ReviewDiagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology
Introduction
Primary CNS lymphomas are extranodal, malignant non-Hodgkin lymphomas of the diffuse large B-cell type that are confined to the brain, eyes, leptomeninges, or spinal cord, in the absence of systemic lymphoma. Primary CNS lymphomas are estimated to account for up to 1% of all lymphomas, 4–6% of all extranodal lymphomas, and about 3% of all CNS tumours.1 After a continuous rise in the incidence of primary CNS lymphoma during the 1980s and 1990s, epidemiological data in high-income countries show a decrease in incidence, particularly among young patients with AIDS.2 By contrast, the incidence of primary CNS lymphoma continues to rise in elderly patients, who represent most patients in immunocompetent populations.3, 4, 5
Although the prognosis of primary CNS lymphoma remains poor, it has substantially improved in the past two decades as a result of better treatment strategies with a curative aim. However, treatment of this disease remains challenging because, despite high chemosensitivity and radiosensitivity, remissions are frequently of short duration. The blood–brain barrier limits the access of many drugs to the CNS. Furthermore, elderly patients are at especially high risk for the development of severe neurotoxic effects related to treatment.
Optimum treatment recommendations result mainly from retrospective series or single-arm phase 2 studies. Only three completed randomised trials are available for primary CNS lymphoma: one phase 3 and two phase 2 trials.6, 7, 8 The objective of this guideline is to provide clinicians with evidence-based recommendations and consensus expert opinions for the management of patients with this disease. The guidelines focus exclusively on immunocompetent populations, which represent most patients. Primary CNS lymphoma in immunodeficient patients and rare, indolent, low-grade lymphomas that occur mainly in the CNS have a distinct pathogenesis with separate diagnostic and therapeutic implications, and will be subject to specific guidelines, beyond the scope of this Review.
Section snippets
Search strategy and selection criteria
The task force was established in 2013 under the auspices of the European Assocation for Neuro-Oncology and represents European-based medical experts from eleven countries. The task force included specialists in the management of primary CNS lymphoma—including neurologists, haematologists, medical oncologists, neurosurgeons, pathologists, ophthalmologists, and radiation oncologists. Based on best available evidence from literature review, the writing group (EB, JB, AFH, KH-X, MP, RR, US, TS,
General recommendations
Consensus statements and recommendations were given for the following aspects of primary CNS lymphoma: pathology, genetics, clinical presentation, diagnostic confirmation, neuropathological changes of corticosteroid-treated primary CNS lymphoma, neuroimaging, cerebrospinal fluid analyses, vitreous analyses, staging, prognostic factors, response criteria to treatment, and treatment-related neurotoxic effects. Consensus statements and recommendations for the general approach to patients with
Surgery
Although few data are available in the scientific literature, surgery has traditionally been deemed to have no role in the treatment of primary CNS lymphoma. This widely adopted opinion is based on small retrospective series, the results of which suggest no clear benefits in the outcome of surgical resection when used as a sole treatment, compared with supportive care (class IIIb)9 and compared with evidence from biopsy samples from patients who received postoperative chemotherapy or
Systemic chemotherapy
The CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen routinely used for widespread non-Hodgkin lymphomas induces responses of brief duration in patients with primary CNS lymphoma. CHOP added to radiotherapy has likewise not improved patient survival in prospective trials (class IIb).14, 15, 16 This inefficacy is probably because the metabolite of cyclophosphamide, phosphoramide mustard, and doxorubicin are not able to cross the blood–brain barrier and therefore eradicate
Intrathecal chemotherapy
Chemotherapeutic drugs given intrathecally have not been prospectively studied. Therefore, their clinical effectiveness in primary CNS lymphoma is controversial. Results of three retrospective studies30, 31, 32 showed that patients given high-dose methotrexate did not benefit from the additional treatment with methotrexate and cytarabine given intrathecally (class IIIb). By contrast, results from two consecutive single-arm trials33, 34 using the same systemic polychemotherapy regimen suggested
Rituximab
The anti-CD20 antibody rituximab has poor CNS penetration because of its large size. Therefore, the highest concentration and resultant efficacy of rituximab probably occurs during the early treatment phase when the integrity of the blood–brain barrier is reduced at the location of the contrast-enhancing tumours. The effect of rituximab when used as monotherapy in patients with primary CNS lymphoma was assessed in a study in which 12 patients with refractory or relapsed primary CNS lymphoma
Radiotherapy
Because of the microscopically diffuse and multifocal nature of primary CNS lymphoma, radiotherapy is used to target the whole brain and the eyes. Despite a high response rate of around 50%, radiotherapy, when used alone, does not provide a substantial survival benefit in patients with primary CNS lymphoma, with a median overall survival of 10–18 months and 5-year overall survival of 5%. A phase 2 trial44 that used radiotherapy as first-line treatment was done by the Radiation Therapy Oncology
Consolidation radiotherapy
Although not formally compared in a randomised trial, results of several studies18, 45, 46, 47, 48, 49, 50, 51, 52, 53 suggest that the combination of high-dose methotrexate with radiotherapy is better than radiotherapy alone, in terms of increasing the proportion of long-term survivors (5-year survival 20–50%) (class IIb, class IIIa, class IIIb) and overall survival by two to four times (median 30–72 months). By contrast with extracerebral non-Hodgkin lymphoma, the optimum dose of
Reduced-dose consolidation radiotherapy
Since not giving consolidation WBRT for patients with complete response to chemotherapy is controversial, reduced-dose WBRT is an alternative approach, particularly for patients younger than 60 years who are at a lower risk of developing neurotoxic effects. In a subset analysis65 from a phase 2 trial that included 25 patients younger than 60 years who achieved a complete response after initial chemotherapy and received either 45 Gy or 30·6 Gy as consolidation treatment, patients who received
High-dose chemotherapy, myeloablative conditioning, and autologous stem-cell transplantation
High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is the standard treatment for chemosensitive systemic relapsing diffuse large B-cell lymphomas. However, there is only one multicentre phase 2 trial67 investigating this treatment in patients with relapsed or refractory primary CNS lymphoma, in which a thiotepa, busulfan, cyclophosphamide conditioning regimen was used, followed by ASCT. 27 (63%) of 43 patients completed the full HDC-ASCT procedure, of whom 60% achieved
Elderly patients
Although the definition of elderly is non-uniform within the literature, studies that have assessed prognostic factors have consistently correlated older age (over 50 or 60 years) with poorer outcome (appendix). Furthermore, older age (greater than 60 years) was associated with a higher risk of neurotoxic effects of chemoradiation (appendix). Therefore, 60 years of age was used as a cutoff to define the elderly population in most of the studies that we examined.
Four prospective studies37, 64, 77
Salvage treatment
About a third of patients with primary CNS lymphoma will present with disease that is refractory to first-line treatment and half of responders will relapse despite the high proportion of patients who respond to initial treatment. The prognosis of progressive or relapsed primary CNS lymphoma is poor, with few treatment options. Salvage treatments for patients with relapsed or refractory primary CNS lymphoma depend on age, performance status, site of relapse within the CNS, previous treatments,
Conclusion
Our guidelines represent the state of knowledge at the time of writing. The European Association for Neuro-Oncology website will provide future updates on these guidelines.
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