Intrathecal Chemotherapy alone is Inadequate Central Nervous System Prophylaxis in Patients with Intermediate-grade Non-Hodgkin's Lymphoma

Chua, Susan; Seymour, John F.; Streater, J; Wolf, M.; Januszewicz, E.; Prince, H. Miles

doi:10.1080/1042819021000006475

Cited by 60 publications

(43 citation statements)

References 34 publications

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“…Whether intrathecal MTX should be administered to patients at high risk to develop CNS relapses (elevated lactate dehydrogenase, poor performance status, and Ͼ1 extranodal site) was not answered in this study. But the rate of 43% of CNS relapses that was observed in this population despite intrathecal prophylaxis, in line with previous retrospective analysis, 3 is very disappointing.…”

Section: Intrathecal Mtx For Dlbcl: From An Inappropriate Prophylactisupporting

confidence: 53%

“…The association seen in these studies is consistent with our work using the SEER database only, although the magnitude of our increase for males treated with radiation was much smaller (standardized incidence ratio [SIR] ϭ 6.59). 3 There are several possible explanations for this difference. Both of the European studies restricted their cohorts to those who had survived HL for more than 5 years, and De Bruin et al restricted HL cases to those diagnosed before age 51.…”

Section: Consistency and Synergymentioning

confidence: 99%

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Response:Intrathecal methotrexate and central nervous system events

Schmitz

Zeynalova

Loeffler

et al. 2009

Blood

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Whether intrathecal methotrexate (MTX) should be administered to diffuse large B-cell lymphoma (DLBCL) patients to prevent central nervous system (CNS) relapse is highly controversial. In a recent issue of Blood, Boehme et al provided further evidence for the inefficacy of this prophylactic procedure. 1 They should be congratulated for this information that is very useful for our daily practice and for patients. One could argue that CNS relapse was not the primary end point of the RICOVER study and that the retrospective analysis was possible because of protocol violations resulting in 42.9% of patients with bone marrow or upper neck involvement not receiving the intrathecal MTX planned in the study design. However, the data are strong and similar to the recent analysis of 899 patients included in the Southwest Oncology Group studies. 2 First, the authors confirmed that CNS relapse in DLBCL patients is a rare event (Ͻ 5%) in the rituximab era, a "low" rate that could be considered as an intrinsic limitation of any prophylactic treatment. Second, they also confirmed that a high proportion of CNS relapses are observed concurrently with systemic relapses or refractory diseases and, thus, reflect failure to control systemic disease rather than the consequences of disease's sanctuary for which a prophylactic measure should be taken. In this regard, it would be interesting to know the number of isolated CNS relapses developing in patients in CR treated or not with intrathecal MTX. Third, and most importantly, intrathecal MTX had no effect on the low rate of CNS relapses observed in DLBCL patients with BM or upper neck involvement treated with R-CHOP14. Whether intrathecal MTX should be administered to patients at high risk to develop CNS relapses (elevated lactate dehydrogenase, poor performance status, and Ͼ1 extranodal site) was not answered in this study. But the rate of 43% of CNS relapses that was observed in this population despite intrathecal prophylaxis, in line with previous retrospective analysis, 3 is very disappointing.Another matter of debate is whether intrathecal MTX is associated with short-and long-term toxicity. The interest of this question could appear to be modest in the field of DLBCL, where this procedure must be abandoned. However, the question is pertinent in other settings where intrathecal prophylaxis has been proven to be beneficial (eg, Burkitt lymphoma, acute lymphoblastic leukemia). The RICOVER trial offers a unique opportunity to address this issue. What is the rate of myelotoxicity, neurotoxicity, renal failure, and mucositis in patients receiving or not intrathecal MTX? Our daily practice suggests that intrathecal MTX may add toxicity to standard polychemotherapy regimen, and, indeed, this was recently shown in 352 children with anaplastic large-cell lymphoma, where 6 cycles of MTX 1 g/m 2 plus intrathecal MTX were significantly more toxic (myelotoxicity, infections, stomatitis) that 6 cycles of MTX 3 g/m 2 . 4 If the toxicity for patients having received intrathecal MTX in the RICOVE...

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Section: Intrathecal Mtx For Dlbcl: From An Inappropriate Prophylactisupporting

confidence: 53%

Section: Consistency and Synergymentioning

confidence: 99%

Response:Intrathecal methotrexate and central nervous system events

Schmitz

Zeynalova

Loeffler

et al. 2009

Blood

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“…MTX reduces CNS disease in DLBCL. 30 Accordingly, current practice of CNS prophylaxis varies widely. While investigators agree that prophylactic treatment of all patients is not justified, the risk groups receiving prophylaxis differ.…”

Section: Org Frommentioning

confidence: 99%

CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

Boehme

Schmitz

Zeynalova

et al. 2009

Blood

286

260

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“…IT methotrexate has been most commonly used historically, 12 but evidence of benefit has been equivocal, with no protective benefit observed in 2 large randomized controlled treatment trials of DLBCL. 2,11,[13][14][15] By contrast, the combination of systemic and IT methotrexate has demonstrated effective reduction in CNS recurrence in DLBCL, 16 suggesting that intravenous methotrexate may be primarily responsible for the risk reduction; however, the protective benefit of intravenous high-dose methotrexate without concurrent IT chemotherapy has never been formally evaluated. In the current study, we present what to the best of our knowledge is the first report of high-dose systemic methotrexate combined with standard chemoimmunotherapy to decrease CNS recurrence in high-risk DLBCL patients.…”

mentioning

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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Intrathecal Chemotherapy alone is Inadequate Central Nervous System Prophylaxis in Patients with Intermediate-grade Non-Hodgkin's Lymphoma

Cited by 60 publications

References 34 publications

Response:Intrathecal methotrexate and central nervous system events

Response:Intrathecal methotrexate and central nervous system events

CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

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

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