Page 176 - 2020_07-Haematologica-web

T.A. Eyre et al.
Table 2. Data extraction table. Data to be extracted
Publication ID
Study aim Study design
Sample characteristics
Item
• Author
• Publication date
• Title/Purpose/Aim
• Study type and design: meta-analysis, late phase clinical trial,
post hoc analysis of late phase clinical trials, cohort study, cross-sectional study, retrospective study, observational study, case-control study
• Key study inclusion criteria for cohort studied if specified in manuscript
• Number of participants
• Years of data collection
• DLBCL subtypes
• Proportion and total number of cohort receiving rituximab-containing
anthracycline-based regimen
• Rituximab or obinutuzumab-containing immunochemotherapy regimen(s) used
for DLBCL treatment
• Proportion of patients (total +/- rituximab or obinutuzumab exposed patients
depending on what is reported) receiving IT prophylaxis
• Type of IT prophylaxis received
• Number of CNS relapses and whether concurrent with systemic relapse or isolated CNS relapse: either of total population or rituximab population. This will be specified in analysis.
• Cumulative incidence of CNS relapse at time point described in manuscript: either of total population or rituximab population. This will be specified in analysis.
• Site of CNS relapse: parenchymal, leptomeningeal, both, unknown: either of total population or rituximab population. This will be specified in analysis.
• Documentation of the analysis of the effectiveness of IT prophylaxis in assessing the CNS relapse risk.
• CASP tool scores and comment on the nature and quality of the statistician analysis
Findings
Strengths and limitations
performed
DLBCL: diffuse large B cell lymphoma; CNS: central nervous system; IT: intrathecal; CASP: Critical Appraisal Skills Programme.
clear, robust univariable and multivariable analysis was limited. A number of studies28,35 within the analysis simply report the hazard ratio or absolute percentage relapse rate comparison between patients receiving IT prophylaxis ver- sus those not in receipt of prophylaxis.
The studies included often show that the rate of CNS relapse is increased in patients receiving prophylaxis. This finding primarily relates to the confounding effects of patient selection i.e. those at higher risk of CNS relapse are those who receive prophylaxis, however, no attempt was made to adjust for these risk factors in a number of the studies. As such, it is difficult to formally discern the value of IT prophylaxis from univariable, unadjusted analysis. A negative or null result i.e. hazard ratio ≥ 1 (or more events in the IT-prophylaxis group) as seen in 8 of 11 studies, or small, non-significant protective effect as seen in 3 of 11 studies does not imply that CNS prophylaxis is harmful or ineffective, but may show that it is simply not enough to overcome the increased baseline risk in the population which were treated.
A single study23 was excluded from the analysis because of concerns regarding the integrity of the data and the quality of the analysis performed. A comparison across the 14 studies was also limited by the variable indications for IT prophylaxis and the different histologies and regi- mens included.
Multivariable analyses could help to reduce the effects of (known) confounding factors but, in this case, there are multiple factors of interest (median 16, range: 11-26) in the 13 papers which quote univariable analysis results) and, given the small number of events (median 20, range: 8-61), all of the cohorts studied would fail the ten-events-per- factor rule,36 which is generally suggested to ensure the stability of a statistical model.
A number of papers2,17,25,32,34,35,37 (Villa et al., Tai et al., Guirguis et al., Tomita et al., Cai et al., Wudhikarn et al. and possibly Song et al.). reduced the number of factors in mul- tivariable analyses by only including those factors with P>/≥0.1 in the univariable analysis. In some cases this meant CNS IT prophylaxis was not included in multivari- able models at all17,25,32 (Villa et al., Guirguis et al., possibly Song et al.), and in others it may have excluded factors which were not significant but did have a confounding effect on the benefit of CNS prophylaxis. Two studies (post hoc analysis of the R-CHOP 14 vs. 21 and GOYA ran- domised controlled trials) presented results adjusted for the CNS-IPI only27 (Gleeson et al.) or within the different CNS-IPI risk levels24 (Klanova et al.), neither found any benefit to IT prophylaxis but, as with reduced the models mentioned above, both could also have suffered from the exclusion of confounders. Kumar and colleagues used a propensity score to match patients with and without CNS
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