BMC Cancer 2009, 9:372 http://www.biomedcentral.com/1471-2407/9/372 Background Despite a wealth of preclinical and clinical research, treat- ment options for malignant gliomas remain scarce, and median survival of patients barely reaches 15 months despite surgery, radiation and chemotherapy [1]. Among several recently discovered biochemical anoma- lies of malignant gliomas, transcription factor NF-kappaB has emerged as a major molecular determinant of tumor progression and treatment resistance [2]. It is constitu- tively activated in most high-grade gliomas [3-8], where it promotes the expression of various pro-invasion, anti- apoptotic and cell-cycle related genes [7,9,10]. Inactiva- tion of NF-kappaB blocks glioma growth in in vitro and in vivo models, and increases their response to radiation, chemotherapy and suicide gene therapy [11-13]. Sulfasalazine, an anti-inflammatory drug, is a known inhibitor of the multimeric kinase complex IKK that is essential to the canonical pathway of NF-kappaB activa- tion [14]. Additionally, this drug inhibits the x(c)-cystine/ glutamate antiporter, an amino-acid transporter protein that is essential for the survival of glial cells [15,16]. Although there is presently a lack of pharmacological data that proves sulfasalazine penetrates the blood brain bar- rier, it was shown to exert a clear anti-tumor effect on rodent and human glioblastomas transplanted in the brain of nude mice [2,12,15]. Because of these promising preclinical data and as Sul- fasalazine has been used clinically for over 4 decades for the treatment of colon and joint inflammatory diseases and causes little toxicity at daily doses up to 6 g/day [17], we initiated ISRCTN45828668, a double-blinded, pro- spective, phase 1/2 clinical trial of Sulfasalazine for the treatment of recurrent or progressive high-grade gliomas [18]. This study was designed as a phase 2, randomized, study looking for tumor responses. Given the fact that no specific safety data was available on the use of Sulfasala- zine in the setting of malignant glial tumors however, the study also looked for treatment toxicities as a primary objective, and an interim review of treatment safety was planned to occur after an accrual of 10 patients. The results of this interim review are reported according to the GNOSIS recommendations in neuro-oncology [19]. Methods Study Design The protocol of ISRCTN45828668, a prospective, rand- omized, double-blinded single-center phase 1-2 study of Sulfasalazine for the treatment of recurrent or progressive high-grade astrocytic gliomas, has been published previ- ously [18]. Briefly, a total of twenty adult patients (over 18 years old), with progressive astrocytic malignant glioma despite surgery, radiation therapy and a first line of chem- otherapy and with a life expectancy of at least 2 month were scheduled for recruitment. After signing an informed consent, patients underwent a clinical, radiological (base- line MRI) and biological examination and were evaluated with respect to our inclusion and exclusion criteria [see additional file 1: Table S1]. Upon enrollment, subjects were randomly assigned to one of four dose regimens of Sulfasalazine, using a randomization software (S-Plus v6.2, Insightful Corp., MathSoft, Seattle, WA, USA). Con- tinuous daily doses of 1.5, 3, 4, or 6 g were taken orally t.i.d. until complete remission, evidence of progression or drug intolerance. Both the patients and the treating physi- cians were blinded to the individual dosages of sulfasala- zine. Drug preparations were conditioned at the CHU of Liege Pharmacy department, and provided in the form of unremarkable capsules allowing both the patient and the physicians to remain blinded with respect to the individ- ual dosage. Given that Sulfasalazine safety had never been assessed in the context of malignant glial tumors however, the two primary endpoints of ISRCTN45828668 were the assess- ment of treatment toxicity and tumor response as meas- ured according to modified (volumetric) MacDonald's criteria [20]. Overall survival and progression-free survival were secondary endpoints. To enforce the assessment of treatment safety, an independent, interim analysis of drug safety was scheduled and conducted after the accrual of ten patients. In order to facilitate the interim analysis of the data by the review committee, the randomization algorithm was weighted so that 8 of the first 10 patients received either the lowest or the highest drug dosage. The protocol was sponsored by the Department of Neuro- surgery, University Hospital of Liège, Belgium. It was reviewed and approved by the Ethics Committee of the Faculty of Medicine of the University of Liège, underwent review and approval by Belgian Federal Health Authorities (authorization reference 548/03/05) and was granted the European Trial database (EudraCT) number 2004- 004392-11. Patients under 18 years old, or with anaplastic oligoden- droglioma (WHO grade 3), allergy to sulfa drugs, porphy- ria, G-6-PD, kidney or liver deficiency or psychiatric disorder deemed incompatible with compliance to the study were excluded, as well as lactating or pregnant women. Blood samples were analyzed every 15 days following treatment initiation, and follow-up visits-including clini- cal examination, history, MRI scan and urinalysis - were performed every 30 days. Adverse events were evaluated according to the NCI common toxicity criteria (CTCAE) Page 2 of 8 (page number not for citation purposes)