Definitions for the quality of the evidence (A–C) and strength of recommendations (strong [grade 1], weak [grade 2]) are given at the end of the "Major Recommendations" field.
Defining High-risk Groups
Central nervous system (CNS) directed therapy should be offered to patients with high-grade non-Hodgkin lymphoma (NHL) AND either:
- A raised (above institutional upper limit of normal [ULN]) serum lactate dehydrogenase (LDH) AND more than one extra-nodal localisation (noting that the spleen is not regarded as an extra-nodal site and also, two lesions within the same system [e.g., bilateral lung lesions] are regarded as a single extra-nodal localization).
- Anatomical sites: testicular, breast and epidural
(Level of evidence: 1B)
Use of Intrathecal (IT) Prophylaxis
All patients requiring CNS-directed therapy should receive 3 to 6 doses of IT methotrexate (MTX) (flat dose of 12–15 mg each dose) during primary therapy, which should be commenced as early as practical during treatment and given at least once per cycle (Level of evidence: 2C).
CNS Prophylaxis with Systemic Chemotherapy
- Systemic high-dose methotrexate (HD-MTX), given at a dose of 3–5 g/m2, with folinic acid rescue, can also be considered as additional CNS-directed therapy in high risk patients. This should be given strictly in line with published schedules and considered in the context of performance status and renal function. The benefit of the additional or alternative use of HD-MTX must be carefully balanced against the risk of toxicity and the resource utilisation consequences of the schedule (Level of evidence: 2B).
- There are no data to confirm that HD-MTX alone can replace IT therapy and if this strategy is followed it is essential that the practice is carefully audited (Level of evidence: 2C).
- For the delivery of intravenous HD-MTX, the use of rapid infusion schedules can be recommended, although the authors acknowledge lack of consensus on this issue (Level of evidence: 2B).
- If given without IT chemotherapy, systemic prophylaxis should be commenced as early as practical during treatment without compromising delivery of rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) chemotherapy (Level of evidence: 1B).
- Further studies to determine the benefit of systemic and/or IT therapy for the prevention of secondary CNS lymphoma are warranted (Level of evidence: 2C).
- The use of systemic agents other than HD-MTX as CNS prophylaxis in addition to or instead of IT chemotherapy and/or HD-MTX have not been shown to be beneficial. Their use is therefore not recommended except where they form part of an established multi-agent regimen or as part of a clinical trial (Level of evidence: 1C).
Recommendations Specific to Primary Testicular Lymphoma
Patients with primary testicular lymphoma should receive 4 or more doses of IT MTX during primary chemotherapy as per the International Extranodal Lymphoma Study Group (IELSG) protocol (Level of evidence: 2B).
Summary and Recommendations
Given that the evidence supporting any single approach is less than strong, it is recommended that patients should be entered in to prospective randomised controlled trials where available, and, in all other settings, prospective audit of practice should be performed to support the approaches taken. Such audit should record not only the nature of prophylaxis administered, but also the type of CNS relapse and if there is any evidence of concurrent systemic relapsed disease (Level of evidence: 2C).
Quality of Evidence
The quality of evidence is graded as high (A), moderate (B) or low (C). To put this in context it is useful to consider the uncertainty of knowledge and whether further research could change what is known or is certain.
(A) High Further research is very unlikely to change confidence in the estimate of effect. Current evidence derived from randomised clinical trials without important limitations.
(B) Moderate Further research may well have an important impact on confidence in the estimate of effect and may change the estimate. Current evidence derived from randomised clinical trials with important limitations (e.g., inconsistent results, imprecision – wide confidence intervals or methodological flaws – e.g., lack of blinding, large losses to follow up, failure to adhere to intention to treat analysis), or very strong evidence from observational studies or case series (e.g., large or very large and consistent estimates of the magnitude of a treatment effect or demonstration of a dose-response gradient).
(C) Low Further research is likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate. Current evidence from observational studies, case series, or just opinion.
Strength of Recommendations
Strong (grade 1): Strong recommendations (grade 1) are made when there is confidence that the benefits do or do not outweigh harm and burden. Grade 1 recommendations can be applied uniformly to most patients. Regard as 'recommend'.
Weak (grade 2): Where the magnitude of benefit or not is less certain a weaker grade 2 recommendation is made. Grade 2 recommendations require judicious application to individual patients. Regard as 'suggest'.