Glioma research

This page containing  just some of the articles of research that I have come across.  I stress that this is not a scientific review and not a reccomenation for anyone else, merely the personal meandering of a single glioma sufferer trying to make sense of everything. So this is not a comprehensive literature search. Much of the lead was taken from survivors testimonies, which contained treatments and remedies to which they attributed their success which was over and above what would have been expected  on standard treatments. These non standard ‘remedies’ that have some basis in science, and my quest was to check out the references. To balnce this view, I am still looking for long term survival  stories  from people who have NOT suppemented good medical care with anything at all.  So far (as in Kelly Turner’s research ) they seem  hard to come by! This does not mean there are none; those who have been more active in their own recovery are maybe likely to be more active in promoting their stories, (although in Dr Turner’s case she actively sought out survivors from medical records)  but it does does make you think, and if the medical profession wants us (sufferes) to ignore these stories it should come up with some some inspirational  testimonies of its own documenting the success of their bog standard protocols.

If anyone has information that can add or conubute to this, I would be grateful for comments.

For now the references are not all linked so you will have to cut and paste those that are not to a browser. I will try and insert links to key ones in time; they should be accessible if you click on the red print for links.

overview

recent advances in treatment. video of a lecture on latest advances and trials.

1. BIOMARKERS that might help with treatment option decisions.

state of the art

Link (red  above) to scientific paper. Or cut and paste:

http://download.springer.com/static/pdf/398/art%253A10.1007%252Fs00401-010-0736-4.pdf?

Link to brain tumour charity summary of biomarkers including MGMT

MGMT methylation status. (To weigh against advantages of chemo/ tamoxifen)’
This refers to methylation status of the O6-methylguanine methyltransferase (MGMT) gene, a molecular marker that encodes a DNA repair protein that causes resistance to DNA alkylating agents, such as temozolomide. Transcriptional silencing of the MGMT gene by promoter hypermethylation is seen in about 50% of glioblastomas and has been linked to prolonged overall survival in glioblastoma patients treated with alkylating agents (Esteller et al., 2000b; Hegi et al., 2005) Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter had a much smaller and statically insignificant benefit.#
In clinical trial 18 months survival was 62% for patients testing positive for a methylated MGMT promoter but reached only 8% in absence of methylation.

 

*How temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas

*Mechanism of the effect of TMZ on tumor cells and resistance to TMZ

*Only patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide  

*clear need for stratifying patients by MGMT status for clinical trials of temozolomide

*Advances and Challenges in the Treatment of Glioblastoma: A Clinician’s Perspective

*Methylation of the MGMT promoter remains the only significant predictor of prognosis 

Molecuar  classification of gliomas http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138801/#!po=19.7917

 

My personal opinion: The tests are not foolproof, and there would be cost implications to testing all patients that might not be returnable in terms of benefit, but as an individual patient, making decisions regarding Chem/radio in relation to quality of life, especially if it turns out that these treatments are difficult to tolerate, it would seem to me to be helpful to know the likely order of benefit they are adding by knowing the MGMT status of the tumour. A 8% benefit compared to 62% benefit is a factor patients should know about when making a treatment decision about toxic drugs.

 

2. AVOIDANCE OF DEXAMETHASONE/STEROIDS

Whilst corticosteroids can reduce cerebral oedema (brain swelling) and  its symptoms, the side effects are considerable such as:

*raising of blood sugar, which is highly undesirable in the case of glioma and survival is linked to raised blood sugar.

*increases risk of thromboembolism which is increased in malignancy anyway and I am told is a risk for 1 in 5 glioma patients undergoing radio/chemo.

*Dexamethasone is has also been shown to detrimental to the effects of TMZ

*And may increase resistance to radiotherapy

*It produces significant immunodeficiency. It is also known that glioblastoma is associated with abnormal patient immunity and dexamethasone has been shown to exacerbate this in numerous ways, which is detrimental to treatment. In combination with radiotherapy this produces serious immunodeficiency .

*Due to averse affect there is need to reduce the usage of dexamethasone and titrate it to need

*This study analysed different regimes for risk/benefit. I note that in 13 patients who were not give p with radiotherapy, 12 has no ill effects.

Possible Alternatives to steroids:

*Boswellia, a natural product  (wikki) derived form Frankincenece  has been successfully used to treated inflammation and avoided higher doses of dexamethasone during radiation. Boswellia is used now used in Germany as a substitute for steroids as a method of reducing the oedema (swelling) of the brain. It is also a potent inhibitor of angiogenesis and cell invasiveness. A review of its action can be found here  It seems that tha age old practice of burning fancincence has scientific proof of benefit!

*celecoxib (Celebrex), in particular has also been used in place of dexamethasone in some instances. This is a non steroidal anti inflammatory (commonly used in pain and joint inflammation) NSAIDs may be of use in cerebral oedema. NSAID’s compare favorably with steroids in diminishing tumor-induced protein extravasation. It is suggested that NSAID’s may prove to be beneficial in clinical instances used either in conjunction with steroid therapy or alone when steroids are contraindicated.

*Acetazolomide has been used for RICP in other conditions and in specific cases of raised pressure in glioma. It actually also inhibits carbonic anhydrase, (which is a factor in poor prognosis in glioma) is shown to have potential for TMZ enhancement rather than the antagonistic action of dexamethasone. In a comparison between ACZ and DXM, ACZ pretreatment enhanced TMZ apoptosis while DXM pretreatment decreased it.

 My personal opinion: I am personally uncomfortable over the ‘prophylactic’ use of dexamethasone in conjunction with radiotherapy and chemo. If it is possible,  forego it until there are signs that it is actually needed, maybe substituting some other less toxic anti-inflammatory that could be used as ‘cover’ if necessary. ( Boswellia is available without prescription)

 

3. ANGIOGENESIS INHIBITORS
This seems to be a very promising line of development including the various agents that combat Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase. It is a complex field and there are many new potential agents under trial and in use for other cancers. One readily available drug of interest is Thalidomide, and of the newer drugs, only bevacizumab (Avastin) is apporved.

Thalidomide
This drug has antiangiogenic and immunomodulatory properties. In early studies, combined with chemo, it showed good improvement in response rates ( Glass: Proceedings of Americal Soc fir Clin oncol. 1999;abstract 551) In a trial comparing a combination of thalidomide with TMZ (TT) with TMZ alone (T), progressive disease was found in only nine patients (36%) of the TT-group and in 13 (68%) of the T-group. Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks for T alone

And, although another study showed no significant advantage to adding Tamoxifen, there did to seem a marked  improvement  in those patients whose tumours had been fully resected. (And in those taking IEAEDs (a certain types of anti epileptic drugs)
http://www.brainlife.org/fulltext/2007/Riva_M070300.pdfj

In the absence of the newer angiogenic drugs (below) which are still under trial, an the relatively low toxicity of thalidomide it is an obvious candidate for supplementation to standard treatments with TMZ

bevacizumab (Avastin)
a humanised monoclonal antibody that targets VEGF (Vascular endothelial growth factor) , was first approved in combination with chemotherapy for colorectal, lung, and breast cancers. Despite initial reluctance to evaluate bevacizumab in patients with brain tumours owing to concerns of intracranial haemorrhage, a series of 29 patients with recurrent malignant gliomas treated with bevacizumab and irinotecan* showed no significant hemorrhage and radiographic response rate of 66% compared with historical rates of 9%. Survival rates improved with approval of avastin but improvement in overall survival rates when used to first line therapy are less certain, and some studies  show no benefit when used as a first line treatment.

(*irinotecan is a topoisomerase 1 inhibitor, with a different mechanism of action than that of alkylating agents such as temozolomide. It is used in colo-rectal cancer and its use here, I believe, was in light of the failure of patients with unmethylated MGMT to benefit from the addition of temozolomide. Although irinotecan has not been useful as a single agent in glioma it has potential for use as a combination therapy. )

Sutent
A new drug targeting angiogenes, is Sutent (made by Pfizer, generic name is sunitinib). Unlike Avastin which is given intravenously, Sutent is taken orally. Also, whereas Avastin targets only one of the signaling channels (VEGF) that stimulate angiogenesis, Sutent targets multiple signals. Sutent has not yet been tested with gliomas, although it has FDA approval for both renal cell cancer and gastro-intestinal stromal tumors, indicating that it likely to have broad applicability. Yet another drug that targets angiogenesis, which received recent approval is Nexaver (made by Bayer, generic name is sorafenib), which like Sutent targets multiple signaling pathways but has not yet been tested with gliomas.

It seems only avastin is currently available for use in glioma and only for recurrents tumours? (Though approved for other cancers)

Boswellia is also an angiogenisis inhibitor (see above)

4. IMMUNO-SUPPORTIVE

vaccines

research video.

Melatonin 
Was pioneered by a group in Italy where it almost doubled survival time for patients with a mixture of different types of cancer, including some glioblastoma cases, in a clinical trial on glioma it significantly   improved outcome and lessened toxicity from radiotherapy and steroid usage. (http://www.ncbi.nlm.nih.gov/pubmed/8570130) It modulates immune function in cancer patients and plays a critical role in host defence against the progression  of neoplasia (http://www.ncbi.nlm.nih.gov/pubmed/961581). It is surprising that, despite various studies in vitro, no proper extensive phase III clinical trials have been carried out. Studies with other cancers have produces excellent results, with no side effects, and have suggested that melatonin also alleviates side effects of chemo, especially platelet count.

further  evidence: http://www.ncbi.nlm.nih.gov/m/pubmed/23551342/#fft and  http://www.ncbi.nlm.nih.gov/m/pubmed/19287962/?i=2&from=/23551342/related

and http://www.ncbi.nlm.nih.gov/m/pubmed/25163989/

review of effects of melatonin (http://www.cristianapaul.com/reviews/Melatonin%20review.pdf)

Life extension review of studies showing effects of melatonin in various cancers http://www.lifeextension.com/magazine/2004/1/report_melatonin/Page-02

And  http://www.ncbi.nlm.nih.gov/pubmed/16207291  a sytematioc review of controlled trials.

Given that in the glioma arm of Lisson’s study (see links above), in the 30 cases of glioblastoma, the one year survival with the addition of 10mg of melatonin was 45% compared to <1% with radiotherapy alone (pre TMZ) and given its low cost and minimal toxicity, I can’t think, try as I may, of any good reasons why one would not take this supplement?

 

Mushroom (polysaccharide krestin PSK)
Many such extracts are widely prescribed in asian countries for cancer, and most of the research has been done in Japan, where treatment with PSK is covered by their national heath insurance.
PSK from the Coriolis mushroom can be given orally but lentinan from shiitake mushrooms is administered by injection. Both enhance the immune system. In vitro they inhibit matrix-degrading enzymes which affect the invasion of adjacent tissues, and inhibition of angiogenesis. They have been shown to reduce side effects and improve  quality of life.

Review of immunosuppressant therapy.
(http://astrocytomaoptions.com/re-educating-the-immune-system/)

Immunotherapy

in 1992 japanese workers discovered substances on T calls that allowed them to ignore cancer cells and not kill them as they normally woud. One such molecule was PD1 (programmed death 1). Various agents to block this substance were developed including ipimumab and nivobumab (yevoy and opdivo) and phase 111 trials are underway in glioblatoma using these or similar drug, sometimes known as check point inhibitors.

vaccines are a form of immutherapy (see research video above)

work is  going on on one such vaccine (Rinepeimut) that targets EGFR (see below) after ph 2 trials (ReACT trial) showed promise.

targetting EGFR (epidernmal growth factor receptors )with immunotlherapy (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291787/)

monoclonal antibodies: lab synthesised molelues that target specific tumour antigens. eg TRCIOS  phase 2 trials in GBM and trials targetting EGfR viii in GBM and many others are underway.

Iscador (eupopean miseltoe)
The ingredients inhibit protein synthesis and stimulate various cytokynes that increase leukocyte counts as well as polyshacchides similar to the mushroom extracts. In studies with glioma patients addition of iscador to standard radiation treatment produced median survival time of 20 months compared with 10 months.
http://www.ncbi.nlm.nih.gov/pubmed/9042260
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485514/
http://www.ncbi.nlm.nih.gov/pubmed/23133496
Various studies in china and Europe indicate that this might be promising. Unfortunately it may need to be given by injection.\

5. ANTIOXIDANTS

These help protect cells from the harmful effects of free radicals, which cause DNA damage. The theory is that this protects the normal cells. This is supposed have benefit in protecting against cancer but their role in cancer treatment is more complex. Indeed different antioxidants affect different cancers in opposing ways. It is often argued that they would undermine one method by which radio and chemo work, which is to increase free radicals. However, normal cells are also affected by attack from free radicals and the protective effect on normal cells by antioxidants could be important.

There have been numerous literature reviews, all of which conclude that antioxidants interfere with neither  radiotherapy, or Chemotherapy but in addition they can mitigate against side effects and also often have benefits in terms of tumour stabilisation and survival. A wide range of antioxidants are included including nutritional ‘over the counter’ products such as vitamin C and E, beta-carotene, selenium, B vitamins, vitamin D3, vitamin K3; as well as glutathione*, melatonin, N-acetylcysteine, ellagic acid and combinations thereof.  Indeed  supplements with nutritional  supplements  including antioxidants  has has been postulated as beneficial.

Pretreatment with vitamin E may have a potential role in sensitizing glioblastoma to radiotherapy.

When oncologists indiscriminately oppose the ingestion of supplemental antioxidants during radio- therapy, they are in effect embracing the notion that the treatment-induced diminution of endogenous antioxidants is an integral part of their proposed treat- ment strategy. Is iatrogenic hypovitaminosis now to be regarded as a component of standard treatment? By what medical theory can such a strategy be defended, given that he preponderance of that data suggests that antioxidants do not conflict with the effectiveness of radiotherapy and may in fact increase the possibility of a beneficial outcome.

Brain tumour stem lines and antioxidants

Current therapies, such as the standard chemotherapy treatment, temozolomide (TMZ), target only cancer cells but not BTSCs. Thus, therapeutic approaches that eradicate the BTSC population must be developed. Studies on brain cancer stem lines suggest that  the antioxidants curcumin, quercetin, and melatonin target stem cell lines in glioma enhancing the efficiency of TMZ, which has its main affect on cancer cells rather than the brain tumour stem cell lines.

Resveratrol
a polyphenol (found in the skins of red grapes)has some antioxidant properties and has also said to have an enhancing effect of TMZ

 

6 .SUBSTANCES WORKING AGAINST BRAIN STEM CELL LINES.

recent advances

Metformin
Metformin was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models, and a study reported that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomasas with lack of significant inhibition of normal human stem cells. It has shown to enchance radiotherpay and in particular eradicates radioresistant cancer stem cells. In a small study looking at the effect of adding metformin to TMZ there was an important difference between TMZ alone and TMZ plus metformin arms in 6 of 8 cases. It is not clear of the action, but it is not merely due to its effect on blood sugar.

more links:

Metformin Inhibits Growth of Human Glioblastoma Cells and Enhances Therapeutic Response.

Understanding the benefit of metformin use in cancer treatment

Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas.

Metformin modulates cell pathways  directly, whle indirectly affecting them through its effect on the metabolic environment.

Possible mechanisms by which metfomin exerts its anti cancer properties

 

 

7. SUBSTANCES THAT INDUCE TUMOUR CELL DEATH

High dose Tamoxifen
High dose tamoxifen, used in breast cancer in lower doses on basis of anti-oestrogen properties, seems to have other anti-cancer properties and has been used in numerous trials, and shown to inhibit protein kinase C, which causes rapid growth of glioma. In one early study on recurrent glioma, 40% of tumours shrank or stabilised and, more specifically, it seems to enhance chemo, pushing two year survival to 45%. In a comparison between TMZ/radio and Tamoxifen/radio, both groups had similar results, suggesting that tamoxifen has equivalent potency asTMZ When used together they have synergistic effects.

Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen.http://www.ncbi.nlm.nih.gov/pubmed/8384328
Phase 2 trial of radiation plus high-dose tamoxifen

In clinical studies of TMX with TMZ, curiously, the outcome did not seem affected by MGMT status. I seems that Tamoxifen decreased the MGMT protein

One main side effect of concern would be potentially more thromboembolism but there is also evidence that for some reason, actually, Tamoxifen if anything reduces thromboembolisms compared to the already high rate of this in glioma patients under stands protocols.

canabinoids
have been shown to be beneficial in treating glioma . Study has shown that D9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumour growth in animal models of cancer

A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma (Sofía Torres)

Cannabis and Cannabinoids–for health professionals

Cannabis extract can have dramatic effect on brain cancer,published in the Molecular Cancer Therapeutics journal. Nov 2014

The antitumor action of cannabinoids on glioma tumorigenesis.

Cannabinoids enhance uptake of chemotherapy.

another human trial is small and only includes patients at late sate of disease with short prognosis, nevertheless results were encouraging.
GW Pharmaceuticals have started clinical trials of Sativex as a treatment for aggressive brain tumour. Sativex was the first cannabis-based medicine to be licensed in the UK, for use in MS. The main active ingredients are tetrahydrocannabinol (THC) and cannabidiol (CBD)

below is a good review found on the brain tumour reserch website.

Cannabis and brain tumours

8. SUBSTANCES THAT INHIBIT TUMOUR CELL GROWTH

 

Acutane
13-cis-renitonic acid (isotretinoin) prescribed for acne. This, it seems, blocks the receptor for the epidermal growth factor factor signal that is a catalyst in glioma cell division. Again early studies the drug produced regression or stabilisation in 45% of cases and median survival time was increases from 5 months to over a year compared to current standard treatment alone. (Young Clinical Cancer Research 1996;2(12):1931-1935)
Since then, research has progressed and some work has shown that IDH1-mutant glioma may be especially sensitive to retinoic acid based therapeutics such as Accutane. Failure to show benefit in some more recent studies may be due to the discovery that Accutane may actually be antagonistic with temozolomide, and so may be best used only as a maintenance therapy after standard-of-care treatments.
http://www.brainlife.org/abstract/2004/see_200407.htm

Celecoxib
Celecoxib is a cyclooxygenase 2-selective nonsteroidal anti-inflammatory drug (NSAID) that exhibits therapeutic activity in cancer. Studies found that celecoxib inhibited the proliferation of various glioblastoma cell lines in vitro much more potently than traditional NSAID.
In a study of temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as post-chemoradiation adjuvant therapy for newly diagnosed glioblastoma, with a median follow-up of over 5 years, the observed median survival of 20 months and a 2-year survival rate of 40% compared very favourably with the 14.6-month median survival and 26% 2-year survival rate observed in the chem-oradiation alone arm.

The benefit of Celecoxib in prevention of oedema has been mentioned under my concerns about dexamethasone.
It also has action against the effects of CMV (The treatment of which can cause tumour gregression. See CMV)
http://www.infectagentscancer.com/content/7/1/33
The below study looks at combination of TMZ with thalidomide, isotretinoin, and/or celecoxib as post-chemoradiation adjuvant therapy for newly diagnosed glioblastoma.
http://neuro-oncology.oxfordjournals.org/content/early/2010/08/20/neuonc.noq100.full\\

 

 

9. OTHER MECHANISMS OF ACTION

chloroquinereports have shown effect of adding chloroquine to TMZ. in this studySurvival time in patients treated with chloroquine was 25 +/- 3.4 months, as compared with that of 11.4 +/- 1.3 months in control subjectsAdding Chloroquine to Conventional Treatment for Glioblastoma Multiforme A Randomized, Double-Blind, Placebo-Controlled Trial. Julio Sotelo el al.


Thiazolidinediones (also know as “glitazones”) developed for type II diabetes, the main uk preparation is pioglitazone.Their mechanism of action for the treatment of diabetes is to increase cellular insulin sensitivity. But laboratory research has identified multiple other mechanisms of action as well that potentially have major benefit for cancer patients, including inhibiting various steps in the cell cycle, induction of cell differentiation, induction of apoptosis and inhibition of angiogenesis. They are synergistic with retinoids such as accutane. Although there are not clinical trials in glioma, a clinical trial with advanced “vascular tumours” was encouraging.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC151148/
http://www.ncbi.nlm.nih.gov/pubmed/21221726
http://onlinelibrary.wiley.com/doi/10.1002/cncr.11775/full

Low low dose naltrexone
Naltrexone in high (50mg) doses was approved for opium addicts, by blocking the blocking opioid receptors, In 1985, Bernard Bihari, MD, a physician with a clinical practice in New York, discovered the effects of a much smaller dose of naltrexone (4.5mg) on the body’s immune system taken at bedtime, was able to enhance a patient’s response to infection by HIV. Then in the mid-1990’s, he found that patients in his practice with cancer (such as lymphoma or pancreatic cancer) could benefit, in some cases dramatically, from LDN. He claims to have treated hundreds of cases and there does seem to be some evidence that it has an effect. There are ongoing trials with glioma patients, results awaited.
https://clinicaltrials.gov/ct2/show/NCT01303835
http://www.lowdosenaltrexone.org/ldn_and_cancer.htm
http://www.mbschachter.com/protocol_for_low.htm
http://www.ncbi.nlm.nih.gov/pubmed/16484716?dopt=Abstract
disulfiram
The drug used for alcoholism is thought to work by producing toxic levels of copper in glioma cells whilst being harmless  to normal cells.
http://ecancer.org/news/3494-anti-alcoholism-drug-could-help-treat-most-common-type-of-adult-brain-cancer.php

Vaccines
Vaccines made from the patient’s own tumour cells have shown promise.
http://www.virtualtrials.com/news3.cfm?item=4856 (also see section on immumotherapy above)
Memantine: used in Alzheimers, this drug slowed the growth of glutamate-secreting tumours in situ and clinical trials are planned.
https://clinicaltrials.gov/ct2/show/NCT01260467

Clomipramine
approved as an antidepressants this drug has been shown to act on mitochondria pathways that induce cell death. Trials in glioma patients were encouraging.

Merbenazone

An anti thread worm medication, freely available. Is found to  act on telomere section of the chromosomes, which dictate how long cell lins reproduce for before they become ‘worn out’and disfuncional, a key factor in cancer cell lines. Clinical trials are underway in gliomas.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096024/

 

10 SUPPLEMENTS AND NUTRIENTS of possible benefit (some of which seem synergic with radio and or chemo)

Summary
Botanical or Herbal Extracts for brain tumour

  • Sulforaphane: Sulforaphane is one of the active compounds in cruciferous vegetables, especially broccoli, responsible for their anti-cancer action. It has been shown to confer neuroprotection and preserve blood-brain-barrier integrity in animal models (Dash PK et al 2009).And numerous studies have shown its benefits in glioma in culture and animal models.
    Resveratrol and sulforaphane act synergistically against brain tumour cells. A 2010 article states, “Combination treatment with resveratrol and sulforaphane inhibits cell proliferation and migration, and reduces cell viability.”       Potential health benefits of sulforaphane: A review of the experimental, clinical and epidemiological evidences and underlying mechanisms.
  • curcumin (turmeric). Curcumin’s mechanisms of action are complex. It acts through multiple pathways, interfering with cancer growth and stimulating cancer destruction (Choi BH et al 2008). Curcumin decreases Glial cell line-derived neurotrophic factor (GDNF), a chemical that promotes tumour migration and invasion (Lu DY et al 2010) it has both anti-angiogenic and antioxidant properties. A study published in the Journal of Neurochemistry reported that curcumin sensitized glioma cells to several of the chemotherapy drugs often utilised to treat brain cancers (cisplatin, etoposide, camptothecin, and doxorubicin) as well as to radiation. “These findings support a role for curcumin as an adjunct to traditional chemotherapy and radiation in the treatment of brain cancer” (Dhandapani KM et al 2007)http://www.ncbi.nlm.nih.gov/pubmed/20087857However, curcumin has long been known for poor bioavilability, requiring high doses to achieve desired blood levels. A novel curcumin formulation, BCM-95®, has been developed. It delivers up to seven times more bioactive curcumin to the blood than earlier curcumin formulations. Human evidence for the increased bioavailability of BCM-95® was published in a 2008 http://www.ijpsonline.com/article.asp?issn=0250-474X;year=2008;volume=70;issue=4;spage=445;epage=449;aulast=Antony
    http://www.curcuminforhealth.com/studies/cancer/
  • Brain Res. 2009 Apr 17;1266:130-8. Epub 2009 Feb 11.
    Curcumin blocks brain tumor formation.
    Purkayastha S1, Berliner A, Fernando SS, Ranasinghe B, Ray I, Tariq H, Banerjee P. Brain Res. 2009 Apr 17;1266:130-8. Epub 2009 …
  • an improved bioavalable form  “therocucuramin ” merits futher study http://www.ncbi.nlm.nih.gov/pubmed/24637610
  • Mol Pharmacol. 2007 Jul;72(1):29-39. Epub 2007 Mar 29.
    Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways.
    Aoki H1, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y.

  • 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 tumour cells, including malignant cell lines (Sundaram N et al 2000, Rooprai HK et al 2007). In a small trial of 32 glioma patients (70% of whom were found to be deficient of selenium) intravenous selenium resulted improvement in symptoms in 90% of cases.
  • Boswellia:
  • The resin from Boswellia serrata (a tree prevalent in India, the Middle East and North Africa. The resin is commonly known as “frankincense”) is neuroprotective, anti-inflammatory.
    Boswellia decreases the brain swelling from glioblastoma, allowing a decrease in the use of prednisone and thus reducing its side effects (Janssen G et al 2000) It has been suggested that boswellia might be considered as an alternative to corticosteroids in reducing cerebral peritumoral edema (Weber CC et al 2006). Boswellic acid is now used in Germany as a substitute for steroids as a method of reducing the oedema associated with gliomas.
    .http://www.langendorff-stiftung.de/pdf/kirste.pdf

 

There have also been reports from in vivo animal laboratory experiments that it has direct anti-cancer effects . It seems plausible that its combination with celebrex or other COX-2 inhibitors might be synergistic.

Summary of Boswellia effects:
http://examine.com/supplements/Boswellia+serrata/

  • Resveratrol and Quercetin:Quercetin is a bioflavonoid common in the plant kingdom, especially high in onions, red wine, and green tea. It enhances glioma cell death (Siegelin MD et al 2009). While killing cancer cells, quercetin protects healthy brain cells (Braganhol E et al 2006).http://www.ncbi.nlm.nih.gov/pubmed/20228458

     

    An especially interesting study tested a combination of quercetin and the chemotherapy drug temozolomide (Temodar®) on astrocytoma tumor cells. This study reported for the first time that quercetin combined with temozolomide was much more effective in inducing apoptosis in glioma cells than was either substance alone.

     quercerin and resveratrol, when taken together presented a strong synergism, suggesting that combining these polyphenols can potentiate their antitumoral activity, thereby reducing the therapeutic concentration needed for glioma treatment.

  • Lycopene : The therapeutic benefit of lycopene is well established for carcinoma of prostate in various clinical trials. Animal models have demonstrated benefit in carcinoma lung, breast and colon. Studies in glioma has also have shown possible clinical benefit
  • Fish oilsThere is concern about the effect of fish oil on chemo, and yet there are many studies demonstrating benefit. . However, the subject is complex.
    Poly-unsaturated fats in the diet are divided into the omega 6 fats which produce GLA and the omega 3 fats which produce EPA and DHA. GLA is of particular interest (below) but it may be that optimum effect is thought a balance of fish oils.
  • GLA  Gama-linolenic acid (GLA) (from omega 6 fish oil)This produces lethal levels of free radicals inside cancer cells and also actvates genes that produce cell differentiation, but is non toxic to normal cells. Human studies injecting GLA into the tumour site produced significant benefit. GLA was injected into the tumour site at operation and infused by catheter for 10 days post op. Survival was increased from 2 to 4 years. A review of the mechanisms, including 3 human trials, especially reports a study in which 15 patients with grade 4 glioma received GLA into the tumour site at primary resection, and showed remarkable response.
    Though there is doubt over whether oral ingestion of GLA has any clinical effects, a recent clinical trial involving its use for breast cancer substantiates that it does. Advanced breast cancer patients received the standard treatment of tamoxifen alone or tamoxifen in combination with GLA, in the form of 2.8 g of GLA/day. The source of GLA was borage seed oil, which is approximately 20-25% GLA, which meant that the patients were taking 12-15 g of borage seed oil per day. With tamoxifen alone, none of the patients had a complete response to treatment, 13% had partial regression, while 81% had stable disease. For tamoxifen + GLA the corresponding percentages were 5, 37, and 55%, a significant improvement.
  • Green Tea and Coffee: People who drink five cups per day of tea or coffee are 40% less likely to get glioma (Holick CN et al 2010). The EGCG(Epigallocatechin gallate ) in green tea reduces the radio-resistance of glioblastoma cells, potentially increasing the benefit of the standard radiation and chemotherapy treatment of this cancer (Karmakar S et al 2006). Caffeine, found in significant quantities in coffee and green tea, inhibits migration of glioblastoma cells and increases survival (Kang SS et al 2010). It also makes glioma cells more sensitive to ionizing radiation and chemotherapy (Sinn B et al 2010). Caffeine enhances the effect of temozolomide in radiation treatments (Chalmers AJ et al 2009Ketogenic diet.
  • Folic Acid To be of use in the body, natural folate from food and folic acid from supplements must be converted into the active form, by the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). In certain people the gene that codes for this enzyme is defective, and the risk for glioma in these people is increased by about 23% (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. Those patients who were best able to convert folate into its active form survived for about 13 months. Those with the less effective genes survived for only seven months (Linnebank M et al 2008). This suggests that supplementing with the active form of folate (5 MSHF) might be helpful.http://neuro-oncology.oxfordjournals.org/content/10/4/548.full
  • Vitamin E: According to a 2005 study, alpha-tocopherol-succinate enhances chemotherapy treatment of drug resistant glioblastoma cells, increasing effectiveness (Kang YH et al 2005).Pretreatment with vitamin E may have a potential role in sensitising glioblastoma to radiotherapy” (Borek C 2004).
    http://www.ncbi.nlm.nih.gov/pubmed/15514309
  • KETOGENIC DIET

The use of low carbohydrate, high fat diet is well established as a theoretical treatment for management of brain tumour, based upon the fact that, unlike normal brain cells, malignant cells are totally dependant upon sugar for energy and indeed are very sugar ‘hungry’ . (The warburg affect) The ketogenic diet has been successfully used for may years to control certain refractory cases of epilepsy in children. The below articles discuss the benefits of such a diet and the various similar approaches suggested for brain cancer.

You tube presentation by Dr Colin Champ (radio-oncologist)
https://m.youtube.com/watch?v=ot96y5-D_K0

A Low Carbohydrate, High Protein Diet Slows Tumor Growth and Prevents Cancer Initiation

Ketogenic diet:  Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. [in patients with advanced cancer, partial remission or stable disease correlated with degree of ketosis acheived]

Ketogenic diet: Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. (Strategy)

Ketogenic diet:  an effective adjuvant to radiation therapy for the treatment of malignant glioma. (Mouse model)

Ketogenic Diet:  Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036197

Ketogenic Diet: Enhances Oxidative Stress and Radio- Chemo-Therapy Responses in Lung Cancer Xenograf
http://clincancerres.aacrjournals.org/content/early/2013/06/25/1078-0432.CCR-12-0287.full.pdf

Role of glucose and ketone bodies in the metabolic control of experimental brain cancer
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394295/

Ketogenic diet: reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma.
http://www.ncbi.nlm.nih.gov/pubmed/20831808

The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer.
http://www.ncbi.nlm.nih.gov/pubmed/17313687

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?
http://www.ncbi.nlm.nih.gov/pubmed/21885251

Case report:
first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874558/
There is even evidence that addition of ketones even in absence of dietary resriction have an effect:

Is There a Role for Carbohydrate Restriction in the Treatment and Prevention of Cancer?
http://www.medscape.com/viewarticle/757713

Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R’s through dietary manipulation
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988521/

Study of long term KD in humans. (Tolerance, side effects)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716748/#!po=35.4167

carbohydrate high fat diet and glioma   https://www.sciencedaily.com/releases/2016/04/160414114159.htm

 

There are ongoing trials
https://clinicaltrials.gov/ct2/show/NCT02046187

 

 

10. INTENSIVE LIFESTYLE CHANGE CAN AFFECT PROGRESSION OF CANCER

diet, exercise,stress mangement

In a prospective study on early grade prostate cancer,  patients who were prescribed an intensive lifestyle program that included a vegan diet supplemented with soy (1 daily serving of tofu plus 58 gm of a fortified soy protein powdered beverage), fish oil (3 gm daily), vitamin E (400 IU daily), selenium (200 mcg daily) and vitamin C (2 gm daily), moderate aerobic exercise (walking 30 minutes 6 days weekly), stress management techniques (gentle yoga based stretching, breathing, meditation, imagery and progressive relaxation for a total of 60 minutes daily) and participation in a 1-hour support group once weekly to enhance adherence to the intervention
http://ornishspectrum.com/wp-content/uploads/Intensive_Lifestyle_Changes_and_Prostate_Cancer.pdf
And in recurrent prostrate cancer
http://ict.sagepub.com/content/5/3/206.abstract?ijkey=055640179df6e097f25285a4d43c4146296b7863&keytype2=tf_ipsecsha

Emotional

emotional well-being has an impact on recovery and survival (meta analyis)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439612/?report=classic

Chemo patients who undertook laughter therapy has signicfantly improved immunity
http://www.ncbi.nlm.nih.gov/pubmed/23984543

Psychological well being has positive effect on mortality in both heathy and diseased subjects.
http://www.ncbi.nlm.nih.gov/pubmed/18725425

Region/spirituality has positive effect on mortality
http://www.ncbi.nlm.nih.gov/pubmed/19142047

 

11. INTERESTING ASSOCIATIONS 

Cycomegalovirus
Overall, the data supports the theory that long-term, low-level CMV infection plays a critical role in the survival and reproduction of glioma stem-like cells and could significantly contribute to GBM development and progression.
In a study of more than 250 cases of glioblastoma only 1 was CMV-negative. And survival was related to level of infection. Retrospective data on patients with glioblastoma who received valganciclovir (teatment for CMV) as an add-on to standard therapy showed rate of survival of treated patients was remarkably high:

other references:

http://www.lef.org/Featured-Articles/2013/9/Brain-Tumor-Treatment-Breakthrough/Page-01

New Study Lends Support to Possible CMV-Glioblastoma Connection


http://www.ncbi.nlm.nih.gov/pubmed/19107226?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pubmed/25289896 (review that concludes insufficient evidence to routinely test)
http://www.braincancer.org/2014/03/31/valcyte-and-cytomegalovirus-cmv-in-the-treatment-of-glioblastoma/ (response to criticism)

My personal opinion: Given the association with CMV, relevance to prognosis and tumour response to treatment, to test for and treat CMV and treat seems, to me, essential. Unfortunately, the treatment of CMV is very expensive. Is it any surprise that testing and treatment are not done?

Toxoplamosis ( a personal interest and concern)
The surprising relationship between  CMV and glioma prompted me to look into anl link between brain tumour and toxoplamosis (for which I know I am positive, having battle with is in various pregnancies, and which has a similar propensity to cause cerebral damage in the foetus and immunosuppression) and I was surprised that there does seem to be an association between toxo and the development of glioma, in both epidemiological and animal studies. An epidemiological study analyzing data from 37 countries for the incidences of adult brain cancers and Toxoplasma infected people associated a nearly two-fold increase in the risk of brain cancers across the range of prevalence in Toxoplasma infection.
Toxo inhibits programmed cell death and Toxoplasma and has been reported to cause gliomas in experimental animals. Schuman et al also convincingly linked astrocytoma with antibodies to T. gondii. Toxoplasma associated miRNA dysregulation may be responsible.
http://blogs.discovermagazine.com/notrocketscience/2011/07/26/is-the-parasite-toxoplasma-gondii-linked-to-brain-cancer/#.VSkRh4akqrU
http://www.sciencedirect.com/science/article/pii/S1567134812000147
.http://rsbl.royalsocietypublishing.org/content/8/1/101
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1227362/pdf/amjphnation00073-0120.pdf
http://www.infectagentscancer.com/content/8/1/8
http://citizensagainsttoxoplasmosis.com/2013/05/15/toxo-and-brain-cancer/
http://www.accord3.com/docs/Vittecoq%20et%20al%202012%20Brain%20cancer%20mortality%20rates%20increase%20with%20gon.pdf
http://dash.harvard.edu/bitstream/handle/1/10594368/3583726.pdf?sequence=1
http://www.bc.edu/offices/pubaf/news/2012-nov-dec/American_Cancer_Society_Grant_for_BC_Research_of_Deadly_Parasite.html

http://www.ncbi.nlm.nih.gov/pubmed/19916846

Toxoplasmosis is a life long disease; it often infects its host ‘silently’, the host builds antibodies and remains asymptomatic , but it lies dormant and in an immunocompromised host (as in cancer, chemotherapy, steroids, AIDS etc) can rekindle into the active form with devastating consequences.
http://www.ncbi.nlm.nih.gov/pubmed/10762601?dopt=Abstract&holding=f1000,f1000m,isrctn

(Understanding toxoplasmosis infection
http://cmr.asm.org/content/25/2/264.full)

It seems there is no doubt that there is a correlation between glioma and previous infection with toxoplasma. I can find no studies yet that look at the effects on tumour progression or of treating the infection (as there are in CMV) but It would seem to me interesting and maybe important to establish my state of immunity to toxoplasma in serum and also its activity within the tumour tissue (as for CMV) and treat accordingly? furthermore it seems even more important to also limit steroid use, as toxosamoiss can be rekindled from it dormant state in immuno-comprised patients.

Heretogenecity in GBM

GBM tumours are a real mix of different tumour cell types. (Hence mutifome) this article (red link above or cut and patste ref below) looks at how that comes about and its implications. http://cancerres.aacrjournals.org/content/71/12/4055.full

 

Hyperbaric Oxygen therapy 

There is evicence that this is beneficial  in comating cancer and helping with radiotherapy. Thelink above takes you to my page on HBOT

 

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