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T.A. Eyre et al.
prophylaxis allowing for a univariable analysis comparing these groups. They also found no difference in CNS relapse risk, but again this would rely on how well matched the groups were and whether this was enough to overcome the issues with confounding.
Analyses, including which factors were or were not
included in multivariable analyses, were often poorly described with some papers using inappropriate methods which did not allow for time31 (Shimazu et al.) when com- paring risk factors, and with a lack of consistency in deal- ing with competing risks (systemic only relapse or death from other causes). This means the cumulative incidences
Table 3B. Studies reporting an efficacy analysis of stand-alone intrathecal prophylaxis in front line diffuse large B-cell lymphoma in rituximab era
Reference: N author,
journal, year
Guirguis et al. 214 Br J Haematol 201217
Kumar et al. 989 Cancer
201229
Data set: type and years
Retrospective, single center; 1999-2005
Prospective
NCCN NHL database, multi- center; 2001-2008
Study inclusion
1st line R-chemotherapy
CNS Relapse
% receiving IT prophylaxis
Median time to CNS relapse (range/95% CI given as available)
17 months (range 6–35)
12.8 months
Cumulative incidence
of CNS relapse (95% CI provided where reported)
Not reported; Overall rate: 3.7%
Not reported;
overall rate: 2.5 year 2%(95CI:1.1-2.9%)
Site of CNS relapse
5 parenchymal; 1 both;
2 leptomeningeal
Evidence CASP
of IT CNS Score prophylaxis
effectiveness?
≥16 years with DLBCL ≥1 cycle of R-CHOP; including transformed indolent NHL
No age
limit defined; untreated DLBCL
No age limit defined; untreated DLBCL
18-80 years
with untreated DLBCL achieving CR1
R-CHOP (100%)
R-CHOP-21
(100%)
Total: 8 Isolated: 6 Concurrent: 2 (post systemic)
Total: 20
Isolated: 14
Concurrent:6 prophylaxis),
most IT (71.8%)
25.6% (46/180) IT MTX
12% (40/322):
4.7% IT MTX prophylaxis
11.8%
Use of IT prophylaxis
did not appear
to decrease CNS relapse on UVA (P=0·994). Only factors with P<0.1 in UVA included in MVA.
2
2
(117/989 CNS
13 parenchymal Overall rates:
only. 7 ‘not prophylaxis (10.9%) parenchymal vs.nil(2.1%),P=0.007. only’. In ≥2 predefined
high-risk features,
CNS relapse not differ significantly: prophylaxis (5.4%) vs. nil (1.4%; P=0.08).
Propensity matched population (n=230) “No difference in OS or PFS” according
to receipt of CNS prophylaxis. Discussion says “not associated with a reduction in CNS relapse or OS”.
Song et al. 180
Medicine (Baltimore) single center;
201532
protective effect on leptomeningeal UVA(HR2.31,range0.73-7.25)
Tomita et al. Leuk Lymphoma 201533
P=0.15: higher in those receiving IT CNS prophylaxis).
Unclear if IT prophylaxis was included in MVA analyses but not reported to be significant in MVA.
7 parenchymal; 3-year risk 8.7% in IT 3
3 both; prophylaxis vs. 2.9% 1 leptomeningeal nil (P=0.14).
IT MTX not associated
with CNS relapse on MVA (HR 0.78, 95% CI: 0.18-3.42; P=0.74) Subgroup analysis for high risk patients only showed “no significant difference”
Retrospective, 2009-2015
Retrospective,
multi-center; 2003-2009
R-CHOP (100%)
R-CHOP
(100%)
Total: 12 Isolated: 12 Concurrent: 0
Total: 11
Isolated: 11 Concurrent: 0
Not reported
8.2 months
Not reported; overall rate: 6.7%
3-year:
3.6%
6 parenchymal; 6
IT prophylaxis 2 showed no
322
4 IT MTX and (range 3.5–34.0) HC after CR
was achieved
*two patients received high dose methotrexate. **five CNS involvement at diagnosis excluded. R = in RCHOP subgroup. ***studies added after initial and post-systematic review scoping. NCCN: National Comprehensive Cancer Network; CNS: central nervous system; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; RDA-EPOCH: rituximab plus dose adjusted etopo- side, prednisolone, vincristine, cyclophosphamide, doxorubicin; O-CHOP: obinutuzumab, cyclophosphamide, doxorubicin, vincristine, prednisolone DLBCL: diffuse large B-cell lymphoma; NHL: non- Hodgkin lymphoma; ASCT: autologous stem cell transplantation; HGT: high grade transformation; CLL: chronic lymphocytic leukaemia; FL: follicular lymphoma; GZ: gray zone; CR1: first complete remis- sion; PMBCL: primary mediastinal B-cell lymphoma; IPI: international prognostic index; IT: intrathecal; MTX: methotrexate; HD: high dose; ara-C: cytarabine; HC: hydrocortisone; HR: hazard ratio; CI: con- fidence interval; UVA: univariable analysis; MVA: multivariable; N/R: not reported; IQR: interquartile range; RR: risk ratio; OS: overall survival; PFS: progression-free survival.
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