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.

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.

Histopathologic examination of basal cell epitheliomas

Histopathologic examination of basal cell epitheliomas reveals collections of cells with dark-staining nuclei and scant cytoplasm. The periphery of the cell masses shows cells in a palisade arrangement resembling the basal layer of the epidermis. Treatment of basal cell epitheliomas consists of complete surgical excision, destruction by curettage and electrodesiccation, or radiation therapy. Cryosurgery has been employed for selected lesions, especially superficial basal cell carcinomas. A margin of seemingly normal tissue should be removed around the tumor to prevent recurrence arising from invasion by strands of tumor cells. The clean margins must be monitored by histopathologic examination.

Recurrent basal cell carcinomas are usually difficult to cure, but Mohs’ microscopic controlled surgery, when it is performed by a specially trained physician, is effective in eradicating the entire tumor. Routine in vivo chemosurgical fixation of the tumor with zinc
chloride paste is no longer required. In the current procedure, fresh tissue is removed after local anesthesia, and frozen sections are examined microscopically. This more efficient method spares a larger amount of normal skin and reduces the discomfort associated with chemical fixation. The tumor is removed layer by layer, and all margins are carefully examined until a tumor-free plane is achieved.

Indications for microscopic controlled excision of skin cancer include recurrent basal cell epitheliomas and squamous cell carcinomas; tumors with indistinct margins, such as sclerosing basal cell epitheliomas; and lesions in such areas as the inner and outer canthus of the eye and the tip of the nose, where maximal preservation of normal skin is desirable. For certain complicated or advanced tumors, the fixed-tissue approach is considered more reliable than the fresh-tissue technique.

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