Treatment Of High-grade Astrocytomas Research Articles

Safety of temozolomide use in adult patients with renal dysfunction.

Temozolomide (TMZ), a cytotoxic DNA alkylating agent, is the main chemotherapy used for the treatment of high grade astrocytomas. The active alkylator, methylhydrazine, is not recovered in urine and thus renal function is not expected to affect clearance. Prescribing information for TMZ states pharmacokinetics have not been studied in adults with poor renal function, eGFR < 36mL/min/1.73 m2. We reviewed our clinical experience with TMZ in patients with impaired renal function to evaluate safety of administering full dose TMZ. The primary endpoint was to characterize the incidence and severity of thrombocytopenia in patients with eGFR < 60mL/min/1.73 m2 who received TMZ for treatment of high grade gliomas (HGG) or primary CNS lymphoma (PCNSL). Secondary endpoints included incidence and severity of neutropenia, lymphopenia hepatotoxicity, and number of TMZ cycles administered. Medical records of patients with HGG or PCNSL treated with TMZ from October 1, 2016-September 30, 2019 were accessed to identify cases for this study. Thirty-two patients were eligible for this study. Of the seven patients with eGFR < 36mL/min/1.73m2, 38/39 cycles (97%) were completed without grade 3-4 thrombocytopenia. No patients experienced grade 3-4 neutropenia, and grade 3-4 lymphopenia occurred in 5 cycles (15%). One patient discontinued TMZ 7days prior to completion of radiation due to thrombocytopenia. Hematologic toxicity in patients with severe renal dysfunction, eGFR < 36mL/min/1.73m2, is similar to that of patients with normal renal function. Severe renal impairment does not preclude use of temozolomide, but cautious monitoring of blood counts is warranted.

ATCT-14CHEMOSENSITIVITY OF PRIMARY AND METASTATIC CNS TUMORS TO 4-DEMETHYL-4-CHOLESTERYLOXYCARBONYLPENCLOMEDINE (DM-CHOC-PEN) AND TEMOZOLOMIDE

BACKGROUND: The efficacy of TMZ in the treatment of high-grade astrocytomas is limited by drug-resistance mediated by O6-methylguanine-DNA methyltransferase (MGMT). Brain metastases are difficult to treat and currently no standard chemotherapeutic therapies exist. 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a polychlorinated pyridine cholesteryl carbonate whose mechanism of action is via alkylation of DNA at N7-guanine. This agent has had early therapeutic success in treating both primary and metastatic CNS malignancies in Phase I and Phase II clinical trials. METHODS: To better understand the sensitivity and mechanisms of resistance in primary and metastatic CNS tumors, we collected tissue from subjects (n = 38) enrolled between March 2014 - January 2015 for chemosensitivity studies. These included high-grade astrocytomas (9), metastatic brain tumors (6) meningiomas (6), and other more benign tumors such as pituitary adenomas (4), hemangioblastoma (1), and chondrosarcoma (1). Using viable tumor cell explants from surgery, cells were grown under standard conditions (RPMI/FBS, 5%CO2, 37°C), in vitro chemosensitivity profiles were obtained comparing DM-CHOC-PEN vs. TMZ and other commonly used anti-cancer agents. RESULTS: Tumor cells exhibited higher susceptibility to DM-CHOC-PEN than to TMZ (RR = 3.19, p = 0.0029, 95% confidence interval [CI], 1.3-7.8 vs. TMZ). In a subgroup analysis of high-grade astrocytomas, atypical meningiomas, and secondary metastases in this cohort, an association was noted between TMZ-resistance (µIC50 = 3.3, S.D. = 0.46) and DM-CHOC-PEN-sensitivity (µIC50 = 1.0, S.D = 0.26) using two-sample independent, Student's t-test with Fisher's exact P-value (p = 0.0001, t(23.72) = 4.5, df = 27.17). CONCLUSIONS: These preliminary results suggest that DM-CHOC-PEN may promote cell death in tumors possessing acquired MGMT-mediated drug-resistance. Furthermore, it supports roles for this promising new agent in the treatment of primary and metastatic brain tumors and in treatment of high-grade astrocytomas, either in combination with TMZ or alone in cases of TMZ-resistance.

Drugs targeting the mitochondrial pore act as citotoxic and cytostatic agents in temozolomide-resistant glioma cells

BackgroundHigh grade gliomas are one of the most difficult cancers to treat and despite surgery, radiotherapy and temozolomide-based chemotherapy, the prognosis of glioma patients is poor. Resistance to temozolomide is the major barrier to effective therapy. Alternative therapeutic approaches have been shown to be ineffective for the treatment of genetically unselected glioma patients. Thus, novel therapies are needed. Mitochondria-directed chemotherapy is an emerging tool to combat cancer, and inner mitochondrial permeability transition (MPT) represents a target for the development of cytotoxic drugs. A number of agents are able to induce MPT and some of them target MPT-pore (MPTP) components that are selectively up-regulated in cancer, making these agents putative cancer cell-specific drugs.ObjectiveThe aim of this paper is to report a comprehensive analysis of the effects produced by selected MPT-inducing drugs (Betulinic Acid, Lonidamine, CD437) in a temozolomide-resistant glioblastoma cell line (ADF cells).MethodsEGFRvIII expression has been assayed by RT-PCR. EGFR amplification and PTEN deletion have been assayed by differential-PCR. Drugs effect on cell viability has been tested by crystal violet assay. MPT has been tested by JC1 staining. Drug cytostatic effect has been tested by mitotic index analysis. Drug cytotoxic effect has been tested by calcein AM staining. Apoptosis has been assayed by Hoechst incorporation and Annexine V binding assay. Authophagy has been tested by acridine orange staining.ResultsWe performed a molecular and genetic characterization of ADF cells and demonstrated that this line does not express the EGFRvIII and does not show EGFR amplification. ADF cells do not show PTEN mutation but differential PCR data indicate a hemizygous deletion of PTEN gene. We analyzed the response of ADF cells to Betulinic Acid, Lonidamine, and CD437. Our data demonstrate that MPT-inducing agents produce concentration-dependent cytostatic and cytotoxic effects in parallel with MPT induction triggered through MPTP. CD437, Lonidamine and Betulinic acid trigger apoptosis as principal death modality.ConclusionThe obtained data suggest that these pharmacological agents could be selected as adjuvant drugs for the treatment of high grade astrocytomas that resist conventional therapies or that do not show any peculiar genetic alteration that can be targeted by specific drugs.

Biological Inhibitory Effects of the Chinese Herb Danggui on Brain Astrocytoma

Objective: Previous studies have demonstrated the utility of the traditional Chinese herb danggui in the treatment of chronic myelogenous leukemia. Our aim was to examine whether it might similarly be used to treat glioblastoma multiforme. Methods: The lipid-soluble active ingredients of danggui were extracted with acetone (AS-AC) or chlorophenol (AS-CH) and their antiproliferative and proapoptotic effects were studiedin vitro on cultured GBM 8401 cells and in vivoon tumors in nude mice. Results: After a 24-hour treatment, either AS-AC or AS-CH at a lower (50 µg/ml) and a higher concentration (100 µg/ml) significantly inhibited the proliferative activity of GBM 8401 cultured cells by 30–50%, as well as the expression of cathepsin B and vascular endothelial growth factor (VEGF). In nude mice, the growth of the tumor was inhibited by 30% by AS-CH or AS-AC (20 mg/kg; p < 0.05) and by 60% by AS-CH or AS-AC (60 mg/kg; p < 0.05). AS-AC and AS-CH also significantly inhibited microvessel formation in the tumors of nude mice. Conclusions: Danggui may inhibit tumor growth by reducing the level of VEGF and the proapoptotic protein, cathepsin B. Thus, danggui may be useful in the treatment of high-grade astrocytomas.

Concomitant accelerated hyper-fractionated radiotherapy and temozolomide in the treatment of high grade astrocytoma: Updated results

11523 Background: The safety and efficacy of accelerated hyper-fractionated radiotherapy (RT) combined with temozolomide (TMZ) in patients with high grade astrocytoma have already been reported.Updated results on survival will be presented. Methods: Twenty-four patients with newly diagnosed and histologically proven high grade astrocytoma were enrolled onto this study. Treatment protocol included RT delivered in fractions of 150 cGy 3 times daily with at least 4-hour intervals between fractions to a total dose 4050 cGy. The target volume was the tumor plus the edema with a 2-cm margin. A boost of 1800 cGy was given to the tumor plus a 2-cm margin to a total dose of 5850 cGy delivered in 39 sessions over 2.5 weeks. TMZ dose was (150 g/m2/day 7 d/wk) given 2 hours prior to RT, throughout the course of RT. Results: Of the 24 patients included 5 (21%) developed G2 &amp; G3 neutropenia, and 4 patients (17%) developed G2 &amp; G3 thrombocytopenia. Non-hematologic toxicities were: G2 &amp; G3 vomiting in 8 (33%) patients, G2 &amp; G3 fatigue in 13 (54%) patients, G2 skin rash in 4 (17%), and G2 acute radiation reaction in 2 (8%) patients. The12 months and 18 months survival rates were 67% and 51.5% respectively. Patients aged &lt;45 years and those who underwent debulking surgery had better survival rates (69% &amp; 70%) in comparison to those aged ≥45 years and those who underwent biopsy only (27% &amp; 36%). Conclusions: The results achieved particularly with respect to survival are promising and should be confirmed. No significant financial relationships to disclose.

Treatments for Astrocytic Tumors in Children

Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0-5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.

Local Treatment of Brain Tumors with Targeted Chimera Cytotoxic Proteins

High-grade astrocytomas (HGA) are the most prevalent brain tumors that represent a unique pharmaceutical challenge. Their cerebral localization and characteristic features of tumor progression primarily dictate this challenge. Targeted chimera conjugate/fusion cytotoxic proteins have become the newest class of investigative drug candidates for the treatment of HGA due to their inherent properties that are compatible with drug deliveries to brain tumors. A conjugate of a human transferrin with bacterial toxin, Diphtheria toxin, has shown clinical efficacy in Phase I and II trials when administered intratumorally through convection-enhanced delivery. This immunotoxin belongs to the first group of immunotoxins that started to live up to early expectations. Other anti-brain tumor cytotoxins have entered or will enter the clinic shortly. The clinical applicability of targeted bacterial toxin-containing cytotoxins in the treatment of brain tumors warrants further development and careful clinical evaluation.

Continuous hyperfractionated accelerated radiotherapy in the treatment of high-grade astrocytomas

Between May 1993 and January 1995, 36 patients with high-grade astrocytomas were treated with 1.05 Gy continuous hyperfractionated accelerated radiotherapy three times daily to a total target dose of 59.85 Gy in 19 days with 6-h intervals. The median age of the patients was 51 years and the median follow-up was 58 weeks. The median survival rate was 58 weeks and the cumulative survival rate was 22% at 2 years. No severe toxicity occurred in patients treated with this fractionation scheme. These results suggest that continuous hyperfractionated accelerated radiotherapy is an altered fractionation schedule for high-grade astrocytomas with tolerable acute toxicity and survival rates comparable to conventional fractionation and to other altered fractionation schedules.

A comparison of two planning techniques for radiotherapy of high grade astrocytomas

The purpose of this study was to compare two planning techniques for the delivery of radical localized postoperative radiotherapy in the treatment of high grade astrocytomas. Conventional orthogonal plain film planning (CONP) was compared with CT planning (CTP) in terms of the size of the target volumes treated, the amount of normal brain irradiated and the accuracy of localization. Twenty consecutive adults with high grade astrocytomas, who were treated with radiotherapy between March and October 1996, were planned with CONP and CTP, using postoperative, contrast-enhanced CT scans to define the tumour volume. The planning target areas, volumes and the 100%, 80% and 50% isodose areas produced using the two planning methods were measured and compared using Student's paired t-test. The target volume length was also measured and compared as an independent factor. The difference between entry points of the central axis of the lateral fields was noted. Nineteen of 20 patients had a reduction in planning target volumes using CTP compared with CONP. The difference between the mean volumes was clinically relevant, with 288 cm 3 representing a 25% reduction, and statistically significant at the P < 0.001 level. The planning target volumes were reduced in 18/20 patients (mean 24 cm 2, 23%, P < 0.001). Similarly, there were highly significant reductions in the 100%, 80% and 50% isodose areas. The target volume lengths were not found to be significantly different. When considering the accuracy of localization, the entry point of the CONP lateral field deviated by a mean distance of 1.6 cm relative to CTP (superiorinferior 1.3 cm; anteriorposterior 0.8 cm; range 0–4.l cm). In two patients, this would have led to a geographical miss of macroscopic disease. In patients with high grade astrocytomas, CTP is preferred to conventional planning. It leads to appreciable reductions in the size of the planning target areas and volumes receiving radical doses of radiation, it significantly reduces the amount of normal brain tissue being irradiated and is more accurate in terms of tumour localization. These differences are likely to lead to a reduction in treatment morbidity. We recommend CTP for all patients receiving radical radiotherapy.

178 High dose rate brachytherapy in treatment of high grade astrocytomas

178 High dose rate brachytherapy in treatment of high grade astrocytomas

Fast neutrons in the treatment of grade IV astrocytomas

In 1981, the Hôpital Tenon group and the Orléans neutron therapy team initiated a collaborative study for the treatment of grade IV astrocytomas using a combination of photons and neutrons. Neutrons were used as boost in a reduced volume. Doses were progressively increased from 6 to 7 Gy and later up to 8 Gy. Since October 1994, a neutron boost of 7.5 Gy has been delivered. At the time of evaluation, 294 patients had a minimum follow-up of 12 months. Univariate analysis indicated that clinical status, tumor location and photon fractionation scheme had no significant influence on survival. In contrast, age, surgical procedure and neutron dose were found to be prognostic factors. In a multivariate analysis, the prognostic value of the surgical procedure disappeared and the only remaining independent prognostic factors up to 11 months after treatment (P = 0.001) were age and the neutron dose. As far as neutron dose was concerned, survival increased with dose from 6 to 7 Gy up to 15 months. However, after 15 months, there was no longer any benefit in survival for the patients treated with 8 Gy, and complications related to overdosage began to appear. There was a long-term survival group: 55 patients were alive 18 months after treatment (18%). The median survival was 26.7 months. The best survival was observed for patients treated with a neutron boost of 7 Gy in eight fractions over 11 days (25 vs 18%). The present study demonstrates the feasibility of a combination of photons (30 Gy total brain) followed by a neutron boost (7 Gy) in the treatment of high-grade astrocytomas. The results are in good agreement with the published data. In the literature, age and surgical procedure are currently considered as the most important prognostic factors. The prevalence of neutron dose over these two other prognostic factors, as shown in this study, is an important additional argument in favor of the use of neutrontherapy in the management of these tumors. A possible benefit when combining external fast neutrontherapy with boron neutron capture therapy (BNCT) could reasonably be expected.

The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: Results of a randomized trial

Fifty-eight patients with high-grade astrocytoma were treated by members of the Childrens Cancer Study Group in a prospective randomized trial designed to study the effectiveness of chemotherapy as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl nitrosourea, vincristine, and prednisone. Treatment with chemotherapy prolonged survival and event-free survival. Five-year event-free survival was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the radiotherapy-alone group. Five-year survival was similarly improved. The differences in outcome due to treatment were statistically significant after correcting for imbalances in important prognostic factors (event-free survival, p = 0.026; survival, p = 0.067). The presence of mitoses or necrosis in the tumor specimen was associated with poorer outcome. Patients whose initial surgery was limited to biopsy, and patients with basal ganglia lesions, also had significantly worse outcome. Chemotherapy administered at the time of recurrence in a small number of patients did not produce any long-term survivors. This study is to our knowledge the only randomized trial to investigate effectiveness of chemotherapy in the treatment of high-grade astrocytoma in children.

Radiotherapy and L-triiodothyronine in the treatment of high-grade astrocytoma.

From January 1983 to March 1984, eight patients with high-grade astrocytoma received postoperative irradiation concomitantly with triiodothyronine at the Radiation Therapy Department of the I. González Martínez Oncologic Hospital in San Juan, Puerto Rico. There were no complications related to treatment. One patient is alive without evidence of disease at 39 months and seven patients died with disease, one of whom lived for 3 yr. The survival curve for these patients is similar to the survival curve of 18 patients treated at the University of Chicago by surgery, radiation, and triiodothyronine. The value of triiodothyronine as an adjuvant in the treatment of high grade astrocytoma should be further investigated.

A phase I study of mixed (neutron and photon) irradiation using two fractions per day in the treatment of high-grade astrocytomas.

A Phase I study of the treatment of 50 patients with high-grade astrocytomas by mixed schedule (neutron and photon) irradiation given in 12 fractions over 4 weeks is reported. The neutron and photon fractions were separated each day by 2-3 h. A total neutron dose of 6.36 Gy (8% gamma) and 20.40 Gy of photons was prescribed. Treatment was well tolerated and there was no clinical evidence of radiation-related morbidity in the brain. The median survival was 6.9 months, similar to that expected after photon irradiation alone. A multivariate analysis of prognostic variables in presented.

Misonidazole and irradiation in the treatment of high-grade astrocytomas: Further report of the Vienna study group

A randomized study investigating the value of misonidazole in patients irradiated for grade III and IV supratentorial astrocytomas was started in June 1977. With a minimum follow-up time of 6 months, 45 patients who completed therapy are available for analysis. All patients received the same radiation treatment (66.5 Gy in 31 fractions over 7.5 weeks, field size reduction after 45 Gy). In the first, second and eighth week, a 4 Gy tumor dose was given on Monday and Thursday. Misonidazole was given 4 hours before irradiation to 18 randomized patients on those 6 treatment days (2.1–2.7 g/m 2 per treatment day). Daily tumor doses of 1.7 Gy were administered Monday through Friday from the third until the seventh week. Median survival for patients treated with misonidazole is 13.8 months; for those treated by irradiation alone it was 9.8 months. The corresponding 1 year survival rates are 64 and 2596, respectively. Survival plots indicate some advantage for the patients treated with misonidazole, however statistically there is no significant difference observed ( p > 0.08). There are no significant differences in Karnofsky performance status, sex and in histological grade or in age distribution between the groups. However, the type of surgery (complete or subtotal) influenced survival markedly: patients with complete surgery lived significantly longer ( p < 0.0009). Neurotoxic side effects of misonidazole were minimal.