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Role of CNS intrathecal prophylaxis in DLBCL
rate this would need to be a very large study. Even if we assume a relatively high risk patient group (e.g. CNS-IPI 4-6) with a 4-6% risk of CNS relapse and aim to detect a large effect size (i.e. a halving of this rate), to achieve 80% power we would require 1,432 (6-3%), 1,722 (5-2.5%) or 2,368 (4-2%) patients. Despite the lack of conclusive evi- dence of its benefit, it may be difficult to persuade many clinicians to randomise patients with multiple baseline risk factors to potentially receive no CNS directed thera- py. A trial performed in patients considered unsuitable for high dose methotrexate due to age, renal impairment, performance status or comorbidities would prove partic- ularly challenging to perform.
CASP analysis
For the 14 studies included within the systematic review, a CASP analysis was performed. Cohort studies were scored as moderate in three studies.24,30,37 These included 2 of the 3 post hoc analyses performed from large prospective randomised clinical trials24,30 and scored mod- erate to low in the remaining 11 studies. The key reasons for the low quality rating scores included: a) retrospec- tive, single centre data; b) low event numbers with unad- justed analyses; c) variable indications and IT prophylaxis regimens used; d) variable histologies included.
Strengths and limitations
No previous systematic review has explored the poten- tial benefit of stand-alone IT prophylaxis in rituximab or obinutuzumab exposed DLBCL patients. To ensure trans- parency and to facilitate scrutiny of this review, a system- atic protocol was registered and published prior to con- ducting the review, which was undertaken according to best practice and reporting guidelines. Each stage of the review process was independently double-screened, and any discrepancies discussed among the research team until consensus was reached. One limitation of the search strategy was restricting the search to publications in English; however the search expansion strategy ensured a comprehensive and sensitive review. The quality of evi- dence reviewed was limited by the small number of CNS relapse events in many of the studies. A number of the studies highlighted were initially powered for other means i.e. the primary end point of the specific clinical trial. As such, within trial GOYA and R-CHOP 14 versus 21 populations, for example, there was a heterogenous approach to the use of IT prophylaxis with variable crite- ria for delivery, dosing schedules and chemotherapy used.
Recommendations
On the basis of the evidence analysed within this sys- tematic review, there are no convincing published data, adjusted for well described confounding variables, that clearly suggest that stand-alone IT chemotherapy CNS prophylaxis reduces the risk of CNS relapse in patients treated with anthracycline-based front-line immunochemotherapy using an anti-CD20 antibody. It must also be recognised however that no individual study
provides strong evidence for lack of benefit of stand-alone IT prophylaxis. The nature of the evidence analysed is limited by the individual study designs, the low event rate, variable prophylaxis protocols used, the retrospec- tive nature of studies, some evidence for lack of compli- ance and the absence of control groups. Although the quality of evidence precludes firm recommendations, the authors suggest that the available evidence should lead to judicious use of stand-alone IT chemoprophylaxis. Our conclusions relate primarily to patients receiving R- CHOP immunochemotherapy and intentionally do not reference the evidence for high dose anti-metabolites. There was only a single study that studied DA-EPOCH-R and as such conclusions related to IT usage in that setting are more limited. The focus of this systematic review was DLBCL histology, and as such we intentionally have made no conclusions regarding the role of IT prophylaxis in other histologies such as Burkitt lymphoma or indeed specific subgroups of DLBCL such as double hit lym- phoma or HIV-associated DLBCL.
Conclusions
There is no strong evidence to support the use of stand- alone IT chemotherapy prophylaxis for patients treated with anthracycline-based chemotherapy in the rituximab era. Conversely, the strength of evidence suggesting a genuine lack of evidence is also weak. The majority (70%) of CNS relapses occurring in anti-CD20 antibody exposed patients treated in our systematic review involved parenchymal tissue. No study within the sys- tematic review reported a toxicity analysis of intrathecal chemotherapy and as such few meaningful conclusions can be made regarding the morbidity of IT prophylaxis from these series. The quality of the data is relatively weak to poor. Although some of the studies included rel- atively large numbers of patients, the absolute number of CNS relapse events limits the power to perform high quality multivariable analysis or adjusted analysis. As such, we conclude that there is little evidence for the ben- efit of stand-alone IT CNS prophylaxis in preventing CNS relapse in DLBCL-treated patients using anthracycline- based immunochemotherapy.
Acknowledgments
We thank Nia Roberts and Tatjana Petrinic, librarians at Oxford’s Bodleian Healthcare Library for their support with the search strategy for this review. Views expressed are those of the authors and not necessarily those of the NHS or the NIHR or the United Kingdom’s Department of Health.
Funding
GPC is supported by the NIHR Biomedical Research Centre, based at Oxford University Hospitals Trust, Oxford. The views expressed are those of the author(s) and not necessarily those of the NHS, Oxford University Hospitals NHS Foundation Trust, the NIHR Biomedical Research Centre or the Department of Health.
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