Interstitial Chemotherapy

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Interstitial chemotherapy involves the placement of a drug or drugs directly into the brain tumor or resection cavity of the brain parenchyma [89]. With this approach, the tumor and surrounding brain are exposed to high concentrations of drug, which is not limited by the BBB. In addition, there is minimal exposure of the drug to the systemic circulation and organs. Interstitial chemotherapy delivery systems were originally developed for application to malignant gliomas, due to their high local recurrence rate and limited potential for systemic metastases [89-92]. Brem and colleagues were able to devise a biodegradable polymer wafer, ''loaded'' via anhydride bonds to BCNU (3.85 per cent; 7.7 mg). After placement of the wafers into the tumor resection cavity, water in the interstitial fluid breaks the anhydride bonds and releases the BCNU in a controlled fashion. The wafer slowly degrades in layers through ''surface erosion'', like a bar of soap. All of the BCNU is released from the polymer by three weeks, and the polymer degrades in the brain after 4-6 months. BCNU can be measured within the CSF and serum; however, the concentrations are negligible. Systemic toxicity that is typical for IV BCNU (e.g., leukopenia, thrombocytopenia, interstitial pulmonary fibrosis) does not occur with the BCNU-loaded polymer.

Recent research by Ewend and co-workers has investigated the use of chemotherapy-loaded wafers as a treatment method for MBT [93-95]. In a mouse model, 20 per cent BCNU-loaded wafers were implanted after surgical resection of melanoma MBT and compared to animals that received only external beam irradiation [93]. Survival was significantly longer in the chemotherapy wafer group (p = 0.032), with 57 per cent of the animals still alive at 150 days follow-up. For the radiation alone group, only 50 per cent of animals were still alive during follow-up after 25 days. In a more extensive study using a mouse model, several different MBT (melanoma, renal cell, colon, lung) and chemotherapy wafer (BCNU, carboplatin, camptothecin) types were studied [94]. Each type of wafer was used against each type of MBT, with or without radiotherapy. The results demonstrated a significant survival benefit for the BCNU-loaded wafer over the carboplatin and camptothecin wafers. In addition, there appeared to be a synergistic effect between the BCNU-polymer and irradiation, for all tumor types, when compared to irradiation alone (p = 0.0005). A similar study, used a BALB/c mouse model, focused on chemotherapy wafer treatment of breast metastases [95]. Mice with intracranial EMT-6 breast tumors were treated with implanted wafers loaded with BCNU, carboplatin, or camptothecin. For each wafer type a control was used. Radiation therapy was administered to half of the control and wafer animals, as well as to each tumor type as sole treatment. The BCNU wafer alone (p <0.0001) or in combination with irradiation (p = 0.02), significantly extended survival time compared to controls or animals implanted with carboplatin or camptothecin.

Based on the successful results of the mouse studies, Ewend and co-workers initiated a multicenter phase I/II study of 25 patients with solitary brain metastases (13 lung, 4 melanoma, 3 renal, 2 breast) [96]. After surgical resection of the metastatic lesion, each patient was implanted with 3.85 per cent BCNU-loaded biodegradable wafers and irradiated. Interstitial placement of the wafers was generally well tolerated, similar to the experience with gliomas, with adverse events in only 7 patients (e.g., seizures, eye pain, re-operation for cerebral edema). No local recurrences were noted in the cohort; there have been 4 remote CNS failures. The median survival in follow-up of 16 evaluable patients was 15.5 months. The authors concluded that the BCNU wafer was well tolerated and active against MBT; and should be tested in a phase III trial. In a recent report of 42 consecutive patients with MBT, Brem and colleagues described their experience with the implantable BCNU wafers [97]. Thirty-four patients were newly diagnosed, while 8 were treated at recurrence. Radiotherapy (3000-4400 cGy) was used, in addition to surgical resection and wafer placement, for all newly diagnosed patients. The majority of the cohort had MBT from non-small-cell lung cancer (20), melanoma (11), renal carcinoma (4), and breast (3). There were no localized recurrences in newly diagnosed patients; 3 patients developed distant CNS recurrences. The overall mean survival was 16.8 months; 17.8 months in newly diagnosed patients and 12.9 months for those with recurrent disease. Similar results have been reported by the PROLONG Study Group in a cohort of 36 patients, with minimal evidence for localized recurrence of implanted MBT [98].

A multi-center, randomized, phase III trial has been initiated at the Ohio State University Medical Center and several other sites [99]. The trial is attempting to compare surgical resection, BCNU wafer placement, and irradiation versus surgical resection and irradiation alone for patients with solitary, resectable MBT. Seventeen evaluable patients (15 with MBT from lung) have been enrolled into the study, with 10 of the cohort receiving the 3.85 per cent BCNU-loaded biodegradable polymers. The mean age of the patients was 62.5 years, with a range of 39-78 years. Placement of the wafers has been well tolerated, with infrequent seizures, cerebral edema, or wound infections. The mean survival has been similar between groups thus far (wafers-40.6+ weeks versus no wafers-39.2+ weeks), although follow-up has been incomplete.

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