DÄ internationalArchive25/2018The Diagnosis and Treatment of Primary CNS Lymphoma

Review article

The Diagnosis and Treatment of Primary CNS Lymphoma

An Interdisciplinary Challenge

Dtsch Arztebl Int 2018; 115(25): 419-26; DOI: 10.3238/arztebl.2018.0419

von Baumgarten, L; Illerhaus, G; Korfel, A; Schlegel, U; Deckert, M; Dreyling, M

Background: Primary central nervous system lymphoma is a diffuse large B-cell lymphoma with exclusive manifestation in the central nervous system (CNS), leptomeninges, and eyes. Its incidence is 0.5 per 100 000 persons per year. Currently, no evidence-based standard of care exists.

Methods: This review is based on pertinent publications (2000–2017) retrieved by a selective search in PubMed.

Results: The clinical and neuroradiological presentation of primary CNS lymphoma is often nonspecific, and histopathological confirmation is obligatory. The disease, if left untreated, leads to death within weeks or months. If the patient’s general condition permits, treatment should consist of a high-dose chemotherapy based on methotrexate (HD-MTX) combined with rituximab and other cytostatic drugs that penetrate the blood–brain barrier. Long-term survival can be achieved in patients under age 70 by adding non-myeloablative consolidation chemotherapy or high-dose chemotherapy with autologous stem cell transplantation (HD-AST) to the induction therapy. Clinical trials comparing the efficacy and toxicity of these two treatment strategies are currently underway. Consolidation whole-brain radiotherapy is associated with the risk of severe neurotoxicity and should be reserved for patients who do not qualify for systemic treatment. Some 30% of patients are refractory to primary treatment, and at least 50% relapse. In patients who are still in good general condition, relapse can be managed with HD-AST. Re-exposure to conventional HD-MTX–based polychemotherapy is another option, if the initial response was durable. The 5-year survival rate of all treated patients is 31%, according to registry data.

Conclusion: Current recommendations for the treatment of primary CNS lymphoma are based on only a small number of prospective clinical trials. Patients with this disease should be treated by interdisciplinary teams in experienced centers, and preferably as part of a controlled trial.

Primary central nervous system lymphomas (PCNSL) are aggressive brain tumors. They are a form of extranodal non-Hodgkin lymphoma (NHL) with exclusive manifestation in the brain, leptomeninges, and spinal cord. Ocular involvement (vitreoretinal lymphoma) is seen in 10% of patients and leptomeningeal tumor spread is found in about 15% of patients (13). Only highly proliferative, diffuse large B-cell lymphomas without systemic manifestation are categorized as PCNSL according to the most recent WHO classification (4).

PCNSLs account for 2% to 4% of all primary brain tumors (5). The incidence is about 0.5/100 000 persons per year, with over-65-year-olds being more commonly affected and a rising incidence in this age group. Men are more commonly affected than women (sex ratio 1.35 : 1) (6, 7). Immunosuppression is one of the risk factors for PCNSL; in this situation, PCNSL is typically associated with Epstein–Barr virus (EBV) (8).

Even though the prognosis of PCNSL has significantly improved over the last decades (median survival improved from 2.5 to 26 months) (7) and intensive treatments can achieve long-term remission in young patients, no evidence-based standard of care exists. Treatment recommendations are based on retrospective case series and few larger prospective studies. Among older patients, highly effective treatments are often associated with serious adverse events and the prognosis in this age group is significantly less favorable with median survival rates between 7 to 19 months, regardless of treatment (7, 9).

PCNSL is a rare cancer that is easily overlooked in the differential diagnosis and that is managed differently from other brain tumors. We therefore set out to provide a summary of the currently available evidence on its diagnosis and treatment.

Methods

We performed a PubMed search for the years 2000–2017, using the search algorithm: “primary central nervous system lymphoma“ AND/OR “pcnsl“; filters activated: “meta-analysis“, “systematic reviews“, “randomized controlled trial“, “guideline“, “clinical trial“, “abstract“, “humans“, “English“, “German“. The search yielded 1175 results. After evaluating the abstracts (LB), 85 high-quality sources, including some older articles, were selected as relevant for our paper and included in our analysis on a consensus basis with the other authors.

Clinical signs and symptoms

The signs and symptoms of PCNSL are nonspecific and rapidly progressive. Frequently (50–70% of cases), patients present with personality changes and cognitive impairments; in addition, 50% of patients experience focal neurological deficits. Signs and symptoms of increased intracranial pressure are less commonly observed at the time of diagnosis. These include headache, nausea, decreased alertness, seizures or, in case of vitreoretinal involvement, ocular symptoms (vitreous floaters, visual impairment).

Although leptomeningeal involvement is usually asymptomatic, it may trigger headache, neck or back pain and radicular symptoms (1, 8).

Imaging studies

Contrast-enhanced cranial magnetic resonance imaging (cMRI) is the most useful imaging modality (2, 10); however, nonspecific findings are not uncommon. It reveals unifocal or, in 35% of patients, multifocal, mainly supratentorial periventricular space-occupying lesions. Contrast enhancement is intense and generally homogeneous, but in 6% to 17% of patients inhomogeneous or missing (<2%) (10, 11). Typically, PCNSLs show significant diffusion restriction due to cell density and appear hypointense on T2-weighted imaging and iso-/hypointense on T1-weighted imaging (10, 11) (Figure 1). Regions of the brain with normal imaging morphology are usually also involved (12).

Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)
Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)
Figure 1
Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)

Differential diagnosis

Imaging alone does not allow reliable discrimination from other malignant brain tumors (CNS metastasis, malignant glioma) or space-occupying inflammatory lesions (multiple sclerosis, sarcoidosis, vasculitis), more rarely of infectious nature (abscess, opportunistic CNS infections and toxoplasma encephalitis, progressive multifocal leukoencephalopathy) (3, 10); therefore, PCNSL should always be included in the differential diagnosis of space-occupying lesions of the brain. Regression of clinical and imaging findings of variable duration (usually weeks to months, rarely longer) is observed under steroid treatment in 40% to 80% of cases (13, 14). The histological picture is dominated by nonspecific inflammatory and reactive changes, while tumor cells are missing (3, 15). Therefore, in patients with suspected PCNSL, steroid treatment should be avoided before biopsies for histology have been taken.

Confirmation of diagnosis

Histopathological confirmation of the diagnosis is essential and should be sought without delay, given the aggressive course of the disease (2). Confirmation is typically achieved by stereotactic serial biopsies which are associated with a low peri-interventional risk for the patient (16). In the case of leptomeningeal or ocular involvement, lymphoma cells can only rarely be detected in the cerebrospinal fluid (CSF) or in the vitreous body aspirate using (immuno)cytological, flow cytometric or molecular biology methods. However, the latter does not allow definite classification of the lymphoma according to the WHO criteria which require immunohistochemistry for confirmation (4). Currently, diagnostic biomarkers (proteins, RNA, DNA) in the cerebrospinal fluid do not play an established role in clinical routine (17).

In case steroid treatment was started before histology samples were obtained, the medication should be tapered off as soon as possible and then biopsies should be taken, because the diagnosis can only be established in 50% to 85% of patients under steroid treatment (15, 18). However, in case of persisting contrast enhancement and a rapidly progressive clinical course or threat to the patient’s life, the biopsy should not necessarily be delayed. In case of inconclusive findings, imaging follow-ups should be performed at close intervals to ensure that patients showing signs of progression undergo a re-biopsy (2).

Diagnosis

If a PCNSL is diagnosed, it is recommended to perform a standardized diagnostic evaluation (Figure 1) (19). In addition to spinal tap and ophthalmological examination, patients should undergo whole-body computed tomography (CT), or positron emission tomography CT (PET-CT), to rule out any systemic manifestation which is found in 10% of patients with cerebral lymphoma (20).

Additionally, the guidelines recommend a bone marrow aspiration to rule out bone marrow involvement, even though it does not change the treatment approach and may be dispensable (21).

Since more than 80% of patients with isolated vitreoretinal lymphoma develop CNS involvement over the course of the disease, cMRI and spinal tap should always be performed. In all patients, clinical chemistry testing (liver and kidney function tests), HIV testing, and hepatitis serology should be undertaken (19).

Histopathology and molecular pathophysiology

PCNSLs are mature B-cell lymphomas characterized by the expression of pan B-cell markers (CD20 and CD79a) (Figure 2) . Typically, they have a high proliferation rate (Ki-67 proliferative index >70%). The tumor cells express germinal center markers, predominantly BCL6 and MUM1/IRF4, but no plasma cell markers (CD38, CD138). They show light-chain restriction and express IgM, but not IgG (22). Frequently, B-cell receptor, Toll-like receptor and NF-κB signaling pathways are activated by changes in regulating genes (2325), stimulating the proliferation of lymphoma cells and preventing their apoptosis.

Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)
Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)
Figure 2
Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)

Prognosis

PCNSLs are highly malignant lymphomas with a median survival of weeks to months if treatment is only symptomatic; however, with anticancer therapy 5-year survival is 31% (6). Old age and poor clinical performance status have the strongest negative impact on prognosis; besides these, increased LDH levels, elevated CSF protein levels, and involvement of deeper brain regions are summarized in the International Extranodal Lymphoma Study Group (IELSG) score (Figure 2) and associated with a poorer prognosis. In low-risk patients, the 2-year survival is 80%, in moderate-risk patients 48%, and in high-risk patients only 15% (26).

Management

Available study data

PCNSL is sensitive to radiation and chemotherapy. Due to the low incidence of PCNSL, it is challenging to conduct large randomized studies. The current treatment recommendations are based on a few prospective treatment studies (Figure 2 and 3, Table). Given the heterogeneity of these studies, the small sample sizes, and the different endpoints, these studies are difficult to compare.

Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Figure 3
Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Histology of the primary CNS lymphoma (PCNSL)
Histology of the primary CNS lymphoma (PCNSL)
Figure 4
Histology of the primary CNS lymphoma (PCNSL)
Studies on the first-line treatment of primary CNS lymphoma
Studies on the first-line treatment of primary CNS lymphoma
Table
Studies on the first-line treatment of primary CNS lymphoma

Surgical resection

A subgroup analysis of the largest PCNSL study conducted so far indicated that tumor resection may improve progression-free survival in patients with single PCNSL lesions (27). However, involvement of deeper brain structures, which is a contraindication for resection, is associated with a poorer prognosis and this was not taken into account. Thus, there is no established role of resection in the management of infiltrative PCNSL (2, 28).

Pharmacotherapy

The first-line treatment for PCNSL is systemic chemotherapy. Chemotherapy regimens for the treatment of systemic lymphoma are ineffective in PCNSL as these drugs do not readily pass the blood–brain barrier. Based on the currently available data, the following treatment strategies can be recommended:

High-dose methotrexate (HD-MTX; ≥ 3 g/m² body surface, given as a 4-hour IV infusion) is the most effective single active agent and a key component of all combination regimens (2). Outside of clinical trials and without subsequent consolidation, HD-MTX–based polychemotherapy should be administered over at least 6 cycles together with adequate supportive care (hydration, urine alkalinization, leucovorin rescue, and monitoring of MTX levels) (2).

HD-MTX monotherapy achieves complete remissions in only 30% to 40% of patients and is comparatively well tolerated (moderate toxicity in <10% of cases) (29, 30). Adverse events include renal failure, blood count abnormalities, liver function abnormalities, pneumonitis, mucositis, and, in the long term, clinically relevant leukoencephalopathy, especially in older patients (31).

Combination chemotherapies with other cytostatic agents capable of crossing the blood–brain barrier, for example high-dose cytarabine (HD-AraC), thiotepa or ifosfamide, increase the overall response rate along with increased toxicity, while treatment-associated mortality remains unchanged (30, 32).

Treatment response to HD-MTX/AraC was further improved by adding rituximab, an anti-CD20 antibody, to the regimen; however, the effect was only significant if thiotepa (MATRIX protocol, [eTable 2]) was also added (overall response rate: 53% versus 74% versus 86%). Even though hematologic adverse events occurred more commonly in the intensified treatment arm, no significant differences were found with regard to the rate of serious infectious complications and treatment-associated mortality (33). However, a point of criticism is that only 54% of all patients reached the consolidation phase of the study. This was due to inadequate stem cell collection, prolonged adverse events, and neurological deterioration despite tumor regression, among others (34). The most commonly used protocols and currently recruiting studies are listed in the eSupplement and in eTable 1 and eTable 2.

Studies currently recruiting in Germany
Studies currently recruiting in Germany
eTable 1
Studies currently recruiting in Germany
Common treatment protocols with dosages
Common treatment protocols with dosages
eTable 2
Common treatment protocols with dosages

Radiotherapy

In the majority of patients, percutaneous fractionated whole-brain radiotherapy leads to fast and usually complete remission; however, recurrences occur early. Median survival is only 12 to 18 months (35). With combined chemoradiotherapy, tumor control can be significantly improved and—in prospective studies—median survival times of 31 to 90 months have been achieved (30, 3640, e1). However, neurotoxicity occurring over a time course of months to years has emerged as a very serious problem. Affected patients show marked leukoencephalopathy, leading to cortical/subcortical atrophy and, in some cases, to severe cognitive deficits, gait abnormalities, incontinence, and need for nursing care (e2). The 5-year incidence of overt neurotoxicity is 12% to 65%; it is associated with mortality rates of 16% to 66% and primarily affects patients aged >60 years (30, 3640, e1, e35). Delayed neurotoxicity is also observed in patients receiving intensive chemotherapy (e1, e6); however, extensive neurocognitive analyses showed that, especially irradiation, has a negative impact on cognitive performance and quality of life (e5, e7).

In the so far largest randomized phase III study, consolidation whole-brain radiotherapy did not improve overall survival compared to HD-MTX–based chemotherapy (e1). Thus, it should not be not be performed on a routine basis (1, 2).

Strategies to maintain long-term remission

Several strategies to intensify conventional chemotherapy have been evaluated in prospective studies, in some cases with promising results; they may be equally effective compared to chemoradiotherapy (34, e3).

Non-myeloablative consolidation chemotherapy achieved an efficacy comparable to that of chemoradiotherapy (median overall survival >59 months) (e8). Likewise, a HD-MTX–based polychemotherapy combined with intensive intraventricular chemotherapy via a reservoir (“Bonn protocol“, [eTable 2]) achieved long recurrence-free survival (>80 months), especially in younger patients (e9, e10). However, the regimen did not find widespread adoption due to the high rate of reservoir infections (19%). Without intraventricular chemotherapy, these good results could not be reproduced (e11). No controlled studies have yet been conducted to further explore the role of intrathecal treatment.

Lymphoma cells persisting in the CNS are reached by myeloablative, high-dose consolidation chemotherapy with autologous stem cell transplantation (HD-ASCT) as this strategy achieves very high drug levels in the CNS. The efficacy of HD-ASCT was evaluated in several phase II studies on younger patients without major comorbidities. In this selected patient population, HD-ASCT was a highly effective treatment option with curative potential (overall response 80–96%, median overall survival 64–104 months) (e1214). More recent data indicate that HD-ASCT provides equal efficacy to consolidation whole-brain radiotherapy, but is associated with less neurotoxic adverse events (34). In prospective studies, HD-ASCT has been associated with a mortality of 0% to 12% (e13, e14), but, because of its toxicity, especially older patients are often not eligible for it. Thus, ongoing studies are evaluating an age-adapted HD-ASCT for patients aged >65 years (eTable 1). The value of the various consolidation strategies (non-myeloablative versus myeloablative) is being explored in randomized trials in Germany too (28, e15) (eTable 1). Until solid data have become available, no reliable conclusions can be drawn.

Management of recurrence

About one third of all PCNSL patients are primarily refractory to treatment and at least half of the patients with initial response to treatment experience a relapse (e16, e17). So far, no standard of care has been established for this situation; the majority of treatment recommendations are based on retrospective and a few prospective studies (28).

According to reviews, the overall response rates of recurrences range from 10% to 85%; however, remissions are short-lived (median progression-free survival [PFS] approx. three months) (28). In patients with long-lasting remission after initial treatment (median 24–26 months), re-exposure to HD-MTX–containing chemotherapy proved effective with a high response rate (85–91%) and a median survival of 41 to 62 months (e18, e19). For patients aged <65 years, promising data on HD-ASCT are available from the Freiburg ZNS-NHL study (2-year survival: 56%) which is now established in many German centers (e20) (eTable 2). With HD-ASCT, long-term remission was achieved even in cases with no response to HD-MTX–based induction (e20, e21). Other published regimens to treat recurrence include pemetrexed (e22), topotecan (e23), temozolomide in combination with rituximab (e24), the PCV regimen (procarbazine, CCNU, and vincristine) (e25), and rituximab and ifosfamide plus etoposide (e26). With response rates of 74% to 79% and a median survival of 10 to 16 months, whole-brain radiotherapy for recurrence is an effective treatment option (e27, e28). However, it should be used late in the course of the disease, if possible, as it is associated with a high rate of severe neurotoxic adverse events among patients with prior intensive chemotherapy (e28).

New active substances and immunotherapies

In refractory patients with multiple previous therapies, substances, such as temsirolimus (e29), lenalidomide (e30) and ibrutinib (e31), which interfere with B-cell receptor signaling and thus have an effect on proliferation and survival of lymphoma cells, and so-called checkpoint inhibitors (e32), which modulate T cell–mediated immune response, show activity, but are associated with significant toxicity in some patients. Should their efficacy and tolerability be confirmed in the currently recruiting studies, new treatment options for patients with PCNSL may become available.

Special patient populations

Management of older patients

The treatment of elderly patients is limited by comorbidities and the increased risk of treatment-related side effects. HD-MTX–based polychemotherapy is safe and effective as long as renal function is taken into account (dose reduction if creatinine clearance <100 mL/min) (29). Complete remissions are achieved in 36% to 60% of patients; however, median overall survival is only 14 to 31 months (e6, e33, e34) (Table). In the German-speaking countries, many centers have adopted the PRIMAIN protocol (rituximab, methotrexate, procarbazine, [eTable 2]) which was evaluated in a large, randomized, multicenter study (e33).

If HD-MTX is contraindicated, patients can be treated with temozolomide for which an overall response of 47% and overall survival of 21 months was found in a retrospective analysis (e35). Given the high risk of neurotoxic adverse events, whole-brain radiotherapy should only be used if other treatment alternatives are not available or have been exhausted (2).

See the eSupplement for the sections “Management of vitreoretinal lymphoma“ and “Management of immunocompromised patients“.

Follow-up care

The follow-up should be based on neurological examination and cranial magnetic resonance imaging; other investigations are only recommended if specific abnormalities are suspected. The requirements for complete remission include the complete disappearance of contrast-enhancing lesions, the absence of malignant cells in the cerebrospinal fluid, and the complete disappearance of previous ocular involvement. All patients should undergo imaging and clinical follow-up examinations at 3-month intervals for 2 years, then at 6-month intervals for 3 years and finally at 1-year intervals for 5 years (2). Additional checks should be performed to assess any suspected abnormalities. With regard to potential neurotoxic late complications, it is advisable that patients receive follow-up care in a neuro-oncological center.

Conclusion

Because of its specific biological and clinical features, the diagnosis and treatment of PCNSL is challenging and requires an interdisciplinary approach. Thus, it is crucial that patients are preferably treated in centers experienced in the management of the disease and in the setting of a clinical study.

Conflict of interest statement
Prof. Illerhaus has received consultancy fees from Riemser. He has received fees for conference participation and reimbursement of travel and accommodation expenses from Riemser and Roche. He has been contracted and received fees for the conduction of clinical trials from Riemser.

Dr. Korfel has received consultancy fees and fees for preparing continuing medical education events from PIQUR, Mundipharma, and Riemser.

Prof. Schlegel has received lecture fees for Neuro-update from medupdate.

Prof. Dreyling has received consultancy fees from Bayer, Celgene, Gilead, Janssen, Mundipharma, Roche, and Sandoz. He has received fees for preparing continuing medical education events from Bayer, Celgene, Gilead, Janssen, and Roche. He has received financial support from Celegne, Janssen, Mundipharma, and Roche for a research project that he initiated.

Dr. von Baumgarten and Prof. Deckert declare that no conflict of interest exists.

Manuscript received on 7 September 2017; revised version accepted on 6 March 2018

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
PD Dr. med. Louisa von Baumgarten
Neurologische Klinik und Poliklinik
Klinikum der Universität München
LMU München
Marchioninistr. 15
81377 München, Germany
Louisa.vonBaumgarten@med.uni-muenchen.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref2518

eSupplement, eTables:
www.aerzteblatt-international.de/18m0419

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e1.
Thiel E, Korfel A, Martus P, et al.: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 2010; 11: 1036–47 CrossRef
e2.
Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 1998; 16: 859–63 CrossRef MEDLINE
e3.
Kasenda B, Loeffler J, Illerhaus G, Ferreri AJ, Rubenstein J, Batchelor TT: The role of whole brain radiation in primary CNS lymphoma. Blood 2016; 128: 32–6 CrossRef MEDLINE PubMed Central
e4.
Correa DD, Shi W, Abrey LE, et al.: Cognitive functions in primary CNS lymphoma after single or combined modality regimens. Neuro Oncol 2012; 14: 101–8 CrossRef MEDLINE PubMed Central
e5.
Doolittle ND, Korfel A, Lubow MA, et al.: Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 2013; 81: 84–92 CrossRef MEDLINE PubMed Central
e6.
Hoang-Xuan K, Taillandier L, Chinot O, et al.: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 2003; 21: 2726–31 CrossRef MEDLINE
e7.
Herrlinger U, Schafer N, Fimmers R, et al.: Early whole brain radiotherapy in primary CNS lymphoma: negative impact on quality of life in the randomized G-PCNSL-SG1 trial. J Cancer Res Clin Oncol. 2017; 143:1815–21 CrossRef MEDLINE
e8.
Rubenstein JL, Hsi ED, Johnson JL, et al.: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013; 31: 3061–8 CrossRef MEDLINE PubMed Central
e9.
Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003; 21: 4489–95 CrossRef MEDLINE
e10.
Juergens A, Pels H, Rogowski S, et al.: Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 2010; 67: 182–9 CrossRef MEDLINE
e11.
Pels H, Juergens A, Glasmacher A, et al.: Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 2009; 91: 299–305 CrossRef MEDLINE
e12.
Illerhaus G, Kasenda B, Ihorst G, et al.: High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 2016; 3: e388–97.
e13.
Illerhaus G, Marks R, Ihorst G, et al.: High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 2006; 24: 3865–70 CrossRef MEDLINE
e14.
Omuro A, Correa DD, DeAngelis LM, et al.: R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 2015; 125: 1403–10 CrossRef MEDLINE PubMed Central
e15.
Schorb E, Finke J, Ferreri AJ, et al.: High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma—a randomized phase III trial (MATRix). BMC Cancer 2016; 16: 282 CrossRef MEDLINE PubMed Central
e16.
Langner-Lemercier S, Houillier C, Soussain C, et al.: Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC Network. Neuro Oncol 2016; 18: 1297–303 CrossRef MEDLINE PubMed Central
e17.
Jahnke K, Thiel E, Martus P, et al.: Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol 2006; 80: 159–65 CrossRef MEDLINE
e18.
Plotkin SR, Betensky RA, Hochberg FH, et al.: Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 2004; 10: 5643–6 CrossRef MEDLINE
e19.
Pentsova E, Deangelis LM, Omuro A: Methotrexate re-challenge for recurrent primary central nervous system lymphoma. J Neurooncol 2014; 117: 161–5 CrossRef MEDLINE PubMed Central
e20.
Kasenda B, Ihorst G, Schroers R, et al.: High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma—a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia 2017; 31:2623–9 CrossRef MEDLINE
e21.
Soussain C, Choquet S, Fourme E, et al.: Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases. Haematologica 2012; 97: 1751–6 CrossRef MEDLINE PubMed Central
e22.
Zhang JP, Lee EQ, Nayak L, et al.: Retrospective study of pemetrexed as salvage therapy for central nervous system lymphoma. J Neurooncol 2013; 115: 71–7 CrossRef MEDLINE
e23.
Fischer L, Thiel E, Klasen HA, et al.: Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol 2006; 17: 1141–5 CrossRef MEDLINE
e24.
Nayak L, Abrey LE, Drappatz J, et al.: Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leuk Lymphoma 2013; 54: 58–61 CrossRef MEDLINE PubMed Central
e25.
Herrlinger U, Brugger W, Bamberg M, Kuker W, Dichgans J, Weller M: PCV salvage chemotherapy for recurrent primary CNS lymphoma. Neurology 2000; 54: 1707–8 CrossRef
e26.
Mappa S, Marturano E, Licata G, et al.: Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy. Hematol Oncol 2013; 31: 143–50 CrossRef MEDLINE
e27.
Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS: Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 2005; 23: 1507–13 CrossRef MEDLINE
e28.
Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE: Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 2007; 69: 1178–82 CrossRef MEDLINE
e29.
Korfel A, Schlegel U, Herrlinger U, et al.: Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol 2016; 34: 1757–63 CrossRef MEDLINE
e30.
Rubenstein JL, Formaker P, Wang X, et al.: Lenalidomide is highly active in recurrent CNS lymphomas: phase I investigation of lenalidomide plus rituximab and outcomes of lenalidomide as maintenance monotherapy. JCO 2016; 34(Suppl): 7502.
e31.
Lionakis MS, Dunleavy K, Roschewski M, et al.: Inhibition of B cell receptor signaling by Ibrutinib in Primary CNS Lymphoma. Cancer cell 2017; 31: 833–43 e5.
e32.
Nayak L, Iwamoto FM, LaCasce A, et al.: PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 2017; 129: 3071–3 CrossRef MEDLINE PubMed Central
e33.
Fritsch K, Kasenda B, Schorb E, et al.: High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia 2017; 31: 846–52 CrossRef MEDLINE PubMed Central
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Department of Neurology, University Hospital Munich LMU, Munich:
PD Dr. med. Louisa von Baumgarten
Department of Hematology, Oncology and Palliative Care, Stuttgart Cancer Center/Tumor Center Eva-Mayr-Stih, Klinikum Stuttgart: Prof. Dr. med. Gerald Illerhaus
Medical Department, Division of Oncology and Hematology, Charité – Universitätsmedizin Berlin: PD Dr. med. Agnieszka Korfel
Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum: Prof. Dr. med. Uwe Schlegel
Department of Neuropathology, University Hospital Cologne: Prof. Dr. med. Martina Deckert
Department of Internal Medicine III, Hospital of the University of Munich (LMU):
Prof. Dr. med. Martin Dreyling
Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)
Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)
Figure 1
Cranial magnetic resonance imaging (cMRI) of a patient with primary CNS lymphoma (PCNSL)
Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)
Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)
Figure 2
Diagnostic algorithm for suspected primary CNS lymphoma (PCNSL)
Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Figure 3
Therapeutic algorithm for histologically confirmed primary CNS lymphoma (PCNSL) ECOG, Eastern Cooperative Oncology Group Performance Scale
Histology of the primary CNS lymphoma (PCNSL)
Histology of the primary CNS lymphoma (PCNSL)
Figure 4
Histology of the primary CNS lymphoma (PCNSL)
Key messages
Studies on the first-line treatment of primary CNS lymphoma
Studies on the first-line treatment of primary CNS lymphoma
Table
Studies on the first-line treatment of primary CNS lymphoma
Studies currently recruiting in Germany
Studies currently recruiting in Germany
eTable 1
Studies currently recruiting in Germany
Common treatment protocols with dosages
Common treatment protocols with dosages
eTable 2
Common treatment protocols with dosages
1.Korfel A, Schlegel U: Diagnosis and treatment of primary CNS lymphoma. Nat Rev Neurol 2013; 9: 317–27 CrossRef MEDLINE
2.Hoang-Xuan K, Bessell E, Bromberg J, et al.: Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol 2015; 16: e322–32 CrossRef
3.Deckert M, Brunn A, Montesinos-Rongen M, Terreni MR, Ponzoni M: Primary lymphoma of the central nervous system—a diagnostic challenge. Hematol Oncol 2014; 32: 57–67 CrossRef MEDLINE
4.Louis DN, Perry A, Reifenberger G, et al.: The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131: 803–20 CrossRef MEDLINE
5.Hoffman S, Propp JM, McCarthy BJ: Temporal trends in incidence of primary brain tumors in the United States, 1985–1999. Neuro Oncol 2006; 8: 27–37 CrossRef MEDLINE PubMed Central
6.Shiels MS, Pfeiffer RM, Besson C, et al.: Trends in primary central nervous system lymphoma incidence and survival in the U.S. Br J Haematol 2016; 174: 417–24 CrossRef MEDLINE PubMed Central
7.Mendez JS, Ostrom QT, Gittleman H, et al.: The elderly left behind—changes in survival trends of primary central nervous system lymphoma over the past four decades. Neuro Oncol 2018; 20:687–94 CrossRef MEDLINE
8.Deckert M, Engert A, Bruck W, et al.: Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 2011; 25: 1797–807 CrossRef MEDLINE
9.Kasenda B, Ferreri AJ, Marturano E, et al.: First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)—a systematic review and individual patient data meta-analysis. Ann Oncol 2015; 7: 1305–13 CrossRef MEDLINE PubMed Central
10.Kuker W, Nagele T, Korfel A, et al.: Primary central nervous system lymphomas (PCNSL): MRI features at presentation in 100 patients. J Neurooncol 2005; 72: 169–77 CrossRef MEDLINE
11.Buhring U, Herrlinger U, Krings T, Thiex R, Weller M, Kuker W: MRI features of primary central nervous system lymphomas at presentation. Neurology 2001; 57: 393–6 CrossRef
12.Lai R, Rosenblum MK, DeAngelis LM: Primary CNS lymphoma: a whole-brain disease? Neurology 2002; 59: 1557–62 CrossRef MEDLINE
13.Pirotte B, Levivier M, Goldman S, Brucher JM, Brotchi J, Hildebrand J: Glucocorticoid-induced long-term remission in primary cerebral lymphoma: case report and review of the literature. J Neurooncol 1997; 32: 63–9 CrossRef
14.Mathew BS, Carson KA, Grossman SA: Initial response to glucocorticoids. Cancer 2006; 106: 383–7 CrossRef MEDLINE
15.Bruck W, Brunn A, Klapper W, et al.: [Differential diagnosis of lymphoid infiltrates in the central nervous system: experience of the network lymphomas and lymphomatoid lesions in the nervous system]. Pathologe 2013; 34: 186–97 CrossRef MEDLINE
16.Kreth FW, Muacevic A, Medele R, Bise K, Meyer T, Reulen HJ: The risk of haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours— a prospective study. Acta Neurochir (Wien) 2001; 143: 539–45; discussion 45–6 CrossRef
17.Royer-Perron L, Hoang-Xuan K, Alentorn A: Primary central nervous system lymphoma: time for diagnostic biomarkers and biotherapies? Curr Opin Neurol 2017; 30: 669–76 CrossRef MEDLINE
18.Porter AB, Giannini C, Kaufmann T, et al.: Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: a pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma. Ann Neurol 2008; 63: 662–7 CrossRef MEDLINE
19.Abrey LE, Batchelor TT, Ferreri AJ, et al.: Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 2005; 23: 5034–43 CrossRef MEDLINE
20.Ferreri AJ, Reni M, Zoldan MC, Terreni MR, Villa E: Importance of complete staging in non-hodgkin‘s lymphoma presenting as a cerebral mass lesion. Cancer 1996; 77: 827–33 CrossRef
21.Jahnke K, Hummel M, Korfel A, et al.: Detection of subclinical systemic disease in primary CNS lymphoma by polymerase chain reaction of the rearranged immunoglobulin heavy-chain genes. J Clin Oncol 2006; 24: 4754–7 CrossRef MEDLINE
22.Brunn A, Nagel I, Montesinos-Rongen M, et al.: Frequent triple-hit expression of MYC, BCL2, and BCL6 in primary lymphoma of the central nervous system and absence of a favorable MYC(low)BCL2 (low) subgroup may underlie the inferior prognosis as compared to systemic diffuse large B cell lymphomas. Acta Neuropathol 2013; 126: 603–5 CrossRef MEDLINE
23.Montesinos-Rongen M, Schafer E, Siebert R, Deckert M: Genes regulating the B cell receptor pathway are recurrently mutated in primary central nervous system lymphoma. Acta Neuropathol 2012; 124: 905–6 CrossRef MEDLINE
24.Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M: Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 2011; 122: 791–2 CrossRef MEDLINE
25.Montesinos-Rongen M, Schmitz R, Brunn A, et al.: Mutations of CARD11 but not TNFAIP3 may activate the NF-kappaB pathway in primary CNS lymphoma. Acta Neuropathol 2010; 120: 529–35 CrossRef MEDLINE
26.Ferreri AJ, Blay JY, Reni M, et al.: Prognostic scoring system for primary CNS lymphomas: the international extranodal lymphoma study group experience. J Clin Oncol 2003; 21: 266–72 CrossRef MEDLINE
27.Weller M, Martus P, Roth P, Thiel E, Korfel A, German PCNSL Study Group: Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol 2012; 14: 1481–4 CrossRef MEDLINE PubMed Central
28.Grommes C, DeAngelis LM: Primary CNS lymphoma. J Clin Oncol 2017; 35: 2410–8 CrossRef MEDLINE
29.Jahnke K, Korfel A, Martus P, et al.: High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma. Ann Oncol 2005; 16: 445–9 CrossRef MEDLINE
30.Ferreri AJ, Reni M, Foppoli M, et al.: High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 2009; 374: 1512–20 CrossRef
31.Cobert J, Hochberg E, Woldenberg N, Hochberg F: Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort. J Neurooncol 2010; 98: 385–93 CrossRef MEDLINE PubMed Central
32.Bergner N, Monsef I, Illerhaus G, Engert A, Skoetz N: Role of chemotherapy additional to high-dose methotrexate for primary central nervous system lymphoma (PCNSL). Cochrane Database Syst Rev 2012; 11: CD009355 CrossRef
33.Ferreri AJ, Cwynarski K, Pulczynski E, et al.: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 2016; 3: e217–27 CrossRef
34.Ferreri AJM, Cwynarski K, Pulczynski E, et al.: Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the international extranodal lymphoma study group-32 phase 2 trial. Lancet Haematol 2017; 4: e510–23 CrossRef
35.Nelson DF: Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol 1999; 43: 241–7 CrossRef
36.DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ, Radiation Therapy Oncology Group Study: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol 2002; 20: 4643–8 CrossRef MEDLINE
37.Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al.: High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 2003; 21: 4483–8 CrossRef MEDLINE
38.Korfel A, Martus P, Nowrousian MR, et al.: Response to chemotherapy and treating institution predict survival in primary central nervous system lymphoma. Br J Haematol 2005; 128: 177–83 CrossRef MEDLINE
39.Glass J, Won M, Schultz CJ, et al.: Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol 2016; 34: 1620–5 CrossRef MEDLINE PubMed Central
40.Morris PG, Correa DD, Yahalom J, et al.: Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol 2013; 31: 3971–9 CrossRef MEDLINE PubMed Central
e1. Thiel E, Korfel A, Martus P, et al.: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 2010; 11: 1036–47 CrossRef
e2.Abrey LE, DeAngelis LM, Yahalom J: Long-term survival in primary CNS lymphoma. J Clin Oncol 1998; 16: 859–63 CrossRef MEDLINE
e3.Kasenda B, Loeffler J, Illerhaus G, Ferreri AJ, Rubenstein J, Batchelor TT: The role of whole brain radiation in primary CNS lymphoma. Blood 2016; 128: 32–6 CrossRef MEDLINE PubMed Central
e4.Correa DD, Shi W, Abrey LE, et al.: Cognitive functions in primary CNS lymphoma after single or combined modality regimens. Neuro Oncol 2012; 14: 101–8 CrossRef MEDLINE PubMed Central
e5.Doolittle ND, Korfel A, Lubow MA, et al.: Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology 2013; 81: 84–92 CrossRef MEDLINE PubMed Central
e6.Hoang-Xuan K, Taillandier L, Chinot O, et al.: Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 2003; 21: 2726–31 CrossRef MEDLINE
e7.Herrlinger U, Schafer N, Fimmers R, et al.: Early whole brain radiotherapy in primary CNS lymphoma: negative impact on quality of life in the randomized G-PCNSL-SG1 trial. J Cancer Res Clin Oncol. 2017; 143:1815–21 CrossRef MEDLINE
e8.Rubenstein JL, Hsi ED, Johnson JL, et al.: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013; 31: 3061–8 CrossRef MEDLINE PubMed Central
e9.Pels H, Schmidt-Wolf IG, Glasmacher A, et al.: Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol 2003; 21: 4489–95 CrossRef MEDLINE
e10.Juergens A, Pels H, Rogowski S, et al.: Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Ann Neurol 2010; 67: 182–9 CrossRef MEDLINE
e11. Pels H, Juergens A, Glasmacher A, et al.: Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study. J Neurooncol 2009; 91: 299–305 CrossRef MEDLINE
e12. Illerhaus G, Kasenda B, Ihorst G, et al.: High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 2016; 3: e388–97.
e13.Illerhaus G, Marks R, Ihorst G, et al.: High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 2006; 24: 3865–70 CrossRef MEDLINE
e14.Omuro A, Correa DD, DeAngelis LM, et al.: R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 2015; 125: 1403–10 CrossRef MEDLINE PubMed Central
e15.Schorb E, Finke J, Ferreri AJ, et al.: High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma—a randomized phase III trial (MATRix). BMC Cancer 2016; 16: 282 CrossRef MEDLINE PubMed Central
e16.Langner-Lemercier S, Houillier C, Soussain C, et al.: Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC Network. Neuro Oncol 2016; 18: 1297–303 CrossRef MEDLINE PubMed Central
e17.Jahnke K, Thiel E, Martus P, et al.: Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol 2006; 80: 159–65 CrossRef MEDLINE
e18.Plotkin SR, Betensky RA, Hochberg FH, et al.: Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res 2004; 10: 5643–6 CrossRef MEDLINE
e19.Pentsova E, Deangelis LM, Omuro A: Methotrexate re-challenge for recurrent primary central nervous system lymphoma. J Neurooncol 2014; 117: 161–5 CrossRef MEDLINE PubMed Central
e20.Kasenda B, Ihorst G, Schroers R, et al.: High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma—a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia 2017; 31:2623–9 CrossRef MEDLINE
e21.Soussain C, Choquet S, Fourme E, et al.: Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases. Haematologica 2012; 97: 1751–6 CrossRef MEDLINE PubMed Central
e22.Zhang JP, Lee EQ, Nayak L, et al.: Retrospective study of pemetrexed as salvage therapy for central nervous system lymphoma. J Neurooncol 2013; 115: 71–7 CrossRef MEDLINE
e23.Fischer L, Thiel E, Klasen HA, et al.: Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol 2006; 17: 1141–5 CrossRef MEDLINE
e24.Nayak L, Abrey LE, Drappatz J, et al.: Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leuk Lymphoma 2013; 54: 58–61 CrossRef MEDLINE PubMed Central
e25.Herrlinger U, Brugger W, Bamberg M, Kuker W, Dichgans J, Weller M: PCV salvage chemotherapy for recurrent primary CNS lymphoma. Neurology 2000; 54: 1707–8 CrossRef
e26. Mappa S, Marturano E, Licata G, et al.: Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy. Hematol Oncol 2013; 31: 143–50 CrossRef MEDLINE
e27. Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS: Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol 2005; 23: 1507–13 CrossRef MEDLINE
e28.Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE: Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 2007; 69: 1178–82 CrossRef MEDLINE
e29.Korfel A, Schlegel U, Herrlinger U, et al.: Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol 2016; 34: 1757–63 CrossRef MEDLINE
e30. Rubenstein JL, Formaker P, Wang X, et al.: Lenalidomide is highly active in recurrent CNS lymphomas: phase I investigation of lenalidomide plus rituximab and outcomes of lenalidomide as maintenance monotherapy. JCO 2016; 34(Suppl): 7502.
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