Open-label phase II evaluation of Imatinib in primary inoperable or incompletely resected and recurrent glioblastoma

$\bf Purpose:$ Preclinical studies indicated that imatinib may have single-agent activity in glioblastoma through inhibition of tyrosine kinase activity and also that it might enhance the efficacy of radiotherapy. We therefore sought to investigate clinical efficacy in patients with newly diagnosed and recurrent glioblastoma in combination with radiotherapy. $\bf Methods:$ We conducted a nonrandomized, 2-arm, open-label phase II trial including patients aged 18 years or older with an ECOG performance status of 0–2 that were either newly diagnosed (arm A) with a measurable tumor (i.e., after incomplete resection or biopsy) or that were diagnosed with progression of a glioblastoma after initial therapy (arm B). Patients in arm A received 600 mg/day imatinib in combination with hypofractionated radiotherapy (2.5 Gy per fraction, 22 fractions). Patients in arm B received 600 mg/day imatinib alone or in combination with re-irradiation at various doses. In case tumor progression occurred, CCNU was added (2 cycles, 100 mg/m$^{2}$) to imatinib. The primary end point was progression-free survival (PFS). The secondary end point was safety, defined as per Common Terminology Criteria for Adverse Events (version 2.0). Overall survival (OS) was analyzed as an exploratory end point. $\bf Results:$ Fifty-one patients were enrolled, of which 19 were included in arm A and 32 in arm B. The median follow-up was 4 (0.5–30) months in arm A and 6.5 (0.3–51.5) months in arm B. The median PFS was 2.8 months (95% CI 0–8.7) in arm A and 2.1 months (95% CI 0–11.8) in arm B. The median OS was 5.0 (0.8–30) months (95% CI 0–24.1) in arm A and 6.5 (0.3–51.5) months (95% CI 0–32.5) in arm B. The major grade 3 events were seizure (present in 17 patients), pneumonia (11 patients), and vigilance decrease (7 patients). $\bf Conclusions:$ Imatinib showed no measurable activity in patients with newly diagnosed or recurrent glioblastoma

Dihydropyrimidine dehydrogenase testing prior to treatment with 5-Fluorouracil, Capecitabine, and Tegafur

$\bf Background:$ 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. $\bf Summary:$ Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. $\bf Key Messages:$ (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring