Methotrexate: Distribution in Cerebrospinal Fluid after Intravenous, Ventricular and Lumbar Injections

Shapiro, William R.; Young, D. C.; Mehta, Bipin M.

doi:10.1056/nejm197507242930402

Cited by 650 publications

(257 citation statements)

References 20 publications

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“…24 Intraventricular administration by means of an implantable Ommaya reservoir improves drug distribution around the brain, but lumbar concentrations remain lower. 24,25 In contrast, intravenous administration of methotrexate produces therapeutic drug levels that are evenly distributed throughout the entire subarachnoid space. 24 All but 2 patients in our analysis received rituximabcontaining therapy.…”

Section: Discussionmentioning

confidence: 99%

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

Abramson

Hellmann

Barnes

et al. 2010

Cancer

210

159

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BACKGROUND:The outcome of patients with systemic diffuse large B-cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high-risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high-dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R-CHOP) chemotherapy to decrease CNS recurrence in high-risk patients. METHODS: A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression-free survival, and overall survival were calculated. RESULTS: Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m 2 with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow-up of 33 months, there were only 2 CNS recurrences (3%) in this high-risk population. The 3-year progression-free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients. CONCLUSIONS: Intravenous methotrexate can be safely administered concurrently with R-CHOP and is associated with a low risk of CNS recurrence in high-risk patients. Cancer 2010;116:4283-90.

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Section: Discussionmentioning

confidence: 99%

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

Abramson

Hellmann

Barnes

et al. 2010

Cancer

210

159

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“…28 The CSF level of leucovorin after systemic administration is 1 to 2 log lower than the serum and so it could be postulated that for adequate CNS rescue a systemic dose 10 to 100 times that required for systemic rescue would be required. Since a 6-hourly folinic acid dose of 50 mg/m2 but not 10 mg/m2 initiated DNA synthesis in bone marrow cells treated with 3.775 g/m2 MTX lo-' after 24 hours, it is not surprising that a 10 mg/m2 folinic acid regimen may be inadequate in preventing leucoencephalopathy when even higher doses of MTX are used.…”

Section: Discussionmentioning

confidence: 99%

Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB)

Cohen

Vogel

Matz

et al. 1986

Cancer

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A 3.5-year-old boy with a multifocal primary lymphoma of the brain was treated successfully without neurotoxicity with a treatment regimen fhat did not include radiation. The protocol of Dexacort (dexamethasone), methotrexate, Oncovin (vincristine), and BCNU (carmustine) (DEMOB), which was developed with the use of MTX pharmocokinetic studies, was given over 7.5 months, and resulted in tumor disappearance on computerized tomography scans and marked improvement in clinical status. The patient remains in good health 3 years after diagnosis (March 1985).Cancer 57:6-11,1986.HE REALIZATION in the Iast few years that microgly-T omas are primary brain lymphomas' raised the hope that, with appropriate antilymphoma therapy, cure could be achieved. We report the first case that, to the best of o u r knowledge, has been treated successfully without radiotherapy. It has been 3 years since diagnosis and 30 months since therapy was completed. Case ReportA 3.5-year-old boy was referred for postoperative treatment of a primary brain tumor in January 1982 from the Neurosurgical Department of this hospital. He had been healthy until August 198 1, when he had an episode of vomiting and a 2-hour loss of consciousness. One week later he had a similar attack. Computerized tomography (CT) (Figs. 1A and IB) showed two foci; one in the left frontoparietal area and the other in the left temporo-occipital area. The frontoparietal focus was not visualized on a further CT 6 weeks later, but the temporo-occipital lesion had grown in size (Fig. 2).He experienced weakness of his left leg and arm and, after a further episode of vomiting and headache, underwent craniotomy with gross resection of the left temporal lesion (December 2 1, I98 I). The tumor was removed piecemeal. The internal border was less clearly demarcated than the superficial border, but no obvious tumor remained after the operation.

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“…Doses less than 3 g/m 2 are probably too low to reach sufficient concentrations in the CSF to kill lymphoma cells [28,29]. A dose of 8 g/m 2 MTX was frequently associated with the need for a dose reduction during the course of the treatment, mostly due to renal toxicity [30,31].…”

Section: Methotrexate Alone or In Combinationmentioning

confidence: 99%

Treatment of Primary CNS Lymphoma

Roth

Stupp

Eisele

2013

Curr Treat Options Neurol

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OPINION STATEMENT: Primary central nervous system lymphoma is a particular challenge in clinical neuro-oncology. In contrast to most other malignant brain tumors, it may be considered a curable disease at least in younger patients who can tolerate intensive treatment regimens. Yet, therapeutic progress has been limited with little measurable improvement in outcome over the last two decades, mainly due to the low incidence of this tumor, which impedes the execution of large randomized clinical trials, and the failure of most large cooperative groups to conduct such trials. Whenever possible, high-dose methotrexate (HD-MTX) is the backbone of the therapeutic regimen. Response rates can be increased by the addition of second agents like ifosfamide or cytarabine, however, their impact on overall survival is less clear. Similarly, the use of the anti-CD20 antibody rituximab, commonly used in the treatment of B cell lymphomas outside the CNS, remains controversial and has not been examined in adequate clinical trials. The prognosis of patients, who do not qualify for HD-MTX-based chemotherapy, is considerably poorer. Radiation therapy is an active treatment with high response rates but does typically not result in long-lasting remissions. It remains an important therapeutic option as a salvage therapy in patients progressing on or no longer responding to HD-MTX-based treatment. The combination of HD-MTX and radiation therapy does not prolong overall survival. It is associated with significant neurotoxicity, and it should be avoided. Another matter of debate is whether consolidation therapy by other means, such as high-dose chemotherapy followed by stem cell support, is the most promising regimen. Given these numerous uncertainties, neuro-oncologists should strive for a treatment of PCNSL patients within clinical trials to allow for the development of improved therapeutic regimens. therapy does not prolong overall survival, is associated with significant (neuro-)toxicity and should be avoided. Whether consolidation therapy by other means such as highdose chemotherapy followed by stem cell support is the most promising regimen, is another matter of debate. Given these numerous uncertainties, neuro-oncologists should strive for a treatment of PCNSL patients within clinical trials to allow for the development of improved therapeutic regimens.

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Methotrexate: Distribution in Cerebrospinal Fluid after Intravenous, Ventricular and Lumbar Injections

Cited by 650 publications

References 20 publications

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high‐risk patients with diffuse large B‐cell lymphoma

Successful non-neurotoxic therapy (without radiation) of a multifocal primary brain lymphoma with a methotrexate, vincristine, and BCNU protocol (DEMOB)

Treatment of Primary CNS Lymphoma

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