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==The Importance of Brain Tumor Centers== | |||
== The Role of MGMT == | When someone is diagnosed with a brain tumor they are faced with a situation about | ||
which they know very little, but nevertheless must develop a treatment plan very quickly, | |||
because GBMs grow very rapidly if left untreated. The first step, if possible, is to have as | |||
much of the tumor removed as possible, because various data show substantially | |||
increased survival times for those with complete resections, relative to those who have | |||
incomplete resections or only biopsies. Accordingly, it is best that patients seek treatment | |||
at a major brain tumor center because neurosurgeons there will have performed many | |||
more tumor removals than general neurosurgeons that typically work in the community | |||
setting. This is especially important in recent times, as surgical techniques have become | |||
increasingly more sophisticated and utilize procedures that community treatment centers | |||
do not have the resources to perform. I know of numerous cases in which a local | |||
neurosurgeon has told the patient the tumor is inoperable, only to have the same tumor | |||
completely removed at a major brain tumor center. | |||
An additional advantage of utilizing a major brain tumor center is that they are better | |||
equipped to do genetic analyses of tumor tissue, which are increasingly important in | |||
guiding treatment decisions. Moreover, they provide a gateway into clinical trials. | |||
==The Standard of Care for Initial Treatment== | |||
===Glioblastoma=== | |||
Although chemotherapy has a long history of being ineffective as a treatment for | |||
glioblastoma, a large randomized European-Canadian clinical trial (EORTC trial | |||
26981/22981) has shown clear benefits of adding the new chemotherapy agent, | |||
temozolomide (trade name Temodar in the USA, Temodal elsewhere in the world) to the | |||
standard radiation treatment (2). This treatment, followed by 6 or more monthly cycles of | |||
temozolomide, has become known as the “Stupp protocol” after Roger Stupp, the Swiss | |||
oncologist who led the trial. In this trial, one group of patients received radiation alone; | |||
the other group received radiation plus Temodar, first at low daily dosages during the six | |||
weeks of radiation, followed by the standard schedule of higher-dose Temodar for days | |||
1-5 out of every 28-day cycle. Median survival was 14.6 months, compared to a median | |||
survival of 12 months for patients receiving radiation only, a difference that was | |||
statistically significant. More impressive was the difference in two-year survival rate, | |||
which was 27% for the patients receiving temodar but 10% for those receiving only | |||
radiation. Longer-term follow-up has indicated that the benefit of temozolomide (TMZ) | |||
persists at least up to five years: The difference in survival rates between the two | |||
treatment conditions was 16.4% vs. 4.4% after three years, 12.1% vs. 3.0% after four years, | |||
and 9.8% vs. 1.9% after five years (3). As a result of these findings, the protocol of TMZ | |||
presented during radiation is now recognized as the "gold standard" of treatment. Note, | |||
however, that all of these numbers are somewhat inflated because patients over the age of | |||
70 were excluded from the trial. | |||
In July of 2016, the National Comprehensive Cancer Network (NCCN) recommended | |||
Optune as a category 2A treatment for newly diagnosed glioblastoma in combination with | |||
the standard temozolomide-based chemotherapy (see press release here). This rating | |||
indicates a uniform consensus by the NCCN that this treatment is appropriate. As the | |||
NCCN is recognized as setting the standards for cancer treatment in the USA and in other | |||
countries abroad which follow its guidelines, Optune in combination with standard | |||
chemotherapy following radiation could now be considered to be a new standard of care | |||
for newly diagnosed glioblastoma. See more detailed information on Optune in Chapter | |||
3. | |||
===Anaplastic astrocytoma=== | |||
Though the “Stupp protocol” of combined temoradiation (concomitant radiation and | |||
temozolomide chemotherapy) followed by monthly cycles of temozolomide has been | |||
routinely applied to anaplastic astrocytoma patients, prospective confirmation of this use | |||
in this patient population has awaited results of the “CATNON” randomized phase 3 trial | |||
for 1p/19q non-codeleted grade 3 gliomas. Results of the interim analysis for this trial | |||
were first released for the ASCO 2016 annual meeting. Between 2007 and 2015, 748 | |||
patients were randomized to receive either i) radiation alone, ii) radiation with | |||
concomitant temozolomide, iii) radiation followed by 12 adjuvant monthly cycles of | |||
temozolomide, or iv) radiation with temozolomide both concurrently and with follow-up | |||
monthly cycles. At the time of the interim analysis (October 2015), significant | |||
progression-free and overall survival benefit was found with adjuvant temozolomide | |||
treatment (arms iii and iv). Median progression-free survival was 19 months in arms i | |||
and ii (not receiving adjuvant temozolomide) versus 42.8 months (receiving adjuvant | |||
temozolomide). 5-year survival rate was 44.1% and 55.9% in arms i and ii versus iii and | |||
iv. Median survival was not yet reached for arms iii and iv. | |||
This analysis did not address the benefit of temozolomide concurrent with radiation, a | |||
question that will be answered with further follow-up, and studies assessing the impact of | |||
IDH1 mutation and MGMT methylation were still ongoing. | |||
===Determining who will benefit=== | |||
A two-year survival rate of less than 30% obviously cannot be considered an effective | |||
treatment, as the great majority of patients receiving the treatment obtain at best a minor | |||
benefit, accompanied with significant side effects (although Temodar is much better | |||
tolerated than previous chemotherapy treatments, especially with respect to the | |||
cumulative toxicity to the bone marrow). This raises the issues of how to determine who | |||
will benefit from the treatment, and, most importantly, how to improve the treatment | |||
outcomes. | |||
One approach to determining whether an individual patient will benefit from | |||
chemotherapy is simply to try 1-2 rounds to see if there is any tumor regression. The | |||
debilitating effects of chemotherapy typically occur in later rounds, at which point there | |||
is a cumulative decline in blood counts. The extreme nausea and vomiting associated | |||
with chemotherapy in the mind of the lay public is now almost completely preventable by | |||
anti-nausea agents, including Zofran (ondansetron), Kytril (granisetron) and Emend. | |||
(aprepitant). Marijuana also can be very effective in controlling such effects, and recent | |||
research has suggested that it has anti-cancer properties in its own right. Thus, for those | |||
patients who are relatively robust after surgery and radiation, some amount of | |||
chemotherapy experimentation should be possible without major difficulties. | |||
An alternative way to ascertain the value of chemotherapy for an individual patient is the | |||
use of chemosensitivity testing for the various drugs that are possible treatments. Such | |||
testing typically requires a live sample of the tumor and thus must be planned in advance | |||
of surgery. Culturing the live cells is often problematic, but a number of private | |||
companies across the country offer this service. Costs range from $1000-$2500, | |||
depending on the scope of drugs that are tested. Such testing is controversial, in part | |||
because the cell population evolves during the process of culturing, which results in cells | |||
possibly different in important ways from the original tumor sample. Nevertheless, | |||
recent evidence has shown that chemosensitivity testing can enhance treatment | |||
effectiveness for a variety of different types of cancer, including a recent Japanese study | |||
using chemosensitivity testing with glioblastoma patients (4). However, this study did not | |||
involve cell culturing but direct tests of chemosensitivity for cells harvested at the time of | |||
surgery. In general, when chemosensitivity testing indicates an agent has no effect on a | |||
patient's tumor the drug is unlikely to have any clinical benefit. On the other hand, tests | |||
indicating that a tumor culture is sensitive to a particular agent do not guarantee clinical | |||
effectiveness, but increase the likelihood that the agent will be beneficial. | |||
=== The Role of MGMT === | |||
A significant advance in determining which patients will benefit from Temodar was | A significant advance in determining which patients will benefit from Temodar was | ||
reported by the same research group that reported the definitive trial combining Temodar | reported by the same research group that reported the definitive trial combining Temodar | ||
Line 155: | Line 271: | ||
includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). | includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). | ||
[[ MGMT| full text ]] | [[ MGMT| full text ]] | ||
===Dexamethasone=== | |||
Most glioma patients will be exposed to dexamethasone (Decadron) at some point, as this | |||
corticosteroid is the first-line treatment to control cerebral edema caused by the leaky | |||
tumor blood vessels. Many also require dexamethasone during radiotherapy, and | |||
perhaps beyond this time if substantial tumor remains post-resection. Dexamethasone is | |||
an analog to the body’s own cortisol, but is about 25 times more potent. Though often | |||
necessary, dexamethasone comes with a long list of adverse potential side effects with | |||
prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, | |||
immunosuppression, weight gain, and psychological effects. | |||
New evidence also shows an association between dexamethasone use and reduced | |||
survival time in glioblastoma. This evidence has to be weighed against the fact that | |||
uncontrolled cerebral edema can be fatal in itself, and that dexamethasone is often | |||
required for its control. However, the attempt should always be made to use | |||
dexamethasone at the lowest effective dose, and to taper its use after control of edema is | |||
achieved, under a physician’s guidance. | |||
In a retrospective study of 622 glioblastoma patients treated at Memorial Sloan Kettering | |||
Cancer Center, multivariate regression analysis showed an independent negative | |||
association of steroid use at the start of radiotherapy with survival (324). A similar | |||
negative association with survival outcomes was found in patients in the pivotal phase 3 | |||
trial that led to temozolomide being approved for glioblastoma in 2005, and for a cohort | |||
of 832 glioblastoma patients enrolled in the German Glioma Network. | |||
Follow up studies in mice helped elucidate these retrospective clinical observations. In a | |||
genetically engineered PDGFB-driven glioblastoma mouse model, dexamethasone alone | |||
had no effect on survival, but pretreatment with dexamethasone for 3 days prior to a | |||
single dose of 10 Gy radiation negatively impacted the efficacy of radiation. This negative | |||
impact of dexamethasone on radiation efficacy was even more dramatic with multiple | |||
doses of dexamethasone given before 5 treatments with 2 Gy radiation, which more | |||
closely mimics what GBM patients are exposed to. In contrast, an antibody against | |||
VEGF, which could be considered a murine surrogate for Avastin, did not interfere with | |||
the efficacy of radiation. | |||
In vivo mechanistic examination revealed that dexamethasone may interfere with | |||
radiation by slowing proliferation, leading to a higher number of cells in the more | |||
radioresistant G1 phase of the cell cycle, and fewer cells in the more radiosensitive G2/M | |||
�phase. This finding has far-reaching implications about the potential interference by | |||
drugs with cytostatic mechanisms of action on the efficacy of radiation therapy. | |||
The authors conclude by suggesting that antibodies against VEGF, most notably | |||
bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation | |||
in place of steroids. However, this use has to be weighed in importance against the | |||
exclusion from certain promising clinical trials due to prior use of Avastin being an | |||
exclusion criteria in some of these trials. | |||
== Treatment Categories == | == Treatment Categories == |
Revision as of 01:48, 29 March 2024
Welcome
Since my own diagnosis of glioblastoma (GBM) in 1995 at age 50, I have spent considerable time researching treatment options, and the following discussion summarizes what I have learned. Most of the information is from medical journals and the proceedings of major cancer conferences. Some information has been contributed by others to various online brain tumor patient support groups, which I have followed up on, and some is from direct communications with various physicians conducting the treatments that are described. References are presented at the end for those who would like their physicians to take this information seriously. Although this discussion is intended to be primarily descriptive of the recent development of new treatment options, it is motivated by my belief that single-agent treatment protocols are unlikely to be successful, and patients are best served if they utilize multiple treatment modalities, and go beyond the “certified” treatments that too often are the only treatment options offered.
The Importance of Brain Tumor Centers
When someone is diagnosed with a brain tumor they are faced with a situation about which they know very little, but nevertheless must develop a treatment plan very quickly, because GBMs grow very rapidly if left untreated. The first step, if possible, is to have as much of the tumor removed as possible, because various data show substantially increased survival times for those with complete resections, relative to those who have incomplete resections or only biopsies. Accordingly, it is best that patients seek treatment at a major brain tumor center because neurosurgeons there will have performed many more tumor removals than general neurosurgeons that typically work in the community setting. This is especially important in recent times, as surgical techniques have become increasingly more sophisticated and utilize procedures that community treatment centers do not have the resources to perform. I know of numerous cases in which a local neurosurgeon has told the patient the tumor is inoperable, only to have the same tumor completely removed at a major brain tumor center.
An additional advantage of utilizing a major brain tumor center is that they are better equipped to do genetic analyses of tumor tissue, which are increasingly important in guiding treatment decisions. Moreover, they provide a gateway into clinical trials.
The Standard of Care for Initial Treatment
Glioblastoma
Although chemotherapy has a long history of being ineffective as a treatment for glioblastoma, a large randomized European-Canadian clinical trial (EORTC trial 26981/22981) has shown clear benefits of adding the new chemotherapy agent, temozolomide (trade name Temodar in the USA, Temodal elsewhere in the world) to the standard radiation treatment (2). This treatment, followed by 6 or more monthly cycles of temozolomide, has become known as the “Stupp protocol” after Roger Stupp, the Swiss oncologist who led the trial. In this trial, one group of patients received radiation alone; the other group received radiation plus Temodar, first at low daily dosages during the six weeks of radiation, followed by the standard schedule of higher-dose Temodar for days 1-5 out of every 28-day cycle. Median survival was 14.6 months, compared to a median survival of 12 months for patients receiving radiation only, a difference that was statistically significant. More impressive was the difference in two-year survival rate, which was 27% for the patients receiving temodar but 10% for those receiving only radiation. Longer-term follow-up has indicated that the benefit of temozolomide (TMZ) persists at least up to five years: The difference in survival rates between the two treatment conditions was 16.4% vs. 4.4% after three years, 12.1% vs. 3.0% after four years, and 9.8% vs. 1.9% after five years (3). As a result of these findings, the protocol of TMZ presented during radiation is now recognized as the "gold standard" of treatment. Note, however, that all of these numbers are somewhat inflated because patients over the age of 70 were excluded from the trial.
In July of 2016, the National Comprehensive Cancer Network (NCCN) recommended Optune as a category 2A treatment for newly diagnosed glioblastoma in combination with the standard temozolomide-based chemotherapy (see press release here). This rating indicates a uniform consensus by the NCCN that this treatment is appropriate. As the NCCN is recognized as setting the standards for cancer treatment in the USA and in other countries abroad which follow its guidelines, Optune in combination with standard chemotherapy following radiation could now be considered to be a new standard of care for newly diagnosed glioblastoma. See more detailed information on Optune in Chapter 3.
Anaplastic astrocytoma
Though the “Stupp protocol” of combined temoradiation (concomitant radiation and temozolomide chemotherapy) followed by monthly cycles of temozolomide has been routinely applied to anaplastic astrocytoma patients, prospective confirmation of this use in this patient population has awaited results of the “CATNON” randomized phase 3 trial for 1p/19q non-codeleted grade 3 gliomas. Results of the interim analysis for this trial were first released for the ASCO 2016 annual meeting. Between 2007 and 2015, 748 patients were randomized to receive either i) radiation alone, ii) radiation with concomitant temozolomide, iii) radiation followed by 12 adjuvant monthly cycles of temozolomide, or iv) radiation with temozolomide both concurrently and with follow-up monthly cycles. At the time of the interim analysis (October 2015), significant progression-free and overall survival benefit was found with adjuvant temozolomide treatment (arms iii and iv). Median progression-free survival was 19 months in arms i and ii (not receiving adjuvant temozolomide) versus 42.8 months (receiving adjuvant temozolomide). 5-year survival rate was 44.1% and 55.9% in arms i and ii versus iii and iv. Median survival was not yet reached for arms iii and iv.
This analysis did not address the benefit of temozolomide concurrent with radiation, a question that will be answered with further follow-up, and studies assessing the impact of IDH1 mutation and MGMT methylation were still ongoing.
Determining who will benefit
A two-year survival rate of less than 30% obviously cannot be considered an effective treatment, as the great majority of patients receiving the treatment obtain at best a minor benefit, accompanied with significant side effects (although Temodar is much better tolerated than previous chemotherapy treatments, especially with respect to the cumulative toxicity to the bone marrow). This raises the issues of how to determine who will benefit from the treatment, and, most importantly, how to improve the treatment outcomes.
One approach to determining whether an individual patient will benefit from chemotherapy is simply to try 1-2 rounds to see if there is any tumor regression. The debilitating effects of chemotherapy typically occur in later rounds, at which point there is a cumulative decline in blood counts. The extreme nausea and vomiting associated with chemotherapy in the mind of the lay public is now almost completely preventable by anti-nausea agents, including Zofran (ondansetron), Kytril (granisetron) and Emend. (aprepitant). Marijuana also can be very effective in controlling such effects, and recent research has suggested that it has anti-cancer properties in its own right. Thus, for those patients who are relatively robust after surgery and radiation, some amount of chemotherapy experimentation should be possible without major difficulties.
An alternative way to ascertain the value of chemotherapy for an individual patient is the use of chemosensitivity testing for the various drugs that are possible treatments. Such testing typically requires a live sample of the tumor and thus must be planned in advance of surgery. Culturing the live cells is often problematic, but a number of private companies across the country offer this service. Costs range from $1000-$2500, depending on the scope of drugs that are tested. Such testing is controversial, in part because the cell population evolves during the process of culturing, which results in cells possibly different in important ways from the original tumor sample. Nevertheless, recent evidence has shown that chemosensitivity testing can enhance treatment effectiveness for a variety of different types of cancer, including a recent Japanese study using chemosensitivity testing with glioblastoma patients (4). However, this study did not involve cell culturing but direct tests of chemosensitivity for cells harvested at the time of surgery. In general, when chemosensitivity testing indicates an agent has no effect on a patient's tumor the drug is unlikely to have any clinical benefit. On the other hand, tests indicating that a tumor culture is sensitive to a particular agent do not guarantee clinical effectiveness, but increase the likelihood that the agent will be beneficial.
The Role of MGMT
A significant advance in determining which patients will benefit from Temodar was reported by the same research group that reported the definitive trial combining Temodar with radiation. Tumor specimens from the patients in that trial were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). full text
Dexamethasone
Most glioma patients will be exposed to dexamethasone (Decadron) at some point, as this corticosteroid is the first-line treatment to control cerebral edema caused by the leaky tumor blood vessels. Many also require dexamethasone during radiotherapy, and perhaps beyond this time if substantial tumor remains post-resection. Dexamethasone is an analog to the body’s own cortisol, but is about 25 times more potent. Though often necessary, dexamethasone comes with a long list of adverse potential side effects with prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, immunosuppression, weight gain, and psychological effects.
New evidence also shows an association between dexamethasone use and reduced survival time in glioblastoma. This evidence has to be weighed against the fact that uncontrolled cerebral edema can be fatal in itself, and that dexamethasone is often required for its control. However, the attempt should always be made to use dexamethasone at the lowest effective dose, and to taper its use after control of edema is achieved, under a physician’s guidance.
In a retrospective study of 622 glioblastoma patients treated at Memorial Sloan Kettering Cancer Center, multivariate regression analysis showed an independent negative association of steroid use at the start of radiotherapy with survival (324). A similar negative association with survival outcomes was found in patients in the pivotal phase 3 trial that led to temozolomide being approved for glioblastoma in 2005, and for a cohort of 832 glioblastoma patients enrolled in the German Glioma Network.
Follow up studies in mice helped elucidate these retrospective clinical observations. In a genetically engineered PDGFB-driven glioblastoma mouse model, dexamethasone alone had no effect on survival, but pretreatment with dexamethasone for 3 days prior to a single dose of 10 Gy radiation negatively impacted the efficacy of radiation. This negative impact of dexamethasone on radiation efficacy was even more dramatic with multiple doses of dexamethasone given before 5 treatments with 2 Gy radiation, which more closely mimics what GBM patients are exposed to. In contrast, an antibody against VEGF, which could be considered a murine surrogate for Avastin, did not interfere with the efficacy of radiation.
In vivo mechanistic examination revealed that dexamethasone may interfere with radiation by slowing proliferation, leading to a higher number of cells in the more radioresistant G1 phase of the cell cycle, and fewer cells in the more radiosensitive G2/M �phase. This finding has far-reaching implications about the potential interference by drugs with cytostatic mechanisms of action on the efficacy of radiation therapy.
The authors conclude by suggesting that antibodies against VEGF, most notably bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation in place of steroids. However, this use has to be weighed in importance against the exclusion from certain promising clinical trials due to prior use of Avastin being an exclusion criteria in some of these trials.
Treatment Categories
Explore the various treatment categories for comprehensive insights and latest developments:
- Repurposed Drugs
- Hormones
- Nutraceuticals
- Antibody-Drug Conjugates and other protein-drug conjugates
- Other Chemotherapy and Cancer Drugs
...
Explore Treatments by Usefulness Rating
Discover treatments that have shown promising results.
Visit our Highly Useful Treatments page to explore treatments rated with a usefulness of 4 or 5.
Hormones
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Repurposed Drugs
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Nutraceuticals and Herbals
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Antibody-Drug Conjugates and other protein-drug conjugates
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Has treatment name | Usefulness Rating | toxicity_level | |
---|---|---|---|
ABT-414 | ABT-414 | 2 | 4 |
MDNA55 | MDNA55 | 3 | 2.5 |
Other Chemotherapy and Cancer Drugs
Explore additional chemotherapy and cancer drug treatments: