Suellen A. Hill

Reversible osmotic blood-brain barrier disruption in humans: implications for the chemotherapy of malignant brain tumors.

The blood-brain barrier seems to be an important factor in drug access to malignant brain tumors. Successful experimental reversible disruption of the blood-brain barrier in animals provided the basis for a clinical evaluation of osmotic disruption in five patients with primary and metastatic malignant brain tumors. Good to excellent blood-brain barrier disruption was achieved in four patients with a single nontransient complication, a superficial wound infection at the burr hole site in the first patient. Reversible, transient osmotic barrier disruption was achieved 15 times in five patients without additional toxicity. Computed tomography and radionuclide brain imaging were shown to be useful noninvasive monitors of the adequacy and extent of barrier disruption. These studies also provide further evidence that the barrier is at least partially intact in human tumors because in one patient a metastsis was seen only after barrier disruption.

Therapeutic efficacy of multiagent chemotherapy with drug delivery enhancement by blood-brain barrier modification in glioblastoma.

Reversible osmotic blood-brain barrier (BBB) modification was used in 38 patients with glioblastoma to enhance the delivery of chemotherapeutic agents. The patients ranged in age from 14 to 70 years (mean, 43), and all had prior surgery and radiation; 5 had also received systemic chemotherapy. Karnofsky Performance Status (KPS) scores ranged from 60 to 100% (mean, 79) on admission to the treatment program. Barrier modification was achieved by intracarotid or intravertebral artery infusion of mannitol, and a chemotherapy regimen of methotrexate, cytoxan, and procarbazine was given in conjunction with barrier modification. The 38 glioblastoma patients were compared to two control groups of patients with glioblastoma; these encompassed 14 patients treated with surgery and radiation and 8 treated with surgery, radiation, and systemic chemotherapy. Survival analysis using the Cox Proportional Hazards Regression Model (corrected for age, sex, presence or absence of necrosis, and functional status) showed that patients receiving chemotherapy with BBB modification had a statistically significant (P = 0.0006) longer expected survival (17.5 months) than the control groups (12.8 and 11.4 months, respectively). Presently 16 patients of the barrier-enhanced treatment group are alive at 5 to 42 months from diagnosis (median, 20) with KPS scores ranging from 40 to 90% (median, 65). The neurological complications seen included a stroke-like syndrome in 3 patients (1 with decreased motor movement in the hand, 1 with marked hemiparesis, and 1 with hemiplegia), transient exacerbation of preexisting neurological deficits lasting 2 to 3 days, and a 15% incidence of seizures during or within 24 hours of the BBB modification. In 2 of the 38 patients, radiographic documentation of central nervous system tumor regression concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic BBB opening was seen. These studies indicate that chemotherapeutic drug delivery to tumors (as well as surrounding brain) can be augmented by osmotic BBB modification and that such therapy can result in a prolongation of survival.

Osmotic blood-brain barrier disruption. Computerized tomographic monitoring of chemotherapeutic agent delivery.

The present study describes a canine model of transient reversible blood-brain barrier disruption with hyperosmolar mannitol infusion into the internal carotid artery. Studies in this model show that osmotic blood-brain barrier disruption before intracarotid infusion of methotrexate results in markedly elevated (therapeutic) levels of drug in the ipsilateral cerebral hemisphere. Levels in the cerebrospinal fluid correlate poorly and inconsistently with brain levels. Computerized tomograms in this canine model provide a noninvasive monitor of the degree, time-course, and localization of osmotic blood-brain barrier disruption.

Successful treatment of primary central nervous system lymphomas with chemotherapy after osmotic blood-brain barrier opening

Three patients with primary central nervous system (CNS) lymphoma have had major tumor regression with multiagent chemotherapy given in association with reversible blood-brain barrier opening used to enhance drug delivery to the tumor. In addition, in one patient barrier modification was carried out in the posterior fossa by mannitol infusion into the vertebral artery without untoward effects, an approach not heretofore accomplished. Computed tomographic (CT) studies documented that discontinuation of steroids rapidly effected an increase in the delivery of contrast agent to the tumor. CT monitoring of the degree of barrier modification showed tumor nodules and tumor size not apparent on the control scans, thereby providing additional evidence of the existence of a blood-brain barrier in CNS tumors. These studies further show that drug (contrast) delivery to the tumor, as well as to the surrounding barrier, is enhanced after reversible blood-brain barrier modification. Finally, chemotherapy administered by this approach resulted in defined, objective tumor responses in these three patients.

Monitoring of methotrexate delivery in patients with malignant brain tumors after osmotic blood-brain barrier disruption.

Reversible transient osmotic blood-brain barrier disruption was used to increase drug delivery to the brain. Methotrexate was administered 33 times to six patients with brain tumors after barrier disruption. No permanent complications were seen. Serial enhanced computed tomographic (CT) scans and quantification by CT tomographic number indicated that disruption increased drug delivery to the tumor and immediate surrounding brain. Neuroradiologic evaluation showed that drug in the tumor persisted longer after barrier disruption than when delivered without disruption. The concentration of methotrexate in spinal fluid did not correlate with the degree of barrier disruption measured by CT and radionuclide scans. In one patient an anatomic variation in the circle of Willis resulted in barrier disruption extending into the posterior fossa without ill effect. Osmotic blood-brain barrier disruption appears to be a safe procedure in man, able to increase drug delivery to both malignant brain tumors and surrounding brain parenchyma.

Osmotic Blood-Brain Barrier Modification and Combination Chemotherapy: Concurrent Tumor Regression in Areas of Barrier Opening and Progression in Brain Regions Distant to Barrier Opening

Chemotherapeutic drug delivery can be enhanced by administering drugs into the internal carotid or vertebral artery circulation after osmotic opening of the blood-brain barrier (BBB). As evidence of the clinical implications of this technique, radiographic documentation of central nervous system (CNS) tumor regression was observed in three patients concurrent with the development of new tumor nodule(s) in portions of the brain distant from the region of osmotic blood-brain barrier opening. These three patients, one with metastatic carcinoma of the breast, one with glioblastoma, and one with primary CNS lymphoma, highlight the importance of drug delivery to CNS malignancies.

Immune responses in patients with brain tumors: Factors such as anti-convulsants that may contribute to impaired cell-mediated immunity

The responsiveness of lymphocytes obtained from patients with brain tumors to in vitro stimulation with mitogenic lectins was examined. The previously reported finding of decreased responsiveness was confirmed. To investigate the factors responsible for the hyporesponsiveness, mitogen (phytohemagglutin and pokeweed mitogen) induced lymphocyte activation was evaluated using lymphocytes from 22 patients with brain tumors and 22 normal individuals. Lymphocytes from 13 patients with brain tumors, showed depressed responsiveness when cultured in autologous serum; in eight this was marked and in five moderate. Normal, rather than autologous, serum corrected lymphocyte function from only one of the markedly hyporesponsive patients, suggesting the existence of an intrinsic lymphocyte abnormality in some patients with brain tumors. However, serum from the hyporesponsive patients depressed mitogen‐induced activation of lymphocytes from both tumor patients and normals. The presence of suppressive serum factors could not be related to the nature of the tumor (benign versus malignant, site, cell type or degree of anaplasia). The present studies showed that significant depression of in vitro lymphocyte responsiveness occurred with exposure to two anti‐convulsant agents (phenytoin and phenobarbital) and dexamethasone. Thus, impaired lymphocyte function in patients with brain tumors may have a complex explanation with drug (corticosteroids, anticonvulsants) induced suppression playing a significant role.