Glioblastoma is an aggressive type of brain tumor.^1,2 Surgery, radiotherapy, and chemotherapy are currently used to treat glioblastoma. Although understanding of glioblastoma has improved in recent years, standard care remains limited in its ability to improve overall survival time.^1,3-6

Recent prominent cases of glioblastoma—including Senators John McCain and Edward Kennedy—have helped raise awareness about this harrowing disease,⁷ and researchers are beginning to uncover promising novel therapies.^5,8 In recent years, tremendous progress has been made toward developing better treatments for glioblastoma.¹

Emerging evidence has identified a potential relationship between a virus called cytomegalovirus (CMV) and the development of glioblastoma.^9,10 Also, a groundbreaking study published in 2013 in the New England Journal of Medicine showed the antiviral drug valganciclovir (Valcyte) improved survival in some glioblastoma patients,¹¹ and follow-up studies published in 2020 have further extended these promising findings.^12,13 Pioneering work at Duke University using a bioengineered poliovirus produced remarkable response rates in glioblastoma patients.^14,15 Evidence of the effects of some off-label drugs in glioblastoma has been encouraging as well.¹⁶ For instance, drugs such as metformin¹⁷ and cimetidine¹⁸ have shown promise in laboratory studies. Also, integrative, natural interventions, such as vitamin D, resveratrol, curcumin, and melatonin are being actively explored, with intriguing preliminary results.^19-22

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:

• Drug Repurposing in Cancer
• Cancer Adjuvant Therapy
• Chemotherapy
• Radiation Therapy
• Cancer Surgery
• Cancer Treatment: The Critical Factors
• Cancer Immunotherapy

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.²³ 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.²⁴ Gliomas have been thought to be derived from glial cells in the brain.²⁵ In 2018, researchers determined that glioblastoma arises from special niches of cells in the brain. This niche is called the subventricular zone and it contains neuronal stem cells. It is aberrations in these stem cells that give rise to glioblastoma.²⁶ This shift in our understanding to a more precise origin of glioblastoma should change our approach to treating this disease in the future.²⁷

Primary brain tumors are given a tumor grade based on how abnormal the tumor cells look when viewed under a microscope.²⁵ For cancers in general, 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 aggressive cancers, however, glioblastoma does not usually spread to other organs outside the central nervous system (brain and spinal cord) except in rare cases.^28-30

Glioblastoma accounts for roughly 16% of all primary brain and central nervous system tumors and nearly half of all gliomas.^31-33 It is estimated that approximately 13,000 Americans will be diagnosed with glioblastoma in 2020.³⁴

Glioblastoma does not have a single definitive cause, but several risk factors for developing glioblastoma have been identified.^35,36

Gender

Men are about 50% more likely to develop glioblastoma than women.^31,37,38 Also, a woman’s risk goes up after menopause.³⁸ 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.^39-41 However, much more research in this area is needed.^38,41

Age

The chances of developing glioblastoma increase with age and peak at age 75 to 84 years.⁴² Because the average lifespan of people in industrialized countries continues to increase, the median age when glioblastoma is diagnosed has risen to 64 years.^33,42

Heritage and Genetics

Glioblastoma is about twice as common in people with European-American ancestry than African-American ancestry.^33,38 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.⁴³ In approximately 5% of cases, glioblastoma may also result from genetic diseases such as tuberous sclerosis, Turcot syndrome, multiple endocrine neoplasia type IIA, and neurofibromatosis type I.^38,43

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.^44,45 In addition, radiation to the head for childhood cancers is also a risk factor for brain cancer development later in life.^2,38,46 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.⁴⁷

Body Composition

Greater height has been associated with increased glioma and glioblastoma risk.^48,49 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.⁴⁹ Interestingly, additional data suggest people who finished growing at a later age were more likely to develop gliomas.⁵⁰ Higher Body Mass Index (BMI) is a risk factor for various types of cancers, including glioblastoma.^51-53

Non-Ionizing Electromagnetic Radiation Exposure

Between the mid-1990s and early 2000s, the use of mobile and cordless phones increased rapidly.⁵⁴ These devices emit electromagnetic radiation from their antennas. Laboratory studies demonstrated that brain cells can be affected by electromagnetic fields.^55,56 Whether mobile phone use is related to the development of brain tumors has been the subject of much debate.³⁸

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.”^54,57,58 This decision was based on data collected from human case-control studies.⁵⁴ 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.⁵⁹ Non-ionizing radiation emitted by cells phones does not damage DNA directly, but researchers have proposed several other mechanisms by which cell phone radiofrequency waves may promote cancer.^60,61 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.^9,10 Over half of adults in the United States have been exposed to CMV, but relatively few have an active viral infection.⁶² A study published in the New England Journal of Medicine described several important findings regarding the relationship between CMV and glioblastoma.⁶³ 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.^63,64 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.^65,66

Signs and symptoms of brain tumors 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. 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.^2,67-69 Symptoms affecting cognitive function can be rapid, including memory, balance, language and/or personality changes.

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 may also arise 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.^2,67-70

Imaging

Magnetic resonance imaging (MRI) is the gold standard non-invasive imaging approach to test whether someone has a brain tumor.^38,67,71 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.^70,72 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.³⁷

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.^70,73 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.^70,72

A computed tomography (CT) scan is an imaging test usually reserved for patients who cannot undergo an MRI for various reasons.²⁵ 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.⁷⁰ 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.^74-76

Biopsy

Although MRI and CT scans can provide valuable information regarding the features of glioblastoma, actual brain tissue is required for a definitive diagnosis.²⁵ During a procedure called a biopsy, a small sample of the brain tumor tissue is removed for further analyses under a microscope.^25,70 The tumor tissue from a biopsy is analyzed by a doctor called a pathologist. In addition to determining whether the tumor is glioblastoma, the pathologist may also request a molecular analysis of the tumor.³⁷ When appropriate, surgical removal of the tumor is done without a biopsy, and this provides the necessary tissue for the pathologist.

Some tumors are biopsied during a surgical procedure called an open biopsy.^25,70 For those patients, the tumor may be removed at the same time. MRI is generally used to locate the best area to biopsy. 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.⁶⁹ Positron emission tomography (PET), a type of imaging that looks for abnormally functioning cells, is undergoing research to determine whether it can improve biopsy accuracy.

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 glioblastoma⁸⁷:

• Age 50 or less⁸⁸
• 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)⁸⁸
• A tumor not located in an “eloquent” brain location, including areas involved in speech, vision, movement, the thalamus, basal ganglia, and internal capsule^87,89
• A tumor that can be completely or almost completely removed in surgery^88,90
• Molecular features of the tumor, such as MGMT methylation or mutations in a gene called IDH1^70,87,91

Before any new cancer tests or treatments are made available, they must first pass through a series of clinical trials to ensure 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 phases⁹²:

• Phase 0 trials are preliminary trials that enroll few (10‒15) people to examine how the drug is absorbed, broken down, and excreted in the human body, as predicted from laboratory and animal studies. These trials determine whether further clinical development should proceed.
• Phase I 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 that can be given safely and without risk of adverse effects.
• If a drug passes phase I, it moves on to a phase II clinical trial. In phase II 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 trials are conducted to compare the new drug to 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. Each trial lists its rules for participation as “inclusion criteria” and “exclusion criteria,” and these details are included in the clinical trial descriptions found at www.clinicaltrials.gov.

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:

• American Brain Tumor Association
  http://www.abta.org
• National Brain Tumor Society
  https://braintumor.org/
• Adult Brain Tumor Consortium
  http://www.abtconsortium.org/index.php
• American Cancer Society
  https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults.html
• National Cancer Institute
  https://www.cancer.gov/types/brain
• National Coalition for Cancer Survivorship
  http://www.canceradvocacy.org/resources/cancer-survival-toolbox
• The National Comprehensive Cancer Network (NCCN)
  https://www.nccn.org/patients
• ClinicalTrials.gov Database
  https://clinicaltrials.gov

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.^93-96 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.^35,70,85,97 Initial surgery to remove as much of the tumor as possible is the mainstay of treatment for most people with glioblastoma, followed by radiotherapy and/or chemotherapy.^70,98

Surgery and Local Chemotherapy

Surgery is an essential part of glioblastoma treatment.⁷⁰ 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.^90,99,100 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.³⁷ Major surgical centers now use a special compound called 5-aminolevulinic acid (5-ALA), colloquially referred to as “pink drink,” which lights up the tumor so the surgeon can see it better. The patient drinks it just before surgery. The surgeon then shines a UV light on the brain tissue during surgery and removes as much of the dyed tissue as possible. This new technique has improved the rate of maximum safe resection.¹⁰¹ When combined with MRI imaging at the time of surgery, both accuracy and precision are greatly improved. The safety profile and documented improvement in outcomes in patients has led experts to advocate for 5-ALA use as standard of care.¹⁰²

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.^103-105

During surgery, some patients may be treated with a form of chemotherapy delivered locally to the tumor site.^70,106 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.²⁵ The wafers dissolve over time after surgery.¹⁰⁷ Although this form of chemotherapy may extend the life of the patient, it can cause complications.^108,109 For example, carmustine may interact with some other drugs and increase their toxicity.⁷⁰ Also, some patients may experience swelling in the brain, seizures, healing problems, or local infections.^110,111 Due to its high toxicity and emerging new agents that continue to show promise, the use of implanted carmustine wafers has declined over time.

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.⁷⁰ Some patients will only receive one drug, usually the alkylating agent temozolomide. Temozolomide damages the DNA.¹¹² Cancer cells are growing and dividing rapidly and are more sensitive to DNA damage.^113,114 Tumors with MGMT methylation may be more sensitive to alkylating agents.^37,81 For some patients, several drugs are used to fight the cancer in multiple ways.⁷⁰

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.⁷⁰ Side effects of systemic chemotherapy 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 count, loss of appetite, nausea, fatigue, vomiting, diarrhea, hair loss, and mouth sores.^115-117

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

Anti-angiogenesis 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.⁷⁰ VEGF signaling is often increased in glioblastoma tumors and contributes to tumor growth. Bevacizumab was approved in 2009 for treatment of recurrent glioblastoma.³⁷ 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.¹²³ Bevacizumab can also lead to reduction in the need for steroids for symptom control.¹²⁴ Side effects can occur with bevacizumab, and patients must be monitored for excessive bleeding or blood clots.^37,123,124

Another anti-angiogenic drug sometimes used when glioblastoma recurs is regorafenib (Stivarga).⁷⁰ This small molecule inhibits several pathways of survival and growth in glioblastoma cells, including some of those involved in promoting angiogenesis. In addition to regorafenib, many other drugs that target angiogenesis are being researched to determine the best means of thwarting new blood vessel growth in glioblastoma.¹²⁵

Radiation Therapy

Some glioblastoma tumors cannot be surgically removed. Patients in these situations are treated with radiation therapy.^70,126 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.²⁵ 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.^127,128 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.⁷⁰ The treatment machinery is adjusted to deliver radiation as carefully as possible to the tumor area, limiting exposure to healthy tissue. The routine addition of three-dimensional (3D) planning tailored for each person before they begin radiation therapy has reduced the damage to normal brain tissue when compared to older protocols.

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.^81,129 The treatment uses patches taped to the patient's head and a portable battery-powered device.^70,130 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.^81,131

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 four months in the temozolomide-only group.¹³² 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.⁸¹ Emerging data have shown that some of the benefit from tumor-treating fields may be due to immune stimulation, making its use alongside immunotherapies intriguing.¹³³

Follow-Up and Continuing Care

MRI scans should be conducted 2‒6 weeks after the end of radiation therapy. Additional scans should be performed every 2‒4 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. MRI scan interpretation can be challenging due to a phenomenon known as pseudoprogression. As the name implies, what appears to be progression on the MRI image is not actual growth of the tumor. Instead, the area of the tumor appears larger due to the treatment stimulation to that brain region. This can happen in the first 1‒3 months of treatment.⁷⁰ Whether there is true progression or pseudoprogression is determined by the neuro-oncologist.

Unfortunately, most glioblastomas grow back.^37,98 MR spectroscopy, MR perfusion, or PET scan may help confirm recurrences.⁷⁰ 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.³⁷ For recurrences, systemic chemotherapy, radiation therapy, bevacizumab, and tumor-treating field therapy may be used.^70,81

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.^37,70 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.^134,135 Supportive care may be the only option for patients with advanced or recurrent glioblastoma.

There are several intriguing glioblastoma therapies supported by emerging evidence. One way to access 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.¹³⁶ However, some cancer cells develop the ability to escape the immune system.¹³⁷ Once cancer cells that are not vulnerable to immune destruction have established themselves in a person’s body, a tumor can start to form.¹³⁸

Immunotherapy aims to manipulate the patient’s immune system to enable it to once again attack and eliminate cancer cells.¹³⁹ 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.¹⁴⁰ Researchers are investigating many different types of immunotherapies for glioblastoma.^141,142

For example, T-cell therapies are being explored. In a phase I study on a 50-year-old man with recurrent glioblastoma¹⁴³ the investigators created a chimeric antigen receptor–engineered (CAR) T cell. This CAR-T cell was designed to target interleukin-13 receptor alpha 2, a marker expressed by many glioblastoma cells.¹⁴⁴ The patient received treatment with these CAR-T cells, which were injected into his brain over a period of 220 days.¹⁴³ 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.¹⁴⁵ CAR-T cells have been designed to target other glioblastoma markers, including HER2 and a form of the epidermal growth factor receptor.^146,147 While T-cell therapies have been approved for other cancers, in the case of glioblastoma it appears they may need to be combined with other treatments to give rise to a robust immune response against glioblastoma.⁸

Checkpoint inhibitors, a type of immunotherapy that helps the immune system recognize cancer cells, can be very effective for several other cancers, but treatment with checkpoint inhibitors after glioblastoma surgery has been disappointing.¹⁴⁸ However, studies suggest the timing of immune treatments may influence their success or failure. In one study, a checkpoint inhibitor called nivolumab (Opdivo) was administered before surgery for glioblastoma. While it did not change outcomes for patients undergoing a second surgery, two of the three participants that were newly diagnosed were still alive after 33 and 28 months (at the time of the paper’s publication).¹⁴⁹ In another study, T cells that target CMV, the virus that has been associated with glioblastoma, were generated from the patients’ own cells. Of the 25 patients in the study, those who were treated before their first progression fared much better than those who had already progressed at least once since their initial surgery. Several of them had no evidence of progression at 24 months.¹⁵⁰

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.^14,151,152 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.¹⁵³ In addition, molecules released from the dying cells activate immune and inflammatory responses that help destroy the cancer cells.^151,154-156 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.^153,154,157

A phase I clinical trial designed to identify optimal doses of PVSRIPO for future clinical trials enrolled 61 patients with recurrent high-grade glioblastoma. Varying doses 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 (the patient developed a grade 4 intracranial hemorrhage).¹⁵⁸ Five of the patients from this original phase I study underwent retreatment with more doses of PVSRIPO. Three of the five were alive at 81, 80, and 52 months after the first dose of PVSRIPO; overall, 21% of participants were still alive at 36 months.²⁷

Cancer vaccines, a type of immunotherapy earning much attention in recent years, may be effective against brain tumors.^1,159,160 One anti-cancer vaccine in clinical trials, called SurVaxM, targets a protein called survivin.¹⁶¹ Survivin is commonly expressed in glioblastoma cells and normally protects cancer cells from death.^162-164 The vaccine is designed to trigger 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. In a phase I trial of patients with recurrent glioblastoma, SurVaxM was safe and improved outcomes for trial participants.¹⁶⁵ The patients on average went 17.6 weeks without worsening of their disease and survived an average of 86.6 weeks.¹⁶¹ The FDA has granted SurVaxM orphan drug status, and a larger trial of SurVaxM in combination with standard therapy is planned for newly diagnosed glioblastoma.¹⁶⁶ SurVaxM is also undergoing clinical study for treatment of recurrence in glioblastoma.¹⁶⁶ This study is using SurVaxM in combination with an approved immunotherapeutic agent (pembrolizumab), which helps the immune system better recognize cancer cells.¹⁶⁷

Rindopepimut (CDX-110) is similar to SurVaxM in that it is a vaccine that targets a particular aberration in glioblastoma. This aberration is in a gene called epidermal growth factor receptor variant III (EGFRvIII), and it occurs in about 60‒70% of glioblastomas. Early studies were promising, but this vaccine did not lead to better outcomes when used alone.^168,169 However, studies of rindopepimut combined with maintenance temozolomide or bevacizumab have demonstrated longer times to progression and better overall survival times.¹⁷⁰ Vaccines that leverage several targets at once are also undergoing clinical trials, with mixed results.¹⁷¹ 

Photodynamic Therapy

Photodynamic therapy uses light, often ultraviolet light, at a specific wavelength to kill tumor cells. This light combines with a chemical “sensitizer” that concentrates in cancer cells but not normal cells. In the case of glioblastoma, 5-ALA, the same dye agent used for lighting up the tumor before surgical removal, is used as the sensitizer. This technique reaches all hard-to-reach areas that extend out from a glioblastoma tumor. It also includes some of the cells that are most resistant to chemotherapy or radiation, such as stem-like glioma cells and dormant cells.^172,173 Ideally, the surgeon physically removes as much tumor as possible, then shines the UV light on the brain. Surgery followed by photodynamic therapy has resulted in better outcomes than surgery alone.¹⁷⁴ Research is also underway to determine if there are ways to improve 5-ALA uptake into glioblastoma cells using various drug combinations.¹⁷⁵ Photodynamic therapy is generally only available in the research setting as of late 2020.¹⁷⁴

Targeted Drugs

Targeted drugs bind to a specific site or compound in cancer cells. Binding to the site or “target” interferes with growth signaling pathways. Several genetic abnormalities can occur in glioblastoma, and this provides the “target” that is not found in normal brain cells nearby. Increasingly, these genetic abnormalities are being tested as part of the initial pathology after biopsy or tumor resection. There is one targeted agent currently recommended for recurrent glioblastoma, regorafenib.⁷⁰ Regorafenib is a small molecule tyrosine kinase inhibitor that targets several cell-signaling pathways involved in cancer pathobiology, including VEGFR1-3, RET, c-kit, PDGFRα and β, among others.¹⁷⁶

Many targeted drugs are still undergoing research, in both preclinical and clinical studies.²⁷ There are many potential drugs that may be appropriate in a limited number of patients with glioblastoma, and many of them target specific molecular abnormalities in a person’s glioblastoma.¹⁷¹ Whether a targeted agent is appropriate to consider should be discussed with your neuro-oncologist.

Metformin

Metformin, a first-line drug for diabetes, can pass from the bloodstream into the brain.¹⁷⁷ A number of preclinical studies have shown that metformin may inhibit the division and migration of glioblastoma cells.^178-183 In laboratory studies, metformin stopped glioblastoma stem cells from dividing,¹⁸³ and metformin and arsenic trioxide helped differentiate glioblastoma stem cells into non-tumorigenic cells.¹⁸²

The anti-cancer effects of metformin may result in part from activation of the enzyme AMP-activated protein kinase (AMPK) and inactivation of the transcription factor STAT3.^181,184-186 AMPK is an important regulator of glucose and fatty acid metabolism that promotes healthy aging and extends lifespan^187,188 while STAT3 controls cell growth and survival and is activated in many cancer types.^189,190 Metformin has also been shown to lower levels of a protein, EZHIP, that causes epigenetic changes that contribute to a type of brain tumor called group A posterior fossa ependymoma (PFA), which occurs more often in children than adults.^488,489 In one study, metformin suppressed metabolic activity in PFA cells and increased survival of mice bearing xenografts of these deadly brain tumors.⁴⁸⁸

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.¹⁹¹ A separate study used a type of glioblastoma cells that were not responding to temozolomide. Treatment with metformin made the cells sensitive to temozolomide.¹⁹² In mice with experimentally induced glioblastoma, metformin improved the effects of temozolomide, and in cell culture studies, it improved the effects of radiation therapy.^193,194 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.¹⁹⁵ An angiogenesis inhibitor called sorafenib (Nexavar) was also more effective when combined with metformin in laboratory research.¹⁷⁹ In another laboratory study, metformin sensitized glioblastoma cells to radiation or radiation combined with temozolomide.¹⁹⁶ Additional findings from animal research showed metformin decreased brain swelling and reduced the leakiness of the blood vessels.¹⁹⁷

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).¹⁹⁸ As of mid-2021, there are five clinical trials (three phase II and two phase I) registered with ClinicalTrials.gov that address the potential benefits of metformin in combination with other therapies in people with glioblastoma.²⁰⁰ Results of these trials will help establish the value of metformin as a component of adjuvant therapy for glioblastoma.

Metformin has also been studied as part of an off-label drug “cocktail” for cancer patients, particularly glioblastoma patients, at the Care Oncology Clinic in London, England.²⁰¹ The clinic’s combination includes metformin, atorvastatin, mebendazole, and doxycycline, each of which has shown some efficacy against glioblastoma and glioblastoma cell lines in preclinical studies as well as in a rodent model and phase I clinical study.^202-206 In the Care Oncology Clinic study, an interim analysis of this retrospective, open-label, single-arm trial found that the addition of the drug combination to standard of care appeared to extend survival in patients with glioblastoma compared with historical standard of care alone. The cohort of patients who received the drug cocktail had a median survival of 27.1 months and 64% of participants survived past two years.²⁰¹ This compared favorably to historical survival of 14.8‒15.8 months with standard of care.^98,487 However, this ongoing study has several key methodological limitations, including lack of direct comparison with a control group as well as biased patient selection. Therefore, much more rigorous study is needed to determine whether this drug combination offers additional survival benefits over standard of care.

Valganciclovir

Valganciclovir is an FDA-approved drug used to treat CMV infection.²⁰⁷ 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.¹¹ 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.⁶³ In a follow-up study, 102 newly diagnosed glioblastoma patients were given valganciclovir in addition to standard treatment. At two years, 49.8% were still alive compared with 17.3% of control patients at the same center.¹² Separately, in a smaller trial of eight glioblastoma patients who had progressing tumors, the addition of valganciclovir resulted in a median survival of 19.1 months versus 12.7 months in those who did not receive it.¹³

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.^11,63 The treatment protocol consisted of 900 mg 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.²⁰⁸ In recent years, dichloroacetate has gained attention for its ability to kill cancer cells and enhance the activity of other cancer therapies.²⁰⁹

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.²¹⁰ 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.²¹¹ This research built on an earlier, smaller trial on five glioblastoma patients treated with dichloroacetate for up to 15 months.²¹² 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.^210,212 Dichloroacetate also has been found to make the inside of the glioblastoma cells dramatically more acidic, which may inhibit their growth.²¹³ 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.^214,215

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.²¹⁶ Additionally, fluoxetine may reduce the amount of MGMT in glioblastoma cells and make them more sensitive to temozolomide.²¹⁷ Other antidepressant drugs, such as imipramine (Tofranil) and amitriptyline (Elavil), have been shown to stop glioblastoma stem cells from producing more stem cells.²¹⁸

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.^219-221 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.^221-223 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.²²² In another study, rapamycin reduced the proliferation of glioblastoma cancer stem cells and their tumorigenic potential.²²⁴

Results of clinical studies using rapamycin have been modest or uncertain.^225,226

Rapamycin showed benefits in a phase I clinical trial in certain patients with glioblastoma²²⁷ but results from phase II clinical trials were not promising. At least in part, this is explained by the interaction with other signaling pathways.²²⁸ 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.²²³ The combined inhibition of the two complexes was also underscored as a promising therapy by other studies on glioblastoma.^229-231

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.

GSK-3ß Inhibition

GSK-3, an enzyme responsible for many reactions in cells, is integrally involved in many aspects of tumor pathobiology, including proliferation, invasion, and survival. While targeting this enzyme has had mixed results for various types of tumors, it appears that inhibiting the GSK-3beta (GSK-3β) form specifically has an anti-glioblastoma effect.²³²

A drug combination called CLOVA (cimetidine, lithium, olanzapine, and valproate) was tested in a small 2017 study on seven glioblastoma patients. The study found that the CLOVA cocktail led to longer-than-expected survival. The mechanism by which this drug cocktail improved survival was thought to involve inhibition of GSK-3β.¹⁵⁵

Kenpaullone is drug that specifically inhibits GSK-3β and has shown early promise in the context of glioblastoma. Kenpaullone was discovered through a screening process of over a thousand chemicals in search of one that effectively inhibits GSK-3β.²³³ By downregulating the activity of GSK-3β, kenpaullone inhibits the proliferation of glioma cells while encouraging their self-destruction pathways (apoptosis). Targeting GSK-3β also results in the reduction of the stem cell like features of glioblastoma, a characteristic tied to its aggressiveness. The effect of kenpaullone may also complement the therapeutic effects of temozolomide through reduction of the cells’ ability to produce MGMT.²³⁴

All-trans Retinoic Acid (ATRA)

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.^235-238 The anti-cancer effects of one retinoid, called all-trans retinoic acid (ATRA), have been examined in several studies.^239-241 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.²⁴² Another study found that ATRA disrupted the movement of stem-like glioma cells and decreased production of chemicals that stimulate blood vessel formation.²⁴³ A recent study found that ATRA enhanced the effects of temozolomide on human glioblastoma cells.²⁴⁴ 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).²⁴⁵ Bexarotene (Targretin), a retinoid used to treat lymphoma,²⁴⁶ inhibited the migration of glioblastoma cells and changed the expression of several cancer-related genes towards a more beneficial profile. The compound also killed tumor cells in a mouse model of glioblastoma.²⁴⁷

The beneficial effects of retinoids have been explored in clinical trials that enrolled patients with glioblastoma.^248-250 Isotretinoin has been explored in several studies as maintenance therapy, intended to help delay tumor recurrence. One retrospective analysis found patients taking isotretinoin lived an average of approximately 25 months without disease progression compared to an average of approximately eight months in those not taking isotretinoin.²⁵¹ The most common side effects were skin-related.²⁴⁸

Multi-Drug Combinations (Repurposed Drugs)

Glioblastoma tumors are well known to eventually become resistant to every chemotherapy drug used to treat them. Since singular pathway inhibition is universally overcome by glioblastoma cells, there is interest in finding multiple drugs that may be used in combination to simply dampen the growth rather than eradicate the disease. The use of multiple repurposed drugs to simultaneously inhibit many pathways at once is undergoing investigation. These are usually combinations of less toxic drugs that are approved for other disease processes. One ongoing combination under investigation is called CUSP9, and uses nine drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram (DSF), itraconazole, ritonavir, and sertraline) to overcome over a dozen pathways of drug resistance to temozolomide.^252,253

One combination that has shown encouraging results in animals is known as FTT (fasudil, tranilast [Rizaben], and temozolomide).²⁵⁴ Fasudil is a vasodilating agent used for stroke victims and tranilast is an anti-allergy drug approved for use in Asian countries that acts on a key inflammatory pathway called TGF-β.²⁵⁴ This combination suppressed tumor growth and increased the time of survival more so than temozolomide alone in animals given glioblastoma. Clinical studies of this combination are needed before any conclusions can be made on its use in humans.

Inhaled Cannabidiol

Cannabidiol (CBD), the second most abundant phytocannabinoid present in cannabis, has garnered interest for its potential benefits in cancer treatment.^492,493 CBD can act as both an agonist and antagonist of the endocannabinoid CB₁ and CB₂ receptors, although it displays low affinity as an agonist.⁴⁹⁴ CB₁ receptors are primarily found in the central nervous system; CB₂ receptors are primarily found on cells in the immune system and hematopoietic cells and are thought to elicit the immune-modulatory effects of CBD.^492,494 Both CB₁ and CB₂ receptors have been found to be expressed in many cancer types, and several preclinical studies suggest CBD may have therapeutic efficacy in the context of some cancers.^492,495 Since CBD does not produce psychoactive effects, in contrast to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), it has remained a focus of intense research.

In a preclinical study, researchers utilized a mouse model of glioblastoma to examine the effect of inhaled CBD (10mg/day) on the tumor microenvironment, which is vital for tumor survival and progression.^496-498 They found that inhalation of CBD limited tumor growth in addition to altering the dynamics of the tumor microenvironment by repressing P-selectin, apelin, interleukin-8 (IL-8), and blocking indoleamine 2,3-dioxygenase (IDO), a key protein that allows tumor cells to escape detection by the immune system. In fact, high expression of IDO is significantly associated with poor prognosis of tumors.⁴⁹⁹ Inhaled CBD also increased CD103 expression, promoted CD8⁺ T-cell immune responses, and decreased innate lymphoid cells within the tumor.⁴⁹⁸

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,²⁵⁵ avoid infections,²⁵⁶ 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.^255,257,258 Diets high in colorful fruits and vegetables contain high amounts of phytochemicals. Many of these phytochemicals are broken down by bacteria in the gut to form compounds that can cross the blood-brain barrier and influence neuronal function.²⁵⁹ One class of phytochemicals, called polyphenols, may confer some protection against the development of glioma by modulating many of the inflammatory pathways involved in glioma formation and growth.²⁶⁰ For some patients, an exercise program may improve mood and quality of life.²⁶¹

Ketogenic Diet

The ketogenic diet emphasizes healthy fats and proteins with very little carbohydrates (typically less than 20 grams net carbohydrates daily).^262-264 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.^262,265

A ketogenic diet has been found to control tumor growth and prolong survival in animal studies.^265-267 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.²⁶⁸ In humans, the diet leads to lower circulating glucose levels, which is associated with better outcomes in those with glioblastoma, and it is generally well tolerated and safe.²⁶⁹ Blood tests can be used to check how well the diet is reducing blood glucose levels and increasing ketone levels.²⁷⁰ A review of 24 human studies found 42% of the studies suggested there may be direct anti-tumor effects of the ketogenic diet.²⁷¹ Quality of life improvements, including sense of overall wellbeing, fewer seizures, and better neurological function was more consistently reported. 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.^272-274

Some research has suggested restricting caloric intake may enhance the effects of a ketogenic diet.^275,276 In one small study of patients with glioblastoma, only the few participants that lost at least 10% of their body weight derived any benefit from the ketogenic diet.²⁷⁷ 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.²⁷⁵

Ketogenic diets may have the dual effect of protecting normal cells and sensitizing cancer cells to therapeutic radiation.²⁷⁸ At the heart of the diet is the production of ketones, which can be used by cells in lieu of glucose to derive energy. One of the primary ketones produced in the body, beta-hydroxybutyrate, functions as a histone deacetylase (HDAC) inhibitor. Aberrant HDAC signaling occurs in several types of cancer, including gliomas. Some researchers have advocated for more widespread use of this therapeutic diet in glioblastoma.^279,280

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. 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.²⁸²

Coffee contains many phytochemicals that may have anti-cancer effects.²⁸³ One of the most interesting compounds is a polyphenol called chlorogenic acid, which has been shown to inhibit glioblastoma cell growth in laboratory studies.^284,285 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.²⁸⁶

Similarly, one of the compounds found in tea, called epigallocatechin gallate (EGCG), has reversed the silencing of MGMT in cell culture experiments.²⁸⁷ EGCG has also been shown to improve the efficacy of temozolomide in a mouse glioblastoma model.^288,289 In addition, EGCG has been shown to reduce invasion, lessen proliferation, and may enhance other therapies such as carmustine.²⁹⁰ One caveat to green tea is that it may interfere with a class of drugs called tyrosine kinase inhibitors, as suggested by one study using bortezomib for multiple myeloma.²⁹¹ While some authors have raised valid criticisms of this study,²⁹² until there is solid evidence refuting interference with cancer drugs, high-dose green tea should be taken with caution alongside tyrosine kinase inhibitors and only under the guidance of an oncologist.

Melatonin

In humans, the natural hormone melatonin is involved in the sleep-wake cycle and in endocrine function. Disturbances in sleep-wake cycles lead to daytime fatigue, and this disturbance is one of the most common symptoms in people with brain tumors.²⁹³ Melatonin can stimulate the immune system and help fight inflammation.^294,295 For some patients with insomnia, melatonin can help improve their quality of sleep.^296-298 As we gain more insight into melatonin’s molecular mechanisms, it is becoming clear that it affects normal cells and cancer cells differently, resulting in selective harm to cancer cells without harming normal cells.²⁹⁹

Recent laboratory evidence has shown that melatonin may inhibit the viability and self-renewal of glioblastoma stem-like cells.²⁹⁴ In a study on glioblastoma stem-like cells isolated from patient surgical samples, melatonin affected cellular signaling pathways involved in cell survival and division.³⁰⁰ Melatonin may block glioblastoma cells from invading new areas by inhibiting genes involved in tissue invasion and new blood vessel formation.³⁰¹ Melatonin may also interfere with the aberrant energy production within glioblastoma cells that otherwise allows them to divide rapidly.³⁰²

In laboratory studies, melatonin boosted the effects of chemotherapy drugs, including temozolomide, indicating it may be especially helpful for patients undergoing conventional treatment.³⁰³ In addition, melatonin may complement the anti-cancer effects of repurposed drugs such as metformin, statins, and anti-inflammatories.³⁰⁴ It has been shown that glioblastoma cells reduce the amount of melatonin produced within their own mitochondria, providing them with a survival advantage.³⁰⁵

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. Those taking melatonin had less hair loss and infections as well. The authors also noted that side effects of radiation were less frequent in the melatonin group.³⁰⁶ The potential for melatonin’s use in glioblastoma needs further clinical trials, but its potential for improved outcomes and better quality of life in those with glioblastoma is promising.²¹

Vitamin D

Vitamin D has piqued the attention of glioblastoma researchers for some time. Italian scientists discovered in the early 1990s that glioblastoma seems to express more vitamin D receptors than lower-grade gliomas.⁵⁰⁰ Subsequent preclinical investigations have shown that vitamin D and some of its analogs can hinder the growth of glioblastoma cells in a petri dish and suppress their propensity to migrate and express invasive characteristics.⁵⁰¹

The hormonally active form of vitamin D, calcitriol or 1,25-dihydroxyvitamin D, has been shown to induce several molecular anti-cancer effects in preclinical studies in glioma cells. These anti-cancer effects are thought to arise in part through modulation of the expression of genes related to cell cycle control, immune response, and apoptosis.² Other preclinical work has shown that calcitriol enhances the anti-glioblastoma effects of the chemotherapeutic drug temozolomide in cell culture.⁵⁰² Some researchers have suggested potential complementary effects of vitamin D in combination with all-trans retinoic acid (a vitamin A derivative) and temozolomide in glioblastoma. Clinical trials testing the efficacy of this therapeutic combination are warranted.⁵⁰¹

Various observational and epidemiological reports have drawn intriguing associations between vitamin D and glioblastoma.

In 2017, researchers in Spain presented a study in which they analyzed the relationship between vitamin D blood levels and survival in 32 individuals diagnosed with glioblastoma. The researchers retrospectively analyzed participants’ vitamin D levels from before they started chemotherapy or radiotherapy. Study participants with vitamin D levels above 30 ng/mL had a significantly longer median progression-free survival (12.24 months) compared to those with lower vitamin D levels (5.14 months). Similarly, the overall survival was significantly longer in the group with higher vitamin D levels (18.11 months) compared to the group with lower levels (7.38 months). The researchers concluded that vitamin D deficiency may be a potential therapeutic target in glioblastoma, but further studies are needed to determine the optimal serum levels for patients with this condition.⁵⁰³

In a case-control study published in 2015, researchers at Ohio State University, the Karolinska Institute in Sweden, and the Cancer Registry of Norway found that higher blood levels of vitamin D were associated with lower risk of being diagnosed with high-grade glioma up to 15 years later among men aged 56 and older. Specifically, vitamin D levels above 26.4 ng/mL on a blood test between two and 15 years before diagnosis were associated with a lower risk of high-grade glioma, and glioblastoma in particular, in men 56 or older. However, there was no association among women or younger people of either sex.⁵⁰⁴

A consortium of researchers from prestigious institutions in the United States and several European countries published an analysis in 2018 of genetically driven variation in vitamin D levels and glioma risk. This kind of study, called a Mendelian randomization study, helps remove the influence of unmeasured confounding factors by sorting study participants according to their genetic makeup. Upon assessing genetic data from 12,488 people with glioma and 18,169 controls, the scientists found no link between genetically influenced vitamin D blood levels and glioma. However, an exploratory analysis (meaning that this was not the main aim of the study) showed that genetically driven higher vitamin D levels were associated with lower glioblastoma risk in one of the models the scientists ran. The authors called for future studies to more closely investigate the potential association between higher vitamin D blood levels and lower glioblastoma risk.⁵⁰⁵

A 2015 report assessed supplement intake among 470 people with glioblastoma who had participated in a case-control study in the southeastern United States. Researchers evaluated participants’ supplement use for up to five years prior to diagnosis as well as current use. About 13% of the study participants reported vitamin D supplementation. Compared with those who did not report vitamin D supplementation, those who took vitamin D supplements had a lower risk of mortality when the data was adjusted for age and some other covariates. However, when the researchers used statistical techniques to account for the influence of multiple other factors, the link between vitamin D and mortality was no longer statistically significant. Nevertheless, the researchers noted that other evidence supported a mechanistic link between vitamin D and improved outcomes in glioblastoma, and that further study was warranted.⁵⁰⁶

Among individuals with brain tumors diagnosed at hospitals in three cities in the United States, being born during winter months was associated with greater glioma risk (glioblastoma is a high-grade glioma).⁵⁰⁷ Vitamin D levels tend to be lower during winter months due to decreased exposure to ultraviolet light, which causes vitamin synthesis in the skin.

The interesting preclinical and observational evidence described above notwithstanding, clinical trials have yet to rigorously test whether vitamin D supplementation can help prevent high-grade gliomas or improve outcomes for patients affected by these cancers. Moreover, not all observational studies have consistently detected an association between vitamin D and glioma risk.⁵⁰⁸ Nevertheless, one preliminary uncontrolled phase 2 trial published in 2001 by French researchers evaluated the effect of a vitamin D analog in 10 people with glioblastoma and one person with anaplastic astrocytoma (another kind of high-grade glioma). The vitamin D analog alfacalcidol was administered with, or after, chemotherapy, surgery, and radiotherapy. Of the 11 study participants, three (two with glioblastoma and one with astrocytoma) had pronounced regression of their tumor on imaging studies. Two of the 10 people with glioblastoma who participated in this study were alive four years later. The investigators concluded that alfacalcidol could be a safe and potentially active adjuvant treatment in this setting, particularly in a subset of responders, but that further studies are needed to verify its efficacy.³¹⁵

Overall, available preclinical and observational evidence provide a reasonable basis for pursuing further controlled interventional studies of vitamin D or its derivatives or analogs in the prevention and/or treatment of high-grade glioma.^509,510

Selenium

Selenium is an essential trace element³¹⁶ and an integral player in brain health, including brain cancers.³¹⁷ 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.³¹⁸ 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.³¹⁹ For instance, sodium selenite decreased cell proliferation and caused cell death in several types of human glioblastoma cells.³²⁰ In another laboratory study, sodium selenite inhibited the proliferation of human glioblastoma cells and rat glioma cells.³²¹ 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.³²² 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.³²³

Boswellia

There are naturally-occurring plant compounds under investigation for their anti-tumor properties, such as boswellic acids, found in the gum resin of Boswellia plants, better known as frankincense.^324-326 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.³²⁷ 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.^327,328 In a mouse model of brain tumors, boswellia reduced tumor growth by normalizing several aspects of aberrant metabolism in the glioma tissue.³²⁹ In another cell model, boswellic acids stopped the process of division in glioma cells.³³⁰

A recent study described experiments designed to determine whether boswellic acids could enhance the anti-cancer 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, afatinib (Gilotrif), or radiation, a combined effect greater than the sum of their separate effects was observed, indicating boswellic acids could be a promising integrative therapy for patients with glioblastoma.^324,331,332

Boswellic acids are also helpful in reducing brain swelling, which may develop as a result of brain tumors or their treatment with radiation therapy.^333-335 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.³³⁵ In a second study, 44 patients with brain tumors took either 4,200 mg boswellia extract daily or placebo while undergoing radiation therapy. The boswellia extract group had a significant decrease in brain swelling compared with placebo. An over 75% reduction of swelling was seen in 60% of patients receiving the extract versus 26% of patients receiving placebo.³³⁶ In an uncontrolled study, a highly absorbable lecithin-based boswellia extract was used in 20 patients with glioblastoma who were receiving standard of care. Each of them consumed 4,500 mg boswellia daily for up to 34 weeks. Swelling around the brain was assessed at 4,12, 22, and 34 weeks after surgery and steroid consumption was tracked. Steroid use was either reduced, stable, or not needed for most of the patients over the course of the study. Two patients achieved dramatic reduction of edema that likely contributed to their improved outcomes. The authors noted that the anti-inflammatory effects of boswellia on the brain likely led to reduction of steroids and their side effects as well as better outcomes.³³⁷

Curcumin

Curcumin, derived from the Curcuma longa plant, is a component of the spice turmeric.³³⁸ 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.^339-342 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.^{20,338,343,344}

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.³⁴⁵ 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 the breakdown of surrounding tissue (extracellular matrix) that otherwise allows for tumor growth.³⁴⁶

In another animal glioblastoma model, rats that were given curcumin and treated with radiation lived longer than when either curcumin or radiation was given as a single agent. The authors concluded that curcumin may be an effective radiosensitizing agent for gliomas.³⁴⁷ However, the dose needed to reach the brain to replicate these rodent studies may be too high for humans to achieve.³⁴⁸ Novel delivery forms of curcumin and curcumin analogues are being researched to overcome this hurdle and appear promising.^349,350

There is also evidence that curcumin may enhance the efficacy of some chemotherapy drugs.³³⁹ 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.³⁵¹ Curcumin may also enhance the effectiveness of temozolomide, and much like combining curcumin with radiation, novel ways to enhance this effect through improved curcumin uptake into the brain are being sought.³⁵²

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.^353-355 This finding is important because increased ceramide has been found to sensitize glioma cells to chemotherapy.³⁵⁶

L-arginine

L-arginine administration has been found, in a controlled clinical trial, to influence metabolic processes and induce radiosensitivity in tumors that have metastasized to the brain. L-arginine acts as a precursor for nitric oxide (NO), which was shown to induce chemo- and radiosensitivity in solid and hypoxic tumors by increasing tumor blood flow and decreasing tumor oxygen consumption. NO is synthesized by NO synthases (NOS), which are found in three isoforms; of these isoforms, nitric oxide synthase 2 (NOS2) has been shown to be transcriptionally upregulated in a cell line of triple-negative breast cancer as well as in patients with brain metastasis due to non-small cell lung carcinoma.⁴⁹⁰

In a preliminary study of five patients with brain metastases, 10 grams of oral L-arginine in water was capable of increasing plasma L-arginine levels by an average of 42%. L-arginine did not alter tumor blood flow but decreased tumor blood volume and lactate concentration compared with placebo, highlighting the suppressive effect of L-arginine on tumor metabolism.⁴⁹⁰

To examine the effect of L-arginine on radiation therapy, the researchers performed a clinical study and recruited 63 patients with unresectable brain metastases that were randomized to receive 10 grams oral L-arginine or placebo 1 hour prior to each fraction of radiation therapy with a median follow up of five months (ranging from 1 to 55 months). There was a significantly greater overall response rate, symptomatic response rate, complete neurological response, and proportion of patients free from neurological progression in those treated with L-arginine compared with placebo.⁴⁹⁰ These novel results demonstrated that oral L-arginine could be an effective strategy to induce radiosensitivity in patients with brain metastases.

L-arginine is also capable of suppressing tumor metabolism and DNA repair in preclinical in vitro and in vivo models; these effects may contribute to its radiosensitizing effects. In triple-negative breast cancer cell lines, L-arginine administration significantly reduced several measures of tumor metabolism.⁴⁹⁰ Further, L-arginine decreased DNA damage repair in cancer cells in vitro and in mice in vivo without altering the amount of radiation-induced DNA damage in tumor-infiltrating lymphocytes, indicating that L-arginine is unlikely to harm immune cells.^490,491 Arginine’s suppression of tumor metabolism was mediated by NOS2 and prevented by pretreatment with a NOS2 inhibitor prior to L-arginine administration.⁴⁹⁰

Resveratrol

Resveratrol is found in certain plants where its role is to protect the plant from infectious microbes.^357-359 Nuts, berries, grapes, red wine, and Japanese knotweed are excellent sources of resveratrol.³⁶⁰ Resveratrol is being explored as a potential anti-cancer treatment because some evidence suggests it helps prevent instability of the genome, reduces the ability of gliomas to invade nearby tissue, and improves the effectiveness of some conventional treatments.^361,362

Resveratrol’s potential as a therapeutic agent for brain tumors hinges in part on its ability to cross the blood-brain barrier as well as its ability to inhibit proliferation, migration, and cell survival.³⁵⁷ In one study, resveratrol inhibited the growth of human glioblastoma cells and caused cell death in a dose-dependent manner.³⁶³ It also inhibited the growth of glioblastoma stem-like cells and suppressed the growth of glioblastoma in a mouse model.³⁶⁴ In another study, resveratrol was able to prevent the cellular changes needed for glioblastoma cells to become invasive.³⁶⁵ Resveratrol inhibited a signaling pathway in these cells and suppressed the production of a protein involved in cellular invasion.³⁶⁶ In a laboratory study that used several glioblastoma cell types, resveratrol inhibited cellular movement and invasiveness by activating a major signaling pathway.²²

Resveratrol may also increase the sensitivity of 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.³⁶⁷ In in vitro studies and mouse models, temozolomide more effectively induced cell death and inhibited cell migration when used together with resveratrol.^367,368 Resveratrol may overcome temozolomide resistance by reducing the amount of MGMT in the resistant cells.^369,370 In a glioma stem cell line resistant to radiation, resveratrol increased the sensitivity of the cells to radiation.³⁷¹ Resveratrol also increased the ability of the chemotherapy drug paclitaxel to kill glioblastoma cells.³⁷²

Quercetin

Quercetin is a naturally occurring plant flavonoid with many potential anti-cancer properties.^373,374 Multiple laboratory experiments have demonstrated that quercetin can kill human glioblastoma cells.³⁷⁵ Quercetin may also inhibit the ability of glioblastoma cells to metastasize,^376,377 reduce their viability,^377,378 decrease their ability to proliferate and migrate,³⁷⁹ and inhibit blood vessel formation.³⁷⁶ Other research found quercetin may increase the sensitivity of glioblastoma cells to temozolomide and radiation.^380,381 Quercetin may also enhance the effects of chloroquine, an antimalarial drug with promise as an anti-cancer agent for glioblastoma.³⁸²

Green Tea and EGCG

Epigallocatechin-3-gallate (EGCG) is a green tea flavonoid with known anti-cancer, antioxidant, and anti-inflammatory activities.^383-385 In laboratory studies that used human glioblastoma cell lines, exposure to EGCG contributed to cell death.^383,386 EGCG targets several cellular events mediated by matrix metalloproteinases, including some pathways that control cellular migration.³⁸⁷ EGCG can also inhibit a protein that makes glioblastoma cells more resistant to chemotherapy and blocks their death.³⁸⁸ In human glioblastoma stem-like cells, EGCG synergized the effects of temozolomide.²⁸⁸ A study found that this synergy may be due to reversal of the resistance mechanism, namely MGMT, within the glioblastoma cells.³⁸⁹

EGCG and other catechins from green tea may fight cancer partly through their ability to inhibit the activity of an important cellular signaling pathway.³⁹⁰ In two different human glioblastoma cell types, EGCG activated cell death pathways. Interestingly, EGCG did not have this effect on healthy human brain cells.³⁹¹ One study showed that green tea led to senescence of glioblastoma cells without harming normal cells.³⁹² Another cell study suggested that the dose derived from drinking green tea may prevent brain tumor development, but glioblastoma cell death is only achieved from much higher concentrations of green tea.³⁹³ 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.²⁸⁹ In a separate study in mice implanted with human gliomas, EGCG slowed tumor growth by interfering with the aberrant metabolic pathway of gliomas.³⁹⁴ Interestingly, application of EGCG to colon cancer cells harboring a mutation in IDH1 led to decreased proliferation.³⁹⁵ Whether this will hold true for IDH1-mutated gliomas has not been studied as of the time of this writing.

Chrysin

Chrysin, a naturally occurring flavonoid found in honey, propolis, and many plants, may fight inflammation and other processes involved in cancer development.³⁹⁶ Chrysin promoted cell death in studies of several glioblastoma cell lines.^397,398 Another study found chrysin reduced the mitochondrial function of glioblastoma cells and decreased the production of a protein involved in tumor invasion.³⁹⁹ In a mouse xenograft model, chrysin inhibited the proliferation, migration, and invasion of glioblastoma cells and suppressed tumor growth.⁴⁰⁰ In an in vitro study, an extract of propolis inhibited the growth of human glioblastoma cells in a dose- and time-dependent manner and enhanced the effects of temozolomide.⁴⁰¹

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.⁴⁰² Apigenin also powerfully suppressed the invasiveness of glioblastoma stem-like cells.⁴⁰³ This is a significant finding because stem-like cells can self-renew and are resistant to radiotherapy and chemotherapy.^404,405 In human glioma cells, apigenin reduced the production of TGF-β1, a signaling molecule involved in migration, invasion, and the formation of blood vessels.⁴⁰⁶ Importantly, apigenin may not have the same effects on normal cells. One study found apigenin activated cell death pathways in two different human glioblastoma cell lines, but not in normal human astrocytes.³⁹¹ Central to any cancer growth is the ability to evade immune destruction. Apigenin was able to reduce glioma cell migration and restore immune attraction toward glioma cells, a necessary component of their eventual destruction.⁴⁰⁷ Apigenin has numerous anti-cancer actions across a diverse array of tumors.⁴⁰⁸

Phytoestrogens

Phytoestrogens are plant compounds that are similar in structure to the hormone estrogen.⁴⁰⁹ Soy beans, flaxseed, and nuts are all good sources.^410,411 Despite their similarities, phytoestrogens appear to play a different role in glioblastoma than the estrogens naturally produced by the body. This may be because they act differently inside cells. Endogenous estrogens have an unpredictable effect in glioblastomas, leading either to growth promotion or inhibition, depending on numerous factors.^408,412,413 In contrast, plant-derived phytoestrogens have been shown to exert beneficial effects in glioblastoma.⁴¹⁴

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.⁴¹⁵ Another study found 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.^416,417 In a preclinical experiment, genistein inhibited a signaling pathway used by glioblastoma cells even at very low concentrations.⁴¹⁸ Glioblastoma cells that were exposed to genistein had more sensitivity to the killing capacity of therapeutic radiation doses, lowering the dose needed to kill the cells.⁴¹⁹ In another experiment, genistein lessened the invasive potential of glioblastoma cells.³⁷⁰

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.⁴²⁰ A lesser-known phytoestrogen called biochanin A (found in red clover⁴²¹ and other plants) enhanced the anti-cancer effects of temozolomide.⁴²²

Honokiol

Honokiol is a natural bioactive polyphenol extracted from the bark of the tree Magnolia officinalis. Honokiol has demonstrated anti-inflammatory, anti-microbial, and anti-cancer effects in laboratory studies.^423,424 Researchers have reported that honokiol can inhibit the division of glioblastoma cells and cancer stem-like cells^422,425 and kill glioblastoma cells by several mechanisms.^426,427 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.⁴²⁸ Another study found honokiol inhibited the interaction between human glioblastoma cells and cells that line the blood vessels, suggesting it may inhibit the spread of tumor cells via the bloodstream.⁴²⁹ In glioblastoma cell culture experiments, honokiol and a similar compound called magnolol were more effective at killing cancer cells when used together.⁴²³

Honokiol is of particular interest for treatment of glioblastoma because studies in mice suggest the compound can cross the blood-brain barrier.⁴³⁰ In a mouse model of human glioblastoma, honokiol caused cell death and significantly prolonged survival of the mice.⁴²⁴ 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.⁴²³

In an experiment using honokiol and a disulfiram/copper complex in a liposomal delivery system, tumor regression via immune attack was observed in a mouse model.⁴³¹ When combined with temozolomide, several studies have shown honokiol may complement the drug’s ability to kill glioblastoma cells.^432-434

Polyunsaturated Fatty Acids

Several types of polyunsaturated fatty acids (PUFAs) have been studied for the treatment of glioblastoma.⁴³⁵ 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.⁴³⁶ 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.⁴³⁷ Open-label clinical studies have suggested GLA may be effective against malignant gliomas.^438,439 In patients with glioma, delivering GLA directly into the tumor was found to be safe, and in some cases, led to tumor regression. Several participants survived without new symptoms for up to two years.⁴⁴⁰

Milk Thistle

Silibinin (silybin) is a biologically active compound in extracts from the seeds of the herb milk thistle (Silybum marianum ).^441,442 Silibinin is capable of affecting many of the classic characteristics or “hallmarks” of cancer that allow the cells to grow and spread unchecked.⁴⁴³ Studies show silibinin caused glioblastoma cells to enter into self-destructive mode through at least two separate mechanisms.^444,445 In another study, silibinin inhibited the invasive features of highly invasive glioblastoma cells.⁴⁴⁶ 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.^447,448

Using several different glioma cell lines, silibinin increased the toxicity of temozolomide on the cells, improving the drug’s cell killing ability.⁴⁴⁹ Silibinin also worked well in combination with arsenic trioxide, a drug approved for treatment of a form of leukemia.^450,451 In glioblastoma cells, the combination of silibinin and arsenic trioxide slowed tumor cell metabolism and increased cell death.⁴⁵² A study found that silibinin increased the accumulation of arsenic inside glioblastoma cells treated with arsenic trioxide. When silibinin was combined with chrysin, arsenic trioxide levels built up inside glioblastoma cells, while the cells were simultaneously hampered in their defenses against it.⁴⁵³

Vitamin E

The term “vitamin E” refers to eight compounds in nature; four tocotrienols and four tocopherols. The tocotrienols, alpha-, beta-, gamma-, and delta-, may help fight cancer and inflammation.^454,455 They target many molecular paths used by cancers, including survival mechanisms, new blood vessel formation, proliferation and invasion.⁴⁵⁶ 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.⁴⁵⁷ Delta-tocotrienol also worked well in combination with extracts from the Tabernaemontana corymbosa plant, a traditional cancer treatment in Bangladesh,⁴⁵⁸ and extracts from plants in the genus Ficus.⁴⁵⁵ In vitro, tocopherols showed anti-glioma effects by controlling cell cycle progression in glioma cells. In this study, gamma-tocopherol was found to exhibit “the most potent and specific control” over glioma cells’ progression through the cell cycle.⁴⁵⁹ Similarly, another in vitro study also found gamma-tocopherol was more potent than alpha-tocopherol in inhibiting proliferation, adhesion, and migration in human glioma cells.⁴⁶⁰

Ellagic Acid

Ellagic acid, a natural compound found in many fruits and plants, may also have health benefits for glioblastoma patients. In general, ellagic acid is being studied for its ability to lessen spread of cancers to distant organs and reduce the production of new blood vessels.⁴⁶¹ 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.⁴⁶² Another study reported ellagic acid dramatically reduced levels of proteins that protect tumor cells from death.⁴⁶³ 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.⁴⁶⁴ When glioblastoma cells were treated with ellagic acid combined with temozolomide, they exhibited a reduction in the invasive and angiogenic capabilities of the cancer cells.⁴⁶⁵ Ellagic acid may also complement bevacizumab, an approved anti-angiogenesis drug for glioblastoma. In a cell study, ellagic acid combined with bevacizumab led to reduced viability of cells.⁴⁶⁶ In the same study, ellagic acid led to downregulation of MGMT expression, which increases glioma cells’ sensitivity to the cytotoxic effects of temozolomide.

Chlorogenic Acid

Chlorogenic acid, a phenolic compound found in coffee, green tea, apples, and pears, has promising anti-cancer potential for many cancers, including brain tumors.⁴⁶⁷ 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.²⁸⁴ Another study found chlorogenic acid inhibited cell migration and the secretion of a protein implicated in tumor invasion.²⁸⁵ In a double-blind placebo-controlled trial, chlorogenic acid improved cognitive function in healthy participants.⁴⁶⁸ This is intriguing given the cognitive difficulties that are common during and after treatment for glioblastoma.

Ginseng

Ginseng (Panax ginseng) root contains compounds called ginsenosides. One ginsenoside in particular, R3, has been shown to have an additive anti-tumor effect when combined with temozolomide in an animal model of glioblastoma.⁴⁶⁹ In another study using several glioma cell lines that were resistant to temozolomide through production of MGMT, R3 was able to block MGMT production and reinstate sensitivity of the cells to temozolomide.⁴⁷⁰ This study also showed ginsenoside R3 prevented the changes in glioma cells that allow them to invade nearby tissue. It appears that at least some R3’s anti-glioblastoma properties are via its antioxidant properties and induction of senescence in glioma cells.⁴⁷¹ R3 ginsenoside is being studied as an anti-cancer agent due to its well defined role in blocking new blood vessel development in many types of cancer, including gliomas.⁴⁷²

Olive Leaf

Olive leaf (Olea europaea) extract exhibited anti-proliferative effects in glioma cells.⁴⁷³ Experiments on glioblastoma cell lines suggest olive leaf extract can prevent the differentiation ability of glioblastoma stem cells.⁴⁷⁴ The anti-glioblastoma effects of olive leaf extract are seen when used alone in high dose, and it has an additive effect in stopping glioma cell growth alongside temozolomide.⁴⁷⁵ Whole leaf extract has generally been studied, and single compounds within the olive leaf, such as oleuropein, also show promise⁴⁷⁶; however, most of the research is preliminary as of late 2020.

Black Cumin

Black cumin (Nigella sativa) seed has been used in traditional herbal medicine for over 2,000 years.⁴⁷⁷ While whole seed extracts have shown effective medicinal qualities, the compound thymoquinone in black cumin has garnered the most interest as an anti-cancer compound.^478,479

Thymoquinone has been shown to affect dozens of pathways inside cancer cells, including those involved in several hallmarks of cancer: immortality, invasion, metastasis, apoptosis, and cellular division.⁴⁸⁰ The anti-glioblastoma effects include increasing cell death and creating cellular stress within glioblastoma cells.^481,482 The benefits of thymoquinone may also extend to preventing ongoing brain-related symptoms as data suggest neuroprotective and anti-seizure effects.⁴⁸³

Niclosamide (Niclocide) is another anti-glioblastoma compound of interest from black cumin.⁴⁸⁴ This compound is thought to be responsible for the traditional use of black cumin seeds in treating parasites and worms in the gut. Niclosamide is also an approved anti-parasitic agent worldwide due to its reliability in killing human worms such as tapeworm.⁴⁸⁵ In one experiment, the combination of thymoquinone and niclosamide was able to lessen the invasive properties of a glioblastoma cell model. The combination also had a similar effect in a rodent model that used implanted human glioblastoma cells.⁴⁸⁶