Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.

OBJECT: The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. METHODS: The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. RESULTS: Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6-12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6-12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). CONCLUSIONS: These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.

Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model.

OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ-pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5-9). Animals were followed for survival for 120 days. Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p < 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p < 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p < 0.0001 and p = 0.0001 vs. oral TMZ/XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ and XRT given alone or in combination in a rodent intracranial gliosarcoma model.

Longitudinal in vivo monitoring of rodent glioma models through thinned skull using laser speckle contrast imaging.

Laser speckle contrast imaging (LSCI) is a contrast agent free imaging technique suited for longitudinal assessment of vascular remodeling that accompanies brain tumor growth. We report the use of LSCI to monitor vascular changes in a rodent glioma model. Ten rats are inoculated with 9L gliosarcoma cells, and the angiogenic response is monitored five times over two weeks through a thinned skull imaging window. We are able to visualize neovascularization and measure the number of vessels per unit area to assess quantitatively the microvessel density (MVD). Spatial spread of MVD reveals regions of high MVD that may correspond to tumor location. Whole-field average MVD values increase with time in the tumor group but are fairly stable in the control groups. Statistical analysis shows significant differences in MVD values between the tumor group and both saline-receiving and unperturbed control groups over the two-week period (p<0.05). In conclusion, LSCI is suitable for investigation of tumor angiogenesis in rodent models. In addition, the statistical difference (p<0.02) between MVD values of the tumor (24.40 ± 1.41) and control groups (15.40 ± 1.60) on the 14th day after inoculation suggests a potential use of LSCI in the clinic in distinguishing tumor environments from normal vasculature.

Minimally invasive circumferential spinal decompression and stabilization for symptomatic metastatic spine tumor: technical case report.

OBJECTIVE: Metastatic epidural spinal cord compression is a potentially devastating complication of cancer and is estimated to occur in 5% to 14% of all cancer patients. It is best treated surgically. Minimally invasive spine surgery has the potential benefits of decreased surgical approach-related morbidity, blood loss, hospital stay, and time to mobilization. CLINICAL PRESENTATION: A 36-year-old man presented with worsening back pain and lower extremity weakness. Workup revealed metastatic adenocarcinoma of the lung with spinal cord compression at T4 and T5. INTERVENTION AND TECHNIQUE: T4 and T5 vertebrectomy with expandable cage placement and T1-T8 pedicle screw fixation and fusion were performed using minimally invasive surgical techniques. RESULT: The patient improved neurologically and was ambulatory on postoperative day 1. At the 9-month follow-up point, he remained neurologically intact and pain free, and there was no evidence of hardware failure. CONCLUSION: Minimally invasive surgical circumferential decompression may be a viable option for the treatment of metastatic epidural spinal cord compression.

A modified frontal-nasal-orbital approach to midline lesions of the anterior cranial fossa and skull base: technical note with case illustrations.

The frontal-nasal-orbital craniotomy has been utilized for craniofacial abnormalities and resection of tumors involving the anterior skull base. We describe modifications of this technique to approach extra-axial and intradural midline lesions of the anterior fossa with or without involvement of the skull base. A craniotomy was planned with an endoscope and image guidance. A modified frontal-nasal-orbital craniotomy encompassing the entire frontal sinus complex was performed in conjunction with osteotomies incorporating the bilateral superior orbital ridges and nasal septum. Removal of the posterior wall of the frontal sinus was completed if necessary. Dural repair and final reconstruction are detailed. Our initial experience using this approach in five patients harboring lesions of the anterior skull base resulted in adequate exposure of the targeted pathology. There were no complications of the procedure. Cosmetic results were acceptable. We present a detailed account of this procedure via photographs and a video. The frontal-nasal-orbital craniotomy provides access to the floor of the anterior fossa while avoiding excessive brain retraction associated with facial incisions. In addition, this approach is associated with a lower incidence of complications, such as CSF leak, brain retraction edema, or infection. The frontal-nasal-orbital craniotomy is a useful technique for midline lesions of the anterior skull base, and it should be in the armamentarium of neurological surgeons.

Epirubicin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers.

Epirubicin (EPI) has strong cytotoxic activity that makes it a potential candidate for the treatment of malignant gliomas. To minimize toxicity and increase CNS penetration, EPI was incorporated into biodegradable polymers, and its in vitro and in vivo properties were studied. 9L, F98, C6, U251, and EMT-6 cell lines were treated with EPI in vitro and cell viability was measured. Toxicity of EPI/polycarboxyphenoxypropane-sebacic-acid (pCPP:SA) polymers was tested in vivo using F344 rats intracranially implanted with EPI polymers (2-50% by weight). The efficacy of 50% EPI:pCPP:SA polymers was determined in F344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. The efficacy of 50% EPI:pCCP:SA polymers administered on Day 5 in combination with oral TMZ was determined in rats intracranially challenged with 9L gliosarcoma. EPI was cytotoxic in all cell lines used in vitro. Intracranial implantation of the EPI polymers in rats generated neither local nor systemic toxicity. Animals receiving intracranial EPI on Day 5 had 50% long-term survivors (LTS), which was superior to local EPI delivered on Day 0 (LTS = 12.5%). Animals receiving intracranial EPI in combination with oral TMZ had 75% LTS whereas no other group had LTS. In those EPI treated animals that died before the controls there was evidence of intracranial hemorrhage. Systemic epirubicin resulted in high toxicity levels and early deaths in all the experiments. EPI polymers, alone or in combination with oral TMZ, is an effective therapeutic modality against experimental 9L gliosarcoma.

A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats.

OBJECT: Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma. METHODS: Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5. RESULTS: Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point. CONCLUSIONS: OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.

Posterior-only approach for total en bloc spondylectomy for malignant primary spinal neoplasms: anatomic considerations and operative nuances.

MALIGNANT PRIMARY SPINAL tumors are rare tumors that are locally invasive and can metastasize. The majority of these tumors have a poor response rate to chemotherapy and conventional radiotherapy. Studies have shown that long-term survival and the potential for cure is best achieved with en bloc surgical excision of these tumors with negative surgical margins. Total en bloc spondylectomy involves removal of vertebral segment(s) in whole to achieve wide tumor excision. Total en bloc spondylectomy can be performed through staged or combined anterior and posterior approaches, or from a posterior-only approach. The posterior-only approach offers the advantage of achieving complete tumor excision and circumferential spinal reconstruction in a single setting. In this report, we discuss the operative management of malignant primary vertebral tumors using the posterior-only approach for total en bloc spondylectomy. The oncological considerations and surgical nuances that allow for safe but aggressive surgical excision of primary spinal tumors to achieve favorable oncological and neurological outcomes are highlighted.

Keyhole to the brain: Walter Dandy and neuroendoscopy.

In the early 1920s, Walter E. Dandy began translating the field of endoscopy to neurosurgery. In the ensuing years, Dandy, who would become known as the "Father of Neuroendoscopy," applied his own ingenuity in combination with guidance from prominent medical contemporaries in the development of the early neuroendoscope. This paper reviews his contributions to the early evolution of this growing and important field of neurosurgery.

Surgical management of thoracic spinal cord herniation: technical consideration.

STUDY DESIGN: This report describes a case of spinal cord herniation (SCH) and the surgical technique used to repair the herniation. OBJECTIVE: To describe a new surgical technique used to provide increased exposure to minimize spinal cord traction for safe repair of the ventral dural defect. SUMMARY OF BACKGROUND DATA: SCH is a relatively rare pathologic condition that is frequently misdiagnosed. It is characterized by the spontaneous herniation and tethering of the spinal cord through a ventral dural defect. A limitation of current surgical management is sufficient exposure of the defect through which the cord herniates. METHODS: This technique entails a posterior decompressive laminectomy and bilateral transpedicular approach, followed by unilateral removal of the pedicle and transverse processes to sufficiently expose the dural defect and SCH. A Gore-Tex graft is then used to repair the dural defect. RESULTS: This approach provided greater exposure of the ventral dural defect and anterior spinal cord, and allowed for safer dissection of dural adhesions. By releasing these adhesions, the spinal cord was returned to its normal position in the thecal sac. The dural defect was then repaired with minimal manipulation of the spinal cord. CONCLUSIONS: We present a rare case of SCH. We describe a new technique used to repair SCH, which adds to the repertoire of existing surgical techniques. By providing a wide exposure, this approach provides wide access to the ventral thecal sac, thus minimizing the requirement for cord traction and allowing for safer closure of the dural defect.

Maximizing the potential of minimally invasive spine surgery in complex spinal disorders.

Minimally invasive surgery (MIS) in the spine was primarily developed to reduce approach-related morbidity and to improve clinical outcomes compared with those following conventional open spine surgery. Over the past several years, minimally invasive spinal procedures have gained recognition and their utilization has increased. In particular, MIS is now routinely used in the treatment of degenerative spine disorders and has been shown to be as effective as conventional open spine surgeries. Although the procedures are not yet widely recognized in the context of complex spine surgery, the true potential in minimizing approach-related morbidity is far greater in the treatment of complex spinal diseases such as spinal trauma, spinal deformities, and spinal oncology. Conventional open spine surgeries for complex spinal disorders are often associated with significant soft tissue disruption, blood loss, prolonged recovery time, and postsurgical pain. In this article the authors review numerous cases of complex spine disorders managed with MIS techniques and discuss the current and future implications of these approaches for complex spinal pathologies.

Meningiomas invading the superior sagittal sinus: surgical experience in 108 cases.

OBJECTIVE: Radical resection of meningiomas invading the superior sagittal sinus (SSS) presents several hazards. Some surgeons consider SSS invasion a contraindication for complete resection, and others advocate total resection with venous reconstruction. There is a lack of published large series to provide definitive guidelines for the surgical treatment of these complex cases. We report our 15-year experience with surgery of parasagittal meningiomas invading the SSS. METHODS: Between 1986 and 2001, 108 patients (73 women, 35 men; age range, 22-83 yr; mean age, 56.2 yr) underwent surgery at the Neurological Institute "C. Besta" of Milan for tumors invading the SSS. Parasagittal meningiomas not invading the SSS were excluded from this series. RESULTS: Simpson Grade I to II removal was achieved in 100 patients. Thirty patients with meningiomas totally occluding the SSS had complete resection of the encased portion of the sinus. Histological examination revealed 86 benign (79.6%), 16 atypical (14.8%), and 4 malignant (3.7%) meningiomas along with 2 hemangiopericytomas. There were two perioperative deaths. Serious complications included brain swelling (nine patients; 8.3%) and postoperative hematoma (two patients; 1.85%). Follow-up ranged from 19 to 223 months (mean, 79.5 mo). One patient was lost to follow-up. Tumors recurred in 15 patients (13.9%). After multivariate analysis, histological type, tumor size, and Simpson grade were confirmed as significant independent prognostic factors for recurrence. CONCLUSION: On the basis of our results, we conclude that if the sinus is partially invaded, it can be opened to obtain as complete a resection as possible and to attempt to preserve the patency of the sinus. If the sinus is obstructed, the portion of the sinus involved can be resected completely. In both situations, extreme care is vital to preservation of cortical veins, which may offer important collateral drainage. With our approach, good results are achieved and it is not necessary to reconstruct the sinus.

Paclitaxel: a review of adverse toxicities and novel delivery strategies.

Better known as Taxol (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.

Endoscopic third ventriculostomy for hydrocephalus associated with tectal gliomas.

OBJECT: Tectal gliomas are a distinct form of pediatric brainstem tumor that present in patients with symptoms related to increased intracranial pressure due to obstructive hydrocephalus. The natural history of these lesions is often uniquely indolent. Thus, initial surgical therapies are directed at treatment of hydrocephalus, usually with ventricular shunt placement. Recently, third ventriculostomy has been used in patients with tectal gliomas, both as an initial procedure and after shunt failures. In this report the authors review their experience with the treatment of hydrocephalus in patients with tectal gliomas. METHODS: The authors reviewed 31 consecutive cases of tectal gliomas and compared the success rates of ventricular shunt placement with the success rates of endoscopic third ventriculostomy (ETV). Shunt placement procedures were associated with a significant number of malfunctions, and most patients required shunt revisions. The ETV procedure was attempted both as an initial treatment and after shunt malfunction. Overall, ETV was attempted in 18 patients and was performed successfully in all cases. At the time of follow-up evaluation, 16 patients (89%) were shunt free. CONCLUSIONS: The authors found that ETV could be performed with good long-term success both as an initial treatment and after shunt failure. Overall, ETV was found to be superior to ventricular shunt placement in the management of hydrocephalus associated with tectal gliomas.

Neuroendoscopy: past, present, and future.

Neuroendoscopy began with a desire to visualize the ventricles and deeper structures of the brain. Unfortunately, the technology available to early neuroendoscopists was not sufficient in most cases for these purposes. The unique perspective that neuroendoscopy offered was not fully realized until key technological advances made reliable and accurate visualization of the brain and ventricles possible. After this technology was incorporated into the device, neuroendoscopic procedures were rediscovered by neurosurgeons. Endoscopic third ventriculostomy and other related procedures are now commonly used to treat a wide array of neurosurgically managed conditions. A seemingly limitless number of neurosurgical applications await the endoscope. In the future, endoscopy is expected to become routine in modern neurosurgical practice and training.

Meningiomas invading the superior sagittal sinus: surgical experience in 108 cases.

OBJECTIVE: Radical resection of meningiomas invading the superior sagittal sinus (SSS) presents several hazards. Some surgeons consider SSS invasion a contraindication for complete resection, and others advocate total resection with venous reconstruction. There is a lack of published large series to provide definitive guidelines for the surgical treatment of these complex cases. We report our 15-year experience with surgery of parasagittal meningiomas invading the SSS. METHODS: Between 1986 and 2001, 108 patients (73 women, 35 men; age range, 22-83 yr; mean age, 56.2 yr) underwent surgery at the Neurological Institute "C. Besta" of Milan for tumors invading the SSS. Parasagittal meningiomas not invading the SSS were excluded from this series. RESULTS: Simpson Grade I to II removal was achieved in 100 patients. Thirty patients with meningiomas totally occluding the SSS had complete resection of the encased portion of the sinus. Histological examination revealed 86 benign (79.6%), 16 atypical (14.8%), and 4 malignant (3.7%) meningiomas along with 2 hemangiopericytomas. There were two perioperative deaths. Serious complications included brain swelling (nine patients; 8.3%) and postoperative hematoma (two patients; 1.85%). Follow-up ranged from 19 to 223 months (mean, 79.5 mo). One patient was lost to follow-up. Tumors recurred in 15 patients (13.9%). After multivariate analysis, histological type, tumor size, and Simpson grade were confirmed as significant independent prognostic factors for recurrence. CONCLUSION: On the basis of our results, we conclude that if the sinus is partially invaded, it can be opened to obtain as complete a resection as possible and to attempt to preserve the patency of the sinus. If the sinus is obstructed, the portion of the sinus involved can be resected completely. In both situations, extreme care is vital to preservation of cortical veins, which may offer important collateral drainage. With our approach, good results are achieved and it is not necessary to reconstruct the sinus.

Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies.

PURPOSE: The purpose of this study was to demonstrate that surgically implanted, controlled-release, biodegradable polilactofate microspheres (Paclimer) can be used safely to bypass the blood-brain barrier and deliver paclitaxel to malignant brain tumors. EXPERIMENTAL DESIGN: The rate of paclitaxel release from Paclimer microspheres submerged in PBS was measured in vitro by high-performance liquid chromatography. In vivo studies of Paclimer were performed as intracranial implants in Fischer 344 rats in the presence or absence of 9L gliosarcoma. Mantel-Cox statistics were used to assess the efficacy of Paclimer at extending survival of tumor-bearing animals compared with control implants. Paclimer implants tagged with [(3)H]paclitaxel were used to measure biodistribution of paclitaxel from the Paclimer implant. RESULTS: Paclimer released paclitaxel at a constant rate for up to 3 months in vitro. In vivo, Paclimer implants placed intracranially in rats released active drug for up to 30 days after implantation and doubled the median survival of rats bearing established 9L gliosarcomas (median survival of paclitaxel-treated animals = 35 days; median survival of control-treated animal = 16 days; P < 0.0001). Active drug was distributed throughout the rat brain based on liquid scintillation counting and TLC. Rats implanted with Paclimer demonstrated no overt signs of neurotoxicity and exhibited local cytopathological changes consistent with exposure to an antimicrotubule agent. CONCLUSIONS: Paclimer extends survival in a rodent model of glioma with minimal morbidity and optimal pharmacokinetics.

Shunt migration into the sphenoid sinus: case report.

OBJECTIVE AND IMPORTANCE: Shunt catheter migration is a potential complication of cerebrospinal fluid shunting procedures. We report an unusual case of proximal shunt migration into the sphenoid sinus. To our knowledge, there have been no previous reports of shunt migration through the bony structures of the cranial base. CLINICAL PRESENTATION: A 41-year-old man who had had a cyst-to-peritoneum shunt placed 21 years earlier for a temporal lobe arachnoid cyst presented with cerebrospinal fluid rhinorrhea. Neuroradiological imaging revealed migration of the shunt catheter through the medial wall of the middle temporal fossa into the sphenoid sinus. INTERVENTION: The patient underwent shunt removal and repair of the dural defect. Intraoperatively, the proximal catheter tip was found in the sphenoid sinus with dural and bony erosion. The patient made an uneventful recovery. CONCLUSION: We present a unique long-term complication associated with intracranial shunt catheters. We hypothesize that excessive proximal catheter length and chronic cerebrospinal fluid pulsations contributed to migration of the catheter into the sphenoid sinus.

Local delivery of mitoxantrone for the treatment of malignant brain tumors in rats.

OBJECT: Mitoxantrone is a drug with potent in vitro activity against malignant brain tumor cell lines; however, its effectiveness as a systemic agent has been hampered by poor central nervous system penetration and dose-limiting myelosuppression. To avoid these problems, we incorporated mitoxantrone into biodegradable polymeric wafers to be used for intracranial implantation, a strategy that has been shown to be safe and successful in the treatment of malignant gliomas. The authors investigated the release kinetics, toxicity, distribution, and efficacy of mitoxantrone delivered from intracranially implanted biodegradable wafers in the treatment of 9L gliosarcoma in Fischer 344 rats. METHODS: Mitoxantrone released from the biodegradable wafer matrix reached therapeutic drug concentrations in the brain for at least 35 days. Only animals with implanted wafers of the highest drug loading dose (20% mitoxantrone by weight) showed signs of significant toxicity. In three separate efficacy experiments, animals treated with mitoxantrone-loaded biodegradable wafers had significantly improved survival compared with control animals. The combined median survival for each treatment group was the following: 0% mitoxantrone wafers, 19 days; 1%, 30 days, p < 0.0001; 5%, 34 days, p < 0.0001; and 10%, 50 days, p < 0.0001. CONCLUSIONS: These findings establish that mitoxantrone delivered from intracranially implanted biodegradable wafers is effective in the treatment of malignant gliomas in rodents and should be considered for future clinical application in humans.