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 They describe fulminant tumor growth and rapid death in some patients in whom steroid therapy was withdrawn, with the intent to perform a diagnostic biopsy when lesions reappeared.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(Drug information on cyclophosphamide), doxorubicin(Drug information on doxorubicin) HCl, Oncovin, and prednisone(Drug information on 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 taken lightly.
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(Drug information on methotrexate) and cytarabine(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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 radiation therapy.
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.