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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 Importance of Brain Tumor Centers

When someone is diagnosed with a brain tumor they are faced with a situation about which they know very little, but nevertheless must develop a treatment plan very quickly, because GBMs grow very rapidly if left untreated. The first step, if possible, is to have as much of the tumor removed as possible, because various data show substantially increased survival times for those with complete resections, relative to those who have incomplete resections or only biopsies. Accordingly, it is best that patients seek treatment at a major brain tumor center because neurosurgeons there will have performed many more tumor removals than general neurosurgeons that typically work in the community setting. This is especially important in recent times, as surgical techniques have become increasingly more sophisticated and utilize procedures that community treatment centers do not have the resources to perform. I know of numerous cases in which a local neurosurgeon has told the patient the tumor is inoperable, only to have the same tumor completely removed at a major brain tumor center.

An additional advantage of utilizing a major brain tumor center is that they are better equipped to do genetic analyses of tumor tissue, which are increasingly important in guiding treatment decisions. Moreover, they provide a gateway into clinical trials.

The Standard of Care for Initial Treatment

Glioblastoma

Although chemotherapy has a long history of being ineffective as a treatment for glioblastoma, a large randomized European-Canadian clinical trial (EORTC trial 26981/22981) has shown clear benefits of adding the new chemotherapy agent, temozolomide (trade name Temodar in the USA, Temodal elsewhere in the world) to the standard radiation treatment (2). This treatment, followed by 6 or more monthly cycles of temozolomide, has become known as the “Stupp protocol” after Roger Stupp, the Swiss oncologist who led the trial. In this trial, one group of patients received radiation alone; the other group received radiation plus Temodar, first at low daily dosages during the six weeks of radiation, followed by the standard schedule of higher-dose Temodar for days 1-5 out of every 28-day cycle. Median survival was 14.6 months, compared to a median survival of 12 months for patients receiving radiation only, a difference that was statistically significant. More impressive was the difference in two-year survival rate, which was 27% for the patients receiving temodar but 10% for those receiving only radiation. Longer-term follow-up has indicated that the benefit of temozolomide (TMZ) persists at least up to five years: The difference in survival rates between the two treatment conditions was 16.4% vs. 4.4% after three years, 12.1% vs. 3.0% after four years, and 9.8% vs. 1.9% after five years (3). As a result of these findings, the protocol of TMZ presented during radiation is now recognized as the "gold standard" of treatment. Note, however, that all of these numbers are somewhat inflated because patients over the age of 70 were excluded from the trial.

In July of 2016, the National Comprehensive Cancer Network (NCCN) recommended Optune as a category 2A treatment for newly diagnosed glioblastoma in combination with the standard temozolomide-based chemotherapy (see press release here). This rating indicates a uniform consensus by the NCCN that this treatment is appropriate. As the NCCN is recognized as setting the standards for cancer treatment in the USA and in other countries abroad which follow its guidelines, Optune in combination with standard chemotherapy following radiation could now be considered to be a new standard of care for newly diagnosed glioblastoma. See more detailed information on Optune in Chapter 3.

Anaplastic astrocytoma

Though the “Stupp protocol” of combined temoradiation (concomitant radiation and temozolomide chemotherapy) followed by monthly cycles of temozolomide has been routinely applied to anaplastic astrocytoma patients, prospective confirmation of this use in this patient population has awaited results of the “CATNON” randomized phase 3 trial for 1p/19q non-codeleted grade 3 gliomas. Results of the interim analysis for this trial were first released for the ASCO 2016 annual meeting. Between 2007 and 2015, 748 patients were randomized to receive either i) radiation alone, ii) radiation with concomitant temozolomide, iii) radiation followed by 12 adjuvant monthly cycles of temozolomide, or iv) radiation with temozolomide both concurrently and with follow-up monthly cycles. At the time of the interim analysis (October 2015), significant progression-free and overall survival benefit was found with adjuvant temozolomide treatment (arms iii and iv). Median progression-free survival was 19 months in arms i and ii (not receiving adjuvant temozolomide) versus 42.8 months (receiving adjuvant temozolomide). 5-year survival rate was 44.1% and 55.9% in arms i and ii versus iii and iv. Median survival was not yet reached for arms iii and iv.

This analysis did not address the benefit of temozolomide concurrent with radiation, a question that will be answered with further follow-up, and studies assessing the impact of IDH1 mutation and MGMT methylation were still ongoing.

Determining who will benefit

A two-year survival rate of less than 30% obviously cannot be considered an effective treatment, as the great majority of patients receiving the treatment obtain at best a minor benefit, accompanied with significant side effects (although Temodar is much better tolerated than previous chemotherapy treatments, especially with respect to the cumulative toxicity to the bone marrow). This raises the issues of how to determine who will benefit from the treatment, and, most importantly, how to improve the treatment outcomes.

One approach to determining whether an individual patient will benefit from chemotherapy is simply to try 1-2 rounds to see if there is any tumor regression. The debilitating effects of chemotherapy typically occur in later rounds, at which point there is a cumulative decline in blood counts. The extreme nausea and vomiting associated with chemotherapy in the mind of the lay public is now almost completely preventable by anti-nausea agents, including Zofran (ondansetron), Kytril (granisetron) and Emend. (aprepitant). Marijuana also can be very effective in controlling such effects, and recent research has suggested that it has anti-cancer properties in its own right. Thus, for those patients who are relatively robust after surgery and radiation, some amount of chemotherapy experimentation should be possible without major difficulties.

An alternative way to ascertain the value of chemotherapy for an individual patient is the use of chemosensitivity testing for the various drugs that are possible treatments. Such testing typically requires a live sample of the tumor and thus must be planned in advance of surgery. Culturing the live cells is often problematic, but a number of private companies across the country offer this service. Costs range from $1000-$2500, depending on the scope of drugs that are tested. Such testing is controversial, in part because the cell population evolves during the process of culturing, which results in cells possibly different in important ways from the original tumor sample. Nevertheless, recent evidence has shown that chemosensitivity testing can enhance treatment effectiveness for a variety of different types of cancer, including a recent Japanese study using chemosensitivity testing with glioblastoma patients (4). However, this study did not involve cell culturing but direct tests of chemosensitivity for cells harvested at the time of surgery. In general, when chemosensitivity testing indicates an agent has no effect on a patient's tumor the drug is unlikely to have any clinical benefit. On the other hand, tests indicating that a tumor culture is sensitive to a particular agent do not guarantee clinical effectiveness, but increase the likelihood that the agent will be beneficial.

The Role of MGMT

A significant advance in determining which patients will benefit from Temodar was reported by the same research group that reported the definitive trial combining Temodar with radiation. Tumor specimens from the patients in that trial were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). full text

Dexamethasone

Most glioma patients will be exposed to dexamethasone (Decadron) at some point, as this corticosteroid is the first-line treatment to control cerebral edema caused by the leaky tumor blood vessels. Many also require dexamethasone during radiotherapy, and perhaps beyond this time if substantial tumor remains post-resection. Dexamethasone is an analog to the body’s own cortisol, but is about 25 times more potent. Though often necessary, dexamethasone comes with a long list of adverse potential side effects with prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, immunosuppression, weight gain, and psychological effects.

New evidence also shows an association between dexamethasone use and reduced survival time in glioblastoma. This evidence has to be weighed against the fact that uncontrolled cerebral edema can be fatal in itself, and that dexamethasone is often required for its control. However, the attempt should always be made to use dexamethasone at the lowest effective dose, and to taper its use after control of edema is achieved, under a physician’s guidance.

In a retrospective study of 622 glioblastoma patients treated at Memorial Sloan Kettering Cancer Center, multivariate regression analysis showed an independent negative association of steroid use at the start of radiotherapy with survival (324). A similar negative association with survival outcomes was found in patients in the pivotal phase 3 trial that led to temozolomide being approved for glioblastoma in 2005, and for a cohort of 832 glioblastoma patients enrolled in the German Glioma Network.

Follow up studies in mice helped elucidate these retrospective clinical observations. In a genetically engineered PDGFB-driven glioblastoma mouse model, dexamethasone alone had no effect on survival, but pretreatment with dexamethasone for 3 days prior to a single dose of 10 Gy radiation negatively impacted the efficacy of radiation. This negative impact of dexamethasone on radiation efficacy was even more dramatic with multiple doses of dexamethasone given before 5 treatments with 2 Gy radiation, which more closely mimics what GBM patients are exposed to. In contrast, an antibody against VEGF, which could be considered a murine surrogate for Avastin, did not interfere with the efficacy of radiation.

In vivo mechanistic examination revealed that dexamethasone may interfere with radiation by slowing proliferation, leading to a higher number of cells in the more radioresistant G1 phase of the cell cycle, and fewer cells in the more radiosensitive G2/M �phase. This finding has far-reaching implications about the potential interference by drugs with cytostatic mechanisms of action on the efficacy of radiation therapy.

The authors conclude by suggesting that antibodies against VEGF, most notably bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation in place of steroids. However, this use has to be weighed in importance against the exclusion from certain promising clinical trials due to prior use of Avastin being an exclusion criteria in some of these trials.

Treatment Categories

Explore the various treatment categories for comprehensive insights and latest developments:

• Repurposed Drugs
• Hormones
• Nutraceuticals
• Antibody-Drug Conjugates and other protein-drug conjugates
• Other Chemotherapy and Cancer Drugs

...

Explore Treatments by Usefulness Rating

Discover treatments that have shown promising results.

	Has treatment name	Usefulness Rating	toxicity_level
Agenus Prophage (Heat-Shock Protein Peptide Complex-96) Vaccine	Agenus Prophage (Heat-Shock Protein Peptide Complex-96) Vaccine	4	2
Anlotinib	Anlotinib	4	3
Anti-CMV Dendritic Cell Vaccine	Anti-CMV Dendritic Cell Vaccine	4	2
BCNU (Carmustine) and Gliadel (Carmustine Wafers)	BCNU (Carmustine) and Gliadel (Carmustine Wafers)	4	4
Bevacizumab (Avastin)	Bevacizumab (Avastin)	4	3
CBD	CBD (Cannabidiol)	4	2
CCNU (Lomustine)	CCNU (Lomustine)	4	4
Cannabis	Cannabis and Cannabis-derived Products (e.g., Sativex)	4	1
Chloroquine	Chloroquine and Hydroxychloroquine	4	1
Chronotherapy	Chronotherapy with Temozolomide (TMZ)	4	Comparable to standard TMZ treatments, but timing affects management of side effects.
Dendritic Cell Vaccine (DCVax-L)	Dendritic Cell Vaccine (DCVax-L)	4	2
Fish oil	Fish Oil (Omega-3 Fatty Acids: EPA and DHA)	4	1
Hyperthermia	Hyperthermia	4	3
ICT-107	ICT-107 (Tumor-associated Antigen Vaccine)	4	2
Keppra	Keppra (Levetiracetam)	4	2
Melatonin	Melatonin	4	1
Metronomic low dose temozolomide (TMZ)	Metronomic Low-Dose Temozolomide (TMZ)	4	3
Next-Generation CAR T-Cell Therapy for GBM	Next-Generation CAR T-Cell Therapy for GBM	4	3
Optune	Optune (Optune Gio® for newer version)	5	2
Proton Radiation Therapy	Proton Beam Therapy (PBT)	4	3
SL-701	SL-701 (Immunotherapy Vaccine)	4	2
Sativex	Sativex (Nabiximols)	4	2
VT-122	VT-122 (Propranolol and Etodolac combination)	4	3
Vitamin D	Vitamin D	4	2
Wilms Tumor 1 (WT1) Peptide Vaccine	Wilms Tumor Peptide Vaccine	4	2

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:

	Drug Name	Usefulness Rating	toxicity_level
Accutane	Isotretinoin (Accutane)	3	3
Celebrex	Celebrex (Celecoxib) and Other NSAIDs	3	2.5
Chloroquine	Chloroquine and Hydroxychloroquine	4	1
Chloroquine and Hydroxychloroquine	Chloroquine and Hydroxychloroquine	Not rated	Not specified
Disulfiram	Disulfiram (Antabuse)	3	2
Keppra	Keppra (Levetiracetam)	4	2
Letrozole	Letrozole	3 - Under investigation	2.5
MN-166	MN-166 (Ibudilast)	3 (awaiting research)	1
Metformin	Metformin	3	2
Methadone	Methadone (D,L-methadone)	3	2
Proton Pump Inhibitors	Proton Pump Inhibitors (e.g., Lansoprazole, Nexium)	3	2
Tamoxifen	Tamoxifen	3	3.5
Thalidomide	Thalidomide	3	4
Trial of three drugs plus temodar	Combination of Repurposed Drugs plus Temodar	3	4
VT-122	VT-122 (Propranolol and Etodolac combination)	4	3
Valproic acid	Valproic Acid/Sodium Valproate (Depakote)	3	3

Nutraceuticals and Herbals

Learn about the potential of nutraceuticals and herbal treatments:

	Drug Name	Usefulness Rating	toxicity_level
CBD	CBD (Cannabidiol)	4	2
CBG	Cannabigerol (CBG)	3	2
Cannabis	Cannabis and Cannabis-derived Products (e.g., Sativex)	4	1
Curcumin	Curcumin	3	1
Ellagic acid	Ellagic Acid	3	1
Fish oil	Fish Oil (Omega-3 Fatty Acids: EPA and DHA)	4	1
Garlic	Garlic (Allium sativum)	3	1
Parthenolide	Parthenolide	3	2
Resveratrol	Resveratrol	3	1
Sulforaphane	Sulforaphane	3	1

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

Explore additional chemotherapy and cancer drug treatments:

	Has treatment name	Usefulness Rating	toxicity_level
BCNU (Carmustine) and Gliadel (Carmustine Wafers)	BCNU (Carmustine) and Gliadel (Carmustine Wafers)	4	4
Bevacizumab (Avastin)	Bevacizumab (Avastin)	4	3
CCNU (Lomustine)	CCNU (Lomustine)	4	4
Gleevec (Imatinib)	Gleevec (Imatinib)	3	3
Platinum Compounds	Platinum Compounds	3	4
Procarbazine	Procarbazine	3	4