EIAEDs).All patients in the phase 2 component were treated at a gefitinib dose of 500 mg;patients receiving EIADSs could be escalated to 750 mg.The most common side effects of gefitinib in combination with radiation were dermatologic and gastrointestinal.Median survival was 11.5 months for patients treated per protocol.There was no overall survival benefit for patients treated with gefitinib + RT when compared with a historical cohort of patients treated with RT alone,matched by RTOG recursive partitioning analysis(RPA) class distribution.Younger age was significantly associated with better outcome.Per protocol stratification,EGFR expression was not found to be of prognostic value for gefitinib + RT-treated patients.CONCLUSIONS: The addition of gefitinib to RT is well tolerated.Median survival of RTOG 0211 patients treated with RT with concurrent and adjuvant gefitinib was similar to that in a historical control cohort treated with radiation alone.     

Results of a pilot study of hyperfractionated radiation therapy for children with brain stem gliomas

The majority of children with brain stem gliomas develop progressive disease within 18 months of diagnosis and treatment. Radiotherapy (RT) is of transient benefit in most patients and higher total doses of RT have been related to improved survival. The amount of RT which can be given is limited by the tolerance of the surrounding brain. Hyperfractionated RT theoretically allows higher doses of RT to be tolerated by the brain. Sixteen children with brain stem gliomas were treated on a hyperfractionated RT schedule, receiving 120 cGy of RT twice daily, to a total dose of 6480 cGy. All patients tolerated treatment well. Eleven of 15 (73%) evaluable patients had a response to treatment and two (13%) others had stable disease. One patient developed progressive disease during treatment. All patients were tapered off steroids by the completion of treatment. Thirteen of 16 (81%) patients developed progressive disease at a median of 7 months after diagnosis and three remain in remission 8, 12, and 15 months following diagnosis. These results were similar to those of historical controls. Two patients were surgically explored at time of relapse and 5 have had an autopsy. No acute or subacute neurologic toxicity was seen; but long-term detrimental effects on brain could not be assessed. The implications of this study are that escalations of the dose of hyperfractionated RT can be entertained for children with brain stem gliomas.     

Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.     

Phase II study of fotemustine in recurrent supratentorial malignant gliomas

38 adults with recurrent supratentorial malignant gliomas, including glioblastoma multiforme (21), anaplastic astrocytomas (9), probably transformed low-grade astrocytomas (6), pinealoblastoma (1) and non-metastatic tumour of unknown histology (1), were treated with fotemustine 100 mg/m² intravenously every week for 3 consecutive weeks followed by a 5-week rest period. Maintenance treatment consisted of one infusion every 3 weeks. Patients were divided into three groups according to treatment effect. 10 objective responses (26%) with a median time without progression of 32.7 weeks, 18 stabilisations (47%) and 10 failures (26%) were observed. Pathological findings of the initial primary tumour and neurological functional status were unequally distributed in these groups. Haematological and liver toxicities were mild, delayed, transient and reversible. Thrombocytopenia and leukopenia were more frequent (30%) in patients treated with prior chemotherapy. Fotemustine is a well tolerated active drug in recurrent malignant gliomas with an original and short treatment schedule.     

Treatment of recurrent malignant supratentorial gliomas with the association of procarbazine,thiotepa and vincristine: A phase II study

Summary Twenty patients previously treated with surgery, radiation therapy and chemotherapy with a nitrosourea for malignant supratentorial gliomas received a combination of procarbazine, thiotepa and vincristin (P.T.V.) at tumor recurrence. Procarbazine was given at a dose of 100 mg/m² per os from day 1 (D1) to day 15 (D15), thiotepa was administered IV at a dose of 35–45 mg/m² at D1, and vincristine at a dose of 1,4 mg/m² at D1 and D8. Courses of therapy were repeated every four weeks. Tolerance was evaluated in 20 patients. Three patients developed peripheral neuropathy after 2 or 3 courses of vincristin which was then discontinued. Blood toxicity over grade I occurred in 8 patients (40%). One patient developed a grade IV pancytopenia. All 20 patients could be evaluated for therapeutic response. A partial response was noted in 3 patients (15%): 1 glioblastoma multiforme, 1 anaplastic oligodendroglioma and 1 anaplastic astrocytoma. In these three patients time to tumor progression was 10, 11 + and 5 months, respectively. Stabilization lasting 4 months was observed in one patient (anaplastic astrocytoma). Estimated median duration of survival for the entire group was 4,5 months following the onset of PTV (13 months following the date of histology).