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Revision as of 10:15, 27 March 2024
Welcome
Since my own diagnosis of glioblastoma (GBM) in 1995 at age 50, I have spent considerable time researching treatment options, and the following discussion summarizes what I have learned. Most of the information is from medical journals and the proceedings of major cancer conferences. Some information has been contributed by others to various online brain tumor patient support groups, which I have followed up on, and some is from direct communications with various physicians conducting the treatments that are described. References are presented at the end for those who would like their physicians to take this information seriously. Although this discussion is intended to be primarily descriptive of the recent development of new treatment options, it is motivated by my belief that single-agent treatment protocols are unlikely to be successful, and patients are best served if they utilize multiple treatment modalities, and go beyond the “certified” treatments that too often are the only treatment options offered.
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.
The Role of MGMT
A significant advance in determining which patients will benefit from Temodar was reported by the same research group that reported the definitive trial combining Temodar with radiation. Tumor specimens from the patients in that trial were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). full text
Treatment Categories
Explore the various treatment categories for comprehensive insights and latest developments:
- Repurposed Drugs
- Hormones
- Nutraceuticals
- Antibody-Drug Conjugates and other protein-drug conjugates
- Other Chemotherapy and Cancer Drugs
...
Explore Treatments by Usefulness Rating
Discover treatments that have shown promising results. Visit our Highly Useful Treatments page to explore treatments rated with a usefulness of 4 or 5.
Hormones
Discover treatments within the Hormones category:
| Name | Usefulness Rating | toxicity_level | |
|---|---|---|---|
| Angiotensin-II Receptor Blockers (ARB) | Angiotensin-II Receptor Blockers (ARB) | 3 | 2 |
Repurposed Drugs
Explore innovative uses of existing drugs within the Repurposed Drugs category:
Nutraceuticals and Herbals
Learn about the potential of nutraceuticals and herbal treatments:
Antibody-Drug Conjugates and other protein-drug conjugates
Investigate the cutting-edge Antibody-Drug Conjugates and other protein-drug conjugates being developed:
| Has treatment name | Usefulness Rating | toxicity_level | |
|---|---|---|---|
| ABT-414 | ABT-414 | 2 | 4 |
| MDNA55 | MDNA55 | 3 | 2.5 |
Other Chemotherapy and Cancer Drugs
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