Browse Author: Canadian pharmacy

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.


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.

How about the use of standard chemotherapy

Well, if we are going to use chemotherapy, particularly for those with anaplastic astrocytomas where we do believe that there is a role for post-radiation chemotherapy, what are the optimal drugs?

Well, there are very few data out there that gives us a lead. The best, or the only data that’s really out there, comes from a randomized trial conducted by NCOG published in 1990. It took patients with high grade astrocytomas, following external beam radiation therapy and randomized them to treatment with either treatment with single agent with BCNU or PCV. If you looked at the groups as a whole there was no significant survival advantage of time to tumor progression difference between these two treatment regimens. However, when a subgroup analysis was done they looked at the minority of patients with anaplastic astrocytoma there appeared to be a very significant survival advantage for patients treated with PCV over BCNU. And hence, the standard recommendation for patients with anaplastic gliomas to be treated with the three drug combination of procarbazine, CCNU and vincristine following standard external beam radiation. It’s important to understand that this is really the only hard data that suggests that PCV is better than BCNU. This is a subgroup analysis and it consisted of only approximately 30-40 patients, and that’s whether in fact this truly is true at this point remains unclear. Nevertheless, it’s unlikely this trial is going to be reproduced so this is the data that we are stuck with.

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. It’s 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, stable disease is often considered a response in most of the literature. Canadian viagra online is a successful way to fight male impotence problems. And stable disease is often not even defined by duration of stable disease. Furthermore, many of the older trials did not have imaging modalities that were accurate. They used old brain scans or some of the older data for some of the older agents only used clinical exam as a way of assessing response.

Many of these trials did not control for steroid dose and we know steroids can certainly affect the clinical symptoms of patients as well as their imaging.

As a matter of fact, I think one has to be very critical, particularly looking at the older data in neuro-oncology. It is clear regardless of what the response rate is, that for most agents, standard chemotherapy agents in the treatment of recurrent high grade gliomas that whatever responses there are tend to be very short. Although the responders may live longer than non-responders, whatever that means, there is clearly no overall survival prolongation in patients treated with chemotherapy. Furthermore, there are few if any significant quality of life studies to suggest the role of chemotherapy. I think the one potential contradiction to this is the recent demonstration that a new drug, temozolomide, has a relatively high – approximately 37% – response rate in patients with anaplastic gliomas treated at the time of recurrence who’ve had one or fewer previous chemotherapy regimens. So temozolomide for recurrent glioma probably offers something to these patients.

The role of chemotherapy

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 and their data is somewhat conflicted, even though they’ve recommended the use of chemotherapy. Why so much controversy and why are the data all over the place? One of the major reasons simply has to do with the power of randomized trials. It takes nearly 250 patients in each arm of a randomized trial in order to have a 80% probability of detecting a 20% increase in median survival. Most single institutional brain tumor trials enrolled less than 30 patients per arm, and even the large multi-institutional brain tumor trials have enrolled less than 50 patients per arm. And that most trials have not been designed to have the power to pick up potential beneficial effects from some type of therapy like chemotherapy.


Meta-analysis is a statistical method that allows one to combine the results from multiple randomized trials in order to pick up small but potentially important clinically significant outcome differences from different therapies. The database that we used were all randomized trials, published in English between 1975 and 1990. The survivals were determined by Kaplan-Meier survival curves and the standard error of survival was determined by Greenwood’s formula.

For patients who were treated with radiation and chemotherapy, there is a higher statistically significant survival advantage compared to those that were treated with radiation alone. When we looked at the two major histology’s usually found within these randomized trials, that being glioblastoma as well as anaplastic astrocytoma, there appeared to be a survival advantage for both sets of patients.

Although a significantly greater survival advantage for anaplastic astrocytomas. So from this meta-analysis what we have concluded is that chemotherapy followed by external beam radiation is advantageous in adults with malignant glioma, although the survival advantage with anaplastic astrocytomas appears to be significantly greater than those with glioblastoma.

It appears that the relatively late survival advantage that we see in patients with glioblastoma – that meaning that if you actually look at those curves we do not begin to see a survival advantage in patients with glioblastoma treated with chemotherapy – to approximately 12-16 months. Discount levitra professional at online Canada pharmacy. a A funny finding when you consider that most patients with glioblastomas die well before that time, suggests to us that treatment with chemotherapy in patients with glioblastoma preferentially benefits patients with more favorable prognostic factors. What are those prognostic factors in glioblastoma? It’s clear that patients who are younger, who have good performance status and who have minimal postoperative residual tumor are the patients who are destined to do better. Thus, if we are going to treat patients with chemotherapy for blastomas this is the group of patients that we would recommend. Where in fact increasingly so, I’ve become less and less enthusiastic about offering standard post-radiation chemotherapy to patients with glioblastoma anyway.

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.

When one looks at the issue of radiotherapy

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 that’s 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. On the other hand, for the grade II astrocytomas where surgery is less effective, or appears to be less effective by the data, one sees a significant benefit from radiation therapy. Thus, we generally do recommend external beam radiation therapy for patients with most low-grade astrocytomas. There again, the dose of radiation, whether one should radiate at the time of diagnosis or wait until time to progression and/or symptoms, remain unknown answers at this time.

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. Death from these tumors is both from local cerebral destruction and increased intracranial pressure. A type I tumor is a tumor where almost all the tumor cells are confined within one relatively localized area, and one can imagine that if the neurosurgeon has access to this lesion, if he can take this lesion out that would be pretty good therapy. In fact, this is how many or most metastatic brain tumors grow, and that is the reason that there is a significant benefit often for the surgical resection of metastatic lesions.

Unfortunately, most primary brain tumors such as astrocytomas and other gliomas do not grow like type I tumors, but rather they grow like type II or type III tumors. And that the essential area of high tumor density and tumor mass. At great distance away from that mass are these infiltrating tumor cells that reach deeply into the normal and functioning cerebrum, and that total surgical resection is never possible because these lesions get into critical areas of the brain. In fact, with astrocytomas, one can even see the most exaggerated form of this, the condition known as gliomatosis cerebri where there is no central mass whatsoever but rather almost the entire brain is just full of individual microscopic infiltrating tumor cells.

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.