Blood-Brain Barrier Disruption Chemotherapy Research Articles

Enhanced Delivery of Rituximab In Combination with Methotrexate-Based Blood-Brain Barrier Disruption for Patients with Newly Diagnosed Primary CNS Lymphoma.

AbstractAbstract 2792 Introduction:Primary CNS lymphoma (PCNSL) is a rare, aggressive, primarily large B-cell lymphoma confined to the CNS and/or eyes at presentation. High-dose (HD) methotrexate (MTX) - based chemotherapy is standard of care in PCNSL and when combined with enhanced delivery results in extended survival without cognitive loss. The addition of rituximab to HD MTX regimens for B-cell PCNSL is widely used primarily by analogy to the positive results attained in systemic B-cell lymphomas. However, recent pre-clinical and clinical use of single agent rituximab provides stronger rationale. Efficacy has been shown using single agent rituximab in nude rats with intracerebrally implanted MC116 human B-cell lymphoma cells, and in patients with recurrent PCNSL by using 111In-ibritumomab to assess delivery and 90Y-ibritumomab to assess efficacy. Next, safety and efficacy of enhanced delivery of rituximab with MTX-based blood-brain barrier disruption (BBBD) was shown in patients with recurrent PCNSL. Based on these results, we treated patients with newly diagnosed PCNSL with rituximab in combination with MTX-based BBBD. Methods:IRB permission was obtained to retrospectively evaluate patients with newly diagnosed B-cell PCNSL, treated with rituximab in combination with MTX-based (intra-arterial [i.a.]) BBBD chemotherapy as first-line treatment. Treatment consisted of MTX (2500mg/day, i.a.) and carboplatin (200mg/m2/day, i.a.) with BBBD, for 2 consecutive days every 4 weeks for up to one year. Rituximab (375mg/m2, i.v.) was given every 4 weeks, 12 hours prior to the MTX with BBBD treatment. Objective response rate, progression free survival (PFS), overall survival (OS), and toxicities were evaluated. Results:Twelve patients (7 female, 5 male) were treated between April 2003 and October 2008. The median age was 65 years (min 49, max 75); 10 patients were older than 60 years. The median Karnofsky Performance Score (KPS) prior to treatment was 55 (min 20, max 80). All patients had brain parenchyma involvement at presentation. Additionally, CSF cytology was positive in 2 patients and one patient had ocular involvement. One patient with pre-existing cardiac disease died 2 weeks after initiation of MTX without BBBD due to myocardial infarction and was not evaluable for response. The overall response rate was 83% (7 CR, 1 CRU, 2 PR, 1 SD). The median PFS was 3.47 years (95% CI: 0.42, not yet attained) and the 2-year PFS in this cohort is 73%. The median OS was 4.42 years (95% CI: 0.28, not yet attained). Eight patients who attained CR or CRU were alive at data-cut-off; 6 of the 8 patients remain in CR 2 years or more after diagnosis. The most frequent toxicities were hematologic. Eight (67%) patients developed grade 3 or 4 hematologic toxicity and 7 (58%) developed grade 3 infection. Conclusions:We previously reported a 2-year PFS of 50% with 25% survival at 8.5 years in 149 newly diagnosed PCNSL patients treated with MTX-based BBBD without rituximab. The addition of rituximab shows manageable toxicity and provides sustained duration of CR in newly diagnosed PCNSL, with 10 of 12 patients over 60 years old and a median KPS of 55. These pilot data suggest the 2-year PFS may be increased to 70% or more with the addition of rituximab to MTX-based BBBD chemotherapy. A multi-center phase II prospective study is underway. Disclosures:No relevant conflicts of interest to declare.

Delivering Drugs Into the Brain: Barriers and Possibilities

Delivering Drugs Into the Brain: Barriers and Possibilities

The treatment of brain metastasis from breast cancer, role of blood-brain barrier disruption and early experience with trastuzumab

Background: Therapeutic approaches in the treatment of metastatic systemic brain tumors from breast cancer have improved. As patients live longer, the potential for CNS sanctuary disease increases. Metastases to the brain are diagnosed in breast cancer patients at a rate of 10 to 20%. Median survival is only 3 to 12 months with current standard therapies of whole-brain radiotherapy, surgery and stereotactic radiosurgery, and can vary with the type of treatment given. Chemotherapy and immunotherapy using trastuzumab may be more effective against brain metastases if delivery to the tumor can be improved. Results: The treatment was well tolerated with acceptable bone marrow toxicity. Median overall survival was 45.4 weeks and the majority of patients achieved symptomatic relief with reduction of steroids. Methods & objectives: We evaluated the use of osmotic blood–brain barrier disruption chemotherapy, with or without monoclonal antibody, for the treatment of brain metastases from breast cancer. We are interested in the prospective evaluation of the combination of a monoclonal antibody, trastuzumab, with enhanced delivery of carboplatin and methotrexate chemotherapy. Discussion: The use of carboplatin and methotrexate with blood–brain barrier disruption showed efficacy in the treatment of metastatic breast cancer to the CNS. This is comparable to other modalities, and without cognitive loss. Quality of life is improved with the withdrawal of steroids. Conclusion: The long-term goal is to use combined chemotherapy and immunotherapy with radiosurgery to increase survival and avoid complications from other treatments.

Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas

The prognosis for patients with diffuse pontine gliomas (DPG) remains poor. New aggressive innovative treatments are necessary to treat this disease. From 1984 to 1998, eight patients (4M/4F), median age 11 years, with DPG were treated with monthly osmotic blood-brain barrier disruption (BBBD) chemotherapy using intraarterial carboplatin or methotrexate and intravenous cytoxan and etoposide. Patients presented for a median duration of 6 weeks with increased intracranial pressure, long tract signs, diplopia, ataxia, and nausea/vomiting. DPG was demonstrated on magnetic resonance (MR) imaging in seven patients and on CT in one. Two patients had biopsies that showed an astrocytoma and an anaplastic astrocytoma. Three tumors enhanced on MR imaging after contrast administration. Three patients had radiation therapy before BBBD chemotherapy and four afterwards. Two patients had chemotherapy (tamoxifen, topotecan) before BBBD chemotherapy and two afterwards. In general, patients were evaluated with MR imaging every 3 months to monitor for a response to treatment. The median number of chemotherapy cycles that were administered by BBBD was 10, mean 10. Three patients also received one, two, or three cycles of intraarterial chemotherapy without BBBD. One patient that was started on carboplatin was converted to methotrexate, and five that were started on the methotrexate protocol were later converted over to carboplatin. One patient received monthly methotrexate followed by 14 days of procarbazine and one patient started on methotrexate was switched to navelbine. MR imaging demonstrated two partial responses, five patients with stable disease, and one with disease progression. The median time to tumor progression was 15 months with the range from <1 to 40 months. The median survival from the time of diagnosis was 27 months, ranging from 7 to 80 months. The median survival time from the first BBBD or intraarterial treatment was 16.5 months, ranging from 5 to 69 months. One patient was lost to follow-up with an unknown date of death. Although the sample size is small, the TTP and survival times are longer than those previously reported in other DPG series. In addition, the ability to demonstrate stable disease or partial responses in DPG on MR imaging argues for the therapeutic benefit of BBBD chemotherapy. The enhanced delivery of chemotherapy afforded by osmotic BBBD supports the further examination of this treatment modality for patients with DPG.

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

The risk of neurotoxicity was evaluated in eight consecutive patients with non-acquired immunodeficiency syndrome (AIDS) primary central nervous system lymphoma who had survived disease free for more than 1 year after completion of treatment with osmotic opening of the blood-brain barrier and chemotherapy (methotrexate, cytoxan, procarbazine, and decadron). Trends in neuropsychological assessment results between baseline and follow-up (1 to 7 years) were analyzed for all eight nonradiated survivors. This serial assessment design addressed the specific issue of neurotoxic risk potential of treatment, when confounding factors of tumor persistence/recurrence and cranial irradiation were ruled out. Follow-up results of an extensive battery of tests to assess higher cortical function provided evidence of the safety of chemotherapy protocol with the blood-brain barrier disruption. These findings stand in contrast to well-known cognitive risks associated with cranial radiotherapy. Long-term follow-up suggests that chemotherapy can be given in conjunction with osmotic opening of the blood-brain barrier in nonradiated patients without cognitive manifestations of neurotoxicity.

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy

Neuropsychological Assessment Outcomes of Nonacquired Immunodeficiency Syndrome Patients with Primary Central Nervous System Lymphoma before and after Blood-Brain Barrier Disruption Chemotherapy