Primary central nervous system lymphoma

Critical Reviews in Oncology/Hematology 113 (2017) 97–110

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Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc

Review

Primary central nervous system lymphoma Giovanni Citterio a , Michele Reni a , Gemma Gatta b , Andrés José Maria Ferreri c,∗ a

Medical Oncology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Italian National Cancer Institute, Milan, Italy c Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy b

Contents 1.

2. 3.

4. 5. 6.

7.

General information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 1.1.1. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 1.1.2. Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 1.2. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.1. Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.2. Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.3. Brain biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.4. Cerebro-Spinal fluid analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.5. Vitreous analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 5.1. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 6.1. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 6.2. Systemic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 6.3. Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 6.4. Intrathecal chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 6.5. Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 6.6. High-dose chemotherapy, myeloablative conditioning, and autologous stem cell transplantation (HDC/ASCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 6.7. Consolidation with non-myeloablative chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6.8. Maintenance therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6.9. Elderly patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6.10. Intraocular lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 6.11. Salvage treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Conflict of interest disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

a r t i c l e

i n f o

Article history: Received 7 November 2016 Received in revised form 24 February 2017 Accepted 15 March 2017 Keywords: PCNSL Radiotherapy Cerebrospinal fluid Methotrexate Cytarabine Thiotepa Rituximab

http://dx.doi.org/10.1016/j.critrevonc.2017.03.019 1040-8428/© 2017 Elsevier B.V. All rights reserved.

a b s t r a c t Primary CNS lymphomas (PCNSL) represent a subgroup of malignancies with specific characteristics, aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumour burden and/or histological type. Despite a high chemo- and radiosensitivity, remissions are frequently shortlasting, mainly because the blood brain-barrier limits the access of many drugs to the CNS. Moreover, survivor patients are at high risk of developing severe treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with side-effects control. Although the prognosis remains poor, it has significantly improved over the past two decades as a result of better treatment strategies with a curative aim. Surgery has no impact on survival, and is reserved to diagnosis by stereotactic biopsy. Actual front-line therapy consists of high-dose methotrexate-based poly-chemotherapy. The optimal drugs combination has not yet been identified even if there is a suggestion for a synergistic role for the adjunction of cytarabine, thiotepa, and rituximab. Radiotherapy retains an important role as salvage therapy in refractory/relapsing patients, while its use is more debated in the setting of response consolidation in patients who achieve a complete remission after induction chemotherapy. High-dose chemotherapy supported by autologous stem-cell transplantation is increasingly used as an effective method aimed to control microscopic disease, and the pros and contras of this approach are outlined. © 2017 Elsevier B.V. All rights reserved.

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1. General information Primary CNS lymphomas (PCNSL) are extranodal malignant lymphomas arising inside the central nervous system (including eyes) in the absence of systemic diffusion at the time of diagnosis. Currently, PCNSL are estimated to account for up to 1% of non-Hodgkin lymphomas (NHL) and about 3% of all primary brain tumours (Villano et al., 2011). 1.1. Epidemiology 1.1.1. Incidence Very few population studies have been published about PCNSL. In general, incidence of lymphoma is given for all forms, without distinguishing between nodal and visceral ones. While lymphoma is a common tumour, PCNSL is a very uncommon cancer. Incidence data belong to the SEER database, Danish and Canadian registries (Olson et al., 2002; Krogh-Jensen et al., 1995; Hao et al., 1999). The first studies covered a similar period from 1973 to 1997. SEER data reported a rate of 1.6 per million a year and a statistical significant increase of incidence during the study period. Actually, SEER data estimated an annual percent change for PCNSL of three-fold higher during the period 1973–1985 compared with the period 1986–1997. In the Alberta Canadian province there was a nonsignificant increase of rates from 0.178 to 1.631 per million. Rates from the Danish registry showed no increasing trend for the nonAIDS related PCNSL. A more recent study based on the SEER data (period of diagnosis 1980–2008) showed a decline of incidence after the peak of 1995. However, a continuous increment for the oldest patients (>75 years) was reported (Villano et al., 2011). 1.1.2. Survival Survival is poor for patients with primary CNS lymphoma. The Danish study (Krogh-Jensen et al., 1995) provided populationbased survival figures. Overall survival was 53%, 38%, and 26% at 1, 2 and 5 years after diagnosis, respectively, for cases diagnosed during the period 1971–1990. For US patients diagnosed between 2000 and 2008, the corresponding survival estimates were 51.4%, 42.6%, and 31.2%. Survival was lower in the elderly and in blacks compared to white in the youngest group of patients (0–49 years) (Villano et al., 2011). A trend toward a survival’s increase in more recent years was noted by Shiels et al. in immunocompetent US population (Shiels et al., 2016), while Zeremsky et al. pointed out that survival’s advantage is more evident in patients enrolled in clinical trials than in “real life” patients (Zeremski et al., 2016). 1.2. Risk factors PCNSL seems to occur with increasing frequency in immunologically impaired individuals and in the acquired immunodeficiency syndrome (AIDS). Risk factors are high in recipients of transplants receiving immunosuppressive therapy and in patients with congenital immunodeficiency disorders (Wiskott-Aldrich syndrome, X linked immunodeficiency, ataxia teleangectasia) (Krogh-Jensen et al., 1995). Several reports have been published on PCNSL as a secondary malignancy (DeAngelis„ 1991) due to the immunosuppressive therapy or an inherent immune impairment. O’Neill et al. (1995a) reported a 30-fold increase risk to develop a PCNSL in families with a history of malignancies. PCNSL was one of the most common AIDS-defining malignancies. In the US, during 1981 and 1990, the HIV infection carried

∗ Corresponding author. E-mail address: [email protected] (A.J.M. Ferreri).

more than 3000-fold increased risk of developing the disease compared with the general population (Coté et al., 1996). The rise of incidence rates occurred since the beginning of the 1980s was an epiphenomenon of the AIDS epidemic and the increasing number of recipient of transplants (Krogh-Jensen et al., 1995). However, the influences of the widespread use of X-ray computer-assisted tomography (CT) scanning may have contribute to the rise of incidence for PCNSL in immunologically normal individuals. Therefore, it is not known to what extent radiodiagnostic tools may influence the incidence rise in immunological normal population. Epstein-Barr virus and c-myc proto-oncogene translocation induce the proliferation of PCNSL in HIV patients by a known mechanism, while PCNSL in apparently immune-competent patients, who constitute the majority of cases, arises in an unknown way. PCNSL are mostly present in individuals who are over 60 years, which is probably related to a reduction in immunological surveillance, particularly of T-lymphocytes. The proliferation of Blymphocytes produced by chromosomal abnormalities or by viral stimulation might develop a monoclonal disease due to the lack of suppressive T-cells activity. This proliferation is particularly facilitated in the extranodal areas, which have unique immunological characteristics, such as the central nervous system.

2. Pathology and biology It is well documented that lymphocytic migration inside the nervous tissue depends on a selective interaction of the lymphocytic molecules of adhesion with the vascular endothelium of the CNS (Constantin, 2008; Venetz et al., 2010). These interactions would at least partially explain the relationship of the neoplastic lymphocytes with the vessels and their successive localization in the perivascular spaces determining the characteristic vasocentric proliferation of the PCNSL. Additionally, the neoplastic cells tend to remain within the CNS with consequent extremely low incidence of systemic spread. Several diseases are associated with immunological impairment that has been widely described as a predisposing factor to lymphoproliferative malignancies. It is possible that either the disease itself or its treatment could induce the immunological suppression responsible for the occurrence of second malignancies (DeAngelis, 1991). PCNSL represent a histologically and immunohistochemically very homogeneous lymphoma type. Typical histological features include centroblastic cytology and perivascular tropism (Deckert and Paulus, 2007; Kluin et al., 2008). The vast majority of PCNSL (>95%) are diffuse large B-cell lymphomas (DLBCL), express B-cell markers such as CD20, CD19, and CD79a, as well as monotypic surface immunoglobulin light chains, and correspond to the non-germinal centre B-cell-like (nonGCB) DLBCL subtype with a CD10- BCL6+ IRF4/MUM1+ pattern (Camilleri-Broët et al., 2006; Lin et al., 2006; Montesinos-Rongen et al., 2008). PCNSL usually show very high proliferative activity with Ki67 indexes of 70–90%. Epstein-Barr Virus (EBV) early RNA transcripts (EBER) are absent in most cases of immuno-competent patients, but are often detectable by in-situ hybridization in immuno-compromised patients. Rare cases of PCNSL correspond to Burkitt lymphoma, low-grade B-cell lymphoma, or T-cell lymphoma. The pathogenesis of PCNSL is still largely unclear and quite complex. Molecular investigations identified an aberrant somatic hypermutation in the VH genes and in PAX5, TTF, MYC, and PIM1 genes (Deckert et al. 2011) as well as a high frequency of somatic mutations in genes involved in important pathways such as the B cell receptor (CD79A), the toll-like receptor (MYD88) and the NF-kappaB pathway (CARD11) (Montesinos-Rongen et al., 2010; Montesinos-Rongen et al., 2012; Gonzalez-Aguilar et al., 2012; Bruno et al., 2014) suggesting that their deregulation are driv-

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ing mechanisms in PCNSL tumorigenesis. Recurring chromosomal losses affected the 6q, 6p21.32 (HLA locus) and 9p21 (CDKN2A locus) regions (Gonzalez-Aguilar et al., 2012; Braggio et al., 2011). More recently, gene-expression profiling studies suggested some genomic differences between PCNSL and non-CNS DLBCL (Lim et al., 2015). The most prominent genes involved are SPP1 and MAG. The alteration of SPP1 gene expression in PCNSL is involved in biological activity, such as CNS tropism, B-cell migration, proliferation, and aggressive clinical behaviour, while MAG may be an important adhesion molecule that contributes to perineural cancer invasion. These findings indeed did not exclude an adjunctive role of the microenvironment in explaining the peculiar behaviour of PCNSL. 3. Diagnosis 3.1. Clinical presentations Presenting symptoms may include, often with subacute onset, cognitive decline and/or personality changes, focal neurological deficits and increased intracranial pressure. Seizures are less frequent (10%) (Bataille et al., 2000). Ocular symptoms, due to an involvement of retina, choroid or vitreous, are represented by floaters and/or blurred vision; they can be either isolated (10%) or coexist with cerebral symptoms (10–20%). However, up to onehalf of patients with PCNSL and ocular involvement have no visual symptoms. Insidious onset and delayed diagnosis of intraocular lymphoma are common (Chan et al., 2011).

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baseline, very high lipid resonances), they are not sufficiently specific in practice to replace pathological confirmation. 3.3. Brain biopsy Diagnosis always needs to be confirmed pathologically, according to the WHO classification (Kluin et al. 2008) in most cases by stereotactic needle biopsy. In equivocal cases PCR testing for clonality may aid the diagnosis (Shaw et al., 2014). It is well known that PCNSL is potentially highly sensitive to corticosteroids, which act not only by restoring the impaired blood-brain barrier but also through a specific cytotoxic activity on lymphoma cells. Transient tumour shrinkage or disappearance of contrast enhancement may occur even after short exposure to steroids in approximately 40% of PCNSL, coupled with significant neurological improvement (Pirotte et al., 1997). Stereotactic or navigation guided needle biopsy in this setting may be non-diagnostic, showing prominent infiltration of macrophages, T lymphocytes and reactive gliosis with lack of large lymphoma cells. Therefore, unless patients are rapidly deteriorating with suggestive radiological features of PCNSL, it is usually recommended to defer corticosteroids until histologic confirmation has been obtained. If, nevertheless, corticosteroids have been given with a subsequent objective response, tapering corticosteroids within one or two weeks and delaying biopsy until tumour regrowth would be a reasonable option. Since regrowth occur in most cases within a few weeks after discontinuation corticosteroids was stopped, a serial MRI follow-up with one-month interval may be recommended (Porter et al., 2008).

3.2. Neuroimaging

3.4. Cerebro-Spinal fluid analysis

Nuclear Magnetic Resonance Imaging (MRI) is the basilar tool in order to define site and extension of the disease. However, although suggestive, all MRI findings are not specific. In immunocompetent patients, cranial MRI with contrast enhancement typically shows intense and homogeneously enhancing single lesions (70%) or multiple lesions (30%) with modest surrounding oedema, usually located in periventricular areas and/or deep grey matter (Bühring et al., 2001; Küker et al., 2005). Indeed, some “less typical” MRI findings have been reported, such as intraventricular mass emanating from the choroid plexus, exclusive leptomeningeal disease or Meckel’s cave infiltration. In immunocompromised patients, a multifocal pattern is more common, often with a peripheral ring enhancement and central necrotic area. Differential diagnosis requires to be made with high-grade gliomas, toxoplasmosis or other infectious diseases (especially in immunocompromised patients), subacute infarction, and tumefactive demyelinating lesions. Advanced imaging techniques, especially FDG-PET (Kawai et al., 2010; Yamashita et al., 2013), diffusion tensor imaging (Toh et al., 2008), dynamic susceptibility contrast MRI (DSC-MRI) (Toh et al., 2013; Kickingereder et al., 2014) and proton MR spectroscopy (Chawla et al., 2010; Lu et al., 2014) can increase the diagnostic accuracy and help in differentiating PCNSL from other brain tumours or non-tumour lesions. In general, lymphoma masses are highly cellular lesions with tightly compacted cells, which translate into high density pictures on computed tomograpy scan, low signal on T2-weighted imaging, and restricted diffusion on diffusion-weighted imaging. In particular, FDG PET appears to provide additional information for differentiating common enhancing malignant brain tumours, namely limphoma, versus high grade glioma and metastatic tumour, particularly when differential diagnosis are difficult to narrow using MRI alone (Das et al., 2011). However, although the above mentioned signatures are highly suggestive of PCNSL, especially when present together (low regional cerebral blood volume ratios, high percentage of signal-intensity recovery at the end of the first pass of contrast agent relative to

The identification of lymphoma cells in the cerebrospinal fluid (CSF) or in a vitreous biopsy, when possible, is sufficient to make the diagnosis without the need for a brain biopsy. CSF is rarely normal, and is characterized by raised protein levels in 75% and mild pleiocytosis in 50% of patients. Lymphoma cells are detected in 10–30% in the CSF, which seems to be underestimated (Balmaceda et al., 1995; Korfel et al., 2012). Cellular immunophenotyping by flow cytometry in the CSF and PCR analysis of immunoglobulin heavy and light chain genes may help to distinguish malignant cells from reactive lymphocytes by identifying clonal B-cell populations even when cytological examination is negative (Hegde et al., 2005; Schroers et al., 2010a). However, low cell numbers in the CSF sample are frequently found and may make flow cytometric analysis difficult. A relatively high ratio of PCR false negatives has been reported in PCNSL (Korfel et al., 2012; Fischer et al., 2008). Different CSF molecular genetic markers and proteins including microRNA (miR-21, miR-19b, 363 and miR-92) (Baraniskin et al., ˜ et al., 2014), antithrombin III (Roy et al., 2011), soluble CD19 (Muniz 2008), free immunoglobulin light chains (Schroers et al., 2010b), interleukin-10 and CXCL13 (Rubenstein et al., 2013a) are potentially useful diagnostic biomarkers for PCNSL but require further validation before being used in routine practice. 3.5. Vitreous analysis Ophthalmologic evaluation includes fundoscopy and slit lamp examination. Fluorescein angiography may be useful for lymphomatous involvement of the retina (Chan et al., 2011). Ophthalmologic involvement has to be confirmed by vitreous biopsy when eyes are the unique site of disease. Positive cytology is obtained in 50% of cases. As for CSF, immunophenotyping and detection of IgH or T-cell receptor rearrangements by PCR analysis indicating monoclonality are helpful tools for diagnosis (Shen et al., 1998; Missotten et al., 2013). High levels of interleukin 10 (IL10) and/or high IL10/IL6 ratio in ocular fluids are strongly sug-

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gestive of B-cell lymphomatous uveitis (Cassoux et al., 2007), but are not diagnostic. 4. Staging The aims of staging are both to specify the extent of the lymphoma within the CNS and to exclude the presence of the disease elsewhere. If not contraindicated and already performed at the diagnostic work-up, all patients should have a lumbar puncture for CSF cytology. Systemic involvement is present in up to 12% of the cases (O’Neill et al., 1995b; Ferreri et al., 1996). Since identification of a systemic site of the lymphoma has important implications for the treatment strategy, an international workshop aimed to standardize baseline evaluation (Abrey et al. 2005) recommended performing at least a CT-scan of the chest, abdomen and pelvis, a bone marrow biopsy, as well as a testicular ultrasound in elderly males. FDG body PET, which is more sensitive than the body CT-scan (Mohile et al., 2008), is not yet an established routine diagnostic investigation, but is used in some European countries as an integral part of diagnostic work-up. An HIV blood test and an ophthalmologic evaluation with a fundoscopy and a slit lamp examination in all patients (even without ocular symptoms) should complete the diagnostic procedures. 5. Prognosis 5.1. Prognostic factors Many prognostic factors have been proposed by various authors (Corry et al., 1998; Blay et al., 1998; Abrey et al., 2006; Bessell et al., 2004; Ferreri et al., 2003), among which bcl-6, MUM1 and Ki-67 expression seem to be particularly intriguing (Cho et al., 2016), although only age and performance status have been consistently identified as treatment-independent prognostic factors. It is recommended to evaluate the individual risk of a PCNSL patient before treatment according to one of the existing prognostic scores, for example the IELSG (Ferreri et al., 2003), the MSKCC (Abrey et al., 2006), or the Nottingham-Barcelona score (Bessell et al., 2001). 6. Treatment 6.1. Surgery Although very few data are available in the literature, surgery has traditionally been considered to have no role in the treatment of PCNSL. This widely adopted opinion is based on small retrospective series suggesting no clear benefit in outcome of surgical resection used as sole treatment compared with supportive care (Henry et al., 1974), and compared with biopsy in patients having received post-operative chemotherapy and/or radiotherapy (Bataille et al., 2000; Bellinzona et al., 2005). This may be explained by the microscopic multifocal and infiltrative nature of PCNSL that may extend beyond the visible border of the lesion (Lai et al., 2002). The high radiosensitivity and chemosensitivity of PCNSL, and the increased risks of postoperative morbidity of this patient population have also contributed to discourage surgery. However, the recommendation to restrict surgical interventions to biopsies is not based on randomized data and, more importantly, not on contemporary data reflecting modern neurosurgery. The German PCNSL Study Group-1 phase III trial included an unusually high rate of operated patients, which allowed the largest and most recent retrospective analysis of an association of surgery and outcome. A significantly longer PFS and OS in patients with subtotal or gross total resections compared with biopsied patients were reported (Weller et al., 2012). This difference in outcome was independent from post-operative

performance status and age. Since biopsied patients more often had multiple and/or deeply seated CNS lesions than resected patients, these features may have contributed to the unfavourable outcome. It has to be stressed that deep cerebral lesions retain both intrinsic unfavourable prognosis and unsuitability to surgery, so the conclusions of the study are very questionable; inasmuch the difference in outcome may be biased by the site (other that the number) of the lesions. When adjusted for the number of lesions (site of the lesions as above mentioned was not analysed in the study), the difference in outcome remained significant in term of PFS but did not reach the significance threshold for OS. Anyway, surgical resection may be considered in patients suffering from a large space occupying lesion with acute symptoms of brain herniation to reduce rapidly increased intracranial pressure, improve PS and allow timely chemotherapy. 6.2. Systemic chemotherapy The CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen commonly used for systemic aggressive lymphomas induces short-lasting response in PCNSL and its addition to radiotherapy has not shown a survival benefit in prospective trials (O’Neill et al., 1995a; Schultz et al., 1996; Mead et al., 2000). This inefficacy is probably due to the fact that cyclophosphamide, vincristine and doxorubicin are not able to cross the blood-brain barrier (BBB) to eradicate microscopic disease. Based on convergent results from various prospective and retrospective studies, high-dose (HD) intravenous (iv) methotrexate (MTX), an antifolate and antimetabolite, is considered the most important and beneficial single agent (Deckert et al., 2011; Glass et al., 1994). Penetration of MTX into the CNS depends both on the total dose and rate of infusion. The optimal dose of MTX has not been determined. It has been estimated that the iv MTX should range between 1 g/m2 and 8 g/m2 to cross the BBB. In the absence of clear evidence for dose-response relationship, and since rapid infusion of MTX ≥3 g/m2 over 3 h achieves cytotoxic levels in the CSF (Lippens and Winograd, 1988); there is a growing consensus to deliver MTX according to this schedule. MTX administration interval should range between 10 days and 3 weeks. The optimal number of MTX injections to deliver is unknown. A minimum of 4–6 injections is delivered in most chemotherapy regimens, especially if no consolidation treatment (radiotherapy and/or intensive chemotherapy) is programmed. For patients who achieved only PR after 4–5 courses of HD-MTX, two additional courses may improve the CR rate (Morris et al., 2013). Infusions of HD-MTX require pre- and post-hyperhydration, urine alkalinization, leucovorin rescue and MTX concentration monitoring. Currently most treatment protocols combine HD MTX with a variety of other chemotherapeutic agents to improve response rate and outcome. The best evidence to support this approach comes from an IELSG randomized phase II study comparing HD MTX alone, administered at 3 g/m2 /d every 21 days, to HD MTX with cytarabine (2 g/m2 twice per day on days 2–3) (Ferreri et al., 2009). Both chemotherapy arms were followed by WBRT. This study showed a significant higher CR rate in the HD MTX-cytarabine arm. Regarding secondary endpoints, a significantly improved ORR, PFS and a trend towards better OS were observed in the HD MTX-cytarabine arm. The combination of methotrexate, alkylating agent, and rituximab has been tested in a few single-arm phase 2 trials (Morris et al., 2013; Omuro et al., 2015a; Rubenstein et al., 2013b). A combination of rituximab, methotrexate, procarbazine, and vincristine followed by low-dose whole-brain radiotherapy was assessed in 52 patients with newly diagnosed primary CNS lymphoma, with an ORR of 79% and a 2-year PFS of 57% (Morris et al., 2013). The same combination followed by consolidative autologous stem cell transplantation was investigated in 33 patients younger than 65

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years, with an ORR of 94% and a 2-year PFS of 79% (Omuro et al., 2015a). A combination of methotrexate, temozolomide, and rituximab followed by consolidative non-myeloablative chemotherapy with high doses of cytarabine and etoposide and without radiotherapy was tested in 44 patients, with an ORR of 77% and a 2-year PFS of 59% (Rubenstein et al., 2013b). Unfortunately, no conclusions can be drawn about the effect of each drug (ie, alkylating agent and rituximab) in these studies in view of the fact that these are small, single-arm trials and that similar results have been reported with high-dose methotrexate monotherapy. Recently, the results of the first part of the IELSG#32 study, a large European multicentric study that enrolled 227 patients from 53 centres of five European country, were published (Ferreri et al., 2016). In this trial, patients were randomly assigned to receive four courses of methotrexate 3.5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group A) or the same combination plus two doses of rituximab 375 mg/m2 on days −5 and 0 (group B) or the same methotrexate-cytarabinerituximab combination plus thiotepa 30 mg/m2 on day 4 (group C). At median follow-up of 30 months, patients treated with rituximab and thiotepa had a significantly higher complete remission rate of 49% (95%CI 38–60), compared with 23% (14–31) of those treated with methotrexate-cytarabine alone and 30% (21–42) of those treated with methotrexate-cytarabine plus rituximab. Importantly, the combination of four drugs, called MATRix regimen, has been associated with a significantly improved PFS and OS, with a 5years OS of 69%; this is the first randomized trial demonstrating a favourable effect on survival of a new therapy in this field. Grade-4 haematological toxicity was more frequent in patients treated with MATRix combination, but infective complications were similar in the three groups. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation (results are ongoing). This trial provided a high level of evidence supporting the use of Methotrexate-cytarabine-thiotepa-rituximab combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. Disappointing results on the other hand have been reported in a pilot study combining HD-MTX (3.5 g/m2 ), thiotepa and cytarabine at a reduced dose of 1 g/m2 suggesting that the cytarabine dose was probably suboptimal to reach cytototoxic levels in the CNS (Ferreri et al., 2011a,b,c), as supported by pharmacokinetic studies (Slevin et al., 1983). Another approach is blood-brain barrier disruption (BBBD) by intra-arterial (IA) infusion of hypertonic mannitol followed by intra-arterial (IA) chemotherapy to increase the drug concentration in the CNS. BBBD with IA MTX administrated in newly diagnosed PCNSL demonstrated a good safety profile and neurocognitive tolerance and achieved comparable outcomes to those observed with HD-intravenous MTX based chemotherapy regimens (Neuwelt et al., 1991; Doolittle et al., 2000; Angelov et al., 2009). This approach would be interesting to evaluate with active agents for lymphoma that do not cross the BBB, but it requires careful patients selection as safety depends on the extent of intracranial mass effect and the procedure is limited to patients with no contraindications for general anaesthesia and no allergy to iodine-based contrast agents. Furthermore, it could be managed only by teams highly trained in BBBD as it requires cannulation of the intracranial vessels. Other drugs emerged from prospective studies are being tested in ongoing trials of new first-line combinations. Temozolomide, an oral alkylating agent largely used in neuro-oncology, is the best example. It has been associated with excellent tolerability, 31% CRR and 1-year OS of 31% in patients with PCNSL relapsed or refractory to HD-MTX (Reni et al., 2007). The combination of temozolomide with HD-MTX was associated with encouraging results, even among elderly patients. Topotecan, a topoisomerase-I

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inhibitor, is another example. It is active in relapsed PCNSL. However, its responses are of brief duration (1-year PFS: 13%) and it is frequently associated with severe leukopenia and neurologic deterioration (Fischer et al., 2006). As above mentioned, the alkylating agent thiotepa, commonly used in conditioning regimens for ASCT (Alimohamed et al., 2012; Cote et al., 2012) has raised increasing interest for its ability to penetrate BBB and this characteristic may be one of the reasons for the superiority of arm C in IELSG#32 study. 6.3. Rituximab Rituximab is a first generation chimeric murine mAb against the CD20 B-cell-specific surface antigen and it has dramatically improved the prognosis of several B cell haematological malignancies including systemic DLBCL (Cote et al., 2012). Based on its poor penetration into the CNS related to its large size (Rubenstein et al., 2003), the maximal concentration and efficacy of rituximab in the CNS might be assumed to occur in the early treatment phase, during blood-brain barrier (BBB) breakdown within the tumours (Jin et al., 2010). The effect of rituximab when used as monotherapy in PCNSL was evaluated in a single study in which 12 patients with refractory or relapsed PCNSL were treated with a weekly iv dose of 375 mg/m2 rituximab infusion for up to 8 doses (Batchelor et al., 2011). MRI responses were observed in 36% of patients, the median progression-free survival was 57 days and the median overall survival was 20.9 months. These data provided evidence of activity of IV rituximab monotherapy in patients with PCNSL and supported the incorporation of this agent into chemotherapy: other studies used iv rituximab in combination with a HD MTX-based chemotherapy regimen as initial treatment for newly-diagnosed PCNSL (Morris et al., 2013; Rubenstein et al., 2013b; Birnbaum et al., 2012; Gregory et al., 2013; Holdhoff et al., 2014) or as salvage treatment for recurrent parenchymal CNS lymphomas (Mappa et al., 2013; Nayak et al., 2013). Three studies suggested that the addition of rituximab to HD MTX-based chemotherapy improves the CR and OS rate (Birnbaum et al., 2012; Gregory et al., 2013; Holdhoff et al., 2014) in patients newly diagnosed with PCNSL based on retrospective comparison with historical controls. Overall, the addition of rituximab to systemic polychemotherapy is well tolerated; except for a higher rate of neutropenia observed in one study (Shah et al., 2007). In IELSG#32 trial, the adjunction of rituximab to methotrexate-cytarabine combination determined a significant increase in CR rate (30% vs. 23%) (Ferreri et al., 2016), supporting its incorporation in front-line chemo-immunotherapeutic combinations. Targeting CD20 tumour cells for selective radioimmunotherapy is another approach whose feasibility has been demonstrated in pilot studies treating patients with relapsed or refractory CNS lymphomas (Doolittle et al., 2007; Iwamoto et al., 2007; Maza et al., 2009). Injection of rituximab into the CSF via either lumbar puncture or by intraventricular administration was evaluated in 2 phase-I studies for refractory or recurrent CNS lymphoma patients (Rubenstein et al., 2007; Rubenstein et al., 2013c). In these studies, objective responses and good tolerability were documented confirming small case series (Antonini et al., 2007; Schulz et al., 2004). 6.4. Intrathecal chemotherapy Intrathecal (IT) chemotherapy administration has not been prospectively studied and its efficacy in PCNSL remains debated. Three retrospective studies did not demonstrate benefit from the addition of intrathecal drugs (MTX, cytarabine) in patients treated with HD MTX dosed at 3 g/m2 (Ferreri et al., 2002a,b; Khan et al., 2002; Sierra Del Rio et al., 2012). In contrast, 2 consecutive single arm trials using the same systemic polychemotherapy regimen

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suggested additional benefit when intraventricular chemotherapy was added (Pels et al., 2003; Pels et al., 2009). In conclusion, there is no consensus on CSF prophylaxis and treatment and recently reported or ongoing PCNSL trials do not use IT/intraventricular chemotherapy. IT chemotherapy (intralumbar or preferably intraventricular through an Ommaya reservoir) could otherwise be proposed in the case of documented meningeal involvement with insufficient response to intravenous HD MTX-based chemotherapy or in patients who are not able to receive a MTX dose of 3 g/m2 or more. 6.5. Radiotherapy Radiotherapy (RT) has a well-established role in the treatment of PCNSL. Due to the microscopically diffuse and multifocal nature of the disease, there is a need for RT to involve the whole brain, including the eyes, even in apparently localised lesions. Lymphoma cells are radiosensitive: when used as monotherapy, RT provides high response rates in the range of 50%. Unfortunately, the responses are short lasting and the disease invariably relapses, with a median OS duration of 10–18 months and a 5-year survival rate of 5%. The only phase II trial, conducted by the RTOG, which delivered a total dose of 40 Gy with an additional 20-Gy boost to contrastenhancing lesions, reported a disappointing 11.6 month OS (Nelson et al., 1992). Of note, the majority of relapses occurred in fields that had received the highest RT dose. Although not formally compared in a randomized trial, a general agreement considers that HD MTX-chemoradiation is superior to RT-alone in front-line therapy, allowing for a 2- to 4-fold increase in OS (median: 30–72 months) and long-term survivors (5-year survival of 20–50%) for many authors (Bessell et al., 2001; Glass et al., 1994; Omuro et al., 2005; Abrey et al., 2000; Poortmans et al., 2003; Gavrilovic et al., 2006; Ghesquières et al., 2010). However, RT alone has uncontested recommendation in patients with contraindication to chemotherapy, in patients with unusual histologic subtypes as curative treatment and finally as salvage therapy for refractory or relapsing patients when systemic chemotherapy is no longer advisable (Citterio et al., 2013). The consolidation therapy after CR obtained with HD-MTXbased chemotherapy is currently the most debated role for RT in PCNSL. Firstly, in contrast to systemic NHL (Lowry et al., 2011), the optimal dose of post-chemotherapy irradiation has never been prospectively investigated in PCNSL. Doses of 23–50 Gy to the whole brain, with or without a tumour bed boost, are currently used, with most of the protocols delivering a total dose of 40–45 Gy without boost, and standard fractionation (1.8–2.0 Gy/fraction). The RTOG-9310 trial did not show a clear benefit with hyperfractionated WBRT (DeAngelis et al., 2002). Secondly, it remains unclear whether consolidation with WBRT provides better disease control or survival in CR patients after front-line CT. Only one randomized trial comparing radiotherapy versus watch-and-wait after chemotherapy for PCNSL was published to date (Thiel et al., 2010). In this study, patients received HD MTX 4 g/m2 iv every 14 days for 6 cycles with or without ifosfamide. Patients who achieved a CR were randomized between consolidating WBRT, 45 Gy in 30 fractions over 6 weeks vs. observation. A total of 551 patients entered the study, of whom 133 experienced various protocol violations. OS was similar in both arms, but in the whole per-protocol population, the WBRT arm was associated with a non-significant trend for better PFS, as compared with the no WBRT arm. This trial presented several critical interpretative issues as pointed out by many authors (Ferreri et al., 2011a,b,c; Cabanillas, 2010; Weller, 2014; DeAngelis, 2014). Some authors considered that the unmet primary endpoint for non-inferiority and the high rate of protocol violations invalidate any conclusion and still recommend consolidation WBRT after HD MTX-based chemotherapy as the standard of care; on the con-

trary, others agreed with the opinion that omission of WBRT from first-line treatment results in shorter PFS but does not compromise OS (Omuro et al., 2011; Ekenel et al., 2008). In addition, several single arm trials suggested that chemotherapy alone plus a deferred RT strategy may obtain comparable survivals with those reported for combined chemo-RT, but with minor neurocognitive deterioration, which represent the principal pitfall of WBRT (Neuwelt et al., 1991; Pels et al., 2003; Batchelor et al., 2003; Fliessbach et al., 2005; Fliessbach et al., 2003; Hoang-Xuan et al., 2003; Juergens et al., 2010). Recent updated results at a median follow-up of 12 years of a phase II trial assessing first-line chemotherapy followed by WBRT showed that 9/41 patients are alive and disease-free, 8 of whom are alive at 10 years. At 10 years from diagnosis, no patient showed chronic hematologic and non-hematologic toxicities, with a MiniMental State Examination score of >29 in all cases but one. (Ferreri et al., 2014). Anyway, delayed treatment-related neurotoxicity is a dramatic occurrence in survival patients, often so disabling to frustrate the beneficial effect of treatment on the disease control. There is a general agreement that the combination of HD MTX and WBRT is associated with disabling neurotoxicity with a cumulative 5-year incidence of 25% to 35% and related mortality of 30% (Blay et al., 1998; Abrey et al., 1998). This deleterious treatment complication typically occurs several months to years after treatment. Neuropsychological examination may confirm impaired psychomotor speed, executive function, attention, and memory (Correa et al., 2007). Affected patients show cortical/subcortical atrophy and leukoencephalopathy (Omuro et al., 2005; Correa et al., 2007; Wassenberg et al., 2001), which may leave them demented, ataxic, and incontinent. Median survival after onset of clinically evident neurotoxicity is less than 1–2 years (Blay et al., 1998; Omuro et al., 2005; Abrey et al., 1998). Autopsy findings include myelin and axonal loss, gliosis, spongiosis, thinning of white matter, small and large vessel disease, and necrosis (Lai et al., 2004). In a retrospective monoinstitutional series analysis of 183 patients (Omuro et al., 2005), only the administration of WBRT was identified as an independent risk factor for the development of late neurotoxicity: in this series, 2% of patients treated with chemotherapy alone developed clinically-evident neurotoxicity, while 33% treated with combination chemo-radiotherapy were affected. The cumulative incidence of neurotoxicity for the whole group was 5% at 2 years and 24% at 5 years, with a higher risk in patients >60 years. The prevalence of treatment-related “subtle” cognitive dysfunction amongst patients treated for PCNSL is probably largely underestimated, as formal psychometric evaluations (Correa et al. 2007) have not been routinely performed in most prospective studies. Small case series identified WBRT, and not chemotherapy, as the primary cause of neurotoxicity in PCNSL (Harder et al., 2004; Correa et al., 2004). These results have been confirmed by 3 long-term evaluations (Juergens et al., 2010; Correa et al., 2012; Doolittle et al., 2013). In the most recent analysis of 80 long-term survivors of PCNSL, free of tumour and having completed treatment with different regimens at least two years prior to evaluation, patients who had received WBRT showed significantly lower mean scores in attention and executive function, motor skills, and neuropsychological composite score, associated with poorer quality of life measures (Doolittle et al., 2013). Moreover, on brain imaging, mean areas of total T2 abnormalities in the WBRT group were more than twice the mean of any other non-WBRT group. These results caution against the routine administration of WBRT as part of upfront treatment and call for the implementation of formal neuropsychometric testing in clinical trials on PCNSL (Correa et al., 2007). For all these reasons, efforts are made in the attempt to avoid RT (high-dose regimens with autologous stem cell transplantation, see next section) or to reduce RT-related neurotoxicity. An approach for diminishing WBRT-related neurotoxicity is to reduce the radiation doses. A subset analysis from a phase II trial that

22 43 28 25 11 33 21 30 Fritsch et al. (2011) Fliessbach et al. (2005) Correa et al. (2007) Ferreri et al. (2014) Harder et al. (2004) Glass et al. (1994) Neuwelt et al. (1991) Abrey et al. (1998)

103 N◦ = Assessable patients; CRR = complete remission rate; WBRT = whole-brain irradiation; TRM = treatment-related mortality. ARAC = cytarabine; BCNU = carmustine; BEAM = carmustine, etoposide, cytarabine, and melphalan; Bu = busulfan; Cy = cyclophosphamide; IFO = ifosfamide; MBVP (regimen) = methotrexate, carmustine, etoposide, and methylprednisolone; MPV (regimen) = methotrexate, vincristine, and procarbazine; R-MPV (regimen) = MPV plus rituximab; TT = thiotepa; VP16 = etoposide. a Performed ASCT was a selection criteria. b Only for patients not achieving a complete remission.

32% 5% 0% 8% 3/11 0% 0% 17% 3-yr: 64% 2-yr: 45% 2-yr: 55% 4-yr: 64% 2-yr: 89% 3-yr: 81% 5-yr: 44% 5-yr: 69% 41 36 28 34 25 45 60 63 No No No Yes Yesb No No Yes Bu/TT/Cy Bu/TT/Cy BEAM BEAM BUCYE Bu/TT/Cy Bu/TT/Cy BCNU/TT 91% 63% 50% 68% 11/11a 81% 100%a 77% 36% 35% 29% 44% 8/11 66% 24% 33% ARAC + VP16 ARAC + VP16 HDMTX→ARAC MBVP→IFO + ARAC HDMTX→ARAC R-MPV→ − MPV→ARAC HDMTX→ARAC + TT Salvage Salvage First First First First First First

CRR to induction Transplanted patients Therapy Line Therapy (induction → intensification) Median age (range) N◦ Refs.

Table 1 Selection of studies focused exclusively on autologous stem cell transplantation in PCNSL.

HDC/ASCT is the standard treatment for chemosensitive relapsing systemic DLBCL. The major obstacles for the translation of this approach in the setting of PCNSL patients are the advanced age and poor general conditions of most patients; this often resulted in excellent results but obtained in highly selected series, mostly constituted by young and fit patients. For patients with relapsed or refractory PCNSL, one multicentre phase II trial evaluated HDC/ASCT, with TBC conditioning regimen (thiotepa, busulfan, cyclophosphamide) in 43 patients. The CR rate was 60%, median PFS and OS were 41 and 58 months, respectively, for the 27 patients who completed the full HDC/ASCT procedure, whilst the intent-to-treat median PFS and OS times were 11 and 18 months, respectively, revealing a toxicity-related mortality in 7% and a severe neurotoxicity in 11% of patients (Soussain et al., 2008) (see also Table 1). An update of this study to which additional cases have been included and an independent retrospective single centre series confirmed the benefit of the TBC regimen followed by ASCT (Soussain et al., 2012; Welch et al., 2015). Experiences with other HDC regimens in this setting of patients are limited to a few cases, which prevent any conclusions being drawn (Mappa et al., 2013; Kasenda et al., 2011). Because of its toxicity risks, the HDC/ASCT is likely to be proposed for younger patients (<60–65 years) with a good performance status, which makes it difficult to compare with other salvage treatments, including second-line conventional chemotherapy regimens and WBRT. However, HDC/ASCT represents an effective treatment option for selected refractory and relapsed PCNSL patients and should be reserved to experienced centres. In early studies, WBRT was administered after HDC/ASCT (Colombat et al., 2006; Illerhaus et al., 2006). An innovative approach is to assess the specific role of HDC/ASCT as consolidation in first-line treatment in alternative to WBRT to avoid the neurocognitive impairment associated to radiotherapy. The first study with HDC/ASCT without WBRT used the BEAM regimen (BCNU, etoposide, cytarabine, and melphalan) as conditioning and reported a disappointing median event-free survival of 9.3 months (Abrey et al., 2003). Subsequently, encouraging studies for which WBRT had been omitted at least in patients in CR after HDC/ASCT have been reported (Alimohamed et al., 2012; Cote et al., 2012; Schorb et al., 2013; Illerhaus et al., 2009). These studies used either HD thiotepa-based conditioning regimens or a combination including busulfan, cyclophosphamide and etoposide (Yoon et al., 2011). Taken together, although direct comparison between used conditioning regimens is difficult, HD thiotepa-based conditioning regimens seem more efficient than BEAM-based regimens,

Conditioning regimen

6.6. High-dose chemotherapy, myeloablative conditioning, and autologous stem cell transplantation (HDC/ASCT)

53 (27–64) 52 (23–65) 53 (25–71) 52 (21–60) 52 (33–65) 57 (23–67) 56 (34–69) 54 (27–64)

WB RT Median f-up (months)

Overall survival

Neuro toxicity

TRM

included 25 patients aged <60 years who achieved a CR after initial chemotherapy and received either 45 Gy or 30.6 Gy as consolidation treatment showed a significantly higher recurrence rate and lower OS rate in the reduced-dose RT group (Bessell et al., 2002). On the other hand, in a retrospective study of 33 patients with PCNSL who achieved CR after MTX-containing chemotherapy and were referred to consolidation WBRT, total doses ≥40 Gy were not associated with improved disease control in comparison with a WBRT dose of 30–36 Gy (Ferreri et al., 2011a,b,c). More recently, in a phase II trial evaluating an immunochemoradiation regimen (RMPVA) including rituximab and HD MTX-based polychemotherapy, the 31 CR patients were treated with reduced dose WBRT (23 Gy) with encouraging results both in term of survival and neurotoxicity (Morris et al., 2013). Based on these results, a randomized study (RTOG-1114) comparing the R-MPV regimen with or without reduced-dose WBRT is currently ongoing (NCT01399372. Available from clinicaltrials.gov).

4% 12% 4% 4% 0/11 12% 24% 3%

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and BCNU-thiotepa combination seems to be equally effective but less toxic that thiotepa-busulfan-cyclophosphamide combination as conditioning regimen (Ferreri and Illerhaus, 2016). Superiority of the HDC/ASCT approach compared to standard combined chemoradiotherapy as first line treatment is currently under investigation in 2 ongoing trials (NCT01011920 and NCT00863460, see for details at www.clinicaltrials.gov), and comparison of HDC/ASCT versus WBRT as consolidation therapy after front-line HD-MTX based CT is investigated in the IELSG-32 and the PRECIS trials. The most numerous phase II study published to date (Illerhaus et al., 2016) recruited 81 patients aged <65 years treated with five courses of intravenous rituximab 375 mg/m2 and four courses of intravenous high-dose methotrexate 8000 mg/m2 (every 10 days) and then two courses of intravenous rituximab 375 mg/m2 (day 1), cytarabine 3 g/m2 (days 2 and 3), and thiotepa 40 mg/m2 (day 3). Three weeks after the last course, patients received intravenous HCTASCT with rituximab, carmustine, thiotepa and infusion of stem cells), irrespective of response status after induction. Radiotherapy was restricted to patients without complete response after HCTASCT. All patients started induction treatment; 73 (92%) underwent HCT-ASCT, and 61 (77%) patients achieved a complete response. Four (5%) treatment-related deaths were recorded (three during induction and one 4 weeks after HCT-ASCT).The authors concluded that HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma. 6.7. Consolidation with non-myeloablative chemotherapy Recently, the CALGB 50202 multicentre phase II trial reported promising results using HD cytarabine combined with etoposide as consolidation without WBRT following a HD MTX-based polychemotherapy as induction regimen (Rubenstein et al., 2013b). Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R (methotrexate, temozolomide, rituximab), and patients who achieved CR received EA (etoposide, cytarabine) consolidation. The CR rate of MT-R was 66% and the overall 2-year PFS was 0.57. The 2-year time to progression was 0.59 and, for patients who completed consolidation, it was 0.77. Patients aged >60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. Given the encouraging results in terms of toxicity, response, and survival achieved in the multicentre setting, the MT-R regimen is being evaluated in an ongoing intergroup, randomized phase II trial – CALGB 51101 (Alliance) – which compares dose intensive EA chemotherapy with myeloablative chemotherapy using carmustine plus thiotepa followed by autologous stem-cell transplantation. 6.8. Maintenance therapy The issue of maintenance therapy in order to achieve the maximum disease control has been addressed by two studies. In the first (Glass et al., 2016), front-line methotrexate, temozolomide (TMZ), and rituximab was followed by hyperfractionated wholebrain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Thirteen patients were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m2 with hepatic and renal dose-limiting toxicities. In phase II, 53 patients were treated, and 2-year OS rate was 80.8%. In the second one (Pulczynski et al., 2015) patients were applied a phase II front-line age-adjusted methotrexate-cytarabine regimen, which in elderly patients responsive to induction therapy included temozolomide maintenance 150 mg/m2 days 1–5 at an interval of 28 days. Maintenance treatment was started one month after completion of

induction and continued for one year or until relapse/progression. Thirty-nine patients aged 18–65 years and 27 patients aged 66–75 years were enrolled. The overall response rate was 69.9% in the younger and 80.8% in the elderly subgroup. Survival in the two age groups was similar (around 60% at 2 years) despite a de-escalation of induction treatment in patients aged over 65 years. Duration of response in elderly patients receiving maintenance temozolomide was (not significantly) longer than in the younger age subgroup. While toxicity during induction was still of concern, especially in the elderly patients, the authors concluded that de-escalation of induction therapy in elderly PCNSL patients followed by maintenance treatment seems to be a promising treatment strategy. 6.9. Elderly patients In the majority of the studies regarding prognostic factors in PCNSL, age over 60 (Bessell et al., 2001; Ferreri et al., 2003) was proved to be an adverse prognostic factor. Even for radiationinduced neurotoxicity, age >60 was found to be a negative prognostic issue (Abrey et al., 1998). Therefore, the age of 60 has been used as the cut-off to define the elderly population, which represents the majority of the PCNSL patients (Villano et al., 2011; Bessell et al., 2011). Some prospective studies have been published on treatment of elderly patients with PCNSL (Illerhaus et al., 2009; Laack et al., 2006; Fritsch et al., 2011) (see also Table 2) and others on patients of all ages but reporting specifically on older patients (Ghesquières et al., 2010; DeAngelis et al., 2002; Roth et al., 2012). As in younger patients, the addition of CHOP/CHOD to radiotherapy did not improve the outcome (O’Neill et al., 1995a; Schultz et al., 1996; Nelson et al., 1992; Laack et al., 2006). In the only multicentre RTOG phase II trial, the median survival was 7.8 months (Nelson et al., 1992). After HD-MTX-based therapy, PFS in patients aged 60 or 65 and older is reported between 6 and 16 months, and OS between 14 and 37 months with OS in the majority of prospective studies less than 2 years (Illerhaus et al., 2009; Fritsch et al., 2011; Roth et al., 2012). Although no direct comparisons have been made between treatment with HD-MTX-based chemotherapy and radiotherapy in this age group, the impression from the single arm studies is that survival after HD MTX-based chemotherapy is at least as good (and probably better) than after radiotherapy. Formal comparisons among different HD MTX-based regimens have not been published, but in a recently randomized phase II study toxicity was identical while CR rate, median PFS and survival appeared (not significantly) better after MPV-A (MTX, procarbazine, vincristine, cytarabine) than after MTX and temozolomide (Omuro et al., 2013). A recent meta-analysis of 741 immunocompetent patients ≥60 years with newly diagnosed PCNSL suggests that there is no difference in survival between patients treated with HD-MTX + oral alkylating agents and more intensive intravenous combinations (Kasenda et al., 2015). As far as chemotherapy toxicity is concerning, HD-MTX-based chemotherapy up to 3.5 g/m2 was well tolerated with 2–7% treatment-related mortality, less than 10% grade 3–4 nephrotoxicity or stomatitis, and 7–10% treatment discontinuation, though MTX dose was reduced because of decreased renal function in 26–44% of patients (Hoang-Xuan et al., 2003; Illerhaus et al., 2009; Fritsch et al., 2011). Retrospective studies substantiate this view, but more dose reductions were needed when higher doses of MTX have been used (Kurzwelly et al., 2010; Omuro et al., 2007). In only one study toxicity was exceedingly high in older patients (Ghesquières et al., 2010). In general, HD-MTX-based treatment is well tolerated by older patients, providing that adequate supportive measures and careful check of renal function are met (Bessell et al., 2011). As discussed above, risk of neurotoxicity is high in patients older than 60 years managed with chemoradiotherapy. For patients treated with HD-MTX-based chemotherapy without radiotherapy, no studies addressing specifically older patients are

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Table 2 A selection of studies focused on elderly patients with PCNSL. Refs.

N

Median age (range)

MTX (g/m2 )

Other drugs

IT

WBRT

PFS

OS

Neuro-toxicity

Fritsch et al. (2011) Illerhaus et al. (2009) Lai et al. (2004) Welch et al. (2015)

50 23 30 17

72 (60–81) 68 (60–79) 70 (57–79) 67 (58–78)

1 3 3 1

CN, P, S Te CN, P MCN, P, S

yes no no yes

no no no no

7 8 6 20

14 35 15 36

8 0 7 0

MTX = methotrexate delivered dose; IT = intrathecal chemotherapy; WBRT = whole-brain irradiation dose; PFS = median progression-free survival (months); OS = median overall survival (months). Other drugs: CN: lomustine, MCN: ranimustine, P: procarbazine, S: steroids, Te: temozolomide.

available, with the exception of a randomised French study (Omuro et al., 2015b) compared methotrexate (3.5 g/m2 ) with temozolomide (150 mg/m2 ) versus methotrexate (3.5 g/m2 ), procarbazine (100 mg/m2 ), vincristine (1.4 mg/m2 ), and cytarabine (3 mg/m2 ) in patients aged 60 years and older. The efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting that attempting treatment in these poor prognosis patients is worthwhile. In general, reports including neuropsychological assessment in whole patients populations (both younger and older) treated without radiotherapy show little or not at all post-treatment cognitive decline (Juergens et al., 2010; Correa et al., 2012), otherwise than irradiated patients. To summarise, HD-MTX-chemotherapy is feasible in elderly patients with adequate performance status and renal function and determines a better outcome than WBRT. In these patients, the risk of delayed neurotoxicity after WBRT (especially if following HD-MTX) is unacceptably high and WBRT at conventional doses should be deferred or avoided. In older patients in poor condition and in the very old (over 80) patients, both with a worse prognosis (Welch et al., 2012), comorbidities and frequent admissions to hospital associated with HD-MTX chemotherapy need to be individually weighed against the more limited survival benefits in this population. 6.10. Intraocular lymphoma The eye is another reservoir for PCNSL tumour cells. Chemotherapy efficacy depends on intraocular pharmacokinetic, which is not well understood for most cytostatics. Systemic administration of MTX and cytarabine can yield therapeutic drug levels in the intraocular fluids and clinical responses have been documented; however, drug concentrations in vitreous humour are unpredictable and intraocular relapse is common. Intraocular infiltration can be the exclusive site of disease at presentation, or as a part of PCNSL with concomitant brain or meningeal disease. The optimal treatment for intraocular lymphoma (IOL) is not known. Data on therapy and outcome are scarce and limited to retrospective case reports or small series with heterogeneous patient populations and treatments. As many as 90% of patients with IOL consequently develop brain involvement over the course of the disease (Chan et al., 2011) and dissemination to the brain is the main cause of death. The median survival of isolated IOL is approximately 60 months (Grimm et al., 2007). Treatment may be focal, including ocular RT (total dose of 35–40 Gy, 2 Gy per fraction using opposed lateral beams to include both globes) (Berenbom et al., 2007) and/or intravitreal chemotherapy. Uncontrolled series have reported clinical benefit with repeated intravitreal MTX (Frenkel et al., 2008) and more recently after rituximab injections (Hashida et al., 2012). Intravitreal MTX is highly active (remission in 100% of treated eyes) but does not affect OS and is associated with important side effects in 73% of treatments and significant deterioration of visual acuity in 27% of patients. On the other side, intravitreal rituximab appears safe and active, but the data are still limited. Treatment may be also extensive, including systemic chemother-

apy and WBRT. Intraocular responses have been reported with HD-MTX, cytarabine, ifosfamide, trofosfamide used as single agent, with MTX-based polychemotherapy and after HDC/ASCT (Batchelor et al., 2003; Jahnke et al., 2009; Soussain et al., 2001). A large retrospective multicentre study did not show any difference in IOL between focal and extensive therapy in terms of disease control and survival (Grimm et al., 2007). Unfortunately, this and other studies failed to provide reliable predictors of brain dissemination in IOL patients. Thus, some experts recommend local therapy for disease confined to the eyes, while others consider that initial treatment of IOL should not differ from that of PCNSL. Local treatments would remain options for refractory or recurrent disease confined to the eyes. The management decision should take into account the individual risk of treatment toxicities (including those related to ocular treatment) and local expertise (Chan et al., 2011). When IOL is concurrent with brain lesions, it has not been identified as an independent prognostic factor and the prognosis is similar to that of the PCNSL without intraocular disease (Grimm et al., 2008). Accordingly, patients with concomitant intraocular and cerebral disease should be treated no differently from PCNSL. The value of additional local ocular treatment (intravitreal chemotherapy or ocular radiotherapy if WBRT has not been delivered) to systemic chemotherapy remains matter of debate, with conflicting results in two retrospective studies (Grimm et al., 2008; Ferreri et al., 2002a,b). As a practice point, since the high risk of brain dissemination and the lacking of reliable predictors for this event, it is worth to treat patients with IOL with HD-MTX-based chemotherapy (with or without WBRT depending on age) as the other PCNSL patients. Local treatment (intravitreal chemotherapy or ocular RT) is a valid approach for patients with systemic chemotherapy contraindications or for elderly patients with relapsing intraocular disease. If consolidation WBRT is proposed, it should include both eyes. Refractory and relapsed IOL should be treated according to the patients’ characteristics and prior treatments. Treatments could include intravitreal injections of MTX, focal radiotherapy, WBRT, systemic chemotherapy and HDC/ASCT. An attempt to identify the best therapeutic choice for these patients was conducted at 17 referral ophthalmologic centres in Europe (Riemens et al., 2015) with a retrospective study that reviewed clinical, laboratory and imaging data on 78 patients with IOL focusing on the incidence of CNS manifestations during the follow-up period. Therapy to prevent CNS dissemination included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), systemic treatment (group B, 21patients), and a combination of ocular and extensive treatment (group C, 23 patients). Overall, CNS Lymphoma (CSNL) developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35%) than in patients without CNSL (68%) and was similar among all treatment groups. This work, albeit commendable for the effort to collect data for this rare entity, raised some criticism (Ferreri, 2015) such as the lack of a central pathology review, the suboptimal systemic therapy and some biases in cases collection. Other limitations regard the inclusion of small patients subgroups receiving variegated treatments,

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analyzed together in an arbitrary way, and spanning along period of time during which diagnosis and treatment of CNS lymphomas changed greatly. In conclusion, available studies suggest that some patients with IOL can be safely treated with local treatment alone, while other patients should be treated with systemic chemotherapy. Unfortunately, efforts to distinguish the best candidates for each strategy remain at present uneffective due to relevant selection and interpretation biases. An international study focused on patients with IOL managed with ocular treatment alone and aimed to establish clinical and pathological predictors of CNS dissemination should be encouraged.

Table 3 Ongoing large randomized trials for PCNSL. IELSG43- High-dose chemotherapy and autologous stem cell transplant or consolidating conventional chemotherapy in primary CNS lymphoma – randomized phase III trial (MATRix). ClinicalTrials.gov Identifier: NCT02531841 PRECIS – Cranial Radiotherapy or Intensive Chemotherapy With Hematopoietic Stem Cell Rescue for Primary Central Nervous System Lymphoma in Young Patients. ClinicalTrials.gov Identifier: NCT00863460 RTOG – Rituximab, Methotrexate, Vincristine Sulfate, Procarbazine Hydrochloride, and Cytarabine With or Without Radiation Therapy in Treating Patients With Primary Central Nervous System Lymphoma. ClinicalTrials.gov Identifier: NCT01399372 NCI – Combination Chemotherapy With or Without Autologous Stem Cell Transplant in Treating Patients With Central Nervous System B-Cell Lymphoma. ClinicalTrials.gov Identifier: NCT01511562

6.11. Salvage treatment About one third of patients with PCNSL will eventually show no response to first-line treatment and, moreover, up to half of responders will relapse. The prognosis of progressive or relapsed PCNSL remains poor with limited treatment options. Salvage treatment depends on age, performance status, site of relapse, prior treatments, and duration of response. Furthermore, the aggressive course of relapsing PCNSL produces a dramatic PS worsening, often preventing physicians from enrolling patients in prospective trials and, sometimes, from recommending any treatment at all. In case no consolidating treatment after the HD MTX-based induction chemotherapy has been performed, WBRT or HDC/ASCT (if permitted by age and/or performance status) should be considered. Two retrospective studies on WBRT delivered in relapsed PCNSL (Nguyen et al., 2005; Hottinger et al., 2007) reported a high rate of objective responses (75%) and a median survival of 11–16 months, quite similar to what is expected with front-line WBRT. Delayed neurotoxicity occurred in 15%–22% of patients. In routine practice, salvage WBRT should be offered to previously non-irradiated, relapsing patients considering that radiotherapy is more active than most salvage chemotherapies. However, in the setting of recurrence, WBRT did not prolong survival compared with non-WBRT-based therapies in the G-PCNSL-SG-1 trial (Thiel et al., 2010). HDC/ASCT is an efficient alternative option, as has been previously discussed, but it could be only proposed for patients aged <60–65 years and with a tumour sensitive to second-line chemotherapy (Soussain et al., 2008; Soussain et al., 2012). Otherwise, if the patient is not suitable for WBRT or HDC/ASCT, conventional chemotherapy can be proposed. Only a limited number of prospective studies are available with single-arm phase II trials thus preventing any comparison across trials. Temozolomide (Nayak et al., 2013), topotecan (Fischer et al., 2006), IA carboplatin (Tyson et al., 2003); pemetrexed (Raizer et al., 2012), bendamustine (Chamberlain, 2014), PCV regimen (Herrlinger et al., 2000), ifosfamide-etoposide (Mappa et al., 2013), cisplatin-cytarabine (Sierra Del Rio et al., 2011), and temsirolimus (Korfel et al., 2016) demonstrated modest activity. These latter treatments achieved objective response rates of 26–50%, 1-year PFS rates of 13–22%, and 1-year OS rates of 25–41%. More recently, intriguing results were reported with lenalidomide and ibrutinib. Preliminary results of two single-arm phase II trials reported as meeting abstracts show an ORR of 67% for lenalidomide and 75% for ibrutinib. Although response was short lasting in most patients, these reports, if confirmed on large series, might open the door to classes of agents, never used before in this setting, with mechanisms of action strongly different from classic immunechemotherapeutic drugs and, moreover, with particular simple way of administration. MTX rechallenge given as single agent or in combination may also yield a high rate of new objective response (CR: 75%) and durable remission in patients who previously achieved prolonged response with front-line HD MTX-based chemotherapy, suggesting retained chemosensitivity to MTX (Pentsova et al., 2014). Extra-CNS relapses account for 7% of failures, and some stud-

ies suggest that extra-CNS relapses are associated with a better prognosis than CNS-involving relapses (Provencher et al., 2011); the best salvage treatment for this condition remains to be defined, but excellent results have been reported with anthracycline-based chemotherapy consolidated or not with HDC/ASCT (Ferreri et al., 2014). 7. Conclusions In the field of lymphomas, PCNSL exhibits a unique pattern of manifestation and requires specific treatment. It solicits an intense cooperation among various specialists: only experts in stereotactic neurosurgery, neurology, ophthalmologists, haemato-oncology and radio-oncology can reliably manage this disease. Although the prognosis remains generally poor, relevant advances in terms of objective responses and, above all, survival have been achieved. The mainstream of the treatment is a HD-MTX-based polychemotherapy, that can safety be administered in centres with adequate expertise. Radiotherapy maintains its role, but it is generally ineffective as the sole treatment and, moreover, carries out neurologic toxicity often dramatically disabling. HDC/ASCT is a promising therapeutic tool that is reserved to younger patients and needs to be confirmed for efficacy/toxicity ratio in ongoing randomized trial. In general, it is recommended to refer patients to qualified centres and to accrual them if possible in clinical trials (see Table 3) in order to provide evidence-based conclusions on each of the main questions still open, in particular on the better front-line HD-MTX polychemotherapy, the need for consolidation WBRT and the precise role for HDC/ASCT. Every effort should be made, paralleling with advances in disease control, in order to reduce the neurotoxicity of treatments, particularly radiotherapy. Finally, an accompanying research programme needs to address questions of PCNSL biology as a valid basis for correlation of clinical and molecular data in order to reveal biomarkers, which may help stratify patients to specific therapeutic regimens, and which may have a prognostic impact on the course and the outcome of this disease. Conflict of interest disclosure the authors declare they have no conflict of interest. Acknowledgment This research was supported by the European Commission with the project “Information network on rare cancers”, grant number 2000111201. References Abrey, L.E., DeAngelis, L.M., Yahalom, J., 1998. Long-term survival in primary CNS lymphoma. J. Clin. Oncol. 16 (3), 859–863. Abrey, L.E., Yahalom, J., DeAngelis, L.M., 2000. Treatment for primary CNS lymphoma: the next step. J. Clin. Oncol. 18 (17), 3144–3150.

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