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Clinical Oncology 24 (2012) 329e338

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Clinical Oncology

journal homepage: www.cl in icaloncologyonl ine.net

Overview

Primary Central Nervous System Lymphoma

E. Gallop-Evans

Velindre Cancer Centre, Cardiff CF14 2TL, UK

Received 29 November 2011; accepted 29 February 2012

Abstract

Primary central nervous system lymphoma is an aggressive lymphoma with a molecular biology and genetic profile that appears to be distinct from other types ofdiffuse large B-cell lymphoma. The median survival after whole brain radiotherapy alone is poor, but is significantly improved after high-dose methotrexate-basedcombination chemotherapy. The rarity of primary central nervous system lymphoma means that randomised studies have proved challenging, particularly as manypatients are elderly and more susceptible to the toxic effects associated with these treatments. Promising treatment strategies are emerging and, wherever possible,patients shouldbe treatedwithinclinical trials.Qualityof lifeandneurocognitivedata shouldbe collectedprospectively toassess theeffectof thediseaseand treatment.� 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Key words: High-dose methotrexate; neurotoxicity; primary central nervous system lymphoma; whole brain radiotherapy

Statement of Search Strategies Used andSources of Information

A systematic literature search was carried out usingMedline up to 21 November 2011. The search also includedreference lists of papers identified.

Introduction

Primary central nervous system lymphoma (PCNSL) is anaggressive diffuse large B-cell lymphoma (DLBCL) and, ifuntreated, has a rapidly fatal course with a median survivalof about 1.5 months. The median survival after whole brainradiotherapy (WBRT) alone ranges from 10 to 18 months,but is significantly improved after chemotherapy with orwithout WBRT. Although current treatment strategies haveprolonged survival, they are not curative in most patients.The disease tends to recur and is eventually fatal. Due to therarity of PCNSL, randomised studies have been very difficultto conduct. Rigorous testing of treatment strategies,including high-dose methotrexate (MTX)-based regimens,autologous stem cell transplantation (ASCT) and WBRT, hasproved challenging because many patients are elderly andmore susceptible to the toxic effects associated withcombined modality treatments.

Author for correspondence: E. Gallop-Evans, Velindre Cancer Centre,Cardiff CF14 2TL, UK. Tel: þ44-2920-316246.

E-mail address: eve.gallop-evans@wales.nhs.uk

0936-6555/$36.00 � 2012 The Royal College of Radiologists. Published by Elsevdoi:10.1016/j.clon.2012.02.009

The other priority is to improve our understanding of themolecular biology and genetic profile of PCNSL, whichseems to be distinct from other types of DLBCL. The paucityof available tissue has made full characterisation of PCNSLdifficult, but new techniques may allow accurate assess-ment of small samples.

Epidemiology

PCNSL is a B-cell non-Hodgkin lymphoma recognised asa discrete entity in the updatedWorld Health Organizationclassification [1]. It represents about 1% of all non-Hodgkinlymphomas and 4% of central nervous system (CNS)tumours. Although PCNSL has been characteristicallyassociated with immunodeficiency, the incidence inimmunocompetent patients is increasing [2]. Most cases ofnon-HIV-related PCNSL are diagnosed in patients between45 and 70 years of age, with amedian age at diagnosis in thefifth decade. Men and women are equally affected, with anannual incidence rate of 0.47 per 100,000 person-years [3].

Presentation

The typical presentation of PCNSL in an immunocom-petent patient involves progressive focal symptoms asso-ciated with a mass lesion. In a series of 248 PCNSL patients,70% presented on admission with a focal neurological

ier Ltd. All rights reserved.

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338330

deficit, 43% with altered mental status, 33% with signs ofincreased intracranial pressure, 14% with fits and 4% withvisual symptoms related to vitreous involvement [4].Empiric treatment with corticosteroids may cause pro-longed remission of clinical signs and symptoms as well asimaging findings; however, remission can also occurspontaneously.

Imaging

Contrast-enhanced magnetic resonance imaging scansare the imaging modality of choice, although computedtomography is also informative (Figure 1). In immuno-competent patients, single or multiple periventricularenhancing lesions are typical, whereas ring-enhancinglesions are seen in immunodeficient patients. The mostcommon sites of involvement are the frontal lobes, followedby the basal ganglia and thalamus. PCNSL can also spreadacross the corpus callosum, giving a typical butterflypattern [5]. Ependymal spread is often seen, particularly inHIV-associated lymphoma. However, even characteristiclesions cannot be unequivocally distinguished from otherCNS lesions [5]. Positron emission tomography with 18F-fluorodeoxyglucose and 11C-methionine, which measureglucose and amino acid metabolism respectively, mayprovide useful information, but although 18F-fluorodeox-yglucose and 11C-methionine are taken up in typical lesions,they are not useful in the detection of atypical lesions [6].

Fig 1. T2 axial magnetic resonance image showing a large massinvolving the right frontal lobe and adjacent corpus callosum. There isoedema and compression of the right lateral ventricle and midlineshift.

Diagnosis and Pathology

The diagnosis of PCNSL should always be confirmedhistologically, as multiple sclerosis, sarcoidosis and occa-sional gliomas can be indistinguishable and also respond tosteroids. This should be done by stereotactic biopsy, ideallybefore steroid therapy, as surgical resection does notcontribute to definitive management. If there is evidence ofocular or cerebrospinal fluid (CSF) involvement, vitrectomyor CSF cytology may establish the diagnosis. Experthaematopathological review should be sought.

About 90% of PCNSL are DLBCLs, the rest being eitherlow-grade, Burkitt or T-cell lymphomas. In normal circum-stances, B cells are not usually found in the CNS, and thecellular and molecular events leading to malignant B-cellinfiltration are unclear [7]. PCNSL has a different geneexpression signature from that of systemic DLBCL, whichsuggests that it develops from mature B cells either at thelate germinal centre or early post-germinal centre stage [8].However, there is no evidence for germinal centre struc-tures in the CNS, raising the possibility that the malignantcells have migrated to the brain. CNS lymphomas showangiotropism, with cells clustering densely around tumourvessels. In most cases, the malignant B cells have a centro-blastic morphology and are CD79aþ, CD20þ PAX-5þ, BCL-2þ, MUM1/IRF4þ. BCL-6 is frequently positive, and CD10 isless so. PCNSL cells also express high levels of c-MYC, whichhas been associated with adverse prognosis in systemicDLBCL [8]. If material is sufficient for flow analysis, thelymphoma cells will show monoclonal surface immuno-globulin. Immunoglobulin Vegene analysis was able toidentify tumour cells in the CNS in 12 patients, as well as inperipheral tissue in three patients [9]. Clonal trackingrevealed tumour cells in the bone marrow and/or blood inall three cases, with evidence for increased V-gene muta-tional activity at peripheral sites, consistent with a greaterdiversification of the original clone. However, there was noevidence of malignant growth at systemic sites, and thelimited diversity within the CNS tumour suggested little orno re-entry into the brain.

In HIV patients, the detection of EpsteineBarr virus DNAin CSF has been considered diagnostic of PCNSL whencombined with typical imaging findings. This specificity hasrecently been questioned, and may reflect the decliningincidence of the disease [10]. EpsteineBarr virus DNA isusually negative in immunocompetent patients.

Staging and Pretreatment Investigations

Standardised guidelines for the baseline evaluation andresponse assessment have been published by the Interna-tional PCNSL Collaborative Group [11]. Apart from theimaging modalities mentioned above, CSF examinationshould include cell count, cytology and flow cytometry [12],protein, glucose and immunoglobulin heavy-chain generearrangement studies. Magnetic resonance imaging of thespine is only warranted in the presence of localisingsymptoms.

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338 331

An ophthalmological examination, including slit lampevaluation, computed tomography of the chest, abdomenand pelvis, and bone marrow biopsy, should be carried out.Blood tests should include HIV and serum lactate dehydro-genase. A testicular ultrasound should be considered inmen.

Prognostic Factors

The International Extranodal Lymphoma study groupreported the following five adverse prognostic factors:

� Age > 60 years� Eastern Cooperative Oncology Group performancestatus > 1

� Elevated serum lactate dehydrogenase� Elevated CSF protein concentration� Involvementof deep regions of the brain (periventricularregions, basal ganglia, brainstem and/or cerebellum)

For 105 assessable patients, 2 year overall survival forscores of 0e1, 2e3 and 4e5 was 80, 48, and 15%, respec-tively. For 75 patients who received high-dose MTX-basedchemotherapy with or without WBRT, 2 year overallsurvival was 85, 57 and 24%, respectively [13].

First-line Management

Steroids

Steroids induce apoptosis in lymphoma cells, and cancause significant regression of PCNSL lesions, with corre-sponding clinical and radiological improvement. Ideallysteroids should not be commenced until after a biopsy, asthis can make it impossible to get a definitive diagnosis.Although a response to steroids is not durable, it can signifya more favourable prognosis, with survival of 117 months inresponders compared with only 5.5 months in non-responders [14].

Whole Brain Radiotherapy

As PCNSL is usually multifocal, but radiosensitive, WBRTwas the first effective treatment to be used. However, therehave been no prospective randomised trials in PCNSL toanswer the question of optimal fields and/or dose.

The Radiation Therapy Oncology Group 8315 study wasa prospective phase II study of 41 patients treated with40 Gy WBRT and a 20 Gy boost to tumour plus a 2 cmmargin [15]. Median survival was 11.6months from the startof treatment. Twenty-six patients had post-treatment scansat 4 months after the start of radiotherapy, with a 62%complete response rate. Forty-eight per cent of patientssurvived 1 year and 28% survived 2 years. In this study, mostrelapses occurred in the high dose volume.

A retrospective survey of 132 patients treated in Japanbetween 1990 and 1999, with WBRT to a median of 40 Gy,showed a median survival of 18 months and a 5 yearsurvival rate of 18% [16].

A retrospective review to examine the effect of WBRTdose was undertaken for 33 patients treated at a singlecentre after a complete response to high-dose MTX-basedchemotherapy [17]. Patients received between 30 and 45 GyWBRT, with a tumour bed boost taking the total dose to36e54 Gy. Twelve patients relapsed, four outside theradiotherapy volume, including extra-cranial sites. Eightpatients relapsedwithin the radiotherapy field; two of thesewithin the boost volume, and a further six within areastreatedwith 45e54Gy. A tumour bed boost of 45Gy ormoredid not reduce the risk of relapse, and there was no differ-ence in outcomes betweenpatients receiving 30e36 Gy, andthose receiving >40 Gy. Neurocognitive impairment wassignificantly worse in older patients (median age 66 years)and those receiving >40 Gy. The current recommendationfor patients in complete remission before WBRT is 36 Gy,with a 9 Gy tumour boost reserved for patients with partialor no response. For patients being treated with palliativeintent, 30.6 Gy in 1.8 Gy fractions may be considered.

The standard treatment volume for WBRT includes thewhole brain and the eyes and optic nerves, while shieldingthe anterior chamber and lens [18,19]. Left and right lateralequally weighted opposed-fields are used, using 6e10 MVphotons. The posterior two-thirds of the orbits should beshielded after 30 Gy, or 36 Gy in the case of intraocularinvolvement. The inferior border encompasses the vertebralbody of C2. If required, the boost volume encompassesresidual tumour with a 1e2 cm margin.

Acute side-effects are tolerable and include fatigue,headaches, hair loss, and skin dryness and/or erythema. Inpatients with significant mass effect, corticosteroids shouldbe prescribed to avoid worsening of cerebral oedema, butcan be tapered reasonably quickly. Acute symptoms ofconfusion are usually mild and transient.

Delayed symptoms, occurring within 7e40 days ofradiotherapy, are thought to result from inhibition of myelinsynthesis. Patients should be warned about the possibilityand evaluated carefully, as this can be misinterpreted asdisease progression.

Chemotherapy With/Without Radiotherapy

Responses to WBRT alone are rarely sustained, and theinitial approach to combined modality treatments incor-porated regimens active in systemic DLBCL [20,21].A Medical Research Council study found that the addition ofcyclophosphamide, doxorubicin, vincristine, prednisolone(CHOP) toWBRT resulted inworse survival thanwithWBRTalone [22], probably because of poor CNS penetration. Theexception to this is intravascular large cell lymphoma withCNS involvement, where the malignant cells are foundwithin blood vessels and, therefore, not protected by thebloodebrain barrier, and R-CHOP is effective [23].

MTX, a reversible inhibitor of dihydrofolate reductase, isable to cross the bloodebrain barrier and enters cells in partby an active transport mechanism where it is bound aspolyglutamate conjugates. Longer periods of drug exposurelead to higher polyglutamate formation, and more cellsenter S phase, resulting in increased cytotoxicity. MTX has

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338332

significant single-agent activity in PCNSL [24]. The additionof MTX-based chemotherapy regimens to WBRT havesignificantly improved outcomes, but have resulted ina higher incidence of late neurotoxicity, particularly inpatients >60 years [25e27].

In most of these studies, WBRT was given as consolida-tion after induction chemotherapy. The CHOD-BVAMregimen (cyclophosphamide, doxorubicin, vincristine,dexamethasone, carmustine, MTX 1.5 g/m2 and cytarabine[ara-C]) was followed by 45 Gy WBRT, or in a second cohortof complete responders, by 30.6 Gy WBRT [28]. The 5 yearsurvival of 57 patients treated was 36%, with a mediansurvival of 40 months. Reducing the WBRT dose from 45 Gyto 30.6 Gy resulted in a fall in 3 year overall survival from92% to 60%. The risk of late cognitive impairment was muchhigher in patients aged over 60 years (60% versus 8%).A recent report of 36 patients treated with CHOD-BVAMand WBRT, albeit with a higher dose of 50.4 Gy for non-responders, found inadequate responses and significantlevels of neurotoxicity, with 28% of evaluable patientshaving at least one grade 3 neurological toxicity [29].

A retrospective population-based study reportedoutcomes of 122 patients treated after 1990 with threeconsecutive treatment strategies e 35 Gy WBRT with/without CHOP/CHOP-like chemotherapy, the addition ofMTX(1g/m2) to combination treatment and, eventually, high-doseMTX alone (8 g/m2), with WBRT reserved for patients withstableorprogressive disease [30]. Themedianoverall survivalof 17months was similar in all three eras. However, a third ofthe patients did not receive the standard treatment strategy,the highest proportion of these in the high-dose MTX era,which also had the highest proportion of toxic deaths.

A meta-analysis of 288 patients treated in prospectivestudies with high-dose MTX-based regimens assessed theeffect of additional treatment factors includingWBRT, otherdrugs and intrathecal chemotherapy [31]. High-dose MTX�3 g/m2, thiotepa and intrathecal chemotherapy improvedoverall survival. In a multivariate analysis of patientsreceiving high-dose MTX � 3 g/m2, the addition of Ara-Cimproved overall survival. Among 119 complete responders,70 received immediate radiotherapy. A radiotherapy dose of�40 Gy to the whole brain or tumour bed did not improveoverall survival, and the 3 year overall survival was similarbetween the immediate and delayed radiotherapy groups.

These results provided the impetus for IELSG-20,a randomised phase II trial of high-dose MTX 3.5 g/m2

alone or in combination with high-dose Ara-C 2 g/m2 twicedaily on 2 days for four cycles [32]. The primary end pointwas complete remission rate after chemotherapy. Seventy-nine patients, aged up to 75 years, were randomised andall patients receivedWBRTafter chemotherapye those�60years and in complete remission received 36 Gy. Patientswith less than a complete response received 36 Gy WBRTfollowed by a tumour bed boost of 9 Gy. The use of WBRT inpatients >60 years in complete remission was left to thediscretion of the centre. Patients with stable or progressivedisease received 40 Gy WBRT with a 9 Gy boost.

Although significant haematological toxicity was seen,particularly in the combination arm, this was manageable.

At the end of chemotherapy, 46% of patients receiving high-dose MTX and high-dose Ara-C had a complete response totreatment compared with 18% of patients receiving high-dose MTX alone. Following radiotherapy, the completeremission rates increased to 64 and 30%, respectively.

A regimen using high-dose MTX, intrathecal MTX,procarbazine and vincristine was tested in 52 patients, 30 ofwhom also hadWBRT [33]. The objective response rate afterchemotherapy was 90%, and after completion of all treat-ment was 94%. The median overall survival was 60 months.Although there was no significant survival differencebetween groups, those with deferred WBRT mostly died ofprogressive disease, whereas the group treated withcombined modality treatment died of complications oftreatment. By 10 years of follow-up, the median survivalhad fallen to 52 months, with younger age and performancestatus being significant prognostic factors [34].

The effect of consolidation treatment including WBRT, inpatients in complete remission after combination chemo-therapy was assessed retrospectively in 122 patients [35].Patients were treated between 1983 and 2005, with MTX-based regimens and received between 1 and 3.5 g/m2 ofMTX. Forty-two patients did not receive any consolidationtreatment. Thirty-seven patients received high-dose Ara-Calone, 29 had high-dose Ara-C and WBRT (median dose45 Gy) and 14 WBRT alone (median dose 47.7 Gy). Patientstreated with WBRT were significantly younger. Failure-freesurvival was longer in patients receiving both WBRT andhigh-dose Ara-C, but there was no difference in overallsurvival. The 5 year incidence of neurotoxicity in patientswho hadWBRT was 21%, compared with 7% in patients whodid not. The median latency for developing neurotoxicityfrom the time of a complete response was 6 months forpatients treated with WBRT, and 58 months for those whowere not.

To define the role of WBRT after a complete response tochemotherapy, 551 patients from 75 centres in Germanywere enrolled in a phase III trial. Patients with a completeresponse to high-dose MTX-based chemotherapy wererandomised to 45 GyWBRTor observation, whereas all otherpatientswere randomised to either high-dose Ara-C orWBRT[36]. Sixty-six patients (13%) died during initial chemo-therapy and were excluded from further survival analyses. Of411 patients who completed first-line chemotherapy, 93patients had a major protocol violation, leaving 318 patientsin a per-protocol treatment analysis. Consolidation WBRTresulted in a significantly better progression-free survival(median of 18 versus 12 months), but no overall survivalbenefit (median 32 versus 37 months). An intention-to-treatanalysis was not carried out, and the study failed to meet theprimary end point for a non-inferiority study.

CNS penetration of MTX is poor at conventional doses,and the total dose and rate of infusion of MTX are importantfactors. Infusion of 3 g/m2 of MTX over 3 h results in highereffective concentrations than 8 g/m2 over 24 h, and the areaunder the curve is an important predictor of outcome [37].Maintaining doses of high-dose Ara-C is also important fortreatment outcomes [38]. These treatment schedulesrequire intensive inpatient management and may not be

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338 333

feasible in elderly patients or in patients with impairedrenal function [39,40]. Of 55 consecutive patients diagnosedwith biopsy-proven PCNSL at a single centre, 25 were not fitenough for high-dose MTX-based regimens and hada median survival of 46 days [39]. Thirty patients receivedhigh-dose MTX, but 16 did not complete treatment due totoxicity, disease progression or death. Patients not fit forhigh-dose MTX-based chemotherapy may be considered forpalliative WBRT if appropriate. A summary and suggestedalgorithm for the management of PCNSL is shown inFigure 2. More detailed guidelines on the diagnosis andmanagement of PCNSL have been produced by the BritishNeuro-Oncology Society [41].

Intrathecal Chemotherapy

The role of intrathecal chemotherapy in the managementof PCNSL is a controversial issue. Historical comparisons havenot shown any survival advantage when intrathecal MTX isadded to high-dose MTX-based regimens [42]. A systemicand intraventricular polychemotherapy regimen withoutradiotherapy (the Bonn protocol) gave durable responses in75% of patients <60 years with PCNSL, but was complicatedby a high rate of Ommaya reservoir infections (19%) and a 9%toxic death rate [43]. The efficacy and toxicity of this regimenwithout intraventricular treatment was subsequently eval-uated in a phase II study, but accrual was prematurelystopped due to a high rate of early relapses [44]. Unless thereis evidence of CSF involvement, intrathecal chemotherapy isnot recommended as part of standard treatment [41].

Fit for HD-MTX-based

chemotherapy.

Consider clinical trial

Complete

response

Partial

response p

≤ 60 yrs > 60 yrs

WBRT

36 Gy

Sa

WBR

pre

C

Su

Observation

Relapse

Fig 2. Suggested algorithm for the management o

High-dose Chemotherapy with Stem Cell Transplant

Studies of high-dose chemotherapy followed by ASCT forpatients with newly diagnosed PCNSL have involved limitednumbers of highly selected patients and yielded mixedresults. Different induction and conditioning regimens andvariable outcomemeasuresmake comparison between trialsdifficult [45e47]. In a multicentre phase II trial, 30 patients<65 years received sequential treatment with high-doseMTX (8 g/m2), Ara-C and thiotepa, followed by high-dosechemotherapy, ASCT and hyperfractionated WBRT [46].Complete responders received 45 Gy in two daily fractions of1 Gy, and partial responders had a total dose of 50 Gy. Atamedian follow-up of 63months, 5 year overall survival was69% for all patients and 87% for the 23 patients receivinghigh-dose chemotherapy. Five of 21 patients who completedall planned treatment developed leucoencephalopathy.

However, preliminary results are encouraging, and high-dose chemotherapy with ASCT may have a role for selectedpatients with PCNSL [48].

Immunotherapy

Most PCNSLs are B-cell lymphomas that express CD20 ontheir cell surface. The addition of rituximab, a humanisedanti-CD20monoclonal antibody, to high-doseMTX regimensis rational because of the benefit seen in systemic B-celllymphomas. After intravenous administration, rituximab canbe reproducibly measured in CSF, albeit at about 0.1% oftherapeutic serum levels [49]. Rituximab transport to the CSF

PCNSL

Not fit for HD-MTX.

Consider clinical trial

Stable or

rogressive

disease

lvage therapy

T 36-45 Gy if not

viously treated

linical trial?

pportive care

Dexamethasone

+/-

WBRT 30-45 Gy

Supportive care

f primary central nervous system lymphoma.

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338334

may occur via leakage across areas of bloodebrain barrier breakdown in lymphoma and/or transportacross an intact bloodebrain barrier.

The addition of rituximab to a high-dose MTX-basedchemotherapy regimen was tested prospectively in 30patients with PCNSL [50]. Patients in complete remissionreceived 23.4 Gy WBRT, whereas all others had 45 Gy, andtwo cycles of high-dose Ara-C were administered afterWBRT. Rituximab increased the risk of significant neu-tropenia compared with historical controls, whereas theoverall response rate of 93% was comparable with thatachieved with methotrexate, procarbazine, vincristine(MPV) alone. The addition of rituximab to high-dose MTXregimens remains investigational.

The addition of rituximab to CHOP regimens for thetreatment of systemic lymphoma may, however, reduce theincidence of CNS relapse. The original GELA trial of ritux-imab added to CHOP in DLBCL did not show any reductionin the risk of CNS relapse [51]. A review by the BritishColumbia Cancer Agency of 435 patients with DLBCL treatedwith CHOP and subsequently R-CHOP, did show an effectwith rituximab [52]. With a median follow-up of 5.7 years,there were 31 CNS relapses and in a multivariate analysis,rituximab significantly reduced the risk of CNS relapse(hazard ratio 0.45, P ¼ 0.034).

One thousand two hundred and twenty-two elderlypatients with aggressive CD20-positive lymphoma treatedin the German Hodgkin Study Group RICOVER-60 trialshowed a significantly lower incidence of CNS disease iftreated with R-CHOP-14 instead of CHOP-14 [53]. R-CHOPreduced the relative risk for CNS disease to 0.58. In youngerpatients treated in the Mabthera International Trial andother German Hodgkin Study Group studies, 56 of 2196patients (2.6%) developed CNS disease [54]. Six hundred

rituxi

HD-M

HD-A

HD-MTX

HD-AC

RESPONSE AS

Complete or partial response

Stable disease

Randomization

PCNS

(≤65 yrs PS 0-3 or

Random

WBRT 36 Gy

± 9 Gy boost

BCNU

thiotepa

ASCT

Fig 3. IELSG-32 d an international multicentre randomised

and twenty patients had received rituximab, which reducedthe relative risk of CNS relapse in patients with a lowage-adjusted International Prognostic Index to 0.3, but hadno effect in patients with a high International PrognosticIndex.

Ten patients with relapsed PCNSL were treated with the90Y-labelled anti-CD20 antibody ibritumomab tiuxetan[55]. Nine patients received radioimmunotherapy and offour responding patients, one had a complete responselasting over 30 months. Target accumulation of the anti-body in four of six patients examined by single photonemission computed tomography (SPECT) imaging showedpenetration and clinical activity at sites of disease.

Clinical Trials

After the IELSG-20 trial showing the efficacy of high-dose MTX/high-dose Ara-C, this has become the standardarm for the current IELSG-32 study, which is open atcentres in the UK [32]. This trial is studying the role ofrituximab and thiotepa in first-line induction regimens,as well as the effectiveness of either ASCT or WBRTfor consolidation of remission (Figure 3). Patients rando-mised to WBRT will receive 36 Gy if in complete remission,or an additional 9 Gy boost to any residual tumour witha 1e2 cm margin. Patients progressing on chemotherapycan be considered for WBRT 36e40 Gy, with a boost ifappropriate.

Salvage Treatment

The feasibility and success of salvage treatment dependson the performance status of the patient at relapse, prior

mab

TX

C

rituximab

thiotepa

HD-MTX

HD-AC

SESSMENT

Progressive disease or toxicity

Insufficient stem cell harvest

L

66-70 yrs PS ≤2)

ization

WBRT 36-40 Gy

± 9 Gy boost

phase II trial open in UK centres. PS, performance status.

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338 335

treatment received and the progression-free interval.Failure after chemotherapy may be successfully treatedwith WBRT alone; in a study of 27 patients, WBRT (mediandose 36 Gy) resulted in an overall response rate of 74% anda median survival of 10.9 months [56]. Re-induction withhigh-dose MTX may also be feasible [57].

Temozolomide is an oral alkylator with good CNS pene-tration. A retrospective series evaluated the use of ritux-imab and temozolomide in 15 patients with relapsed orrefractory PCNSL (median age 69 years) [58]. The objectiveresponse rate was 53%, with a median overall survival of 14months. Side-effects were tolerable and includedmyelosuppression.

A second retrospective series of seven patients evalu-ated a different schedule of rituximab and temozolomide[59]. Five patients achieved a complete response, where-as two had partial responses. The median survivalwas 8 months and the median response duration was6 months.

Topotecan is a selective inhibitor of topoisomerase I inthe S-phase of the cell cycle with a different mechanism ofaction from that of MTX and Ara-C. It shows good CSFpenetration and has single-agent activity in relapsed andrefractory PCNSL [60].

Primary Intraocular Lymphoma

Vitreoretinal lymphoma is the most common and mostaggressive intraocular lymphoma [61]. It may present withsymptoms of blurred vision, decreased visual acuity andfloaters, and patients may be given steroids for presumeduveitis. Involvement of one eye at diagnosis is usual,but 60e90% patients ultimately develop bilateraldisease and PCNSL [62]. Median survival is 3 years.Treatment with radiotherapy alone is associated witha high rate of relapse, and although there is no interna-tional consensus, combined modality treatment regimenssimilar to those used for PCNSL are recommended[41,62e65]. Radiotherapy is given to both eyes and orbits,including the optic nerves and conus, and doses between30 and 50 Gy have been used, with a median of 40 Gy. Therole of WBRT is unclear. Patients with primary intraocularlymphoma will be eligible for treatment in the IELSG-32trial.

HIV-associated Primary Central NervousSystem Lymphoma

The incidence of PCNSL is lower in the highly active anti-retroviral therapy (HAART) era than in the pre-HAART era(1.2 versus 3.0 cases per 1000 patient-years), and themediansurvival is also higher (48 versus 32 days) [66]. Standardmanagement has been HAART together with WBRT [67], butthere is evidence that high-dose MTX is feasible, safe andeffective [68]. Comprehensive guidelines for the treatment ofPCNSL and other HIV-associated malignancies have beenproduced by the British HIV Association [69].

Secondary Central Nervous SystemLymphoma

CNS relapse occurs in about 5% of patients with systemicDLBCL treated in the R-CHOP era and may involve the brainparenchyma, spinal cord, leptomeninges or eyes [50e53]. Inmost cases, CNS relapse is seen in conjunction withsystemic relapse and has a very poor prognosis. IsolatedCNS relapse is much less common, but may be potentiallytreatable. An international review of 113 patients, most ofwhom had DLBCL, found that the median time to CNSrelapse was 1.8 years and the median overall survival was1.6 years. Sixty patients (53%) received WBRT (6e54 Gy,median 30 Gy) with or without chemotherapy. Only age<60 years at relapse and MTX use were significantly asso-ciated with longer survival in a multivariate model [70].

Neurotoxicity and Late Effects

The major drawback to the use of WBRT in conjunctionwith high-dose MTX-based chemotherapy is the high inci-dence of cognitive impairment and white matter damage.In total, 185 patients treated for PCNSL between 1985 and2000 were reviewed [71]; 129 patients hadWBRT as part oftheir treatment, 111 of these having additional high-doseMTX-based chemotherapy; 54 patients had chemotherapyalone. The median age at diagnosis was 60 years and themedian follow-up was 3.6 years. The median overallsurvival was 2.9 years, and for 43 patients who developedneurotoxicity, median survival after onset was 1.8 years.The 5 year cumulative incidence of neurotoxicity was 24%.Radiotherapy was the only independent risk factor onmultivariate analysis. Neurotoxicity presented as a rapidlyprogressive dementia characterised by psychomotor slow-ing, executive and memory dysfunction, behaviouralchanges, gait ataxia and incontinence. Imaging findings in12 patients revealed diffuse white matter disease andcortical atrophy. Post-mortem changes in five patientsincluded white matter damage with gliosis, thickening ofsmall vessels and demyelination. Other studies havereported even higher frequencies of clinical neurotoxicitywith regimens that include WBRT, and it remains uncertainwhether there is a ’safe dose’ for WBRT in this setting.

Although most ongoing clinical trials are collectingquality-of-life data, few studies have reported long-termoutcomes. Most published trials have had a relatively shortfollow-up that may underestimate the long-term effect oftherapy and overestimate disease control [72]. Evaluation ofcognitive function before and after treatment can determinethe contribution of disease-related factors and the benefit oftherapy while screening for treatment-related neuro-cognitive impairment [73]. At this point, there are no stan-dard neuropsychological tests in common use. Despite itslow sensitivity, the Mini-Mental Status Examination is sug-gested as the minimum requirement at baseline and serialfollow-up for all patients. Monitoring of neurological func-tion, especially gait and neuro-imaging changes, is impor-tant, and assessment intervals should be standardised [73].

E. Gallop-Evans / Clinical Oncology 24 (2012) 329e338336

Conclusion

PCNSL remains a challenging disease with a poor prog-nosis. Patients are frequently started on steroids beforereferral to neurosurgeons and/or oncologists, and surgeonscan be reluctant to carry out biopsies in the presence ofcharacteristic imaging findings. However, the toxicity ofavailable treatments mandates histological confirmationand patients also need to be offered the chance of partici-pation in clinical trials. Diagnostic tests with improvedsensitivity and specificity could replace the need for aninvasive biopsy, particularly in patients with more inac-cessible lesions. The use of high-dose MTX- and high-doseAra-C-based chemotherapy regimens that penetrate thebloodebrain barrier have improved survival, but whencombined with WBRT, result in significant late neurotox-icity. Radiotherapy fields and doses have not changedsignificantly over the last few decades, and better selectionof patients may be critical. The use of additional inductiontreatments and different consolidation strategies includinghigh-dose chemotherapy may allow deferral of WBRT, andthese approaches are being tested in clinical trials.

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