Browse Tag: Neuro oncology

Brain metastasis from an unknown primary

The last thing I’d like to just mention about, and it’s 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. The important thing to know about these tumors however is that there is a subset of these patients who can actually do quite well. All these patients were treated with whole brain radiation, 30 gray, and that intracranial disease-free survival at five years was 72% of these patients. And that the overall median survival of these patients was well over a year, whereas 12% of these patients surviving eight years and probably effectively cured of their disease.

What this says is that, particularly if you have a young middle aged person, good performance status, who has a solitary metastasis with no known primary, that that patient should indeed be treated very aggressively, both with surgery and radiation. Because that patient has a very good chance of having a long term disease-free survival, and potentially even cured.

Surgical resection of solitary lesions

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. Women complaining about lack of desire find female viagra very helpful. 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 patient’s brain again, particularly because of what we discussed; the issue of long term neuro-cognitive deficits? That study was recently published in JAMA and the answer is yes.

You probably should radiate the brain following removal of the lesion. There were patients who did receive radiation therapy compared to randomized patients who didn’t receive radiation following completion of their surgical resection had a much higher incidence of relapse in the brain, compared to the others who got radiation therapy. The relapses were local as well as distant. Although the median survival did not reach significant differences, there was a trend toward higher survival in patients who received radiation therapy. But at least from the point of view of neurologic sequelae and quality of life relative to neurologic symptoms, I think there clearly is a role for radiation therapy for most patients who have undergone resection for solitary brain lesions.

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. It’s often said, “Oh, you can’t 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. And generally, if you have a chemotherapy-sensitive tumor, whether it be in the lungs or whether it be in the brain, you have a very high likelihood of obtaining a response to chemotherapy.

I think the perfect examples of that are the experience in breast cancers. So for instance, here is one experience with the treatment of breast cancer metastasis to the brain where patients were treated with either CMF or CAF in patients who had previously not received chemotherapy, and the objective tumor responses in the brain were between 50-76% with a median duration of neurologic remission being 30 weeks. So it does appear that patients who have chemotherapy-sensitive tumors can significantly benefit from chemotherapy, even though their disease is in their brain. A similar type of experience has been seen with small cell lung cancer, where 116 patients from 12 series were treated with chemotherapy for brain metastases from small cell lung cancer, with an overall response rate of 76% in patients who had not received prior radiation therapy, compared to only 43% in those who had failed standard radiation therapy. So again, if you have a chemotherapy-sensitive disease it’s very possible that you can obtain very significant responses in the brain in treating brain metastasis. The problem is most diseases, like lung cancer and melanoma that have metastasized to the brain are intrinsically chemotherapy-resistant and thus if they are chemotherapy-resistant systemically they are going to likewise be chemotherapy-resistant in the brain.


Let’s 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 you’ll 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. They are particular rare in the young or the elderly.

Standard treatment for this disease is complete surgical resection, if they are standard low grade oligodendrogliomas.

If you can remove them, patients are often tumor free for years, sometimes for decades. Radiation therapy appears to be of more questionable benefit in these patients than for astrocytic tumors. They appear to be more radio-resistant. There is a sub-group of oligodendrogliomas however that are known as anaplastic or malignant oligodendrogliomas. These are tumors that can infiltrate widely and also spread throughout the craniospinal axis via the CSF. Even rarely spread systemically. Again, these are relatively radio-resistant tumors however recently it has been demonstrated that these tumors can be exquisitely chemotherapy sensitive. And in fact can be some of the most chemotherapy sensitive of all solid tumors anywhere.

A number of different agents have been shown to be potentially effective in the treatment of this disease, mostly alkylating agents have been shown to be most effective. The first and probably the most complete demonstration of the potential chemotherapy sensitivity of these tumors was a study published by Conquest Group out of the National Cancer Institute of Canada where 24 eligible patients with anaplastic oligodendrogliomas were treated. Of those 24 patients there were 17 objective responses, including 7 complete remissions, some of which were maintained for several or a number of years without further therapy. These can be extremely chemotherapy sensitive tumors. These are rare tumors but a potentially even more significant finding was the realization that a more common tumor, known as a mixed glioma – which are tumors composed of both astrocytic components as well as oligodendroglioma components – may in fact also be similarly chemotherapy sensitive as shown by this rather complicated slide here. Mixed gliomas actually can account for almost one-third of all gliomas. So what’s beginning to be seen is the possibility that oligodendroglioma features within a tumor may in fact predict for chemotherapy sensitivity.

High-grade astrocytomas

High-grade astrocytomas are often very heterogeneous in their histology and that there can be areas of low-grade histology immediately adjacent to areas of high-grade histology. Tumors will behave according to whatever the highest-grade histology is. One can imagine that with the small sections that are obtained via, for instance, stereotactic biopsies that one could therefore through sampling error come up with the wrong histologic grade. Thus by being able to just physically remove that mass, patients in fact often get significantly better. They are able to better tolerate radiation therapy, which has often been a problem when patients have large masses secondary to increased cerebral edema that can occur following radiation therapy. And that patients are at least palliated by removal of large masses. It probably increases survival when one looks retrospectively at the data. Again, patients who have had large resections tend to do better than patients who haven’t, but again there has been no randomized trial to prove this.

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. Canadian cymbalta 20 mg – effective major depressive disorder medication. 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 to a median of nine months. So while radiation therapy clearly makes a difference, it is not optimal.

However, if one actually looks at the data from radiation therapy, one can see that there appears to be a significant dose response and dose survival curve to radiation therapy. That as those patients get treated with higher and higher doses of radiation, that one begins to see increased survival. Unfortunately, as one gets the higher doses of radiation therapy one gets into more radiation toxicity with the most worst toxicity being radiation necrosis, which in many ways is as bad as the tumor itself, causing cerebral edema and local tissue destruction which is permanent and can be permanently debilitating. There are a number of different technical ways in which we can deliver high doses of boost radiation following the standard fraction of the external beam radiation. From these techniques you’ve probably heard about that they include the things like different types of modified linear accelerators or proton beam therapy. In that sense the idea is always the same, and the idea is to be able to deliver high-dose, focal radiation to the tumor while avoiding important and eloquent intracerebral structures.

In fact most of the phase II and many of the phase II studies looking at high dose focal radiation boost, whether it is done with brachytherapy or whether it’s done with one of these external beam techniques that I’ve just talked about, have shown us what appear to be significant survival advantages in patients treated with this boost focal technology.

The pathogenesis of most primary brain tumors

For the most part we still don’t truly understand the pathogenesis of most primary brain tumors, or the epidemiology as far as predisposing risk. There are certainly several genetic disorders for which there seems to be a predilection for primary brain tumors. They include neurofibromatosis, tuberous sclerosis, Turcot syndrome. But these account for well less than 1% of all the cases of primary brain tumors. We still are somewhat in the dark, relative to the etiology of this disease.

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. There are a number of different grading systems. The oldest and original one was the Kernohan system, which was a four-tier system. With grades I and II of four being classified as low-grade astrocytomas or grades III and IV being high grade astrocytomas. A grade III of four is an anaplastic astrocytoma, while grade IV of four is a glioblastoma multiforme. The problem with the Kernohan system is that, although the system did pretty well as far as prognosticating between low- and high-grade tumors, it was not very good at separating out prognostic variables between grades I and II, versus grades III and IV. And because of this discrepancy, back in the 1980s, many people went to a simpler system, a three-tier system, originally designed by ECOG. In this system grade I of three is considered a low grade astrocytoma, grade III of three is considered a glioblastoma and grade II of three is considered an anaplastic astrocytoma. If you look at survival curves in this three-tier system, you do indeed see very nice separations of the curves. The problem is that the vast majority of the patients fall into a category of grade II of three, astrocytoma.

Although low grade astrocytomas have a long natural history, these are not benign diseases. Given that these patients are young, generally speaking, this again cannot be in any way classified as a benign tumor. In fact, these are infiltrative, slowly but progressively growing tumors. Radiographically, they appear on CT scan as low- attenuating, poorly defined, non-contrast enhancing masses. While on MRI scan one generally sees increased P2 signal and they are non gadolinium enhancing. Unfortunately there is very little randomized data to suggest optimum management for these patients. The reason for this is twofold: It’s been very difficult to conduct clinical trials secondary to both the relatively long natural history of this disease and the relative rarity. So most of our recommendations relative to low-grade gliomas are based on biases and anecdotal and/or retrospective data. Currently in most large brain tumor centers, is if a low-grade glioma can be safely resected, then all attempts are made to do so. On the other hand, as one gets to a higher-grade tumor, grade II astrocytoma, it appears as though the benefits of more full resections are less pronounced. In fact the role for surgery for lower-grade tumors.

Neuro oncology

Neuro-oncology encompasses both primary brain tumors as well as secondary tumors. In other words, tumors from systemic cancers that involve the central nervous system. It’s really much too large an area to cover in one hour, so what I thought I would do is spend the majority of time talking to you about primary brain tumors, because I think most medical oncologists are least familiar with these tumors. Yet, increasingly so, medical oncologists are going to be seeing these tumors.

When one actually looks at SIR data from the NCI one can see a bi-modal distribution in the incidence of primary brain tumors. It can peak for the first few years of life, which then falls off and then begins to rise in late adolescence, peaking around the age of 60. In fact, these tumors represent very significant problems. They are the second leading cause of cancer mortality in patients under the age of 34, and the fourth leading cause of death in patients between the ages of 34 and 54. And in fact, primary brain tumors – now that leukemia has been cured in 70-80% of children – has really become the primary oncologic problem in the pediatric population. Plus, primary brain tumors do in fact present a significant cancer problem in the United States.

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 – do medical oncologists see these patients.

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. With the more readily available access to CAT scans and MRI scans, we are picking up patients earlier in the course of their disease, and that the number of patients who are actually presenting with significant increased intracranial pressure has significantly decreased.