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Clinical Oncology
journal homepage: www.clinicaloncologyonline.net
Overview
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
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
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
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].
331
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
332
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
PCNSL
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
Relapse
333
Supportive care
Fig 2. Suggested algorithm for the management of primary central nervous system lymphoma.
334
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
WBRT 36 Gy
9 Gy boost
BCNU
thiotepa
ASCT
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.
335
336
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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