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.

Primary CNS lymphoma relative to chemotherapy

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.

Oigodendrogliomas and chemotherapy

So where do we currently stand with the story of oligodendrogliomas and chemotherapy?

It is clear that anaplastic oligos are very chemotherapy sensitive tumors, at least 80-90% of them. Recently several genetic and chromosomal abnormalities have been shown to predict for chemotherapy sensitivity, including 1P10Q deletions. Anaplastic mixed gliomas appear to be chemotherapy sensitive although it is not clear that they are as sensitive as the pure oligos. One of the questions however remains that whether low grade oligodendrogliomas are chemotherapy sensitive.

There are some preliminary reports that suggest that they may be, but again I think this remains investigational. Cialis & Viagra limited supply at a special prices. Other questions that remain outstanding as far as the practical use of chemotherapy in these tumors is when to use chemotherapy. Should it be used prior to radiation? Should it be used following radiation therapy? Should it only be saved for time of recurrence? Currently the RTOG is running a multi-national, multi-group trial asking the question of the timing of PCV. But the results of that trial will not be available for a number of years given the relative rarity of these tumors. Also, how about the optimal regimen? We talked about standard PCV but actually in fact the original reports from the National Cancer Institute of Canada and other reports have used a slightly modified regimen using intensive PCV, which is certainly more toxic than PCV. Is that really necessary?

And finally, what is the length of treatment? No one really has the answers on any of these questions.

The last primary brain tumor I’d 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-Hodgkin’s 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% of all these cases. Recently however there has been significant increase in the incidence of primary CNS lymphoma in both populations at risk. Those being immunocompetent patients who have no predisposing reason to have this disease as well as the immunocompromised patients, such as patients with HIV disease and iatrogenic immunocompromised patients such as organ allograft recipients as well as in certain congenital immunodeficiencies.

Oligodendroglioma

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.