Therapeutic Efficacy of Multiagent Chemotherapy with Drug Delivery Enhancement by Blood-Brain Barrier Modification in Glioblastoma

Abstract

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.

Ultrasound-induced opening of the blood-brain barrier to enhance temozolomide and irinotecan delivery: an experimental study in rabbits

“…Although several methods have been proposed to increase the permeability of the BBB, 6,21,39 pulsed ultrasound is one that has shown significant promise in laboratory studies conducted over the past decade. Using a pulsed ultrasound source in combination with an ultrasound contrast agent (UCA), the application of low-power sonications on brain parenchyma can safely and temporarily open the BBB for durations of 6-8 hours.…”

Intra-Arterial Chemotherapy for Malignant Gliomas: A Critical Analysis

“…the uptake of higher molecular weight agents, such as monoclonal antibodies, which can be 150,000 daltons, is even further diminished. Preclinical 21,[29][30][31][32][33] and clinical studies 28,34,35 have shown that the BBB function can be reversibly modified to be more permeable leading to a significantly higher uptake of intraarterially delivered drugs compared to the nonaltered BBB 36 . for instance, hypertonic solutions such as mannitol can be used to reversibly increase cerebrovascular permeability 11,28,[37][38][39][40] .…”

“…In summary, rodent animal models have been established within the last decade to fursevere side-effects such as seizures and brain edema 34 . Since individual factors need to be taken into account, an exact formula of the concentration and infusion time is difficult to determine.…”

Structural Changes in the Rat Brain After Carotid Infusions of Hyperosmolar Solutions: A Light Microscopic and Immunohistochemical Study

“…The BBB also restricts the passage of many drugs from the blood into the brain, for instance chemotherapeutic agents and monoclonal antibodies tried in the treatment of malignant brain tumours (Neuwelt et al, 1980(Neuwelt et al, , 1981(Neuwelt et al, , 1983(Neuwelt et al, , 1986(Neuwelt et al, , 1987.…”

“…Rapoport and coworkers have developed a method for transient opening of the BBB by intracarotid infusion of hyperosmolar solutions such as mannitol and urea (Rapoport, 1970;Rapoport, Bachman & Thompson, 1972a;Rapoport, Hori & Klatzo 1972b;Rapoport & Thompson, 1973;Brightman et al, 1973;Rapoport et al, 1977;Rapoport, Ohata & London, 1981a;Rapoport et al, 1981b). Drug entry and uptake into the brain parenchyma can in this way be increased (cf., Tomiwa, Hazama & Mikawa, 1983;Inoue et al, 1987) and the method has been tried in clinical situations as well, mainly to enhance the uptake of chemotherapeutic agents in the treatment of malignant brain tumours (Neuwelt et al, 1980(Neuwelt et al, , 1981(Neuwelt et al, , 1986(Neuwelt et al, , 1987Suda, Nakasu & Saito, 1985).…”