Brain tumors and conventional medicine
The National Cancer Institute (NCI) and the American Cancer Society (ACS) estimate that 22,020 primary malignant brain tumors will be diagnosed in 2010 (Porter KR et al 2010). The American Brain Tumor Association, since they count both malignant and benign brain tumors, predicts twice as many cases (Jemel A et al 2008). Secondary brain tumors, which originate elsewhere in the body, outnumber primary tumors four-to-one, so add another 100,000 cases a year to get an idea of the total number of people who will be diagnosed with brain cancer each year (Davis FG et al 2001).
The medical treatment of primary brain tumors typically consists of two steps: surgical excision followed by combined radiation and chemotherapy. For advanced or high-grade tumors, the benefit of these therapies seems small. “After conventional treatments, the survival rate for patients with astrocytomas or glioblastomas is about 50% at 1 year, 25% at 2 years, and 10 to 15% at 5 years” (Online Merck Manual, accessed Oct, 2010). Thus, many patients wisely seek complementary therapies hoping to improve their odds.
In the last few years, tremendous progress has been made toward developing successful treatments for advanced brain tumors. A groundbreaking study published in 2013 in the New England Journal of Medicine showed that the antiviral drug valganciclovir (Valcyte) improved survival of glioblastoma patients (Soderberg-Naucler 2013). Also, pioneering work at Duke University using a bioengineered poliovirus-based therapy led to remarkable response rates in glioblastoma patients and was featured on "60 Minutes" in 2015 (Inman 2016). Other exciting emerging treatments include the antidiabetic drug metformin (Kast 2011) and cimetidine, an over-the-counter heartburn medication (Lefranc 2006).
The risk factors for brain tumor are almost unknown, though there are hints that suggest early exposure to certain chemicals might play a role.
In 2010, the Fred Hutchinson Cancer Research Center in Seattle reported that children who develop brain tumors are likely both to have been exposed to higher than average amounts of pesticides and to have been born with a reduced ability to detoxify these chemicals (Barrett JR 2010, Nielsen SS et al 2010).
Other studies also point to chemical exposure as a potential risk factor. The children of women who had high exposure to beauty-products are at increased risk for brain tumors (Efird JT et al 2005). Personal hair dye use increased risk in one study. Using brown hair dye for 20 years, for example, almost quadrupled risk of glioma in women (Bluhm EC et al 2007). Individuals who engage in a hobby that involves using glue are at 18 times the average risk (Spinelli V et al 2010).
A 2009 review found that people who used cell phones for at least 10 years had a 2.4-fold greater risk of developing an acoustic neuroma in the ear to which they routinely held their phone, but had no change in risk for other types of cancer (Han YY et al 2009).
The idea that nitrosamines in processed meats may increase the risk of glioma has been circulating for several decades (Michaud DS et al 2009), yet a July 2010 paper found only a modest increase in risk in people who ate large amounts of nitrosamines compared to those who ate very little (Dubrow R et al 2010).
There are no tests to predict risk of brain cancer, or steps we can take to prevent it. Our focus is on preventing recurrence, or at least slowing down the disease.
Common Virus Linked to Deadly Brain Cancer
Few people would ever suspect that one of the most deadly forms of brain cancer is caused by a common virus carried by the majority of people. Yet according to a number of new studies in prestigious medical journals, that is exactly the case.
In the same way that cervical cancer and head and neck cancer have been linked to certain strains of the HPV virus, the most common and deadly type of brain cancer, glioblastoma, has been linked to a virus in the herpes family called CMV (short for cytomegalovirus) (Tommasino 2014; Cobbs 2011).
Glioblastoma carries a grim prognosis, with population studies indicating typical overall survival rates of less than a year. And unfortunately, this deadly form of brain cancer is the most common malignant brain tumor in the United States (Krex 2007).
Establishing a link between this deadly cancer and a common virus is an enormous step in understanding how to treat, and potentially prevent, early and unnecessary deaths. And more importantly, it led to the discovery of a drug that dramatically extended the lives of those already diagnosed with this deadly disease (Soderberg-Naucler 2013)!
Valganciclovir – A Brain Tumor Treatment Breakthrough
A study published in the September 5, 2013 edition of the New England Journal of Medicine represents a significant advance in treating glioblastoma multiforme.
Doctors followed 75 glioblastoma multiforme patients and found the median overall survival of those with low-grade cytomegalovirus infection was 33 months. In patients with high-grade cytomegalovirus infection, median overall survival was only 13 months (Soderberg-Naucler 2013).
The cytomegalovirus has been suspected of facilitating the initiation and promotion of brain cancers (Dziurzynski 2012; Barami 2010; Soroceanu 2011). From 50% to as many as 80% of U.S. adults show exposure to cytomegalovirus, but relatively few harbor active viral infection (CDC 2016).
All but one of the 75 glioblastoma multiforme patients studied had active cytomegalovirus infection, indicating this virus may be involved in the development of this lethal malignancy (Soderberg-Naucler 2013).
In glioblastoma multiforme patients with high-grade cytomegalovirus infection, median 2-year survival was 17.2%. Patients with low-grade cytomegalovirus infection had median 2-year survival rates of 63.6%. This suggests high-grade active cytomegalovirus infection accelerates tumor progression.
Valganciclovir is an FDA-approved drug used to treat cytomegalovirus infection.
In a double-blind clinical trial of valganciclovir involving 42 patients with glioblastoma, an exploratory analysis of 22 patients receiving at least six months of antiviral therapy showed 50% overall survival at two years compared with 20.6% of contemporary controls. This study showed that valganciclovir-treated patients have a median overall survival of 24.1 months compared with 13.7 months in patients not treated with valganciclovir.
Owing to the promising results of this pilot study, glioblastoma multiforme patients at the world famous Karolinska University Hospital received valganciclovir and results were then compared to a control group. Both groups received standard conventional therapy and had a similar disease stage and surgical-resection grade.
The researchers retrospectively analyzed the data on 50 of these brain cancer patients and found the 2-year rate of survival in the valganciclovir group was 62% versus only 18% in the control group.
In 40 glioblastoma multiforme patients who received valganciclovir for at least 6 months, the 2-year survival rate was 70%, with a median overall survival of 30.1 months.
Twenty-five glioblastoma multiforme patients that received continuous valganciclovir treatment after the first 6 months had a 2-year survival rate of 90%, with median overall survival of 56.4 months (4.7 years)! This contrasts sharply with the current median survival time of glioblastoma multiforme patients, which is only 12–14 months.
Cimetidine is another intriguing off-label drug that may have potential as a brain tumor treatment. Cimetidine is a common heartburn drug that has shown several remarkable ancillary effects, including anti-tumor activity against several types of cancer. In an animal model of human glioblastoma, combining cimetidine with a typical drug treatment (temozolomide [Temodar]) improved survival compared with temozolomide alone (Lefranc 2006). A small 2017 study on seven glioblastoma patients found that a cocktail of drugs (cimetidine, lithium, olanzapine [Zyprexa], and valproate [Depakote]) led to longer-than-expected overall survival; the mechanism by which this cocktail improved survival was thought to involve inhibition of the enzyme GSK3β, whose activity may contribute to brain aging (Furuta 2017).
Duke University’s Landmark Glioblastoma Treatment Success
In 2015, the CBS News program “60 Minutes” featured a story about research emanating from Duke University Medical Center showing complete responses in terminal glioblastoma patients who were administered a re-engineered poliovirus directly into their brain tumor. The re-engineered virus prompted a powerful immune response against the viral-infected cancer cells, which in some patients appeared to eradicate their glioblastoma. You can watch this "60 Minutes" episode here: www.LifeExtension.com/glio.
Glioblastoma cells express high levels of the poliovirus receptor, so the virus-based therapy readily infects them and causes cell death. However, because of the unique way the poliovirus is bioengineered and combined with a rhinovirus—the type of virus that causes common colds—it does not replicate and spread throughout the body.
Treatment with this groundbreaking therapy received a “breakthrough therapy” designation from the FDA in May of 2016 (Inman 2016). This means more FDA resources will be allocated to assist researchers move their studies along as quickly as possible.
As of June 2017, Duke University Medical Center is enrolling patients with grade-IV malignant glioma in a Phase 2 study. More information about the study is available on the ClinicalTrials.gov website or through Duke’s Preston Robert Tisch Brain Tumor Center.
Dichloroacetate and Brain Tumors
Dichloroacetate (DCA) is an investigational drug that modulates mitochondrial energy metabolism. In recent years, it has gained attention as a potential anti-cancer compound in its own right, and for its potential to enhance the activity of other cancer therapies (Kankotia 2014). Early research is promising: An open-label phase 1 trial on 15 adults with grade III – IV gliomas found that DCA treatment was feasible and well-tolerated (Dunbar 2014). A similar trial in 24 patients with advanced solid tumors used 28-day cycles of DCA at different doses and found only mild side effects (Chu 2015). This research built upon an earlier, smaller trial on five glioblastoma patients in which DCA treatment for up to 15 months led to some indications of laboratory and clinical efficacy (Michelakis 2010). Studies on cancer cells in vitro have shown that DCA increases cancer cell apoptosis and suppresses the recruitment of new blood vessels (angiogenesis), which is a key mechanism by which tumors spread (Dunbar 2014). Ongoing research into the therapeutic potential of DCA in solid malignant tumors is likely to focus at least in part on dose selection, as individual responses vary widely (James 2017; James 2016).
Metformin—Potential Benefits for Brain Tumor Patients
Metformin, a first-line antidiabetic therapy, crosses the blood-brain barrier and has been shown to block tumor growth through its effects on glioblastoma stem cells—brain stem cells that generate tumor cells (Carmignani 2014). A number of preclinical studies found metformin inhibits proliferation and migration and promotes cell death in glioblastoma stem cells (Seliger 2016; Aldea 2014; Wurth 2013; Ferla 2012).
A clinical study that included 276 glioblastoma patients examined the possible effects of metformin on outcomes. All participants were undergoing radiation therapy, and 167 were being treated with temozolomide. Forty participants had diabetes prior to their diagnosis with glioblastoma; 20 were receiving metformin and 19 were receiving other antidiabetic medications. Although metformin use did not influence overall survival rates, average progression-free survival was significantly longer in diabetics receiving metformin (10.1 months) than in other diabetics (4.7 months) and nondiabetics (6.7 months) (Adeberg 2015). Another study that examined data from 67 glioblastoma patients receiving single-drug therapy for diabetes reported median overall survival of 10 months in those using metformin compared with six months among those receiving other single-drug anti-diabetic therapies (Welch 2013).
Positive outcomes have been described in the case of an individual with glioblastoma who was treated with metformin and niacinamide in addition to chemo-radiotherapy and biological therapy: despite a poor prognosis with average survival time of 15 months, this patient experienced progressive improvement in his condition and had no evidence of recurrence 30 months after initiating treatment (Rios 2016). Findings from animal research suggest metformin may decrease tumor-induced blood vessel permeability and subsequent cerebral edema, resulting in clinical improvements (Zhao 2016).
The anticancer effects of metformin appear to be due in part to activation of the enzyme AMP-activated protein kinase (AMPK) and inactivation of the transcription factor STAT3 (Elmaci 2016; Leidgens 2017; Sato 2012; Ferla 2012). AMPK is an important regulator of glucose and fatty acid metabolism that promotes healthy aging and extends lifespan (Burkewitz 2014); the STAT3 gene is a regulator of cell growth and survival that is persistently activated in malignancies (Demaria 2014). Also, metformin may act synergistically with some cancer treatments. Metformin increased cytotoxicity of temozolomide against cancer cells from brain tumor patients (Soritau 2011), and partially restored temozolomide sensitivity in a resistant glioblastoma cell line (Yang 2016). In mice with experimentally induced glioblastoma, metformin improved treatment effects of both temozolomide and radiation therapy (Sesen 2015; Yu 2015). Metformin has also enhanced the effectiveness of the biological cancer agent sorafenib (Nexavar) against glioblastoma stem cells (Aldea 2014).
Brain Tumor Nutritional Protocol
Hormones and Brain Tumors
Vitamin D: Vitamin D deficiency that occurred before birth may have set the stage for brain tumor formation later in life. Vitamin D deficiency during gestation causes long-term effects on brain development (Levenson CW et al 2008).
Vitamin D remains important after birth, as it activates chemical pathways, in particular the sphingomyelin pathway, which kills glioblastoma cells (Magrassi L et al 1998). Vitamin D3, the chemical form of vitamin D made in the skin and sold as a nutritional supplement, calcitriol (1,25-dihydroxy vitamin D), the active form of vitamin D, and various chemical analogs and metabolites of vitamin D, have all been shown to inhibit growth and trigger apoptosis in neuroblastoma and glioma cells (Naveilhan P et al 1994, Baudet C et al 1996, Elias J et al 2003, van Ginkel PR et al 2007).
A 2009 report on brain tumor death statistics from Finland alludes to the benefit of vitamin D. Mortality from brain tumors is highest in patients who were diagnosed and underwent surgery during the late winter, particularly from February to March. This is the time of year when vitamin D levels are at their lowest (Hakko H et al 2009). Similar seasonal variations in cancer survival rates are seen for lung (Porojnicu AC et al 2007), breast (Stajner I et al 2010), and colon cancer (Robinson D 2010). The explanation tendered in all these studies is that in the winter people have lower vitamin D levels and are less capable of fighting the cancer.
Another data analysis from Spain revealed a direct correlation between latitude and brain cancer incidence. The higher the latitude, that is the further from the equator someone lives, the greater their risk for brain cancer (Grant WB et al 2007). The further people live from the equator, the lower their vitamin D levels (Genuis SJ et al 2009).
Melatonin: Melatonin is often suggested for treating various forms of cancer, particularly breast, lung and colorectal cancers. Lissoni has conducted repeated studies demonstrating that patients with advanced cancers given melatonin survive longer than patients receiving a placebo (Lissoni P et al 2007).
There is growing evidence suggesting melatonin may be useful in treating primary brain tumors. An in vitro experiment showed that melatonin, at physiologic concentrations, inhibits growth of neuroblastoma cells (Cos S et al 1996). A 2006 paper published in Cancer Research reported that melatonin stopped the growth of gliomas that had been implanted into rats (Martín V et al 2006). As a result, some researchers suggest melatonin might be useful in treating glioma (Wion D et al 2006).
The strongest evidence for the use of melatonin in brain cancer is in treating pituitary tumors. Melatonin given to rats inhibits the chemical-induced formation of pituitary tumors (Gao L 2001). Giving melatonin to rats with pituitary tumors halts tumor growth and triggers apoptosis, especially if the tumor secretes prolactin (Yang QH et al 2006).
Vitamins and Minerals
Folic Acid and 5-MTHF: To be of use in the body, natural folate from food and folic acid from supplements must be converted into the active form, 5-MTHF (5-methyltetrahydrofolate), by the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). In certain people the gene that codes for this enzyme produces a less effective enzyme. In some studies, the risk for glioma in these people is increased by about 23% while meningioma risk is more than doubled (Sirachainan N et al 2008, Bethke L et al 2008, Kafadar AM et al 2006).
People can compensate for this genetic problem by taking a supplement of active 5-MTHF and bypassing the need for the MTHFR enzyme.
A German study compared survival times of patients with glioblastoma multiforme with their MTHFR gene variants. Those patients who were best able to convert folate into its active form survived for about 13 months. Those with the less effective MTHFR genes survived for only seven months (Linnebank M et al 2008). This suggests that supplementing with the active form of folate might be helpful.
Selenium: Selenium is another antioxidant that patients with brain tumors should consider. Many oncologists fear that any nutritional supplement classified as an antioxidant will interfere with the ability of radiation or chemotherapy to kill cancer cells. Though this theory sounds logical, there is little published evidence to support it.
In the case of selenium, a 2004 paper in the journal Anticancer Research, reports a “radiosensitizing effect” on glioma cells (Schueller P et al 2004). Exposing brain cancer cells to selenium makes them more sensitive to, and more likely to die after, radiation therapy.
Selenium also inhibits growth and invasion, and induces apoptosis in various types of brain tumor cells, including malignant cell lines (Sundaram N et al 2000, Rooprai HK et al 2007).
Vitamin E: Vitamin E is another antioxidant of particular interest in connection with brain cancer. According to a 2005 study, alpha-tocopherol-succinate enhances chemotherapy treatment of drug resistant glioblastoma cells, increasing effectiveness (Kang YH et al 2005).
A researcher from Tufts University described the use of vitamin E in treating glioblastoma multiforme in a 2004 article in the Journal of Nutrition. “Glioblastoma multiforme is the most common and aggressive brain cancer in humans and resists all forms of therapy. Vitamin E (succinate) induces apoptosis in glioblastoma cells in a dose-related manner; we find that a 48-h exposure to 50 micromol/L vitamin E results in a 15% increase in apoptosis in the glioblastoma cells over control. Pretreatment with vitamin E may have a potential role in sensitizing glioblastoma to radiotherapy” (Borek C 2004).