Clinical Relevance of the Dose of Cytarabine in the Upfront Treatment of Primary CNS Lymphomas with Methotrexate-Cytarabine Combination

Ferreri, Andrés J.M.; Licata, Giada; Foppoli, Marco; Corazzelli, Gaetano; Zucca, Emanuele; Stelitano, Caterina; Zaja, Francesco; Fava, Sergio; Paolini, Rossella; Franzin, Alberto; Politi, Letterio S.; Ponzoni, Maurilio; Reni, Michele

doi:10.1634/theoncologist.2010-0361

Cited by 30 publications

(9 citation statements)

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“…A recent multi-centre phase II trial reported promising outcomes with 52 patients treated with R-MPV induction therapy followed by reduced or standard dose WBRT (23.4Gy (n = 31) or 45Gy) and cytarabine consolidation [ 10 •], achieving median PFS and OS of 3.3 and 6.6 years, respectively. The addition of thiotepa to HD-MTX and cytarabine was piloted in a small multi-centre study (n = 20), with inferior results compared to the IELSG20 trial, attributed to a 50 % protocol reduction in cytarabine dose (1 g/m 2 for four doses) [ 44 ], although the optimal thiotepa dose in this setting has not been ascertained. The role of thiotepa is currently being evaluated in the ongoing, randomised IELSG32 study (EudraCT number 2009-012432-32).…”

Section: Treatmentmentioning

confidence: 99%

Primary CNS Lymphoma

Phillips

Fox

Cwynarski

2014

Curr Hematol Malig Rep

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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.

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Section: Treatmentmentioning

confidence: 99%

Primary CNS Lymphoma

Phillips

Fox

Cwynarski

2014

Curr Hematol Malig Rep

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“…40 A recent study highlighted the importance of ara-C dose, suggesting that 4 doses of 2 g/m 2 is an appropriate choice. 41 Although it was not addressed in a phase 3 trial, the MTX-ara-C combination is the current standard chemotherapeutic approach for de novo PCNSL as it is supported by the highest level of evidence available (Figure 4). …”

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confidence: 99%

How I treat primary CNS lymphoma

Ferreri¹

2011

Blood

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109

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Primary CNS lymphoma (PCNSL) is a rare malignancy with peculiar clinical and biologic features, aggressive course, and unsatisfactory outcome. It represents a challenge for multidisciplinary clinicians and scientists as therapeutic progress is inhibited by several issues. Molecular and biologic knowledge is incomplete, limiting the identification of new therapeutic targets, and the particular microenvironment of this malignancy, and sanctuary sites where tumor cells grow undisturbed, strongly affects treatment efficacy. Moreover, active treatments are known to be associated with disabling neurotoxicity, posing the dilemma of whether to intensify therapy to improve the cure rate or to de-escalate treatment to avoid sequels. The execution of prospective trials is also difficult because of the rarity of the tumor and the impaired general condition and poor performance status of patients. Thus, level of evidence is low, with consequent uncertainties in therapeutic decisions and lack of consensus on primary endpoints for future trials.Despite this unfavorable background, laboratory and clinical researchers are coordinating efforts to develop new ideas, resulting in the recent publication of studies on PCNSL's biology and molecular mechanisms and of the first international randomized trials. Herein, these important contributions are analyzed to provide recommendations for everyday practice and the rationale for future trials. (Blood. 2011;118(3):510-522) IntroductionPrimary CNS lymphoma (PCNSL) is an aggressive malignancy arising exclusively in the CNS, that is, the brain parenchyma, spinal cord, eyes, cranial nerves, and/or meninges. 1 This lymphoma represents 4% of intracranial neoplasms and 4%-6% of all extranodal lymphomas but some registry studies suggest that its incidence in immunocompetent patients is progressively increasing. 2 PCNSL exhibits peculiar clinical and biologic features and constitutes a diagnostic and therapeutic challenge for multidisciplinary clinicians and scientists. Its outcome remains unsatisfactory if compared with that of patients with extra-CNS lymphomas of a similar stage and histotype, and several factors prevent therapeutic progress. First, molecular and biologic knowledge is insignificant compared with other lymphomas, which limits the identification of new therapeutic targets. Second, patients with PCNSL usually exhibit impaired general condition and poor performance status (PS) more often than subjects with other lymphomas. 1 This usually interferes with the enrollment of patients in prospective trials. In fact, current therapeutic knowledge is only based on 3 randomized trials, some single-arm phase 2 trials, anecdotal meta-analyses, and a few multicenter retrospective studies. Thus, available level of evidence is low, with consequent uncertainties in therapeutic decisions and lack of consensus on primary endpoints for future trials.In this manuscript, I discuss available clinical and biologic data on PCNSL in immunocompetent patients and provide recommendations for everyday pract...

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“…This study used a relatively low dose of Ara‐C (1 g/m 2 × 4), in an effort to minimize the toxicity of the regime. More recently available data in PCNSL suggested worse outcomes in patients receiving 1 g/m 2 (treated outwith a clinical trial) compared to those who had received 2 g/m 2 in the International Extranodal Lymphoma Study Group trial (IELSG20) (Ferreri et al , , ). No direct comparison has been made, however.…”

Section: Discussionmentioning

confidence: 99%

Treatment of diffuse large B‐cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS‐penetrating R‐IDARAM chemotherapy

et al. 2015

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Diffuse large B-cell lymphoma with secondary involvement of the central nervous system (SCNS-DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS-DLBCL treated with R-IDARAM (rituximab 375 mg/m(2) IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m(2) /day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1-3; cytosine arabinoside 1000 mg/m(2) /day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m(2) IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation ('new disease'), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded - 6 (26%) complete response, 8 (35%) partial response. Grade 3-4 haematological toxicity was seen in all cycles, with no grade 3-4 or long-term neurological toxicity. Median follow-up for surviving patients was 49 months. At 2 years, estimated progression-free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5-year estimated PFS of 50% and OS 75%. R-IDARAM is a well-tolerated regimen with encouraging efficacy in patients with SCNS-DLBCL, although patients with relapsed or refractory disease continue to fare poorly.

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Clinical Relevance of the Dose of Cytarabine in the Upfront Treatment of Primary CNS Lymphomas with Methotrexate-Cytarabine Combination

Cited by 30 publications

References 10 publications

Primary CNS Lymphoma

Primary CNS Lymphoma

How I treat primary CNS lymphoma

Treatment of diffuse large B‐cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS‐penetrating R‐IDARAM chemotherapy

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