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New Treatments for Brain Tumors

Neuro-oncology encompasses both primary brain tumors as well as secondary tumors brain tumor, brain cancer, cell phones. In other words, tumors from systemic cancers that involve the central nervous system. When one actually looks at SIR data from the NCI one can see a bi-modal distribution in the incidence of primary brain tumors.

Depending on the classification, there are as many as 15-30 different primary brain tumors. Meningiomas are very common but they are generally restricted to surgical management and radiation and only occasionally - for rare syndromes where we see malignant meningiomas.

When we talk about brain tumors almost regardless of the type of histology, we can group the syndromes, as far as how patients present, into the following signs and symptoms. The common presenting symptom is one of headaches. Seizures are seen in approximately half the patients, as are mental status changes and some kind of motor deficits.

Astrocytomas are the most common primary brain tumor in adults and represents the most significant problem in adults. When we speak of astrocytomas, we divide them into low- and high-grade tumors. The high-grade tumors include tumors known as anaplastic astrocytomas, which include glioblastoma multiforme. When we talk about the grading system for astrocytomas, it is in fact somewhat complicated.

When one looks at the issue of radiotherapy for low grade gliomas, one sees the opposite type of paradigm as one sees with surgery. And thatís for the low-grade astrocytomas radiation therapy does not appear to make a significant different in either a five- or ten-year survival, and that may be because surgery is such a good therapy for these patients.

The more common astrocytomas are high-grade astrocytomas, which are bad tumors. These are rapidly growing, infiltrative and destructive lesions. Radiographically on CT scan they appear as low-attenuating, contrast-enhancing masses. On MRI scans they appear as increased P2 signal representing both tumor and edema, and they are gadolinium enhanced.

In surgery, the one thing that is clear in the treatment of high-grade astrocytoma is that radiation therapy remains the optimal and the most prudent therapy for this disease. There has been a series of randomized trials dating back to the 1970s and the 1980s that have clearly shown a significant survival advantage for patients treated with external beam standard fractionated radiation therapy. Nevertheless, the role of surgery still remains somewhat limited in that although radiation therapy can nearly triple the survival of patients with high grade gliomas - in the case of glioblastoma that means going from a median survival of three months without radiation therapy.

The role of chemotherapy as part of the initial treatment for high-grade gliomas remains somewhat of a question and problematic. This is true even though there have been more than 20 randomized trials, because if one looks at those randomized trials the data on whether chemotherapy is really effective, as far as adding something to the radiation, remains very conflicted. The brain tumor cooperative group itself has conducted three multi-center trials.

How about the use of standard chemotherapy at the time of recurrence? Well, if you look through the literature you will see various reports of various combinations, single agent chemotherapy trials and combination chemotherapy that give relatively high response rates. Itís important to understand that the reporting of these response rates are often very over-inflated for a number of reasons. One of the major reasons is that response criteria in the neuro-oncology community have not been agreed upon and for instance.

Letís go on and talk about another tumor type, that being oligodendroglioma. Although this is a very uncommon tumor, I think medial oncologists will increasing see a number of these patients for reasons youíll see in a second. Oligodendrogliomas are only about one-tenth as common as astrocytic tumors with peak incidence of this tumor occurs in young to middle-age adults, accounting for approximately 6% of all intracranial neoplasms in this age group.

The last primary brain tumor Iíd like to talk to you about is primary central nervous system lymphoma, again a tumor that I think we are going to be increasingly seeing. Neurologic involvement of the central nervous system from systemic non-Hodgkinís lymphoma is relatively common, occurring in approximately 5-29% of all patients with systemic lymphomas. However in the past primary CNS lymphoma only accounted for approximately 1-2%.

The pathology of primary CNS lymphoma is always one of diffuse histology since there are no lymph node structures within the central nervous system. Although we see all subtypes of non-Hodgkinís lymphoma within the brain, the prognostic significant of the histologic subtypes do not appear to be as significant or as important as they are for the subtypes with systemic lymphomas. Although pure T-cell primary CNS lymphomas have been reported occasionally.

The diagnosis of primary CNS lymphoma can occasionally be made relatively non-invasively, and that about 10-20% of patients will develop a lymphomatous uveitis that actually can be detected on slit lamp exam, if in fact one is astute enough to suspect primary CNS lymphoma radiographically and have the patient seen by an ophthalmologist. Although lumbar puncture and CNS examination will give you a clear cytosis in approximately 80% of the patients, actual lymphomatous involvement as called by the cytologist is generally found in less than 10%.

What is the treatment for primary CNS lymphoma? Well, opposed to what we talked about for gliomas the role for surgery is much more restricted, mostly for diagnostic purposes. And that extensive resection is really not optimal in this case. One, because of the severely infiltrative nature of this disease, not just locally but throughout the craniospinal axis, but also because the other therapies, radiation therapy and chemotherapy.

When you look at the historical data of how patients have done when treated with either no therapy, radiation therapy or radiation chemotherapy, one gets a hint that maybe chemotherapy ultimately might have a role in this disease, at least for immunocompetent patients. On the other hand, it is not clear at all that any type of treatment for patients with full-fledged AIDS makes a big difference. The reason for that is that even if you treat this disease with radiation therapy.

There remain a number of questions of primary CNS lymphoma relative to chemotherapy, such as who benefits from chemotherapy? We talked about the issue of immunocompetent versus immunodeficient patients. Prognostic factors seem to make a difference, with age being the most important. That elderly patients do not tolerate the chemotherapy as well or they donít tolerate the chemotherapy side effects, and indeed they do not appear to benefit.

Iíd like to just finish up by talking a little bit about, and mentioning a few of the recent developments, in the treatment of brain metastasis. A problem that medical oncologists obviously see quite frequently. The reason for that is that 20-40% of all cancer patients will develop brain metastases, accounting for 170,000 cases per year. The majority of these patients have lung cancer. Most of the metastases occur in the gray white matter, of which 80% is supratentorial. The few tumor types that can metastasize to the dura are breast and prostate.

As far as the management of patients with brain metastases, generally we donít instantly go to the use of steroids unless the patient needs them. If the patient needs them, meaning that they have significant symptoms of increased cerebral edema, then we recommend starting out at high doses of steroids, such as 4 mg four times a day, but within an aggressive taper. The patients are going to need to be on long term steroids. If you are not able to wean them off the steroids then one should consider Pneumocystis prophylaxis.

As far as the standard treatment for patients with brain metastases, particularly multiple brain metastases, radiation therapy remains the main form of treatment. There have been a number of studies, including several RTOG studies, that have tried to define the optimal dose. It appears that the optimal dose is somewhere between 20-40 gray. What has become clear however is that the standard way that radiation therapy used to be given - which is in 3 gray fractions.

How about the treatment of single brain metastasis? That represents a more questionable and changing area of management in these patients. If one looks at the data by CT scan one can see that approximately 50% of patients have brain metastasis of single lesions. However, when one uses more selective MRI scans the number reduces down to approximately 30% of patients with brain metastasis. The average or median diameter of these lesions is approximately 2.5 centimeters. About 5-10% of these are invasive, which means that 90-95% of these tumors.

There was a growing interest in the use of surgical resection of solitary lesions, and in fact there have now been two randomized trials that have shown a substantial benefit. But as far as local control, neurologic relapse and actual overall survival in patients who were randomized to surgical resection of solitary lesions compared to standard radiation therapy. The most famous of these is the Patrick study, published in the New England Journal where it was shown that patients did much better if they had surgical treatment. Other positive prognostic signs were absence of extra-cranial disease, young age and a long time to CNS metastasis. A similar study was recently published that again showed a particularly significant survival advantage for surgery, also younger age and absence of extra-cranial disease were other important prognostic signs. Then of course came the question, if you do surgically resect a solitary brain metastasis should you radiate the patientís brain again, particularly because of what we discussed; the issue of long term neuro-cognitive deficits?

The question often comes up for patients who have already had radiation therapy or who have potentially chemotherapy-sensitive tumors, what is the role for chemotherapy for the treatment of brain metastases, particularly multiple brain metastases? One of the important things to understand about brain metastasis is the issue of the blood-brain barrier. Itís often said, "Oh, you canít get drugs into a brain metastasis because of blood-brain barrier." However, it should be recognized that the blood-brain barrier in brain metastasis is virtually destroyed by the tumor, particularly in the middle of those metastases. This is in contradiction to what we see with primary gliomas where in fact the blood-brain barrier remains very much intact, or at least to a variable extent intact. So actually drug delivery is a much bigger problem for the treatment of gliomas than it is for brain metastasis.

The last thing Iíd like to just mention about, and itís an important point, is the issue of brain metastasis from an unknown primary. If one looks at a series from M.D. Anderson, 220 patients with brain metastasis. Approximately 39 of those patients, or 18%, were without a known systemic site. The median age of these patients is approximately 55. Most of them had good performance status. About half of those lesions were multiple, however half of them were single. One actually looked at the histology of those tumors. Approximately 31% were adenocarcinomas, representing by far the greatest number. In the few patients where a primary was eventually found, usually at autopsy, lung represented the most common primary site.