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.
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.
