Pharmacokinetics of neocarzinostatin in patients with malignant glioma. Quantitative analysis of tissue concentration

Because of technical difficulties, the pharmacokinetics of neocarzinostatin (NCS) have not been thoroughly evaluated in patients with malignant glioma. The authors produced anti-NCS antibody by immunizing rabbits with NCS and established a means of quantifying tissue levels of NCS with enzyme-linked immunosorbent assay. In one patient given a bolus injection of 1 mg of NCS intra-arterially, the concentration of drug in neoplastic tissue at 25 minutes (0.1136 micrograms/g) was higher than that in blood at 20 minutes and was retained for a longer period. Rapid entry of NCS into the tumor cavity was observed at 5 minutes. In two postoperative cases, NCS applied topically to the tumor site (50 and 100 micrograms) was retained at high levels (0.2941 and 3.33 micrograms/ml) even after 48 hours, although no NCS was detected in blood after 60 minutes. NCS concentrations as low as 1 microgram/ml demonstrated cytocidal effects, and a delay in tumor growth was observed even at an NCS level of 0.1 microgram/ml, despite the fact that the half-life of NCS is extremely short (3 seconds in serum). Because its cytotoxic effect seems to be very rapid, it appears more important to obtain a high initial NCS concentration than to maintain a constant blood level.     

Uptake and localization of neocarzinostatin in malignant glioma. Experimental study by immunofluorescent staining method

The authors studied the localization of neocarzinostatin (NCS) in cultured cells and in tumor-bearing rats by means of immunofluorescent staining. Anti-NCS antibody was obtained through immunization of rabbits with NCS. Cellular uptake of NCS was dose-dependent (1.0 to 1000 micrograms/ml) in 9L rat gliosarcoma cells in monolayer. In monolayer cells of 9L, KMG-4 (derived from human glioblastoma), and KMS II (human ependymoma) treated with 1 mg/ml of NCS, drug uptake occurred within a few seconds. Accumulation was much higher in the cytoplasm than in the nucleus and, although nuclear uptake increased slightly over time, there appeared to be no increase in total cellular uptake. Mitotic cells, which were spherical in culture, showed greater intracellular accumulation than other cells. There was no significant difference in uptake among non-mitotic cells. Cells surviving 20 hours of treatment retained accumulation as high as that in killed cells. In KMG-4 monolayers, cytoplasmic and nuclear NCS distribution still differed, whereas 9L monolayers exhibited more even intracellular distribution. In 9L spheroid models treated with 1 mg/ml of NCS, the drug permeated almost all layers within 10 minutes, and at 120 minutes had heavily accumulated in the central necrotic areas. In rats with transplanted brain tumors, NCS selectively accumulated in neoplastic tissues following intra-arterial administration. However, NCS uptake by arterial endothelium was also seen, which suggests the potential for vascular toxicity. The therapeutic value of NCS is discussed in terms of its pharmacokinetic characteristics.     

Multicentric malignant glioma.

Multicentre gliomas are a well recognized entity but the occurrence of such tumours both above and below the tentorium remains uncommon. We report the case of an 11-year-old boy who underwent stereotactic biopsy of a brain stem ring enhancing tumour with histology of an anaplastic astrocytoma (Grade 3). Nine months following his radiotherapy a large left frontal mass was biopsied and found to be a malignant glioma (Grade 4). Advances in neuroradiological imaging will readily show multiple cerebral lesions and multicentre glioma should be considered in the differential diagnosis of such lesions and biopsy is indicated.     

The role of interstitial BCNU chemotherapy in the treatment of malignant glioma

BACKGROUND: Use of interstitial BCNU wafers in the treatment of malignant glioma is currently a controversial topic among neurosurgeons. Initial clinical studies indicated implantation of BCNU wafers into the postoperative tumor bed to be an acceptably safe, partially effective treatment for glioblastoma multiforme. Yet a more recent study has put the efficacy of this treatment in doubt, and there are potential complications associated with BCNU wafer use. OBJECTIVE: This article presents a review of the information presently available on BCNU wafers-both pro and con-to aid in the clinical decision-making process. The article focuses on studies of clinical efficacy (for initial use as well as in the setting of recurrent tumor), complications associated with BCNU wafers, and the experimental data, particularly related to BCNU penetration into the brain. RESULTS: Animal studies and computer simulations have shown that the depth of penetration of BCNU from wafers is limited. Yet in actual clinical use, the interstitial pressure within the wafer-laden tumor bed might be higher, convective flow greater, and delivery of BCNU to the brain more significant than predicted. CONCLUSION: Based on current information, use of interstitial BCNU wafers continues to be an option for treating malignant glioma. Additional clinical studies of BCNU wafers are currently underway.     

Role of chemotherapy in long-term survival of malignant glioma (author's transl)]

Effect of chemotherapy was evaluated from the view point of postoperative survival rate in 102 consecutive cases of histologically verified glioblastomas treated during past 16 years. As a result of the study, the "additive effect" of chemotherapy on the ordinary surgical operation and radiation therapy could not be clarified. However, the effect of chemotherapy was worth to note among 6 cases which survived more than 5 years after operation. Then, combination of various treatment including chemotherapy should be repeatedly applied in individual cases of glioblastoma.     

Intraoperative radiation therapy for malignant glioma.

Intraoperative radiation therapy (IORT) was used as part of the initial therapy for malignant glioma in 32 of 73 patients with histologically verified anaplastic astrocytoma (grade III astrocytoma) and glioblastoma multiforme. The initial treatment for all cases was subtotal or total tumor resection combined with external irradiation and chemotherapy. IORT was performed 1 week after tumor resection, with doses of 10-50 Gy (mean 26.7 Gy) in one session. Fourteen of 32 cases had IORT two times because of tumor recurrence. The IORT patients had survival rates at 24 and 36 months after initial treatment of 57.1 and 33.5% (median survival 26.2 months). The other 41 patients had 23.6 and 13.1% survivals (median survival 20.7 months), which were significantly lower (p less than 0.01). Tumor recurrence within the original lesion site was suspected because of clinical condition, computed tomography, and magnetic resonance imaging studies in 65.6% of the IORT group (21 cases) 12 months after initial treatment. Twenty cases of death in the IORT group, including five autopsy cases, demonstrated regional tumor recurrence with a high incidence of intraventricular tumor invasion. The authors consider IORT is beneficial for selected malignant glioma patients, including tumor recurrence, because of prolonged survival.     

Local immunotherapy with interleukin-2 delivered from biodegradable polymer microspheres combined with interstitial chemotherapy: a novel treatment for experimental malignant glioma

OBJECTIVE: Local delivery of carmustine (BCNU) from biodegradable polymers prolongs survival against experimental brain tumors. Moreover, paracrine administration of interleukin-2 (IL-2) has been shown to elicit a potent antitumor immune response and to improve survival in animal brain tumor models. We report the use of a novel polymeric microsphere delivery vehicle to release IL-2. We demonstrate both in vitro release of cytokine from the microspheres and histological evidence of the inflammatory response elicited by IL-2 released from the microspheres in the rat brain. These microspheres are used to deliver IL-2, and biodegradable polymer wafers are used to deliver BCNU, directly at the site of an intracranially implanted glioma in the rat. The two agents administered locally show a synergistic effect. METHODS: Fischer 344 rats challenged intracranially with 9L gliosarcoma received an intracranial implant of either empty microspheres or microspheres containing IL-2 (IL-2 MS). Five days later, animals in each group were randomized to receive polymer implants loaded with 0, 3.8, or 10% BCNU at the tumor site. RESULTS: Animals that received the combination of IL-2 MS and 3.8% BCNU polymer (median survival, 28.5 d) or IL-2 MS and 10% BCNU polymer (median survival, 45.5 d) showed significantly improved survival compared with animals that received monotherapy with IL-2 microspheres (median survival, 24 d), 3.8% BCNU polymer (median survival, 24 d), or 10% BCNU polymer (median survival, 32.5 d). Control animals had a median survival of 18 days. The combination of either 3.8 or 10% BCNU polymer with IL-2 MS resulted in 7 and 25% long-term survivors, respectively. CONCLUSION: By showing synergy of IL-2 and BCNU in an animal glioma model and using a reproducible synthetic delivery system for each agent (i.e., one that did not rely on genetically engineered cells or viruses), we hope that the combination of local immunotherapy and chemotherapy can take an important step closer to clinical application in patients with malignant brain tumors.     

Chromosome arm 1q gain associated with good response to chemotherapy in a malignant glioma. Case report

The authors describe the case of a patient with a glioblastoma multiforme who showed remarkably good response to chemotherapy. A genetic analysis using comparative genomic hybridization (CGH) revealed that the tumor had a gain on the q arm of chromosome 1 (1q). Using CGH for a series of genetic analyses of more than 180 patients with gliomas, six were found to have a demonstrated 1q gain. Although the tumors in all six of these cases were histopathologically diagnosed as high-grade gliomas, compared with other malignant gliomas they demonstrated a good prognosis because of their favorable chemotherapeutic sensitivity. In immunohistochemical tests, most of the tumor cells in these cases were negative for O6-methylguanine-DNA methyltransferase, which antagonizes the effect of DNA-alkylating chemotherapeutic agents. The authors believed that a gain of 1q could be produced through the genetic events that cause loss of 1p, because these chromosomal aberrations have an imbalance of DNA copy number in common (1p < 1q). A gain of 1q is an infrequent chromosomal aberration and its clinical importance should be investigated in a larger study; however, patients with malignant gliomas demonstrating a 1q gain possibly show longer survival and good response to chemotherapy similar to patients with tumors demonstrating 1p loss. The importance of using genetic analysis for gliomas is emphasized in this report because it may help in selecting cases responsive to chemotherapy and because appropriate treatment for these patients will lead to progress in the treatment of malignant gliomas.     

Salvage immunotherapy of malignant glioma

We present the preliminary results of a phase I trial of adoptive immunotherapy for recurrent or residual malignant glioma. The protocol is based on surgical debulking followed by implantation into the tumor bed of autologous lymphocytes that have been stimulated with phytohemagglutinin-P and then cultured in vitro in the presence of interleukin 2. Fifty-five patients with a mean Karnofsky rating of 64 were treated between February 1985 and March 1987. No significant toxicity was associated with the immunotherapy. Fifty patients had a positive initial response to therapy, nine patients had early recurrence (two to four months after treatment), and 22 patients died. We comment on major differences between the protocol described and other immunotherapy protocols.     

药敏指导下的脑恶性胶质瘤超选择动脉内化疗的近期疗效分析

目的探讨脑恶性胶质瘤在体外的药敏指导下的超选择动脉内化疗的临床效果。方法自2003年1月至2006年12月,对25例脑恶性胶质瘤患者术后进行了体外药敏试验,并进行个体化超选择动脉内化疗。结果用顺铂(DDP)、盐酸司莫司汀(ACNU)、长春新碱(VCR)、威猛(VM-26)、足叶乙甙(VP-16)以MTT法进行体外药敏实验。25例患者中共有19例肿瘤有敏感药物,其中敏感11例,低度敏感8例;不敏感(耐药)6例。23例化疗后随访6个月~2年,客观有效率(CR+PR)为69.6%,疾病控制率(CR+PR+SD)为78.3%。化疗前后肿瘤体积变化差异有统计学意义(P<0.01)。并与34例行手术+放疗恶性胶质瘤组,进行回顾性研究,其差异有统计学意义(P<0.05)。结论在体外药敏指导下的脑恶性胶质瘤超选择动脉内化疗能有较好的近期疗效。     

Clinical trial of bradykinin-enhancing chemotherapy for a recurrent malignant glioma: a case report]

Patients with malignant glioma undergo a combined treatment with surgical resection, radiotherapy, and chemotherapy. Although those treatments usually show some restraining effects on the tumor, a relapse occurs in most of the patients within a few years. We have investigated the feasibility and safety of intra-arterial chemotherapy for malignant brain tumors by enhancing vascular permeability using intra-arterial bradykinin infusion. In 2001, The Committee of Ethics in Kyushu University approved our clinical trial of the bradykinin-enhancing chemotherapy for recurrent malignant gliomas. We here report the first case of our clinical trial. A 31-year-old man, who had undergone surgical resection followed by chemotherapy and irradiation for malignant progression of the left frontal astrocytoma over a period of 2 years, had a relapse of the tumor in the bilateral frontal lobes. After obtaining informed consent, bradykinin and carboplatin were infused through a microcatheter at the left A1 portion under general anesthesia. By dose escalation of bradykinin, the enhanced lesion in the bilateral frontal lobes diminished on magnetic resonance imaging after 3 trials with 3-week intervals, regardless of new lesions outside of the treated area. No neurological or physiological complication including myelosuppression was noted. Bradykinin-enhancing chemotherapy appeared to be effective and safe for malignant glioma. Because it was able to increase drug delivery to the tumor, it was possible to reduce the size of the dose of chemotherapeutic agent, which resulted in minimum complication.     

CyberKnife stereotactic radiotherapy for patients with malignant glioma.

OBJECTIVE: The CyberKnife is a new frameless image-guided radiosurgical modality. The authors report on their experience using the CyberKnife in 25 patients with malignant gliomas. METHODS: Twenty-five patients with histologically proven malignant gliomas (18 glioblastoma: GB, 7 anaplastic astrocytoma: AA) were treated with the CyberKnife at Konan St. Hill Hospital between June 1998 and November 2002. CyberKnife therapy was performed on 44 lesions (31 GB lesions, 13 AA lesions) in the 25 patients. The median target volume was 19.1 mL (range: 0.3 - 90.2). The median prescribed dose was 20.3 Gy (range: 13.9 - 26.4). Patient-, tumor-, and treatment-related variables were analyzed by univariate analysis, and survival curves were generated by the Kaplan-Meier product limit. RESULTS: In the 18 GB patients, the median survival after diagnosis was 20.7 months (82.6 weeks) with a mean follow-up of 85.7 weeks. Of the 7 AA patients, 6 were alive at the time of analysis with follow-up periods ranging from 11.4 to 52.8 months. Patients younger than 70 years had a median survival after diagnosis of 37.1 months, compared to 12.4 months for older patients (p = 0.003). Similarly, patients with well-controlled lesions had a median survival after diagnosis of 39.8 months compared to 16.0 months for those with uncontrolled lesions (p = 0.031). Late delayed radiation necrosis was seen in 1 GB patient. No other patient suffered acute or delayed neurological morbidity after CyberKnife therapy. CONCLUSION: This is the first report of CyberKnife stereotactic radiotherapy applied to the treatment of malignant gliomas. The frameless and painless CyberKnife stereotactic radiotherapy has the potential to be as useful for treatment of malignant glioma as other radiosurgical modalities.     

Cancer immunoediting in malignant glioma

Significant work from many laboratories over the last decade in the study of cancer immunology has resulted in the development of the cancer immunoediting hypothesis. This contemporary framework of the naturally arising immune system-tumor interaction is thought to comprise 3 phases: elimination, wherein immunity subserves an extrinsic tumor suppressor function and destroys nascent tumor cells; equilibrium, wherein tumor cells are constrained in a period of latency under immune control; and escape, wherein tumor cells outpace immunity and progress clinically. In this review, we address in detail the relevance of the cancer immunoediting concept to neurosurgeons and neuro-oncologists treating and studying malignant glioma by exploring the de novo immune response to these tumors, how these tumors may persist in vivo, the mechanisms by which these cells may escape/attenuate immunity, and ultimately how this concept may influence our immunotherapeutic approaches.