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<div class="mw-collapsible mw-collapsed">
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.
<div class="mw-collapsible-content">
 
Amore extensive account of my philosophy of treatment, and the reasons for it, are
provided in my (2002) book, Surviving "Terminal" Cancer: Clinical Trials, Drug
Cocktails, and Other Treatments Your Doctor Won't Tell You About.
Currently, it is available only at Amazon.com, where reviews of the book also are
available.
 
When I began my search for effective treatments, the available options offered little
chance for surviving my diagnosis. The standard treatment included surgery, radiation,
and nitrosourea-based chemotherapy, either BCNU alone or CCNU combined with
procarbazine and vincristine (known as the PCV combination). While this treatment has
helped a small minority of people, its 5-year survival rate has been only 2-5%. Median
survival has been about a year, which is 2-3 months longer than for patients receiving
radiation alone without chemotherapy. Fortunately, as will be discussed in the next
section, the past ten years has produced a new “gold standard” of treatment for newly
diagnosed patients: the combination of radiation with a new chemotherapy agent,
temozolomide (trade name Temodar in the USA and Temodal elsewhere in the world).
While this new standard appears to produce a notable improvement over previous
treatments, it still falls far short of being effective for the great majority of patients.
 
Also available now are three other treatments that have FDA approval for tumors that
have recurred or have progressed after initial treatment: Gliadel, Avastin, and an
electrical field therapy named Optune (formerly known as NovoTTF). All of these are
considered standard of care for recurrent tumors (which is important for insurance
reasons), and can legally also be used for newly diagnosed patients as well. Each will be
discussed later in this article.
There are three general premises to the approach to treatment that will be described. The
first is borrowed from the treatment approach that has evolved in the treatment of AIDS.
Both viruses and cancer cells have unstable genetic structures susceptible to mutations.
This implies that the dynamics of evolution will create new forms that are resistant to
whatever the treatment may be. However, if several different treatments are used
simultaneously (instead of sequentially, which is typically the case), any given mutation
has a smaller chance of being successful. A mathematical model instantiating these
assumptions has recently been developed and has been shown to describe the pattern of
tumor growth for melanoma (1).
 
The second premise is that cancer treatments of all sorts are probabilistic in their effects.
None work for everyone, in part because any given cancer diagnosis is an amalgam of
different genetic defects that respond in different ways to any given treatment agent. This
is especially true for glioblastomas, which have a multiplicity of genetic aberrations that
vary widely across individuals and sometimes even within the same tumor of a given
individual. As a result it is common that any given "effective" treatment agent will
 
benefit only a minority of patients, often in the range of 10-35%, but do little if anything
for the majority. The result is that the chances of finding an effective treatment increase
the more different treatment agents that are utilized. Probabilistic effects can and do
summate.
 
An important implication of the genetic diversity of GBM tumors is that tests of
treatment agents presented individually will often fail, not because they lack
effectiveness, but because they target only one or sometimes two growth pathways,
leaving other growth pathways to be upregulated to maintain the growth of the tumor.
Thus, even at the level of clinical trials, tests of individual treatment agents in isolation
may be a misguided strategy. A drug that fails in isolation might in fact be effective when
combined with other drugs that target the additional alternative growth pathways.
 
A third general principle is that any successful treatment needs to be systemic in nature
because it is impossible to identify all of the extensions of the tumor into normal tissue.
Moreover, cancer cells are typically evident in locations in the brain distant from the
main tumor, indicating that metastases within the brain can occur, although the great
majority of tumor recurrences are within or proximal to the original tumor site. Localized
treatments such as radiosurgery may be beneficial in terms of buying time, but they are
unlikely to provide a cure, except in cases when the tumor is detected early and is very
small. Even if the localized treatment eradicates 99% of the tumor, the small amount of
residual tumor will expand geometrically, eventually causing significant clinical
problems.
 
Until the development of immunological treatments in just the last few years, which will
be discussed in a later section, the only systemic treatment available has been cytotoxic
chemotherapy, which historically has been ineffective except for a small percentage of
patients. An important issue, therefore, is whether chemotherapy can be made to work
substantially better than it typically does. Agents that facilitate or augment its effects are
critically important. As will be seen, a number of older drugs developed for other
purposes have been shown in laboratory studies to be effective against cancer, often with
minimal toxicity. The availability of these treatments raises the possibility that some
combination of these new agents can be packaged that provide effective treatment based
on several different independent principles. Thus, the AIDS-type of combination
approach is now a genuine possibility whereas it would not have been fifteen years ago.
Because many of these relatively nontoxic new agents were developed for purposes other
than cancer, or for different kinds of cancer, their utilization in the treatment of
glioblastomas is "off-label", with the result that many oncologists have been hesitant to
prescribe them. Thus, patients themselves need to become familiar with these new agents
and the evidence available regarding their clinical effectiveness. It is possible, although
by no means proven, that some combination of these newly repurposed agents offers the
best possibility for survival.
 
Patients may or may not learn about the treatments that will be described from their
physicians. To appreciate why, it is important to understand how American medicine has
been institutionalized. For most medical problems there is an accepted standard of what
is the best available treatment. Ideally, such treatments are based on phase III clinical
trials in which patients are randomly assigned to receive the new treatment or some type
of control condition. Treatments that have been studied only in nonrandomized phase II
trials will rarely be offered as a treatment option, even if the accepted "best available
treatment" is generally ineffective. What happens instead is that patients are encouraged
to participate in clinical trials. The problem with this approach is that most medical
centers offer few options for an individual patient. Thus, even though a given trial for a
new treatment may seem very promising, patients can participate only if that trial is
offered by their medical facility. Yet more problematic is that clinical trials with new
treatment agents almost always initially study that agent in isolation, usually with
patients with recurrent tumors who have the worst prognoses. For newly diagnosed
patients this is at best a last resort. What is needed instead is access to the most
promising new treatments, in the optimum combinations, at the time of initial diagnosis.
 
In the discussion to follow, it is important to distinguish between treatment options at the
time of initial diagnosis versus those when the tumor either did not respond to the initial
treatment or responded for a period of time and then recurred. Different measures of
treatment efficacy are often used for the two situations, which sometimes makes
treatment information obtained in one setting difficult to apply to the other. The
recurrent tumor situation is also complicated by the fact that resistance to the initial
treatment may or may not generalize to new treatments given at recurrence.
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.
</div>
</div>
 
==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 1 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.
 
Research summarized here: https://virtualtrials.org/optune/NVCR_Clinical_Evidence_Flipbook_9.5.23.pdf
 
=== Cancer Stem Cells (CSCs) in Glioblastoma: Challenges with Standard of Care (SOC) ===
 
==== What Are Cancer Stem Cells? ====
Cancer stem cells (CSCs) are a small subpopulation of cells within tumors that possess capabilities similar to those of normal stem cells, such as self-renewal and differentiation. In the context of glioblastoma, these cells are often referred to as glioma stem cells (GSCs). They are believed to be crucial drivers of tumor growth, resistance to treatment, and recurrence.
 
==== Standard of Care for Glioblastoma ====
The current standard of care for glioblastoma typically includes surgical resection followed by radiation therapy and chemotherapy with temozolomide. While these treatments can initially reduce tumor size and manage symptoms, they do not effectively target GSCs, which can survive treatments and cause tumor recurrence.
 
==== Why Does SOC Fail to Prevent Recurrence? ====
* '''Resistance to Treatment:''' GSCs are highly resistant to chemotherapy and radiation. They have efficient DNA repair mechanisms and can remain dormant during treatment, evading the effects of SOC that target rapidly dividing cells.
* '''Microenvironment Protection:''' GSCs reside in protective niches within the tumor microenvironment that shield them from the effects of SOC. These niches provide support and maintain the stem-like qualities of GSCs, promoting their ability to regenerate the tumor.
* '''Tumor Regeneration:''' After treatment, surviving GSCs can regenerate the tumor, often leading to a recurrence that is more aggressive and resistant to further treatment. This cycle is a significant challenge in the management of glioblastoma.
 
==== Research and Future Directions ====
Understanding the biology of GSCs has led to the exploration of targeted therapies aimed at these cells. Strategies include developing drugs that specifically target the molecular pathways essential for GSC survival and proliferation, disrupting the tumor microenvironment, and using immunotherapy to enhance the body's natural defenses against these cells.
 
==== Conclusion ====
The recurrence of glioblastoma post-SOC is largely due to the presence and behavior of GSCs. Efforts to improve glioblastoma treatment outcomes must focus on effectively targeting these cells. Ongoing research into the molecular and environmental underpinnings of GSCs holds promise for developing more effective therapies that can prevent recurrence and extend patient survival.
 
<div style="background-color: #ffffcc; padding: 10px; margin-top: 10px; border-left: 6px solid #ffeb3b;">
'''Note:''' While alternatives to SOC are not proven to always work, exploring such options is crucial because without trying different approaches, recurrence is almost guaranteed.
</div>
 
 
==== Alternative Therapies Targeting GSCs ====
Various alternative therapies have been explored for their potential to target glioma stem cells (GSCs) in glioblastoma. These are considered experimental and have been primarily studied in preclinical trials or ongoing research settings:
 
* '''[[Curcumin]]''': This compound, derived from turmeric, has anti-inflammatory properties and has been studied for its potential to disrupt pathways involved in cancer stem cell growth and survival.
 
* '''[[Resveratrol]]''': Found in grapes and berries, resveratrol has been researched for its ability to inhibit the growth of cancer stem cells and induce apoptosis in various cancer cell models, including glioblastoma.
 
* '''[[Sulforaphane]]''': A compound in cruciferous vegetables like broccoli, sulforaphane targets cellular processes that are critical for cancer cell growth and survival, impacting cancer stem cells.
 
* '''[[CBD]]''': Research suggests that CBD may affect glioblastoma by targeting the stem-like properties of GSCs, potentially reducing their ability to contribute to tumor growth.
 
* '''[[Metformin]]''': While primarily used for diabetes management, metformin has shown potential in preclinical studies for its anti-cancer effects and ability to target cancer stem cells in glioblastoma.
 
* '''[[Disulfiram]]''': Traditionally used for treating alcohol dependency, disulfiram has been studied for its capacity to target cancer stem cells in glioblastoma, particularly when used in combination with copper.
 
* '''[[Parthenolide]]''': This compound, from the herb feverfew, is being researched for its ability to induce oxidative stress and apoptosis in glioblastoma stem cells.
 
* '''Repositioned Drugs''': Drugs approved for other conditions, such as antidepressants or antipsychotics, have been explored for their ability to interfere with signaling pathways critical for the maintenance of cancer stem cells and tumor resistance.
 
These therapies are still under investigation for their effectiveness and safety in treating glioblastoma and are generally considered for clinical trial settings. Patients should consult with healthcare professionals and consider clinical trials where these treatments are being tested.
 
===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).  
[[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.
 
 
=== Radiation ===
 
====The Role of Radiation====
 
For many years the only treatment (other than surgery) offered to patients with
glioblastomas was radiation, due to radiation being the only treatment found to improve
survival time in randomized clinical trials. This continued to be the case in Europe until
the last decade, but in this country chemotherapy (usually BCNU) gradually came to be
accepted as a useful additional treatment component despite the absence of definitive
evidence from clinical trials. Part of the reason for this acceptance of chemotherapy has
been that very few patients receiving only radiation survive longer than two years (3-
10%), compared to 15-25% of patients also receiving chemotherapy.
 
The initial approach to using radiation to treat gliomas was whole-head radiation, but this
was abandoned because of the substantial neurological deficits that resulted, sometimes
appearing a considerable time after treatment. Current clinical practice uses a more
focused radiation field that includes only 2-3 cm beyond the periphery of the tumor site.
Because of the potential for radiation necrosis, the current level of radiation that is
considered safe is limited to 55-60 Gy. Even at this level, significant deficits may occur,
often appearing several years after treatment. The most common causes of these deficits
are damage to the myelin of the large white fibers, which are the main transmitters of
information between different centers of the brain, and damage to the small blood
vessels, which results in an inadequate blood supply to the brain and also increases the
likelihood of strokes. An additional risk, not yet proven clinically because of the typical
short survival times of glioblastoma patients, is the growth of secondary tumors due to
the radiation damage to the DNA. However, experimental work with animal models has
supported the reality of this risk (208). Three-year-old normal rhesus monkeys were
�given whole brain radiation using a protocol similar to the common human radiation
protocol and then followed for 2-9 years thereafter. A startling 82% of the monkeys
developed glioblastoma tumors during that follow-up period. It is currently unclear to
what degree a similar risk occurs for human patients who are long-term survivors.
 
The major additional use of radiation in the treatment of gliomas has been localized
radiation to the tumor field, after the external-beam radiation treatment is finished (or
sometimes concurrently), either by use of implanted radiation seeds (typically radioactive
iodine), a procedure known as brachytherapy, the use of radiosurgery (including gamma
knife), or by the insertion into the tumor cavity of an inflatable balloon containing
radioactive fluid (gliasite). Previous editions of this treatment summary devoted
considerable discussion to these treatments. However, these treatments now are used
much less frequently. Two different randomized trials of brachytherapy failed to show a
statistically significant survival benefit even though the procedure causes considerable
toxicity in terms of radiation necrosis (209). A recent randomized study of radiosurgery
(210) similarly failed to show a benefit. Gliasite has yet to be studied in a randomized
trial.
 
The usual interpretation of the failure to find a benefit in the randomized trials is that the
initial studies indicating a survival benefit (usually increasing survival time about a year)
involved a highly selected patient population, who otherwise had a good prognosis
regardless of whether they received the procedure. However, selection bias seems not to
account for all of the benefits of the procedure. For example, the use of gliasite for
recurrent GBM tumors produced a median survival time of 36 weeks (211), which
compares favorably with a median survival time of only 28 weeks when gliadel wafers
were implanted for recurrent tumors, even though eligibility criteria were similar for the
two procedures. Moreover, when patients receiving gliasite as part of the initial
treatment (212) were partitioned according to according to established prognostic
variables, and each partition was compared to its appropriate historical control, survival
time was greater for patients receiving gliasite in each of the separate partitions.
 
Perhaps the best results reported involving radiation boosts comes from the combination
of permanent radioactive iodine seeds with gliadel (212). Median survival for patients
with recurrent glioblastomas was 69 weeks, although accompanied by considerable brain
necrosis. The use of gliadel alone in the same treatment center, by comparison, produced
a median survival time of 28 weeks, while the use of the radiation seeds alone produced a
median survival of 47 weeks.
 
Impressive results have also been obtained with the addition of fractionated radiosurgery
to the standard Stupp protocol for newly diagnosed patients (213). For 36 GBM patients
median survival (from diagnosis) was 28 months and two-year survival was 57%. Median
progression-free survival (from study entry) for the GBM patients was 10 months.
�The foregoing results suggest that supplementary radiation procedures do provide some
benefit, but it is important to appreciate that all only a portion of patients will be eligible
for such treatment. Radiation necrosis caused by the treatment must be considered as
well.
 
====Hyberbaric oxygen and other radiosensitizers====
 
A potentially important modification of the standard radiation protocols involves the use
of hyperbaric oxygen prior to each radiation session. In a study conducted in Japan (214),
57 high-grade glioma patients received the standard radiation protocol with the addition
of hyperbaric oxygen 15 minutes prior to each radiation session. Four rounds of
chemotherapy were also administered, the first during the radiation period of treatment.
For the 39 glioblastoma patients, the median survival time was 17 months, with a very
high rate of tumor regression. For the 18 patients with anaplastic astrocytoma, median
survival was 113 months. Two-year survival was reported separately for recursive
partioning categories I-IV and V-VI, the latter including only glioblastoma patients. For
categories I- IV, two-year survival was 50%; for categories V and VI, two-year survival
was 38%.
A long-standing goal of radiation oncology has been to find a radiation sensitizer that
does not increase toxicity to normal tissue. One of the most promising advances toward
this goal was reported at the 2011 ASCO meeting (215). A new drug derived from the
taxane family, with the name OPAXIO, was combined with the standard Temodar +
radiation protocol during the radiation phase of the treatment. The response rate for 25
patients (17 GBM) was 45% with 27% having a complete response. With a median
follow-up of 22 months, median progression-free survival was 14.9 month (13.5 months
for GBM patients). Median overall survival had not been reached at the time of the
report. Note that the median PFS for the standard treatment without OPAXIO is 6.9
months.
 
====Proton radiation therapy====
{{#ask: [[Has treatment name::Proton Beam Therapy (PBT)]]
|?Has common side effects=Common Side Effects
|?Has OS without=Overall Survival without PBT
|?Has OS with=Overall Survival with PBT
|?Has PFS without=Progression-Free Survival without PBT
|?Has PFS with=Progression-Free Survival with PBT
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|?Has Toxicity Explanation=Toxicity Explanation
|format=table
|limit=1
}}
 
An alternative to the standard X-ray radiation is the use of proton beams, although only a
few treatment centers have the required equipment. To date, there has been no
meaningful comparison of the efficacy of proton-beam radiation and the normal
procedure. However, one recent study in Japan did report unusually positive results
when the two forms of radiation were combined, the standard procedure in the morning,
and the proton-beam radiation in the afternoon (216). Also used was ACNU, a chemical
cousin of BCNU and CCNU. Median survival for 20 patients was 21.6 month, with -1-
year and 2-year progression-free rates of 45% and 16%. However, there were six cases of
radiation necrosis that required surgery, indicating a considerably higher toxicity than
normally occurs with the standard radiation procedure.
 
====Gamma Knife Radiosurgery (GKRS) for GBM====
{{#ask: [[Has treatment name::Gamma Knife Radiosurgery (GKRS) for GBM]]
|?Has common side effects=Common Side Effects
|?Has OS without=Overall Survival without GKRS
|?Has OS with=Overall Survival with GKRS
|?Has PFS without=Progression-Free Survival without GKRS
|?Has PFS with=Progression-Free Survival with GKRS
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|?Has Toxicity Explanation=Toxicity Explanation
|format=table
|limit=1
}}
 
 
The Gamma Knife radiosurgery (GKRS) for glioblastoma (GBM) showcases a potential treatment path with a lower toxicity profile, according to recent studies. This method, particularly through fractionated sessions using the Gamma Knife ICON, maintains progression-free and overall survival rates comparable to conventional treatments. The advantage lies in its safety and practicality for specific GBM patients, highlighting an approach that balances efficacy with reduced side effects. For detailed insights, refer to the study in BMC Cancer [here](https://bmccancer.biomedcentral.com/articles/10.1186/s12885-022-10162-w).
 
====Radiation via Monoclonal Antibodies====
{{#ask: [[Has treatment name::Radiation via Monoclonal Antibodies]]
|?Has common side effects=Common Side Effects
|?Has OS without=Overall Survival without
|?Has OS with=Overall Survival with
|?Has PFS without=Progression-Free Survival without
|?Has PFS with=Progression-Free Survival with
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|?Has Toxicity Explanation=Toxicity Explanation
|format=table
|limit=1
}}
 
An alternative for providing a radiation boost beyond the standard external field
radiation involves attaching radioactive iodine-131 to a monoclonal antibody that targets
a specific antigen, tenascin, which occurs on almost all high-grade glioma tumors and not
on normal brain cells. The monoclonal antibodies are infused directly into the tumor
cavity over a period of several days, and reportedly produces much less radiation necrosis
than either brachytherapy or radiosurgery. The median survival time from a phase 2
clinical trial of this treatment for recurrent GBM tumors was 56 weeks (217). In the first
study that reported using this approach as initial treatment (218) patients received the
monoclonal antibodies, followed by the standard external-beam radiation and then a year
of chemotherapy. Of 33 patients, only one required re-operation for necrotic tissue caused
by the radiation. Median survival time was 79 weeks for the patients with glioblastoma
(27 of 33 of total patients) and 87 weeks for all patients. Estimated two-year survival rate
for GBM patients was 35%. A subsequent report of the results for an expanded number
of patients indicated a mean progression-free survival of 17.2 months, compared to 4-10
months for other treatment procedures (219). Median overall survival measured from the
time of diagnosis was 24.9 months. At the present time, however, only one treatment
center (Duke University) has used this procedure. A multi-center clinical trial was
planned, but the company sponsoring the trial apparently has shelved those plans for the
indefinite future.
A second type of monoclonal antibody treatment, developed at Hahneman University
Medical School in Philadelphia, targets the epidermal growth factor receptor, which is
overexpressed in the majority of GBM tumors (220) For patients who received the MAB
treatment in combination with standard radiation, median survival time was 14.5 months;
For patients who received the same protocol but with the addition of temodar, median
survival was 20.4 months.
A third type of monoclonal antibody, named Cotara, is designed to bind with proteins that
are exposed only when cells are dying, with the result that adjacent living tumor cells are
radiated by the radiation load carried by the monoclonal antibody. This rationale is based
on the fact that that centers of GBM tumors have a large amount of necrosis. This
approach has been under development by Peregrine Pharmaceuticals, a small biotech
with limited funding. Recently they reported the long-term results from 28 recurrent
GBM patients studied over a nine-year period (221). Seven of the 28 patients survived
more than one year, while 3 of the 28 survived longer than five years (2 more than 9
years). Median survival was 38 weeks.
 
==Strategies for improving the Standard of Care==
 
===Combatting chemoresistance===
 
There are several ways that cancer cells evade being killed by cytotoxic chemotherapy.
Already mentioned is that the damage inflicted by the chemotherapy is quickly repaired
before actually killing the cell (due to the activity of the MGMT repair enzyme). A second
source of resistance is that the chemo agent is extruded from the cancer before the next
cell division (chemotherapy typically affects only those cells in the process of dividing). A
third way is that the chemo agent doesn’t penetrate the blood-brain barrier. While
Temodar is generally believed to cross the blood-brain-barrier effectively, empirical
studies of its concentration within the tumor tissue have shown that its penetration is
incomplete.
 
A major source of chemo-resistance for many types of cancer comes from glycoprotein
transport systems (technically called ABC transporters) that extrude the chemotherapy
agent before it has the chance to kill the cell. This is important because chemotherapy is
effective only when cells are dividing, and only a fraction of the cell population is dividing
at any given time. The longer the chemotherapy remains in the cell, the more likely it will
be there at the time of cell division. If extrusion of the chemotherapy drug could be
inhibited, chemotherapy should in principle become more effective. Calcium channel
blockers, which include commonly used medications for hypertension such as
verapamil, have thus been studied for that purpose (11).
 
Unfortunately, these agents have potent effects on the cardiovascular system, so that
dosages sufficiently high to produce clinical benefits usually have not been achievable.
However, a recent study (12) did report a substantial clinical benefit for patients with
breast cancer with a relatively low dosage (240 mg/day). An earlier randomized trial with
advanced lung cancer (13) also demonstrated a significant benefit of verapamil, using a
dose of 480 mg/day, both in terms of frequency of tumor regression and survival time. In
addition, the combination of verapamil with tamoxifen (which itself blocks the extrusion
by a somewhat different mechanism) may possibly increase the clinical benefit (14). In
laboratory studies, the calcium channel blockers nicardipine and nimodipine (15, 16)
have also been shown to effectively increase chemotherapy effectiveness, and may have
direct effects on tumor growth themselves. Quinine derivatives such as quinidine and
chloroquine also inhibit the extrusion pump. Among the strongest inhibitors of the
extrusion pump is a common drug used in the treatment of alcoholism, Antabuse, also
known as disulfiram (17,18). Yet another class of drugs that keep the chemo inside for
longer time periods are proton pump inhibitors used for acid reflux (e.g., Prilosec) (19).
One approach to blocking the glycoprotein pump without the high toxic doses is to
combine several agents together, using lower doses of each individual agent, as combining
different agents has been shown to be synergistic in laboratory studies (20).
 
The most promising clinical results for combatting chemo-resistance has come from the
addition of chloroquine, an old anti-malaria drug, to the traditional chemotherapy
agent, BCNU. See Chapter 5, Chloroquine section for further details.
 
Disruption of the blood-brain-barrier (BBB) is also potentially very important and has
been extensively investigated. The issue is complicated by the fact that tumor tissue
already has a substantially disrupted BBB (which is the basis of using contrast agents to
identify the tumor). However, this disruption is incomplete, so any chemotherapy agent
that does not cross the intact BBB will not contact all portions of the tumor. Various
ways of disrupting the BBB have been studied, but none has been generally successful,
primarily because of their systemic side effects. Recently, however, the common erectile
dysfunction drugs (Viagra, Levitra, Cialis) have been discovered to disrupt the BBB in
laboratory animals. In a rat brain tumor model, the addition of Viagra or Levitra to a
common chemotherapy agent, Adriamycin, substantially improved survival time (26).
 
===Optimizing the Schedule of Chemotherapy===
 
The standard schedule for using full-dose Temodar is days 1-5 out of every 28-day cycle.
The large phase 3 EORTC-NCIC study (2005) also added daily Temodar during radiation
at a lower dosage, followed by the standard five-day schedule after radiation was
completed. But there has never been a persuasive rationale for why this standard schedule
should be preferred over various alternatives.
 
In addition to the standard schedule, three other schedules have been studied: (1) a
“metronomic” low-dose daily schedule; (2) an alternating week schedule; (3) a “dose-
intense” schedule in which Temodar is used on days 1-21 of every 28-day cycle. While it
is possible to compare the outcomes of these different studies across different clinical
trials, only a few studies have compared the different schedules within the same clinical
trial.
�In one single-center randomized trial with newly diagnosed patients, the alternating week
schedule of 150 mg/m2 on days 1-7 and 15-21 was compared with the metronomic
schedule of 50 mg/m2 daily (29). Patients completing 6 cycles of adjuvant Temodar were
switched to maintenace therapy with 13-cis retinoic acid (aka Accutane). One-year
survival rates were 80% vs. 69%, and two-year survival rates 35% vs. 28%, both favoring
the alternating week schedule. However, neither difference was statistically significant.
Median survival times for the alternating week and metronomic schedules were 17.1 vs.
15.1 months.
 
A second very large randomized trial compared the standard 5-day schedule with a dose-
intense schedule (75-100 mg/mz2 on days 1-21). The rationale of the dose-intense schedule
was that it would better deplete the MGMT enzyme (30). Median PFS favored the
dose-dense arm (6.7 months vs. 5.5 months from the time of study randomization,
p=0.06), while median overall survival favored the standard schedule (16.6 vs. 14.9
months from randomization). While neither difference was considered statistically
significant, the dose-intense schedule had substantially more toxicity and hence cannot be
recommended.
 
In a more recent retrospective study (313), 40 patients undergoing the standard 5-day
temozolomide schedule and 30 patients undergoing a metronomic schedule (75 mg/m2)
were included in the final analysis. The metronomic temozolomide schedule led to
statistically significant increases in both progression-free survival and overall survival,
and in both univariate and multivariate analysis. Even more importantly, this study found
that the benefit of the metronomic schedule mainly occurs for those patients with EGFR
overexpression (EGFR protein expression in over 30% of tumor cells), or EGFR gene
amplification. Median overall survival for patients with EGFR overexpression treated with
metronomic temozolomide was 34 months, compared to 12 months with standard
schedule. EGFR overexpressing patients treated with metronomic temozolomide had
highly statistically significantly improved progression-free survival and overall survival
compared to all other groups (the other groups being EGFR overexpressing treated with
standard schedule, and EGFR non-overexpressing treated with either schedule).
 
The investigators furthermore analysed tumor tissue samples from patients who
underwent repeat resection at the time of recurrence. Interestingly, they found that
samples from EGFR overexpressing tumors treated with metronomic temozolomide had
significantly fewer cells positive for NF-kB/p65 (a promoter of cell proliferation and
survival) compared with untreated tumors from the same patients at the time of
diagnosis. No such change was observed between the primary and recurrent EGFR
overexpressing tumors from patients treated with the standard schedule. Recurrent
EGFR amplified tumors treated with the metronomic schedule showed fewer EGFR
amplified cells and weaker EGFR staining at the time of recurrence compared with the
primary tumor. No such difference was observed in EGFR amplified tumors treated with
�the standard schedule. The authors draw the conclusion that this metronomic schedule
impairs survival of EGFR expressing GBM cells more effectively than the standard
schedule. These findings will hopefully lead to testing in prospective clinical trials. A
major caveat when reviewing this study is that there is no explanation for why some of the
patients were selected for the higher dose metronomic schedule rather than the standard
schedule and it’s possible that these patients were healthier at baseline and that selection
bias contributed to the different outcomes.
 
The lowest Temodar dose in metronomic chemotherapy reported to date was presented to
newly diagnosed glioblastoma patients (44). After completion of standard radiation
treatment, continuous daily doses of temozolomide approximately 1/10 of the typically
used full dose were used in combination with Vioxx (aka rofecoxib, a discontinued COX-2
inhibitor which was later replaced by celecoxib in studies by this group). Median
progression-free survival was 8 months and overall survival for 13 patients was 16
months, with minimal toxicity. A second retrospective study (45) from the same medical
group compared the very low-dose schedule (20 mg/m2) with a more typical metronomic
dosage (50 mg/meter-squared), although only 17 patients and six patients were included
in the former and latter groups. Also included were patients who received only radiation.
Median survival was 17 months and 21 months, respectively, for the two metronomic
chemotherapy groups vs. 9 months for the radiation-only patients.
 
Although clinicians will likely resist any alternative to the standard temozolomide
schedule for newly diagnosed patients outside of clinical trials, a medium-dose
metronomic schedule is worthy of consideration for patients with unmethylated MGMT
status, and especially for those patients with unmethylated MGMT status and amplified
EGFR. For patients unfit to receive the standard high dose temozolomide schedule, a very
low dose metronomic schedule of TMZ may provide some benefit, perhaps through
selective toxicity to immune suppressor cells, and in combination with COX-2 inhibition
as in the German studies above.
 
===How many cycles of TMZ?===
 
An important question is how long the use of TMZ should be continued. The Stupp
clinical trial continued it for only six cycles after radiation, but many patients have
continued that protocol for longer period of times.
 
In what is perhaps the only randomized, prospective trial comparing different numbers of
cycles of adjuvant temozolomide, 20 newly diagnosed glioblastoma patients were
assigned to six cycles and another 20 patients were assigned to 12 cycles (355). Median
progression-free survival outcomes were 12.8 months in the 6-month group and 16.8
months in the 12-month group, which was borderline statistically significant (p=0.069).
Median overall survival was 15.4 versus 23.8 months, and achieved statistical significance
despite the low numbers of patients included in the trial (p=0.044). A serious limitation
of this study is that no information on MGMT status of the patients was collected, and
therefore it’s possible that the proportion of patients with MGMT promoter methylated
tumors was not equal in the two arms.
 
A retrospective study done in Canada (51) compared patients who received the standard
six cycles of temozolomide with those who had more than six cycles (up to 12) Patients
receiving six cycles had a median survival of 16.5 months, while those receiving more than
six cycles had a median survival of 24.6 months.
 
The latest attempts to define the optimal length of monthly temozolomide (TMZ) therapy
were published as abstracts for the SNO 2015 annual meeting. In the first of these studies
(reference 325, abstract ATCT-08), a large team of investigators retrospectively analyzed
data from four large randomized trials with the aim of comparing 6 cycles of monthly
TMZ to >6 cycles. Only patients who had completed 6 cycles of TMZ and had not
progressed within 28 days of completing cycle 6 were included. Important prognostic
factors such as age, performance status, extent of resection and MGMT status were
incorporated into the analysis. For these patients, treatment with more than 6 cycles of
TMZ was associated with significantly improved progression-free survival [HR=0.77,
p=0.03] independently of the examined prognostic factors, and was particularly beneficial
for those with methylated MGMT status. Surprisingly, overall survival was not
significantly different between the two groups (p=0.99).
 
In the second abstract (reference 326, abstract ATPS-38), a Japanese group attempted to
clarify whether more than 12 cycles of TMZ was beneficial in terms of increased survival.
Patients in this study were divided into four groups: a) 12 cycles, b) 24 cycles, c) more
than 24 cycles until relapse, and d) beyond 12 cycles (this group includes the b) and c)
groups). 12, 14, 12, and 40 patients were included in each of these groups. No significant
progression-free survival difference was detected between groups a) and b), implying a
lack of benefit of 24 versus 12 cycles. Importantly, patients who were able to continue
TMZ treatment for at least 12 cycles (all the patients in this study) had a median
progression-free survival of 4.3 years and median overall survival of 6.3 years. This study
failed to show a benefit of continuing TMZ cycles beyond 12.
 
===Combining the Standard Treatment with Additional Agents===
 
Few oncologists believe that single-agent treatments are likely to be curative. The issue is
finding the optimal combinations, based on toxicities and differences in the mechanisms
of actions. Prior to the introduction of temozolomide, the PCV combination of
procarbazine, CCNU, and vincristine had been the most widely used combination
treatment for glioblastomas, but its use has never been shown to produce a better
outcome than treatment with BCNU as a single agent. Nevertheless, there is now a large
amount of research studying the effects of combining temozolomide with other therapies,
most of which supports the view that such combinations improve treatment outcome,
sometimes substantially. A variety of additional therapies are discussed in the following
chapters.
 
 
==Available Treatments==
 
===Optune (formerly NovoTTF-100A) by Novocure===
 
{{#ask: [[Category:Innovative Cancer Therapies]]
|?Has treatment name=Drug Name
|?Has Usefulness Rating=Usefulness Rating
|?Has OS with=OS_with
|?Has OS without=OS_without
|?Has Toxicity Level=toxicity_level
|?Has Toxicity Explanation=toxicity_explanation
|format=table
}}
 
 
{{#ask: [[Has treatment name::Optune (Optune Gio® for newer version)]]
|?Has original text
|format=template
|template=CustomTextDisplay
}}
 
 
In the spring of 2011, the FDA approved the fourth treatment ever for glioblastoma.
Unlike the previous three (gliadel, temozolomide, and Avastin), the new treatment
involves no drugs or surgery, but instead uses a “helmet” of electrodes that generates a
low level of alternating electrical current. A biotech company called Novocure has
developed the device, called Optune, based on experimental findings that electro-
magnetic fields disrupt tumor growth by interfering with the mitosis stage of cell
division, causing the cancer cells to die instead of proliferating (138). Healthy brain cells
rarely divide and thus are unaffected. The treatment involves wearing a collection of
electrodes for 18 or more hours per day, which allows the patient to live otherwise
normally. This approval in 2011 was the outcome of a randomized phase 3 trial for
recurrent glioblastoma, in which Novo-TTF (now called Optune) treatment was equally
effective as physician’s choice chemotherapy, but with reduced toxicity and better quality
of life (139, 140).
 
====Optune plus chemoradiation, the next standard of care?====
 
EF-14 is a phase 3 randomized clinical trial for newly diagnosed glioblastoma which
compared standard of care chemoradiation followed by Optune (NovoTTF) and
monthly cycles of Temodar, versus chemoradiation followed by monthly cycles of
Temodar alone.
 
In November 2014, at the annual SNO meeting in Miami Beach, Roger Stupp made a
“late-breaking” presentation before a packed audience, describing interim survival
outcomes from the EF-14 trial, essentially ushering in what may become the new standard
of care for newly diagnosed glioblastoma. This trial is the first major phase 3 trial since
the “Stupp protocol” was established in 2005 to report a positive, statistically significant
survival benefit for newly diagnosed glioblastoma. In fact, the trial was so successful
that it was terminated early and on December 2, Novocure announced that the FDA had
approved an investigational device exemption (IDE) supplement allowing all the control
patients in the EF-14 trial to begin receiving therapy with Optune tumor treating fields.
�The interim results presented in Miami were based on the first 315 patients enrolled in
the trial, who had at least 18 months of follow-up. Of these, 105 were randomized into the
control arm and 210 were randomized to receive tumor treating fields. Survival and
progression-free survival were measured from the time of randomization, which was a
median of 3.8 months after diagnosis. Median progression-free survival was 7.1 months in
the Optune arm versus 4 months in the control arm (hazard ratio 0.63, with a high degree
of statistical significance, p=0.001). Median overall survival from randomization was 19.6
months in the Optune arm versus 16.6 months in the control arm (hazard ratio 0.75,
statistically significant, p=0.034). 2-year survival was 43% in the Optune arm versus 29%
in the control arm. It must be kept in mind that all these statistics are measured from
randomization, roughly 4 months from diagnosis, meaning that median overall survival in
the Optune arm approaches 24 months from diagnosis. The statistics above are for the
intention-to-treat (ITT) population, which includes all patients randomized, as opposed
to the as-treated (per-protocol) population, which excludes patients who did not start
their second course of temozolomide or had major protocol violations.
 
An October 5, 2015 press release announced that the FDA had approved Optune in
combination with temozolomide for newly diagnosed glioblastoma, not quite a year after
the first survival data from the trial was publicized. This is the first approval of a therapy
for newly diagnosed glioblastoma since temozolomide was approved for this indication in
March 2005. Two months later, in December 2015, the preliminary results of the EF-14
trial were published in the Journal of the American Medical Association (327). This
publication detailed results for the first 315 patients enrolled, the same patients reported
upon at the SNO 2015 annual meeting. Additional survival analysis on the per-protocol
population (as opposed to the intention-to-treat population) gave an overall survival from
randomization of 20.5 months in the Optune group and 15.6 months for the control group
(that is, about 24.3 months and 19.3 months from diagnosis) (HR=0.64, p=0.004).
 
Outcomes for the entire trial population of 695 patients were published for the 2016 SNO
conference, with an updated press release from Novocure coming in April 2017.
Confirming the results of the interim analysis, median progression-free survival was
significantly improved in the Optune group by just under 3 months (6.7 versus 4 months
from randomization). Median overall survival from randomization was improved by
neatly five months (20.8 versus 16 months). Survival rate at 2 years from randomization
was 42.5% in the Optune group versus 30% in the control group. The April 2017 update
also reported on 5 year survival rate, which was 13% in the Optune arm versus 5% in the
control arm.
 
As of July 2016, the National Comprehensive Cancer Network (NCCN) had given Optune
a 2A listing for newly diagnosed glioblastoma, indicating uniform consensus amongst the
NCCN panel that this treatment is appropriate. As the NCCN is known as setting the
standard treatment guidelines for cancer in the USA, this formalizes the concept of
Optune as part of a new standard of care for newly diagnosed glioblastoma. Although its
status as part of a new standard of care may still be disputed by some, Novocure has
announced that Optune is now available at over 600 treatment centers in the USA (click
here for a list of these US centers), as well as 350 additional institutions internationally,
including locations in Germany, Switzerland, Austria, and Japan.
 
=== Treatment Categories ===
Explore the various treatment categories for comprehensive insights and latest developments:
 
* [[:Category:Repurposed Drugs|Repurposed Drugs]]
* [[:Category:Hormones|Hormones]]
* [[:Category:Nutraceuticals|Nutraceuticals]]
* [[:Category:Antibody-Drug Conjugates and other protein-drug conjugates|Antibody-Drug Conjugates and other protein-drug conjugates]]
* [[:Category:Other Chemotherapy and Cancer Drugs|Other Chemotherapy and Cancer Drugs]]
...
 
 
 
 
=== Explore Treatments by Usefulness Rating ===
Discover treatments that have shown promising results.
 
{{#ask: [[Has Usefulness Rating::4]] OR [[Has Usefulness Rating::5]]
| ?Has treatment name
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
| format=table
}}
 
 
Visit our [[:Category:Highly Useful Treatments|Highly Useful Treatments]] page to explore treatments rated with a usefulness of 4 or 5.
 
=== Hormones ===
 
Unlike traditional cancer chemotherapy, which kills cancer cells through directly cytotoxic
mechanisms, a different approach may also prove to be effective: manipulation of the
body’s balance of circulating hormones to achieve the most unwelcoming environment for
the growth of tumors.
 
{{#ask: [[Category:Hormones]]
|?Has treatment name=Name
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|format=table
}}
 
=== Repurposed Drugs ===
 
There are a large number of drugs that were developed initially for various different
purposes that subsequent laboratory research demonstrated to have significant
anti-cancer properties. Given these old drugs have been used for years, have well-defined
toxicity profiles, and are generally cheaper due to being off-patent, they offer the
possibility of augmenting the benefits of the current standard treatment without
significant additional toxicity. However, because their FDA approval is for different
purposes, many if not most neuro-oncologists have been reluctant to take advantage of
their possible benefits as components of a treatment cocktail. Some of these drugs have
been investigated as single agents for brain cancer treatment and some have also been
combined with the now standard Stupp protocol.
 
{{#ask: [[treatment_category:Repurposed Drugs]]
|?Has treatment name=Drug Name
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|format=table
}}
 
{{:Over-the-Counter Drugs and Supplements}}
 
{{:Nutraceuticals and Herbals}}
 
=== Other Chemotherapy and Cancer Drugs ===
Explore additional chemotherapy and cancer drug treatments:
 
{{PropertyTableFormat|Other Chemotherapy and Cancer Drugs}}
 
 
====CCNU (lomustine)====
 
A report from Germany combined TMZ with CCNU (lomustine), the nitrosourea
component of the PCV combination (52). Patients (N=39) received CCNU on day 1 of
each 6-week cycle, and TMZ on days 2-6. Eight patients received intensified doses of
both drugs, with somewhat better survival results (but with substantially increased
toxicity). For present purposes, the results of all patients are aggregated. Median survival
time was 23 months, and survival rates were 47%, 26%, 18%, and 16% at 2, 3, 4, and5
years, respectively. Four of the 39 patients had no recurrence at the 5-year mark. Only 23
of the 39 patients were assessable for the status of the MGMT gene. Those with
methylated MGMT had a median survival of 34 months, while those with unmethylated
MGMT had a median survival of only 12.5 months.
 
These results, including a 5-year survival rate of 16%, are among the best yet reported,
albeit with a relatively small number of patients. But it also should be appreciated that
patients who suffered a recurrence received extensive salvage therapy of various types,
which may have contributed substantially to survival time. The addition of CCNU to
standard therapy for newly diagnosed glioblastoma is currently being tested in a phase 3
trial in Germany.
 
====BCNU (carmustine) and Gliadel (carmustine wafers)====
 
The combination of Temodar with BCNU, the traditional chemotherapy for glioblastomas,
has also been studied, but has been complicated by issues of toxicity and the optimal
schedule of dose administration for the two drugs. However, a recent published report
involving patients with tumors recurring after radiation but no prior chemotherapy failed
to show any benefit of combining BCNU with Temodar, compared to Temodar alone, as
the PFS-6 for the combination was only 21%, accompanied by considerable toxicity (53).
 
An important variation in the use of BCNU has been the development of polymer wafers
known as gliadel. A number of such wafers are implanted throughout the tumor site at the
time of surgery. BCNU then gradually diffuses from the wafers into the surrounding
brain. A possible problem with the treatment is that the drug will diffuse only a small
distance from the implant sites, and thus fail to contact significant portions of the tumor.
However, a phase III clinical trial has demonstrated that survival time for recurrent high-
grade gliomas is significantly increased by the gliadel wafers relative to control subjects
receiving wafers without BCNU, although the increase in survival time, while
 
statistically significant, was relatively modest (54). Probably the best estimate of the
benefit of gliadel as an initial treatment comes from a randomized clinical trial,
conducted in Europe (55), which reported a median survival of 13.9 months for patients
receiving gliadel compared to a median survival of 11.6 months for patients implanted
with placebo wafers. As with other forms of chemotherapy, larger differences were
evident for long-term survival. After a follow-up period of 56 months, 9 of 120 patients
who received gliadel were alive, compared to only 2 of 120 of those receiving the
 
placebo. However, the results were not reported separately for glioblastomas vs. other
high-grade gliomas, suggesting that the outcome results would have been more modest
for the glioblastoma patients alone.
 
When gliadel has been combined with the standard TMZ + radiation protocol, survival
time seems to be significantly improved, as assessed in three different retrospective
clinical studies. In the first, from the Moffitt Cancer Center in Florida (56), the
combination produced a median overall survival of 17 months, and a 2-year survival rate
of 39%. In a second clinical trial reported by Johns Hopkins, where gliadel was
developed (57), 35 patients receiving the combination had a median survival time of 20.7
months and a 2-year survival of 36%. In a third trial conducted at Duke University (58),
36 patients receiving gliadel in addition to the standard TMZ protocol had a median
survival of 20.7 months and a 2-year survival of 47%. The Duke cohort also received
rotational chemotherapy (which included TMZ) subsequent to radiation. It is important
to keep in mind that patients eligible to receive gliadel must have operable tumors, which
excludes patients who have received a biopsy only and have a generally poorer prognosis
as a result. The effect of this selection bias is difficult to evaluate but it is likely to
account for a significant fraction of the improvement in survival time when gliadel
+TMZ is compared to TMZ alone.
 
A major advantage of gliadel is that it avoids the systemic side effects of intravenous
BCNU, which can be considerable, not only in terms of low blood counts but also in
terms of a significant risk of major pulmonary problems. But gliadel produces its own
side effects, including an elevated risk of intracranial infections and seizures. However,
the lack of systemic toxicity makes gliadel a candidate for various drug combinations.
Especially noteworthy is a recent phase II trial with 50 patients with recurrent tumors
that combined gliadel with 06-BG, a drug that depletes the MGMT enzyme involved in
repair of chemotherapy-induced damage, but also causes unacceptable bone marrow
toxicity when chemotherapy is given systemically. Survival rates at six months, one year
and two years were 82%, 47%, and 10%, respectively (59) which seems notably better than
the earlier clinical trial with recurrent tumors using gliadel without the 06-BG, in which
the corresponding survival rates were 56%, 20%, and 10%. Median survivals were also
notably improved by the addition of 06-BG (50.3 weeks versus 28 weeks).
 
====Platinum compounds====
 
An improvement in results relative to those obtained with Temodar alone has also been
reported when Temodar has been combined with cisplatin. In a pair of clinical studies
performed in Italy (61, 62) with patients with recurrent tumors, the PFS-6 was 34% and
35%. A treatment protocol with newly diagnosed patients that also seems to have
produced better results than Temodar as a single agent combined Temodar with both
cisplatin and etoposide (VP-16), given through the carotid artery (63). Cisplatin and
etoposide were given after surgery and continued for three cycles spaced every 3 weeks
apart, followed by the standard protocol of radiation plus low-dose Temodar, then
high-dose Temodar on the schedule of days 1-5 of every month. For 15 patients studied,
median survival was 25 months.
 
====Procarbazine====
 
Temodar has also been combined with procarbazine (64). While the report of that study
did not include the PFS-6 statistic, it did report an unusually high percentage of tumor
regressions, suggesting that this combination might be effective.
 
====Bevacizumab (Avastin)====
 
The most notable development in drug combinations has been the addition of the anti-
angiogenic drug, Avastin (also known as bevacizumab), to the standard Stupp protocol.
As will be discussed later, Avastin has FDA approval for the treatment of glioblastomas
that have recurred or progressed after initial treatment. Several clinical trials have now
investigated its combination with the gold standard Temodar protocol.
 
Recently, there have been two large randomized phase III clinical trials comparing
 
the Stupp protocol and the Stupp protocol + Avastin, for newly diagnosed patients. In the
first of these (70), known as the AVAglio trial, median PFS was 10.6 months for those
receiving Avastin versus 6.2 months for those receiving only the Stupp protocol, a
statistically significant difference. However, median overall survival was not different
(16.8 months vs. 16.7 months). It should be noted that patients in the control group
typically received Avastin after tumor progression occurred, so that the comparison was
really between Avastin given early versus Avastin given only after recurrence. Additional
results were that 72% of the Avastin group was alive at one year, compared to 66% of the
control group, while two year survival was 34% vs. 30%.
 
In the second of these large trials (71), conducted by the RTOG consortium, the design
was essentially similar to the AVAglio trial, as were the results. Median PFS was 10
months for those receiving Avastin vs. 7.3 months for the control group (again statistically
significant), while median overall survival was 15.7 months for the Avastin group
compared to 16.1 months for the control, a nonsignificant difference.
 
The best interpretation of these results is that patients have a longer time without tumor
progression, and presumably a better quality of life, when Avastin is used as part of the
initial treatment. However, there is no benefit for overall survival, when compared to
withholding Avastin until recurrence is detected. An additional feature of the results, not
emphasized by the authors of the reports, is that the overall survival times were not
notably better, and in many cases worse, than those obtained when the Stupp protocol is
combined with various other treatment agents.
 
EGFR inhibitors: Iressa, Tarceva, and Erbitux (gefitinib, erlotinib, and
cetuximab)
 
These three drugs, which have FDA approval for several different types of cancer, have
the common feature that they target a growth-signaling channel known as the epidermal
growth factor. Overexpression or mutation of EGF receptors is involved in the growth
many different kinds of cancer, including more than half of glioblastomas. In general, use
of these drugs as single agents has produced disappointing results, although occasional
long-term survivors have occurred. More promising results have occurred when EGFR
inhibitors have been used in combination with the Stupp protocol.
 
When Tarceva has been added to the standard Temodar protocol for newly diagnosed
patients, median survival was 15.3 months (N=97) in one study (72) and 19.3 months
(N=65) in a second study (73). The results of the second study were compared to two
previous phase II trials involving a similar patient population, in which Temodar was
combined with either thalidomide or accutane. Median survival for those trials was 14.1
months.
 
The moderately positive results of the just described trial are in conflict with a very
similar trial (N=27) conducted at the Cleveland Clinic (74). In that trial median survival
was only 8.6 months, notably worse than the outcomes obtained when temodar has been
used without tarceva. How the conflicting results can be reconciled is unclear.
Erbitux (also known as cetuximab) is a monoclonal antibody, which differs from Iressa
and Tarceva, which are small molecules, Because monoclonal antibodies are not believed
to cross the blood-brain barrier, the natural expectation is that Erbitux would be
ineffective against brain tumors. As a single agent, this seems to be true, as PFS-6 was
only 10% for patients with recurrent high-grade gliomas (75). But when Erbitux was
added during the radiation phase of the standard temozolomide protocol for 17 newly
diagnosed patients (76), 87% of patients were alive at the end of one year and 37% were
progression free. The median survival time had not been reached at the time of the report
(an abstract at a meeting). It is possibly important to note that some investigators believe
that radiation temporarily disrupts the blood-brain-barrier, which would allow a
monoclonal antibody such as erbitux to reach the tumor.
 
An important development for identifying patients likely to respond to Tarceva has come
from a study (77) of glioma patients whose tumor pathologies were also assessed for their
levels of a second protein called PKB/AKT. This is a signaling channel that results from
inactivation of the PTEN gene, a tumor suppressor gene commonly mutated in
glioblastomas. None of the tumors with high levels of PKB/AKT responded to treatment
with Tarceva, whereas 8 of 18 tumors with low levels did respond to the treatment. A
refinement of this approach tested for three different proteins: expression of PTEN,
expression of EGFR, and of a mutation of the EGFR protein known as EGFR variant III
(78). The level of EGFR was not related to clinical outcome, whereas the co-expression
of EGFR variant III and PTEN strongly predicted clinical outcome.
 
Because the inhibition of PKB/AKT should plausibly increase the effectiveness of EGFR
inhibitors, a treatment strategy now being tested is the combination of EGFR inhibitors
with rapamycin (trade name rapamune, generic name sirolimus), an existing drug used
for organ transplants to suppress the immune system and prevent organ rejection, but
which also inhibits mTOR complex 1, a tumor growth promoter downstream of AKT. A
phase I trial (79) combined Iressa with rapamycin for 34 patients (25 GBM) with
recurrent tumors; two patients had a partial tumor regression and 13 patients achieved
stable disease. PFS-6 was 24%. A second clinical trial (80) with 28 heavily pretreated
patients with low performance status (median Karnofsky score of 60) received either
Iressa or Tarceva in combination with rapamycin, with the result that 19% of patients had
tumor regression while 50% had stable disease, with a PFS-6 value of 25%. Yet a third
clinical trial (81) that combined tarceva and sirolimus for recurrent GBM had much worse
results, with PFS-6 value of only 3%.
 
The foregoing results of the use of EGFR inhibitors for GBM treatment range from
moderately positive to minimal efficacy. The reasons for this variability are not obvious,
although treatment efficacy is likely dependent on numerous genetic markers. Thus,
without a genetic analysis of individual tumors, it is hard to see a basis for recommending
their use.
�One recent paper (83) of potential major importance has noted that tumors may not
respond to anti-EGFR drugs because of activation of the gene for a second growth factor
known as the insulin-like growth factor receptor I (IGF1R). IGF1R has also been
implicated as a source of resistance to tamoxifen and various other treatment agents. It is
noteworthy, therefore, that two of the supplements to be discussed, silibinin and
lycopene, are known to inhibit IGF-I. This suggests that silibinin and lycopene might
substantially increase the effectiveness of any treatment that relies on EGFR inhibition.
Metformin, a widely used diabetes drug, is also known to reduce the level of IGF-1,
currently is under investigation as a treatment for several different kinds of cancer.
 
An important issue is how the effectiveness of EGFR inhibitors are related to the findings
discussed earlier that metronomic schedules of Temodar produce a large survival
improvement for GBMs that have EGFR overexpression. All of the clinical trials
discussed in this section used the standard Temodar schedule, so it is unclear whether a
metronomic schedule might produce different outcomes.
 
====Gleevec (imatinib)====
 
Gleevec (also known as imatinib), a small molecule which targets a specific gene involved
in the growth of a form of leukemia, received a great deal of publicity because of its
unprecedented effectiveness. As will be discussed later, this general strategy of
identifying the growth signals for tumor growth and then targeting those signals, or their
receptors, is one of the major new areas in cancer research. Such growth signaling
channels often are involved in several different types of cancer. Although Gleevec was
developed specifically for chronic myelogenous leukemia, it also has been shown to
inhibit a more general type of growth signal, platelet-derived growth factor (PDGF),
which is also involved in the growth of gliomas and other forms of cancer (e.g., small-
cell lung cancer). Laboratory research has supported the importance of this similarity in
that gleevec has been shown to strongly inhibit glioma growth, with the result that there
now have been a number of studies reporting its use with high-grade gliomas.
 
The generally disappointing results using gleevec for brain tumors may have occurred
 
for several different reasons. It may not readily cross the blood-brain-barrier, and it may
engender different mechanisms of resistance than other treatment agents. In the study of
gleevec for leukemia, for example, high levels of autophagy have been observed, which
can be inhibited by the concurrent use of chloroquine or other autophagy inhibitors.
 
An important variation in the use of gleevec was to restrict its usage to patients with
recurrent tumors who tested positive for overexpression of the platelet-derived growth
factor receptor (90). PDGFR is overexpressed in 50-65% of tumors, especially tumors
labeled secondary glioblastomas, which are believed to have evolved from lower-grade
tumors (in contrast to de novo glioblastomas that occur without such evolution). For this
restricted patient population, the PFS-6 value was 53%.
 
=== Treatments for Recurrent Glioblastoma ===
 
While Temodar is now the drug of choice for the initial treatment of glioblastoma, the
majority of patients will receive minimal benefit. Patients who have failed the standard
treatment protocol often proceed to other chemotherapy drugs. These include the
nitrosoureas, BCNU and CCNU (and ACNU in Europe and Japan), and also the platinum
drugs, and irinotecan, a drug developed for colon cancer known also known as CPT-11.
 
{{#ask: [[Category:Other chemotherapy agents at recurrence]]
|?Has treatment name
|?Has OS without=Overall Survival without PBT
|?Has OS with=Overall Survival with PBT
|?Has PFS without=Progression-Free Survival without PBT
|?Has PFS with=Progression-Free Survival with PBT
|?Has Usefulness Rating=Usefulness Rating
|?Has Toxicity Level=toxicity_level
|?Has Toxicity Explanation=Toxicity Explanation
|format=table
}}
 
==Promising new Treatments ==
=== Antibody-Drug Conjugates and other protein-drug conjugates ===
Investigate the cutting-edge Antibody-Drug Conjugates and other protein-drug conjugates being developed:
 
{{PropertyTableFormat|Antibody-Drug Conjugates and other protein-drug conjugates}}
 
===Immunological Approaches===
Because cancer cells have a genetic structure different from normal cells they generate
foreign proteins that in principle should be detected by the immune system and evoke the
same type of immune reaction as any foreign virus or bacteria. This basic fact suggests
that augmenting one's immune system might be an effective approach to cancer
treatment. Such an approach has an immediate appeal because it is surely preferable to
reinforce the immune system than to poison the entire body in the hope the cancer cells
will be killed before the body is depleted of vital resources. However attractive this
philosophy may be, translating it into an effective cancer treatment has proven to be
extraordinarily difficult. Contrary to general belief, immunological treatments are not
�benign to implement. Interferon treatment has very definite debilitating effects, as do
cytokines such as interleukin-2 and tumor necrosis factor, because their modus operandi
are essentially to create an inflammatory immune reaction not unlike a severe allergic
reaction. When this inflammatory process is too severe, it can in fact be fatal.
 
==== Vaccines ====
The holy grail of immunological approaches to cancer treatment is the development of
effective vaccines. In principle this should be possible because of the differences in the
protein structure of cancer cells and normal cells. But, two general problems must be
overcome. The first is that different individuals have tumors with different collections of
antigens (proteins), so that generic vaccines are unlikely to be effective; thus patient-
specific vaccines are required. The second problem is that the immune system is not an
efficient detector of the tumor's foreign antigens. In part this is due to the tumor secreting
enzymes that in effect provide a protective cloak preventing such detection. The larger the
tumor the stronger is its defense mechanisms to counteract immune-system detection.
This is one reason that most vaccines work best when there is a minimum of tumor
burden.
 
=====Personalized vaccines=====
 
======DCVax and other lysate-pulsed dendritic cell vaccines======
 
 
=====Tumor-associated antigen vaccines=====
{{PropertyTableFormat|Tumor-associated antigen vaccines}}
 
 
 
 
 
 
based on this book: [https://virtualtrials.org/pdf2017/treatment_options_gbm_2017.pdf Treatment Options for GBM - 2017 By Ben Williams]
 
 
If you want to add treatments, you can use [https://chatgpt.com/g/g-N3d5rwrSJ-glioblastomatreatments-wiki-helper this GPT to help research and format the results]
 
 
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Latest revision as of 23:22, 13 November 2024

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