This is an informative article about the uncommon but vexing problem
of primary central nervous system (CNS) lymphoma. This is a rare
disease, but its rising incidence (even outside of the setting of the
acquired immune deficiency syndrome [AIDS]), its distinctive clinical
features, and its traditionally dismal outlook have drawn
considerable attention. Since Dr.DeAngelis and her coworkers,
including Dr. Nasir, have been major contributors to the literature
on this topic, their perspective is based on broad experience.
Largely because we know so little about the biology of primary CNS
lymphoma, this topic receives little attention in the article by Drs.
Nasir and DeAngelis. Primary CNS lymphoma is virtually always a
B-cell process. In the setting of AIDS, Epstein-Barr virus (EBV)
almost certainly plays a role.
Beyond these facts, however, our knowledge is limited, even with
respect to basic issues, such as how this process takes up residence
in an immunologic sanctuary site. Primary CNS lymphoma appears to
derive from germinal center B cells, based on the expression of human
Bcl-6 in virtually all of AIDS-unrelated, and half of AIDS-related,
primary CNS lymphoma. With systemic lymphoma, predisposing
clinical and biological (eg, CD56 expression) features correlate
with the risk of spread to the CNS. We need to gain a better
understanding of the biology of primary CNS lymphoma, too, hopefully
in a way that can be exploited therapeutically.
Use of Steroid Therapy
In addition to providing a broad perspective on the published
literature, Drs. Nasir and DeAngelis add some useful anecdotes from
their experience. The confusion that can be generated by the use of
steroid therapy before biopsy proof of diagnosis requires some
further comment. The authors observation that steroids can lead
to radiographic resolution of all evidence of disease within 1 day is
notable and startling. Personally, I have not performed repeat
imaging on such a short-term basis; the New York third-party payors
must be more intellectually curious than ours in Texas.
Another useful and sobering anecdote from Drs. Nasir and DeAngelis is
that waiting for a steroid-induced regression to declare itself is a
recipe for disaster. They describe fulminant tumor growth and rapid
death in some patients in whom steroid therapy was withdrawn, with
the intent to perform a diagnostic biopsy when lesions reappeared.
Multicentricity of Primary CNS Lymphoma
The authors emphasize that primary CNS lymphoma is often multicentric
within the CNS. Due to the frequency of meningeal disease and the
potential for vitreous disease, slit-lamp examination and
cerebrospinal fluid analysis are key components of the work-up of
these patients. The apparent favorable impact of intrathecal
chemotherapy is testimony of another sort that primary CNS
lymphoma is often more widespread in the CNS than meets the eye.
However, there are some paradoxes that we do not understand well
enough. The multicentricity observation applies to CNS sites; but,
even in an era in which we are witnessing longer survival of patients
with primary CNS lymphoma, systemic relapse remains uncommon.
Moreover, in contradistinction to systemic lymphoma, in-field
relapse is the rule in primary CNS lymphoma. The stumbling block of
the blood-brain barrier can be used to explain the shortcomings of
such chemotherapy regimens as cyclophosphamide, doxorubicin HCl,
Oncovin, and prednisone (CHOP). But whole-brain radiotherapy should,
in a logical world, minimize the occurrence of in-field relapse. And
it does not. Clearly, the biology of primary CNS lymphoma differs
from that of systemic lymphoma.
An anecdote by Drs. Nasir and DeAngelis that I question pertains to
the relative impact of CNS and systemic lymphoma, in cases where both
are found. The authors suggest that the systemic disease is usually
not an overriding concern. That is not necessarily true. In the
setting of CNS spread of systemic lymphoma, the CNS disease often can
be controlled, and the systemic disease ultimately often dominates
the clinical course.[6,7] Perhaps Drs. Nasir and DeAngelis observed
selected cases in which the CNS disease was dominant and the systemic
disease was occult. However, in some common scenarios of systemic
lymphoma and simultaneous CNS disease (eg, aggressive lymphoma with
extensive marrow infiltration), the systemic disease should not be
Concerning treatment, Drs. Nasir and DeAngelis conclude that
great advances have been made, but another recent review
observes that the median survival of patients with primary CNS
lymphoma remains disappointingly short. Which view is
correct? I feel that we are only now waking up to the realization
that whole-brain irradiation alone is not effective enough. We may
have come a long way, but we have much farther to go.
Evidence does indicate that chemotherapy adds to or improves on the
results that can be attained with radiotherapy, and this is a lead
that deserves to be pursued. The virtual absence of randomized
studies has necessitated analyses that use historical controls or
meta-analytic approaches. Yet, in a disease in which half of the
patients die within 1 to 1.5 years and < 5% of patients survive 5
years with whole-brain irradiation alone, I am not interested, as
a physician (nor would I be as a patient!), in a trial in which the
control arm consists of radiation therapy alone.
Combination Chemotherapeutic Regimens
So, which chemotherapy should we choose? Unfortunately, a perfect
choice has not yet been found. There is a need for better agents and
for innovative approaches to overcome the issue of the blood-brain
barrier. The blood-brain barrier disruption and intracarotid artery
chemotherapy approach of Neuwelt et al in Oregon, effective as it
seems, has not been widely adopted, probably because of the
complexity of the program and the frequent debility of the primary
CNS lymphoma patient. Moreover, since about 50% of patients in the
Oregon experience eventually cross over to radiation therapy anyway,
even this approach does not make the chemotherapy uniformly effective.
In essence, without some strategy that circumvents the blood-brain
barrier, we are constrained by the very limited number of agents that
cross that barrier and have an established, major role in lymphoma
therapy: Basically, methotrexate and cytarabine (ara-C) are the only
agents that meet these criteria.
Might other agents play a role? Lets hope so. As an adjuvant
following radiation therapy, the regimen of procarbazine, CCNU, and
vincristine (PCV) has had a modestly favorable impact. New
agents, such as temozolamide (Temodar), deserve to be tested in
primary CNS lymphoma. As a B-cellspecific monoclonal
antibody, rituximab (Rituxan) could conceivably have some impact in
this disease. Yet, we know nothing about its penetration into the
cerebrospinal fluid (CSF) or the brain parenchyma.
With respect to primary CNS lymphoma, we know the most about
methotrexate, and to date, it remains our best agent. Yet, in
systemic lymphoma, methotrexate is a relatively minor agent; its
inclusion in CHOP-type regimens appears to add little benefit.
In any event, is single-agent chemotherapy enough? Drs. Nasir and
DeAngelis think not, and I agree. Even in Burkitts
lymphomawhich is a rare example of a systemic lymphoma in which
a single agent (cyclophosphamide [Cytoxan, Neosar]) can be
curativewe have moved to combination chemotherapy. Surely, the
same will pertain to primary CNS lymphoma, especially in light of the
problem of leukoencephalopathy with methotrexate.
Our group has explored the utility of variants of the regimen of
dexamethasone, high-dose ara-C, Platinol (DHAP) in primary CNS
lymphoma, usually in conjunction with whole-brain irradiation. The
DHAP regimen has established efficacy in systemic lymphoma.[14,15] As
with all single-institution studies, our primary CNS lymphoma patient
numbers are small. We have observed responses, including durable
ones. Although we have generally tried to limit methotrexate to 1 to
2 doses in conjunction with the DHAP variants, we, too, have seen
leukoencephalopathy in patients who received chemotherapy followed by
The AIDS-Related Primary CNS Lymphoma Dilemma
Unfortunately, AIDS-related primary CNS lymphoma remains a dismal
disease. The most encouraging development, if it holds up, would be a
decreased incidence of primary CNS lymphoma in the era of highly
active antiretroviral therapy. However, since primary CNS lymphoma is
a late manifestation of AIDS, further follow-up of long-term
survivors with AIDS will be needed to confirm this observation.
With respect to the treatment of primary CNS lymphoma in the AIDS
patient, the encouraging words by Drs. Nasir and DeAngelis should be
placed into perspective: In their experience, patients likely to
benefit from therapy are those with a good performance status and
relatively high CD4 cell counts. This represents a formidable
Catch-22, since most AIDS-related primary CNS lymphoma patients do
not fit this description. For AIDS-related primary CNS lymphoma,
especially, we need innovative therapy that will not predispose to
infection or contribute to the dementia that can occur with AIDS.
I agree with Drs. Nasir and DeAngelis that exciting advances have
been made in the management of primary CNS lymphoma. However, these
advances are tantalizing in nature. The majority of patients are
still devastated by this disease or its treatments. We need to do better.
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