Treatment of Relapsed Central Nervous System Lymphoma with High-Dose Methotrexate

Harvard University, Cambridge, Massachusetts, United States
Clinical Cancer Research (Impact Factor: 8.72). 10/2004; 10(17):5643-6. DOI: 10.1158/1078-0432.CCR-04-0159
Source: PubMed


Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma.
Patients with relapsed disease were eligible if they achieved a complete response to initial treatment with methotrexate-based chemotherapy or received methotrexate after gross total resection or interstitial radiation. All of the patients were retreated with a regimen containing high-dose methotrexate (>/=3 g/m(2)).
Twenty-two patients with a median age of 58 years were included in the study. Overall response rates were 91% to first salvage (20 of 22 patients) and 100% to second salvage (4 of 4 patients). Median survival was 61.9 months after first relapse (95% confidence interval, 42.1- infinity ) and 91.9 months overall (95% confidence interval, 47.2- infinity ). Toxicity was primarily hematologic with 10 episodes of grade 3 or 4 toxicity during 566 cycles of chemotherapy.
These results indicate that high-dose methotrexate remains effective for relapsed central nervous system lymphoma in patients who initially respond to methotrexate and raise the possibility of deferring more toxic salvage regimens in this select group of patients.

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    • "Rechallenge with HD-MTX has been shown to be effective in patients that had previously responded to it. In a multicenter retrospective review of 22 patients, 91 % had a radiographic response to first salvage treatment with HD-MTX and 100 % to second salvage [62]. The median OS from first salvage was 61.9 months. "
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    ABSTRACT: Opinion statement Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn’t been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity.
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    • "Treatment in the refractory patient and at relapse The optimal therapy of recurrent tumor is not established, but drug resistance is seldom documented and most patients benefit from reinduction with chemotherapeutic agents [Reni et al. 2007; Pels and Schlegel, 2006]. Patients with recurrent lymphoma after initial long-lasting response to chemotherapy are at least 50% likely to achieve a complete reinduction with MTX [Plotkin et al. 2004] suggesting that brain lymphoma may not recur as a function of drug resistance alone. In patients younger than 65 years and eligible for myeloablative therapy, intensive chemotherapy followed by hematopoietic stem-cell rescue is strongly recommended as a potentially curative salvage treatment option analogous to the situation in systemic relapsed high-grade malignant B-cell NHL. "
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    ABSTRACT: Primary CNS Lymphoma (PCNSL) accounts for 3% of all primary brain tumors with a median age at onset of about 62 years. In the vast majority of cases, PCNSL presents as unifocal or multifocal enhancing lesions on MRI, frequently adjacent to the ventricles. Stereotactic biopsy is the diagnostic procedure of choice revealing high-grade malignant non-Hodgkin's B-cell lymphoma in more than 90% of cases. Therapy is not evidence based. When eligible, patients should be included in clinical trials. In patients younger than 60 years cure is the aim. Polychemotherapy based on high-dose methotrexate (MTX) or alternatively high-dose chemotherapy with autologous stem cell rescue should be offered to patients eligible for this regimens. For patients over 60 years of age no curative regimen with acceptable toxicity has yet been established. An MTX-based chemotherapy, for example, in combination with temozolomide, is recommended. The role of radiotherapy as part of the initial treatment is not established; however, the combination of radiotherapy with MTX-based chemotherapy potentially leads to severe long-term neurotoxic sequelae. Therefore, radiotherapy as part of the initial therapy is not recommended by the author outside clinical trials. At relapse or in cases of refractory disease, patients will frequently benefit of salvage therapy, which depends on the initial treatment.
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    ABSTRACT: This review article provides guidelines for the diagnosis, staging, and management of primary nervous system lymphoma based on the results of clinical trials conducted during the last decade. Recent progress in our understanding of the pathogenesis of primary nervous system lymphoma is summarized, and implications of these findings for the development of diagnostic tools and new therapeutic strategies are outlined. We performed a search of the PubMed database (National Center for Biotechnology Information) for articles on primary nervous system lymphoma published between 1970 and May 2005. Primary nervous system lymphoma affects the brain, eye, and meninges as well as cranial, spinal, and peripheral nerves. Although important lessons have been learned from the pathogenesis of extraneural non-Hodgkin's lymphoma, the unique organotropism of primary nervous system lymphoma remains poorly understood. Diagnosis is facilitated by modern imaging techniques and molecular markers. Clinically recognizable "precursors" may exist but frequently elude specific diagnosis. Insight into the peculiar pharmacokinetics of chemotherapy aimed at tumors within the nervous system has led to the development of methotrexate-based regimens that can achieve prolonged progression-free survival without the use of radiation. Long-term survival and, in selected cases, even a cure are possible in primary nervous system lymphoma. Treatment should be provided in specialized multidisciplinary centers. In spite of remarkable progress through methotrexate-based chemotherapy, the majority of patients experience relapse within a few years. Better diagnostic tools are required for earlier diagnosis and monitoring of treatment response. A deeper understanding of the pathogenesis of primary nervous system lymphoma may reveal new therapeutic targets.
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