BMC Cancer 2009, 9:372 http://www.biomedcentral.com/1471-2407/9/372 phopenia and thrombopenia in 1 patient each). Four patients also presented reduced serum levels of the anti- epileptic drugs sodium valproate (n = 4), phenytoin (n = 2) and carbamazepine (n = 1). No correlation was observed between sulfasalazine dose and the occurrence of these decreases. Grade 4 AEs consisted of increased neurological deficits, epilepsy, cognitive dysfunction, altered consciousness, confusion, ataxia and one case of decreased sodium val- proate and phenytoin serum levels. Death occurred in this latter patient as the result of inhalation pneumonia, fol- lowing status epilepticus, after four weeks of Sulfasalazine treatment. Another patient developed a rapidly progres- sive cognitive deterioration within 5 days of sulfasalazine intake, followed by progressive loss of consciousness and death within a month despite medication withdrawal. Even though the initial KPS of these patients were 40 and 50 respectively at the time of inclusion, these adverse events were considered as probably related to the study drug. Primary objective #2: Tumor response Only one tumor appeared to be stabilized for two month under sulfasalazine treatment (patient #3), whereas all other lesions progressed. Defining tumoral growth as the ratio between the final and initial tumor volumes, the increase during the treatment duration was on average 2.0 ± 0.7 (range: 1.4 - 3.2) and was highly significant (p < 0.0001). The growth was neither related to the dose of the sulfasalazine treatment (r = 0.45, p = 0.22) nor to treat- ment duration (r = -0.06, p = 0.88). The tumoral growth rate per day was defined as the difference between the final and the initial volume over the period of sulfasala- zine treatment. The growth rate was on average 2.1 ± 1.8 ml/day (range: 0.4 - 5.9 ml/day, Figure 2) and was signif- icantly different from 0 (p = 0.005). The growth rate was not related to the dose (r = 0.26, p = 0.50). Secondary objectives: Progression-free and overall survival The overall survival was defined as the time (days) between the initiation of the sulfasalazine treatment and the death of the patient. Patients survived on average 100 ± 76.9 days (range: 32 - 270 days, median: 70.5 days; Fig- ure 3 and Table S2B [see additional file 2]). Treatment was discontinued due to tumor growh (9 patients) and/or side effects (2 patients) after a mean of 35 ± 25.7 days (Progression Free Survival: median: 31.5 days, range: 5- 94). After sulfaslazine discontinuation, one patient was reop- erated, and 4 patients (including the latter) received a sal- vage course of BCNU chemotherapy. The survival time after the end of the sulfasalazine treatment was on average 65.2 ± 55.8 days (range: 0 - 176 days, median: 44.5 days). Discussion The ISRCTN45828668 study was designed to assess the safety and potential efficacy of Sulfasalazine, an IKK and X-cystine transporter inhibitor, for the treatment of recur- rent astrocytic malignant gliomas. As scheduled, an interim analysis of the outcome of the first ten patients included in the study was performed prior to the inclusion of the second half of the planned study population. As described in the results section, this interim analysis revealed a high incidence of serious side effects as well as a lack of efficacy. Several side effects were observed in our patients, two of which are particularly relevant in the setting of neurosur- gical patients. Five patients developed T2 MRI changes characterized by an increase in the apparent peritumoral edema. Sulfasalazine was previously reported to induce encephalopathies and T2 MRI hyperintesities in rheuma- tologic [23,24], or Crohn's disease patients [25] and to cause intracranial hypertension [26]. It was also reported to aggravate experimental auto-immune encephalomyeli- tis, a phenomenon thought to result from immune effects and hypersensitivity reactions to the drug [27]. None of our patients, however, presented any rash or other sign of sulfasalzine hypersensitivity. We thus suspect that sul- fasalzine more directly increased the permeability of (peri)tumoral vessels in our patients. Such an effect is however unlikely to result from sulfasalazine-mediated NF-kappaB inhibition, as this transcription factor is known to contribute to the vascular leakage in response to LPS and various cytokines [28]. More probably, inhibition of the x(c)-cystine/glutamate antiport could reduce intra- cellular gluthatione levels in endothelial cells and result in blood-brain barrier dysfunction [29]. Whatever the exact mechanism, and although tumor progression may also have contributed to this effect, sulfasalazine treatment induced a significant brain edema in 50% of our recurrent glioma patients, which likely contributed to worsening of their headaches and neurological condition. Sulfasalzine treatment correlated with decreased serum levels of anti-epileptic drugs in 5 patients, namely sodium valproate (n = 5), phenytoin (n = 3) and carbamazepine (n = 1). The cause of this side effect remains unclear, as we did not find evidence of any correlation between sul- fasalazine dosage and AED level decrease. Seizure activity nevertheless increased in two of these patients, leading to a worsening of their clinical condition and to the death (by inhalation pneumonia) of one of them. Tumor growth was at best unaffected in our patients fol- lowing sulfasalazine treatment, in contrast to previous reports of tumor growth inhibition in preclinical in vivo models of human malignant gliomas [2,15]. Several fac- Page 4 of 8 (page number not for citation purposes)