**2. Early experience**

#### **2.1. Topical application**

Various methods have been attempted for locoregional therapy. The initial experience started with topical application. In 1963, Heppner and Diemath (5) treated brain tumor patients with local chemotherapy by placing gelatin sponges soaked with endoxan. Similarly, Ringkjob applied gelatin sponges filled with cytostatic agents including 5‐fluorouracile (5‐FU), methylene hydrazine, and thiophosphoramide to the resection cavity in patients with gliomas and brain metastases (6). Although the adverse effects were minimal in both studies, the clinical benefits were either hard to define or inappreciable. As a result, topical application of chemotherapeutics was gradually disregarded.

#### **2.2. Direct injection**

Direct injection is another early strategy to give local therapy. A subcutaneous reservoir (e.g., Ommaya reservoir) is implanted with its catheter into the resection cavity during surgery of brain tumors. Repeated injection of multiple chemotherapeutic agents can be done trough the reservoir postoperatively. Because direct injection is easy and repeatable, a number of studies have been done to explore the efficacy. In a Phase I/II trial, Boiardi et al. (7) implanted Ommaya reservoir in 12 patients with recurred malignant glioma. Two cycles of mitoxantrone were directly delivered into intratumoral cavity through Ommaya reservoir with or without systemic chemotherapy. The treatment was well tolerated in all patients. Either response or stable disease was found in 9 of 12 patients. A Japanese group investigated the histopatho‐ logical changes after local chemotherapy via Ommaya reservoir (8). Massive coagulation necrosis surrounded by abundant reactive collagenous tissues, gliomesenchymal tissue, and infiltrating lymphocytes was found in the tumor bed, especially in areas around the catheter tip of Ommaya reservoir. This finding suggested the effectiveness of local chemotherapy. In 2008, Boiardi and colleagues (9) reported a non‐randomized study with a large sample size. Two hundred and seventy‐six patients with recurrent GBM were enrolled. Among them, 161 cases (Group A) were only treated systemically with oral temozolomide (TMZ), while 50 patients (Group B) were re‐operated and received TMZ therapy postoperatively, and 50 cases (Group C) were treated with re‐operation, postoperative TMZ, and locoregional therapy with mitoxantrone. The overall survival for Group C, B, and A was 27, 26, and 15.5 months, respectively (*p* = 0.1). The median survival after tumor recurrence was 16.8, 12, and 6.6 months for Group C, B, and A (*p* = 0.001), respectively. The authors therefore suggested that a second surgery combined with local chemotherapy would prolong the survival of patients with recurrent malignant gliomas.

The exact mechanisms underlying the intractability of malignant gliomas have not been fully understood, but the inherent resistance and the sheltering environment of brain have been proposed to protect the disease from conventional treatments. First of all, the infiltrative growth pattern of glioma cells makes the complete surgical resection almost impossible. Second, the existence of blood–brain barrier (BBB), which is tightly formed by capillary endothelial cells together with astrocytes, restricts the entry of most systemically adminis‐ tered chemotherapeutic agents into the tumor parenchyma (3). Third, the inherent and acquired insensitivity to radiation and chemotherapy through the disturbance of signaling pathway in glioma cells results in the resistance to current therapies (4). Because gliomas seldom metastasize outside the CNS and usually recur within 1–2 cm from the original tumor site, it is reasonable to expect the efficacy of directly delivering potent chemotherapeutic drugs into the tumor mass and its adjacent area. By this means, not only a higher drug concentra‐

Various methods have been attempted for locoregional therapy. The initial experience started with topical application. In 1963, Heppner and Diemath (5) treated brain tumor patients with local chemotherapy by placing gelatin sponges soaked with endoxan. Similarly, Ringkjob applied gelatin sponges filled with cytostatic agents including 5‐fluorouracile (5‐FU), methylene hydrazine, and thiophosphoramide to the resection cavity in patients with gliomas and brain metastases (6). Although the adverse effects were minimal in both studies, the clinical benefits were either hard to define or inappreciable. As a result, topical application of

Direct injection is another early strategy to give local therapy. A subcutaneous reservoir (e.g., Ommaya reservoir) is implanted with its catheter into the resection cavity during surgery of brain tumors. Repeated injection of multiple chemotherapeutic agents can be done trough the reservoir postoperatively. Because direct injection is easy and repeatable, a number of studies have been done to explore the efficacy. In a Phase I/II trial, Boiardi et al. (7) implanted Ommaya reservoir in 12 patients with recurred malignant glioma. Two cycles of mitoxantrone were directly delivered into intratumoral cavity through Ommaya reservoir with or without systemic chemotherapy. The treatment was well tolerated in all patients. Either response or stable disease was found in 9 of 12 patients. A Japanese group investigated the histopatho‐ logical changes after local chemotherapy via Ommaya reservoir (8). Massive coagulation necrosis surrounded by abundant reactive collagenous tissues, gliomesenchymal tissue, and infiltrating lymphocytes was found in the tumor bed, especially in areas around the catheter tip of Ommaya reservoir. This finding suggested the effectiveness of local chemotherapy. In

tion around the tumor but also a minimal systemic toxicity can be achieved.

**2. Early experience**

318 Neurooncology - Newer Developments

**2.1. Topical application**

**2.2. Direct injection**

chemotherapeutics was gradually disregarded.

In addition to chemotherapeutics, other agents have also been investigated for local therapy via direct injection. For example, Mamelak and colleagues (10) evaluated the safety and biodistribution of iodine‐131 (131I)‐TM‐601, a synthetic radioiodinated targeting peptide, for recurrent malignant gliomas in a Phase I trial. A total of 18 patients received a single dose of 131I‐TM‐601 from one of the three dosing panels (0.25, 0.50, or 1.0 mg of TM‐601). The agent was injected into the tumor cavity via a subcutaneous reservoir 2 weeks after surgery. The dosimetry analysis demonstrated a long‐term retention of the agents around the injection site. The median half‐life in the cavity margin was more than 50 h. No severe adverse effects were found during the delivery. Among 11 patients who completed the 180‐day follow‐up, two patients with recurrent GBM survived more than 30 months. The median survival was as long as 77.6 weeks in a subgroup of patients who received 0.5‐mg dose of 131I‐TM‐601. In another study, Prados and colleagues investigated the safety and efficacy of local gene therapy in recurrent GBM patients. Virus‐producing cells (VPC) containing the herpes simplex virus thymidine‐kinase (HSV‐Tk) gene were injected into tumor cavity directly during debulking surgery and postoperatively via reservoir, followed by ganciclovir treatment (11). Among 30 patients enrolled in the study, 16 had severe adverse events such as infection, skin necrosis, and myelosuppression. The median survival of the series of 30 patients was 8.4 months. Six patients (20%) survived more than 1 year from the date of enrollment. The authors conclud‐ ed that the direct delivery of gene therapy demonstrated some evidence of efficacy, while the improvement of procedures was needed to decrease the toxicity. Other studies also evaluat‐ ed the feasibility to treat gliomas locally with immunotherapeutic agents such as autologous lymphocytes and immunomodulators (12, 13).

Although antecdotal reports of success achieved by direct injection of chemotherapeutics for glioma patients can be frequently found in literatures, no large‐scale well‐designed Phase III trial has been ever performed. In fact, local chemotherapy through direct injection has its own limitations. Firstly, repeated puncture and injection through the reservoir are associated with increased risk of intracranial infection and hemorrhage. Secondly, the injected drugs hetero‐ geneously distribute in the tumor cavity through this approach. A sharp drug distribution gradient has been found, with an extremely high concentration around the tip of the cathe‐ ter and a significant drop in the adjacent area. Therefore, the clinical exploration of local chemotherapy via direct injection dramatically declined.
