Table 2.

Treatment recommendations (adapted and updated from the previous EANO guidelines. Hoang-Xuan et al, Lancet Oncol 16:e322-e332, 2015¹⁷)

Surgery	Reference
Surgical resection may be considered in patients suffering from a large space occupying lesion with acute symptoms of brain herniation to reduce rapidly intracranial pressure (Good practice point).
Limited and only retrospective data exist regarding surgical resection or biopsy in an unifocal and resectable lesion suspected of PCNSL. No consensus was met in the panel for a recommendation.	19–21
Induction chemotherapy, immunochemotherapy
HD-MTX is the drug of choice in PCNSL and chemotherapy should include MTX at HD (≥3 g/m2) both to cross the BBB and yield cytotoxic levels in the CSF. It should be delivered in 2–3 h iv infusions for a minimum of 4–6 injections and at intervals that should not exceed 2–3 weeks (level B).	22
Combination of HD-MTX with other chemotherapeutic agents improves the response and progression-free survival rates with respect to HD-MTX alone (Level B).	22
Chemotherapeutic agents to combine with HD MTX should be selected among active drugs known to cross the blood-brain-barrier, such as HD cytarabine and combinations used in large and/ or randomized prospective trials have to be preferred (Level B).	7,9,11,14,23
HD-MTX-based chemotherapy is feasible in elderly patients with adequate performance status and renal function (Level B).	8,24–26
Most combinations addressed in large clinical trials include HD-MTX associated with an alkylating agent (procarbazine, carmustine, temozolomide, and thiotepa) (Level B).	7,9,11,14,23,27
The value of IT chemotherapy is unclear. IT chemotherapy (intralumbar or preferably intraventricular through an Ommaya reservoir) can be proposed in case of documented meningeal involvement with insufficient response to iv HD MTX (>3g/m2) based chemotherapy (Good Practice Point).
Conflicting data exist regarding iv Rituximab combined with a chemotherapy regimen in PCNSL. No consensus was met in the panel for recommendation (Level B).	7,9,12,28
Consolidation treatment
Radiotherapy
WBRT and the combination of HD-MTX with WBRT expose patients to an increased risk of neurotoxicity (Level A).	29–32
The role of consolidation WBRT following HD-MTX based chemotherapy remains debated and, if considered, the optimal dose is not yet defined. Risk of neurotoxicity and alternative consolidation options (eg, ASCT) or omitting consolidation should be weighed in the individual patient (Level B).	10–13,33
Reduced dose WBRT consolidation (23.4–30 Gy in 1.8–2.0 Gy fractions) in CR patients is a therapeutic option that is currently being investigated in randomized trials. (Good Practice Point).	14
In patients with progressive or significant residual disease after primary chemotherapy, a total dose of 36–40 Gy with a 1.8–2 Gy dose/fraction appears advisable. With such doses, there is no evidence to add a focal boost on the enhancing lesions (Good Practice Point).
In patients >60 years, the risk of delayed neurotoxicity, after WBRT especially if following HDMTX, is unacceptably high and WBRT should be avoided in these elderly patients (Level B).	29–32
Consolidation treatment
High dose chemotherapy with autologous stem cell transplantation (HDC/ASCT)
HDC/ASCT as consolidation is an effective treatment for younger (age up to 65–70) patients with newly-diagnosed PCNSL, though risk of acute toxicity should be taken into account (Level B).	10–13
HDC/ASCT is an effective consolidation treatment with efficacy at least comparable to that of WBRT	10–13
High-dose thiotepa-based conditioning chemotherapy should be preferred over the BEAM regimen (Level B).	34,35
Non myeloablative chemotherapy
The value of nonmyeloablative consolidation chemotherapy and maintenance chemotherapy is currently under investigation in clinical trials (Good Practice Point)	36,37 NCT02531841, NCT01511562 NCT03495960 NCT02313389
Primary vitreoretinal lymphoma (PVRL)
HD-MTX-based chemotherapy seems to improve OS in PVRL (level C), though local relapses occur frequently. Whether the addition of local treatment reduces local relapses is uncertain.	38
Local treatment (intravitreal immuno/chemotherapy or ocular RT) is a valid approach for patients with systemic chemotherapy contraindications or for elderly patients with relapsing intraocular disease (Good Practice Point).	39,40
Patients with concurrent intraocular and CNS lymphoma should be treated no differently from other patients with PCNSL (Good Practice Point).
If consolidation WBRT is proposed, it should include both eyes (Good Practice Point).
Refractory and relapsed PVRL should be treated according to the patients’ characteristics and prior treatments. Treatments include intravitreal injections of MTX, focal radiotherapy, WBRT, systemic chemotherapy, targeted treatment and HDC/ASCT (Good Practice Point).
Salvage treatment
Patients with relapsed/ refractory PCNSL should be enrolled into clinical trials (Good Practice Point).
HDC/ASCT is a valid therapeutic option in patients aged <70 years with chemosensitive relapsing PCNSL especially in patients without prior ASCT (Level B).	41–43
Salvage WBRT may be proposed in radiotherapy-naïve patients; it may be preceded by induction chemotherapy (Good Practice Point).	44,45
Salvage chemotherapy can be delivered as induction therapy before WBRT or HDC/ASCT, or as exclusive treatment in patients not eligible for these therapies.	46,47
MTX re-challenge should be considered in recurrent PCNSL patients who previously responded to HD MTX (Level C).	48–50
Isolated extra-CNS relapses should be managed with anthracycline-based chemotherapy followed or not by HDC/ASCT (Good Practice Point).
Bruton Tyrosine kinase inhibitors, imids, immune checkpoint inhibitors and CART have shown clinical activity as single agents in relapsing PCNSL and may be considered in salvage treatments.	51–57
HIV related patients
Initiation, if not yet done, or modification of ART should be done in conjunction with the infectious disease specialist (Good Practice Point).	58,59
Patients with adequate performance status (arbitrarily defined as KPS≧60) and able to tolerate it (adequate renal function, absence of pleural or abdominal effusion) should be offered treatment with HD-MTX based chemotherapy. Polychemotherapy should be preferred to MTX monotherapy (Good Practice Point).	60–62
In HIV-related PCNSL patients the risk of delayed neurotoxicity from WBRT is significant and radiation should therefore be avoided (Good Practice Point).
If HD-MTX based regimens cannot be considered, combination of ART with other chemotherapeutic agents or with palliative WBRT may be an alternative (Good Practice Point).
Combinations of chemotherapy with antiviral treatments against EBV, rituximab, immune check point inhibitors or targeted therapies need further evaluation in this population (Good Practice Point).
PCNS-post-transplant lymphoproliferative disorder (PTLD) patients
Immunosuppression should be reduced to the lowest level possible, in close collaboration with transplant specialists (Good Practice Point). Further antitumor treatment needs to be tailored to patient’s age and performance status, and transplanted organ functioning (Good Practice Point).	63,64
Extrapolated from its use in systemic PTLD, systemic chemotherapy including HD-MTX based regimens should be considered in order to increase response rates and reduce the high risk of relapse (Good Practice Point).
On the basis of its efficacy in systemic PTLD, treatment with rituximab might also be considered when possible, especially in patients with underlying renal failure that precludes usage of HD-MTX (Good Practice Point)
There is lack of evidence supporting treatment with antiviral agents, and other therapeutic strategies need further evaluation in this population (Good Practice Point).