Recurrent Malignant Astrocytoma Research Articles

Phase I clinical trial of AXL1717 for treatment of relapsed malignant astrocytomas: analysis of dose and response.

PurposeEarly phase I study of safety of AXL1717 in patients with recurrent or progressive malignant astrocytomas and evaluation of preliminary anti-tumor efficacy.Patients and methodsNine patients fulfilling the set criteria were enrolled. Eight had recurrent glioblastoma and one gliosarcoma. Patients were treated with an oral suspension of AXL1717 (215-400 mg bid) cycle-by-cycle in 35-day cycles (28 days bid and 7 days off). Patients with progressive disease and/or toxicity-related dose delay of more than 14 days were withdrawn.ResultsFour patients had tumor responses (44%) to AXL1717 treatment. Two of these had stable disease for 12 months (10 cycles at 215-300 mg bid). Due to MRI-detected progression they were then taken off the study. They died 8 and 12 months later, respectively. One patient was treated 8 months (6 cycles with 215 mg bid). He was withdrawn because of disease progression but died after another 25 months. The fourth patient having stable disease died of sepsis due to pancytopenia in the end of cycle 2 on 400 mg bid. A fifth patient underwent surgery after two cycles with 300 mg bid. Pathological analysis demonstrated abundant necrosis and small areas of viable tumor. After one more cycle with 300 mg bid he was withdrawn due to clinical and radiographic worsening and died 11 months later. The other 4 patients did not have any detectable responses and died within 3-13 months after trial entry. Neutropenia was the main adverse effect, which was easily detected and reversible in all but one patient.ConclusionThis clinical phase I study indicates that AXL1717 as a single agent is capable of producing prolonged stable disease and survival of patients with relapsed malignant astrocytomas. The drug was well tolerated. A new formulation of the drug will be used in further investigations in order to better define the optimal dose.

Heidelberg Ion Therapy Center (HIT): Initial clinical experience in the first 80 patients

The Heidelberg Ion Therapy Center (HIT) started clinical operation in November 2009. In this report we present the first 80 patients treated with proton and carbon ion radiotherapy and describe patient selection, treatment planning and daily treatment for different indications. Patients and methods. Between November 15, 2009 and April 15, 2010, 80 patients were treated at the Heidelberg Ion Therapy Center (HIT) with carbon ion and proton radiotherapy. Main treated indications consisted of skull base chordoma (n = 9) and chondrosarcoma (n = 18), malignant salivary gland tumors (n=29), chordomas of the sacrum (n = 5), low grade glioma (n=3), primary and recurrent malignant astrocytoma and glioblastoma (n=7) and well as osteosarcoma (n = 3). Of these patients, four pediatric patients aged under 18 years were treated. Results. All patients were treated using the intensity-modulated rasterscanning technique. Seventy six patients were treated with carbon ions (95%), and four patients were treated with protons. In all patients x-ray imaging was performed prior to each fraction. Treatment concepts were based on the initial experiences with carbon ion therapy at the Gesellschaft für Schwerionenforschung (GSI) including carbon-only treatments and carbon-boost treatments with photon-IMRT. The average time per fraction in the treatment room per patient was 29 minutes; for irradiation only, the mean time including all patients was 16 minutes. Position verification was performed prior to every treatment fraction with orthogonal x-ray imaging. Conclusion. Particle therapy could be included successfully into the clinical routine at the Department of Radiation Oncology in Heidelberg. Numerous clinical trials will subsequently be initiated to precisely define the role of proton and carbon ion radiotherapy in radiation oncology.

Carmustine Wafers (Gliadel) Plus Concomitant Temozolomide Therapy After Resection of Malignant Astrocytoma: Growing Evidence for Safety and Efficacy

Menei and colleagues have performed a thorough analysis in their retrospective cohort study from 26 centers in France. They report the overall survival and complication rate associated with the adjuvant use of implantable biodegradable carmustine wafers (Gliadel; MGI Pharma, Bloomington, MN; now Eisai Inc.) for the treatment of primary and recurrent malignant astrocytoma (MA). The authors also investigate the independent association of morbidity and overall survival with combination therapy of temozolomide (TMZ, Stupp protocol) and Gliadel implantation after surgical resection. 1,2 In their series of 83 primary and 80 recurrent MA treated with surgical resection plus Gliadel implantation, the authors report a median survival of 7 months after revision resection of recurrent MA and 17 months after primary resection of MA. For the 43 patients receiving both Gliadel and Stupp protocol after primary resection of MA, a median survival of 608 days (approximately 19.9 months) was observed. Consistent with previous studies, factors independently associated with survival were fractionated radiotherapy, Karnofsky performance score, and extent of resection. The proportions of these prognostic variables were comparable to prior Gliadel series. This series of Gliadel implantation used a variety of adjuvant radiation and chemotherapy regimens. Hence, the overall survival was greater than those previously reported in randomized trails of Gliadel for primary MA. 3,4 Although the retro

Tumorprogress versus therapieinduzierte Veränderungen (Pseudoprogression) bei malignen Astrozytomen

The diagnosis and treatment of recurrent malignant astrocytoma are challenging. On the basis of a case presentation of a patient with suggestive tumor recurrence, the difficulties in differentiating tumor recurrence from treatment-related imaging abnormalities and therapeutic strategies for the treatment of recurrent malignant astrocytomas are discussed.

Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan

The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Targeted toxin therapy for malignant astrocytoma.

The poor prognosis associated with malignant astrocytoma has led investigators to seek new, innovative methods of treatment. Targeted toxins represent a unique form of therapy that has two components, a carrier molecule with high specificity for tumor-associated antigens and a potent protein toxin. These compounds are extremely cytotoxic to malignant astrocytoma cell lines in vitro. Animal studies have shown prolongation of survival and complete tumor regression when targeted toxins were administered by a variety of routes. The promising results seen in vivo have formed the basis for proceeding with clinical trials in humans with leptomeningeal neoplasia and malignant brain tumors, in which these agents are administered intrathecally or directly into tumor, respectively. To date, in these clinical trials, targeted toxins have been delivered safely without significant neurological toxicity, and cytological analysis of cerebrospinal fluid and radiological findings have shown evidence of a therapeutic response. These studies have confirmed the existence of a therapeutic window between normal brain tissue and malignant cells that can be exploited with targeted therapy directed against the transferrin receptor. The successful delivery of targeted toxins directly into malignant brain tumors has established this route of administration as practical and feasible. Identification of other receptors that are preferentially expressed on brain tumors, such as the interleukin-4 receptor, has resulted in the creation of a fusion protein against this receptor that contains a modified toxin from the bacteria Pseudomonas aeruginosa. This chimeric fusion toxin is currently under investigation in a Phase I clinical trial with patients with recurrent malignant astrocytoma, and other targeted toxins are under development for the treatment of these uniformly fatal tumors. Owing to these recent advances in targeted toxin therapy for malignant primary brain tumors, a review of the development of these agents for practicing neurosurgeons seems timely.

Thermoradiotherapy for brain tumors. Three cases of recurrent malignant astrocytoma and review of clinical experience.

Three patients with symptomatic, recurrent supratentorial malignant astrocytoma were retreated with combined interstitial iridium-192 brachytherapy (RT) and hyperthermia (HT): 50 Gy at 50 cGy/h was delivered 10 mm outside the computed tomography (CT) enhancement border through stereotactically placed plastic tubes, and 915-MHz microwave antenna heating was done for 60 min within 30 min either before or after irradiation. Invasive thermometry data were obtained from the tumor and adjacent brain tissue. The patients tolerated the treatment well and two thirds improved. All patients developed cerebral edema, one also developed scalp infection, and another patient developed meningeal infection. Exceeding the expectancy without treatment, overall survival was 7, 12, and 15 months. On autopsy, two of the patients' brains revealed no active tumor in the treated regions, but one displayed tumor in untreated parts. The HT-RT treatment was very effective, but the original tumor extent was not apparent by the CT imaging technique. A postimplant resection approach may be advisable to minimize postimplant edema. Our data are in agreement with the available literature on more than 400 patients. However, our aim of extending survival decisively could not be realized.

Brachytherapy for recurrent malignant astrocytoma

Purpose : To assess the efficacy of interstitial brachytherapy in the treatment of patients with recurrent malignant astrocytoma. Methods and Materials : Forty-six patients with recurrent malignant astrocytoma were treated with stereotactic high-activity temporary iodine-125 implants between September, 1986 and October, 1992. All patients had been initially treated for malignant asctrocytoma (44) or low-grade astrocytoma (2) with surgery and external fractionated radiation. The median time between initial diagnosis and recurrence treated with brachytherapy was 12.5 months. Twenty-five patients received chemotherapy prior to brachytherapy. Results : All but four patients have died; median survival time following brachytherapy is 46 weeks. Twelve patients underwent reoperation for radiation necrosis at a median interval of 6.5 months after treatment (26%). Five patients incurred complications directly due to brachytherapy (11%). Forty-four patients are evaluable regarding pattern of failure following brachytherapy. Six of these 44 patients (13.6%) recurred at a distance from the treatment volume (4 in brain and 2 in spinal subarachnoid space). Conclusion : Brachytherapy confers modest but meaningful prolongation of survival in selected patients with recurrent malignant astrocytoma, but complications are significant, reoperation frequently required, and recurrence outside the treatment volume common.

Phase II evaluation of fludarabine phosphate in patients with central nervous system tumors

Twenty-three patients with malignant central nervous system tumors were treated with fludarabine phosphate (2-FAMP) on a 5 day bolus schedule. One brief partial response was observed in 20 malignant astrocytoma patients. 2FAMP as given in this protocol is inactive in previously treated patients with recurrent malignant astrocytomas.

ImuVert® Therapy in the Treatment of Recurrent Malignant Astrocytomas: Nursing Implications

Malignant astrocytoma is a fatal, primary brain tumor affecting adults in the prime of life. Even with optimal treatment, median life expectancy from time of diagnosis is 51 weeks. Standard therapy consists of surgical debulking, radiation therapy and chemotherapy. Immunotherapy, utilizing biologic response modifiers (BRMs), affords one of the more promising treatment modalities. ImuVert, a BRM derived from Serratia marcescens, was recently granted orphan drug status by the Food and Drug Administration. In phase I and II clinical trials in patients with advanced malignant tumors, toxicities ranged from mild local reaction at injection sites to hypotension requiring vasopressors. ImuVert is currently being tested in a multicenter clinical trial as a treatment for recurrent malignant astrocytoma in adult patients. A comprehensive toxicity profile of brain tumor patients receiving ImuVert and techniques of managing adverse effects is presented.

Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure

The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.

Phase II trial of Serratia marcescens extract in recurrent malignant astrocytoma.

Nineteen assessable patients with recurrent malignant astrocytomas who had failed standard therapy (surgery, radiation, and/or chemotherapy) were treated on a phase I-II trial with a biologic extract of Serratia marcescens (ImuVert; Cell Technology, Boulder, CO) a new biologic response modifier (BRM). Two complete responses (CRs) were seen, of 63 and 77+ weeks duration. One minor response (MR) occurred, of 6 weeks duration. There were four additional stable (S) patients, with durations of 58+, 39, 12, and 7 weeks. Median time to progression and median survival in the CR plus MR patients were 63 and 129+ weeks, respectively. Overall, median time to progression and median survival were 12 and 19 weeks, respectively. Three patients are alive greater than or equal to 2.5 years from study entry. Common toxicities included transient (less than 72 hours) tenderness, induration, and erythema at the injection sites. Systemic toxicities were less frequent and included fever, chills, nausea/vomiting, headache, arthralgia, and hypotension. The response rate (CR plus MR) to this new BRM is modest (16%). However, the observation of CRs in patients with advanced recurrent malignant astrocytomas, with acceptable overall toxicity, warrants further study of this agent.

Interstitial Brachytherapy for Malignant Brain Tumors: Preliminary Results

Abstract The authors report their experience with interstitial brachytherapy in 46 patients with malignant brain tumors. Twentythree patients received implants after external radiation for newly diagnosed malignant astrocytoma, as part of a randomized study (Group I). Eighteen patients received implants for recurrent malignant astrocytoma (Group II) and 3 for recurrent solitary cerebral metastasis from adenocarcinoma of the lung (Group III). Two additional patients received implants as part of their initial therapy for a radiation-induced malignant astrocytoma and a malignant fibrous histiocytoma. In all patients high-activity iodine-125 sources were implanted temporarily by a stereotactic technique. To date 50 patients have been entered in the randomized study with a maximum follow-up of 31 months. The small numbers and short follow-up preclude any conclusions regarding the efficacy of brachytherapy used as part of initial therapy. The median survival to date in the 23 patients in this group who received implants is 60 weeks. The median survival to date for the 18 patients who received implants for recurrent malignant astrocytoma is 44 weeks postimplant. Two of the three patients who received implants for recurrent solitary metastasis are alive at 41 and 49 weeks postimplant; a third died at 39 weeks postimplant. Significant complications attributable to interstitial brachytherapy have been observed in 10 of 46 patients (21.7%). A second operation for clinical and radiological deterioration was performed in 12 patients (26.1%) 8 to 105 weeks after brachytherapy. The authors conclude that interstitial brachytherapy is beneficial for selected patients with recurrent malignant astrocytoma and solitary recurrent metastasis. The role for this therapy as part of the initial management of patients with malignant astrocytoma remains to be adequately determined in ongoing randomized studies.

Interstitial brachytherapy for malignant brain tumors

The authors report their experience with interstitial brachytherapy in 46 patients with malignant brain tumors. Twenty-three patients received implants after external radiation for newly diagnosed malignant astrocytoma, as part of a randomized study (Group I). Eighteen patients received implants for recurrent malignant astrocytoma (Group II) and 3 for recurrent solitary cerebral metastasis from adenocarcinoma of the lung (Group III). Two additional patients received implants as part of their initial therapy for a radiation-induced malignant astrocytoma and a malignant fibrous histiocytoma. In all patients high-activity iodine-125 sources were implanted temporarily by a stereotactic technique. To date 50 patients have been entered in the randomized study with a maximum follow-up of 31 months. The small numbers and short follow-up preclude any conclusions regarding the efficacy of brachytherapy used as part of initial therapy. The median survival to date in the 23 patients in this group who received implants is 60 weeks. The median survival to date for the 18 patients who received implants for recurrent malignant astrocytoma is 44 weeks postimplant. Two of the three patients who received implants for recurrent solitary metastasis are alive at 41 and 49 weeks postimplant; a third died at 39 weeks postimplant. Significant complications attributable to interstitial brachytherapy have been observed in 10 of 46 patients (21.7%). A second operation for clinical and radiological deterioration was performed in 12 patients (26.1%) 8 to 105 weeks after brachytherapy. The authors conclude that interstitial brachytherapy is beneficial for selected patients with recurrent malignant astrocytoma and solitary recurrent metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Patterns of second recurrence of malignant astrocytomas

CT scans of 12 patients who underwent resection of recurrent malignant astrocytoma and who had a radiographically documented second tumor recurrence were studied. Second tumor recurrence was histologically verified in four patients. Eight of 12 second recurrences were no more than 2.0 cm from the contrast-enhancing margin of the first recurrence. The remaining four patients had tumor recurrence within 2.2, 4.6, 5.1 and 6.9 cm of the enhancing margin of the first tumor recurrence. Peritumoral edema at the time of initial recurrence had no relationship to the patterns of second recurrence. It is concluded that patients who undergo reoperation for recurrent malignant astrocytoma are still primarily at risk for local tumor failure, as opposed to diffuse dissemination of disease throughout the brain.

Inability of computed tomography appearance of recurrent malignant astrocytoma to predict survival following reoperation.

Computed tomographic (CT) scans of 39 patients who underwent reoperation for recurrent malignant astrocytoma at Memorial Sloan-Kettering Cancer Center from 1980 through 1987 were reviewed and correlated with the patients' clinical course. Histologic diagnosis (anaplastic astrocytoma v glioblastoma multiforme) had a statistically significant impact on survival following reoperation (P = .038). Patients with high preoperative performance status (P = .29), total resection by postoperative CT scan (P = .15), and frontal lobe tumors (P = .17) tended to survive longer following reoperation. The size of the tumor at the time of recurrence did not correlate with survival following reoperation. Patients with a small amount of peritumoral edema at the time of recurrence tended to survive longer, but the effect was small (P = .16). Prognosis following reoperation cannot be accurately predicted on the basis of tumor appearance on CT scan.

Diagnostic yield in CT-guided stereotactic biopsy of gliomas.

Twenty-seven patients underwent 29 computerized tomography (CT)-guided stereotactic biopsy procedures for untreated or recurrent malignant astrocytomas. Biopsies were obtained from the hypodense center, enhancing margin, and hypodense periphery as seen on contrast-enhanced CT scans, with diagnostic yields of (number of biopsies yielding tumor/number of biopsies obtained): 34/61 (56%), 68/101 (67%), and 8/22 (36%) from these three zones, respectively. Although tumor was identified in all three zones, diagnostic yield was significantly higher in the hypodense center and enhancing margin. Comparison of patients with untreated tumors to those with recurrent tumors demonstrated no statistical difference in tumor distribution, although there was a trend toward a higher yield from the hypodense periphery in the recurrent tumor group. Tumor was found up to 15 mm beyond the CT-enhancing margin, in addition to extending beyond the area of abnormality on T2-weighted magnetic resonance images. These findings suggest that serial stereotactic biopsies should be targeted to the hypodense center and enhancing margin for improved diagnostic yield. Biopsy material obtained from the hypodense periphery that demonstrates tumor also indicates that a tumor volume beyond the confines of the CT-enhancing margin should be considered when calculating dosimetry for interstitial radiation.

Reoperation for malignant astrocytoma

We evaluated 15 consecutive patients with malignant astrocytomas who were reoperated for functional status and survival. Their Karnovsky Performance Status (KPS) was not changed by surgery. None suffered perioperative death, wound infection, or complications. Patients with glioblastoma maintained KPS unchanged for a mean of 13 weeks (median, 10 weeks); with anaplastic astrocytoma, mean, 37.2 weeks (median, 24 weeks). Life spans were approximately twice that of non-reoperated historical controls. Reoperation for patients with recurrent malignant astrocytoma should be seriously considered when a gross total re-resection can be the goal in a patient whose tumor is in an accessible brain region.

Phase II evaluation of dibromodulcitol in the treatment of recurrent medulloblastoma, ependymoma, and malignant astrocytoma.

The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

Single-Agent Chemotherapy of Brain Tumors

Identification of effective single chemotherapeutic agents for brain tumors must precede the rational use of multiple drug combinations. In phase 2 trials beginning in 1968, 158 patients with intrinsic brain tumors (mostly recurrent malignant astrocytomas) were considered evaluable. The larger trials with more effective drugs produced these results: carmustine (BCNU) response rate, 47%, with median duration of nine months; lomustine (CCNU), 44%, with median duration of six months; procarbazine hydrochloride, 52%, with median duration six months; carmustine and vincristine sulfate combined, 44%, with median duration of only four months; and BIC (5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide), 38%, with median duration of five months. Administration of glucocorticoids was not found to bias the frequency of response. Forty-seven patients, 26 of whom had responded to the initial drug, received a second drug. Among 26 patients who were evaluable, only four responded to the second drug.