Ferreri, A. J. et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374, 1512-1520

Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy.
The Lancet (Impact Factor: 45.22). 09/2009; 374(9700):1512-20. DOI: 10.1016/S0140-6736(09)61416-1
Source: PubMed


Chemotherapy with high-dose methotrexate is the conventional approach to treat primary CNS lymphomas, but superiority of polychemotherapy compared with high-dose methotrexate alone is unproven. We assessed the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary CNS lymphoma.
This open, randomised, phase 2 trial was undertaken in 24 centres in six countries. 79 patients with non-Hodgkin lymphoma exclusively localised into the CNS, cranial nerves, or eyes, aged 18-75 years, and with Eastern Cooperative Oncology Group performance status of 3 or lower and measurable disease were centrally randomly assigned by computer to receive four courses of either methotrexate 3.5 g/m(2) on day 1 (n=40) or methotrexate 3.5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice a day on days 2-3 (n=39). Both regimens were administered every 3 weeks and were followed by whole-brain irradiation. The primary endpoint was complete remission rate after chemotherapy. Analysis was by intention to treat. This study is registered with, number NCT00210314.
All randomly assigned participants were analysed. After chemotherapy, seven patients given methotrexate and 18 given methotrexate plus cytarabine achieved a complete remission, with a complete remission rate of 18% (95% CI 6-30) and 46% (31-61), respectively, (p=0.006). Nine patients receiving methotrexate and nine receiving methotrexate plus cytarabine achieved a partial response, with an overall response rate of 40% (25-55) and 69% (55-83), respectively, (p=0.009). Grade 3-4 haematological toxicity was more common in the methotrexate plus cytarabine group than in the methotrexate group (36 [92%] vs six [15%]). Four patients died of toxic effects (three vs one).
In patients aged 75 years and younger with primary CNS lymphoma, the addition of high-dose cytarabine to high-dose methotrexate provides improved outcome with acceptable toxicity compared with high-dose methotrexate alone.
Swiss Cancer League.

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    • "To improve on outcomes with single-agent HD-MTX, the IELSG20 trial assessed the role of combined antimetabolite therapy, with HD-MTX and cytarabine [43]. This study demonstrated a superior CR rate of 46 % compared to HD-MTX alone (18 %, p = 0.006), with significant improvements in PFS but not OS (three-year OS 46 % vs. 32 %, p = 0.07). "
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    ABSTRACT: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system is an aggressive malignancy that exhibits unique biological features and characteristic clinical behaviour, with overall long-term survival rates of around 20-40 %. Clinical outcome has improved following the advent of chemoradiation protocols incorporating high-dose methotrexate in the mid-1980s, but disease relapse and adverse neurocognitive sequelae remain major clinical challenges. To address this, investigators have focused on improving drug therapy with novel cytotoxic combinations, monoclonal antibody therapy, and intensive chemotherapy consolidation approaches, in an attempt to improve disease control whilst reducing the requirement for whole-brain radiotherapy. Outcomes for patients that are older, immunocompromised, or have relapsed/refractory disease remain unsatisfactory and there is a paucity of clinical trial data to guide treatment of these groups. This review highlights recent advances in pathobiology, imaging, and clinical management of PCNSL and looks ahead to research priorities for this rare and challenging lymphoid malignancy.
    Preview · Article · Jun 2014 · Current Hematologic Malignancy Reports
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    • "Shibamoto and colleagues reported a median survival of 18 months in a retrospective analysis of 132 patients treated in the 1990s with WBRT monotherapy at different doses [11]. Later studies demonstrated that high doses of methotrexate could achieve therapeutic concentrations in the brain, and when combined with WBRT led to sustained response [12–15]. Most of these studies used high doses of WBRT up to 45 Gy and some included focal boost. "
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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.
    Preview · Article · Dec 2013 · Current Treatment Options in Oncology
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    • "On the other hand, treatment results with a high-dose methotrexate (alone or in combinations) in our series were inferior to the ones reported in the literature. Namely, the overall response rate of 55.5% in case of combination of a high-dose methotrexate and a high-dose cytarabine was lower than the one reported for a high-dose methotrexate in mono-therapy by Glass et al.33 and other authors14,34 and substantially lower than the 69% overall response rate reported by Ferreri et al. with the same combination in a randomized trial.35 Also, the survival in the group receiving a high-dose methotrexate regimens (46.3% at two years) was inferior to the two year survival of 60–65% reported by the same authors.14,33,34 "
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    ABSTRACT: Background. Primary central nervous system lymphomas (PCNSL) are rare variants of extranodal non-Hodgkin’s lymphomas that are nowadays primarily treated with high-dose methotrexate or methotrexate-based chemotherapy with or without radiation therapy. The optimal treatment of PCNSL is still unknown and there are differences in clinical practice. Patients and methods. With a retrospective research we evaluated our series of patients with PCNSL in regards to the patient’s characteristics, treatment results, disease specific survival and overall survival. Fifty nine patients who attended the Institute of Oncology Ljubljana between 1995 and 2010 were treated according to the protocol that was valid at the time of the patient’s admission. Between 1995 and 1999, the systemic treatment was classical CHOP (cyclophosphamide, doxorubicin, vincristine, steroids) chemotherapy, and later on high-dose methotrexate either alone or in combination with other agents. From 1999 onwards, radiation therapy was applied according to the patient’s age and response to chemotherapy, prior to that all patients treated with CHOP were also irradiated. Patients ineligible for the systemic treatment were treated with sole radiation therapy. Results. There was a strong female predominance in our series and the median age at diagnosis was 59.8 years. Patients had predominantly aggressive B cell lymphomas (69.5%), one patient had marginal cell lymphoma and two patients T cell lymphoma. In total, 20.3% of patients were treated just with chemotherapy, 33.9% with combined therapy and 42.4% with sole radiation therapy. The overall response rate to the primary treatment in patients treated with sole chemotherapy was 33.3%, in patients treated with combined therapy 65% and in patients treated only with radiation therapy 56%, respectively. In terms of response duration, significantly better results were achieved with combined therapy or radiation therapy alone compared to sole chemotherapy (p<0.0006). The median overall survival of the whole cohort was 11 months and the overall survival was significantly affected by the patient’s age. The longest overall survival was observed in patients treated with combined therapy (median survival of 39 months). Patients treated just with radiation therapy had a median overall survival of 9 months and those treated with sole chemotherapy of 4.5 months, respectively. Conclusions. The treatment outcomes in ordinary clinical practice are definitely inferior to the ones reported in clinical trials. The now standard treatment with high-dose methotrexate with or without radiation therapy is sometimes too aggressive and, therefore, a careful selection on the basis of patient’s age, performance status and concomitant diseases of those eligible for such treatment is mandatory. According to our results from a retrospective study, radiation therapy should not be excluded from the primary treatment.
    Full-text · Article · Dec 2012 · Radiology and Oncology
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