Therapeutic challenges in primary CNS lymphoma

Therapeutic challenges in primary CNS lymphoma Patrick G Morris, Lauren E Abrey Optimum treatment for patients with primary CNS lymphoma remains challenging because there have not been any large randomised clinical trials of this rare tumour. Drugs used in treating systemic non-hodgkin lymphoma have mostly proven ineffective because of difficulties crossing the blood brain barrier. The recognition of the efficacy of high-dose methotrexate was a substantial therapeutic breakthrough and further advances, such as the development of polychemotherapy regimens, have built on this. Whole-brain radiotherapy can consolidate response to chemotherapy, but the associated toxic effects of chemoradiation can be unacceptable. Other effective approaches include disruption of the blood brain barrier and the use of high-dose chemotherapy. Recently, there have been attempts to optimise multi-drug chemotherapy regimens by focusing on improving survival and reducing toxic effects. A promising area of research is the incorporation of novel targeted drugs into standard treatment frameworks. In the future, greater cooperation between research groups should hopefully lead to further therapeutic advances. Introduction Primary CNS lymphoma (PCNSL) is a rare B-cell variant of non-hodgkin lymphoma that is confined to the brain, leptomeninges, spinal cord, and eyes. Although PCNSL accounts for less than 7% of brain tumours, its incidence is increasing, particularly in immunocompetent individuals. 1 By contrast with most primary brain tumours, PCNSL is sensitive to corticosteroids, chemotherapy, and radiotherapy. Durable complete responses and long-term survival are possible with these treatments; however, outcome for patients with PCNSL is substantially worse than that for patients with a similar stage of systemic non-hodgkin lymphoma. Advances in treatment have been limited not only because PCNSL is a rare tumour and large randomised clinical trials have not been successfully done, but also because of a lack of consensus about which questions these studies should address. Several other difficulties also exist; for example, many patients with PCNSL are older at diagnosis, have substantial comorbidities, and have worse performance status than do other groups with systemic non-hodgkin lymphoma. Modern combination chemotherapy regimens used for the treatment of systemic non-hodgkin lymphoma have mostly proven ineffective in PCNSL because of the drugs poor penetration of the CNS and their inability to cross the blood brain barrier. Despite these obstacles, substantial progress has been made. A growing body of evidence from phase II clinical trials has shown the efficacy of several treatment strategies. Results from several studies of high-dose methotrexate have shown improved disease control and longer survival. 2 6 Effective combination chemotherapy regimens have been developed to incorporate methotrexate and whole-brain radiotherapy. 2 4,6 Immunotherapy, which revolutionised the treatment of systemic non-hodgkin lymphoma, also seems to offer benefits for patients with PCNSL. Substantial progress has also been made in the treatment of subpopulations with PCNSL, such as patients with intraocular lymphoma and PCNSL associated with HIV. However, the optimum treatment for patients with PCNSL remains challenging and at present there is no universally accepted therapeutic approach for patients with newly diagnosed disease. Relapse is a common problem with little consensus on appropriate second-line treatments. For patients with durable remission, substantial treatment-related neurotoxicity has emerged as a major problem one that is particularly prominent in patients older than 60 years at diagnosis. 7 In this Review, we discuss the recent progress in the management of PCNSL and identify specific challenges for the future. More general overviews of the epidemiology, staging, and diagnosis of PCNSL are provided in other comprehensive reviews. 8,9 Newly diagnosed PCNSL Chemotherapy High-dose methotrexate Initial attempts to treat PCNSL with chemotherapy focused on standard drugs with proven efficacy for non-hodgkin lymphoma. One of the most active and commonly used regimens was the four-drug combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Although regimens such as CHOP induced an initial radiographical response in PCNSL, these responses were not durable and patients relapsed rapidly. Similar problems are reported with corticosteroids when used as monotherapy for the treatment of PCNSL. The major difficulty with these chemotherapeutic drugs in PCNSL is their apparent inability to cross the blood brain barrier and eradicate microscopic disease. The observation that patients with systemic non-hodgkin lymphoma who had CNS relapse responded to high doses of methotrexate drew attention to this drug as a potentially important and active treatment for PCNSL. 10,11 Methotrexate, a folate antagonist that interrupts DNA synthesis, is now the most widely studied drug for PCNSL. Penetration of methotrexate into the CNS is poor when given at conventional doses (<100 mg/m²) used in the treatment of other malignancies. This problem has been overcome by the use of so-called high-dose methotrexate, in doses ranging from 1 g/m² to 8 g/m². 2 9,12 18 Additionally, multiple dosing schedules, including rapid intravenous infusion, 24-h continuous infusion, and intracarotid infusion with disruption of the Lancet Neurol 2009; 8: 581 92 Department of Medicine (P G Morris MD) and Department of Neurology (L E Abrey MD), Memorial Sloan-Kettering Cancer Center, New York, NY, USA Correspondence to: Lauren E Abrey, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA abreyl@mskcc.org www.thelancet.com/neurology Vol 8 June 2009 581

blood brain barrier, have been used in an effort to improve efficacy (table 1). To optimise drug delivery to the brain parenchyma and cerebrospinal fluid, both the total dose and rate of infusion of methotrexate are important. Patients treated with less than 3 g/m² do not reliably achieve cytocidal concentrations of methotrexate in the cerebrospinal fluid (1 µmol/l). 27 Rapid infusion of 3 g/m² of methotrexate over 3 h will consistently achieve cytocidal concentrations in the cerebrospinal fluid, whereas this concentration is not reliably obtained with a 24-h continuous infusion of 8 g/m². 28,29 Clinical trials have not shown a clear advantage in the use of methotrexate doses above 3 g/m². Although a direct comparison of different studies with varying entry criteria and treatment regimens has limitations, a phase II trial that used two cycles of 1 g/m² of methotrexate monotherapy plus six doses of intrathecal methotrexate (12 mg per dose) resulted in a 64% objective radiographical response rate (before whole-brain radiotherapy and all partial responses) 13 as compared with a higher, but comparable, response rate of 74% (52% complete response) reported in another phase II trial that used 8 g/m² of methotrexate monotherapy. 3 This observation has important clinical implications. High doses of methotrexate (>3 g/m²) require intensive inpatient management and might not be feasible in older patients (>60 years) or in patients with impaired renal function. Lower methotrexate doses can be safely given in an outpatient setting, with substantial reductions in the cost of health care and in patient morbidity. Lower doses could also be easier to incorporate into multi-drug chemotherapy regimens than high-dose methotrexate. All patients who receive at least 1 g/m² methotrexate require adequate creatinine clearance and rigorous attention to supportive care, including aggressive WBRT alone n Median age (years) Methotrexate dose (g/m²) Response rate (complete and partial responses [%]) Median overall survival (months) WBRT 19 41 66 63 11 6 NR Chemotherapy alone Methotrexate 14 37 60 8 0 35 NR 13 7 Methotrexate 3 25 60 8 0 74 23 0 12 8 Methotrexate and temozolomide 20 23 68 3 0 55 35 0 8 0 Median progressionfree survival (months) Methotrexate, lomustine, procarbazine, methylprednisolone, and 50 72 1 0 48 14 3 6 8 intrathecal chemotherapy 5 Methotrexate, thiotepa, vincristine, dexamethasone, and intrathecal 14 57 8 4 100 NR 16 5 chemotherapy 17 Methotrexate, vincristine, ifosfamide, cyclophosphamide, cytarabine, 65 62 5 0 71 50 0 21 0 and intrathecal chemotherapy 15 Methotrexate, cytarabine, BEAM, and autologous stem-cell 28 53 3 5 57 NR 5 6 transplantation 12 Methotrexate, etoposide, cyclophosphamide, procarbazine, and blood 74 60 5 0* 68 41 0 NR brain barrier disruption 21 Chemotherapy with WBRT Methotrexate, intrathecal chemotherapy, and cytarabine 13 31 58 1 0 93 42 5 41 0 Methotrexate 6 46 58 1 0 NR 33 0 >24 0 Methotrexate, procarbazine, vincristine, intrathecal chemotherapy, 52 65 3 5 94 60 0 NR cytarabine 2 Methotrexate, procarbazine, vincristine, intrathecal chemotherapy, and 102 57 2 5 94 37 0 24 0 cytarabine 4 Methotrexate, carmustine, teniposide, methylprednisolone, and 52 51 3 0 81 46 0 NR intrathecal chemotherapy 16 Methotrexate, thiotepa, procarbazine, and intrathecal chemotherapy 22 17 53 1 0 88 32 0 18 0 Rituximab, methotrexate, procarbazine, vincristine, and cytarabine 23 30 57 3 5 93 37 0 40 0 Methotrexate, cytarabine, thiotepa, and iarubicin 24 41 57 3 5 83 15 0 NR Methotrexate, cytarabine, thiotepa, carmustine, and autologous stemcell 30 54 8 0 77 60 0 NR 25 transplantation Methotrexate, etoposide, carmustine, methylprednisolone, ifosfamide, cytarabine, BEAM, autologous stem-cell transplantation, and intrathecal chemotherapy 26 BEAM=carmustine, etoposide, cytarabine, and melphalan. NR=not reported. WBRT=whole-brain radiotherapy. *g per cycle. Table 1: Treatment regimens for primary CNS lymphoma 25 51 3 0 84 34 0 40 0 582 www.thelancet.com/neurology Vol 8 June 2009

hydration, urine alkalinisation, and folinic acid rescue to reduce morbidity. Patients who receive doses of at least 3 g/m² should be monitored in an inpatient setting with daily assessment of methotrexate concentrations and close monitoring of renal function. Dose adjustments with consecutive cycles are needed for impaired glomerular filtration rate. If this schedule is closely adhered to, patients older than 60 years can be safely treated with high-dose methotrexate, although further dose reductions might be needed. 30 Up to 42% of patients with PCNSL are estimated to have leptomeningeal involvement at diagnosis. 31 Cerebrospinal fluid cytology can reliably identify leptomeningeal disease in about 15% of patients. 1 Flow cytometry might be a more sensitive technique; hence, leptomeningeal dissemination could be underdiagnosed with the use of cytology alone. In support of this possibility, in a series of patients with systemic non-hodgkin lymphoma who were at high risk of CNS involvement, flow cytometry was more sensitive than cerebrospinal fluid cytology in the detection of leptomeningeal involve ment (22% vs 2%). 32 However, recent data from a large study that compared different diagnostic techniques suggested that the reported incidence of leptomeningeal disease remains low even when sensitive methods, such as PCR, are used. 33 This study also drew attention to the risk of discordance between modern methods and standard cytology. Therefore, results of flow cytometry and PCR should be interpreted with caution and alongside conventional cerebrospinal fluid cytology. For patients with proven leptomeningeal disease, intrathecal chemotherapy (usually methotrexate or cytarabine) used to be the standard treatment. In the more recent setting of high-dose methotrexate-based regimens, the use of intrathecal treatment is controversial. Patients who receive at least 3 g/m² of methotrexate obtain adequate concentrations in the cerebrospinal fluid; therefore, patients who receive this dose and who do not have evidence of positive cerebrospinal fluid cytology can probably safely omit intrathecal treatment. In the absence of intrathecal treatment, the available data lend support to a recommendation for a methotrexate dose of at least 3 g/m² given over 3 h in all patients who have PCNSL and who have adequate renal function. Patients who receive a lower dose of systemic methotrexate, or who have other evidence of leptomeningeal dissemination, should have sup plemental treatment with intrathecal methotrexate. Methotrexate monotherapy versus methotrexate-based multi-drug regimens Despite the improved outcomes seen with methotrexate, relapse after primary treatment for PCNSL is still a major problem. Therefore, clinical trials have attempted to increase the proportion of durable responses with the development of multi-drug methotrexate-based regimens. The rationale for this approach can again be extrapolated from similar approaches in systemic non-hodgkin lymphoma, for which polychemotherapy regimens that use drugs with different mechanisms of action and non-overlapping side-effect profiles have been developed to overcome tumour resistance, optimise disease control, and improve long-term outcomes. Single-drug and multi-drug methotrexate-based regimens have both been used effectively in the management of PCNSL. However, the incremental benefit of additional chemotherapeutic drugs is unclear and the selection of specific drugs incorporated into the multi-drug regimens has been mostly empirical (table 1). 2,4,5,12,15 17,20,22,24 As high-dose methotrexate can penetrate the CNS, it is an attractive option for the treatment of PCNSL; therefore, other lipophilic drugs that can cross the blood brain barrier have also been studied. Radiographical response rates and disease-free survival seem to be slightly higher in trials that use multi-drug methotrexate-based chemotherapy regimens than in those that use methotrexate monotherapy, although rates often overlap between these trials. Methotrexate-based polychemotherapy regimens are, therefore, often preferred over methotrexate monotherapy. One commonly used methotrexate-based regimen is the three-drug combination of methotrexate, procarbazine, and vincristine (MPV). These three drugs have different mechanisms of action and different toxic effects. Vincristine, a vinca alkaloid, is commonly used for the treatment of non-hodgkin lymphoma and Hodgkin s disease. By binding to the central portion or vinca-binding site of the β-tubulin subunit, vincristine causes destabilisation of microtubules. Vincristine does not cross the intact blood brain barrier but, when the blood brain barrier is disrupted by the tumour, this drug seems to reach areas of bulky disease. 34 Procarbazine is an oral alkylating drug that has been used in the treatment of Hodgkin s disease and is sometimes used for various brain tumours as it is lipophilic and can cross the blood brain barrier. Therefore, although the incorporation of these drugs into polychemotherapy regimens was based on empirical evidence, there is a reasonable rationale for their use. The Radiation Therapy Oncology Group and Southwest Oncology Group 93-10 study used this three-drug regimen, followed by whole-brain radiotherapy and two cycles of cytarabine, and showed a 94% response rate. 4 This study was the first multicentre trial to show better survival with the combination of chemotherapy and radiotherapy than with the historical control of radiotherapy alone. This regimen has subsequently been modified (table 2) on the basis of methotrexate dosing and the omission of intrathecal chemotherapy for appropriate patients, but is still a proven active treatment schedule. High-dose cytarabine has been used as a consolidation strategy in several studies. A large retrospective analysis www.thelancet.com/neurology Vol 8 June 2009 583

Drug class MPV* (repeat cycles every other week), WBRT, and cytarabine Schedule Methotrexate 3 5 g/m², iv (with folinic acid rescue) Antimetabolite Day 1 Procarbazine 100 mg/m², po Alkylating drug Days 1 7, every other cycle Vincristine 1 4 mg/m², iv Antimicrotubule drug Day 1 Cytarabine 3 g/m², iv (after WBRT for two cycles once every 3 weeks) MBVP 16 (repeat cycles every 4 weeks) and WBRT Antimetabolite Days 1 and 2 Methotrexate 3 g/m², iv (with folinic acid rescue) Antimetabolite Days 1 and 15 Carmustine 100 mg/m², iv Alkylating drug Day 4 Teniposide 100 mg/m², iv Topoisomerase inhibitor Days 2 and 3 Methylprednisolone 60 mg/m², po Corticosteroid Days 1 to 5 Methotrexate 15 mg, it Antimetabolite Days 1 and 15 Cytarabine 40 mg, it Antimetabolite Days 1 and 15 Hydrocortisone 25 mg, it Corticosteroid Days 1 and 15 MATILDE 24 (repeat cycles every 3 weeks) and WBRT Methotrexate 3 5 g/m², iv (with folinic acid rescue) Antimetabolite Day 1 Cytarabine 2 g/m², iv 2 Antimetabolite Day 2 Idarubicin 15 mg/m², iv Anthracycline antibiotic Day 2 Thiotepa 25 mg/m², iv Alkylating drug Day 3 iv=intravenous. it=intrathecal. MATILDE=methotrexate, cytarabine, thiotepa, and idarubicin. po=oral. MBVP=methotrexate, carmustine, teniposide, and methylprednisolone. MPV=methotrexate, procarbazine, and vincristine. WBRT=whole-brain radiotherapy. *Adapted from reference 23. Table 2: Commonly used combination chemotherapy regimens for primary CNS lymphoma from the International Extranodal Lymphoma Study Group (IELSG) found that cytarabine use was a significant independent treatment variable. 7,35 Furthermore, data from a recent randomised phase II trial offered clear evidence of the benefit of incorporating high-dose cytarabine into methotrexate-based regimens. 36 In this study, 79 patients with newly diagnosed PCNSL were randomly assigned to receive four cycles of high-dose methotrexate (3 5 g/m²) on day 1 of a 21-day cycle alone or in combination with high-dose cytarabine (2 g/m²) on days 2 3. Chemotherapy was then followed by whole-brain radiotherapy. The addition of cytarabine to methotrexate increased the rate of complete response (the primary endpoint) from 18% to 46% (p=0 006). Additionally, the overall response rate was improved in the combination group (69% vs 43%, p=0 009), and at a median follow-up of 30 months combination treatment seemed to be associated with longer event-free survival and overall survival than methotrexate alone. As noted earlier, randomised trials have proven challenging and this is the first randomised study in PCNSL with completed accrual of patients. The results of this landmark study have several important implications. First, the incorporation of high-dose cytarabine into methotrexate-based regimens increases response rates and is an appropriate strategy to improve long-term disease control. Second, for the first time there are now data showing the benefits of metho trexatebased polychemotherapy over methotrexate monotherapy. The use of prednisone as an active drug in systemic non-hodgkin lymphoma has raised the possibility that corticosteroids could have a therapeutic role in the management of PCNSL. Additionally, many patients with PCNSL receive dexamethasone to manage tumour-related oedema. However, there are concerns about the toxic effects of high-dose corticosteroids, particularly when given for protracted periods. Nevertheless, some studies have shown that regimens containing corticosteroids are active in PCNSL. 5,16,17,26 For example, in trial 20962 undertaken by the European Organisation for Research and Treatment of Cancer (EORTC) lymphoma group, 16 52 patients were treated with combination chemotherapy (methotrexate, teniposide, carmustine, and methyl prednisolone) plus intrathecal chemotherapy and subsequent whole-brain radiotherapy (table 2). A high response rate (81%) and a notable overall survival (median 46 months) were seen (table 1); however, five (10%) patients died, probably because of infectious complications. These deaths should engender caution among clinicians that these multi-drug chemotherapy regimens are associated with substantial toxicity even when undertaken at specialist centres. In general, the incorporation of corticosteroids into multi-drug treatment regimens has not increased response rates compared with non-steroid containing regimens. Therefore, with no definite benefit and the associated risk of side-effects, many physicians strive to keep the use of corticosteroids to a minimum. Other active combination chemotherapy regimens have been investigated in clinical trials. Methotrexate with cytarabine, thiotepa, and idarubicin (MATILDE) is another methotrexate-based regimen that does not incorporate high-dose steroids or intrathecal treatment and is also associated with a high response rate (tables 1 and 2). 24 These various combination regimens have not been directly compared in a randomised trial but all seem to have similar response rates (table 1). The optimum duration of chemotherapy is also unclear. A standard course of MPV involves five cycles of high-dose methotrexate, and other regimens have used similar durations of treatment. For patients who do not achieve a complete response after five cycles, the addition of two further cycles of treatment can be a useful strategy to improve response rates. 23 For patients older than 60 years who are not suitable candidates for combination chemotherapy, temozolomide and methotrexate followed by maintenance temozolomide might be appropriate as this approach has been associated with some durable responses. 20 Disruption of the blood brain barrier An alternative strategy for the deliver of chemotherapy into the CNS is the disruption of the blood brain barrier. This approach involves cannulation of the carotid or vertebral arteries under general anaesthesia, osmotic disruption of the blood brain barrier with mannitol 584 www.thelancet.com/neurology Vol 8 June 2009

infusion, and intra-arterial chemotherapy. 21 This strategy has been successfully used without the need for whole-brain radiotherapy with reasonable response rates (table 1), but seems to be less active than other standard intravenous chemotherapy combinations followed by whole-brain radiotherapy. The major drawback with this approach is the need for general anaesthesia and cannulation of the intracranial vessels; as such, this procedure should not be undertaken outside a specialist institution. High-dose chemotherapy with autologous stem-cell transplantation For patients with relapsed or refractory systemic non-hodgkin lymphoma, the use of high-dose chemotherapy with autologous stem-cell transplantation is an effective treatment option. 37 Because PCNSL can be thought of as a high-risk form of non-hodgkin lymphoma, there is a strong rationale for the use of stem-cell transplantation. In PCNSL, results from several phase II studies, some of which have also incorporated whole-brain radiotherapy, have shown that this approach is feasible and is associated with a reasonable response rate (table 1). 12,25,26,38 41 A recent review analysed data from seven trials involving 132 patients with newly diagnosed PCNSL who were treated with high-dose methotrexatebased induction chemotherapy followed by conditioning chemotherapy and autologous stem-cell transplantation. 42 These studies used either carmustine, etoposide, cytarabine, and melphalan (BEAM) or thiotepa-based conditioning regimens. Direct comparison between these groups is difficult, but thiotepa-based regimens seem to be associated with greater efficacy than BEAM-based regimens. This finding can be partly explained by the high CNS penetration of drugs such as busulfan, thiotepa, and carmustine. There are some notable limitations of these data. The patients enrolled in these studies tended to be younger than patients in other studies and, therefore, probably represented a group with better performance status and prognosis. Furthermore, many patients who reached the transplantation stage have already been shown to have chemotherapy-sensitive disease. Whether these same younger patients with chemotherapy-sensitive disease would have done equally well with standard high-dose methotrexate-based chemotherapy such as MPV is unknown because these approaches have not been compared. Additionally, these studies showed treatment-related mortality of up to 14% and significant morbidity; therefore, this approach should be considered only in specialist centres. Whole-brain radiotherapy In the era of modern methotrexate-based chemotherapy, the role of radiotherapy has been increasingly questioned. Historically, whole-brain radiotherapy was the standard of care for patients newly diagnosed with PCNSL. Since then it has become clear that adding methotrexate-based chemotherapy to whole-brain radiotherapy commonly results in a notable improvement in disease control and overall survival (table 1). Following the further advances with polychemotherapy regimens and a resultant increase in proportion of long-term survivors, the long-term neurotoxic effects of whole-brain radiotherapy became increasingly evident. These varying effects can include treatment-related dementia, gait disturbance, and urinary incontinence. Patients who are older than 60 years and those who receive high-dose methotrexate seem to be at particular risk. 7 As a result, and in an effort to reduce the risk of treatment-related neurotoxicity, many recent studies and clinical practice guidelines have chosen to defer or avoid whole-brain radiotherapy in patients who achieve a complete response with initial chemotherapy. The major concern with this approach is that eliminating the use of whole-brain radiotherapy could compromise disease control. In two large retrospective analyses, the addition of whole-brain radiotherapy to combination chemotherapy did not improve survival in patients treated with high-dose methotrexate, but was associated with improvements in long-term disease control. 35,43 In another comparison of older patients (>60 years) treated with methotrexate-based chemotherapy, with or without whole-brain radiotherapy, no difference was found in overall survival. However, disease control was compromised in the group that did not receive whole-brain radiotherapy, whereas the incidence of neurotoxic effects was higher in patients who did receive this treatment. 44 Many clinicians defer whole-brain radiotherapy in older patients (>60 years), but defining an appropriate age limit is too simplistic and a more individualised approach might be needed, depending on comorbidities and treatment response. Finally, the contribution of other factors, such as comorbidities, or the risk of neurotoxic effects is unclear and merits further study. In an attempt to keep toxic effects to a minimum without impairing outcomes, several studies have investigated the possibility of modifying whole-brain radiotherapy, either by giving a low total dose or by use of focused radiotherapy. A hyperfractionated schedule of whole-brain radiotherapy with a reduced total dose of 3600 cgy was compared with 4500 cgy standard fractionation as a subset analysis in a large study by the Radiation Therapy Oncology Group. However, no significant change in the rate of tumour recurrence or neurotoxicity was recorded. 4,45 The Nottingham and Barcelona group reported that young patients who received a low total dose (3060 cgy) of whole-brain radiotherapy after a complete response to induction chemotherapy had a significantly higher risk of relapse and shorter overall survival than patients who received full-dose (4500 cgy) radiotherapy. 46 Focal radiotherapy, either as a boost delivered in combination with whole-brain radiotherapy or as stereotactic radiotherapy, www.thelancet.com/neurology Vol 8 June 2009 585

Progression-free survival (%) Survival (%) A 100 75 50 25 0 0 B 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 Time (years) Overall survival Progression-free survival 0 1 2 3 4 Time (years) Figure: Progression-free survival from two phase II studies of methotrexate (A) Methotrexate, procarbazine, and vincristine treatment. 4 (B) Methotrexate, procarbazine, and vincristine combined with rituximab treatment. 23 has had disappointing results with high rates of tumour recurrence in the radiated field. 13,47,48 A 2007 study found that delivering reduced doses of whole-brain radiotherapy (2340 cgy) after a complete response to methotrexate-based chemotherapy resulted in excellent disease control with no evidence of delayed neurotoxic effects on detailed neurocognitive follow-up. 23 The available data suggest that whole-brain radiotherapy probably has an important role in optimising disease control for patients with PCNSL. However, the side-effects associated with full-dose treatment are unacceptable to most patients and practitioners, particularly for elderly patients. Preliminary phase II data 23 suggest that lowering the dose of whole-brain radiotherapy could be safe and feasible in patients who achieve a complete remission with methotrexate-based chemotherapy, but these data should ideally be confirmed in a prospective multicentre trial. The question of the omission of radiotherapy for patients responding to high-dose methotrexate is being investigated in a randomised trial. 49 In this study, patients who achieve a complete response after methotrexate-based chemotherapy will be randomly assigned to immediate treatment with 4500 cgy whole-brain radiotherapy or to observation and then the same dose of whole-brain radiotherapy at first recurrence. The results of this study could help to define a cohort of patients who can safely avoid whole-brain radiotherapy as part of their initial treatment. In the future, if standard treatment regimens are successfully modified to omit or adapt radiotherapy, it might also be necessary to develop alternative or intensified chemotherapy strategies to consolidate disease control. Immunotherapy An important active area of research is the investigation of novel targeted drugs. The development of monoclonal antibodies and small-molecule tyrosine kinase inhibitors represents a major breakthrough in many areas of oncology. In systemic non-hodgkin lymphoma, these advances have focused on CD20, a cell-surface protein that occurs almost exclusively on mature B cells. The addition of rituximab (a humanised monoclonal antibody to CD20) to CHOP increased the response rate and prolonged survival in non-hodgkin lymphoma; 50 therefore, rituximab with CHOP has now replaced CHOP as the standard of care for diffuse large B-cell lymphoma. As PCNSL is almost exclusively a disease of B lymphocytes, there is a strong rationale for incorporating drugs such as rituximab into multi-drug treatment. Despite concerns that rituximab might not cross the blood brain barrier, several reports document some single-drug activity in PCNSL, although the overall response rates are modest. 51 53 The optimum use of rituximab in non-hodgkin lymphoma seems, however, to be in combination with chemotherapy. In PCNSL, results from a phase II trial of 30 patients showed that the addition of rituximab to MPV treatment was feasible and was associated with a high response rate (table 1 and figure). 23 After up to seven cycles of rituximab with MPV, 78% of patients had a complete response and the overall response rate was 93%. In this study, the addition of rituximab to methotrexate-based chemo therapy resulted in an increased rate of neutropenia that required growth factor support. Although direct comparisons of clinical trials are difficult, survival from this approach seems to be improved compared with standard MPV (figure). Several points should be noted in making this comparison between studies the Radiation Therapy Oncology Group study (figure) enrolled three times as many patients and had a longer follow-up and so might give a more accurate indication of survival than the study incorporating rituximab. Additionally, this study used a low dose of methotrexate, which might also account for the worse outcome compared with rituximab plus MPV. theless, the incorporation of rituximab into MPV polychemotherapy is a potentially important advance. Longer follow-up from this study and the results of other studies are awaited to establish whether the addition of rituximab does indeed improve disease control or survival. 586 www.thelancet.com/neurology Vol 8 June 2009

Alternative strategies for rituximab administration have also been studied. In a phase I study of direct intrathecal administration of rituximab given twice weekly, six of ten patients responded. 54 Monthly maintenance doses of rituximab were effective for maintaining remission in a small series of patients with PCNSL who were at high risk for relapse. 55 This strategy has been used in systemic non-hodgkin lymphoma in certain situations. In recurrent or refractory PCNSL, rituximab delivered in combination with temozolomide for patients with recurrent or refractory PCNSL resulted in a 50% radiographical response. 56 Monoclonal antibodies labelled with low-energy radiation are being used to deliver targeted radioimmunotherapy. When used in PCNSL, there were some concerns that these drugs would be unable to penetrate the blood brain barrier, but this concern has not been justified. Ibritumomab is a murine anti-cd20 antibody, which can be conjugated via a linker chelator (tiuxetan) to radioisotopes for both imaging studies and radioimmunotherapy. In a pilot study of the radiolabelled monoclonal antibody ¹¹¹In-ibritumomab tiuxetan, there was evidence of brain lymphoma targeting, which suggests that these radioimmunotherapies could be delivered as a component of PCNSL treatment. 57 A more recent phase II study in heavily pretreated patients confirmed that this approach was feasible, although responses tended to be of a short duration. 58 Overall, these studies of rituximab and ibritumomab provide preliminary evidence that the targeting of CD20 is a Study phase Study description Radiotherapy dose per protocol Newly diagnosed primary CNS lymphoma RTOG I/II Pre-irradiation chemotherapy with methotrexate, rituximab, and temozolomide, and post-irradiation with temozolomide 59 MSKCC II Rituximab, methotrexate, procarbazine, and vincristine followed by high-dose chemotherapy with autologous stem-cell rescue 60 OHSU II Methotrexate, procarbazine, lomustine, dexamethasone, and cytarabine 61 OHSU II Rituximab, carboplatin, cyclophosphamide, and etoposide given in conjunction with osmotic blood brain barrier disruption, high-dose thiosulfate, and cytarabine 62 IELSG II Randomised trial on primary chemotherapy with high-dose methotrexate, alone or associated with high-dose cytarabine, followed by response-tailored and age-tailored radiotherapy 36 CALGB II Rituximab, methotrexate, and temozolomide followed by cytarabine and etoposide 63 ECOG II Rituximab in combination with standard methotrexate, procarbazine, vincristine, and cytarabine 64 ANOCEF II Randomised study of methotrexate and temozolomide compared with methotrexate, procarbazine, and vincristine for patients older than 60 years of age 65 UTSW II Pre-vaccine treatment with methotrexate, thiotepa, and wholebrain radiotherapy followed by tumour-derived immunoglobulin idiotype-keyhole limpet haemocyanin conjugate vaccine 66 Hoffman La Roche Canada Charite University, Germany Recurrent primary CNS lymphoma 3600 cgy (120 cgy twice daily for 15 days) Complete response following chemotherapy (3600 cgy) Partial response following chemotherapy (3600 cgy and boost 900 cgy) Progressive disease following chemotherapy (4000 cgy and boost 900 cgy) II Rituximab, methotrexate, and cytarabine 67 Whole-brain radiotherapy IV Whole-brain radiotherapy after high-dose methotrexate 49 4500 cgy after chemotherapy or 4500 cgy at first recurrence NABTC II Rituximab and temozolomide followed by maintenance methylprednisolone 68 Baylor II Temozolomide and topotecan 69 IELSG II Idarubicin 70 OSU II Blood brain barrier disruption and chemotherapy with rituximab, carboplatin, cyclophosphamide, etoposide, and cytarabine 71 NABTT II Rituximab 72 ANOCEF=Association des Neuro-Oncologues d Expression Française. CALGB=Cancer and Leukemia Group B. ECOG=Eastern Cooperative Oncology Group. IELSG=International Extranodal Lymphoma Study Group. MSKCC=Memorial Sloan-Kettering Cancer Center. NABTC=North American Brain Tumor Coalition. NABTT=New Approaches to Brain Tumor Therapy. OHSU=Oregon Health and Sciences University. OSU=Ohio State University. RTOG=Radiation Therapy Oncology Group. UTSW=University of Texas Southwestern. Table 3: Selected ongoing clinical trials for primary CNS lymphoma www.thelancet.com/neurology Vol 8 June 2009 587

n Response rate (complete response and partial response [%]) Median overall survival (months) WBRT without previous radiotherapy exposure 74 48 79 16 10 WBRT without previous radiotherapy exposure 75 27 74 11 9 7 Rituximab and temozolomide 56 15 53 14 7 7 Cytarabine, etoposide, thiotepa, busulfan, cyclophosphamide, and autologous 43 47 18 NR stem-cell transplantation 79 ⁹⁰Y-ibritumomab tiuxetan 57 6 33 3 5 1 5 Topotecan 80 15 40 32 2 Topotecan 76 27 33 8 2 Procarbazine, lomustine, and vincristine 81 7 86 12 NR Temozolomide 82 36 31 3 9 2 8 Ifosfamide, etoposide, and cytarabine 83 16 37 NR 5 Carboplatin, etoposide, cyclophosphamide, and blood brain barrier disruption 84 37 37 7 NR NR=not reported. WBRT=whole-brain radiotherapy. Table 4: Salvage regimens for primary CNS lymphoma Median progression-free survival (months) potentially useful therapeutic strategy in PCNSL. So far, however, the available data are too preliminary to provide support for any specific recommendations to routinely incorporate rituximab or ¹¹¹In-ibritumomab tiuxetan into PCNSL treatment outside the setting of a clinical trial. Several ongoing clinical trials are investigating the use of rituximab for use in both primary and relapsed PCNSL (table 3). In the future, it is hoped that drugs such as rituximab will be incorporated into standard therapeutic options and, ultimately, will improve patient outcomes. Recurrent or refractory PCNSL Despite treatment advances, relapse from PCNSL remains a substantial problem. Salvage treatment is needed for patients who develop recurrent or refractory PCNSL after initial treatment; best estimates suggest that up to half of patients will relapse after initial remission and 10 15% of patients will have primary refractory PCNSL. 73 Unfortunately, there are few available data for the optimum approach to management in this setting. Additionally, treatments for relapsed or refractory disease are frequently limited by worsening performance status and treatment-related toxic effects. With this in mind, the selection of treatments for recurrent disease is individualised on the basis of both tumour-related and patient-related characteristics. Treatment options at the time of tumour progression are mostly determined by the treatment given at diagnosis and by the timing of tumour progression (table 2). Patients who had whole-brain radiotherapy deferred at diagnosis can be effectively treated with whole-brain radiotherapy at a later stage, although the risk of treatment-related neurotoxicity is a concern. 74,75 Reinduction with high-dose methotrexate can be successful if a reasonable time interval has elapsed from initial methotrexate-based treatment. 76 78 Other effective salvage chemotherapy regimens have been reported (table 4); 56,79 85 however, several of these studies were limited by small sample sizes or by their retrospective design. Single-drug treatment with either topotecan or temozolomide has been shown to be effective. 76,80,82 Alternative strategies to consolidate a second remission such as myeloablative chemotherapy, maintenance immunotherapy, or disruption to the blood brain barrier can extend disease control and survival. 55,79,84 Ocular lymphoma Ocular lymphoma can present in isolation, as primary intraocular lymphoma, or as an extension of parenchymal brain lymphoma. Primary intraocular lymphoma on its own is very rare and probably occurs in only 100 200 patients every year in the USA. This disease is diagnostically challenging as many patients present with symptoms that are identical to nonspecific uveitis; how ever, primary intraocular lymphoma eventually becomes refractory to topical steroid application. Diagnosis is usually made by cytological assessment of a vitrectomy specimen, although supplemental analysis of the vitreous body, including cytokines (interleukins 10 and 6), flow cytometry, and PCR, can be helpful. 86 These patients are therapeutically challenging because of a high risk of developing brain involvement, which has been reported to be as high as 80% in small series. 87,88 As a result, many authors have advocated the treatment of patients who have primary intraocular lymphoma with systemic chemotherapy in addition to focal treatment directed at the ocular compartment. However, in a large international retrospective series of primary intraocular lymphoma, no clear benefit was found in terms of disease control or survival for patients who received aggressive treatment. 89 Therefore, many clinicians treat patients who have primary intraocular 588 www.thelancet.com/neurology Vol 8 June 2009

lymphoma with directed ocular treatment (either ocular radiotherapy or intraocular methotrexate) and with careful neurological follow-up to monitor relapse in the CNS or within the eye. 90 Patients with parenchymal brain lymphoma and ocular dissemination remain a challenge as the eyes are a potential reservoir for partly treated lymphoma. For this reason, a detailed ophthalmological examination, including slit-lamp examination, is crucial as part of the initial staging assessment for any patient with newly diagnosed PCNSL. Failure to recognise that the eyes are involved can result in suboptimum treatment or clinical follow-up. Results from a large international retrospective series found that directed ocular treatment (either ocular radiotherapy or intraocular methotrexate) improved disease control. 91 Evidence from a small series showed that 8 g/m² of methotrexate can produce cytocidal concentrations in the vitreous body, although intravitreal drug concentrations might not predict therapeutic efficacy. 92 This study lends support to the notion that high doses of methotrexate can penetrate the eye and, therefore, could be effective in the management of patients with both parenchymal brain and ocular lymphoma. 92 HIV-related PCNSL Acquired immunodeficiency is the only established risk factor for PCNSL, but since the advent of highly active antiretroviral drugs, incidence in this population has been declining. Current National Comprehensive Cancer Network guidelines 93 recommend the use of high-dose methotrexate, whole-brain radiotherapy, or initiation of highly active antiretroviral therapy for patients with HIV-associated PCNSL. However, recent population-based data suggest that many patients do not receive any chemotherapy or whole-brain radiotherapy because they are being treated with highly active antiretroviral therapy. Although the incidence of PCNSL has decreased over the past decade with widespread use of highly active antiretroviral therapy, 94 97 PCNSL is now a more common AIDS-defining illness than before this therapy was available. 98 Various chemotherapy regimens have shown activity in HIV-related PCNSL, and the immunomodulatory treatment with highly active antiretroviral therapy alone can induce tumour responses. 99 101 Whole-brain radiotherapy might be effective, but the potential increased risk of leucoencephalopathy in patients with HIV should be taken into consideration for selected patients who have a better than usual disease prognosis. Conclusions and future challenges Although PCNSL is a rare brain tumour, its sensitivity to several therapeutic strategies makes it unique in neurooncology. Historically, whole-brain radiotherapy and corticosteroids were the mainstay of treatment but the development of high-dose methotrexate has radically Search strategy and selection criteria References for this Review were identified through searches of PubMed with the search terms PCNSL, primary AND CNS lymphoma, and CNS AND lymphoma. No date restriction was set all papers were searched up to February, 2009. Articles were also identified through searches of the authors own files. Only papers published in English were reviewed. altered modern treatments. Methotrexate has successfully been incorporated into multi-drug chemotherapy regimens, which are associated with notable improvements in response and survival. Alternative strategies, including blood brain barrier disruption and the use of high-dose chemotherapy with stem-cell transplantation, are associated with durable responses but are limited to specialist centres. Recently, the development of targeted drugs such as rituximab might have improved the disease prognosis for patients with PCNSL, although the optimum use of these drugs is mostly unknown so far. Despite these welcome advances, there are still substantial challenges. Although initial response rates are high, a notable proportion of patients have disease relapse and for long-term survivors substantial neurotoxicity can be disabling. Additionally, there are substantial uncertainties about the optimum therapeutic strategy for relapsed disease. To meet these challenges, more large clinical trials are needed along with increased consensus between specialist centres about the optimum design of these studies. An increased understanding of the natural history and biology of PCNSL will hopefully lead to improved individualisation of treatments in the future. Investigators should work together to prioritise the most important questions and focus efforts on designing new trials and research avenues. With this in mind, over the past several years an international group of investigators (the International Primary CNS Lymphoma Collaborative Group) has been working to define current standards, establish consensus guidelines for the reporting of clinical trials, and develop new research proposals. Hopefully, through similar collaborations, recent breakthroughs can be continuously built upon and disease prognosis of patients with PCNSL improved. Contributors Both authors contributed equally to the preparation of this Review. Conflicts of interest PGM has received honoraria from Eisai, Genomic Health, Pfizer, Haymarket media, Bristol-Myers Squibb, Genentech, Novartis, and OrthoBiotech. LEA has received honoraria from and has consulted for Genentech. References 1 Miller DC, Hochberg FH, Harris NL, et al. 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