Primary Central Nervous System Lymphoma-PART 2: Modern Therapeutic Management and Future Directions

Oncology (Williston Park). 32(2):e11-e19.

Table 1. Systemic Therapy Trials for Primary CNS Lymphoma

Table 2. Overview of Therapeutic Management of Primary CNS Lymphoma

Primary central nervous system (CNS) lymphoma, a rare CNS neoplasm associated with high mortality, is responsive to therapeutic interventions. In Part 1 of our two-part coverage of this entity, we provided an overview of the epidemiology of primary CNS lymphoma, followed by a discussion of the diagnostic and staging evaluation, and a review of current prognostication systems. In Part 2, we discuss the management of primary CNS lymphoma, focusing in particular on systemic therapies and radiation. With respect to systemic therapies, we provide details of a variety of regimens built around a backbone of high-dose methotrexate. Future directions for the treatment of primary CNS lymphoma are reviewed as well. These include optimization of consolidation regimens and the pursuit of novel agents.

Introduction

Primary central nervous system (CNS) lymphoma is a rare and aggressive CNS neoplasm with a high morbidity and often fatal outcomes. However, a subset of patients may be cured. Along with timely and accurate diagnosis, optimal management is key to maximizing a patient’s chances of a good outcome. Once initiated, therapeutic management most often centers on systemically delivered chemotherapy. Systemic therapies have been evaluated alone or in conjunction with intrathecally administered agents, as well as in combination with radiation therapy (RT). Most studies have been retrospective series and uncontrolled trials. The paucity of randomized trials has made the therapeutic landscape and recommendations complicated and occasionally contradictory. Treatment decisions need to be guided by clear therapeutic objectives and goals (eg, symptom control, delay of progression, or cure), taking into account the patient’s general condition. Even in patients without evidence of disease after treatment, there is the potential for disease recurrence; thus, long-term (5 years or more) imaging follow-up is recommended.

Improved understanding of this disease will facilitate optimization of its management both now and in the future. Our goal in this review is to provide clinicians with a comprehensive overview by covering the key investigations that have brought us to our current state of knowledge, as well as studies that may guide future interventions.

Although no single regimen has been established as the standard of care for newly diagnosed or recurrent primary CNS lymphoma, some central principles are generally agreed upon-which we will elucidate. We will also provide interpretations of the results of the single phase III trial and the numerous phase II trials that help inform clinical care-which currently varies considerably at the regional, institutional, and individual physician levels. We have structured our discussion by treatment modality-ie, surgical interventions, RT, systemic therapies, and intrathecal therapies (Table 1).

Surgical Interventions

Primary CNS lymphoma is a disseminated CNS disease with the potential to recur outside of the boundaries of focal therapies such as surgery and focal RT. It is also very responsive to both systemic therapies and RT. Consequently, surgical interventions other than diagnostic tissue biopsy have no established role at this time in the management of most patients with primary CNS lymphoma. Historical data have shown an inferior overall survival (OS) in patients who underwent tumor resection as opposed to biopsy only,[1] further supporting this recommendation. Nevertheless, given improved imaging and surgical techniques, some investigators have recently been reconsidering the role of surgical resection.[2-4] An unplanned post-hoc analysis of the German Primary CNS Lymphoma Study Group 1 trial, a phase III study of 526 patients that investigated the role of RT, found a significant improvement in OS (hazard ratio [HR], 1.33; P = .024) and progression-free survival (PFS; HR, 1.39; P = .005) in the patients who underwent craniotomy with some tumor resection (n = 137) compared with those who had biopsy alone (n = 379).[3] Interestingly, no difference in OS or PFS was noted between patients who underwent gross total resection and those who underwent subtotal resection.[3] At most academic centers, however, biopsy alone in suspected primary CNS lymphoma is still the most frequently employed approach and is recommended by the majority of thought leaders in the field, although data on national and international trends are lacking.

RT

After a diagnosis of primary CNS lymphoma is established, patients move forward with treatment that may incorporate RT, systemic therapy, intrathecal therapy, or a combination of these. RT, while rarely used nowadays as a single treatment modality for newly diagnosed primary CNS lymphoma, had early on demonstrated a clear therapeutic benefit.[5] RT covering both the whole brain and posterior orbits, termed whole-brain radiotherapy (WBRT), is the most frequently utilized approach because of the potential for out-of-field failures.[6] Focal RT is not routinely recommended due to the diffuse nature of the disease. Although rates of response to radiation monotherapy are high, responses are usually short-lived and patients tend to have disease recurrence within a few months. In a series of 132 patients treated with radiation monotherapy in Japan in the 1990s, the median OS was 18 months and the 5-year OS was poor as well, with survival rates below 20%.[5] The required radiation dose threshold is higher in primary CNS lymphoma than in the visceral manifestation of lymphoma: doses between 30 and 50 Gy are required. Among patients who had a complete response (CR) to chemotherapy, higher relapse and reduced survival rates were observed in patients who received WBRT at a dose of 30.6 Gy, compared with patients who received 45 Gy.[7] In the phase II Radiation Therapy Oncology Group (RTOG) 8315 trial, 41 patients with primary CNS lymphoma were treated with RT only; patients received 40 Gy of WBRT followed by a 20-Gy boost to the tumor plus a 2-cm margin. Median OS was 12 months, and recurrence in the brain occurred in 61% of patients, with more relapses in the 60-Gy region, suggesting that there is no clear dose-response relationship for doses greater than 40 Gy.[8] Currently, radiation monotherapy is considered in patients with poor performance status or medical comorbidities (eg, renal failure, pleural effusion, ascites) that preclude the effective use of systemic therapies. In this setting, RT alone can palliate symptoms, induce radiographic regression of tumor, and prolong survival.

RT is also utilized as consolidation therapy after induction with systemic therapy in patients younger than 60 years. In patients who received initial high-dose methotrexate (HD-MTX) regimens (detailed further on), WBRT was employed as a component of the consolidation regimen. While HD-MTX regimens followed by WBRT lead to high response rates and sustained responses in many patients, a subset of patients can develop serious neurotoxicity about 7 months after treatment; this is typically characterized by dementia, ataxia, and urinary incontinence (a clinical picture suggestive of normal-pressure hydrocephalus). In one phase II trial, patients ≥ 60 years old who had received both HD-MTX and WBRT had a 100% incidence of neurotoxicity at 24 months, while those < 60 years old had a 30% incidence at 96 months.[9] This syndrome of neurotoxicity can be caused by both MTX and RT, but the combination is synergistic and more toxic if RT precedes the MTX.

Concerns of synergistic neurotoxicity have led to consideration of avoiding WBRT consolidation following chemotherapy in patients with primary CNS lymphoma, especially if they are older than 60 years. Studies have demonstrated that eliminating WBRT from treatment regimens results in a higher likelihood of recurrence, but this difference does not appear to translate into an OS decrement. The German Primary CNS Lymphoma Study Group phase III trial randomized 524 patients to HD-MTX–based chemotherapy with or without WBRT to 45 Gy in 1.5-Gy fractions.[10] The addition of upfront WBRT significantly prolonged PFS, most prominently in patients who did not achieve a CR following chemotherapy, but this benefit did not translate into an OS difference. In patients with disease less sensitive or insensitive to HD-MTX, WBRT was observed to be more effective than high-dose cytarabine. The addition of upfront WBRT led to greater decreases in patient-reported cognitive functioning and global health status, as well as lower values on the Mini–Mental State Examination.[11]

Current research is focusing on reducing the risk of neurotoxicity from RT without compromising long-term disease control. A phase II study evaluated the effectiveness and toxicity of reduced-dose WBRT (23.4 Gy) in patients who achieved a CR following MTX-based chemotherapy.[12] The estimated 2-year OS and PFS rates in these 19 patients were 89% and 79%, respectively. At a follow-up of 12 months, none of the patients treated with reduced-dose RT had developed treatment-related dementia on neurocognitive studies. This approach was further evaluated in a multicenter phase II study of rituximab, MTX, procarbazine, and vincristine (R-MPV) followed by consolidative WBRT to 23.4 Gy in patients who achieved a post-chemotherapy CR.[13] Consolidative cytarabine was given after RT. Of the 52 patients enrolled, 60% achieved a CR after R-MPV, with a 2-year PFS rate of 77% and a 3-year OS rate of 87%. Cognitive assessments demonstrated improvement in executive function and verbal memory after R-MPV, with stability of follow-up scores.

Systemic Therapies

As with other CNS malignancies, the ability to reach therapeutic concentrations of efficacious agents has been a central concern in the utilization of systemic therapies in the treatment of primary CNS lymphoma. The blood-brain barrier (BBB) limits the ability of many substances to reach the CNS. However, this barrier is abnormal in the setting of contrast-enhancing disease, and is anatomically variable as well as temporally dynamic with respect to its robustness.[14]

A number of methods have been used in attempts to overcome the limitations on treatment efficacy associated with the BBB. The first clearly successful effort in primary CNS lymphoma involved the use of HD-MTX (> 2 g/m²; Table 2). While lower doses of MTX are unable to penetrate into the CNS in effective concentrations, higher doses are able to do so.[15] The serum area under the curve of MTX, and thus the CNS concentrations associated with it, correlates with survival outcomes in patients with primary CNS lymphoma.[16] Because MTX is renally cleared, baseline and close ongoing monitoring of renal function is essential. In addition, MTX can crystalize in the renal tubules, further impairing renal function. Thus, aggressive pre- and posttreatment hydration and urine alkalinization are necessary. Dose reduction is necessary in some patients because of impaired renal clearance. In some patients with very poor renal function, HD-MTX is not a therapeutic option. Additionally, because MTX accumulates in third-space fluids, such as pleural effusions or ascites, its use is typically avoided in patients in whom these entities are found. Finally, HD-MTX regimens are highly immunosuppressive. This can be further exacerbated by concomitant steroid treatment. Immunosuppression leads to a risk of infection, including Pneumocystis carinii pneumonia (PCP). Therefore, patients undergoing chemotherapy for primary CNS lymphoma will often require growth factor support and prophylaxis against PCP, most often with trimethoprim/sulfamethoxazole (3 times a week) or pentamidine inhalation (monthly).

Newly diagnosed primary CNS lymphoma

An HD-MTX–based regimen has been deemed part of the standard of care for the past few decades in newly diagnosed primary CNS lymphoma. It is often also utilized in recurrent disease as a rechallenge, although the optimal management is often guided by more patient-specific factors in that setting and is less clear. There are few randomized trial data to help guide treatment. Concepts that have been explored in an effort to increase the efficacy of HD-MTX regimens include further dose escalation; combinatorial regimens involving other chemotherapeutic agents and biologics (both systemic and intrathecal); and various consolidation regimens, ranging from RT to high-dose chemotherapy with autologous stem cell transplantation (ASCT).

The earliest studies of “escalated”-dose MTX utilized relatively low doses (200 mg/m² to 1 g/m²) but were able to produce an efficacy signal.[1] The pivotal multicenter phase II RTOG 93-10 trial utilized HD-MTX (2.5 g/m² every 2 weeks) for 5 cycles in conjunction with vincristine (every 2 weeks) and procarbazine (days 1–7; weeks 1, 5, and 9), all given intravenously (MPV regimen), as well as intrathecal MTX administration (12 mg; in weeks 2, 4, 6, 8, and 10 of the induction phase). Subsequent consolidation included WBRT (45 Gy in 1.8-Gy fractions, in weeks 11–15) and cytarabine chemotherapy (3 g/m²/d, on days 1 and 2; weeks 16 and 19). This trial demonstrated a substantial improvement in survival (median OS, 36.9 months) compared with the median OS of ~12 months in historical controls evaluating RT alone.[17] Because of their superior efficacy, regimens built around an HD-MTX backbone became the standard of care for newly diagnosed primary CNS lymphoma. Various iterations have been subsequently investigated, predominantly in single-arm studies.

HD-MTX regimens that include the addition of rituximab, the anti-CD20 antibody used in extra-CNS lymphomas, have also been investigated and have demonstrated favorable results, with CR rates nearing 80%.[12,13,18] Systemically administered rituximab, however, achieves only very low concentrations (0.1% of serum) in the cerebrospinal fluid (CSF).[19] Although the CSF concentration may not optimally reflect the concentration in the brain-and most importantly, intratumoral concentrations of the drug-these low values raise the question of how much rituximab contributes to potential efficacy.

In the New Approaches to Brain Tumor Therapy 96-07 trial, even higher doses of MTX, up to 8 gm/m², were shown to be tolerable and efficacious, with an impressive median OS of 55.4 months (95% CI, 16.5 months–not achieved). In this study, patients were treated every 2 weeks until either they demonstrated a CR or 8 cycles were completed. Patients who achieved a CR in the induction phase went on to receive 2 consolidation cycles at 14-day intervals, followed by 11 maintenance cycles administered every 28 days.[20,21]

A randomized phase II study comparing single-agent HD-MTX (3.5 g/m²) vs HD-MTX plus cytarabine demonstrated superiority of the combination regimen.[22] These, and other studies, have led to the frequent use of higher doses of MTX and combination regimens. One frequently employed regimen studied in the phase II Cancer and Leukemia Group B/Alliance 50202 trial[18] utilizes HD-MTX (8 g/m² on day 1) along with the oral alkylating agent temozolomide (150 mg/m² on days 7–11, odd cycles only) and rituximab (375 mg/m² on day 3, cycles 1–6). For this MTX/temozolomide/rituximab regimen, patients receive 10 14-day cycles in the induction phase. Both of the added agents had previously been evaluated in recurrent disease without HD-MTX.[23-27] The induction regimen is followed by consolidation with high-dose cytarabine (2 g/m² every 12 hours for 8 doses) and etoposide (40 mg/kg continuously over 96 hours). Results are encouraging: a 66% CR rate prior to consolidation and a 70% 2-year survival rate. Despite the very high dose of MTX-8 g/m²-the regimen was well tolerated, even by elderly patients.[18]

Since intense consolidation regimens appeared feasible, the possibility of further intensification warranted additional study. Treatment with cytarabine (2 g/m²/d as a 3-hour infusion on days 2–5, and 50 mg/m²/d as a 12-hour infusion on days 1–5) and etoposide (200 mg/m²/d as a 2-hour infusion on days 2–5) (CYVE regimen) for 2 cycles, followed by high-dose thiotepa (250 mg/m²/d on days −9 through −7), busulfan (10 mg/kg PO or 8 mg/kg IV on days −6 through −4), cyclophosphamide (60 mg/kg/d on days −3 and −2), and ASCT (harvested after the first course of CYVE and reinfused on day 0) has appeared promising for treating recurrent disease; this approach has achieved near-perfect (96%) CR rates and a favorable 2-year survival rate (69%) in those patients who underwent transplant.[28] A subsequent single-institution phase II trial using rituximab plus MPV (for 5–7 cycles) followed by high-dose thiotepa (250 mg/m² on days −9 through −7), busulfan (3.2 mg/kg on days −6 through −4), cyclophosphamide (60 mg/kg on days −3 and −2), and ASCT (reinfused on day 0) appeared to have favorable results in the newly diagnosed setting, with a good response rate and a 2-year survival rate of 81%.[29] This approach is currently being studied in a randomized cooperative group trial (discussed further on).

It should be noted that, although many groups have been investigating the intensification of treatment regimens, others have looked at de-escalation. One recent multicenter phase II trial utilized a short course of somewhat lower-dose MTX (1 g/m² on days 1 and 8) followed by WBRT (45 Gy with a 4.5-Gy boost). Two-year survival (62%) was comparable to outcomes seen with more intense regimens.[30]

Recurrent and progressive primary CNS lymphoma

Therapeutic management for recurrent or progressive primary CNS lymphoma is even less codified than that for newly diagnosed disease[23] and has been less well studied. If a patient’s disease progresses during frontline therapy, there is concern that subsequent regimens will have a low likelihood of durable efficacy. For such patients, management can range from hospice care to an aggressive multimodality approach; in the absence of an established standard, patients are ideally treated within the context of a clinical trial.

Retreatment with HD-MTX (≤ 3 g/m²) has demonstrated excellent response rates (> 90%) in patients who had experienced a CR with prior HD-MTX. Median time to first relapse after the initial HD-MTX regimen was 24.4 months (range, 2–100 months).[31]

Single-agent temozolomide (150 mg/m² on days 1–5 of a 28-day cycle for 6 cycles) has demonstrated radiographic responses (CR rate, 21%; partial response rate, 4%) with good tolerability.[24] The combination of temozolomide plus rituximab, while also well tolerated, demonstrated a limited response rate (rate of sustained CR, 14%). For this regimen, a single 28-day induction cycle of temozolomide (150 mg/m² on days 1–7 and 15–21) and rituximab (750 mg/m² on days 1, 8, 15, and 22) was followed by 6 consolidation cycles of single-agent temozolomide (150–200 mg/m² on days 1–5).[25]

Pemetrexed is a second-generation folate antagonist and antimetabolite. Single-agent pemetrexed (900 mg/m² every 3 weeks in 6-week cycles) has also demonstrated biological activity (response rate, 55%; median PFS, 5.7 months; median OS, 10.1 months), although at the price of a somewhat more pronounced toxicity profile in heavily pretreated patients.[32]

More robust response rates, favorable-appearing OS (median, 18.3 months), and 2-year survival rates (43%) have been seen with more intense chemotherapy regimens together with ASCT.[28,29]

The results of these studies provide clinicians with a range of potential regimens to choose from to help tailor management to each patient with respect to goals regarding efficacy and tolerability. In daily practice, numerous patient-, physician-, institution-, and country/region–specific factors influence the management of both newly diagnosed and recurrent primary CNS lymphoma.

Intrathecal Therapies

Retrospective studies have demonstrated no clear survival benefit from intrathecal therapies in newly diagnosed primary CNS lymphoma.[33-35] Nevertheless, intrathecal therapies have been featured in a number of primary CNS lymphoma regimens. A variety of agents have been utilized, including MTX, cytarabine, a long-acting liposomal preparation of cytarabine, thiotepa, and most recently rituximab.

While there has been a general trend away from utilizing intrathecal cytotoxic chemotherapies in newly diagnosed primary CNS lymphoma, intrathecal rituximab in the setting of recurrent disease appears promising, particularly when the disease burden is predominantly in the CSF, as can be seen in extra-CNS lymphoma with CNS involvement. Intrathecal rituximab (10–50 mg) is very well tolerated.[19] It is thought that some of its activity results from complement activation in the CSF.[36] Its use at a dose of 25 mg every 2 weeks in combination with intrathecal MTX (12 mg) also appears tolerable. Both cytologic and radiographic responses have been seen with this regimen, including a parenchymal response.[37] With intrathecal administration, BBB penetration is less of a problem but parenchymal penetration may be more of an issue. In any event, intrathecal therapy is not a component of routine management for CNS lymphoma at most centers.

Future Directions

Important questions regarding the management of primary CNS lymphoma are being actively investigated. For the immediate future, most therapeutic management strategies for newly diagnosed disease will be built on an induction regimen with an HD-MTX backbone. For newly diagnosed primary CNS lymphoma, a key question that remains is what is the optimal consolidation regimen? As noted earlier, in older patients (> 60 years of age) WBRT is typically omitted. In younger patients, it is often omitted as well. If WBRT is needed, low-dose RT (23.4 Gy) would decrease neurotoxicity. While some studies have not demonstrated benefit for WBRT,[19] other recent studies have shown promising results that favor its inclusion. The recently completed NRG Oncology RTOG 0227 phase I/II trial demonstrated a 2-year OS rate of 80.8% and 2-year PFS rate of 63.6% in the phase II component. This is a significant improvement over historical controls.[38] Of course, these results must be weighed against the potential neurocognitive toxicity in a potentially curable patient population.

Given its efficacy in the recurrent disease setting, the role of high-dose chemotherapy and ASCT in newly diagnosed primary CNS lymphoma is also undergoing active investigation. The feasibility of using such an approach has been demonstrated in a phase II trial. In this study, MTX (3.5 g/m²) and cytarabine (3 g/m²) for 2 continuous days were followed by carmustine, etoposide, cytarabine, and melphalan (BEAM regimen), and then by ASCT. However, median event-free survival was only 5.3 months (9.3 months for patients who underwent transplant), and there was one grade 5 toxicity.[39] Thus, use of this type of regimen in the upfront setting is not standard of care. There is, however, an ongoing randomized cooperative group study (ClinicalTrials.gov identifier: NCT01511562), which employs an induction regimen consisting of HD-MTX, temozolomide, and rituximab[18] and then randomizes participants to a consolidation regimen of either cytarabine and etoposide or thiotepa and carmustine with ASCT. This study has completed accrual. In another ongoing cooperative group phase III trial, patients receive induction with HD-MTX, rituximab, cytarabine, and thiotepa followed by randomization to induction with either rituximab, dexamethasone, etoposide, ifosfamide, and carboplatin (R-DeVIC) or carmustine and thiotepa with ASCT (HCT-ASCT).[40] Results of these studies are eagerly awaited.

Novel therapies have the potential to revolutionize the treatment of primary CNS lymphoma. While traditional cytotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) with the addition of rituximab (R-CHOP) has been utilized as the frontline treatment for extra-CNS diffuse large B-cell lymphoma, novel small-molecule targeted therapies have been under active investigation for this entity.[41] Of particular interest are agents that target Bruton tyrosine kinase, which plays a key role in the B-cell receptor signaling on which most B-cell malignancies depend. Primary CNS lymphoma appears to be especially dependent upon B-cell receptor signaling. An early-phase trial demonstrated robust response rates (77%) with ibrutinib monotherapy (560–840 mg daily) in recurrent/refractory primary CNS lymphoma. Lack of response correlated with the presence of specific mutations in CD79B and CARD11, known to be associated with ibrutinib resistance in other malignancies. Preclinical work supports potential synergy of ibrutinib with a combinatorial approach that includes phosphoinositide 3-kinase/mammalian target of rapamycin blockade.[42] When ibrutinib (on days 1–10) was used in conjunction with a multidrug regimen that included dose-adjusted temozolomide (100 mg/m²/d IV on days 2–5), etoposide (50 mg/m²/d IV on days 2–5), doxorubicin (50 mg/m² on day 2), dexamethasone (10 mg/m² PO twice a day on days 1–5), and rituximab (375 mg/m² on days 1 and 2) (DA-TEDDi-R), CR rates of 86% to 100% were seen in cohorts that included both newly diagnosed and recurrent/refractory primary CNS lymphoma.[43,44] Median PFS in the recurrent/refractory patients was 15.3 months, and median OS has not yet been reached.[43] These results occurred in the setting of an increased risk of aspergillosis, thought to be secondary to ibrutinib’s inhibition of nuclear factor kappa B–mediated macrophage activity.[43,45]

In addition to molecularly targeted therapies, there is a growing interest in immune checkpoint inhibitors, stemming in part from the durable responses that have been seen with these agents in other malignancies, including Hodgkin lymphoma. No prospective trials have been completed, but cases of sustained responses have been described with the programmed death 1 antibody nivolumab either alone, in combination with rituximab, in combination with dendritic cell vaccination, or given shortly after WBRT.[46,47]

The evolving epidemiologic landscape of primary CNS lymphoma requires more study. Currently, there is no definitively identified driver for the increasing incidence of primary CNS lymphoma in the immunocompetent elderly population. However, there is some evidence that at least some of this increase is associated with Epstein-Barr virus infection.[48,49] As the elderly population increases in size, optimal management of primary CNS lymphoma in older patients will become more important. In this subset of patients, balancing efficacy and tolerability will be necessary.

Finally, in light of the notable continued improvements in survival of HIV-positive patients in the era of highly active antiretroviral therapy, evaluation of aggressive management regimens for primary CNS lymphoma in this patient population is justified.[50]

Conclusions

Primary CNS lymphoma is a rare primary CNS tumor associated with substantial morbidity and mortality. Although treatment-related neurotoxicity can become an issue, primary CNS lymphoma is curable in a subset of patients. Thus, there is value in understanding the diagnosis, prognostication, and therapeutic management of this disease. The field of primary CNS lymphoma management has evolved substantially in recent decades and will continue to do so. Ongoing studies are helping answer central management questions in this disease. Over time, it is hoped that this improved understanding will lead to meaningful impacts on patient survival.

Financial Disclosure:Dr. Stupp’s spouse works for Celgene and Novartis and has equity in both companies. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. DeAngelis LM, Yahalom J, Heinemann MH, et al. Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy. Neurology. 1990;40:80-6.

2. Bellinzona M, Roser F, Ostertag H, et al. Surgical removal of primary central nervous system lymphoma (PCNSL) presenting as space occupying lesions: a series of 33 cases. Eur J Surg Oncol. 2005;31:100-5.

3. Weller M, Martus P, Roth P, et al. Surgery for primary CNS lymphoma? Challenging a paradigm. Neuro Oncol. 2012;14:1481-4.

4. Yun J, Iwamoto FM, Sonabend AM. Primary central nervous system lymphoma: a critical review of the role of surgery for resection. Arch Cancer Res. 2016;4:71.

5. Shibamoto Y, Ogino H, Hasegawa M, et al. Results of radiation monotherapy for primary central nervous system lymphoma in the 1990s. Int J Radiat Oncol Biol Phys. 2005;62:809-13.

6. DeAngelis LM. Whither whole-brain radiotherapy for primary CNS lymphoma? Neuro Oncol. 2014;16:1032-4.

7. Bessell EM, Lopez-Guillermo A, Villa S, et al. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol. 2002;20:231-6.

8. Furst-Nelson D, Martz KL, Bonner H, et al. Non-Hodgkin’s lymphoma of the brain: can high-dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys. 1992;23:9-17.

9. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18:3144-50.

10. Korfel A, Thiel E, Martus P, et al. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015;84:1242-8.

11. Herrlinger U, Schäfer N, Fimmers R, et al. Early whole brain radiotherapy in primary CNS lymphoma: negative impact on quality of life in the randomized G-PCNSL-SGI trial. J Cancer Res Clin Oncol. 22 Apr 2017. [Epub ahead of print]

12. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25:4730-5.

13. Morris PG, Correa DD, Yahalom J, et al. Rituximab, methotrexate, procarbazine and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013;31:3971-9.

14. Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA. Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances. Adv Pharmacol. 2014;71:203-43.

15. Borsi JD, Moe PJ. A comparative study of the pharmacokinetics of methotrexate in a dose range of 0.5 g to 33.6 g/m2 in children with acute lymphoblastic lymphoma. Cancer. 1987;60:5-13.

16. Joerger M, Huitema AD, Krähenbühl S, et al. Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: a pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial. Br J Cancer. 2010;102:673-7.

17. DeAngelis LM, Seiferheld W, Schold SC, et al. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002;20:4643-8.

18. Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31:3061-8.

19. Rubenstein JL, Li J, Chen L, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013;121:745-51.

20. Batchelor T, Carson K, O’Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21:1044-9.

21. Gerstner ER, Carson KA, Grossman SA, Batchelor TT. Long-term outcome in PCNSL patients treated with high-dose methotrexate and deferred radiation. Neurology. 2008;70:401-2.

22. Ferreri AJ, Reni M, Foppoli M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase II trial. Lancet. 2009;374:1512-20.

23. Reni M, Mazza E, Foppoli M, Ferrei AJ. Primary central nervous system lymphomas: salvage treatment after failure to high-dose methotrexate. Cancer Lett. 2007;258:165-70.

24. Reni M, Mason W, Zaja F, et al. Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer. 2004;40:1682-8.

25. Nayak L, Abrey LE, Drappatz J, et al. Multicenter phase II study of rituximab and temozolomide in recurrent primary central nervous system lymphoma. Leuk Lymphoma. 2013;54:58-61.

26. Makino K, Nakamura H, Hide T, Kuratsu J. Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and the assessment of the MGMT status. J Neurooncol. 2012;106:155-60.

27. Jiang X, Reardon DA, Desjardins A, et al. O6-methylguanine DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma. J Neurooncol. 2013;114:135-40.

28. Soussain C, Hoang-Xuan K, Taillandier L, et al. Intensive chemotherapy followed by hematopoietic stem cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Françcaise de Greffe de Moëelle Osseuse-Thérapie Cellulaire. J Clin Oncol. 2008;26:2512-8.

29. Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015;125:1403-10.

30. O’Brien P, Roos D, Pratt G, et al. Phase II multicenter study of brief single-agent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol. 2000;18:519-26.

31. Plotkin SR, Betensky RA, Hochberg FH, et al. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res. 2004;10:5643-6.

32. Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012;118:3743-8.

33. Karmali R, Nabhan C, Petrich A, et al. Impact of treatment variability on survival in immune-competent and immune-compromised patients with primary central nervous system lymphoma. Br J Haematol. 2017;177:72-9.

34. Khan RB, Shi W, Thaler HT, et al. Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma? J Neurooncol. 2002;58:175-8.

35. Dalia S, Forsyth P, Chavez J, et al. Primary B-cell CNS lymphoma clinicopathologic and treatment outcomes in 89 patients from a single tertiary care center. Int J Hematol. 2014;99:450-6.

36. Kadoch C, Li J, Wong VS, et al. Complement activation and intraventricular rituximab distribution in recurrent central nervous system lymphoma. Clin Cancer Res. 2014;20:1029-41.

37. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol. 2007;25:1350-6.

38. Glass J, Won M, Schultz CJ, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and post-radiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016;34:1620-5.

39. Abrey LE, Moskowitz CH, Mason WP, et al. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent to treat analysis. J Clin Oncol. 2003;21:4151-6.

40. Schorb E, Finke J, Ferreri AJ, et al. High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma-a randomized phase III trial (MATRix). BMC Cancer. 2016;16:282.

41. Amin AD, Peters TL, Li L, et al. Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud. 2017;3:a001719.

42. Grommes C, Pastore A, Palaskas N, et al. Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov. 2017;7:1018-29.

43. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31:833-43.

44. Dunleavy K, Lai CE, Roschewski M, et al. Phase I study of dose-adjusted-Teddi-R with ibrutinib in untreated and relapsed/refractory primary CNS lymphoma. Blood. 2015;126:abstr 472.

45. Grommes C, Younes A. Ibrutinib in PCNSL: the curious cases of clinical responses and aspergillosis. Cancer Cell. 2017;31:731-3.

46. Nayak L, Iwamoto FM, LaCasce A, et al. PD-1 blockade with nivolumab in relapsed/refractory central nervous system and testicular lymphoma. Blood. 2017;129:3071-3.

47. Furuse M, Nonoguchi N, Omura N, et al. Immunotherapy of nivolumab with dendritic cell vaccination is effective against intractable recurrent primary central nervous system lymphoma: a case report. Neurol Med Chir (Tokyo). 2017;57:191-7.

48. Sugita Y, Muta H, Oshima K, et al. Primary central nervous system lymphomas and related diseases: pathological characteristics and discussion of the differential diagnosis. Neuropathology. 2016;36:313-24.

49. Jamal SE, Li S, Bajaj R, et al. Primary central nervous system Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly: a clinicopathologic study of five cases. Brain Tumor Pathol. 2014;31:265-73.

50. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 10 May 2017. [Epub ahead of print]

51. Illerhaus G, Kasenda B, Ihorst G, et al. High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single arm, phase 2 study. Lancet Haematol. 2016;3:e388-e397.

52. Thiel E, Korfel A, Martus P, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol. 2010;11:1036-47.

53. Poortmans PM, Kluin-Nelemans HC, Haaxma-Reiche H, et al. High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II trial 20962. J Clin Oncol. 2003;21:4483-8.

54. Fritsch K, Kasenda B, Hader C, et al. Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 2011;22:2080-5.

55. Illerhaus G, Marks R, Muller F, et al. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol. 2009;20:319-25.