Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain.

Polymeric interstitial chemotherapy increases survival of humans with recurrent gliomas and animals with transplanted tumors in the brain, but the relationship between rates of drug release from polymer implants and drug concentration in brain tissue is unknown. This work presents a pharmacokinetic framework for application of this new modality of chemotherapy delivery in primates. Either [3H]carmustine, 4-hydroperoxycyclophosphamide (4-HC), or paclitaxel was encapsulated in a polyanhydride pellet (28-41 microCi/animal, 40 mg/animal), which was implanted intracranially in cynomolgus monkeys (Macaca fascicularis); (n = 17) for up to 30 days. Drug concentrations in the brain, blood, and cerebrospinal fluid were measured by quantitative autoradiography, TLC, and scintillation counting. High drug concentrations (0.5-3.5 mM for carmustine, 0.3-0.4 mM for 4-HC, and 0.2-1.0 mM for paclitaxel) were measured within the first 3 mm from the polymer implant; significant (0.4 microM for carmustine, 3 microM for 4-HC, and 0.6 microM for paclitaxel) concentrations were measured up to approximately 5 cm from the implant as long as 30 days after implantation. Pharmacokinetic analysis indicated that tissue exposure to carmustine area under concentration-time curve achieved by polymeric delivery was 4-1200 times higher than that produced by i.v. administration of a higher dose.

Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models.

Local chemotherapy with biodegradable polymers prolongs survival with minimal morbidity in patients with intracranial high-grade gliomas. However, use of local chemotherapy for metastatic brain tumors has not been defined. We studied the safety and the efficacy of locally delivered chemotherapy with and without concurrent radiation therapy in treating tumors that frequently metastasize to the brain. The chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), carboplatin, and camptothecin were incorporated into controlled-release polymers and tested individually against intracranial challenges with one of four tumors (lung carcinoma, renal cell carcinoma, colon carcinoma, and melanoma). For each combination of drug and tumor type, four groups were tested: (a) empty polymer (no drug); (b) external beam radiotherapy (XRT) alone; (c) local chemotherapy from biodegradable polymer alone; and (d) local chemotherapy and XRT together. Polymers were implanted 5 days after tumor inoculation; XRT was given on days 7-9 (300 cGy/day). BCNU and XRT together were effective against all four tumors. BCNU polymer alone significantly prolonged survival in mice with intracranial melanoma or renal cell carcinoma. Carboplatin alone was effective against both melanoma and colon carcinoma and in combination with XRT against colon and renal cell carcinomas. Camptothecin was effective only with XRT against melanoma. These studies demonstrate that local delivery of chemotherapy with concurrent radiation therapy is safe and can significantly prolong survival in models of common intracranial metastatic tumors. Concurrent use of local chemotherapy with standard XRT appears to be more effective than either treatment alone. Local chemotherapy may also be of benefit to patients who have previously received maximal cranial irradiation but suffer an intracranial recurrence.

Interstitial delivery of carboplatin via biodegradable polymers is effective against experimental glioma in the rat.

PURPOSE: Carboplatin has shown promise experimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and several solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from intracranial sustained release polymers in the treatment of experimental gliomas in rodents. METHODS: Two biodegradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carboplatin and dose escalation studies evaluating toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers containing the highest tolerated doses were implanted at the site of tumor growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. RESULTS: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P < 0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best systemic dose tested. CONCLUSIONS: Carboplatin can be safely delivered intracranially by biodegradable sustained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.

Failed back surgery syndrome: 5-year follow-up after spinal cord stimulator implantation.

Spinal cord stimulation, in use for more than 20 years, has evolved into an easily implemented technique, with percutaneous methods for electrode placement. We have reviewed our experience with this technique in treating "failed back surgery syndrome," and have assessed patient and treatment characteristics as predictors of long-term outcome. A series of 50 patients with failed back surgery syndrome (averaging 3.1 previous operations), who underwent spinal cord stimulator implantation, was interviewed by impartial third parties, at mean follow-up intervals of 2.2 years and 5.0 years. Successful outcome (at least 50% sustained relief of pain and patient satisfaction with the result) was recorded in 53% of patients at 2.2 years and in 47% of patients at 5.0 years postoperatively. Ten of 40 patients who were disabled preoperatively returned to work. Improvements in activities of daily living were recorded in most patients for most activities; loss of function was rare. Most patients reduced or eliminated analgesic intake. Statistical analysis (including univariate and multivariate logistic regression) of patient characteristics as prognostic factors showed significant advantages for female patients and for those with programmable multi-contact implanted devices. These results, in patients with postsurgical lumbar arachnoid and epidural fibrosis and without surgically remediable lesions, compare favorably with the results in two separate series of patients with failed back surgery syndrome, in whom 1) surgical lesions were diagnosed and repeated operation performed; and 2) monoradicular pain syndromes were diagnosed and dorsal root ganglionectomies performed at our institution. This suggests the need for further assessment of selection criteria, critical analysis of treatment outcome, and prospective study of spinal cord stimulation and alternative approaches to failed back surgery syndrome.

Local delivery of chemotherapy prolongs survival in experimental brain metastases from breast carcinoma.

OBJECTIVE: Despite improved systemic control of metastatic breast cancer, the incidence of brain metastases from breast carcinoma continues to rise, in part because most systemically administered agents have poor central nervous system penetration. Therefore, as a method of optimizing drug delivery into the central nervous system, we studied the safety and efficacy of chemotherapy delivered locally via biodegradable polymers in a mouse model of breast carcinoma metastases to the brain. METHODS: The chemotherapeutic agents carmustine (BCNU), carboplatin, and camptothecin were incorporated into controlled release polymers and tested individually against intracranial challenges of EMT-6 breast tumor in BALB/c female mice. For each drug, four groups were tested: Group 1, empty polymer (no drug); Group 2, external beam radiotherapy (XRT) alone; Group 3, local chemotherapy from biodegradable polymer alone; and Group 4, local chemotherapy and XRT together. Polymers were implanted 5 days after intracranial tumor inoculation; XRT was administered on Days 7 through 9 (300 cGy/d). RESULTS: BCNU polymer alone (n = 10; median survival time, >200 d; P < 0.0001) and BCNU and XRT together (n = 10; median survival time, 41 d; P = 0.02) significantly improved survival in mice with intracranial EMT-6 breast cancer in comparison with control animals (n = 20; median survival time, 17 d). Carboplatin and camptothecin, either with or without XRT, and XRT alone did not have any significant effect on survival. CONCLUSION: Local delivery of BCNU with biodegradable polymers can significantly prolong survival in a murine model of intracranial metastatic breast cancer. Surgical resection and placement of BCNU polymers into the resection cavity may decrease the incidence of local recurrence of breast cancer metastases with minimal morbidity.

Histiocytic lesion mimicking intrinsic brainstem neoplasm. Case report.

This 10-year-old girl presented with a 1-month history of progressive bulbar palsy and a solitary enhancing mass originating within the floor of the fourth ventricle. Results of initial imaging studies and presentation were suggestive of neoplasia. Subtotal resection was performed and pathological examination revealed the mass to be a histiocytic lesion, with no evidence of a glioma. The patient had no other stigmata of histiocytosis and was treated with steroid medications, resulting in prolonged resolution of the lesion. This case demonstrates that for discrete brainstem lesions the differential diagnosis includes entities other than glioma for which treatment is available. Biopsy sampling should be considered when technically feasible.

Treatment of melanoma metastases in the brain.

Melanoma is prone to spread to the brain and is the third most common source of intracranial metastasis. Patients usually present with signs and symptoms of increased intracranial pressure, a new focal neurologic deficit, or seizures. Contrasted magnetic resonance imaging (MRI) is the single most valuable imaging modality. Surgical therapy is the appropriate choice for single lesions that are accessible, especially if they are causing significant mass effect or are located in the posterior fossa. Patients with several intracranial metastases who undergo resection of all lesions may have a similar prognosis to those with single resected lesion. Stereotactic radiosurgery appears to provide good local control of small lesions. External beam radiotherapy may provide some benefit to patients, and is often used in conjunction with surgery or stereotactic radiosurgery. To date, chemotherapy has been limited because of chemo-resistance and drug delivery issues. Future directions for treatment may include local sustained delivery of either chemotherapy or immunoregulatory molecules.

Cystic prostate metastases to the brain parenchyma: report of two cases and review of the literature.

Prostate carcinoma is among the leading causes of cancer death for American men. Intracranial metastases from prostatic adenocarcinoma are unusual, and cystic metastases are rare. Two cases of cystic intraparenchymal metastases from prostatic adenocarcinoma are reported. Our comprehensive literature review revealed that prostatic adenocarcinoma metastases are rarely diagnosed antemortem. If these lesions are detected early and treated with surgery and radiation therapy, survival time for patients with prostatic adenocarcinoma may be increased; however, given the rarity of these cases, routine CNS imaging of men with metastatic prostate cancer does not seem warranted.

The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial.

The results of a multi-institutional phase I trial evaluating the safety of surgically implanted biodegradable 1,3-bis(chloro-ethyl)-1-nitrosourea (BCNU) impregnated polymer as the initial therapy for malignant brain tumors are reported. This is the first study of locally delivered BCNU and standard external beam radiation therapy (XRT) given concurrently. Twenty-two patients were treated at three hospitals. The entry criteria were: single unilateral tumor focus larger than 1 cm3; age over 18 years; Karnofsky Performance Score (KPS) of at least 60 h; and an intra-operative diagnosis of malignant glioma. Twenty-one of twenty-two patients had glioblastoma multiforme. After surgery, seven or eight BCNU-loaded polyanhydride polymer discs (7.7 mg BCNU each) were placed in the resection cavity. Postoperatively, all patients received standard radiation therapy; none received additional chemotherapy in the first 6 months. Neurotoxicity, systemic toxicity, and survival were assessed. No perioperative mortality was seen. Neurotoxicity was equivalent to that occurring in other series of patients undergoing craniotomy and XRT without local chemotherapy. Systematically, no significant bone marrow suppression occurred, and there were no wound infections. Median survival in this group of older patients (mean age = 60) was 42 weeks, 8 patients survived 1 year, and 4 patients survived more than 18 months. Interstitial chemotherapy with BCNU-polymer with subsequent radiation therapy appears to be safe as an initial therapy. Several long-term survivors in this group of older patients with predominantly glioblastoma suggests efficacy in some patients. Dose escalation and efficacy trials are planned to further evaluate interstitial chemotherapy for the initial treatment of malignant gliomas.

Complications of lumbar drainage after thoracoabdominal aortic aneurysm repair.

OBJECTIVES: Paraplegia remains a frequent complication of thoracoabdominal aortic aneurysm (TAAA) repair. Many adjunct therapies have been developed to address this complication. Lumbar drainage is frequently used in an attempt to decrease intrathecal pressure and improve intramedullary perfusion pressure. The effectiveness of this therapy is unclear, and the complications of lumbar drainage used for this indication are unknown. We present a case of intraspinal hematoma with significant neurologic deficit after TAAA repair and review the associated complications of lumbar drains placed for TAAA. METHODS: The charts of all patients undergoing operations for TAAA repair were reviewed. Patients who underwent perioperative placement of a lumbar drain were included regardless of aneurysm type or etiology. Demographics, Crawford grade, and perioperative parameters and complications were reviewed. RESULTS: Sixty-five patients underwent TAAA repair with 62 (95%) receiving a preoperative lumbar drain. There were two (3.2%) intraspinal hemorrhagic complications, including one patient with a poor neurologic outcome. No infections or other complications directly related to drainage were identified. Multivariate logistic regression analysis failed to demonstrate a significant association between lumbar drain complications and perioperative and intraoperative parameters such as blood loss or hypotension, level of drain placement, and Crawford grade. CONCLUSIONS: Lumbar drainage is a frequent adjunct to TAAA repair. However, placement of the drain itself can be associated with significant complications whose aggravating factors may be unidentifiable. Complications resulting from lumbar drainage should be considered in any patient who has postoperative lower extremity neurologic deficits.

Brain metastases.

Metastatic tumors to the brain are an increasing cause of morbidity and mortality in patients with systemic cancers. Many new therapies used to treat systemic cancers do not penetrate the central nervous system (CNS) and do not protect patients from the development of brain metastases. Surgery, radiosurgery, and radiation therapy are all used to treat brain metastases. It is in our opinion a mistake to use only one or two of these modalities to the exclusion of other(s). The role of systemic chemotherapy is still limited, due to both the issues of drug delivery caused by the blood brain barrier and to the relative resistance of many of these tumors to chemotherapy. Traditionally, brain metastases have been grouped together regardless of the origin of the tumor and have been treated with a single algorithm. As we encounter more patients for whom treatment of the brain metastases is an important determinant of survival, we must tailor our treatment strategies to individual tumor types. Also, we must recognize differences in each tumor's sensitivity to chemotherapy and radiotherapy and differences in their biology.

Systemic and local paracrine cytokine therapies using transduced tumor cells are synergistic in treating intracranial tumors.

Development of an effective immunotherapeutic approach for treatment of CNS tumors must take into account the unique anatomic and immunologic features of the brain. We explored the antitumor immune response in the brain elicited by nonreplicating melanoma cells genetically engineered to produce either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2 (IL-2) in a paracrine fashion. Using a new model of intracranial melanoma in C57BL/6 mice, the cytokine-producing cells were given either as a subcutaneous vaccine to induce systemic antitumor immunity or as a direct injection into the brain as local immunotherapy. We found that GM-CSF-transduced cells, as a subcutaneous vaccine but not as an intracranial injection, afforded some protection from intracranial challenge with the wild-type tumor. In contrast, direct intracranial injection of tumor cells secreting IL-2 was protective whereas flank vaccination with IL-2 transductants was not. Combination therapy with both the subcutaneous GM-CSF-transductants as a vaccine and local administration of IL-2-transductants in the brain achieved a synergistic response. These findings provide a basis for the application of paracrine cytokine delivery to brain cancer therapy both as a systemic vaccine and via local administration. The demonstration of synergy between paracrine cytokine therapies holds promise as a novel therapy for brain tumors.

Intracranial paracrine interleukin-2 therapy stimulates prolonged antitumor immunity that extends outside the central nervous system.

To explore the potential efficacy of local cytokine delivery against tumors in the central nervous system (CNS), C57BL6 mice were simultaneously given intracranial injections of tumor challenge and of irradiated B16F10 melanoma cells transduced to secrete interleukin-2 (IL-2). Intracranial IL-2 therapy generated antitumor responses capable of extending the survival of animals that received simultaneous intracranial tumor challenge either locally or at distant sites in the brain. Nontransduced melanoma cells had little effect. Animals that survived intracranial IL-2 therapy and tumor challenge showed prolonged survival compared with controls when challenged with a second tumor dose 70 days after initial treatment. In addition, animals that rejected intracranial tumors were also protected from tumor growth upon rechallenge at sites outside the CNS (i.e., subcutaneous tumor challenge). Conversely, identical or 10-fold larger doses of IL-2-transduced cells administered by subcutaneous injection failed to generate protection against intracranial tumor challenges. Elimination of T-cell and natural killer (NK) subsets using gene knockout mice and antibody-depletion techniques demonstrated that NK cells were most important for the initial antitumor response, whereas CD4+ T-cells were not necessary. These studies demonstrate that local IL-2 therapy in the brain not only generates an immediate local antitumor immune response, but also establishes long-term immunologic memory capable of eliminating subsequent tumor challenges within and outside of the CNS. Furthermore, the antitumor response to paracrine IL-2 in the brain differed significantly from that in the flank, suggesting that the intrinsic CNS cells involved in initiating immunity within the brain have different cytokine requirements from their peripheral counterparts.