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T.A. Eyre et al.
Table 4. Recommendations for central nervous system prophylaxis within individual studies.
Reference: author, year, journal
Boehme et al., Blood, 200930
Shimazu et al., Int J Hematol 200931 Villa et al., Ann Oncol 200925
Tai et al., Ann Oncol 20112
Guirguis et al., Br J Haematol 201217
Kumar et al., Cancer, 201229
Song et al., Medicine (Baltimore), 201532
Tomita et al., Leuk Lymphoma, 201533
Cai et al., Chin J Cancer, 201634
Kanemasa et al., Ann Oncol 201628
Gleeson et al., Ann Oncol201727
Malecek et al., Am J Hematol 201726 Wudhikarn et al., Ann Hematol 201735
Klanova et al., Blood, 201924
CNS: central nervous system; ECOG: Eastern co-operative oncology group; PS: performance status, LDH: lactate dehydrogenase; DLBCL: diffuse large B cell lymphoma.
Recommendations for CNS intrathecal prophylaxis
Mandatory for ‘high risk’ sites
Discretion of treating physician,
but recommendations provided Discretion of treating physician, but recommendations provided
Discretion of treating physician.
Per ‘high-risk’ DLBCL according
to our locally published haematology site group
Discretion of treating physician. Discretion of treating physician,
but recommendations provided
A written strategy prior to the study, even if it not necessarily followed.
Discretion of the local investigator but recommendations provided Discretion of treating physician, but recommendations provided Discretion of the local investigator but recommendations provided Discretion of treating physician. Not reported
High risk disease sites or clinical features for which CNS prophylaxis recommended
Bone marrow, testes, upper neck or head including
nasal sinuses, orbital, oral cavity, tongue, and salivary glands.
Nasal sinuses, testis or vertebra
Pre-2002: bone marrow or peripheral blood involvement, epidural, advanced-stage testicular lymphoma, or sinus
involvement. After 2002, only sinus involvement. Not defined
Unavailable
Not defined
Given to patients with high intermediate/high IPI
or involvement of testis, breast, nasal cavity or orbit. In general, ≥1 risk factor: LDH ≥2 ULN; bulk ≥10 cm; ECOG PS 2; or involvement of the bone marrow, skin, testis, nasal/ paranasal tissue, bone or breast.
High level of Ki-67; and involvement
of the testis, breast, or kidney.
Testis, breast, paranasal sinuses, or bone marrow.
Bone marrow, peripheral blood, nasal/paranasal sinuses, orbit and testis. Not defined
Not defined
Discretion of treating physician.
Not defined
may not be comparable between studies, with just two making it clear that they treated deaths as a competing risk31,35 (Shimazu et al. and Wudhikarn et al.) and none of the studies appearing to consider systemic only relapse as a competing risk, even those that did not include CNS relapse post systemic relapse as an event.
Perhaps the most convincing evidence of the lack of efficacy of IT CNS prophylaxis in the rituximab era comes from the RICOVER-60 trial.30 All patients considered high-risk (infiltration of bone marrow and testes or sites in the upper neck or head), should have been treated with IT MTX. There was significant non- compliance to this rule with only 57.1% receiving CNS prophylaxis. This allowed Boehme and colleagues to per- form as subgroup analysis. They found that, in a multi- variable Cox model including IPI factors, there was a sig- nificant interaction between IT MTX exposure and ritux- imab exposure (RR=6.1), with risk of CNS relapse signif- icantly reduced with IT MTX in the CHOP group but with no difference seen in the R-CHOP group. The effect of rituximab was significant regardless of IT MTX. This is a non-randomised comparison in a small subset of patients (47-67 per group and only six events in the R- treated cohort) who were all aged over 60 years and not all had DLBCL. However, it is the only paper to provide
any evidence of a differential effect of IT MTX in ritux- imab-treated versus non-rituximab treated patients, which is not simply based on lower rates of CNS relapse when compared to data from the pre-rituximab era.
Although none of these papers show any evidence of a benefit in giving CNS IT prophylaxis in either univariable analyses or multivariable analyses, they are also all unable to convincingly rule one out due to small numbers of events and the confounding caused by the indications for CNS prophylaxis.
Subsequent to the completion of the systematic review, we have recently published outcomes of 690 elderly patients (≥70 years) treated with R-CHOP (full or dose attenuated).38 Our results are consistent with those present- ed within the systematic review but suffer from similar issues of small event number and the risk of confounding factors. We also showed no clear benefit for stand-alone IT prophylaxis although we found that IT prophylaxis was associated with an increased risk of infection-related hos- pital admission during R-CHOP (odds ratio vs. no prophy- laxis) 2.20 (95% CI: 1.31-3.67; P=0.01).
The only real method to formally answer this question is with a randomised clinical trial of IT CNS prophylaxis vs no IT CNS prophylaxis in patients deemed unsuitable for high dose MTX. Unfortunately, due to the low event
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