Pcnsl

From bloodjournal.hematologylibrary.org by guest on July 25, 2011. For personal use only.

2011 118: 510-522
Prepublished online May 25, 2011;
doi:10.1182/blood-2011-03-321349

How I treat primary CNS lymphoma
Andrés J. M. Ferreri

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How I treat

How I treat primary CNS lymphoma
Andres J. M. Ferreri1
´
1Unit

of Lymphoid Malignancies, Department of Onco-Hematology, San Raffaele Scientific Institute, Milan, Italy

Primary CNS lymphoma (PCNSL) is a rare
malignancy with peculiar clinical and biologic features, aggressive course, and
unsatisfactory outcome. It represents a
challenge for multidisciplinary clinicians
and scientists as therapeutic progress is
inhibited by several issues. Molecular and
biologic knowledge is incomplete, limiting the identification of new therapeutic
targets, and the particular microenvironment of this malignancy, and sanctuary
sites where tumor cells grow undisturbed, strongly affects treatment effi-

cacy. Moreover, active treatments are
known to be associated with disabling
neurotoxicity, posing the dilemma of
whether to intensify therapy to improve
the cure rate or to de-escalate treatment
to avoid sequels. The execution of prospective trials is also difficult because of
the rarity of the tumor and the impaired
general condition and poor performance
status of patients. Thus, level of evidence
is low, with consequent uncertainties in
therapeutic decisions and lack of consensus on primary endpoints for future trials.

Despite this unfavorable background, laboratory and clinical researchers are coordinating efforts to develop new ideas,
resulting in the recent publication of studies on PCNSL’s biology and molecular
mechanisms and of the first international
randomized trials. Herein, these important contributions are analyzed to provide
recommendations for everyday practice
and the rationale for future trials. (Blood.
2011;118(3):510-522)

Introduction
Primary CNS lymphoma (PCNSL) is an aggressive malignancy
arising exclusively in the CNS, that is, the brain parenchyma,
spinal cord, eyes, cranial nerves, and/or meninges.1 This lymphoma
represents 4% of intracranial neoplasms and 4%-6% of all extranodal lymphomas but some registry studies suggest that its incidence in immunocompetent patients is progressively increasing.2
PCNSL exhibits peculiar clinical and biologic features and constitutes a diagnostic and therapeutic challenge for multidisciplinary
clinicians and scientists. Its outcome remains unsatisfactory if
compared with that of patients with extra-CNS lymphomas of a
similar stage and histotype, and several factors prevent therapeutic
progress. First, molecular and biologic knowledge is insignificant
compared with other lymphomas, which limits the identification of
new therapeutic targets. Second, patients with PCNSL usually
exhibit impaired general condition and poor performance status
(PS) more often than subjects with other lymphomas.1 This usually
interferes with the enrollment of patients in prospective trials. In
fact, current therapeutic knowledge is only based on 3 randomized
trials, some single-arm phase 2 trials, anecdotal meta-analyses, and
a few multicenter retrospective studies. Thus, available level of
evidence is low, with consequent uncertainties in therapeutic decisions
and lack of consensus on primary endpoints for future trials.
In this manuscript, I discuss available clinical and biologic data
on PCNSL in immunocompetent patients and provide recommendations for everyday practice and the rationale for future trials.

Clinical presentation and imaging
Which are the most common presentations?

In immunocompetent patients,3,4 the median age at diagnosis is
60 years, with a male:female ratio of 1.2:1.7. The most common
symptoms, which often span weeks to months, are focal deficits,

Submitted March 7, 2011; accepted May 9, 2011. Prepublished online as Blood
First Edition paper, May 25, 2011; DOI 10.1182/blood-2011-03-321349.

510

personality changes, and increased intracranial pressure (Figure 1).
B symptoms are rare.3 Intraocular involvement is observed in
10%-20% of patients. It can be the sole expression of lymphoma
(primary intraocular lymphoma), or can be followed by the onset of
brain lesions after weeks or months. Tumor cells can infiltrate the
vitreous humor, the retina, the choroid, and optic nerve. Only half
of these patients experience visual complaints such as floaters,
blurred vision, visual field defects, and diminished visual acuity.
PCNSL tends to infiltrate the subependymal tissues, disseminating through the cerebrospinal fluid to the meninges. Concurrent
meningeal involvement, often asymptomatic, is detected by conventional cerebrospinal fluid cytology examination in 16% of patients,3 while isolated leptomeningeal lymphoma represents Ͻ 5%
of all PCNSL. Spinal cord lymphoma is the rarest manifestation of
PCNSL.3 This lymphoma often arises in the upper thoracic or lower
cervical regions of the spinal cord and presenting symptoms
depend on the level of the spinal cord involved. Their prognosis is
poor mainly because of delayed diagnosis and the sparse literature
suggests that they should be treated similarly to other PCNSL.
Lymphomas arising in the spinal nerves and ganglia (“neurolymphomatosis”), cauda equina, and the sciatic nerve are extremely rare.5
Diagnosis is confirmed by nerve biopsy in 88% of cases, with
positive cerebrospinal fluid cytology in 40% of patients. Neurolymphomatosis should be distinguished from neural infiltration by a
systemic lymphoma.
Which is the best neuroimaging modality?

The above-mentioned symptoms usually lead to neuroimaging
assessment. Contrast-enhanced cranial magnetic resonance imaging (MRI) is the best imaging modality for assessing PCNSL
patients. Lesions are often isointense to hypointense on T2-weighted
MRI, with variable surrounding edema and a homogeneous and

© 2011 by The American Society of Hematology

BLOOD, 21 JULY 2011 ⅐ VOLUME 118, NUMBER 3


HOW I TREAT PCNSL

511

Figure 1. Flow chart of management of PCNSL from presentation to therapeutic decision in ordinary clinical practice. MRI indicates magnetic resonance imaging; CT,
computerized tomography; CSF, cerebrospinal fluid; LDH, lactate dehydrogenase serum level; and ADC, average diffusion coefficient. Deep regions refers to basal ganglia,
corpus callosum, periventricular areas, brain stem, and/or cerebellum. (1) Ocular examination should include slit-lamp examination, indirect ophthalmoscopy,and ophthalmic
ultrasonography. (2) Cerebrospinal fluid evaluation should include cell counts, protein and glucose levels, cytology, flow cytometry, and IgHV gene rearrangement studies.

strong pattern of enhancement (Figure 1-2).6 In cases of MRI
contraindications, contrast-enhanced cranial computed tomography (CT)
scans are recommended. PCNSL presents as a solitary intracranial

mass lesion in 60%-70% of patients, mostly located in the
hemispheres, basal ganglia, corpus callosum, and periventricular
regions (Figure 1). Gliomas, metastases, toxoplasmosis, sarcoidosis, and

512

FERRERI


Figure 2. Neuroimaging example of PCNSL. MRI of the
brain showing an expansive mass lesion in the right frontal
lobe, which is hypointense in noncontrasted T1 scans
(A), isointense with respect to cortex in T2-weighted images
(C), with reduced average diffusion coefficient (B), and
homogeneous contrast enhancement in contrasted T1 weighted
scans (D arrows). Lesion is surrounded by modest edema
(A arrows). CT and MRI findings are attributed to the high cell
density and scant cytoplasm. Enhancement along the
Virchow-Robin spaces, although not constant, is a highly
specific feature of PCNSL.

progressive multifocal leukoencephalopathy are the main differential diagnoses, requiring brain biopsy for definitive diagnosis.

Diagnosis
When is tumor resection indicated?

Stereotactic-guided biopsy is the chosen method to diagnose
PCNSL. Its morbidity is very low and permits the rapid detection of
tumor cells in intraoperative analysis; however, samples are small
and it could have a negative effect on diagnosis and biologic
investigations. Patients with a radiologic suspicion of gliomas,
metastasis, meningiomas, or other tumors are routinely referred for
complete resection, sometimes resulting in an unexpected diagnosis of lymphoma. Conversely, I advise strongly against gross tumor
resection if PCNSL is suspected because it can induce neurologic
deficits and treatment delays and has not been associated with
survival benefits according to a meta-analysis of 50 published
prospective and retrospective series.7 In these patients, tumor
resection should be reserved for the timely control of neurologic
deterioration because of brain herniation or ventricle dilation to
provide prompt treatment in “fit” patients.

Should steroids be interrupted before biopsy?

As with most patients who have been newly diagnosed with an
intracranial mass, steroids are also routinely prescribed to PCNSL
patients to rapidly improve neurologic performance and to reduce
the risk of complications. Mass shrinking is obtained through
antiedema and cytotoxic effects, causing radiographic regression in
ϳ 40% of patients (“vanishing tumor”), which is suggestive for
PCNSL. As many others, I believe that detection of a “vanishing
tumor” should not be considered as diagnostic of PCNSL because
sarcoidosis, multiple sclerosis, acute encephalomyelitis, and other
malignancies can also exhibit a dramatic response to steroids.8
Steroid effects can interfere with histopathologic diagnosis.
Although some authors reported that PCNSL can be successfully
diagnosed without stopping steroids,9 there is consensus that these
drugs should be withheld in patients with a presumptive diagnosis
of PCNSL until tissue is obtained, limiting its use to cases of
osmotherapy inefficacy.10 In our institution, we interrupt steroid
therapy for at least 7-10 days before biopsy to improve diagnostic
yield. However, this measure is not needed in patients who
experience MRI-confirmed disease progression under steroids.
Steroid administration during antilymphoma therapy should be
modified according to clinical requirements. During chemotherapy,


HOW I TREAT PCNSL

513

I recommend maintaining steroids until radiologic confirmation of
response, and then tapering them as soon as possible to reduce their
immunosuppressive effect. I am against any superfluous use of
steroids, which aims to reassure physicians rather than to control
symptoms or prevent complications, even in prospective trials,
where response to steroids can be erroneously attributed to
investigational chemotherapy activity, generating important interpretation biases.
Which are the most important histopathologic and molecular
features?

Ninety-five percent of PCNSLs are diffuse large B-cell lymphomas
(DLBCL). Neoplastic B lymphocytes usually grow forming perivascular cuffings (Figure 3), with an almost constant expression of
pan-B-cell markers and markers of germinal center and late
germinal center B cells, while are rarely positive for CD10
(Ͻ 10%), and are negative for EBV.11 Proliferating index is usually
high. Other lymphoma categories like Burkitt, lymphoblastic,
marginal zone, and small lymphocytic lymphoma are uncommon
differential diagnoses. T-cell PCNSLs are ϳ 2% of cases in
Western countries3 and, in my opinion, should be treated similarly
to standard PCNSL, with the obvious exclusion of anti-CD20
agents, and expecting similar results.12 Neuroepithelial tumors,
metastatic lesions, histiocytic lesions, and inflammatory disorders
like vasculitis and multiple sclerosis are the main nonlymphomatous differential diagnoses.
Molecular studies focused on PCNSL development showed
some interesting features, such as a high load of somatic mutations,
frequent ongoing somatic hypermutation patterns and biased usage
of VH gene segments (IGHV4-34 rearranged in 50%-80% of
cases), suggesting a role for antigen(s) triggering13,14; important
differences in IG and BCL6 translocations with respect to nodal
DLBCL15; mutations in oncogene and tumor suppressor gene loci
(CD95, CMYC13, PAX5, PIM1, PRDM114, and TTF)15; and
deregulation of specific pathways (NF-␬B, CARD11, MALT1, and
p50).16,17 Moreover, studies of chemokines showed that CXCL9/
CXCL12 coexpression is a strong chemoattractant stimulus for
both CXCR4ϩ/CXCR3ϩ/CD8ϩ tumor-infiltrating lymphocytes and
CXCR4ϩ/CXCR3Ϫ malignant B cells in the perivascular microenvironment.18 Gene expression profiling (GEP), array comparative
genomic hybridization, and single-nucleotide polymorphism (SNP)–
chip analyses were used to characterize biologic mechanisms. SNP
and GEP results appear consistent and suggest an improved
proliferation and harmed apoptosis in tumor cells; however, the
comprehensive interpretation of resulting data are far from being
established. GEP results on a CNS signature were conflicting,
mostly because of the small size of investigated samples and
differences in platforms and algorithms.19-21 Gene silencing because of epigenetic phenomena like CpG islands promoter hypermethylation could be related to lymphomagenesis and lymphocyte
motility. Some of them, such as RFC and MGMT, may have
important therapeutic implications.22,23

Staging and pretreatment evaluations
Which staging procedures should be performed?

By definition, PCNSL is a stage I disease. The involvement of
different CNS areas such as eyes, meninges, and/or cranial nerves,
does not imply a more advanced stage with a worse prognosis.
Pretreatment “staging” procedures have 2 main goals in PCNSL: to

Figure 3. Classic histopathologic picture of PCNSL of diffuse large B-cell
lymphoma category. Tumor cells (filled arrows) usually grow forming classic
perivascular cuffings, are CD20 positive, and express other pan-B-cell markers
(CD19, CD20, CD22, CD79a), markers of germinal center B cells (bcl-6; 60%-80% of
cases), and markers of late germinal center B cells (MUM1; 90%), while are CD3
negative. A reactive T-cell infiltrate (open arrows) constituted by a perivascular rim of
small lymphocytes interposed between vessel (VL) and neoplastic cells is observed
in one-third of cases. These lymphocytes are smaller than neoplastic ones, and are
CD20 negative and CD3 positive. The presence of this reactive infiltrate is associated
with significantly better outcome in patients treated with modern approach.

define the extension of the disease in different CNS structures and
to exclude concomitant systemic lymphoma. Conventional lymphoma staging demonstrates the presence of extraneural disease in
4%-12% of patients with presumptive diagnosis of PCNSL.24
Specific baseline evaluations and staging have been standardized
by The International PCNSL Collaborative Group (Figure 1).10
During staging, we pay particular attention to ophthalmic examinations, which allow the detection of asymptomatic ocular involvement in 5% of PCNSLs. The suspicion of ocular infiltration should

514

FERRERI

be confirmed by vitrectomy for cytologic examination and flow
cytometry, mostly in patients with primary intraocular lymphoma.
IgHV gene rearrangements analyses and intravitreal levels of IL-10
and IL-6 are, probably, adjuncts for intraocular lymphoma diagnosis.25 Cerebrospinal fluid sampling should be performed in every
patient with suspected or confirmed PCNSL. Increases in the white
blood cell count and protein concentrations are often present, while
glucose concentration is usually normal.3 Cytology and PCR
should be regarded as complementary methods because of the high
rate of discordant results.26 A contrasted whole-spine MRI may be
useful if lumbar puncture is contraindicated. I recommend that a
testicular ultrasound examination is performed in elderly patients
because of frequent CNS involvement in testicular lymphomas.
The clinical relevance of positron emission tomography (PET) requires
prospective evaluation. In a retrospective study,27 18FDG-PET
disclosed concomitant systemic lymphoma in 7% of patients with a
presumptive diagnosis of PCNSL, with detection of other malignancies in 5% of cases and false positives in 13%.
Are there reliable prognostic factors?

The identification of reliable prognostic factors is the first step
toward a risk-tailored treatment of PCNSL. Virtually all studies
confirm the importance of age and PS, whereas the International
Prognostic Index does not discriminate among risk groups. The
combination of 5 independent predictors of response and survival,
that is, age, PS, serum lactate dehydrogenase level, cerebrospinal
fluid protein concentration, and the involvement of deep structures
(Figure 1), distinguishes 3 risk groups based on the presence of 0-1,
2-3, or 4-5 unfavorable features (IELSG [International Extranodal
Lymphoma Study Group] prognostic score).28 Currently, we include the IELSG score as a stratification criterion in randomized
trials, and I strongly recommend its use in choosing individualized
risk-tailored treatment. Another scoring system that only uses age
and PS also distinguishes 3 risk groups.29 Several biochemical,
histopathologic, and molecular variables were suggested as prognostic
indicators. However, none of these observations were confirmed.

First-line treatment
For decades, radiotherapy was the exclusive treatment for patients
with PCNSL, while the addition of chemotherapy has significantly
improved their outcome. Even though this was not confirmed in a
randomized trial, there is consensus that combined chemoradiotherapy is superior to radiotherapy alone and this is the most commonly
used approach.1 With variable chemotherapy regimens and radiation doses, upfront chemoradiotherapy has been addressed in
several trials, obtaining complete remission rates (CRR) of 30%87% and 5-year overall survival (OS) rates of 30%-50% (Table 1).
These strategies are often associated with severe neurotoxicity,
especially among elderly patients. Therefore, the dilemma posed
by PCNSL treatment is the choice between strategies designed to
intensify therapy to improve cure rate and treatment de-escalation
strategies to avoid neurotoxicity.
Chemotherapy

Chemotherapy plays a central role in the management of PCNSL.
Its efficacy is limited by several factors including the biology and
microenvironment of this malignancy, which is protected by the
blood-brain barrier (BBB). This results in the formation of
chemotherapy sanctuaries, such as cerebrospinal fluid, meninges,


and eyes, where tumor cells grow undisturbed. For this reason,
I suggest taking into account the ability to cross the BBB and
achieve therapeutic concentrations in the CNS as an important drug
selection parameter for treating PCNSL patients. Most regimens
include drugs able to cross the BBB at conventional doses (ie,
steroids, some alkylating agents) and cytostatics with low to
moderate ability to cross the BBB that can be safely administered at
high doses to improve CNS bioavailability (ie, methotrexate,
cytarabine). Conversely, drugs with poor BBB penetration that
cannot be administered at high doses because of dose-limiting
toxicity (ie, anthracyclines, vinca-alkaloids) are inefficient in PCNSL.
Does CHOP regimen play any role in PCNSL?

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
regimen represents the backbone for treating extra-CNS DLBCL
but exhibits negligible activity in PCNSL; this has been confirmed
in a randomized trial with incomplete accrual.30 In retrospective
series, the addition of CHOP to high-dose methotrexate (HDMTX) resulted in higher toxicity without improved outcome
compared with HD-MTX alone.31 Most patients treated with
CHOP have an immediate radiographic response followed by early
progression, probably because of the normalization of the disrupted
BBB. This suggests that the bulky tumor not protected by the BBB
responds, while the microscopic tumor is not adequately treated
and progresses. In line with this evidence, we have abandoned
CHOP chemotherapy in classic PCNSL. However, I prescribe
CHOP-rituximab combined with good CNS bioavailability agents
to patients with neurolymphomatosis5 or intravascular large B-cell
lymphoma with CNS involvement32 as tumor cells of these lymphomas
mostly grow in structures (nerves and blood vessels, respectively)
variably, or not, protected by physiologic barriers (Figure 4).
Which is the backbone of upfront chemotherapy?

Antimetabolites such as MTX and cytarabine (ara-C) constitute the
backbone of most anti-PCNSL regimens with proven efficacy in
prospective trials (Table 1). MTX doses up to 8 g/m2 are feasible in
PCNSL patients; both dose and infusion rate are important for
MTX delivery to the brain parenchyma and cerebrospinal fluid.33
MTX doses Ն 1 g/m2 result in tumoricidal levels in the brain
parenchyma and doses Ն 3 g/m2 yield tumoricidal levels in the
cerebrospinal fluid.34 Conversely, doses up to 8 g/m2 delivered in a
24-hour continuous infusion do not achieve an adequate cerebrospinal fluid level.35 HD-MTX (8 g/m2) monochemotherapy yielded
activity and efficacy similar to those recorded in trials assessing
polychemotherapy with a MTX dose of 3.5 g/m2, but it requires
more frequent dose reductions because of impaired creatinine
clearance.36 As many others, I believe tolerability and activity of
MTX 3.5 g/m2 suggest this may be a good compromise between
safety and efficacy for combination regimens. In the future,
individualized dosing of MTX using creatinine clearance or
glomerular filtration rates may have the potential to improve
outcome in PCNSL patients.33,37,38
Noncomparative studies suggesting an improvement of survival
by adding HD–ara-C to HD-MTX3,39 were the background of the
first randomized trial with completed accrual in PCNSL.40 In this
trial, named IELSG no. 20, 79 patients have been assigned to
4 courses of MTX 3.5 g/m2, alone or combined with ara-C (4 doses
of 2 g/m2) in both arms followed by whole-brain irradiation
(WBRT). The addition of ara-C has resulted in significantly
improved response (CRR ϭ 46% vs 18%; P ϭ .006) and survival
rates (3-year OS: 46% vs 32%; P ϭ .07) compared with HD-MTX


HOW I TREAT PCNSL

515

Table 1. Published prospective trials in immunocompetent patients with PCNSL
Primary chemotherapy†
No.

TS*

Drugs

M dose

it CHT

ORR, %‡

CRR, %§

OS, %

Median
follow-up, mo

2y

5y

Neurotoxicity,
%

Chemotherapy alone
31

C

M

8 g/m2/14 d

—

100

NR

31

63

NR

25

C

M

8 g/m2/14 d

—

74

52

23

70

NR

5

65

C

MVICA

5 g/m2/28 d

ivM/a

71

61

26

69

43

3

37

C

M

8 g/m2/14 d

—

35

30

56

51

25

20

46

C

M R Te–a E

8 g/m2/14 d

—

NR

63

40

71

NR

0

0

HD-MTX plus RT
25

CR

M

3.5 g/m2/21 d

—

88-92

56-88

60

58

38

8

46

CR

M

1 g/m2/7 d

a¶

NR-95

NR-82

36

62

37

22ʈ

31

CRC

M

1 g/m2/7 d

M

64-87

NR-87

97

72

22

32

0

HD-MTX-containing
chemotherapy plus RT
25

CR

AaCMOP

3 g/m2/21 d

M/a/P

72-72

67-78

24

70

56

57

CRC

aBnMO Ϯ CHOP

1.5-3 g/m2/14 d

—

68-71

62-64

59

60

36

NS

56

CR

Bn M N P

1.5 g/m2/28 d

M

71-100

54-61

8

86

NS

29

31

CR

ABCMOP

2 g/m2/15 d

M/a/P¶

89-67

24

48

36

7

52

CRC

MNO

3.5 g/m2/7 d

M

90-94

56-87

60

75

40

25

102

CR

MNO

2.5 g/m2/14 d

M

94-NR

58-NR

56

64

32

15

52

CR

Bn M O P

3 g/m2/14 d

M

NR-81

33-69

27

69

NR

12

41

CR

AIMT

3.5 g/m2/21 d

—

76-83

44-56

49

50

41

NR

30

CRC

MNOR

3.5 g/m2/14 d

M¶

93-NR

44-77

37

67

NR

NR

99

CR

AaCMO

3 g/m2/21 d

M/P

70-68

33-49

83

55

34

32

CR

M

3.5 g/m2/21 d

—

40-40

18-30

30

Ma

3.5 g/m2/21 d

—

69-74

46-64

M

4 g/m2/14 d

—

50

32

MI

3 g/m2/14 d

—

65

42

Randomized trials
79
CϮR
551

39

26

20

56

46

6

Only trials on 25 patients or more and published as original articles are considered. Trials on high-dose chemotherapy supported by ASCT (Table 2) and focused on elderly
patients (Table 3) are excluded. Updated from 40.
No. indicates number of enrolled patients; NS, not specified; and NR, not reported.
*Treatment sequence: C indicates chemotherapy alone; CR, chemotherapy followed by radiotherapy; and CRC, chemotherapy followed by radiotherapy and further
chemotherapy.
†Primary chemotherapy: A or H, adriamycin; a, cytarabine; B, bleomycin; Bn, BCNU; C, cyclophosphamide; Cn, CCNU; E, etoposide; I, ifosfamide; M, methotrexate; N,
procarbazine; O, vincristine; P, prednisone or other corticoids; R, rituximab; T, Thiotepa; Te, temozolomide; and V, teniposide.
‡ORR indicates overall response rate; in series treated with combined modality, response rate after chemotherapy and (—) after the entire planned treatment is reported.
§CRR, Complete remission rate; in series treated with combined modality, response rate after chemotherapy and (—) after the entire planned treatment is reported.
¶Series using intrathecal chemotherapy (it CHT) exclusively in patients with positive CSF cytology at diagnosis.
ʈFive-year risk rate.

alone (Table 1), with manageable hematologic toxicity and uncommon nonhematologic side effects.40 A recent study highlighted the
importance of ara-C dose, suggesting that 4 doses of 2 g/m2 is an
appropriate choice.41 Although it was not addressed in a phase
3 trial, the MTX-ara-C combination is the current standard
chemotherapeutic approach for de novo PCNSL as it is supported
by the highest level of evidence available (Figure 4).
Are there other active drugs?

Some active drugs have emerged from prospective studies and are
being tested in ongoing trials of new first-line combinations.
Temozolomide, an oral alkylating agent largely used in neurooncology, is the best example. It has been associated with excellent
tolerability, 31% CRR and 1-year OS of 31% in patients with
PCNSL relapsed or refractory to HD-MTX.42 As upfront monotherapy, temozolomide was associated with 47% CRR, and median
OS of 21 months in elderly patients.23 The combination of temozolomide with HD-MTX was associated with encouraging results,
even among elderly patients.43,44 Topotecan, a topoisomerase-I
inhibitor, is another example. It is active in relapsed PCNSL.
However, I do not prescribe this drug as its responses are
short-lived (1-year PFS: 13%) and it is frequently associated with
severe leukopenia and neurologic deterioration.45

Is there a role for rituximab in the treatment of PCNSL?

Rituximab is used in PCNSL patients because of its positive effect
in extra-CNS DLBCL patients. However, as a large protein, it
shows poor CNS penetration and its ability to prevent CNS
dissemination of DLBCL remains debatable. Promising effects of
rituximab were reported, both as salvage monotherapy46 (Table 4)
and combined with HD-MTX47 (Table 1). Although the level of
evidence supporting rituximab for the treatment of PCNSL remains
very low, its use is encouraged by several hematologists. I believe
rituximab should only be used in PCNSL patients in prospective
trials, at least until its role is defined by the 2 large ongoing
randomized trials focused on this issue (NCT01011920; NTR2427).
Treatment of relapsed PCNSL with the anti-CD20 radioimmunoconjugate 90Y-ibritumomab-tiuxetan is feasible.48 Although capable of targeting brain lymphoma, this radio-immunoconjugate cannot treat microscopic lesions with intact BBB adequately,
resulting in high relapse rates.49
Is intrathecal chemotherapy needed?

Cerebrospinal fluid acts as a reservoir for PCNSL tumor cells; the
persistence of tumor cells in this chemotherapy sanctuary results in
increased risk of failure. Some authors advised including intrathecal/

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FERRERI


Figure 4. Flow chart of therapeutic management of PCNSL in everyday practice. (1) Mostly marginal zone B-cell lymphoma, small lymphocytic lymphoma, and
lymphoplasmacytic lymphoma. (2) Mostly intravascular large B-cell lymphoma and neurolymphomatosis. (3) Conclusion from the IELSG no. 20 trial.40 (4) Several regimens are
available (Table 3). (5) A higher amount of available evidence suggests WBRT. The discussion with selected patients about the pros and cons of the use of consolidation WBRT
or HDC/ASCT is recommended. (6) Available literature suggesting that some elderly patients in CR after primary chemotherapy could be watchful waited without
OS impairment is constituted by a few small retrospective series. However, to delay WBRT until relapse is an acceptable strategy considering the increased risk of disabling
neurotoxicity in these patients. (7) Radiation field and dose should be chosen on the bases of response to primary chemotherapy. WBRT dose reduction to 23-30 Gy in patients
in CR after chemotherapy is recommended. DLBCL indicates diffuse large B-cell lymphoma; HD-MTX, high-dose methotrexate; ara-C, cytarabine; WBRT, whole-brain
radiotherapy; CR, complete remission; PR, partial response; SD, stable disease; PD, progressive disease; and HDC/ASCT, high-dose chemotherapy supported by autologous
stem cell transplantation.

intraventricular drug delivery as part of primary chemotherapy to
improve disease control. However, this suggestion is questionable
as systemic HD-MTX can clear the cerebrospinal fluid of neoplastic cells. Moreover, intrathecal/intraventricular chemotherapy has
not been studied prospectively, only one phase 1 trial suggests
transient activity of intraventricular rituximab.50 Two large retrospective studies have not demonstrated benefits from adding
intrathecal drug delivery in patients treated with HD-MTX.3,51
Conversely, the comparison of 2 single-arm trials seems to suggest
some benefit from intraventricular chemotherapy.52,53 In the first
trial,52 65 PCNSL patients were treated with MTX–ara-C–based
chemotherapy combined with intraventricular delivery of MTX,
ara-C, and steroids, resulting in a median EFS of 21 months, with
57% of young patients alive at a median follow-up of 100 months.
In the second trial,53 18 patients received the same chemotherapy
without intraventricular treatment to reduce Ommaya reservoir
infections. Despite a similar response rate, more than half of the
responders relapsed within the first year, prompting premature
termination of the trial, which was attributed to the omission of
intraventricular chemotherapy. Overall, there is no consensus on

cerebrospinal fluid prophylaxis and treatment but most recently
reported or ongoing PCNSL trials do not use intrathecal/
intraventricular chemotherapy. In our institution, we do not use
intrathecal/intraventricular chemotherapy in PCNSL patients as it
is based on a low level of evidence and is associated with additional
risk of infective complications, neurotoxicity, and chemical
meningitis.
How should intraocular lymphoma be treated?

The eye is another reservoir for PCNSL tumor cells. Chemotherapy
efficacy depends on intraocular pharmacokinetics, which are not
well understood for most cytostatics. Systemic administration of
MTX and ara-C can yield therapeutic drug levels in the intraocular
fluids and clinical responses have been documented; however, drug
concentrations in vitreous humor are unpredictable and intraocular
relapse is common.54 For these reasons, I treat patients with
PCNSL and intraocular disease with HD-MTX–based chemotherapy followed by WBRT and ocular irradiation, which results in
better disease control.55 Some authors are investigating the role of


HOW I TREAT PCNSL

517

Table 2. Prospective phase 2 trials on high-dose chemotherapy supported by autologous stem cell transplantation
No. of
patients

Median age,
y (range)

87

22

53 (27-64)

Salvage

araC ϩ VP16

Bu/TT/Cy

59

43

52 (23-65)

Salvage

araC ϩ VP16

Bu/TT/Cy

88

6

53 (30-66)

First-line

MBVP3IFO ϩ araC

Ref.

Treatment
line

Therapy,
induction3intensification

Conditioning
regimen

Outcome,
%

Neurotoxicity,
%

Median
follow-up, mo

TRM,
%

No

3-yOS:64

32

41

4

No

2-yOS:45

5

36

7

BEAM

Yes

2-yOS:40

33

41

0
4

WBRT

89

25

52 (21-60)

First-line

MBVP3IFO ϩ araC

BEAM

Yes

4-yOS:64

8

34

61

28

53 (25-71)

First-line

HD-MTX3araC

BEAM

No

2-yOS:55

0

28

4

90

23

55 (18-69)

First-line

HD-MTX3

Bu/TT

Yes*

2-yOS:48

39

15

13

91

7

56 (41-64)

First-line†

HD-MTX3araC

Bu/TT/Cy

No

3-yOS:50

0

28

14

92

30

54 (27-64)

First-line

HD-MTX3araC ϩ TT

BCNU/TT

Yes

5-yOS:69

17

63

3

78

13

54 (38-67)

First-line

HD-MTX3araC ϩ TT

BCNU/TT

Yes*

3-yOS:77

0

23

0

araC indicates cytarabine; BCNU, carmustine; BEAM, carmustine, etoposide, cytarabine, and melphalan; Bu, busulfan; Cy, cyclophosphamide; IFO, ifosfamide; MBVP
(regimen), methotrexate, carmustine, etoposide, and methylprednisolone; OS, overall survival; TRM, treatment-related mortality; TT, thiotepa; VP16, etoposide; and WBRT,
whole-brain irradiation.
*Only for patients not achieving a complete remission.
†One patient received the treatment as salvage therapy.

direct intravitreal injection of cytostatics. Intravitreal MTX is
highly active (remission in 100% of treated eyes) but does not
affect OS and is associated with important side effects in 73% of
eyes and significant deterioration of visual acuity in 27% of
patients.56,57 Among the other drugs examined, intravitreal rituximab appears safe and active.58
Is HDC/ASCT indicated?

Overall, high-dose chemotherapy with autologous stem cell transplantation (HDC/ASCT) is used as a dose intensification treatment
to overcome drug resistance. In PCNSL, HDC/ASCT should
improve CNS drug bioavailability and replace WBRT to reduce
neurotoxicity. In patients with relapsed or refractory PCNSL (Table
2), HDC/ASCT has been associated with 60% CRR, a 2-year OS of
45%, with treatment-related mortality of 16% and severe neurotoxicity in 12% of cases.59 First-line HDC/ASCT was investigated in a
few small phase 2 trials (Table 2), suggesting a curative effect in
young patients.60 However, efficacy data are controversial because
of different induction and conditioning combinations. Cumulative
results suggest that HD-MTX–based polychemotherapy induction
is more active than monochemotherapy, while intensification with
HD–ara-C, alone or in combination, was useful as mobilizing
regimen but did not improve response rates. Among conditioning
regimens, those containing thiotepa seem to be more effective but
more toxic, in particular, the busulfan-thiotepa combination.60
BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen, which was chosen because widely used for other aggressive
lymphomas, was ineffective in PCNSL, with median EFS of
9.3 months.61 I believe the discrepancies in effectiveness between
BEAM and thiotepa-based regimens may be related to the different

capability of drugs to cross the BBB. In fact, busulfan, thiotepa,
and carmustine (BCNU) exhibit excellent CNS penetration, with
cerebrospinal fluid levels exceeding 50%-80% serum levels, while
CNS penetration rates of agents used in BEAM range from
5%-22%.62 Interestingly, a small phase 2 study suggested that
HDC/ASCT could replace consolidation radiotherapy, with a
3-year OS of 77% (Table 2, last line). However, the real impact of
HDC/ASCT on neurocognitive functions was not defined because
treated patients were not prospectively assessed with adequate
neuropsychologic tests. At our institution, we do not use HDC/
ASCT as part of first-line therapy because it remains an experimental approach; in routine practice, we use HDC/ASCT with a
BCNU-thiotepa conditioning combination as part of salvage treatment for selected patients. I am convinced that the comparison
between WBRT and HDC/ASCT in 2 ongoing randomized trials
(NCT01011920; NCT00863460) will establish the most effective
and better-tolerated strategy to consolidate response to primary
chemotherapy.
Which chemotherapy for elderly patients?

Age has a profound influence on prognosis and treatment choices in
PCNSL.28,29 A large proportion of PCNSL patients is more than
60 years old and is still treated with radiotherapy alone, with
disappointing results.63,64 The addition of HD-MTX–based chemotherapy resulted in improved outcome in selected elderly patients
(Table 3). As many others, I believe the interpretation of these
results is biased because “the elderly patient” has not been clearly
defined in PCNSL. With a few exceptions (Table 3), studies
focused on the “elderly” include patients with a median age
Յ 70 years, with the lowest age oscillating between 54 and

Table 3. Reported studies focused on elderly patients with PCNSL
MTX, g/m2

Ref.

N

Median age, y (range)

43

23

68 (60-79)

3

66

10

73 (66-75)

8

Other drugs

IT

WBRT

PFS, mo

OS, mo

Neurotoxicity

Te

No

No

8

35

0

—

No

No

18

36

0

22

70 (54-89)

3.5

O, P

Yes

No

NR

33

5

79

12

67 (60-72)

3.5

O, P

Yes

Yes

NR

32

83

93

13

76 (54-89)

1-3.5

A, O, P, T

Yes

No

NR

31

0

94

50

72 (60-81)

1

CN, P, S

Yes

No

7

14

8

95

30

70 (57-79)

3

CN, P

No

No

6

15

7

96

17

67 (58-78)

1

MCN, P, S

Yes

No

20

36

0

MTX indicates methotrexate delivered dose; PCNSL, primary CNS lymphoma; IT, intrathecal chemotherapy; WBRT, whole-brain irradiation dose; —, not applicable;
PFS, median progression-free survival; and OS, median overall survival.
Other drugs: A indicates cytarabine; CN, lomustine; MCN, ranimustine; O, vincristine; P, procarbazine; S, steroids; T, thiotepa; and Te, temozolomide.

518

FERRERI

60 years, which suggests important selection biases because of the
inclusion of several “young” patients. In my opinion, the age upper
limit currently used for clinical trials (70-75 years old for conventional-dose combinations or 70 in HDC/ASCT trials) represents an
acceptable cutoff point to define elderly patients.
I am for treating all elderly patients with primary chemotherapy
and I choose a chemotherapy regimen on the basis of PS and
comorbidity. Despite common perception that HD-MTX is too
toxic for the elderly, some studies suggest that older patients can
tolerate this therapy, provided their renal and liver functions are
preserved (Figure 4).65,66 MTX 1-3 g/m2 in combination with
alkylating agents resulted in median survival ranging from 14 to
36 months (Table 3), but median PFS was usually disappointing,
often requiring salvage WBRT to prolong disease control.67,68
However, this approach is associated with severe neurocognitive
decline, which, added to the lack of safe and active salvage
therapies, strongly condition outcome in elderly patients.
Is there a role for BBB disruption and intra-arterial
chemotherapy?

Reversible BBB disruption by intra-arterial infusion of mannitol
followed by intra-arterial chemotherapy aims to increase drug
concentrations in the lymphoma-infiltrated brain, with particular
value in the delivery of agents unlikely to traverse the BBB.69 In
institutions with adequate expertise, this strategy was associated
with a 58% CRR, a 5-year PFS of 31% and acceptable morbidity
and neurotoxicity.69 I do not expect that BBB disruption and
intra-arterial chemotherapy will be used worldwide in the next
years because its efficacy is similar to that of conventional
treatments but it is a procedurally intensive treatment, requiring
monthly intravascular interventions under general anesthesia over
the course of 1 year.
Radiotherapy

PCNSL is a radiosensitive tumor and radiotherapy has been the
standard treatment for decades. In these patients, the whole brain
should be irradiated because of the diffuse infiltrative nature of
PCNSL and the inclusion of the eyes within the radiation volume is
suggested.55 Focal brain radiotherapy attempts resulted in high
recurrence rates. Although microscopic cerebrospinal fluid dissemination is common, craniospinal irradiation does not confer additional survival benefit and is associated with significant morbidity.7
Most trials have used conventional photons font and standard
fractionation. As an exception, a RTOG (Radiation Therapy
Oncology Group) trial failed to show a clear benefit when
hyperfractionated WBRT was used.70 WBRT and tumor bed doses
are variable in published trials, these parameters depending on the
use of radiotherapy as exclusive or complementary treatment.
Who are the best candidates for radiation therapy alone?

WBRT alone is rarely curative in PCNSL patients because response
is usually short-lived, with median survivals ranging from 10 to
18 months.71 The optimal dose of WBRT is controversial, but a
dose of 40-50 Gy has been suggested, resulting in a 19% CRR.
Doses Ͼ 50 Gy and the addition of a boost are associated with
increased risk of neurotoxicity without further efficacy.71 WBRT
40-50 Gy appears advisable as exclusive treatment when chemotherapy is contraindicated (Figure 4). Encouraging results were
obtained with steroid maintenance after primary WBRT,72 but
confirmatory studies are needed.


As exclusive treatment, radiotherapy plays a palliative role in
patients with cerebrospinal fluid dissemination. Conversely, it is a
curative strategy in indolent lymphomas (13% of all PCNSLs3).
Patients with marginal zone, small lymphocytic, or lymphoplasmacytic lymphoma, mostly arising in the meninges, have excellent
long-term prognosis with local therapy alone (Figure 4) and
consolidation radiotherapy may be unnecessary after complete
resection. Experience with HD-MTX suggests modest activity.73
Isolated CNS plasmacytoma and Hodgkin lymphoma are other
suitable candidates for radiotherapy alone. Plasmacytoma can be
successfully managed with involved field irradiation with 50 Gy,
preceded by chemotherapy in patients with large lesions.74 WBRT
35-45 Gy followed by a 5-15 Gy boost was proposed for CNS
Hodgkin lymphoma, with a median OS from CNS involvement of
44 months.75
Is consolidation radiotherapy really needed?

Consolidation after HD-MTX–based chemotherapy represents the
best role for radiotherapy in patients with PCNSL (Figure 4).
However, this strategy is associated with disabling neurotoxicity,
with a cumulative 25%-35% incidence at 5 years and related 30%
mortality.76 Long-term impairment in the areas of attention,
executive function, memory, and psychomotor speed are the most
commonly reported. The mechanisms by which treatment produces
CNS damage are unknown, but demyelination, necrosis, and
microcavitary changes have been described. Neurotoxicity in
PCNSL patients has not been clearly defined because it is usually
assessed in small series and rarely in prospective trials. Importantly, a panel of neuropsychologic tests to assess, quantify and
follow-up treatment-related neurologic deterioration in PCNSL
patients was recently established.77 I expect its wide use will allow
better definition of this severe complication both in prospective
trials and everyday practice.
To avoid postchemotherapy, WBRT was proposed as the main
strategy to reduce neurotoxicity risk. Feasibility and impact of this
approach should be analyzed separately in subgroups of patients
divided according to response degree after chemotherapy. Complementary WBRT in patients with residual disease after chemotherapy is unavoidable in routine practice because of the lack of
valid alternatives. The small group of available active drugs has
shown a significantly lower activity in PCNSL patients unresponsive to upfront chemotherapy; only HDC/ASCT has shown some
activity in these patients,78 but this remains an experimental
approach. In my opinion, the use of any second-line chemotherapy
in not irradiated patients should be confined to prospective trials. In
everyday practice, I strongly recommend WBRT 40-45 Gy for
patients with residual disease after primary chemotherapy.
Recommendations on consolidation WBRT in patients in complete remission (CR) after chemotherapy are less clear. Some small
experiences, mostly on elderly patients, suggest that avoiding
consolidation WBRT is feasible and results are similar to those
obtained with chemoradiation combinations.79 A CALGB (Cancer
and Leukemia Group B) phase 2 trial recently reported in abstract
form,44 assessed a combination of HD-MTX, temozolomide, and
rituximab followed by consolidation with HD-araC and HD-VP16
without WBRT in 46 patients, with a 3-year PFS and OS of 50%
and 67%, respectively, a single toxic death and no evidence for
significant iatrogenic neurotoxicity. These encouraging results,
suggesting that consolidation WBRT can be deferred until relapse,
deserve to be assessed in future randomized trials. In a recent
randomized trial,80 551 patients treated with HD-MTX–based
chemotherapy were randomly allocated to receive WBRT 45 Gy


HOW I TREAT PCNSL

519

Table 4. Salvage treatment for PCNSL
Treatment, Ref.

Study

No.

Median
age, y

Prior
RT, %

CR ؉ PR,
%

PFS

OS

1-y OS,
%

Grade 3-4
neutropenia, %

Grade 3-4
thrombocytopenia, %

Other
toxicities, %

VP16 ϩ Ifosfamide ϩ Ara-C97

R

16

54

100

37 ϩ 0

4.5

6.0

41

69

50

37

i. a. Carboplatin Ϯ VP16 Ϯ

R

37

57

24

24 ϩ 11

3.0

6.8

25

22

19

Ͼ 30

Methotrexate85

R

22

58

14

73 ϩ 19

26

26

70

5

5

36

Temozolomide ϩ rituximab99

R

15

69

13

40 ϩ 13

2.2

10.5

58

7

27

7

Topotecan45

P

27

51

52

19 ϩ 14

2.0

8.4

39

26

15

11

Temozolomide42

P

36

60

86

25 ϩ 6

2.8

4.0

31

6

3

3

Rituximab46

P

9

NR

9

11 ϩ 22

3.7

NR

NR

0

0

44*

Radiotherapy68

R

27

67

—

37 ϩ 37

9.7

10.9

49

NR

NR

15†

Radiotherapy100

R

20

NR

—

60 ϩ NR

NR

19.0

NR

NR

NR

58†

CTX Ϯ RT98

Studies focused on HDC/ASCT are reported in Table 2.
P indicates prospective; R, retrospective; RT, radiotherapy; PCNSL, primary CNS lymphoma; CR, complete response; PR, partial response; PFS, median progression-free
survival; OS, median overall survival; i.a., intra-arterial; VP16, etoposide; ara-C, high-dose cytarabine; —, not applicable; NR, not reported; and CTX, cyclophosphamide.
*Allergic reaction, fatigue, anxiety, and pain.
†Neurotoxicity.

versus observation in the case of CR after chemotherapy or versus
HD-araC in the case of partial or no response. The results indicate
that consolidation WBRT is associated with a significantly better
PFS (median ϭ 18 vs 12 months), but does not change OS
(median ϭ 32 vs 37 months). Unfortunately, this trial is fraught
with design and execution flaws resulting in important interpretation biases and unreliable conclusions.81,82 In fact, this trial exhibits
major protocol violations in 30% of patients, biased analyses of
these violations, evident unbalanced comparisons resulting from
randomization caveats in ϳ 20% of patients, inconsistent data on
iatrogenic neurotoxicity, and 10% of patients lost to follow-up.
Moreover, it has low statistical power (60%) and failed to prove the
primary hypothesis. As many others,81,82 I believe this trial does not
provide reliable conclusions on the role of consolidation WBRT. In
my opinion, the optimization of radiation parameters is a valid
alternative to radiation withdrawal in PCNSL. Two recent studies
suggested that WBRT dose reduction to 23-30 Gy in patients in CR
after chemotherapy is associated with similar outcomes to receiving higher radiation doses, with better neurotolerability.83,84 These
observations deserve to be addressed in multicenter prospective
trials, with standardized neuropsychologic assessment.
In our institution, we discuss with selected patients the pros and
cons of using consolidation WBRT or alternatives in everyday
practice (Figure 4). I strongly encourage the enrolment of patients
in prospective trials comparing consolidation WBRT with experimental approaches because these studies will furnish important
data useful to minimize neurotoxicity. Hopefully, I expect that
future clinical, biologic, and technologic investigations will provide relevant information on how to maintain neuropsychologic
performance in these patients.

Salvage treatment
A variety of salvage therapies was successfully used in selected
subgroups of patients with recurrent or refractory PCNSL (Table
4). Although these therapies may be used in routine practice, I am
convinced that patients with failed disease must be entered into
phase 1/2 trials assessing new drugs and combinations. Although
the amount of trials assessing first-line treatments is increasing and
failure rates in those trials range between 40% and 70%, the
number of reported studies on salvage therapy remains negligible.
This is because of the hasty and aggressive course of relapsing
PCNSL that produces a drastic PS impairment preventing physi-

cians from enrolling patients in prospective trials and, sometimes,
from recommending any treatment.
In routine practice, salvage treatment should be chosen on the
basis of the patient’s age, PS, the site of relapse, prior therapy, and
duration of previous response. At our institution, we give WBRT to
patients who experienced failure after chemotherapy alone (Table
4). This strategy is associated with a median survival after relapse
of 16 months, but with increased risk of neurotoxicity.67,68 In a few
studies, previously nonirradiated, relapsing patients have been
treated with salvage chemotherapy to improve disease control
while reducing neurotoxicity; reinduction with HD-MTX is an
example.85 In my opinion, salvage WBRT should be offered to
previously nonirradiated, relapsing patients considering that radiotherapy is more active than most salvage chemotherapies and that
the majority of cytostatics used in these combinations were not
previously addressed in ad hoc prospective trials.
Single drugs or chemotherapy combinations as well as HDC/
ASCT have produced encouraging results in patients relapsing
after chemoradiation therapy (Table 4). Isolated systemic (extraCNS) dissemination (3%-7% of failures3) seems to be associated
with a significantly better outcome with respect to CNS relapses,
in particular if treated with conventional antilymphoma
chemotherapy.86

Future perspectives
I expect that future therapeutic progress in PCNSL will be mainly
based on the expansion of molecular and biologic knowledge, the
improvement of diagnostic sensitivity and specificity, the conduction of well-designed prospective trials, and the prevention of
iatrogenic neurotoxicity. All these goals will require multidisciplinary and international efforts. Laboratory research will allow us
to better understand important tumor mechanisms and to identify
new therapeutic targets. Molecular and biologic studies will require
adequate amounts of freshly stored biologic samples; neurosurgeons should be encouraged to consider investigational purposes
other than diagnostic suitability and sequel risk when making a
decision on sample size. The use of new, more expensive laboratory techniques for research in this “orphan” malignancy will
require additional funding from scientific institutions and societies.
Modern functional neuroimaging will help us to establish a
suspicion of PCNSL earlier, resulting in timely treatment and less
CNS damage. Conducting well-designed trials is key to improve

520


FERRERI

therapeutic efficacy. IELSG no. 2040 and G-PCNSL-GS180 studies
opened the era of randomized trials in PCNSL and both randomized
trials and phase 2 trials testing new drugs in relapsing patients
should be encouraged. All these approaches should be associated
with the development of strategies aimed to prevent iatrogenic
neurotoxicity given the importance and fragility of organs where
this lymphoma arises.

ana Marturano (Unit of Lymphoid Malignancies), Michele Reni
(Medical Oncology Unit), Maurilio Ponzoni, Maria Rosa Terreni
and Claudio Doglioni (Pathology Unit), Marco Foppoli and
Federico Caligaris-Cappio (Internal Medicine Unit), Fabio Ciceri
(BMT and Hematology Unit), Anna Chiara (Radiotherapy Unit),
Alberto Franzin and Piero Picozzi (Neurosurgery Unit), Letterio
Politi and Andrea Falini (Neuroradiology Unit), Giulio Modorati
(Ophthalmology Unit), Giulio Truci (Neurology Unit), and
coworkers.

Acknowledgments
I am thankful to the Colleagues and Friends of the International
PCNSL Collaborative Group (IPCG). The continuous update and
discussion with them led me to improve my own knowledge on this
demanding malignancy. Our debates on new concepts and clinical
trials, even if sometimes a little spicy, are the fertile background for
future improvements in the management of PCNSL patients.
I appreciate the excellent support of scientists and clinicians
from the San Raffaele Scientific Institute (Milan, Italy), in particular: Silvia Govi, Silvia Mappa, Marta Bruno Ventre and Emerenzi-

Authorship
Contribution: A.J.M.F. wrote the entire manuscript.
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: Andres J. M. Ferreri, MD, Unit of Lymphoid
´
Malignancies, Department of Onco-Hematology, San Raffaele
Scientific Institute, Via Olgettina 60, 20132-Milan, Italy; e-mail:
andres.ferreri@hsr.it.

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