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Clinical Oncology 24 (2012) 329e338

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Clinical Oncology
journal homepage: www.clinicaloncologyonline.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 prole that appears to be distinct from other types of
diffuse large B-cell lymphoma. The median survival after whole brain radiotherapy alone is poor, but is signicantly improved after high-dose methotrexate-based
combination chemotherapy. The rarity of primary central nervous system lymphoma means that randomised studies have proved challenging, particularly as many
patients are elderly and more susceptible to the toxic effects associated with these treatments. Promising treatment strategies are emerging and, wherever possible,
patients should be treated within clinical trials. Quality of life and neurocognitive data should be collected prospectively to assess the effect of the disease and 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 and


Sources of Information
A systematic literature search was carried out using
Medline up to 21 November 2011. The search also included
reference lists of papers identied.

Introduction
Primary central nervous system lymphoma (PCNSL) is an
aggressive diffuse large B-cell lymphoma (DLBCL) and, if
untreated, has a rapidly fatal course with a median survival
of about 1.5 months. The median survival after whole brain
radiotherapy (WBRT) alone ranges from 10 to 18 months,
but is signicantly improved after chemotherapy with or
without WBRT. Although current treatment strategies have
prolonged survival, they are not curative in most patients.
The disease tends to recur and is eventually fatal. Due to the
rarity of PCNSL, randomised studies have been very difcult
to conduct. Rigorous testing of treatment strategies,
including high-dose methotrexate (MTX)-based regimens,
autologous stem cell transplantation (ASCT) and WBRT, has
proved challenging because many patients are elderly and
more susceptible to the toxic effects associated with
combined modality treatments.
Author for correspondence: E. Gallop-Evans, Velindre Cancer Centre,
Cardiff CF14 2TL, UK. Tel: 44-2920-316246.
E-mail address: eve.gallop-evans@wales.nhs.uk

The other priority is to improve our understanding of the


molecular biology and genetic prole of PCNSL, which
seems to be distinct from other types of DLBCL. The paucity
of available tissue has made full characterisation of PCNSL
difcult, but new techniques may allow accurate assessment of small samples.

Epidemiology
PCNSL is a B-cell non-Hodgkin lymphoma recognised as
a discrete entity in the updated World Health Organization
classication [1]. It represents about 1% of all non-Hodgkin
lymphomas and 4% of central nervous system (CNS)
tumours. Although PCNSL has been characteristically
associated with immunodeciency, the incidence in
immunocompetent patients is increasing [2]. Most cases of
non-HIV-related PCNSL are diagnosed in patients between
45 and 70 years of age, with a median age at diagnosis in the
fth decade. Men and women are equally affected, with an
annual incidence rate of 0.47 per 100,000 person-years [3].

Presentation
The typical presentation of PCNSL in an immunocompetent patient involves progressive focal symptoms associated with a mass lesion. In a series of 248 PCNSL patients,
70% presented on admission with a focal neurological

0936-6555/$36.00 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.clon.2012.02.009

330

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

decit, 43% with altered mental status, 33% with signs of


increased intracranial pressure, 14% with ts and 4% with
visual symptoms related to vitreous involvement [4].
Empiric treatment with corticosteroids may cause prolonged remission of clinical signs and symptoms as well as
imaging ndings; however, remission can also occur
spontaneously.

Imaging
Contrast-enhanced magnetic resonance imaging scans
are the imaging modality of choice, although computed
tomography is also informative (Figure 1). In immunocompetent patients, single or multiple periventricular
enhancing lesions are typical, whereas ring-enhancing
lesions are seen in immunodecient patients. The most
common sites of involvement are the frontal lobes, followed
by the basal ganglia and thalamus. PCNSL can also spread
across the corpus callosum, giving a typical buttery
pattern [5]. Ependymal spread is often seen, particularly in
HIV-associated lymphoma. However, even characteristic
lesions cannot be unequivocally distinguished from other
CNS lesions [5]. Positron emission tomography with 18Fuorodeoxyglucose and 11C-methionine, which measure
glucose and amino acid metabolism respectively, may
provide useful information, but although 18F-uorodeoxyglucose and 11C-methionine are taken up in typical lesions,
they are not useful in the detection of atypical lesions [6].

Diagnosis and Pathology


The diagnosis of PCNSL should always be conrmed
histologically, as multiple sclerosis, sarcoidosis and occasional gliomas can be indistinguishable and also respond to
steroids. This should be done by stereotactic biopsy, ideally
before steroid therapy, as surgical resection does not
contribute to denitive management. If there is evidence of
ocular or cerebrospinal uid (CSF) involvement, vitrectomy
or CSF cytology may establish the diagnosis. Expert
haematopathological review should be sought.
About 90% of PCNSL are DLBCLs, the rest being either
low-grade, Burkitt or T-cell lymphomas. In normal circumstances, B cells are not usually found in the CNS, and the
cellular and molecular events leading to malignant B-cell
inltration are unclear [7]. PCNSL has a different gene
expression signature from that of systemic DLBCL, which
suggests that it develops from mature B cells either at the
late germinal centre or early post-germinal centre stage [8].
However, there is no evidence for germinal centre structures in the CNS, raising the possibility that the malignant
cells have migrated to the brain. CNS lymphomas show
angiotropism, with cells clustering densely around tumour
vessels. In most cases, the malignant B cells have a centroblastic morphology and are CD79a, CD20 PAX-5, BCL2, MUM1/IRF4. BCL-6 is frequently positive, and CD10 is
less so. PCNSL cells also express high levels of c-MYC, which
has been associated with adverse prognosis in systemic
DLBCL [8]. If material is sufcient for ow analysis, the
lymphoma cells will show monoclonal surface immunoglobulin. Immunoglobulin Vegene analysis was able to
identify tumour cells in the CNS in 12 patients, as well as in
peripheral tissue in three patients [9]. Clonal tracking
revealed tumour cells in the bone marrow and/or blood in
all three cases, with evidence for increased V-gene mutational activity at peripheral sites, consistent with a greater
diversication of the original clone. However, there was no
evidence of malignant growth at systemic sites, and the
limited diversity within the CNS tumour suggested little or
no re-entry into the brain.
In HIV patients, the detection of EpsteineBarr virus DNA
in CSF has been considered diagnostic of PCNSL when
combined with typical imaging ndings. This specicity has
recently been questioned, and may reect the declining
incidence of the disease [10]. EpsteineBarr virus DNA is
usually negative in immunocompetent patients.

Staging and Pretreatment Investigations

Fig 1. T2 axial magnetic resonance image showing a large mass


involving the right frontal lobe and adjacent corpus callosum. There is
oedema and compression of the right lateral ventricle and midline
shift.

Standardised guidelines for the baseline evaluation and


response assessment have been published by the International PCNSL Collaborative Group [11]. Apart from the
imaging modalities mentioned above, CSF examination
should include cell count, cytology and ow cytometry [12],
protein, glucose and immunoglobulin heavy-chain gene
rearrangement studies. Magnetic resonance imaging of the
spine is only warranted in the presence of localising
symptoms.

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

An ophthalmological examination, including slit lamp


evaluation, computed tomography of the chest, abdomen
and pelvis, and bone marrow biopsy, should be carried out.
Blood tests should include HIV and serum lactate dehydrogenase. A testicular ultrasound should be considered in men.

331

Steroids induce apoptosis in lymphoma cells, and can


cause signicant regression of PCNSL lesions, with corresponding clinical and radiological improvement. Ideally
steroids should not be commenced until after a biopsy, as
this can make it impossible to get a denitive diagnosis.
Although a response to steroids is not durable, it can signify
a more favourable prognosis, with survival of 117 months in
responders compared with only 5.5 months in nonresponders [14].

A retrospective review to examine the effect of WBRT


dose was undertaken for 33 patients treated at a single
centre after a complete response to high-dose MTX-based
chemotherapy [17]. Patients received between 30 and 45 Gy
WBRT, with a tumour bed boost taking the total dose to
36e54 Gy. Twelve patients relapsed, four outside the
radiotherapy volume, including extra-cranial sites. Eight
patients relapsed within the radiotherapy eld; two of these
within the boost volume, and a further six within areas
treated with 45e54 Gy. A tumour bed boost of 45 Gy or more
did not reduce the risk of relapse, and there was no difference in outcomes between patients receiving 30e36 Gy, and
those receiving >40 Gy. Neurocognitive impairment was
signicantly worse in older patients (median age 66 years)
and those receiving >40 Gy. The current recommendation
for patients in complete remission before WBRT is 36 Gy,
with a 9 Gy tumour boost reserved for patients with partial
or no response. For patients being treated with palliative
intent, 30.6 Gy in 1.8 Gy fractions may be considered.
The standard treatment volume for WBRT includes the
whole brain and the eyes and optic nerves, while shielding
the anterior chamber and lens [18,19]. Left and right lateral
equally weighted opposed-elds are used, using 6e10 MV
photons. The posterior two-thirds of the orbits should be
shielded after 30 Gy, or 36 Gy in the case of intraocular
involvement. The inferior border encompasses the vertebral
body of C2. If required, the boost volume encompasses
residual tumour with a 1e2 cm margin.
Acute side-effects are tolerable and include fatigue,
headaches, hair loss, and skin dryness and/or erythema. In
patients with signicant mass effect, corticosteroids should
be prescribed to avoid worsening of cerebral oedema, but
can be tapered reasonably quickly. Acute symptoms of
confusion are usually mild and transient.
Delayed symptoms, occurring within 7e40 days of
radiotherapy, are thought to result from inhibition of myelin
synthesis. Patients should be warned about the possibility
and evaluated carefully, as this can be misinterpreted as
disease progression.

Whole Brain Radiotherapy

Chemotherapy With/Without Radiotherapy

As PCNSL is usually multifocal, but radiosensitive, WBRT


was the rst effective treatment to be used. However, there
have been no prospective randomised trials in PCNSL to
answer the question of optimal elds and/or dose.
The Radiation Therapy Oncology Group 8315 study was
a prospective phase II study of 41 patients treated with
40 Gy WBRT and a 20 Gy boost to tumour plus a 2 cm
margin [15]. Median survival was 11.6 months from the start
of treatment. Twenty-six patients had post-treatment scans
at 4 months after the start of radiotherapy, with a 62%
complete response rate. Forty-eight per cent of patients
survived 1 year and 28% survived 2 years. In this study, most
relapses occurred in the high dose volume.
A retrospective survey of 132 patients treated in Japan
between 1990 and 1999, with WBRT to a median of 40 Gy,
showed a median survival of 18 months and a 5 year
survival rate of 18% [16].

Responses to WBRT alone are rarely sustained, and the


initial approach to combined modality treatments incorporated regimens active in systemic DLBCL [20,21].
A Medical Research Council study found that the addition of
cyclophosphamide, doxorubicin, vincristine, prednisolone
(CHOP) to WBRT resulted in worse survival than with WBRT
alone [22], probably because of poor CNS penetration. The
exception to this is intravascular large cell lymphoma with
CNS involvement, where the malignant cells are found
within blood vessels and, therefore, not protected by the
bloodebrain barrier, and R-CHOP is effective [23].
MTX, a reversible inhibitor of dihydrofolate reductase, is
able to cross the bloodebrain barrier and enters cells in part
by an active transport mechanism where it is bound as
polyglutamate conjugates. Longer periods of drug exposure
lead to higher polyglutamate formation, and more cells
enter S phase, resulting in increased cytotoxicity. MTX has

Prognostic Factors
The International Extranodal Lymphoma study group
reported the following ve adverse prognostic factors:
 Age > 60 years
 Eastern Cooperative Oncology Group performance
status > 1
 Elevated serum lactate dehydrogenase
 Elevated CSF protein concentration
 Involvement of deep regions of the brain (periventricular
regions, basal ganglia, brainstem and/or cerebellum)
For 105 assessable patients, 2 year overall survival for
scores of 0e1, 2e3 and 4e5 was 80, 48, and 15%, respectively. For 75 patients who received high-dose MTX-based
chemotherapy with or without WBRT, 2 year overall
survival was 85, 57 and 24%, respectively [13].

First-line Management
Steroids

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

signicant single-agent activity in PCNSL [24]. The addition


of MTX-based chemotherapy regimens to WBRT have
signicantly improved outcomes, but have resulted in
a higher incidence of late neurotoxicity, particularly in
patients >60 years [25e27].
In most of these studies, WBRT was given as consolidation after induction chemotherapy. The CHOD-BVAM
regimen (cyclophosphamide, doxorubicin, vincristine,
dexamethasone, carmustine, MTX 1.5 g/m2 and cytarabine
[ara-C]) was followed by 45 Gy WBRT, or in a second cohort
of complete responders, by 30.6 Gy WBRT [28]. The 5 year
survival of 57 patients treated was 36%, with a median
survival of 40 months. Reducing the WBRT dose from 45 Gy
to 30.6 Gy resulted in a fall in 3 year overall survival from
92% to 60%. The risk of late cognitive impairment was much
higher in patients aged over 60 years (60% versus 8%).
A recent report of 36 patients treated with CHOD-BVAM
and WBRT, albeit with a higher dose of 50.4 Gy for nonresponders, found inadequate responses and signicant
levels of neurotoxicity, with 28% of evaluable patients
having at least one grade 3 neurological toxicity [29].
A retrospective population-based study reported
outcomes of 122 patients treated after 1990 with three
consecutive treatment strategies e 35 Gy WBRT with/
without CHOP/CHOP-like chemotherapy, the addition of MTX
(1 g/m2) to combination treatment and, eventually, high-dose
MTX alone (8 g/m2), with WBRT reserved for patients with
stable or progressive disease [30]. The median overall survival
of 17 months was similar in all three eras. However, a third of
the 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 prospective
studies with high-dose MTX-based regimens assessed the
effect of additional treatment factors including WBRT, other
drugs and intrathecal chemotherapy [31]. High-dose MTX
3 g/m2, thiotepa and intrathecal chemotherapy improved
overall survival. In a multivariate analysis of patients
receiving high-dose MTX  3 g/m2, the addition of Ara-C
improved 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 improve
overall survival, and the 3 year overall survival was similar
between 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 twice
daily on 2 days for four cycles [32]. The primary end point
was complete remission rate after chemotherapy. Seventynine patients, aged up to 75 years, were randomised and
all patients received WBRT after chemotherapy e those 60
years and in complete remission received 36 Gy. Patients
with less than a complete response received 36 Gy WBRT
followed by a tumour bed boost of 9 Gy. The use of WBRT in
patients >60 years in complete remission was left to the
discretion of the centre. Patients with stable or progressive
disease received 40 Gy WBRT with a 9 Gy boost.
Although signicant haematological toxicity was seen,
particularly in the combination arm, this was manageable.

At the end of chemotherapy, 46% of patients receiving highdose MTX and high-dose Ara-C had a complete response to
treatment compared with 18% of patients receiving highdose MTX alone. Following radiotherapy, the complete
remission rates increased to 64 and 30%, respectively.
A regimen using high-dose MTX, intrathecal MTX,
procarbazine and vincristine was tested in 52 patients, 30 of
whom also had WBRT [33]. The objective response rate after
chemotherapy was 90%, and after completion of all treatment was 94%. The median overall survival was 60 months.
Although there was no signicant survival difference
between groups, those with deferred WBRT mostly died of
progressive disease, whereas the group treated with
combined modality treatment died of complications of
treatment. By 10 years of follow-up, the median survival
had fallen to 52 months, with younger age and performance
status being signicant prognostic factors [34].
The effect of consolidation treatment including WBRT, in
patients in complete remission after combination chemotherapy was assessed retrospectively in 122 patients [35].
Patients were treated between 1983 and 2005, with MTXbased regimens and received between 1 and 3.5 g/m2 of
MTX. Forty-two patients did not receive any consolidation
treatment. Thirty-seven patients received high-dose Ara-C
alone, 29 had high-dose Ara-C and WBRT (median dose
45 Gy) and 14 WBRT alone (median dose 47.7 Gy). Patients
treated with WBRT were signicantly younger. Failure-free
survival was longer in patients receiving both WBRT and
high-dose Ara-C, but there was no difference in overall
survival. The 5 year incidence of neurotoxicity in patients
who had WBRT was 21%, compared with 7% in patients who
did not. The median latency for developing neurotoxicity
from the time of a complete response was 6 months for
patients treated with WBRT, and 58 months for those who
were not.
To dene the role of WBRT after a complete response to
chemotherapy, 551 patients from 75 centres in Germany
were enrolled in a phase III trial. Patients with a complete
response to high-dose MTX-based chemotherapy were
randomised to 45 Gy WBRT or observation, whereas all other
patients were randomised to either high-dose Ara-C or WBRT
[36]. Sixty-six patients (13%) died during initial chemotherapy and were excluded from further survival analyses. Of
411 patients who completed rst-line chemotherapy, 93
patients had a major protocol violation, leaving 318 patients
in a per-protocol treatment analysis. Consolidation WBRT
resulted in a signicantly better progression-free survival
(median of 18 versus 12 months), but no overall survival
benet (median 32 versus 37 months). An intention-to-treat
analysis was not carried out, and the study failed to meet the
primary 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 important
factors. Infusion of 3 g/m2 of MTX over 3 h results in higher
effective concentrations than 8 g/m2 over 24 h, and the area
under the curve is an important predictor of outcome [37].
Maintaining doses of high-dose Ara-C is also important for
treatment outcomes [38]. These treatment schedules
require intensive inpatient management and may not be

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

feasible in elderly patients or in patients with impaired


renal function [39,40]. Of 55 consecutive patients diagnosed
with biopsy-proven PCNSL at a single centre, 25 were not t
enough for high-dose MTX-based regimens and had
a median survival of 46 days [39]. Thirty patients received
high-dose MTX, but 16 did not complete treatment due to
toxicity, disease progression or death. Patients not t for
high-dose MTX-based chemotherapy may be considered for
palliative WBRT if appropriate. A summary and suggested
algorithm for the management of PCNSL is shown in
Figure 2. More detailed guidelines on the diagnosis and
management of PCNSL have been produced by the British
Neuro-Oncology Society [41].
Intrathecal Chemotherapy
The role of intrathecal chemotherapy in the management
of PCNSL is a controversial issue. Historical comparisons have
not shown any survival advantage when intrathecal MTX is
added to high-dose MTX-based regimens [42]. A systemic
and intraventricular polychemotherapy regimen without
radiotherapy (the Bonn protocol) gave durable responses in
75% of patients <60 years with PCNSL, but was complicated
by a high rate of Ommaya reservoir infections (19%) and a 9%
toxic death rate [43]. The efcacy and toxicity of this regimen
without intraventricular treatment was subsequently evaluated in a phase II study, but accrual was prematurely
stopped due to a high rate of early relapses [44]. Unless there
is evidence of CSF involvement, intrathecal chemotherapy is
not recommended as part of standard treatment [41].

High-dose Chemotherapy with Stem Cell Transplant


Studies of high-dose chemotherapy followed by ASCT for
patients with newly diagnosed PCNSL have involved limited
numbers of highly selected patients and yielded mixed
results. Different induction and conditioning regimens and
variable outcome measures make comparison between trials
difcult [45e47]. In a multicentre phase II trial, 30 patients
<65 years received sequential treatment with high-dose
MTX (8 g/m2), Ara-C and thiotepa, followed by high-dose
chemotherapy, ASCT and hyperfractionated WBRT [46].
Complete responders received 45 Gy in two daily fractions of
1 Gy, and partial responders had a total dose of 50 Gy. At
a median follow-up of 63 months, 5 year overall survival was
69% for all patients and 87% for the 23 patients receiving
high-dose chemotherapy. Five of 21 patients who completed
all planned treatment developed leucoencephalopathy.
However, preliminary results are encouraging, and highdose chemotherapy with ASCT may have a role for selected
patients with PCNSL [48].
Immunotherapy
Most PCNSLs are B-cell lymphomas that express CD20 on
their cell surface. The addition of rituximab, a humanised
anti-CD20 monoclonal antibody, to high-dose MTX regimens
is rational because of the benet seen in systemic B-cell
lymphomas. After intravenous administration, rituximab can
be reproducibly measured in CSF, albeit at about 0.1% of
therapeutic serum levels [49]. Rituximab transport to the CSF

PCNSL

Fit for HD-MTX-based


chemotherapy.

Not fit for HD-MTX.


Consider clinical trial

Consider clinical trial

Complete
response

> 60 yrs

Partial
response

Stable or
progressive
disease

Dexamethasone
+/WBRT 30-45 Gy
Supportive care

60 yrs
Salvage therapy

Observation

WBRT
36 Gy

WBRT 36-45 Gy if not


previously treated
Clinical trial?

Relapse

333

Supportive care

Fig 2. Suggested algorithm for the management of primary central nervous system lymphoma.

334

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

may occur via leakage across areas of bloode


brain barrier breakdown in lymphoma and/or transport
across an intact bloodebrain barrier.
The addition of rituximab to a high-dose MTX-based
chemotherapy regimen was tested prospectively in 30
patients with PCNSL [50]. Patients in complete remission
received 23.4 Gy WBRT, whereas all others had 45 Gy, and
two cycles of high-dose Ara-C were administered after
WBRT. Rituximab increased the risk of signicant neutropenia compared with historical controls, whereas the
overall response rate of 93% was comparable with that
achieved with methotrexate, procarbazine, vincristine
(MPV) alone. The addition of rituximab to high-dose MTX
regimens remains investigational.
The addition of rituximab to CHOP regimens for the
treatment of systemic lymphoma may, however, reduce the
incidence of CNS relapse. The original GELA trial of rituximab added to CHOP in DLBCL did not show any reduction
in the risk of CNS relapse [51]. A review by the British
Columbia Cancer Agency of 435 patients with DLBCL treated
with CHOP and subsequently R-CHOP, did show an effect
with rituximab [52]. With a median follow-up of 5.7 years,
there were 31 CNS relapses and in a multivariate analysis,
rituximab signicantly reduced the risk of CNS relapse
(hazard ratio 0.45, P 0.034).
One thousand two hundred and twenty-two elderly
patients with aggressive CD20-positive lymphoma treated
in the German Hodgkin Study Group RICOVER-60 trial
showed a signicantly lower incidence of CNS disease if
treated with R-CHOP-14 instead of CHOP-14 [53]. R-CHOP
reduced the relative risk for CNS disease to 0.58. In younger
patients treated in the Mabthera International Trial and
other German Hodgkin Study Group studies, 56 of 2196
patients (2.6%) developed CNS disease [54]. Six hundred

and twenty patients had received rituximab, which reduced


the relative risk of CNS relapse in patients with a low
age-adjusted International Prognostic Index to 0.3, but had
no effect in patients with a high International Prognostic
Index.
Ten patients with relapsed PCNSL were treated with the
90
Y-labelled anti-CD20 antibody ibritumomab tiuxetan
[55]. Nine patients received radioimmunotherapy and of
four responding patients, one had a complete response
lasting over 30 months. Target accumulation of the antibody in four of six patients examined by single photon
emission computed tomography (SPECT) imaging showed
penetration and clinical activity at sites of disease.

Clinical Trials
After the IELSG-20 trial showing the efcacy of highdose MTX/high-dose Ara-C, this has become the standard
arm for the current IELSG-32 study, which is open at
centres in the UK [32]. This trial is studying the role of
rituximab and thiotepa in rst-line induction regimens,
as well as the effectiveness of either ASCT or WBRT
for consolidation of remission (Figure 3). Patients randomised to WBRT will receive 36 Gy if in complete remission,
or an additional 9 Gy boost to any residual tumour with
a 1e2 cm margin. Patients progressing on chemotherapy
can be considered for WBRT 36e40 Gy, with a boost if
appropriate.

Salvage Treatment
The feasibility and success of salvage treatment depends
on the performance status of the patient at relapse, prior

PCNSL
(65 yrs PS 0-3 or 66-70 yrs PS 2)
Randomization

rituximab
thiotepa
HD-MTX
HD-AC

rituximab
HD-MTX
HD-AC

HD-MTX
HD-AC

RESPONSE ASSESSMENT

Complete or partial response


Stable disease
Randomization

WBRT 36 Gy
9 Gy boost

BCNU
thiotepa
ASCT

Progressive disease or toxicity


Insufficient stem cell harvest

WBRT 36-40 Gy
9 Gy boost

Fig 3. IELSG-32 d an international multicentre randomised phase II trial open in UK centres. PS, performance status.

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

treatment received and the progression-free interval.


Failure after chemotherapy may be successfully treated
with WBRT alone; in a study of 27 patients, WBRT (median
dose 36 Gy) resulted in an overall response rate of 74% and
a median survival of 10.9 months [56]. Re-induction with
high-dose MTX may also be feasible [57].
Temozolomide is an oral alkylator with good CNS penetration. A retrospective series evaluated the use of rituximab and temozolomide in 15 patients with relapsed or
refractory PCNSL (median age 69 years) [58]. The objective
response rate was 53%, with a median overall survival of 14
months. Side-effects were tolerable and included
myelosuppression.
A second retrospective series of seven patients evaluated a different schedule of rituximab and temozolomide
[59]. Five patients achieved a complete response, whereas two had partial responses. The median survival
was 8 months and the median response duration was
6 months.
Topotecan is a selective inhibitor of topoisomerase I in
the S-phase of the cell cycle with a different mechanism of
action from that of MTX and Ara-C. It shows good CSF
penetration and has single-agent activity in relapsed and
refractory PCNSL [60].

Primary Intraocular Lymphoma


Vitreoretinal lymphoma is the most common and most
aggressive intraocular lymphoma [61]. It may present with
symptoms of blurred vision, decreased visual acuity and
oaters, and patients may be given steroids for presumed
uveitis. Involvement of one eye at diagnosis is usual,
but 60e90% patients ultimately develop bilateral
disease and PCNSL [62]. Median survival is 3 years.
Treatment with radiotherapy alone is associated with
a high rate of relapse, and although there is no international consensus, combined modality treatment regimens
similar 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 between
30 and 50 Gy have been used, with a median of 40 Gy. The
role of WBRT is unclear. Patients with primary intraocular
lymphoma will be eligible for treatment in the IELSG-32
trial.

HIV-associated Primary Central Nervous


System Lymphoma
The incidence of PCNSL is lower in the highly active antiretroviral therapy (HAART) era than in the pre-HAART era
(1.2 versus 3.0 cases per 1000 patient-years), and the median
survival is also higher (48 versus 32 days) [66]. Standard
management has been HAART together with WBRT [67], but
there is evidence that high-dose MTX is feasible, safe and
effective [68]. Comprehensive guidelines for the treatment of
PCNSL and other HIV-associated malignancies have been
produced by the British HIV Association [69].

335

Secondary Central Nervous System


Lymphoma
CNS relapse occurs in about 5% of patients with systemic
DLBCL treated in the R-CHOP era and may involve the brain
parenchyma, spinal cord, leptomeninges or eyes [50e53]. In
most cases, CNS relapse is seen in conjunction with
systemic relapse and has a very poor prognosis. Isolated
CNS relapse is much less common, but may be potentially
treatable. An international review of 113 patients, most of
whom had DLBCL, found that the median time to CNS
relapse was 1.8 years and the median overall survival was
1.6 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 signicantly associated with longer survival in a multivariate model [70].

Neurotoxicity and Late Effects


The major drawback to the use of WBRT in conjunction
with high-dose MTX-based chemotherapy is the high incidence of cognitive impairment and white matter damage.
In total, 185 patients treated for PCNSL between 1985 and
2000 were reviewed [71]; 129 patients had WBRT as part of
their treatment, 111 of these having additional high-dose
MTX-based chemotherapy; 54 patients had chemotherapy
alone. The median age at diagnosis was 60 years and the
median follow-up was 3.6 years. The median overall
survival was 2.9 years, and for 43 patients who developed
neurotoxicity, median survival after onset was 1.8 years.
The 5 year cumulative incidence of neurotoxicity was 24%.
Radiotherapy was the only independent risk factor on
multivariate analysis. Neurotoxicity presented as a rapidly
progressive dementia characterised by psychomotor slowing, executive and memory dysfunction, behavioural
changes, gait ataxia and incontinence. Imaging ndings in
12 patients revealed diffuse white matter disease and
cortical atrophy. Post-mortem changes in ve patients
included white matter damage with gliosis, thickening of
small vessels and demyelination. Other studies have
reported even higher frequencies of clinical neurotoxicity
with regimens that include WBRT, and it remains uncertain
whether there is a safe dose for WBRT in this setting.
Although most ongoing clinical trials are collecting
quality-of-life data, few studies have reported long-term
outcomes. Most published trials have had a relatively short
follow-up that may underestimate the long-term effect of
therapy and overestimate disease control [72]. Evaluation of
cognitive function before and after treatment can determine
the contribution of disease-related factors and the benet of
therapy while screening for treatment-related neurocognitive impairment [73]. At this point, there are no standard neuropsychological tests in common use. Despite its
low sensitivity, the Mini-Mental Status Examination is suggested as the minimum requirement at baseline and serial
follow-up for all patients. Monitoring of neurological function, especially gait and neuro-imaging changes, is important, and assessment intervals should be standardised [73].

336

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

Conclusion
PCNSL remains a challenging disease with a poor prognosis. Patients are frequently started on steroids before
referral to neurosurgeons and/or oncologists, and surgeons
can be reluctant to carry out biopsies in the presence of
characteristic imaging ndings. However, the toxicity of
available treatments mandates histological conrmation
and patients also need to be offered the chance of participation in clinical trials. Diagnostic tests with improved
sensitivity and specicity could replace the need for an
invasive biopsy, particularly in patients with more inaccessible lesions. The use of high-dose MTX- and high-dose
Ara-C-based chemotherapy regimens that penetrate the
bloodebrain barrier have improved survival, but when
combined with WBRT, result in signicant late neurotoxicity. Radiotherapy elds and doses have not changed
signicantly over the last few decades, and better selection
of patients may be critical. The use of additional induction
treatments and different consolidation strategies including
high-dose chemotherapy may allow deferral of WBRT, and
these approaches are being tested in clinical trials.

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