Over-the-Counter Drugs and Supplements to Fight Glioblastoma (Part One)

Here we are at the ninth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is the first part of chapter 7 of the guide which, like the previous chapter, is very long and has been divided into two parts. In this first part we talk about PSK and other polysaccharides, Gamma-Linolenic Acid, Limonene, Metabolic Therapy, Nutraceuticals and Herbs, Berberine, Boswelic Acids and Cannabis. The advice is still to use this information to discuss it with the medical team that is following you. You can also point then to the references to the supporting scientific works.
The Glioblastoma.it campaign for CUSP-ND for Emanuele is continuing slowly. I ask you once again to share the link and to spread the word in order to raise awareness as many people as possible.
I’m happy to inform you that the chatbot that I recommend you to use has officially entered the RASA show case, one of the most important developers of these technologies based on artificial intelligence. At this link they talk about our Gliobot! Enjoy the reading!

The treatments discussed above generally require the cooperation of a doctor to prescribe them. However, there are a number of agents available over the counter that have promising anti-cancer properties and it is reasonable to believe that these can increase the chances of survival. Some of these with supporting clinical trials (e.g. proton pump inhibitors such as Prilosec) have already been discussed. A frequent conflict between patients and their oncologists is that patients, often desperately looking for therapeutic agents that improve their chances of survival, are eager to use such additional treatment while their oncologists generally oppose the use of such additional agents on the grounds that they could interfere with the standard treatment. Although negative interactions are possible, there have been very few documented cases to date.
Given the bleak prognosis of a glioblastoma diagnosis, my belief is that concerns about negative interference are misplaced and hinder useful additional treatments. However, it is important to pay attention to the evidence of support for the use of any specific agent , as there are many products on the market that are advertised, supported only by dubbing testimonials.

PSK and other polysaccharides

PSK is the abbreviation for krestin polysaccharide (sometimes simply known as krestin), which is an extract of the Coriolus versicolor mushroom. It has become a standard component of cancer treatment protocols in Japan (a Chinese version of the same extract is known as PSP) for many different types of cancer, based on the assumption that it is an immune system enhancer. Effects on the immune system that have been identified include gamma-interferon production, interleukin-2 production, and increased T-cell activity. Other effects include inhibition of matrix-degrading enzymes that are underlying tumor invasion of adjacent tissue and inhibition of angiogenesis. Numerous clinical trials have been conducted in Japan comparing chemotherapy regimens with the same regimens with the addition of PSK, for a variety of different types of cancer, most frequently stomach and colon cancer.
In a representative study, with non-small cell lung cancer (233), stage I patients who received PSK (3 g / day) had a five-year survival rate of 39% compared with 22% for patients who they did not receive PSK. For stage III patients, the 5-year survival rate with PSK was 16% versus only 5% for those who did not receive PSK. Both differences were statistically significant. A meta-analysis of several colorectal cancer clinical trials (over 1000 patients) that were randomized to receive standard chemotherapy or standard chemotherapy in combination with 3.0 g / day of PSK showed that the addition of PSK increased both survival rate and duration of disease-free survival, with relative risks of .71 and .72, respectively (234). The three-year disease-free survival rate was 81% for patients who received PSK, compared with 69% for those who received chemotherapy alone. I found only one study that used PSK in the treatment of glioma, in combination with ACNU (a chemical cousin of BCNU) and vincristine (235). The survival rate for 25 GBM patients after one, two, and three years was 56%, 37%, and 12%, respectively. No control conditions such as patients not given PSK have been studied, so it is not clear what exactly its effect is. Note, however, that two- and three-year survival rates are substantially higher than those typically seen for GBM after traditional treatment with chemotherapy alone.
The source we used for PSK information is JHS Natural Products in Eugene, Oregon, now known as Mushroom Science. Other sources can no doubt be found through a web search. Other mushroom extracts that also have long-chain polysaccharides (beta-glucans) which appear to be the active ingredient of PSK are more readily available. These include maitake, reishi, and shiitake mushrooms. However, none of these have the same level of scientific evidence for the effectiveness of the treatment in human clinical trials. Maitake fraction D appears to be a particularly promising mushroom extract based on a laboratory study of chemically induced tumors in mice (236). Tumor growth was inhibited by 90% when the mushroom extract was combined with chemotherapy versus an inhibition of only 50% when chemotherapy was used alone for subjects belonging to the control group.

Gamma-Linolenic Acid (GLA)

We currently recommend fish oil containing omega-3 fatty acids, rather than GLA oil, as rodent studies suggest that GLA does not cross the central nervous system or brain tumors with oral administration (353). GLA is also not detectable in human cerebrospinal fluid (without supplementation), while the long-chain omega-3 fatty acids EPA and DHA are detected (354). The omega-3 fatty acids in fish oil are less expensive and are much more likely to enter the central nervous system after oral administration. Their mechanisms of action are similar.

Perillyl Alcohol / Limonene

These closely related chemical compounds are derived from citrus oils and have been extensively studied as anti-cancer agents even in several early stage clinical trials. Unfortunately, the gastrointestinal side effects of these compounds have delayed their clinical development. A recent clinical study in patients with recurrent glioma, conducted in Brazil, circumvented this problem by administering perillil alcohol nasally four times a day. In the initial report, out of 29 GBM patients with recurrent tumors who received treatment, one achieved a partial response and 13 stabilized the disease, for a PFS-6 value of 48% (255). In a subsequent study of 89 patients with GBM, who had failed at least three previous treatments (and therefore had a particularly poor prognosis), patients with primary GBM were separated from those with secondary GBM (tumors that evolved from lower-grade tumors). ), the median survival for primary GBM was 5.9 months, while that for secondary GBM was 11.2 months. Median survival for a control group that received only supportive care was 2.3 months (256). It was also noted that patients with tumors in the midbrain area benefited more from the treatment than patients with tumors in the brain lobes.

Metabolic therapy with sodium R lipoate plus hydroxycitrate

Following in vivo studies and previous reports with mixed groups of cancer patients, a research group based in France published the results of 11 brain tumor patients (8 primary, 4 metastatic) treated with sodium-based metabolic therapy. R lipoate (a form of alpha-lipoic acid) and hydroxycitrate (357). In newly diagnosed patients this treatment was combined with standard radiation and chemotherapy, and in some patients, low-dose naltrexone or a ketogenic diet was combined with lipoate and hydroxycitrate. Previous publications referred to this metabolic therapy as METABLOC. In this study, sodium R lipoate was the form of alpha lipoic acid used. Unless otherwise indicated, alpha-lipoic acid typically consists of a racemic mixture (50/50) of R and S forms of lipoic acid. These shapes are mirror images of each other, but have different properties. Only the R form is found in nature. Alpha-lipoic acid is a cofactor of pyruvate dehydrogenase and, similarly to dichloroacetate, can increase the flow of pyruvate into the mitochondria, counteracting the Warburg effect whereby pyruvate is fermented into lactate outside the mitochondria. Hydroxycitrate is derived from the tropical plant Garcinia cambogia and is an inhibitor of ATP citrate lyase, an enzyme involved in the preparatory stages of the synthesis of fatty acids.
In this study, of the eight patients with primary glioma, six were treated with R-lipoate and hydroxycitrate prior to tumor recurrence, along with standard initial treatment (radiotherapy and temozolomide chemotherapy).
A 59-year-old GBM patient died 11 months after starting conventional therapy and 4 months after starting metabolic therapy, the only short-term survivor of the six newly diagnosed patients. The remaining five patients in the newly diagnosed group were followed for 23, 24, 25, 36, and 87 months of diagnosis and were all still alive at the time of publication, all with no disease progression except the 87-month survivor. This long-term survivor was 38 years old and we cannot exclude that the mutant IDH1 status is responsible for the long survival since no information on the IDH status is provided. Four of these patients were over 50 years old, and apart from the only short-term survivor, these patients survived for 2-3 years from diagnosis without disease progression, including one patient who had unresectable glioblastoma (3 years without progression, treated with temozolomide, lipoate, hydroxycitrate and low dose naltrexone). Another patient with glioblastoma had a 60% tumor reduction after starting the lipoate, hydroxycitrate and ketogenic diet.
While the authors acknowledge that a small number of cases do not provide definitive evidence of efficacy, the longer than expected progression-free survival in most of these patients, including one with unresectable glioblastoma, provides justification for considering these to be “excellent results “.

Nutraceuticals and Herbs

Oncologists routinely warn their patients not to use supplements, usually based on the belief that antioxidant supplements interfere with radiation and chemotherapy. Although the matter is extremely complex, my assessment of the relevant evidence strongly disagrees with this view. As a result, I published my analysis of the clinical trial results in a separate article available at this link: The Role of Supplements in Cancer Treatment. In this publication you will find the list of the supplements that seem to be most effective, based on the wide availability of experimental data. Unfortunately, few clinical results are available to support the experimental data, especially since supplements cannot be patented and therefore there is no financial incentive to develop their clinical use. As a result, little information is available on the best dosage and bioavailability, which is often a problem. However, much is known about the mechanisms of action of the various supplements, which often overlap with those of conventional drug therapy. A detailed discussion of these mechanisms is not possible here, as it would require a solid foundation in molecular biology. A special issue (2009, Vol. 269, Issue 2) of the journal, Cancer Letters, was devoted to the molecular targets of many of the individual agents to be considered. A more general revision is provided in Reference 257.
The list of supplements to consider is necessarily selective. Undoubtedly, there are numerous other agents that could be useful that have been omitted.

Berberine

This is an alkaloid extract of the Coptides rhizome commonly used in China as a herbal medicine. It is also found in high concentration in a widely used supplement, goldenseal. In a laboratory study on the use of various types of glioma cell cultures and tumors implanted in rodents (289), the cytotoxic effects of berberine were compared with those of BCNU and with the combination of berberine and BCNU. Berberine alone produced a 91% kill rate in cell cultures, compared with 43% in BCNU. The combination produced a 97% kill rate. Comparable results were obtained with in vivo implanted tumors. Such findings suggest that berberine is among the most promising treatment agents, but very little research has been reported using it to date. Part of the reason could be that berberine is poorly absorbed from the gastrointestinal tract. It seems that the structure of berberine is closely related to Ukraine, a drug that combines an alkaloid from a plant called celandine with an old chemotherapy agent called thiotepa. After years of using Ukraine only in alternative medicine, the license for commercial development was recently granted. A recent clinical study using it for pancreatic cancer yielded impressive results (290).

Boswellic acids

This is a collection of aromatic acids related to the biblical spice, incense. Its relevance for cancer treatment is that it is a potent inhibitor of the inflammatory pathway of lipoxygenase, one of the two major sources of inflammation associated with cancer progression. Cyclooxgenenase is the other pathway that can be inhibited by famousx. Both pathways should be suppressed to inhibit inflammation as much as possible. Of more immediate interest to glioma patients is the consideration that boswellic acid is a potent inhibitor of edema caused by tumor growth, which is the main reason why many brain tumor patients require steroids to suppress swelling. In a randomized double-blind study conducted in Germany, 44 brain tumor patients received boswellia serrata (one of several forms of boswellia) and placebo (298). Both groups also received radiation. Compared to baseline, patients who received boswellia had a 75% reduction in edema, while patients treated with placebo had a 26% reduction. There were no significant side effects of boswellia. Given the numerous side effects of steroids, boswellia offers the promise of substantially improving the quality of life. However, the boswellia dose used in this study was 4200 mg / day.

Cannabis

After years of government obstacles to research on cannabis (the plant from which marijuana is derived), in recent years there has been a proliferation of research on its mechanisms of action. One result of this research is the discovery that cannabis inhibits the growth of various types of cancer cells, including gliomas (294). In a recent article (295), cannabinoids were shown to significantly inhibit angiogenesis in gliomas implanted in mice, which was accompanied by a significant inhibition of glioma growth.
A subsequent study in which cannabis was combined with temozolomide in mice, reported a strong synergy (296).
The direct anti-cancer effect of cannabis is noteworthy because it is also one of the most effective anti-nausea agents, without many of the side effects of the drugs commonly used (Zofran and Kytril) for the purpose. Additionally, a liquid form of cannabis (Sativex) has been approved by the government in both Canada and various European countries (for neuropathic pain) and can be used as an aerosol using an asthma inhaler.
Preliminary efficacy data from the first study of Sativex for glioblastoma was released by GW Pharmaceuticals in February 2017. The summary of the presentation at the ASCO 2017 conference is available at this link. In this clinical study, 12 patients with recurrent GBM were randomly selected to receive Sativex with hard dose temozolomide and 9 patients received hard dose temozolomide plus placebo. Median survival from the start of the study was 369 days (12.1 months) in the placebo + TMZ group and over 550 days (18 months) in the Sativex + TMZ group. One-year survival was 56% for the placebo group and 83% in the Sativex group, a difference that reached statistical significance (p = 0.042) despite the small number of patients involved in the study. This study provides the first prospective data from clinical studies showing the efficacy of cannabis-based products in the treatment of gliomas.

___

(233) Hayakawa, K., et al. Effect of krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer research, 1993, Vol. 13, pp. 1815-1820. 
(234) Sakamoto, J., Morita, S. Oba, K. et al. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a metaanalysis of centrally randomized controlled clinical trials. Cancer Immunology and Immunotherapy, 2006, 55(4), 404-411. 
(235) Kaneko, S., et al. Evaluation of radiation immunochemotherapy in the treatment of malignant glioma. Combined use of ACNU, VCR and PSK. Hokkaido Journal of Medical Science, 1983, Vol. 58, pp. 622-630. 
(255) Da Fonseca. C. O., Schwartsmann, G., Fischer, J. et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surgical Neurology, 2008, 70, 259-67. 
(256) Da Fonseca, C. O., Simao, M., Lins, I. R., et al. Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J. Cancer Res. Clin. Oncol., 2010, e-pub, April 18. 
(257) Aggarwal, B. B., & Shishodia, S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharm, 2006, 71, 1397-1421
(289) Zhang, R. X., et al. Laboratory studies of berberine used alone and in combination with 1,3-bis (2-chloroethyl)-1-nitrosourea to treat malignant brain tumors. Chinese Medical Journal, 1990, 103, 658-665. 
(290) Gansauge F, et al. The clinical efficacy of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer. Hepatogastroenterology. 2007 Apr-May; 54(75): 917-20. 
(294) Velasco, G., et al., et al. Hypothesis: cannabinoid therapy for treatment of gliomas? Neuropharmacology, 2004, 47, 315-323. 
(295) Blasquez, C., et al. Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Research, 2004, 64, 5617-5623 (296) Torres S., Lorente, M., Rodriguez-Fornes, F., et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Brit. J Cancer, 2006, 95, 197-203. 
(297) Guzman, M. et al. A pilot clinical study of Delta (9)-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British Journal of Cancer 2006, 95 (2), 197-203. 
(298) Kirste, S., Trier, M., Wehrie, S. J., et al. Boswellia serrate acts on cerebral edema in patients irradiated for brain tumors: A prospective, randomized, placebocontrolled, double-blind pilot trial. Cancer, 2011, 117(16), 3788-95. 
(353) Nasrollahzadeh, Javad et al. “The influence of feeding linoleic, gamma-linolenic and docosahexaenoic acid rich oils on rat brain tumor fatty acids composition and fatty acid binding protein 7 mRNA expression.” Lipids in health and disease 7.1 (2008): 1. 
(354) Guest, Jade et al. “Relationship between central and peripheral fatty acids in humans.” Lipids in health and disease 12.1 (2013): 1. 
(355) Bhandari, Menal. “Comparative Study of Adjuvant Temozolomide six Cycles Versus Extended 12 Cycles in Newly Diagnosed Glioblastoma Multiforme.” Journal Of Clinical And Diagnostic Research, 2017, doi:10.7860/jcdr/2017/27611.9945. 
(356) Chi, Kwan Hwa. “Sirolimus and Hydroxychloroquine as an Add-On to Standard Therapy for Glioblastoma Multiforme: Case Report.” Journal of Biomolecular Research & Therapeutics, vol. 5, no. 2, 2016, doi:10.4172/2167-7956.1000141. 
(357) Schwartz, Laurent. “Combination of Metabolic Treatment of Aggressive Primary Brain Tumour and Multiple Metastases of the Brain.” Cancer Research and Oncology: Open Access, Volume 2, Issue 3, 2016.

Super! I hope you enjoyed reading, I have been as faithful as possible. Very soon the second and last part of the chapter!