Progressive Glioblastoma Multiforme Research Articles

501 POSTER Imatinib plus hydroxyurea: safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts) — an update on the initial 30 pts

501 POSTER Imatinib plus hydroxyurea: safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts) — an update on the initial 30 pts

Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series

Grade IV malignancies of the brain, such as glioblastoma multiforme (GBM), are associated with a dismal prognosis. Autocrine and paracrine loops of platelet-derived growth factor (PDGF) signaling, as well as other signal transduction pathways, have been postulated to play a role in glioblastoma transformation, and molecules involved in these pathways can potentially serve as targets for therapeutic inhibitory agents. Imatinib, an inhibitor of PDGF receptors alpha and beta, as well as other selected tyrosine kinases, is indicated for treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Unfortunately, imatinib, as with many conventional chemotherapeutic agents, has limited efficacy as monotherapy in GBM. In preclinical studies, the chemotherapeutic agent hydroxyurea is demonstrated to have cytotoxic effects additive with imatinib. We tested the combination of hydroxyurea and imatinib in 30 grade IV progressive GBM patients refractory to chemo- and radiotherapy. All 30 patients were evaluable after a median 19 weeks observation time. Combination therapy with imatinib and hydroxyurea resulted in a 20% response rate, including complete and partial responses. Patients experiencing response or stable disease yielded a combined clinical benefit rate of 57%. Median time to progression was 10 weeks and median overall survival was 19 weeks. Three patients continue to survive on combination therapy, with the shortest duration being 106 weeks. Six-month and 2-year progression-free survival rates were 32% and 16%, respectively. The efficacy results, combined with findings that imatinib and hydroxyurea were well tolerated, suggest that this combination shows promise as therapy for GBM.

Imatinib (STI 571)/ plus hydroxyurea: Safety and efficacy in pre-treated, progressive Glioblastoma Multiforme (GBM) patients (pts): An update on the initial 30 pts

1516 Background: GBM is one of the most aggressive malignancies with a median survival of about 1 year. In newly diagnosed GBM combined treatment including surgery and chemo-/ radiotherapy leads to 2 years progression free survival (PFS) of 11% and 2 years overall survival of 26%. In recurrent GBM prognosis is even worse. Many malignancies of the brain including GBM express platelet derived growth factor receptors (PDGF-R). Imatinib, a tyrosine kinase inhibitor of Bcr-Abl, PDGF-Rs and the Kit receptor, showed remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours. In GBM, however, single agent efficacy was limited due to the blood brain barrier (BBB). Therefore Hydroxyurea (HU) which freely penetrates and potentially modulates the BBB was combined with Imatinib to study if efficacy could be improved. Methods: : From June 2001 to September 2003 30 GBM pts refractory to radiation therapy and chemotherapy containing ACNU and temozolomide were treated with Imatinib, 400 mg/day and HU, 1000 mg/day as continuous daily, oral dosing, followed by clinical examination and magnetic resonance imaging every 6 weeks. Results: All 30 pts are evaluable for safety and efficacy. Initial ECOG-performance status was 1–2, the median age was 44 yrs (16–71). Results after a median treatment period of 19 weeks (4–145) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 3 months (3–29), 11 stable diseases (SD) for a median of 6 months (3–33) and 13 progressive disease (PD). There were no grade 3 or 4 toxicities. 26 deaths occurred. 2 pts died of pulmonary embolism and 24 pts of disease progression, 1 pt after a 2 years period of SD. Six months PFS was 32%, 2 years PFS was 13%, 4 pts remain alive without progression for 34, 28, 25 and 23 months, respectively. Conclusions: Combination of Imatinib and HU was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 20% (CR + PR) and a clinical benefit rate of 57% (including SD), 2 years PFS was 13%. Based on these results, additional studies have been initiated to further explore this regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis

Imatinib (STI571) plus hydroxyurea: Safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts)

1550 Background: Imatinib (I) is a tyrosine kinase inhibitor of Bcr-Abl, platelet-derived growth factor receptors (PDGF-Rs) and the Kit receptor, with remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours (GIST). Many malignancies of the brain including GBM express these receptors, yet preliminary results of previous studies have shown a low response rate when used as single agent therapy. Hydroxyurea (H) freely penetrates the brain and cerebrospinal fluid (CSF), and in fact may modulate the blood-brain barrier to facilitate uptake of other drugs. For this reason, we suggested that the combination H with I could potentiate it's activity in GBM. Methods: From June 2001 to November 2003, an exploration of combination therapy with H plus I in 26 GBM pts refractory to multiple prior therapies, including radiation therapy and chemotherapy containing ACNU and temozolomide, was started. Pts were treated with I (400 mg) and H (1000 mg) as continuous daily, oral dosing and followed by clinical examination and magnetic resonance imaging (MRI) every 6 weeks. Results: Fourteen patients are currently evaluable for safety and efficacy. ECOG-performance status at the start of therapy was 1–2, the median age was 40 yrs (31–68), and WHO classification of tumours IV only. Results after a median treatment period of 29 weeks (4–104) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 8 months (1–24), 4 stable disease (SD) for a median of 12 months (3–23) and 5 progressive disease (PD). There were no grade 3 or 4 toxicities. Twelve deaths occurred, 1 pt with PR and 1 pt with SD died of pulmonary embolism, and 10 pts died of PD. The median progression free survival (PFS) was 29 weeks and median overall survival (OS) was 37 weeks. Two pts remain alive without progression for 16 and 24 months, respectively. Conclusions: In summary, combination therapy with I and H was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 36% and a PFS greater than 6 months. Based on these results, a Phase II study with I plus H in GBM has been started. No significant financial relationships to disclose.

Imatinib (STI571) plus hydroxyurea: Safety and efficacy in pre-treated, progressive glioblastoma multiforme (GBM) patients (pts)

1550 Background: Imatinib (I) is a tyrosine kinase inhibitor of Bcr-Abl, platelet-derived growth factor receptors (PDGF-Rs) and the Kit receptor, with remarkable clinical efficacy in chronic myeloid leukaemia and gastrointestinal stromal tumours (GIST). Many malignancies of the brain including GBM express these receptors, yet preliminary results of previous studies have shown a low response rate when used as single agent therapy. Hydroxyurea (H) freely penetrates the brain and cerebrospinal fluid (CSF), and in fact may modulate the blood-brain barrier to facilitate uptake of other drugs. For this reason, we suggested that the combination H with I could potentiate it's activity in GBM. Methods: From June 2001 to November 2003, an exploration of combination therapy with H plus I in 26 GBM pts refractory to multiple prior therapies, including radiation therapy and chemotherapy containing ACNU and temozolomide, was started. Pts were treated with I (400 mg) and H (1000 mg) as continuous daily, oral dosing and followed by clinical examination and magnetic resonance imaging (MRI) every 6 weeks. Results: Fourteen patients are currently evaluable for safety and efficacy. ECOG-performance status at the start of therapy was 1–2, the median age was 40 yrs (31–68), and WHO classification of tumours IV only. Results after a median treatment period of 29 weeks (4–104) were one complete response (CR) lasting 12 months, 4 partial responses (PR) lasting a median of 8 months (1–24), 4 stable disease (SD) for a median of 12 months (3–23) and 5 progressive disease (PD). There were no grade 3 or 4 toxicities. Twelve deaths occurred, 1 pt with PR and 1 pt with SD died of pulmonary embolism, and 10 pts died of PD. The median progression free survival (PFS) was 29 weeks and median overall survival (OS) was 37 weeks. Two pts remain alive without progression for 16 and 24 months, respectively. Conclusions: In summary, combination therapy with I and H was well tolerated and effective in this group of recurrent, refractory GBM pts, with a response rate of 36% and a PFS greater than 6 months. Based on these results, a Phase II study with I plus H in GBM has been started. No significant financial relationships to disclose.

Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results

1558 Background: Erlotinib (Tarceva, OSI-774) is an orally available small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. We have initiated the first phase II trial of erlotinib in single agent therapy of recurrent glioblastoma multiforme (GBM). Methods: Patients with documented recurrent or progressive GBM who have received previous radiation therapy and cytotoxic chemotherapy were eligible for enrollment. No enzyme-inducing anti-epileptic agents were allowed. Patients were treated with 150 mg of erlotinib per day until tumor progression or study withdrawal. Tumor response was determined by MRI. Analysis for EGFR amplification was performed. Results: Interim analysis has been performed on a total of 16 of 31 planned patients as of December, 2003. Of these, 4 patients have shown partial responses, 1 showed a partial response of his original tumor but then developed a separate unresponsive focus and 4 have had disease stabilization for greater than 3 months. Seven patients have...

Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent Glioblastoma Multiforme: Interim results

1558 Background: Erlotinib (Tarceva, OSI-774) is an orally available small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. We have initiated the first phase II trial of erlotinib in single agent therapy of recurrent glioblastoma multiforme (GBM). Methods: Patients with documented recurrent or progressive GBM who have received previous radiation therapy and cytotoxic chemotherapy were eligible for enrollment. No enzyme-inducing anti-epileptic agents were allowed. Patients were treated with 150 mg of erlotinib per day until tumor progression or study withdrawal. Tumor response was determined by MRI. Analysis for EGFR amplification was performed. Results: Interim analysis has been performed on a total of 16 of 31 planned patients as of December, 2003. Of these, 4 patients have shown partial responses, 1 showed a partial response of his original tumor but then developed a separate unresponsive focus and 4 have had disease stabilization for greater than 3 months. Seven patients have had tumor progression within 3 months of starting erlotinib. Although a response has been seen in 50% of patients (4 PR + 4 SD), the responses have not been durable; the median time to progression of responders has been 145 days after the start of therapy. Eleven patients have died since the start of the study. The pattern of subsequent treatment failure in responders has suggested a diffuse spread of tumor (e.g. gliomatosis cerebri or leptomeningeal spread). One patient had a tumor-associated cyst in which the steady state OSI-774 level was determined and found to be approximately 40% of that observed in plasma. Approximately one-half of the tumors have had EGFR amplification, but EGFR amplification has not ensured a response to erlotinib and responses have been observed in the absence of amplification. Conclusions: Although these results are preliminary in nature, we are encouraged by the response rate observed to date. The apparent lack of durability of response and the pattern of post-response failure may be due, in part, to reduced drug penetration into the brain, an inadequate dose and/or tumor heterogeneity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech

Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme.

This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirty-eight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score > or =60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150-500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy.

Treatment of Progressive or Recurrent Glioblastoma Multiforme in Adults with Herpes Simplex Virus Thymidine Kinase Gene Vector-Producer Cells Followed by Intravenous Ganciclovir Administration: A Phase I/II Multi-Institutional Trial

To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.

Phase II Trial of Temozolomide Plus the Matrix Metalloproteinase Inhibitor, Marimastat, in Recurrent and Progressive Glioblastoma Multiforme

PURPOSE: Novel therapies are needed for patients with recurrent glioblastoma multiforme (GBM). Because there is evidence that temozolomide (TMZ) has some activity in GBM and is well tolerated, and because of laboratory evidence that metalloproteinases are important in glioma cell invasion, the combination of TMZ and the matrix metalloproteinase inhibitor marimastat (MRM) in patients with recurrent GBM was studied. PATIENTS AND METHODS: Forty-four patients with recurrent GBM after standard radiotherapy were enrolled. For 19 patients, this therapy was their first chemotherapy after tumor progression after irradiation; 25 others had received chemotherapy previously. TMZ 150 to 200 mg/m2 days 1 to 5 and MRM 50 mg days 8 to 28 was administered at 28-day intervals for two cycles; then patients were reevaluated. Treatment continued until progression of tumor or toxicity developed. RESULTS: Joint and tendon pain was the major therapy-related toxicity and was reported in 47% of patients. Five patients (11%) were r...

Boron neutron capture therapy for glioblastoma multiforme: interim results from the phase I/II dose-escalation studies

OBJECTIVE: The primary objective of these Phase I/II dose-escalation studies is to evaluate the safety of boronophenylalanine (BPA)-fructose-mediated boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM). A secondary purpose is to assess the palliation of GBM by BNCT, if possible. METHODS: Thirty-eight patients with GBM have been treated. Subtotal or gross total resection of GBM was performed for 38 patients (median age, 56 yr) before BNCT. BPA-fructose (250 or 290 mg BPA/kg body weight) was infused intravenously, in 2 hours, approximately 3 to 5 weeks after surgery. Neutron irradiation was begun between 34 and 82 minutes after the end of the BPA infusion and lasted 38 to 65 minutes. RESULTS: Toxicity related to BPA-fructose was not observed. The maximal radiation dose to normal brain varied from 8.9 to 14.8 Gy-Eq. The volume-weighted average radiation dose to normal brain tissues ranged from 1.9 to 6.0 Gy-Eq. No BNCT-related Grade 3 or 4 toxicity was observed, although milder toxicities were seen. Twenty-five of 37 assessable patients are dead, all as a result of progressive GBM. No radiation-induced damage to normal brain tissue was observed in postmortem examinations of seven brains. The minimal tumor volume doses ranged from 18 to 55 Gy-Eq. The median time to tumor progression and the median survival time from diagnosis (from Kaplan-Meier curves) were 31.6 weeks and 13.0 months, respectively. CONCLUSION: The BNCT procedure used has been safe for all patients treated to date. Our limited clinical evaluation suggests that the palliation offered by a single session of BNCT is comparable to that provided by fractionated photon therapy. Additional studies with further escalation of radiation doses are in progress.

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Interim Results from the Phase I/II Dose-Escalation Studies

OBJECTIVE: The primary objective of these Phase I/II dose-escalation studies is to evaluate the safety of boronophenylalanine (BPA)-fructose-mediated boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM). A secondary purpose is to assess the palliation of GBM by BNCT, if possible. METHODS: Thirty-eight patients with GBM have been treated. Subtotal or gross total resection of GBM was performed for 38 patients (median age, 56 yr) before BNCT. BPA-fructose (250 or 290 mg BPA/kg body weight) was infused intravenously, in 2 hours, approximately 3 to 5 weeks after surgery. Neutron irradiation was begun between 34 and 82 minutes after the end of the BPA infusion and lasted 38 to 65 minutes. RESULTS: Toxicity related to BPA-fructose was not observed. The maximal radiation dose to normal brain varied from 8.9 to 14.8 Gy-Eq. The volume-weighted average radiation dose to normal brain tissues ranged from 1.9 to 6.0 Gy-Eq. No BNCT-related Grade 3 or 4 toxicity was observed, although milder toxicities were seen. Twenty-five of 37 assessable patients are dead, all as a result of progressive GBM. No radiation-induced damage to normal brain tissue was observed in postmortem examinations of seven brains. The minimal tumor volume doses ranged from 18 to 55 Gy-Eq. The median time to tumor progression and the median survival time from diagnosis (from Kaplan-Meier curves) were 31.6 weeks and 13.0 months, respectively. CONCLUSION: The BNCT procedure used has been safe for all patients treated to date. Our limited clinical evaluation suggests that the palliation offered by a single session of BNCT is comparable to that provided by fractionated photon therapy. Additional studies with further escalation of radiation doses are in progress.

Permanent I-125 brain stem implants in children.

Between 1988 and 1997, 28 children have had iodine-125 implants for CNS tumors performed in our institution. Ten had stereotactic implantation in the brain stem region, and nine had the diagnosis of brain stem glioma (8 diffuse pontine, 1 midbrain tumor). Their ages ranged from 1.8 to 12 years. All patients had histological confirmation of malignancy (7 high-grade glioma, 2 low-grade glioma, 1 PNET). Diffuse pontine glioma patients received external beam radiation (50 Gy) followed by a fractionated stereotactic boost of 3 Gyx4 fractions. After 4-6 weeks, patients were reevaluated for stereotactic interstitial I-125 therapy. The planned implant dose was 82.9 Gy to the enhancing tumor (4 cGy per h). Preliminary results indicated that no surgical complications were associated with the catheter placement. Four patients have died (7-9 months from diagnosis) and four patients remain alive (5-38 months from diagnosis, median 10 months). Two autopsies confirmed the presence of progressive glioblastoma multiforme and intralesional necrosis. In one patient who received an implant alone for midbrain LGA, necrosis without tumor was found on biopsy after 36 months. He was successfully treated with hyperbaric oxygen therapy. The implementation of permanent I-125 implants appears to have a role in the management of pediatric CNS malignancy. This study confirms the results of previous reports regarding the safety of stereotactic interstitial brachytherapy in the brain stem. Tumor control for patients with high-grade brain stem glioma remains poor even with high focal radiation doses.

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)