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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.

The management of patients with brain metastases

As far as the management of patients with brain metastases, generally we don’t 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. Viagra professional works faster and lasts longer than you’ve ever known. If you are not able to wean them off the steroids then one should consider Pneumocystis prophylaxis which usually consists of a double strength Bactrim three times per week. There is no data to support the routine use of anticonvulsants and thus we only recommend anticonvulsants in patients who have already had a seizure. If patients are on anticonvulsants, one has to worry about a relatively high rate of Dilantin/Tegretol reactions, particularly in the setting of receiving radiation therapy where there is this syndrome of Dilantin-steroid taper where patients develop this inflammatory red rash on their skin which tends to progress to a Stevens-Johnson-like syndrome. So anticonvulsants are not a benign drug.

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 or higher – can result in a significant amount of neuro-cognitive deficits if patients live long enough; meaning usually at least a year. Thus for patients who have relatively good prognostic factors, who you think might otherwise actually live for a year or longer, if you are going to treat them with external beam radiation therapy as far as whole brain radiation, one should significantly consider the use of lower fraction sizes, such as 2 to 2.5 grays in order to try to reduce the chances of long term significant neuro-cognitive sequelae.

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 are that type I CNS lesion that I talked about earlier, where almost all the tumor cells reside locally. This is the reason that surgery can offer a significant benefit for patients with brain metastasis. Another important area to recognize is that approximately 11% of patients with brain metastasis have no known systemic primary and just as importantly, approximately 15% of lesions seen on MRI scans in patients with known systemic cancer are not brain metastasis so one cannot just innocently assume that an abnormality on a scan represents metastasis in the brain.

Just to give you an idea of what types of responses you can have

Just to give you an idea of what types of responses you can have. This is a 52-year-old man, presented with a huge mass in his right temporal parietal lobe. This was found on biopsy to be a CNS lymphoma and after two cycles on a regimen that we use, consisting of high dose methotrexate, cyclophosphamide and vincristine, after two cycles this was his scan. This is before radiation therapy. So again a very satisfying disease to treat.

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 don’t tolerate the chemotherapy side effects, and indeed they do not appear to benefit as much as younger patients. But what the age cut-off is and why this should be the case remains totally unknown. Issues relative to performance status, pathology and extent of disease appear to be less significant, at least for immunocompetent patients being treated with chemotherapy. There also continue to be significant and growing questions about the appropriate role for radiotherapy, such as what is the optimal dose and fractionation scheme, since combining chemotherapy and radiation now patients are living longer, one begins to have to worry about long term neuro-cognitive sequelae. One is beginning to question, with optimal chemotherapy, does one even need to use radiation therapy. So these are questions that still remain outstanding in primary CNS lymphoma. Again, a difficult problem in answering these questions given the relative rarity of the disease.

I’d 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, while the two tumor types that appear as hyperdense lesions without contrast are renal cell carcinoma, melanoma and actually sarcoma. But most of the other metastases appearing as hypo or iso-dense lesions.

The standard treatment for primary CNS lymphoma

The standard treatment for primary CNS lymphoma in the past is radiation therapy. There is probably somewhat of a dose response curve, but the good news about using radiation for primary CNS lymphoma is that more than 80% of patients have complete radiographic responses. And not just radiographically. Often one can get significant, and usually one does get significant palliation of their neurologic symptoms. So it can be a very satisfying disease to treat with radiation. Unfortunately, as fast as the tumor goes away if often comes back. With most patients being treated with radiation alone, median survivals of only approximately 16 months. When these patients relapse they relapse with local disease as well as distant disease. Distant being defined as distantly within the craniospinal axis.

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 and the disease goes away, most patients will ultimately succumb to their HIV disease within several months. Again, the reason for that is – at least prior to the age of triple therapy and effective retroviral therapy – is that most patients with AIDS who develop primary CNS lymphoma were at the end-stage of the natural history of their AIDS disease, with median CD4 counts being below 50. However, with effective antiviral therapies the nature of primary CNS lymphoma in this patient population is changing and in fact there is a significant percentage of patients who present with CNS lymphoma as their AIDS defining illness, while their CD4 counts are still relatively high. That needs to be, and is being, a significant reassessment of beginning to treat these patients more aggressively, much like their immunocompetent counterparts. But again, that is still work in progress.

Going back to the immunocompetent patients however, this type of data suggests – retrospectively anyway – that there may indeed be a role for chemotherapy. Accordingly, there have been a number of trials published in the literature that have looked at various combinations of chemotherapy regimens used either prior to radiation therapy or a few alone that have clearly shown that chemotherapy can change the natural history of the this disease. Propecia is used in male patients to prevent vertex hair from falling. If one just takes a purview here of the median survival of these patients it is significantly higher than what we almost ever saw with radiation alone. The chemotherapy drugs that are used remain varied, and an optimal treatment regimen has not been established. What we can say however is that I think most investigators would agree that high dose methotrexate still remains the mainstay of treatment and is the most effective regimen.

Other drugs that potentially can be used or drugs that either have the ability to cross the blood-brain barrier and have anti-lymphoma activity, or drugs that at least marginally cross the blood-brain barrier in times of blood-brain barrier disruption, such as when the tumor first presents, and of course must also have anti-lymphoma activity.

Primary CNS Lymphoma Treatment

Radiographically, the major difference between these two patient populations is that there is approximately twice the incidence of multiple lesions seen at the time of presentation radiographically in AIDS patients and that about half of those lesions were characteristic ring-enhancing lesions in AIDS patients, a radiographic finding that is very uncommon, actually, in immunocompetent patients. Just to give you a typical kind of MRI scan in an AIDS patient with CNS lymphoma; you can see the multiple lesions, you can see the typical ring-enhancing lesion and their distribution in a ventricular manner, with a relatively small amount of associated edema in contrast with what you see in high grade gliomas.
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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% of the cases. And that surgery is still often required to make the diagnosis in this disease. The question often comes up that once one has made the diagnosis of lymphoma in the brain, how much systemic staging should be done. And although this remains an area of somewhat debate and controversy and personal preference, the bottom line is this: that for a patient who presents with neurologic symptoms, has radiographic evidence of a tumor on MRI scan or CAT scan, then goes on to have a biopsy and it is shown to be lymphoma, if you do a good physical exam on those patients, you do a chest x-ray, standard blood work including liver function tests and you do not detect any obvious abnormality, the likelihood of finding an occult systemic lymphoma with the more extensive work-up with tests such as body CT scans, gallium scans, bone marrow biopsies, is essentially zero. Although there may be one in a hundred or more cases that you’ll finally pick up. Because the pick up rate is so small we actually do not recommend doing that type of extensive analysis. So again, our recommendations are: good physical exam, standard blood work, chest x-ray. If there’s no signs of systemic lymphoma then almost by definition they have primary CNS lymphoma and should be treated accordingly.
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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, are so much more effective than they are for astrocytic tumors. The only problem with stereotactic biopsies for this tumor is that sometimes the histologic diagnosis from such a small sample can be difficult, in that the pathologist may say, well we see some lymphocytes but we can’t tell you whether this is an inflammatory lesion or lymphoma. However, increasingly so with molecular diagnostics such as through PCR looking for immunoglobulin gene rearrangements one can often make the diagnosis from very small tissue samples.

The pathology of primary CNS lymphoma

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-Hodgkin’s 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 in the literature, the vast majority of primary CNS lymphomas tend to be of B-cell origin. Finally, Epstein-Barr virus can be found in almost 100% of primary CNS lymphoma cells in immunocompromised patients but interestingly, almost never found in the lymphoma cells in the immunocompetent patients, again suggesting that there is probably a difference in the natural history and the biology of CNS lymphoma in these two patient populations. When you actually look at the pathophysiology of primary CNS lymphoma we can see that the vast majority of patients present as focal lesions. Though other types of presentations are possible, including a more diffuse type of picture, uveal presentation and leptomeningeal or intramedullary presentation. No matter how this tumor presents however, this is always a diffusely infiltrative disease and is never a localized process. This tumor spreads along the CSF pathways, although interestingly even at times of advanced disease and at time of death of patients with widespread cranial spinal disease, we rarely see this tumor outside the central nervous system, probably less than 10% of the time. Just to give you an idea of the infiltrative and diffuse nature of this disease, this is a high-power section of the brain of a patient with a CNS lymphoma. You can see these lymphoma cells throughout the cerebral cortex and spreading along the pia mater and into the Virchow-Robin spaces of the brain. When you actually look at a whole mount of a brain of a patient who died of a CNS lymphoma you can see the diffuse infiltrative nature of this disease, really in every component of the brain.

In order to get a better idea about the natural history and the characteristics of this disease, we actually did a significant literature review where we reported the characteristics of every case of primary CNS lymphoma reported in the literature between 1980 and 1993 in patients who were both immunocompetent as well as AIDS patients. This group of patients encompassed almost 800 immunocompetent patients and over 300 HIV-positive patients. We saw several significant differences. The first one of course is the male to female ratio, with that being much higher obviously in the HIV population, as well as the fact that the HIV population tended to be younger when they developed the disease. Again, I think this reflects more of the epidemiology of AIDS, at least in the period of 1980 to 1993 than it necessarily represents a statement about the biology of primary CNS lymphoma. We also looked at the clinical presentation. One of the interesting differences that we saw is that patients with AIDS tended to present much more with mental status changes and seizures as opposed to patients who were immunocompetent tended to present much more with more focal types of symptoms, suggesting that the disease in patients with AIDS tended to be a much more diffuse presenting disease as opposed to patients who were immunocompetent, who presented more like patients with other types of primary CNS tumors.