Recurrent High-grade Astrocytoma Research Articles

Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences

Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

Phase I dose-escalation study of procaspase-activating compound-1 in combination with temozolomide in patients with recurrent high-grade astrocytomas.

Procaspase-3 (PC-3) is overexpressed in various tumor types, including gliomas. Targeted PC-3 activation combined with chemotherapy is a novel strategy for treating patients with high-grade gliomas, with promising preclinical activity. This study aimed to define safety and tolerability of procaspase-activating compound-1 (PAC-1) in combination with temozolomide (TMZ) for patients with recurrent high-grade astrocytomas. A modified-Fibonacci dose-escalation 3 + 3 design was used. PAC-1 was administered at increasing dose levels (DL; DL1 = 375 mg) on days 1-21, in combination with TMZ 150 mg/m2/5 days, per 28-day cycle. Dose-limiting toxicity was assessed during the first 2 cycles. Neurocognitive function (NCF) testing was conducted throughout the study. Eighteen patients were enrolled (13 GBM, IDH-wild type; 2 astrocytoma, IDH-mutant, grade 3; 3 astrocytoma, IDH-mutant, grade 4). Dose escalation was discontinued after DL3 (ie, PAC-1, 625 mg) due to lack of additional funding. Grade 3 toxicity was observed in 1 patient at DL1 (elevated liver transaminases) and 1 at DL 2 (headache). Two partial responses were observed at DL1 in patients with GBM, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated. Two patients had stable disease, and 11 experienced progression. NCF testing did not show a clear relationship between PAC-1 dose, treatment duration, and declines in NCF. Combination of PAC-1 and TMZ was well tolerated up to 625 mg orally daily and TMZ orally 150 mg/m2/5 days per 28-day cycle. The maximum tolerated dose was not reached. Further dose escalation of PAC-1 in combination with TMZ is advised before conducting a formal prospective efficacy study in this patient population.

Selected Articles from This Issue

Zotiraciclib, a cyclin-dependent kinase 9 (CDK9) inhibitor, was previously shown to synergize with temozolomide (TMZ) in preclinical studies. To translate this finding to the clinic, Wu and colleagues performed a clinical trial of zotiraciclib plus TMZ in recurrent high-grade astrocytoma. This two-stage phase I trial simultaneously optimized the dosing and schedule of the combination of zotiraciclib and temozolomide using a BOIN dose-finding design. In addition to establishing the optimal dosing schedule for zotiraciclib and temozolomide, in-depth analyses of zotiraciclib-induced neutropenia, PK/p. and longitudinal symptom burden analysis were performed. The comprehensive information from this multifaceted early-stage investigation supports further clinical trials of this agent.Nuclear exporter protein exportin1/XPO1 overexpression in hematological malignancies leads to cytoplasmic mislocalization and functional inactivation of tumor suppressors. Specific inhibitor of nuclear export (SINE) compounds block XPO1-mediated protein transport, retaining tumor suppressors in the nucleus. Seymour and colleagues demonstrate preclinical efficacy and clinical validation of XPO1 inhibitor selinexor in non-Hodgkin lymphoma with a phase I study of R-CHOP plus weekly selinexor as frontline treatment of NHL. This combination was well tolerated, and an MTD was not reached. An ORR of 100% and a CR rate of 90% were observed. Further study of this combination in lymphoma is warranted.While neoadjuvant chemoradiation (nCRT) has improved the survival of patients with resectable esophageal adenocarcinoma (rEAC), nearly half of patients succumb to their disease within 5 years. To assess improving this treatment strategy, van den Ende and colleagues assessed the combination of nCRT with PD-L1 inhibition in patients with rEAC. The pathological complete response rate was 25%, but there was no significant improvement in survival compared with nCRT alone. However, potential biomarkers of response were identified. An IFNy signature was associated with response, while low levels of cytotoxic lymphocytes or the presence of checkpoint inhibition correlated with lack of response. Further study is necessary to clarify the therapeutic potential of this combination in rEAC.IL-15 is an important cytokine for the function of NK cells, and IL-15 activation has been proposed as a strategy for immunotherapy. Foltz and colleagues conducted a clinical trial of N-803, an IL-15 receptor superagonist complex, with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma. This combination was well tolerated and led to prolonged responses in a subset of patients. N-803 treatment led to the activation of NK cells, CD8+ T cells, and monocytes. Further clinical study of N-803 is needed to identify patient populations for whom this agent will be beneficial, as well as appropriate combination treatments.

ACTR-62. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR RECURRENT HIGH-GRADE ASTROCYTOMA IN ADULTS

Abstract BACKGROUND Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells and synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent high-grade astrocytomas. Phase I results are reported here. METHODS Adults with recurrent high-grade astrocytoma, KPS≥60, adequate organ function, < 2 prior relapses were enrolled. Primary endpoint was dose limiting toxicity (DLT) in cycle1 in each arm. Bayesian optimal interval design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days1,12,15, and 26) and temozolomide, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm1) or metronomic (MN; 50mg/m2/d, Arm2) dosing schedule on a 28-day cycle. RESULTS Thirty-eight patients were evaluable; median age 50.7, KPS 90. Of 18 evaluable patients in Arm1, at TG02 dose-level 200mg, 1/6 had a DLT: Gr3 diarrhea; at dose-level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm2, at TG02 dose-level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia; at dose-level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia; at dose-level 300mg,1 of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST. TG02 dose-level of 250mg was declared as the MTD in both Arms. Using the MDASI-BT, patients with high symptom burden had increased symptoms during cycle1 but became stable as they continued treatment. CONCLUSION The combination of TG02 at the MTD of 250mg with DD or MN temozolomide was tolerated. Cohort expansion continues at the MTD in both arms. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation.

Phase I trial of TG02 plus dose-dense or metronomic temozolomide for recurrent anaplastic astrocytoma and glioblastoma in adults.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

Regorafenib in patients with recurrent high-grade astrocytoma.

Antiangiogenic treatment approaches have failed to improve outcome in randomized trials of high-grade astrocytoma. One key mechanism of resistance to antiangiogenic treatment may concern the upregulation of alternative pro-angiogenic pathways. Regorafenib is a potent multikinase inhibitor that may alter some of those pathways. In this retrospective study, we investigated efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma. We screened for patients with high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence. A total of 6 patients met eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient. This retrospective study indicates a very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion.

ACTR-69. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR ADULTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA AND GLIOBLASTOMA

Most therapies for recurrent high grade gliomas have not been successful, largely due to the complexity of the disease. Our preclinical studies have demonstrated the anti-glioma effects of TG02 and the synergy with temozolomide (TMZ) through modulation of transcription and metabolism. We hypothesize that given the multiple mechanisms of TG02 and established efficacy of TMZ, combined treatment may be effective for malignant gliomas. We launched a phase I/II trial and herein report the phase I results. Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, no more than 2 prior relapses, and no prior bevacizumab were enrolled. A Bayesian Optimal Interval design was employed to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off) or metronomic (MN; 50mg/m2/d) dosing schedule on a 28-day cycle. A total of 15 patients have been enrolled; 80% are male, median age 50.6. Nine patients were enrolled in DD TMZ arm; 1/6 receiving TG02 at 200mg had grade 4 diarrhea, a dose-limiting toxicity (DLT); 1/3 patients receiving TG02 at 250mg in the DD arm had grade 4 neutropenia, a DLT. In MN TMZ arm, 0/3 patients receiving TG02 at 200mg had a DLT. 1/3 patients receiving TG02 at 250mg had a DLT of grade 4 lymphopenia. To date, although not a primary endpoint, 2 partial objective responses have been observed in ongoing patients receiving 200mg TG02 in combination with TMZ. The combination of TG02 at 200mg and DD/MN TMZ is well tolerated. Dose escalation continues in both DD/MN arms (currently at TG02 250mg) with determination of MTD anticipated soon. Additionally, objective responses have been observed suggesting activity for this regimen.

A phase 2 study to determine the efficacy and safety of TVB-2640 in combination with bevacizumab in patients with first relapse of high grade astrocytoma.

TPS2080 Background: The mainstay of treatment for Glioblastoma Multiforme (GBM) remains surgical removal followed by combined chemotherapy with temozolomide and radiation therapy. Second line Bevacizumab (Bev) is indicated upon progression, but unfortunately the responses are not very long lasting, and there are no therapeutic options available at that point. We have learned that antiangiogenic resistance in GBM is promoted by hypoxia; moreover, metabolomic profile of GBM under such conditions reveals an increased presence of long chain fatty acids. On second hand, tumor cells compared to normal cells depend more on palmitate, and is Fatty Acid Synthase (FASN) the enzyme capable of catalyzing its biosynthesis. Further studies have shown how GBM overexpress FASN and how its inhibition selectively inhibits growth and viability of tumor cells by inducing tumor cell apoptosis. TVB-2640 emerges as a novel agent that selectively inhibits FASN. This study represents a phase 2 clinical investigation of TVB-2640, which is to be conducted in patients with Recurrent High Grade Astrocytoma. Methods: This is a prospective, randomized, phase 2 study of TVB-2640 in combination with Bev or Bev alone in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Patients 18 years or older, with ECOG 0 to 2 and GBM progression following standard combined modality treatment will qualify for the study. Patients will be randomized into 2 separate arms. Patients in arm number one will receive Bev every 2 weeks in combination with TVB-2640 while patients in arm number two will receive Bev alone every 2 weeks. MR-Spectroscopy will be obtained on all patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive Bev in combination with TVB-2640. A total sample size of 24 patients will provide 90% power to detect a 4 months difference in PFS (3 months for Bev alone (historic controls) versus 7 months for TVB-2640 in combination with Bev, i.e., a hazard ratio of 0.43) using a one-sided log-rank test with alpha = 0.1. The trial is open and enrollment will begin in Feb 2017. Clinical trial information: NCT03032484.

P07.09 Textiloma mimicking a recurrent high-grade astrocytoma

P07.09 Textiloma mimicking a recurrent high-grade astrocytoma

(18)F-FDG PET-CT-Negative Recurrent High-Grade Anaplastic Astrocytoma Detected by (18)F-FDOPA PET-CT.

A 37-year-old woman with grade 3 anaplastic astrocytoma (AA) of the left frontal lobe, underwent surgical excision, chemotherapy and external beam radiation therapy in 2004. After being in remission for 5 years, recurrence was suspected clinically when she presented with seizures. The result of contrast-enhanced magnetic resonance imaging (MRI) was equivocal for recurrence and radiation necrosis (not available). The patient was then referred for 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT), as the initial primary tumour was high grade in nature. 18F-FDG PET-CT was negative for recurrence and demonstrated only post-operative changes in the left frontal region (Fig. 1a, b, arrow). Due to strong clinical suspicion, 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine (18F-FDOPA) PET-CT was done, 5 days after 18F-FDG PET-CT. The study revealed an 18F-FDOPA-avid mass lesion in the left frontal region (Fig. 1c, d, arrow), thereby confirming the presence of recurrent disease. The patient underwent surgical resection of the mass, and it was confirmed by histopathology as grade 3 AA. However, after a short asymptomatic period of 4 months the patient became symptomatic again. Follow-up MRI after 6 months of surgery revealed presence of ipsilateral and contralateral multifocal contrast enhancing recurrent mass lesions (Fig. 1e, f, arrow), suggesting the progression of disease. The patient was started on temozolamide but she died after 8 months’ follow-up. Fig. 1 a, b 18F-FDG PET-CT. c, d 18F-FDOPA. e, f Six-month follow-up MRI Though MRI is routinely used in assessment of brain tumours, its ability to differentiate between treatment-induced changes and residual or recurrent tumour is limited [1]. 18F-FDG PET was the first tracer used for assessment of brain tumours [2]; however, it has a low tumour-to-background ratio in brain, limiting its utility. 18F-FDG uptake correlates with tumour grade, with high-grade gliomas (grades III and IV) showing higher uptake than low-grade gliomas [3, 4]. Therefore, in spite of its limitations, 18F-FDG PET-CT is used for imaging of high-grade glioma. Amino acid PET radiotracers including 18F-FDOPA display superior contrast to 18F-FDG because of low uptake of amino acids in normal brain tissue [5]. They have particularly special value in the detection of low-grade gliomas [6]. However, 18F-FDOPA tumour uptake cannot provide reasonable predictions about tumour grade and proliferation in recurrent tumours that have undergone treatments [7]. Also, their difficult synthesis or need for an on-site cyclotron limits their widespread use. The present case shows the utility of 18F-FDOPA PET-CT in detection of a recurrent high-grade AA that was missed by 18F-FDG PET-CT. It highlights that 18F-FDG PET-CT can be falsely negative, even in high-grade recurrent gliomas and, therefore, in cases with strong clinical suspicion 18F-FDOPA PET-CT can be an alternative imaging modality to rule out recurrence even when 18F-FDG PET-CT is negative.

Should we reoperate for recurrent high-grade astrocytoma?

Despite optimal treatment of post-operative radiotherapy and chemotherapy for newly diagnosed high-grade astrocytoma, nearly all patients eventually recur. However, the efficacy of reoperation for recurrent astrocytoma is still debatable as to different surgical indications. To investigate the therapeutic effect of reoperation on patients with recurrent high-grade astrocytoma more objectively, a retrospective case-matched study was carried out. The clinical data of 63 cases of recurrent high-grade astrocytoma treated between January 2006 and December 2008 were studied. A total of 21 cases received reoperation immediately after tumor recurrence, while 42 cases without reoperation were matched by gender, age, Karnofsky Performance Scale (KPS) score, histopathology, recurrent interval after the first operation, extent of initial surgery, adjuvant treatment and characteristics of recurrent tumor. The study showed that the median survival time was 7 months in the reoperation group, while in non-reoperation group, it was 4 months. There was significant difference on univariate analysis (P < 0.001). Moreover, the median duration time of progression-free survival (PFS) after tumor recurrence was significantly (P < 0.001) longer in the reoperation group (5 months) than that in the non-reoperation group (2.5 months). The prognostic factors of recurrent high-grade astrocytoma included reoperation, KPS score and tumor location. It was indicated that reoperation could prolong the survival time and improve the quality of survival in patients of recurrent high-grade astrocytoma.

Diagnosis and Treatment of Recurrent High-Grade Astrocytoma

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-α delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas

Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.

An inflatable balloon catheter and liquid 125I radiation source (GliaSite Radiation Therapy System) for treatment of recurrent malignant glioma: multicenter safety and feasibility trial.

In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection. The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (lotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device. Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9-15.3 months). The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium.

9-Aminocamptothecin (9-AC) was administered as a 72-h i.v. infusion every 2 weeks to a total of 99 adults with high-grade astrocytomas. Fifty-one patients with newly diagnosed glioblastoma multiforme received 9-AC treatment prior to radiation therapy and 48 patients with high-grade astrocytomas were treated at the time of tumor recurrence. Upon entrance into these research protocols, all patients had measurable disease that was evaluated on a monthly basis with volumetric CT or MRI scans. A partial response was defined by > or =50% reduction in the contrast enhancing volume on stable or decreasing doses of glucocorticoids. The study specified that all apparent responders would have central review of their radiologic studies and histopathology. The initial patients treated with 9-AC were also receiving anticonvulsants and were noted to have minimal myelosuppression with this chemotherapy. Thus, 9-AC doses were escalated from the previously reported maximum tolerated dose (MTD) of 850 microg/m2/24 h. We then established new MTDs for patients receiving enzyme-inducing anticonvulsants. We defined these MTDs to be 1,776 microg/m2/24 h for newly diagnosed, previously untreated patients and 1,611 microg/m2/24 h for patients with recurrent disease. Twenty-two patients with newly diagnosed glioblastoma multiforme received 9-AC at doses > or =1,776 microg/m2/24 h. Of these, 18 had evaluable disease on central review, and 0 of 18 (0%) demonstrated a partial or complete response. Twenty-one patients with recurrent high-grade astrocytomas were treated at 1,611 microg/m2/24 h; 20 had evaluable disease and 0 of 20 (0%) had a partial or complete response. Thus, the overall response rate in the 38 evaluable patients treated at the MTD was 0 of 38 (0%). Furthermore, of the 51 evaluable patients who were treated at doses less than the MTD, only one partial response was observed, yielding an overall response rate of 2%. Evidence of drug failure was rapid with tumor progression in one-half of patients after 2 drug cycles. 9-AC lacks evidence of substantial activity in patients with newly diagnosed or recurrent high-grade astrocytomas.

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma

Platinum analogues in the treatment of recurrent high grade astrocytoma

Primary brain tumours are a major cause of cancerrelated morbidity and mortality in the United States. Despite the development of aggressive multi-modality therapy regimens, median survivals for patients with these malignancies remain poor (1). Surgery followed by radiation therapy increases survival from a median of 14 weeks with surgery alone to 35-48 weeks when followed by radiation (2). Multimodality therapy including chemotherapy is the standard clinical approach in many centers in the U.S., although the addition of cytotoxic chemotherapy to the treatment regimen has only a modest effect on median survival. A recent meta-analysis showed that adding chemotherapy to surgery and radiation improved the median survival duration from 9.4 to 12 months (3). At present, the nitrosoureas, particularly carmustine (BCNU) and lomustine (CCNU), are the most frequently used agents in primary brain tumors (4). These drugs are highly lipid soluble, readily cross the blood-brain barrier and are considered among the most effective against these tumours. In recurrent glioma, the response data are difficult to interpret owing to heterogeneity in clinical trials and the use of varying response criteria. Nonetheless, objective response rates for patients with recurrent high grade glioma treated with BCNU are reported to range from 2030% (4). Unfortunately, these statistics are based on a number of studies conducted before the availability of computerized tomography (CT). Few studies exist which examine other single-agent therapies for recurrent glioma. Some of the other chemotherapeutic

Phase II study of acivicin in patients with recurrent high grade astrocytoma

Acivicin, an antimetabolite which inhibits enzymes necessary for glutamine utilization, was administered to 16 patients with recurrent high grade astrocytoma. The dose was 12 mg/m 2/day intravenously over 30 min, daily for 5 days to be repeated every 3 weeks. All patients had previously received cranial irradiation. There were no objective responders, two patients remained stable, two were not evaluable for response and the other 12 progressed on treatment. The median survival of the patients was 128 days. The major toxicity was reversible neurological toxicity, with episodes of WHO grade 3 symptoms in two patients, grade 2 in 19 and grade 1 in six patients. Non-neurological toxicities were infrequent with two patients with grade 2 vomiting and two patients developing infections on treatment, although no severe myelosuppression occurred. Three patients developed mild rashes. The lack of activity and the neurological toxicity makes a daily for 5 days schedule of acivicin unsuitable for further study in central nervous system tumours.

Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen.

The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13 M, 12 F) suffering from recurrent high-grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m2 twice daily). Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Tamoxifen and metabolites were analysed by h.p.l.c. Steady-state plasma concentrations (mean microM +/- s.d.) were determined for tamoxifen (2.94 +/- 3.44), N-desmethyltamoxifen (4.37 +/- 2.13), N-desdimethyltamoxifen (1.49 +/- 0.54), 4-hydroxytamoxifen (0.13 +/- 0.05) and tamoxifen primary alcohol (1.07 +/- 0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone-treated patients than untreated patients: 3.94 +/- 4.35 microM (95% C.I.: 1.43-6.46) vs 1.67 +/- 0.84 microM (95% C.I.: 1.11-2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85 +/- 0.87 microM (95% C.I.: 1.37-2.34) vs 4.58 +/- 5.05 microM (95% C.I.: 0.97-8.19), with vs without. The differences approached but did not reach statistical significance (P = 0.065 and 0.078 respectively). There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.