Intravenous administration of temozolomide as a useful alternative over oral treatment with temozolomide capsules in patients with gliomas

Abstract

For the last 10 years, oral anticancer agents have been increasingly administered for the treatment of various types of cancers. Of all the cancer therapies under clinical trial development, 20–25% is expected to be oral. The intravenous (IV)-oral switch and the development of oral anticancer therapies for long-term daily use will most likely continue to evolve. Oral temozolomide (TMZ) is a widely used bioactive alkylating agent that has been approved as the standard treatment for patients with high-grade gliomas (HGG). It provides 100% oral bioavailability and readily crosses the blood–brain barrier. However, patients with gliomas, as well as the elderly and children, often experience swallowing difficulties or dysphagia. These patients may have difficulties in orally ingesting the solid TMZ capsules. Some of these patients may require feeding tubes to help them maintain normal nutrition. In nursing homes or in longterm care settings, the nurses generally crush the capsules and mix them with liquids or other foods so that these patients with dysphagia can easily consume this medicine. However, the Institute for Safe Medication Practices (http://www.ismp.org/) has listed TMZ as an oral medicine that should not be crushed. This organization has specified that the TMZ capsule is designed for slow release and that opened or damaged capsules require rigorous precautions to avoid inhalation or contact with the skin or mucous membranes. The newly approved IV formulation of TMZ provides patients with an important alternative method of administration and offers flexibility in the dose regimen and a convenient alternative form of packaging. Furthermore, IV formulation of TMZ provides the same pharmaco-dynamics as oral administration if it is infused for 90 min [1]. Here, we show the effectiveness, toxicity, and safety of IV TMZ therapy. Patients with HGG, including those with a diffuse intrinsic pontine glioma (DIPG), who had difficulties in swallowing oral TMZ agents, were eligible for this study conducted between May 2010 and April 2011 at our institution. The patient characteristics at the start of the IV TMZ therapy are summarized in Table 1. The study population comprised 6 patients with DIPG and 2 patients with recurrent HGG. These patients included 4 men and 4 women aged between 3 and 40 years (median, 16.5 years). The median preoperative Eastern Cooperative Oncology Group performance status (ECOG PS) score at diagnosis was 2 (range, 2–3). Patients with DIPG, especially the children, showed a good indication for IV TMZ because of dysphagia and esophageal immaturity. A vial of TMZ (100 mg) was reconstituted with 40 ml water to obtain 2.5 mg/ml. All patients received IV TMZ at the same dose as the standard Stupp regimen for 90 min. During the period of administration, 3 patients showed partial response, 4 showed stable disease, and 1 showed progressive disease. Of note, 1 patient (Case 1 in Table 1) treated with only IV TMZ achieved a good response without concomitant radiotherapy (Fig. 1). He presented with right abducens palsy, tinnitus, and gait disturbance, which worsened gradually. A magnetic resonance imaging (MRI) scan of the brain obtained at the time of admission revealed a DIPG measuring approximately 4.0 cm in diameter and involving the medulla oblongata (A). An irradiation dose of 54 Gy was delivered to the tumor bed in conventional fractions. However, 2 months later, the patient’s respiratory condition deteriorated severely, resulting in the need for K. Motomura A. Natsume (&) T. Wakabayashi Department of Neurosurgery, Nagoya University School of Medicine, Nagoya 466-8550, Japan e-mail: anatsume@med.nagoya-u.ac.jp