Brain Tumor - Glioblastoma

Brain Tumor - Glioblastoma

1 Introduction

Summary and Quick Facts

  • Glioblastoma accounts for roughly 16% of all primary brain and central nervous system tumors and about half of all gliomas. There were about 12,400 new glioblastoma cases in the United States in 2017.
  • This protocol aims to empower people affected by glioblastoma with knowledge about the disease and how it is typically managed, as well as emerging treatment strategies potentially accessible through clinical trials. The protocol will also present evidence for the potential complementary role of dietary and integrative interventions in glioblastoma management.
  • Surgery, radiotherapy, and chemotherapy are currently used to treat glioblastoma, but are far from ideal interventions, as they can cause side effects and have limited efficacy. Good nutrition can help patients manage the side effects of cancer treatment, maintain energy, avoid infections and even fight the disease.

Glioblastoma multiforme is an aggressive type of brain tumor for which new and better treatment options are urgently needed (Paolillo 2018; Alexander 2017). Surgery, radiotherapy, and chemotherapy are currently used to treat glioblastoma, but are far from ideal interventions, as they cause many side effects and have limited efficacy (Paolillo 2018; Arevalo 2017; Bianco 2017; Polivka 2017; Anjum 2017).

Recent cases of glioblastoma in prominent individuals—including Senators John McCain and Edward Kennedy—have helped raise awareness about this harrowing disease (Razmara 2018), and researchers are beginning to uncover promising novel therapies (Polivka 2017). In recent years, tremendous progress has been made toward developing better treatments for glioblastoma (Paolillo 2018).

Emerging evidence has identified a virus called cytomegalovirus (CMV) and a potential relationship with the development of glioblastoma (Dziurzynski 2012; Barami 2010). Also, a groundbreaking study published in 2013 in the New England Journal of Medicine showed that the antiviral drug valganciclovir (Valcyte) improved survival in some glioblastoma patients (Soderberg-Naucler 2013). Pioneering work at Duke University using a bioengineered poliovirus produced remarkable response rates in glioblastoma patients (Brown 2014; Inman 2016). New evidence on the effects of some off-label drugs in glioblastoma has been encouraging as well (Abbruzzese 2017). For instance, drugs such as metformin (Kast 2011) and cimetidine (Berg 2016) have shown promise in laboratory studies. Also, integrative, natural interventions, such as vitamin D, quercetin, selenium, and melatonin are being actively explored, with intriguing preliminary results (Park 2017; Yakubov 2014).

This protocol aims to empower people affected by glioblastoma with knowledge about the disease and how it is typically managed, as well as emerging treatment strategies potentially accessible through clinical trials. This protocol will also present evidence for the potential complementary role of dietary and integrative interventions in glioblastoma management.

This protocol should be consulted along with other relevant protocols, including:

2 Background

There are two main categories of brain cancers: primary cancers, which originate in the brain, and metastatic cancers, which originate elsewhere in the body and spread to the brain. Primary brain cancers may affect people of all ages, although they occur most frequently in children and older adults (ABTA 2014a). This protocol focuses on primary brain cancers and glioblastoma in particular.

Primary brain cancers are usually named after the type of brain cells from which the tumor arises (ABTA 2014b). Gliomas are tumors formed from glial cells (NCI 2018). Glial cells provide support and nutrition to neurons, the cells that transmit signals in the brain (ABTA 2014b). Primary brain tumors are given a tumor grade based on how normal the tumor cells look when viewed under a microscope (NCI 2018; NCCN 2016). The tumor grade provides some information on how quickly a tumor is likely to grow and spread to other tissues. Grade I tumor cells largely resemble normal cells and are referred to as “well-differentiated.” Glioblastoma is a grade IV glioma. The tumor cells do not look like normal cells and are referred to as “undifferentiated.” Glioblastomas tend to grow rapidly and spread into neighboring brain tissues faster than lower-grade tumors. Unlike many other types of grade IV cancers, however, glioblastoma does not usually spread to other organs outside the central nervous system (brain and spinal cord) (Costa 2017; Wu 2017; Seo 2012).

Glioblastoma accounts for roughly 16% of all primary brain and central nervous system tumors and about half of all gliomas (Ostrom 2014; Ostrom 2018; Thakkar 2014). There were about 12,400 new glioblastoma cases in the United States in 2017 (ABTA 2014a).

3 Risk Factors

Glioblastoma does not have a single definitive cause, but several factors have been identified (Weller 2013).

Gender

Men are about 50% more likely to develop glioblastoma than women (Davis 2016; Urbanska 2014; Ostrom 2014). Also, a woman’s risk goes up after menopause (Urbanska 2014). This finding, along with evidence that some gliomas express estrogen receptors, has led to the suggestion that hormones may play a role in the disease (Felini 2009; Andersen 2015; Lan 2017). However, much more research in this area is needed (Lan 2017; Urbanska 2014).

Age

The chances of developing glioblastoma increase with age and peak at age 75 to 84 years (Ostrom 2013). Because the average lifespan of people in industrialized countries continues to increase, the median age when glioblastoma is diagnosed has risen to 64 years (Ostrom 2013; Thakkar 2014).

Heritage and Genetics

Glioblastoma is about twice as common in people with European-American ancestry than in those with African-American ancestry (Thakkar 2014; Urbanska 2014). Also, an increased risk of glioblastoma can be inherited within families. About 10 genetic mutations that increase risk of developing glioma have been identified, but most of them confer a relatively small increase in risk (Rice 2016). Glioblastoma may also result from genetic diseases such as tuberous sclerosis, Turcot syndrome, multiple endocrine neoplasia type IIA, and neurofibromatosis type I (Rice 2016; Urbanska 2014).

Radiation Exposure

People who have been treated with radiation for medical conditions affecting their ears or skin have an increased risk of developing brain tumors (Bondy 2008; Hanif 2017). In addition, radiation to the head for childhood cancers is also a risk factor for brain cancer development later in life (Urbanska 2014; McNeill 2016; Alexander 2017). Some limited evidence suggests repeated CT scans of the head and neck region may increase glioma risk in some patients, although these findings have not been firmly established (Davis 2011).

Body Composition

Greater height has been associated with increased glioma and glioblastoma risk (Wiedmann 2017; Kitahara 2012). One study found that men over 190 centimeters (about six feet three inches) were about twice as likely to develop glioblastoma as men between 170 and 174 centimeters (Kitahara 2012). Interestingly, additional data suggest people who finished growing at a later age were more likely to develop gliomas (Little 2017).

Non-Ionizing Electromagnetic Radiation Exposure

Between the mid-1990s and early 2000s, the use of mobile and cordless phones increased rapidly (Carlberg 2014). These devices emit electromagnetic radiation from their antennas. Laboratory studies demonstrated that brain cells can be affected by electromagnetic fields (Xu 2017; Kaplan 2016). Whether mobile phone use is related to the development of brain tumors has been the subject of much debate (Urbanska 2014).

In 2011, the World Health Organization International Agency for Research on Cancer warned that the electromagnetic fields generated by mobile phones and other devices that emit similar non-ionizing electromagnetic radiation are “possibly carcinogenic to humans” (Baan 2011; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans 2013; Carlberg 2014). This decision was based on data collected from human case-control studies (Carlberg 2014). A 2017 review and meta-analysis found that long-term mobile phone use (10 years or more) significantly increased the risk of glioma, but also emphasized that the available evidence is of low quality and more original research is needed before a better conclusion can be drawn (Yang 2017). Non-ionizing radiation emitted by cells phones doesn’t damage DNA directly, but researchers have proposed several other mechanisms by which cell phone radiofrequency waves may promote cancer (Havas 2017; Carlberg 2017). More research is needed to clarify the relationship, if any, between cell phone use and brain cancers.

Cytomegalovirus

Emerging evidence has explored whether a virus called cytomegalovirus (CMV) may be related to the development of glioblastoma (Dziurzynski 2012; Barami 2010). Approximately 50% to 80% of adults in the United States have been exposed to CMV, but relatively few have an active viral infection (CDC 2017). A study published in the New England Journal of Medicine described several important findings regarding the relationship between CMV and glioblastoma (Soderberg-Naucler 2013). Of the more than 250 glioblastoma patients, the authors detected the presence of CMV in all but one of the participants. Moreover, patients with lower numbers of virus-infected tumor cells survived 33 months on average, while those with higher numbers survived only 13 months. The authors speculated that CMV infection accelerated tumor progression (Soderberg-Naucler 2013; Rahbar 2013). Studies to validate this research have had mixed results, and researchers continue to study whether CMV has a role in the development of glioblastoma or whether it can affect the course of the disease (Garcia-Martinez 2017; McFaline-Figueroa 2017).

4 Signs and Symptoms

Signs and symptoms of glioblastoma depend on the size of the tumor and its location within the brain. Headaches are often an initial symptom caused by the pressure placed on the inside of the skull or on the brain's ventricular system. Nausea and vomiting are also common symptoms. Seizures occur in about one-quarter of patients with newly diagnosed glioblastoma and are usually controlled with anticonvulsant drugs throughout the course of the disease (Batash 2017; Alexander 2017; Reni 2017; DeAngelis 2012; NCCN 2016).

Tumors in some parts of the brain may cause weakness or numbness in the arms, legs, or face; loss of vision; or changes in speech. More subtle symptoms, such as cognitive dysfunction, mood disorders, personality changes, fatigue, and mild memory problems can also be observed in patients with larger tumors located in the frontal or temporal lobes, or in the corpus callosum, a structure that connects the two hemispheres of the brain (DeAngelis 2012; NCCN 2016; Alexander 2017; Batash 2017; Reni 2017).

5 Diagnosis

Imaging

Magnetic resonance imaging (MRI) is the gold standard non-invasive imaging approach to test whether someone has glioblastoma (Urbanska 2014; Batash 2017; Rees 2011). This test uses a magnetic field and radio waves to generate images of the brain. It can not only find tumors but also provide information that helps guide treatment decisions (NCCN 2016; Mullen 2017). Some imaging tests use a dye called gadolinium, which is injected into a patient's vein. This dye provides what is referred to as “contrast” and helps distinguish tumor tissue from normal tissue. Patients with suspected glioblastoma may have MRI scans both with and without contrast (Davis 2016; Felix 1985).

Other types of imaging tests may be used to complement MRI findings. One of these tests, called MR perfusion, can measure blood flow in tumors and requires a contrast dye (NCCN 2016; Abrigo 2018). Another imaging test called MR spectroscopy couples MRI scans with tests to determine what kinds of chemicals are present in the tumor and in the normal surrounding tissues (NCCN 2016; Mullen 2017).

A computed tomography (CT) scan is an imaging test usually reserved for patients who cannot undergo an MRI for various reasons (NCI 2018). For example, patients with pacemakers, or those with certain kinds of cardiac monitors or surgical clips are not candidates for MRI because of the magnetic fields that MRI requires (NCCN 2016). CT scans use X-rays instead of magnetic fields and are also done with and without contrast to provide detailed pictures of the brain.

Additional, more sophisticated imaging tests may be needed to distinguish glioblastomas from cancers that spread from other body parts to the brain (Kamson 2013; Fink 2013; Neska-Matuszewska 2018).

Biopsy

Although MRI and CT scans can provide valuable information regarding the features of glioblastoma, actual brain tissue is required for a definitive diagnosis (NCI 2018; Urbanska 2014). During a procedure called a biopsy, a small sample of the brain tumor tissue is removed for further analyses under a microscope (NCI 2018; NCCN 2016). The tumor tissue from a biopsy is analyzed by a doctor called a pathologist. In addition to confirming glioblastoma, the pathologist may also request a molecular analysis of the tumor (Davis 2016).

Some tumors are biopsied during a surgical procedure (NCI 2018; NCCN 2016). For those patients, the tumor may be removed at the same time. For brain tumors located in parts of the brain that are difficult to reach or in areas that are vital for survival, a stereotactic biopsy is preferred. This method uses fine computer-guided instruments and produces less trauma. However, about 2% of stereotactic biopsies result in hemorrhages that impair brain functioning (DeAngelis 2012; NCCN 2016).

Biomarker-Guided Treatment Decisions

Temozolomide (Temodar), a type of drug called an alkylating agent, causes damage to the DNA of cancer cells. The MGMT gene encodes a DNA repair protein (NCI 2018). When the MGMT protein is abundant in cancer cells, the cells can repair the damage caused by temozolomide and survive.

In some glioblastomas, the MGMT gene is inactivated in a process called DNA methylation (NCCN 2016). These tumors have very little or no MGMT protein available to repair the damage caused by temozolomide. As a result, these tumors tend to respond well to temozolomide (Thomas 2017).

Temozolomide usually has to be given in high doses, and prolonged administration may lead to side effects, which may be more severe in older patients (Lee 2017; Saito 2014; Straube 2017). Testing a patient’s tumor for MGMT methylation has become a valuable biomarker to predict their response to temozolomide, and can help them and their doctors decide whether they are good candidates (Fernandes 2017; Snyder 2017; Seystahl 2016). Patients without MGMT methylation might be better candidates for other therapies, such as radiation therapy instead (Malmstrom 2012; NCCN 2016; Thon 2013; Hau 2016).

Assessing Prognosis

Another part of the diagnostic process involves gathering information on a patient's prognosis, which is an estimation of the likely course of his or her disease. A small group of prognostic factors associated with improved patient outcomes have been identified for patients with glioblastoma (Theeler 2015):

  • Age 50 or less (Lacroix 2001)
  • A score of 70 or more on an assessment tool for functional impairment called the Karnofsky Performance Scale (KPS) Index (lower scores indicate greater levels of impairment) (Lacroix 2001)
  • A tumor not located in an “eloquent” brain location, including areas involved in speech, vision, movement, the thalamus, basal ganglia, and internal capsule (Theeler 2015; Awad 2017)
  • A tumor that can be completely or almost completely removed in surgery (Lacroix 2001; Li, Suki 2016)
  • Molecular features of the tumor, such as MGMT methylation or mutations in a gene called IDH1 (Theeler 2015; NCCN 2016; Chen 2017)

6 Participating in a Clinical Trial

Before any new cancer tests or treatments are made available, they must first pass through a series of clinical trials to ensure that they are effective and safe in patients. For some patients with glioblastoma, participation in one of these clinical trials may be the best or perhaps only option. Ask your medical team about available clinical trials when they are presenting treatment options and work with them to decide if being part of a clinical trial is right for you.

Clinical trials that eventually lead to approved treatments are conducted in five phases (IOM 2012; Kummar 2008; Prielipp 2016):

  • Phase 0 clinical trials are preliminary trials that enroll few (10‒15) people to examine whether an intended drug would have an effect on the human body, as predicted from laboratory and animal studies. These trials determine whether further clinical development should proceed.
  • Phase I clinical trials involve a small number of people (around 20‒80). They mostly focus on testing the safety of a drug, and seek to find the highest dose of the drug that can be given safely and without the risk of adverse effects.
  • If a drug has passed phase I, it moves on to a phase II clinical trial. In phase II clinical trials, which involve larger groups of people (100‒300), researchers gather data on how effective the drug is for treating a specific type of disease, and study its safety in more detail.
  • If phase II results are promising, phase III clinical trials are conducted to compare the new drug to the standard treatment. These trials usually involve large numbers of people (hundreds or thousands) and are critical for demonstrating the value of the new drug to the Food and Drug Administration (FDA) and the medical community.
  • Lastly, phase IV trials are conducted on already-approved treatments to examine their long-term effects on even larger groups of people. Sometimes phase IV trials examine other potential benefits of the drug or discover additional side effects.

Clinical trials have strict rules on who can participate. For instance, a trial might be restricted to patients who have not yet been treated for their disease or have tumors with a specific characteristic.

Participation in a trial has some risks, such as unexpected side effects, and the new treatment may not be effective. However, participants may be among the first to have access to cutting-edge treatments and will receive the highest standard of patient care. Regardless of the trial outcome, every participant helps researchers improve treatment options for future patients.

The following websites may be helpful for finding out more about clinical trials and clinical trial participation:

7 Conventional Treatment

Determining the Treatment Approach

Glioblastoma is notoriously difficult to treat effectively, partly because every patient’s tumor has different molecular and cellular characteristics. These characteristics can vary even within the same tumor. Research continues to examine ways to personalize glioblastoma treatment, with the hope of improving outcomes by creating a treatment plan specific for each tumor’s unique characteristics. Most treatment planning is still based largely on more general characteristics, such as patient age, functional status (KPS Index score), and more recently, MGMT methylation status (Thon 2013; Weller 2012; Colombo 2015). Initial surgery is the mainstay of treatment for most people with glioblastoma, followed by radiotherapy and/or chemotherapy (NCCN 2016; Stupp 2005).

Surgery and Local Chemotherapy

Surgery is an essential part of glioblastoma treatment (NCCN 2016). Surgical removal (resection) of a glioblastoma tumor can relieve symptoms, extend life, and decrease the need for corticosteroids to reduce brain swelling. The amount of tumor that can be removed through surgery depends on its location, as well as the patient's age and health status. Ideally, surgeons aim for what is referred to as a maximum safe resection, which will remove most or all of the tumor (Roder 2014; Kuhnt 2011; Li, Suki 2016). In some cases, glioblastoma tumor cells spread in different directions so that the tumor may not be a simple solid mass, making total resection impossible (Davis 2016). Within three days after surgery, and preferably within the first 24 hours, MRI scans are necessary to determine how much of the tumor was removed. For those unable to undergo MRI, CT scans with and without contrast can be performed (Pirzkall 2009; Sanghvi 2015; Kumar 2013).

During surgery, some patients may be treated with a form of chemotherapy delivered locally to the tumor site (NCCN 2016; Zhang, Dai 2014). A drug called carmustine is contained in a wafer, and up to eight wafers may be placed into the space where the tumor was. Placing the wafers directly into the brain helps the drug target any remaining tumor cells without damaging healthy cells in other parts of the body (NCI 2018). The wafers dissolve over time after surgery (Mangraviti 2015). Although this form of chemotherapy may extend the life of the patient, it can cause complications (Lara-Velazquez 2017; Bock 2010). For example, carmustine may interact with some other drugs and increase their toxicity (NCCN 2016). Also, some patients may experience swelling in the brain, seizures, healing problems, or local infections (Sabel 2008; Giese 2010).

Systemic Chemotherapy

Unlike carmustine wafers, some other chemotherapeutic drugs are delivered to the whole body through the bloodstream. This is called “systemic” therapy and is accomplished by using pills taken orally or liquids injected into a vein (NCCN 2016). Some patients will only receive one drug, usually the alkylating agent temozolomide. Temozolomide damages the DNA (Erasimus 2016). Cancer cells are growing and dividing rapidly and are more sensitive to DNA damage (O'Connor 2015; Baskar 2014). Tumors with MGMT methylation may be more sensitive to alkylating agents (Fernandes 2017; Davis 2016). For some patients, several drugs are used to fight the cancer in multiple ways (NCCN 2016).

Because systemic chemotherapy can be hard on a patient’s body, the treatments are normally spaced out in a series of cycles, typically two to four weeks each (NCCN 2016). Side effects of systemic chemotherapy will depend on the drug, dose, and individual patient. Because chemotherapy drugs typically target rapidly dividing cells, healthy cells that also divide rapidly, such as those in the digestive tract, blood, and hair follicles, may also be affected by the drug. Common side effects of systemic chemotherapy include low blood cell counts, loss of appetite, nausea, fatigue, vomiting, diarrhea, hair loss, and mouth sores (Hershman 2008; Rahnama 2015; Stein 2010; Mustian 2011).

More general information about chemotherapy, including strategies to reduce chemotherapy side effects, is available in the Chemotherapy protocol.

Temozolomide Resistance

Temozolomide has improved glioblastoma treatment outcomes over the past two decades. However, not all cancers are sensitive to temozolomide, and even those that start out sensitive typically develop ways to overcome the drug (Ramirez 2013).

Finding ways to overcome or prevent temozolomide resistance is a critical area of research. Many of the compounds discussed in the Integrative Interventions section, such as melatonin, vitamin D, and selenium, are being tested in laboratory studies to see if they can make glioblastoma cells more sensitive to temozolomide.

Repurposed drugs like metformin and cimetidine are also being analyzed in the same way. In one recent study, researchers selected 21 drugs promising or already known to work against various kinds of cancer (Teng 2017). They tested whether the drugs would make glioblastoma cells more sensitive to temozolomide. One drug called hydroxyurea, a treatment for sickle cell disease and some types of cancer, was clearly the standout. Hydroxyurea sensitized all types of glioblastoma cells and tumors in mice to temozolomide, regardless of the MGMT methylation status.

Another drug called trans sodium crocetinate (TSC) is designed to make tumors more sensitive to temozolomide and radiation, possibly by increasing the oxygen content (Sheehan 2010). In a phase II clinical trial, 36% of patients treated with TSC in addition to temozolomide and radiation were still alive after two years (Gainer 2017). Preparation for a phase III clinical trial is currently underway to compare TSC-treated patients to a control group.

Antiangiogenesis Therapy

Tumors rely on the growth of new blood vessels or angiogenesis to provide nutrition to each cell. A monoclonal antibody called bevacizumab (Avastin) prevents angiogenesis by blocking the vascular endothelial growth factor (VEGF) signaling pathway (NCCN 2016). VEGF signaling is often increased in glioblastoma tumors and contributes to tumor growth. Bevacizumab was approved in 2009 for treatment of recurrent glioblastoma (Davis 2016). A review study found that bevacizumab could improve patients’ median survival by four months for recurrent glioblastoma, as compared to those not taking the drug (Diaz 2017). Side effects can occur with bevacizumab, and patients must be monitored for excessive bleeding or blood clots (Diaz 2017; Davis 2016).

Radiation Therapy

Some glioblastoma tumors cannot be surgically removed. Patients in these situations are treated with radiation therapy (NCCN 2016; Tamura 2017). Additionally, radiation therapy can be used to treat patients after surgery, with the goal of killing any cancer cells that may have been left behind (NCI 2018). This form of therapy uses high-energy, highly focused rays to damage and destroy cancer cells. Modern radiation therapy uses techniques designed to minimize damage to nearby healthy tissues (Narayana 2006; Gzell 2017). Most patients with glioblastoma receiving radiotherapy will be treated with a method called external beam radiation therapy (EBRT), in which radiation from a large machine passes through the skin and bone and into the brain tissue (NCCN 2016). The treatment machinery is adjusted to deliver radiation as carefully as possible to the tumor area, limiting exposure to healthy tissue.

For more complete information on radiation therapy techniques and side effects, see the Radiation Therapy protocol.

Tumor-Treating Fields

Tumor-treating fields, or alternating electric field therapy, is a technique that utilizes low-intensity electromagnetic energy to stop cells from dividing (Fernandes 2017; Hottinger 2016). The treatment uses patches taped to the patient's head and a portable battery-powered device (NCCN 2016; Saria 2016). The patches must be worn at least 18 hours per day. This technique is relatively safe, and mild-to-moderate local skin irritation is the most commonly reported side effect (Fernandes 2017).

In a 2017 randomized controlled trial, 695 people with glioblastoma were treated with tumor-treating fields along with temozolomide or temozolomide alone. The median time to survival without disease progression was 6.7 months in the tumor-treating field group, as compared with 4 months in the temozolomide-only group (Stupp 2017). The FDA initially approved tumor-treating fields for patients with recurrent glioblastoma in 2011, and expanded that approval in 2015 to include patients newly diagnosed with glioblastoma (Fernandes 2017).

Follow-Up and Continuing Care

MRI scans should be conducted two to six weeks after the end of radiation therapy (NCCN 2016). Additional scans should be performed every two to four months to check for any new brain tumors as early as possible. Those who cannot undergo MRI (such as those with certain types of pacemakers or defibrillators) can receive CT scans with and without contrast.

Most glioblastomas grow back (Stupp 2005; Davis 2016). MR spectroscopy, MR perfusion, or another scanning technique called positron emission tomography (PET) may help confirm recurrences (NCCN 2016). Treatment options for recurrences are similar to options for newly diagnosed disease. Surgery with or without carmustine wafers may be an option for recurrent tumors that are not widespread. In some cases, the goal of surgery is to alleviate symptoms (Davis 2016). For recurrences, systemic chemotherapy, radiation therapy, bevacizumab, and tumor-treating field therapy may be used (Fernandes 2017).

Supportive Care

Supportive (or palliative) care is not intended to treat the cancer, but may enhance the patient’s quality of life and alleviate symptoms (Davis 2016; NCCN 2016). Examples of supportive interventions include the use of glucocorticoids, a type of steroid, to reduce swelling in the brain. Additionally, supportive care may involve treating a patient's depression or fatigue, decreasing delirium or agitation, improving cognition, and controlling seizures (Seekatz 2017; Koekkoek 2016). Supportive care may be the only option for patients with advanced or recurrent glioblastoma.

8 Novel and Emerging Strategies

There are several intriguing glioblastoma therapies supported by emerging evidence. One way to gain access to some of these therapies may be through participation in a clinical trial. Ask your medical team about available clinical trial options. Alternatively, innovative physicians familiar with the latest research may be willing to incorporate some of the more widely available off-label drugs described here into a conventional treatment plan.

Immunotherapy

Immunotherapy is a major research focus in the field of oncology. Under healthy conditions, the immune system is able to keep cancer in check (Finn 2018). However, some cancer cells develop the ability to escape the immune system (Beatty 2015). Once cancer cells that are not vulnerable to immune destruction have established themselves in a person’s body, a tumor can start to form (Marcus 2014).

Immunotherapy aims to manipulate the patient’s immune system to enable it to once again attack and eliminate cancer cells (Marin-Acevedo 2018). Recent advances in using immunotherapy for various cancers opened interest towards applying this strategy for glioblastoma, and a better understanding of the tumor microenvironment is critical for these developments (Boussiotis 2018). Researchers are investigating many different types of immunotherapies for glioblastoma (Felthun 2018).

For example, a very novel form of immunotherapy was presented in a recent phase I study on a 50-year-old man with recurrent glioblastoma (Brown 2016). In this study, the investigators created a chimeric antigen receptor–engineered (CAR) T cell, which had been designed to target a marker expressed by many glioblastoma cells, called interleukin-13 receptor alpha 2 (Brown, Badie 2015). The patient received treatment with these cells, which were injected into his brain over a period of 220 days (Brown 2016). The patient had a dramatic clinical response without any serious negative effects. His original tumors disappeared and the response continued for 7.5 months. However, his cancer recurred at new sites after treatment was stopped. Given these intriguing findings, the researchers are expanding an ongoing study to administer the CAR T cells to more patients and are optimizing the treatment (Brown 2018; Brown 2016). CAR T cells have been designed to target other glioblastoma markers, including HER2 and a form of the epidermal growth factor receptor (Migliorini 2017; Ahmed 2017).

In 2013, research conducted at Duke University Medical Center reported complete clinical responses in patients with recurrent glioblastoma that were treated with a modified poliovirus that had been altered using genetic material from a rhinovirus (a type of virus that causes common colds). This poliovirus-rhinovirus hybrid, called PVSRIPO, is engineered to not infect non-cancerous cells (Brown 2014; Brown, Gromeier 2015; Desjardins 2013). However, because glioblastoma cells commonly have high levels of a receptor that binds to poliovirus, the poliovirus hybrid can infect them and trigger cell death (Goetz 2011). In addition, molecules released from the dying cells activate immune and inflammatory responses that help destroy the cancer cells (Brown, Gromeier 2015; Holl 2016; Brown 2017; Denniston 2016). Due to positive reports from early research and lack of effective therapies for glioblastoma, PVSRIPO received “breakthrough therapy” designation from the FDA in May 2016, allowing further investigations to proceed rapidly (Fong 2016; Holl 2016).

A phase I clinical trial designed to identify optimal doses for future clinical trials enrolled 61 patients with recurrent high-grade glioblastoma. Varying doses of PVSRIPO were applied directly to their tumors using catheters. A survival rate of 21% was noted at both 24 and 36 months among those treated with PVSRIPO versus 14% at 24 months and 4% at 36 months in a comparison group of 104 similar patients not treated with this therapy. The non-infectiousness of PVSRIPO was confirmed, and while adverse effects occurred frequently, only one treatment-limiting side effect was observed in a participant receiving the maximum tested dose (Desjardins 2018). Information about current and future clinical trials using this promising therapy can be found at www.ClinicalTrials.gov.

Cancer vaccines, a type of immunotherapy earning much attention in recent years, may be effective against brain tumors (Paolillo 2018; Steiner 2004; Huang 2017). One anticancer vaccine in clinical trials, called SurVaxM, targets a protein called survivin (Fenstermaker 2016). Survivin is commonly expressed in glioblastoma cells and normally protects cancer cells from death (Saito 2017; Tang 2015; Mellai 2008). The vaccine is designed to cause the body's immune system to develop an immune response against survivin, just like a flu vaccine makes the body recognize the virus that causes flu. Early studies showed that the vaccine produced an anti-tumor immune response against gliomas in mice (Fenstermaker 2014). In a phase I trial of patients with recurrent glioblastoma, SurVaxM was safe and improved outcomes for trial participants. The patients on average went 17.6 weeks without worsening of their disease and survived an average of 86.6 weeks (Fenstermaker 2016). This early trial did not have a control group, but a similar patient group would be expected to survive only about 25 weeks (Wong 1999). The FDA has granted SurVaxM orphan drug status, and a larger trial of SurVaxM in combination with standard therapy is underway as of early 2018 in patients with newly diagnosed glioblastoma (Fenstermaker 2018).

Another vaccine under development for treating glioblastoma is called DCVax-L. This strategy involves modulating the patient’s immune cells in the lab so they are primed to attack the patient’s specific cancer (Polyzoidis 2015; Polyzoidis 2014). The cells are then re-introduced into the patient’s body. Promising results were noted in a phase II trial, and a phase III trial is underway as of the time of this writing in early 2018 (Hdeib 2015; Felthun 2018).

Aptamers

Aptamers are small chains of nucleic acids (Lakhin 2013). Like monoclonal antibodies, these small molecules can be designed to recognize and bind specific targets, such as those that occur in glioblastoma cells (Yang 2007). Aptamers have the advantage of being much smaller than antibodies and thus can penetrate into tissue—including the central nervous system—more efficiently (Catuogno 2017). Researchers are exploring ways to use aptamers to improve imaging in the brain (Tang 2017), but they may also be useful for treating brain tumors. For instance, chemotherapy agents can be attached to aptamers designed to target specific markers on a patient’s cancer cells. Numerous aptamers that target different markers on glioblastoma cells are being developed. Laboratory research continues to improve the structure and potential utility of aptamers, with the hope of starting clinical trials soon (Hays 2017).

Metformin

Metformin, a first-line drug for diabetes, can pass from the bloodstream into the brain (Yarchoan 2014). A number of preclinical studies have shown that metformin may inhibit the division and migration of glioblastoma cells (Seliger 2016; Aldea 2014; Wurth 2014; Ferla 2012; Carmignani 2014; Gritti 2014). In laboratory studies, metformin stopped glioblastoma stem cells from dividing (Gritti 2014), and metformin and arsenic trioxide helped differentiate glioblastoma stem cells into non-tumorigenic cells (Carmignani 2014). 

The anticancer effects of metformin may result in part from activation of the enzyme AMP-activated protein kinase (AMPK) and inactivation of the transcription factor STAT3 (Ferla 2012; Elmaci 2016; Leidgens 2017; Sato 2012). AMPK is an important regulator of glucose and fatty acid metabolism that promotes healthy aging and extends lifespan (Burkewitz 2014; Riera 2016), while STAT3 controls cell growth and survival and is activated in many cancer types (Demaria 2014; Carpenter 2014).

Metformin may synergize with some existing cancer treatments. For example, in one study, metformin improved the ability of temozolomide to destroy human brain cancer cells (Soritau 2011). A separate study used a type of glioblastoma cells that were not responding to temozolomide. Treatment with metformin made the cells sensitive to temozolomide (Yang 2016). In mice with experimentally induced glioblastoma, metformin improved the effects of temozolomide, and in cell culture studies, it improved the effects of radiation therapy (Sesen 2015; Yu 2015). In another study, mice with glioblastoma treated with high-dose metformin combined with temozolomide lived significantly longer than those treated with metformin or temozolomide alone (Lee 2018). An angiogenesis inhibitor called sorafenib (Nexavar) was also more effective when combined with metformin in laboratory research (Aldea 2014). In another laboratory study, metformin sensitized glioblastoma cells to radiation or radiation combined with temozolomide (Adeberg 2017). Additional findings from animal research showed that metformin decreased brain swelling and reduced the leakiness of the blood vessels (Zhao 2016).

Initial data in human glioblastoma patients have also been encouraging. One study analyzed data from 276 glioblastoma patients treated with either radiation or radiation plus temozolomide. Forty of the patients had diabetes, and 20 of these were taking metformin. Survival time without evidence of disease worsening was significantly longer in diabetics receiving metformin (10 months) than in other diabetics (less than 5 months) and nondiabetics (7 months) (Adeberg 2015). As of early 2018, there are five clinical trials (two phase II and three phase I) registered with ClinicalTrials.gov that address the potential benefits of metformin in people with glioblastoma (ClinicalTrials.gov 2018). Results of these trials will help establish the value of metformin as an adjuvant therapy for glioblastoma.

Cimetidine

Cimetidine is another intriguing off-label drug that may have potential as a brain tumor treatment. This common heartburn drug has several unanticipated effects, including anti-tumor activity against several types of cancer (Pantziarka 2014). In an animal model of human glioblastoma, combining cimetidine with temozolomide prolonged survival compared with temozolomide alone (Berg 2016). A small 2017 study on seven glioblastoma patients found that a cocktail of drugs (cimetidine, lithium, olanzapine, and valproate) led to longer-than-expected survival; the mechanism by which this cocktail improved survival was thought to involve inhibition of the enzyme glycogen synthase kinase 3 beta (GSK3β), a molecule involved in glioblastoma progression (Furuta 2017).

Valganciclovir

Valganciclovir is an FDA-approved drug used to treat CMV infection (Kalil 2009). In a phase I/II clinical trial of valganciclovir involving 42 patients with glioblastoma, an exploratory analysis of 22 patients receiving at least six months of antiviral therapy found that 50% were still alive after two years compared with 20.6% of the control group not receiving valganciclovir. After four years, about 27% of patients who received valganciclovir for greater than six months and almost 6% of control participants were still alive (Stragliotto 2013). In a similar study, researchers compared data from glioblastoma patients treated with valganciclovir and a control group. Both groups received standard conventional therapy and had similar disease characteristics. After two years, 62% of the valganciclovir group and 18% of the control group were still alive. Among the 40 patients who received valganciclovir for at least six months, 70% were still alive after two years (Soderberg-Naucler 2013).

Based on these results, patients with glioblastoma and evidence of CMV-positive tumor tissue should consider consulting with their oncologist to see if they are eligible to receive the treatment protocol described in the aforementioned studies (Soderberg-Naucler 2013; Stragliotto 2013), which resulted in unprecedented survival improvements. The patients took 900 mg of valganciclovir twice daily for three weeks and then 450 mg twice a day. The dose can be adjusted if any side effects arise such as kidney impairment or bone marrow suppression.

Dichloroacetate

Dichloroacetate is an investigational drug that has shown benefits for certain genetic diseases (Stacpoole 2008). In recent years, dichloroacetate has gained attention for its ability to kill cancer cells and enhance the activity of other cancer therapies (Kankotia 2014).

Early research has been promising: an open-label phase I trial on 15 adults with grade III or IV gliomas or brain metastases from other cancers found that dichloroacetate treatment was feasible and well-tolerated (Dunbar 2014). A similar trial in 24 patients with advanced solid tumors used 28-day cycles of dichloroacetate at different doses and found only mild side effects; this trial was not designed to assess how well the treatment worked (Chu 2015). This research built on an earlier, smaller trial on five glioblastoma patients treated with dichloroacetate for up to 15 months (Michelakis 2010). The authors found evidence of glioblastoma cell death and reduced formation of new blood vessels (angiogenesis) in these patients’ tumors. Studies on cancer cells in the lab have also shown that dichloroacetate increases cancer cell death and decreases angiogenesis, which is necessary for tumors to spread (Dunbar 2014; Michelakis 2010). Dichloroacetate also has been found to make the inside of the glioblastoma cells dramatically more acidic, which may inhibit their growth (Albatany 2018). Ongoing research into the therapeutic potential of dichloroacetate in solid cancers is likely to focus, at least in part, on finding the best dose, as individual responses vary widely (James 2017; James 2016).

Antidepressants

Antidepressant drugs are also being examined for possible effects on glioblastoma cells. For example, fluoxetine (Prozac), a common antidepressant drug, has been shown to selectively kill glioblastoma cells in laboratory experiments (Liu, Yang 2015). Additionally, fluoxetine may reduce the amount of MGMT in glioblastoma cells and make them more sensitive to temozolomide (Song 2015). Other antidepressant drugs, such as imipramine (Tofranil) and amitriptyline (Elavil), have been shown to stop glioblastoma stem cells from producing more stem cells (Bielecka-Wajdman 2017).

Rapamycin and mTOR Inhibition

Rapamycin is an immunomodulating drug first identified in soil samples from Easter Island in the 1970s. Since its discovery, much has been learned about how rapamycin functions in the body. The drug inhibits signaling through a pathway called the mammalian target of rapamycin (mTOR). The mTOR signaling pathway integrates growth signals with cellular metabolism and is involved in many cellular processes, including growth, cell division, protein synthesis, and cell death (Li 2014; Laplante 2012; Jhanwar-Uniyal 2017). To perform its cellular activities, mTOR functions as part of two distinct multi-protein complexes, mTORC1 and mTORC2, which have different functions and respond differently to rapamycin (Masui 2015; Neil 2016; Jhanwar-Uniyal 2017). Studies in recent years have identified many interesting properties of the mTOR pathway, and revealed its potential as a target for cancer therapy.

In glioblastoma, increased mTOR signaling has been linked to stem cell proliferation, relapses, and resistance to treatment. In a study that used glioblastoma cells obtained from patients, rapamycin inhibited cell growth, and in mice that had human-derived glioblastomas, it almost doubled the survival time of the animals (Arcella 2013). In another study, rapamycin reduced the proliferation of glioblastoma cancer stem cells and their tumorigenic potential (Mendiburu-Elicabe 2014).

Results of clinical studies using rapamycin have been modest or uncertain (Chheda 2015; Fan 2018).

Rapamycin showed benefits in a phase I clinical trial in certain patients with glioblastoma (Cloughesy 2008), but results from phase II clinical trials were not promising. At least in part, this is explained by the interaction with other signaling pathways (Li, Wu 2016). Additionally, even though targeting mTOR is a promising strategy for glioblastoma, neither of the two complexes is completely inhibited by rapamycin or rapamycin analogs. However, an experimental compound that inhibited both mTORC1 and mTORC2 together was able to block the growth and migration of glioblastoma cells, underscoring the promise of this approach (Neil 2016). The combined inhibition of the two complexes was also underscored as a promising therapy by other studies on glioblastoma (Gulati 2009; Luchman 2014; Kahn 2014).

As of the time of this writing, researchers are exploring ways to manipulate the mTOR pathway that might improve outcomes for people with glioblastoma. Existing drugs that target mTOR do not appear well suited as glioblastoma therapies for the time being.

9 Dietary and Lifestyle Considerations

The American Cancer Society and American Brain Tumor Association have several dietary and lifestyle recommendations for cancer patients. Good nutrition can help patients manage the side effects of cancer treatment, maintain energy (Toles 2008), avoid infections (Di Furia 2015), and even fight the disease. In general, patients’ diets should be rich in a variety of vegetables and healthy sources of protein and unsaturated fats (ACS 2015; Vanderwall 2012; Toles 2008). For some patients, an exercise program may improve mood and quality of life (Levin 2016).

Ketogenic Diet

The ketogenic diet emphasizes healthy fats and proteins with very little carbohydrates (typically less than 20 grams net carbohydrates daily) (Winter 2017; Paoli 2015; Westman 2008). This diet is sometimes recommended to reduce seizure frequency in children and adults with epilepsy, but may also be helpful in those with glioblastomas because these tumors are known to rely on carbohydrates for energy (Varshneya 2015; Winter 2017).

A ketogenic diet has been found to control tumor growth and prolong survival in animal studies (Varshneya 2015; Klement 2016). Other studies have found that the diet may boost immune response to tumor cells and provide benefits when used in combination with other treatments, such as radiation (Lussier 2016). In humans, the diet is well tolerated and safe (Champ 2014). Blood tests can be used to check how well the diet is reducing blood glucose levels and increasing ketone levels (Meidenbauer 2015). Several phase I or II interventional trials have been conducted or are underway to investigate whether a ketogenic diet can improve outcomes for people with glioblastoma (Lin 2016; Klein 2016a; Klein 2016b; Martin-McGill 2017).

Some research has suggested restricting caloric intake may enhance the effects of a ketogenic diet (Maroon 2015; Seyfried 2012). Caloric restriction may be accomplished by reducing daily intake or by intermittent fasting. However, patients with advanced cancer should work with a nutritional oncologist to ensure they are consuming adequate nutrition (Maroon 2015).

Coffee and Tea Consumption

Coffee and tea have also been explored as a potential dietary intervention for reducing the risk of developing gliomas. In a large study of participants from 10 European countries, daily intake of 100 mL (about half a cup) or more of coffee or tea was associated with a lower risk of developing glioma. The association was slightly stronger in men (Michaud 2010). This same beneficial effect was reported in another study that examined the intake of coffee and tea in people from the United States. This US-based study reported that those drinking five or more cups of coffee and/or tea per day were less likely to develop gliomas than those who drank less than one cup per day (Holick 2010).

Coffee contains a compound called chlorogenic acid, which has been shown to inhibit glioblastoma cell growth in laboratory studies (Xue 2017; Belkaid 2006). Other compounds in coffee include kahweol and cafestol, which have been shown in animals to increase the activity of MGMT, which is commonly silenced in glioblastoma cells (Huber 2003). Additionally, one of the molecules found in tea, called epigallocatechin gallate (EGCG), can reverse the silencing of MGMT in cell culture experiments (Fang 2003). EGCG has also been shown to improve the efficacy of temozolomide in a mouse glioblastoma model (Zhang 2015; Chen 2011).

10 Integrative Interventions

Melatonin

In humans, the natural hormone melatonin is involved in the sleep-wake cycle and in endocrine function. Melatonin can stimulate the immune system and help fight inflammation (Zheng 2017; Zisapel 2018). For some patients with insomnia, melatonin can help improve their quality of sleep (Kurdi 2016; Wade 2007; Wade 2010).

Recent laboratory evidence has shown that melatonin may inhibit the viability and self-renewal of glioblastoma stem-like cells (Zheng 2017). In a study on glioblastoma stem-like cells isolated from patient surgical samples, melatonin affected cellular signaling pathways involved in cell survival and division (Chen 2016). Melatonin may block glioblastoma cells from invading new areas by inhibiting genes involved in tissue invasion and new blood vessel formation (Zhang 2013). In laboratory studies, melatonin boosted the effects of chemotherapy drugs, including temozolomide, indicating it may be especially helpful for patients undergoing conventional treatment (Martin 2013).

In one early clinical trial, 30 patients with glioblastoma were randomized to either radiation therapy plus oral melatonin (20 mg per day) or radiation therapy alone. After one year, six of 14 patients taking melatonin and only one of 16 patients in the control group were still alive. The authors also noted that side effects of radiation were less frequent in the melatonin group (Lissoni 1996).

Vitamin D

Vitamin D and some of its metabolites can stop glioblastoma cells from dividing in a laboratory setting (Garcion 2002; Magrassi 1998; Magrassi 1995). Intriguingly, one study found that levels of the vitamin D receptor are increased in glioblastoma tissue samples compared with non-cancerous brain tissue. Patients with the vitamin D receptor present in their tumors had a better outcome in one retrospective analysis (Salomon 2014). A laboratory study showed that vitamin D enhanced the toxicity of temozolomide against glioblastoma cells. Also, combined treatment with temozolomide and vitamin D prolonged survival and reduced tumor progression in a rat model of glioblastoma (Bak 2016).

Selenium

Selenium is an essential trace element (Tinggi 2008). The first clinical evidence of a link between selenium and brain cancers came when it was found that selenium levels in the blood were significantly lower in patients with brain malignancies than in healthy individuals (Philipov 1988). Clinical studies have not yet confirmed the benefit of selenium supplementation for glioblastoma patients, but laboratory studies suggest selenium may reduce some of the negative effects of chemotherapies while making cancer cells more sensitive to chemotherapies (Yakubov 2014). For instance, sodium selenite decreased cell proliferation and caused cell death in several types of human glioblastoma cells (Hazane-Puch 2016). In another laboratory study, sodium selenite inhibited the proliferation of human glioblastoma cells and rat glioma cells (Zhu 1995). A mixture of nutrients that contained several ingredients, including selenium, lysine, proline, ascorbic acid, and green tea extract, significantly decreased the ability of glioma cells to invade through a gelatinous material used in the laboratory to study tumor dissemination (Roomi 2007). A study that chemically linked selenium to temozolomide reported that the new compound was effective against temozolomide-resistant glioma cells; also, in human glioblastoma cells, the new compound caused DNA breaks and killed the cells more effectively than temozolomide alone (Cheng 2012).

Carotenoids

Carotenoids, which are precursors of vitamin A, and retinoids, which are derivatives structurally similar to vitamin A, have shown anti-oxidative properties and protective effects against certain cancer types (Niles 2000; Uray 2016; Milani 2017; Shapiro 2013). The anticancer effects of one retinoid, called all-trans retinoic acid (ATRA), have been examined in several studies (Haque 2007; Yang 2018; Yin 2017). ATRA, either alone or in combination with a drug called rapamycin, stimulated glioblastoma cancer stem cells to change into specialized cells and slowed their movement (Friedman 2013). Another study found that ATRA disrupted the movement of stem-like glioma cells and decreased production of chemicals that stimulate blood vessel formation (Campos 2010). A recent study found that ATRA enhanced the effects of temozolomide on human glioblastoma cells (Shi 2017). The treatment of human glioblastoma cells with ATRA or another retinoid, called 13-cis retinoic acid or isotretinoin, made the cells more likely to die when exposed to the chemotherapy drug paclitaxel (Taxol) (Das 2008). Bexarotene (Targretin), a retinoid used to treat lymphoma (Zhang 2006), inhibited the migration of glioblastoma cells and changd the expression of several cancer-related genes towards a more beneficial profile. The compound also killed tumor cells in a mouse model of glioblastoma multiforme (Heo 2016).

The beneficial effects of retinoids have been explored in clinical trials that enrolled patients with glioblastoma (Yung 1996; See 2004; Levin 2006). Isotretinoin has been explored in several studies as maintenance therapy, intended to help delay tumor recurrence. One retrospective analysis found that patients taking isotretinoin lived for an average of approximately 25 months without disease progression, as compared to an average of approximately 8 months in those not taking isotretinoin (Chen 2014). The most common side effects were skin-related (Yung 1996).

Boswellia

There are naturally-occurring plant compounds under investigation for their anti-tumor properties, such as boswellic acids, which are gum resin extracts of Boswellia plants (Schneider 2016; Strowd 2015). Boswellic acids have shown promise in cell culture experiments and animal studies against several cancer types, including colorectal cancer, glioma, prostate cancer, pancreatic cancer, and leukemia (Roy 2016). In particular, these potent compounds can induce cell death, suppress inflammation, decrease tissue invasion and blood vessel formation, and inhibit signaling pathways that stimulate cancer development (Roy 2016; Winking 2000).

A recent study described experiments designed to determine whether boswellic acids could enhance the anticancer effects of standard therapies, such as temozolomide or radiation. The treatment of human glioblastoma cells with boswellic acids led to cell death. When boswellic acids were used in combination with temozolomide or radiation, a combined effect greater than the sum of their separate effects was observed, indicating that boswellic acids could be a promising complementary medicine for patients with glioblastoma (Schneider 2016). Boswellic acids are also helpful in reducing brain swelling, which may develop as a result of brain tumors or their treatment with radiation therapy (Lin 2013; Brandes 2008; Streffer 2001). One study tested the effects of H15, a boswellic acid-containing extract from the gum resin of the Boswellia serrata plant, on brain swelling in 12 patients with brain tumors. Swelling was reduced in two of seven glioblastoma patients (Streffer 2001). In a second study, 44 patients with brain tumors took either 4,200 mg daily of a Boswellia extract or a placebo while undergoing radiation therapy. The Boswellia extract group had a significant decrease in brain swelling compared with the placebo group. An over 75% reduction of swelling was seen in 60% of patients receiving the extract versus 26% of patients receiving placebo (Kirste 2011).

Curcumin

Curcumin (diferuloylmethane), derived from the Curcuma longa plant, is a component of the spice turmeric (Sordillo 2015). Several laboratory studies have examined the cellular effects of curcumin on glioblastoma cells. Curcumin affects several cancer pathways necessary for cell division, survival, invasion, and metastasis (Klinger 2016; Rodriguez 2016). Curcumin may reduce or even eliminate glioblastoma stem cells, which are notoriously unaffected by chemotherapy, by reducing their number, killing them, or changing them into a less dangerous cell type (Sordillo 2015; Fong 2010; Zhuang 2012).

One study used a form of curcumin bound to an antibody to help target curcumin to the glioblastoma cells and nearby microglia, a type of support cell in the central nervous system. The combination was used to treat mice with glioblastoma. Remission of the glioblastoma was noticed in half of the animals. Laboratory analyses indicated curcumin killed the glioblastoma cells and improved the ability of the microglial cells to kill nearby cancer cells (Mukherjee 2016). In another study in mice, animals were transplanted with human glioblastoma cells and treated with curcumin. Curcumin crossed into the brain, inhibited the formation of new blood vessels, and decreased the hemoglobin concentration in the tumors (Perry 2010).

There is also evidence that curcumin may enhance the efficacy of chemotherapy drugs (Klinger 2016). In a laboratory study on glioblastoma cells, curcumin increased the anti-proliferation, anti-migration, and cell death activities of nimustine hydrochloride, a chemotherapy drug widely used for treating glioblastoma. This combined treatment might be a promising therapeutic approach (Zhao 2017). Curcumin may also have an effect on cancer cells through its ability to increase the production of ceramide, a type of fat molecule (lipid) found within the membranes of cells, where it has important roles in signaling (Moussavi 2006; Burgert 2017; Stancevic 2010). This finding is important because increased ceramide has been found to sensitize glioma cells to chemotherapy (Grammatikos 2007).

Resveratrol

Resveratrol is found in certain plants (Valentovic 2018). Blueberries and grapes are excellent sources (Zeng 2017). Resveratrol is being explored as a potential anticancer treatment that may affect each of the three major stages of cancer development: initiation, promotion, and progression (Jang 1999).

In one study, resveratrol inhibited the growth of human glioblastoma cells and caused cell death in a dose-dependent manner (Mirzazadeh 2017). It also inhibited the growth of glioblastoma stem-like cells and suppressed the growth of glioblastoma in a mouse model (Clark 2017). A research study examined glioblastoma-initiating cells, which are tumor cells with increased invasive potential (Mughal 2015) that have been linked to resistance to treatment (Rivera 2013). Resveratrol inhibited a signaling pathway in these cells and suppressed the production of a protein involved in cellular invasion (Jiao 2015). In a laboratory study that used several glioblastoma cell types, resveratrol inhibited cellular movement and invasiveness by activating a major signaling pathway (Xiong 2016).

Resveratrol may also increase the sensitivity of the cancer cells to temozolomide and radiation. In one study, glioblastoma-initiating cells were isolated from two patients with glioblastoma. Resveratrol sensitized these cells to temozolomide (Li, Liu 2016). In in vitro studies and mouse models, temozolomide more effectively induced cell death and inhibited cell migration when used together with resveratrol (Li, Liu 2016; Yuan 2012). Resveratrol may overcome temozolomide resistance by reducing the amount of MGMT in the resistant cells (Huang 2012). In a glioma stem cell line resistant to radiation, resveratrol increased the sensitivity of the cells to radiation (Wang 2015).

Quercetin

Quercetin is a naturally occurring plant flavonoid with many potential anticancer properties (Vidak 2015; Natural Medicines Database 2017). Multiple laboratory experiments have demonstrated that quercetin can kill human glioblastoma cells. Quercetin may also inhibit the ability of glioblastoma cells to metastasize (Liu, Tang, Yang 2017; Liu, Tang, Lin 2017; Kim 2013), reduce their viability (Pan 2015; Kim 2013), decrease their ability to proliferate and migrate (Michaud-Levesque 2012), and inhibit blood vessel formation (Liu, Tang, Yang 2017). Other research found that quercetin may increase the sensitivity of glioblastoma cells to temozolomide and radiation (Sang 2014; Pozsgai 2013). 

Green Tea and EGCG

Epigallocatechin-3-gallate (EGCG) is a green tea flavonoid with known anticancer, antioxidant, and anti-inflammatory activities (Siegelin 2008; Chu 2017). In laboratory studies that used human glioblastoma cell lines, exposure to EGCG contributed to cell death (Siegelin 2008; Yokoyama 2001). EGCG targets several cellular events mediated by matrix metalloproteinases, including some pathways that control cellular migration (Annabi 2002). EGCG can also inhibit a protein that makes glioblastoma cells more resistant to chemotherapy and blocks their death (Bhattacharjee 2015). In human glioblastoma stem-like cells, EGCG synergized the effects of temozolomide (Zhang 2015). EGCG and other catechins from green tea may fight cancer partly through their ability to inhibit the activity of an important cellular signaling pathway (Sachinidis 2000). In two different human glioblastoma cell types, EGCG activated cell death pathways. Interestingly, EGCG did not have this effect on healthy human brain cell (Das 2010). Research in mice with glioblastoma is also encouraging. EGCG significantly improved the therapeutic effects of temozolomide, and the combination extended survival of the mice compared with temozolomide alone (Chen 2011).

Chrysin

Chrysin, a naturally occurring flavonoid found in honey, propolis, and many plants, may fight inflammation and cancer (Mani 2018). Chrysin promoted cell death in studies of several glioblastoma cell lines (Han 2017; Noureddine 2017). Another study found that chrysin reduced the mitochondrial function of glioblastoma cells and decreased the production of a protein involved in tumor invasion (Santos 2015). An extract of propolis killed human glioblastoma cells and enhanced the effects of temozolomide (Markiewicz-Zukowska 2013).

Apigenin

Another plant-derived compound called apigenin inhibited cellular pathways involved in glioblastoma cell proliferation and survival. Apigenin treatment caused the cells to stop at a certain point in their cell division process (Stump 2017). Apigenin also powerfully suppressed the invasiveness of glioblastoma stem-like cells (Kim 2016). This is a significant finding, because stem-like cells can self-renew and are resistant to radiotherapy and chemotherapy (Yi 2016; Gursel 2011). In human glioma cells, apigenin reduced the production of TGF-beta 1, a signaling molecule involved in migration, invasion, and the formation of blood vessels (Freitas 2011). Importantly, apigenin may not have the same effects on normal cells. One study found that apigenin activated cell death pathways in two different human glioblastoma cell lines, but not in normal human astrocytes (Das 2010).

Phytoestrogens

Phytoestrogens are compounds from plants that are similar in structure to the hormone estrogen (Khani 2011). Soy beans, flaxseed, and nuts are all good sources (Carmichael 2011; Cotterchio 2006). In a mouse model of human glioblastoma, a phytoestrogen called genistein inhibited tumor growth after 10 days of treatment. Cellular and molecular analyses suggested genistein slowed tumor growth by decreasing the formation of new blood vessels in the tumor (Liu, Liu 2015). Another study found that genistein may decrease the proliferation of glioblastoma cells by stopping their division and lowering the activity of telomerase, an enzyme that cancer cells need to protect the ends of their chromosomes and survive (Khaw 2012; Jafri 2016).

Daidzein is another phytoestrogen. One study found that daidzein can help activate cellular pathways involved in cell death in glioblastoma cells. Healthy brain cells were not affected by this treatment (Siegelin 2009).

Honokiol

Honokiol is a natural bioactive polyphenol extracted from the bark of the tree Magnolia officinalis. Honokiol had anti-inflammatory, anti-microbial, and anticancer effects in laboratory studies (Cheng 2016; Lin, Chang 2016). Researchers have reported that honokiol can inhibit the division of glioblastoma cells and cancer stem-like cells (Lai 2015) and kill glioblastoma cells by several mechanisms (Zhang, Ren 2014; Liang 2014). The ability of honokiol to cause glioblastoma cell death may result, at least in part, from its ability to stimulate a protein that causes cell death and inhibit a protein that prevents cell death (Jeong 2012). Another study found that honokiol inhibited the interaction between human glioblastoma cells and cells that line the blood vessels, suggesting that it may inhibit the spread of tumor cells via the bloodstream (Joo 2014). In glioblastoma cell culture experiments, honokiol and a similar compound called magnolol were more effective at killing cancer cells when used together (Cheng 2016).

Honokiol is of particular interest for treatment of glioblastoma because studies in mice suggest the compound can cross from the blood into the brain (Lin 2012). In a mouse model of human glioblastoma, honokiol caused cell death and significantly prolonged survival of the mice (Lin, Chang 2016). A number of genes involved in regulating the cell cycle were activated in the treated mice. In a similar study, the combination of honokiol and magnolol inhibited tumor progression and killed cancer cells more efficiently than the chemotherapy drug temozolomide (Cheng 2016).

Polyunsaturated Fatty Acids

Several types of polyunsaturated fatty acids (PUFAs) have been studied for the treatment of glioblastoma. Treating glioblastoma cells with docosahexaenoic acid (DHA), an omega-3 PUFA, led to several cellular and molecular changes that indicate cell death. The authors followed up with an additional experiment in mice with glioblastomas. The mice were altered to express an enzyme that converts omega-6 PUFAs to omega-3 PUFAs. The increase in omega-3 PUFAs was associated with a decrease in tumor volume (Kim 2018). When various types of glioma cells were exposed to different PUFAs, including arachidonic acid, gamma linolenic acid (GLA), and DHA, the expression of certain genes involved in cell death increased (Farago 2011). Open-label clinical studies have suggested GLA may be effective against malignant gliomas (Das 2007; Das 2004). In patients with glioma, delivering GLA directly into the tumor was found to be safe, and in some cases, it led to tumor regression. Several participants survived without new symptoms for up to two years (Das 1995).

Milk Thistle

Silibinin (silybin) is a biologically active compound in extracts from the seeds of the herb milk thistle (Silybum marianum) (Zou 2017; Ham 2018). In a laboratory study, silibinin inhibited the invasive features of highly invasive glioblastoma cells (Momeny 2010). Another strategy tested silibinin in combination with luteolin, another plant-derived compound. The combination inhibited the growth of glioblastoma cells more effectively than temozolomide, slowed cell migration, and caused glioblastoma cells and glioblastoma stem cells to die (Chakrabarti 2016; Chakrabarti 2015).

Silibinin also works well in combination with arsenic trioxide, a drug approved for treatment of a form of leukemia (Khairul 2017; Lengfelder 2012). In glioblastoma cells, the combination of silibinin and arsenic trioxide slowed tumor cell metabolism and increased cell death (Dizaji 2012). A recent study found that silibinin increased the accumulation of arsenic inside glioblastoma cells treated with arsenic trioxide (Gulden 2017).

Vitamin E

Alpha-, beta-, gamma-, and delta-tocotrienol are compounds belonging to the vitamin E group and may help fight cancer and inflammation (Comitato 2017; Abubakar 2015). In a laboratory study, alpha-, gamma-, and delta-tocotrienols inhibited the growth of human glioblastoma cells and caused DNA breaks. Delta-tocotrienol killed the cells more effectively than alpha- and gamma-tocotrienol (Lim 2014). Delta-tocotrienol also worked well in combination with extracts from the Tabernaemontana corymbosa plant, a traditional cancer treatment in Bangladesh (Abubakar 2016), and extracts from plants in the genus Ficus (Abubakar 2015).

Ellagic acid

Ellagic acid, a natural compound found in many fruits and plants, may also have health benefits for glioblastoma patients. In human glioblastoma cells, ellagic acid inhibited the viability and proliferation of the cells and damaged their DNA. The authors then confirmed these results in mice with glioblastoma and found that ellagic acid inhibited signaling pathways involved in cancer cell proliferation and invasion (Wang 2017). Another study reported that ellagic acid dramatically reduced levels of proteins that protect tumor cells from death (Wang 2016). A root extract of Leonurus sibiricus L, a traditional medicinal plant found in China, Japan, Korea, Vietnam, and southern Siberia, contains ellagic acid and several other polyphenolic compounds. The extract effectively killed human glioblastoma cells by regulating genes involved in cell death (Sitarek 2016).

Chlorogenic Acid

Chlorogenic acid is a phenolic compound found in coffee, green tea, apples, and pears. The compound inhibited the growth of glioblastoma cells and reduced the growth of glioblastomas in mice. Some of the immune cells in the tumors of these treated mice were changed to a form that can more readily destroy tumor cells (Xue 2017). Another study found that chlorogenic acid inhibited cell migration and the secretion of a protein implicated in tumor invasion (Belkaid 2006).

Folate and Folic Acid

Folate (vitamin B9) is an essential nutrient belonging to the group of B vitamins. Its synthetic analogue is folic acid. Folate is found in a variety of dark green vegetables such as spinach, as well as avocados, strawberries, and orange juice (Bannink 2015; Donnelly 2001; Milman 2012). Folate is required for the synthesis of DNA and RNA and provides the methyl groups that can affect the expression of genes such as MGMT (Greenberg 2011; Blom 2011). A laboratory study showed that exposing glioma cells to folate leads to certain beneficial DNA methylation changes, including methylation of MGMT. The methylation changes were associated with reduced proliferation and increased sensitivity to temozolomide (Hervouet 2009). In glioma cells, exposure to folate also affected the methylation status of the growth factor gene PDGF-B, and significantly decreased cellular proliferation (Zhou 2014).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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