Page 173 - 2020_07-Haematologica-web

Role of CNS intrathecal prophylaxis in DLBCL
therapy. The evidence base for the efficacy of HDMTX in the rituximab era is relatively weak but has been demon- strated in retrospective single or multicentre series.7–9 No randomised prospective studies have been performed. HDMTX is given either following10 or in an intercalated fashion alongside rituximab-based immunochemotherapy.7 HDMTX prophylaxis is widely administered for this pur- pose; however its toxicity profile typically limits its use to patients under 70 years of age, without serous effusions and with adequate renal function.
Intrathecal (IT) anti-metabolites, typically methotrexate (MTX) and/or cytarabine (ara-c), have also been employed either as stand-alone therapy in patients deemed at high risk of CNS relapse, or as adjunctive therapy to high dose intravenous anti-metabolites. The theoretical basis for IT prophylaxis has historically been extrapolated from the management of other lymphoid cancers such as Burkitt lymphoma11 and acute lymphoblastic leukemia.12 Although not a universally applied practice, many centres continue to employ stand-alone IT prophylaxis in DLBCL patients at higher risk of CNS relapse who are otherwise being treated with curative intent but who are considered unsuitable can- didates for HDMTX due to, for example, age, inadequate renal function, or patient/physician preference. Historical studies have demonstrated that IT methotrexate does not achieve therapeutic concentrations within the brain parenchyma13 and IT chemotherapy administration has the potential for well described morbidity14 as well as resource and administrative burden.
Although it is clear that rituximab reduces systemic relapse and improves survival in DLBCL,15 summarised data within a systematic review published in 2015 are conflict- ing as to whether rituximab reduces CNS relapse.5 There is some evidence that leptomeningeal recurrence may have become less common since the introduction of rituximab, with the majority of CNS relapses being parenchymal in origin.10–12 There are few data suggesting that IT prophylaxis may reduce CNS relapse, although this is based on relative- ly small single or multicentre retrospective studies in het- erogenous cohorts primarily from the pre-rituximab era.19,20
To date, there is no international consensus regarding which patients should receive stand-alone IT prophylaxis alongside rituximab and anthracycline-based frontline immunochemotherapy and no systematic reviews have been specifically performed to help answer this important question. An initial scoping review found a relatively small number of publications directly related to this question, and as such a comprehensive systematic review was deemed necessary. The purpose of this systematic review was, therefore, to identify evidence of effectiveness of stand- alone IT prophylaxis in patients treated in the front-line setting for DLBCL with anthracycline-based curative chemotherapy in the anti-CD20 monoclonal antibody era. Our systematic review was not designed to assess the rela- tive value of combined IT and high dose intravenous anti- metabolite prophylaxis or high dose intravenous anti- metabolite prophylaxis alone as strategies to reduce CNS relapse risk.
Method
Search strategy
The review was conducted systematically in accordance with the Preferred Reporting Items for Systematic Review and Meta-
Analysis Protocols (PRISMA-P) guidelines21,22 and was regis- tered on the PROSPERO database (CRD42019121174). A com- prehensive search was conducted following a systematic search strategy using the electronic databases: Ovid MEDLINE®, Ovid EMBASE® and Cochrane Central Register of Controlled Trials. Boolean operators ‘AND’ and ‘OR’ were employed, as well as truncation (*).
Searches included the title and abstract where possible and were restricted to English language only. The search strategy was date restricted from 2002 until January 2019 as the pivotal trial establishing the benefit of rituximab in combination with CHOP was published in January of the year 2002.15 Search strategy comprised three main components, using relevant Medical Subject Headings (MESH) terms where possible. Disease component(s) were searched for using the following search terms: diffuse large B-cell lymphoma, DLBCL, central nervous system relapse, CNS relapse, central nervous system recurrence, CNS recurrence, central nervous system progres- sion, CNS progression. Prior therapies component(s) were searched for using the following search terms: rituximab, dox- orubicin, anthracycline, R-CHOP, EPOCH and R-CHOEP. Intervention component(s) were searched for using the follow- ing search terms: central nervous system prophylaxis, CNS pro- phylaxis, intrathecal, intrathecal prophylaxis, intrathecal chemotherapy, intrathecal methotrexate, intrathecal cytarabine.
Full search strategies are summarised in the Online Supplementary Tables S1-3. The search was expanded using ret- rospective snowballing from the reference lists of initial studies included to ensure a sensitive and comprehensive search.
Screening search results
Search results were independently double-screened by the research team both at abstract and full text screening stages using eligibility criteria displayed in Table 1. Disagreements between any two researchers were referred to a third researcher to reach a consensus.
Quality appraisal and data extraction
Standardised Critical Appraisal Skills Programme (CASP) tools (https://casp-uk.net/casp-tools-checklists) were utilised to appraise the quality of study design, methodology and data reporting. CASP tools used were specific to each study type reviewed (e.g. clinical trial, cohort study). Studies were assigned a quality rating score as follows: 5 (high), 4 (moderate to high), 3 (moderate), 2 (moderate to low), or 1 (low). Limitations iden- tified from reported data in individual studies were reported including low quality rating papers, which were also transpar- ently reported in the review.
Data extraction and analysis
Extracted data were reviewed by all the research team (FD, TAE, GPC) and tabulated to summarise key findings. Key data extracted from each study were: author and year of publication, design, sample characteristics (type of rituximab-containing immunochemotherapy, key inclusion criteria), and reported outcomes (cumulative incidence of CNS relapse, site of CNS relapse, concurrence of systemic relapse and a documented analysis of the effectiveness of IT prophylaxis in preventing CNS relapse). For studies including patients treated both with and without rituximab, presented data for rituximab-exposed patients where available (superscript ‘R’, Table 2). The research design(s) and study characteristics, clarity of reporting, and sta- tistical significance of reported data were assessed to determine the strengths and limitations of the evidence. All included stud- ies underwent full statistical analysis (AAK).
haematologica | 2020; 105(7)
1915