A phase I trial of carboplatin administered by convection-enhanced delivery to patients with recurrent/progressive glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour in adults. Standard treatment comprises surgery, radiotherapy and chemotherapy; however this condition remains incurable as these tumours are highly invasive and involve critical areas of the brain making it impossible to remove them surgically or cure them with radiotherapy. In the majority of cases the tumour recurs within 2 to 3 cm of the original site of tumour resection. Furthermore, the blood–brain barrier profoundly limits the access of many systemically administered chemotherapeutics to the tumour. Convection-enhanced delivery (CED) is a promising technique of direct intracranial drug delivery involving the implantation of microcatheters into the brain. Carboplatin represents an ideal chemotherapy to administer using this technique as glioblastoma cells are highly sensitive to carboplatin in vitro at concentrations that are not toxic to normal brain in vivo.

This protocol describes a single-centre phase I dose-escalation study of carboplatin administered by CED to patients with recurrent or progressive GBM despite full standard treatment. This trial will incorporate 6 cohorts of 3 patients each. Cohorts will be treated in a sequential manner with increasing doses of carboplatin, subject to dose-limiting toxicity not being observed.

This protocol should facilitate the identification of the maximum-tolerated infused concentration of carboplatin by CED into the supratentorial brain. This should facilitate the safe application of this technique in a phase II trial, treating patients with GBM, as well as for the treatment of other forms of malignant brain tumours, including metastases.

Introduction

Glioblastoma multiforme (GBM) is the most common and most aggressive form of primary brain tumour with an incidence of 2.8 cases per 100,000 per year in the United States [1]. The age-specific incidence of GBM is bimodal, peaking in childhood and to a much greater extent between 50 and 60 years of age [2].

Despite extensive research the prognosis for patients with GBM remains bleak. Current treatment involves a combination of surgery, systemic chemotherapy and radiotherapy. However, due to the highly infiltrative nature of GBM and the intrinsic chemoresistance of GBM cells, 80% of tumours recur within 2 cm of the original tumour mass [3]. As systemic dissemination of GBM is extremely rare and the median survival for recurrent GBM is typically less than 1 year [4], there is a clear and rational need to develop effective strategies to improve local tumour control.

The need for improved local tumour control is reflected by the number of clinical trials that have been performed involving the instillation of chemotherapeutics locally into the brain. These have included the direct infusion or implantation of conventional chemotherapeutics such as carmustine [5], paclitaxel [6] and topotecan [7], or novel cytotoxic agents, including oncolytic herpes simplex and adenoviral vectors [8], [9], [10], [11], [12], viral and non-viral mediated gene therapy [13], [14], [15], [16], and immunotoxins such as IL13-PE38QQR [17], into the tumour mass, resection cavity or peritumoural tissue. To date, the only technique of localised drug delivery that has become clinically useful is the implantation of carmustine wafers (Gliadel) into the tumour resection cavity. However, a recent Cochrane Review of the use of Gliadel wafers concluded that in combination with radiotherapy, Gliadel has survival benefits in the management of primary disease, in a “limited number” of patients, but has “no demonstrable survival benefits in patients with recurrent disease” [18].

There remains an overwhelming need to develop new strategies for targeting tumour cells that have infiltrated into normal brain. Local chemotherapy delivery to the peritumoural tissue is a rational way for achieving this objective, but more careful consideration must be made of the technique of chemotherapy delivery and cytotoxic agent employed. This clinical trial involves the use of an appropriate cytotoxic agent in combination with a rational and effective means of drug delivery to the peritumoural tissue.