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What is Primary Central
Nervous System Lymphoma (PCNSL) and why is it important? PCNSL is an interesting but rare brain tumor that has unique attributes, having the characteristics of both other non-Hodgkin's lymphomas and other brain tumors. First, it appears to arise within the brain, retinas of the eyes, or meninges, without any relationship to lymph nodes. |
This is unusual because the more common lymphomas, non-Hodgkin's lymphomas and Hodgkin's disease, are usually found in lymph nodes or in organs with large numbers of lymphocytes. Second, although it can occur in otherwise normal persons, it is more common in persons with some form of immune system deficiency; for example, AIDS patients or organ transplant recipients. Third, it can regress dramatically with steroid treatment such as dexamethasone, even to the point of disappearing prior to a biopsy. Fourth, it can be successfully treated without surgical resection and without radiation therapy, which makes it somewhat unique among brain tumors. Some researchers consider PCNSL a model for a chemo-sensitive brain tumor.
| How is PCNSL
diagnosed? Like most other brain tumors, PCNSL presents with symptoms that vary with its location. PCNSL can present as multiple tumors throughout the brain. It can also present with visual blurring or "floaters", because lymphoma cells can be present in the retina or the gel-like interior of the eye, the vitreous. MRI scans of PCNSL patients typically show one or more deep tumors that enhance with contrast. However, PCNSL can show a great deal of variation in its appearance. Sometimes the coverings of the brain and spinal cord, the leptomeninges, show enhancement too. Although there are rarely changes in the eyes than can be seen on MRI, visible changes in the retina or vitreous can suggest the diagnosis to an experienced ophthalmologist. Spinal fluid, the vitreous fluid, or the brain may reveal lymphoma cells, and a biopsy or sampling of any of these is necessary for definitive diagnosis. |
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It is not unusual to perform two or three procedures before a final diagnosis can be rendered, because lymphoma cells can be difficult to distinguish from normal lymphocytes.
Occasionally a neurosurgeon will resect a lymphoma initially thought to be a different kind of tumor. However, often if the diagnosis is suspected pre-operatively, a needle biopsy may be sufficient to confirm it, sparing the patient a much more extensive resection.
How has the treatment of PCNSL evolved?
For more than thirty years, radiation therapy was usually recommended for
PCNSL. When it was recognized that patients receiving radiation therapy did not
necessarily require a resection of the tumor to do equally as well as patients
having a biopsy only, surgical resection became a necessity only for those
patients having a very symptomatic tumor.
Most brain tumors present as single masses, but lymphoma can appear throughout the brain and spinal fluid. For this reason, whole-brain radiation was recommended and until quite recently was considered "standard" therapy. Whole brain radiation has two drawbacks: first, it does not cure PCNSL, although many patients will achieve a remission of several months. Moreover, radiation to the whole brain, particularly at high doses, can cause cognitive decline, particularly in memory. Patients who have malignant cells in the spinal fluid need additional therapy because the tumor cells can cause weakness, pain, and sensory disturbances.
It seems logical to add chemotherapy to radiation therapy because of the high success rate in treating other lymphomas in other parts of the body with chemotherapy. However, some drugs interact adversely with radiation therapy and cause more long-term side effects on the normal brain.
Over the past ten years many researchers have investigated drugs or combinations of drugs instead of offering radiation therapy. The most common drug used in PCNSL is methotrexate, given at high doses with an antidote, leucovorin, which "rescues" normal cells from the toxic effects of methotrexate. Dr. Edward Neuwelt in Oregon pioneered the use of intra-arterial chemotherapy in PCNSL, and this approach has been used in other areas of the country as well. Other investigators, including Dr. Fred Hochberg in Boston have used high-dose methotrexate intravenously with good results.
At the National Cancer Institute, we used a combination of drugs which included methotrexate, thiotepa, vincristine, dexamethasone, and cytarabine. Most of our patients received chemotherapy in the hospital for a few days, every three weeks, for a total of eighteen weeks. Our goal was to develop a regimen that was effective, could avoid radiation therapy, and did not have long-term side effects. Virtually every patient had either partial or complete eradication of their tumor, although some later relapsed. I use the same regimen for many patients now because I have never used anything that has worked better.
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Magnetic resonance imaging (MRI) scans of a patient's
brain |
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Recently, three new drugs have been used in clinical trials for PCNSL. One drug, topotecan, can be given intravenously or administered directly into the spinal fluid (intrathecally). Another drug, Temodar, is an oral drug approved last year for the treatment of astrocytoma, a different type of brain tumor. The third drug, Rituxan, a monoclonal antibody used to treat other lymphomas, has shown some effectiveness, although apparently is not effective against lymphoma cells in the spinal fluid.
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With so many different types
of treatment, how do you decide which treatment option to use? If the patient is eligible for a clinical trial, particularly for one of the new drugs or drug combinations, I would encourage them to consider that. On the other hand, there are patients who are too frail to take chemotherapy or even radiation therapy and some of those patients benefit from steroids to control symptoms. Radiation therapy is still a reasonable option for some patients, particularly those with other serious medical conditions, such as AIDS. |
High-dose methotrexate is the cornerstone for many treatment regimens, but I do not recommend it in combination with radiation therapy because of the serious brain damage (neurotoxicity) seen in some patients. Older patients are at more risk for neurotoxicity and may have problems even with high-dose methotrexate alone.
I have treated patients who relapsed after treatment with methotrexate with cytarabine (Ara-C), BCNU, AZQ, topotecan, cisplatin, and Rituxan, and Temodar. These drugs all work, to some extent; none of them have yet proven superior to methotrexate but some are less toxic.
Are patients with PCNSL ever cured?
Yes, in the sense that they may never relapse in the brain. Because lymphoma
can relapse in the brain or in another organ several years after a remission, it
is difficult to say with certainty that a patient is cured. There certainly are
more PCNSL patients living five years or longer, making it even more important
that permanent brain damage does not occur as a result of treatment.
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