To evaluate the incidence, risk factors, and outcome of central nervous system (CNS) recurrence in adult patients with non-Hodgkin's lymphoma, we evaluated 605 newly diagnosed patients with large-cell and immunoblastic lymphoma who participated in prospective chemotherapy studies. The Kaplan-Meier estimate of probability of CNS recurrence at 1 year after diagnosis was 4.5% (95% confidence interval [CI], 4.4 to 4.6). Twenty-four patients developed CNS recurrence after a median of 6 months from diagnosis (range, 0 to 44 months). In univariate analysis, an increased risk for CNS recurrence was associated with an advanced disease stage (P = .0014), an increased LDH (P = .0000), the presence of B-symptoms (P = .0037), involvement of more than one extranodal site (P = .0000), poor performance status (P = .0005), and B-cell phenotype (P = .008). Bone marrow involvement (P = .005), involvement of parenchymal organs (P = .03), and involvement of skin, subcutaneous tissue, and muscle (P = .002) were also associated with an increased risk for CNS disease. Multivariate logistic regression analysis identified only involvement of more than one extranodal site (P = .0005) and an increased LDH (P = .0008) as independent predictors of CNS recurrence. Established CNS recurrence had a poor prognosis. Only 1 of 24 patients remains alive and the Kaplan-Meier estimate of probability of survival at 1 year after the diagnosis of CNS recurrence is only 25.3% (95% CI, 6.9 to 43.7). Intrathecal treatment provided symptomatic benefit in only 1 of 6 patients. Radiation treatment provided symptomatic improvement in 6 of 9 patients treated. However, remissions were short and followed by systemic or CNS recurrence. Serum LDH and involvement of more than one extranodal site are independent risk factors for CNS recurrence in patients with large-cell lymphoma. The presence of both risk factors identifies a patient group at high risk for CNS recurrence. Established CNS recurrence can be rapidly fatal. Transient responses occur after radiation treatment.

Summary. Neurotoxicity is a significant complication of the use of tacrolimus. From April 1998 to December 2001, we identified 10 patients (six women, four men) who developed 11 episodes of tacrolimus-associated posterior reversible encephalopathy syndrome (PRES) after allogeneic haematopoietic stem cell transplantation for haematological malignancies. The diagnosis was made by characteristic clinical findings (mental status changes, seizures, neurological deficits) with the exclusion of other causes and characteristic imaging findings. The median age was 35AE5 years (range 19-57 years). Seven patients received a matchedunrelated donor transplant and three received a cord blood transplant. The overall incidence of PRES was 1AE6%, while the incidence in matched-unrelated, mismatched-related and cord blood transplants was 3AE5%, 4AE9% and 7AE1% respectively. Mental status changes, cognitive deficits, seizures and lethargy were the most common clinical findings. Eight of 10 patients had characteristic findings of hyperintensity of the white matter on T2-weighted images and FLAIR (fluid-attenuated inversion recovery) sequence on magnetic resonance imaging of the brain. Serum tacrolimus levels were within the therapeutic range in most patients. Tacrolimus treatment was continued (n ¼ 4) or temporarily withheld (n ¼ 7) for 1-14 d. One patient was changed to cyclosporine. In most patients, subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity.

Fourteen cancer patients had evidence of persistent neurotoxicity of interferon-alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity, they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy, disease status, or other medical problems. The pattern of deficits was consistent with frontal-subcortical dysfunction. Of the four patients who had follow-up assessment, two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible.

Object Seizures are a potentially devastating complication of surgical resection of brain tumors. Consequently, many neurosurgeons administer prophylactic anti-epileptic drugs (AEDs) in the peri-operative period. However, it is currently unclear whether peri-operative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Consequently, we conducted a prospective, randomized trial examining the use of phenytoin for post-operative seizure prophylaxis in patients with supratentorial brain metastases or gliomas undergoing surgical resection. Method Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days following tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events (AEs). Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a type I error of 0.05 and a type II error of 0.20, a target accrual of 142 patients (71 per treatment arm) was planned. Results The trial was closed before completion of accrual because Bayesian Predictive Probability analyses performed by an independent Data Monitoring Committee indicated that the probability that at the end of the study prophylaxis would prove superior to observation was 0.3% and the probability that there would be insufficient evidence at the end of the trial to choose either arm as superior was 99.7%. At the time of trial closure, 123 patients (77 metastases, 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no-prophylaxis (observation group). The incidence of all seizures was 18% in the observation group compared with 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (<30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more AEs (18% vs. 0%, p = <0.01). Therapeutic phenytoin levels were maintained in 80% of patients. Conclusions The incidence of seizures after surgery for brain tumors is low (8%, 95%-CI 3-18%) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rates of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.