NOTE: The following is a message which was posted in the brain-research group by John Williams on 2/5/09, and which has been copied (with permission) into this website verbatim, except for minor editorial revisions.  This message has not been peer reviewed, and is not offered as medical advice.  No liability is accepted by John or anyone else related to use of any of the information or opinions presented in this message. 

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Hello Everyone,

To start off the year, I'd like to offer a summary of many important adjuvant treatment topics which I feel are important for any brain tumor patient, especially high-grade brain tumor patients.  My comments in general will be directed to high-grade brain tumor patients, such as gliomas, since they have the greatest need for extra treatments.  I will purposely avoid discussing aspects of standard treatment, since you should be familiar with that via your doctor.  But, as a point of fact, as you all should hopefully understand by now, there are many evidence-based treatment options you will not hear about from your doctor. It is those that this article will focus on.

Caveats

I am not a doctor, nor do I possess any formal medical training.  I do have a physical science degree (geology), so my suggestions come purely through experience, books and research.

Because I am only offering suggestions here, it is important to discuss these options with your medical team.  And as important as that is, it's also critical for you to recognize that you are ultimately the only one responsible for the decisions regarding your medical care.  Your options are many.  You may need to present peer-reviewed evidence to your doctor and discuss the options.  If your doctor is not treating your disease the way you wish it to be treated,
you should start by finding a new doctor.

I've broken down these treatment topics into several categories.  This is a rough draft.  This summary will soon find permanent residence on my ongoing web site, www.TreatingGlioblastoma.com.

Important Issues for Newly Diagnosed Patients

All newly diagnosed patients should be aware of the following subjects ASAP:
--Radiation options, especially proton beam radiosurgery and IMRT
--Clinical trials, especially vaccine/immunotherapy trials which require resected tumor tissue
--Gliadel wafers
--Ben Williams' book "Surviving Terminal Cancer", as well as the annual online update at: http://www.virtualtrials.com/williams.cfm
--Molecular testing of resected tumor tissue
--Chemosensitivity testing of resected tumor tissue

Radiation Treatment Topics

--All patients undergoing radiation treatment (RT) should be thoroughly up to speed with the subject of radiosensitizing agents.  I have an article on the subject at:
http://www.treatingglioblastoma.com/treatment_radiosensitizers.htm
--The basic idea with radiosensitizing is to avoid excessive intake of anti-oxidants, while increasing intake of substances which result in oxidative stress, preferably selective oxidative stress in cancerous cells.

The Rationale for Using Adjuvant Treatments

There are a wide variety of widely available, relatively affordable, evidence-based, relatively low-toxicity adjuvant (added to improve primary treatments) treatments for high-grade brain tumor patients.  I personally believe all high-grade patients should explore all of these options.

The incentives high-grade patients have for trying additional treatments above and beyond what doctors are able to provide are the following:

--Only two new treatments for brain tumors have been approved by the US FDA in the past 25 years: Gliadel Wafers in 1996 and temozolomide (Temodar or TMZ) in 1999 & 2005.
--Most effective treatments are not yet approved by the FDA for use in high-grade patients.  Even Avastin and Tarceva are not yet approved for use in high-grade tumors, however many insurers will now cover these.
--Doctors are heavily restricted by law and insurance companies to stick to FDA-approved (government-approved) treatments.
--Even with the best care from brain tumor centers, statistics for Grade IV brain tumors are grim.  Most GBM patients die within 2 years.  This statistic begs for novel approaches.
--There is compelling research showing that a wide variety of substances have efficacy against high-grade tumors, including many relatively non-toxic substances.
--There is compelling research showing that a cocktail treatment approach, where multiple, non-overlapping tumor mechanisms are attacked simultaneously, is more effective than a simple monotherapy approach.
--Anecdotally, it appears that most long-term high-grade survivors have one thing in common: they have tried unique treatment strategies above and beyond standard treatment, ranging from clinical trials to herbal supplements.

There may be interactions and contraindications between the substances mentioned below and common high-grade treatments, however I'm not a pharmacist or pharmacologist, and one should ideally be consulted in order to have a measure of safety before trying any cocktail treatment.  If you need suggestions on how to get any of these substances, please don't hesitate to ask.  I suggest you consider adding as many of these substances as possible to a cocktail treatment, once a doctor and pharmacist have approved of the strategy.

Off-Label Adjuvant Treatment Substances

Chloroquine.  This anti-malarial drug is inexpensive, with mild side-effects and a long history of safe use in humans so long as standard dosages are not exceeded.  It's currently in clinical trials as an adjuvant with temozolomide for newly diagnosed GBM patients (ClinicalTrials.gov Identifier: NCT00486603).  Chloroquine is thought to increase oxidative stress and may facilitate p53 binding to the promoters of apoptotic genes.  With these mechanisms, it also shows promise as a radiosensitizer.  Neuro-oncologists at the University of Goettingen in Germany sum up chloroquine's benefits as thus: "Its effectiveness in killing glioma cells and its long history of safe clinical use make chloroquine an attractive candidate drug that may be used to complement existing glioma therapies."  There are a wide variety of studies available demonstrating both the in vitro and in vivo human benefits of adjuvant chloroquine in high-grade brain tumors.  See:

http://www.brain-treatments.net/Bricenoetal2003.pdf
http://www.brain-treatments.net/Soteloetal2006.pdf
http://www.brain-treatments.net/Bricenoetal2007.pdf
http://www.ncbi.nlm.nih.gov/pubmed/17341043

Noscapine.  All glioma and high-grade patients should consider taking noscapine as an adjuvant therapy because it is cheap, easy to get over the counter, almost devoid of side-effects, easy and safe to administer yourself, has few adverse drug interactions, and is supported a wide number and variety of studies.  It's mechanism is microtubule function interference, bradykinine b-2 receptor inhibition, and hypoxia-inducible factor (HIF)-1 inhibition.  One
notable adverse drug interaction may be between noscapine and warfarin.  See:

http://www.ncbi.nlm.nih.gov/pubmed/15297423
http://www.ncbi.nlm.nih.gov/pubmed/18525314
http://www.ncbi.nlm.nih.gov/pubmed/16596228

DCA (dichloroacetate).  All glioma and high-grade patients should consider taking DCA as an adjuvant therapy. DCA is easy to administer yourself or you may work with an integrative cancer clinic in Canada called Medicor. DCA's side-effects are easy to limit in most patients and its well-studied pharmacokinetics do not appear to interfere with any other common drug.  It's primary mechanism is thought to be down-regulation of glycolysis and up-regulation of normal mitochondrial function, which may help increase apoptosis and even help restore cancerous cells to normal function.  Initial consultation with Medicor costs around $1500 the first month and charges are variable after that.  DCA is easy to obtain and administer, however I recommend working with Medicor if possible.  See:

http://www.medicorcancer.com/DCAtherapy.html

Accutane (13-cis-retinoic acid).  Many high-grade patients have taken Accutane, which is a powerful Vitamin A analogue.  The main side-effect is dry skin.  Millions of teenagers have successfully taken Accutane for acne. Unfortunately, if you take it with Tarceva you end up with both acne AND dry skin, according to UCSF.  Efficacy as an adjuvant drug is pretty well-established and Accutane is currently in several clinical trials and is already part of the standard protocol for some types of brain tumors.  It will require a doctor's prescription.  See:

http://www.ncbi.nlm.nih.gov/pubmed/12805331

Cimetidine.  Similar to noscapine, this drug is cheap, easy to get over the counter, nearly devoid of adverse side-effects, easy and safe to administer yourself, and very promising in an adjuvant setting.  However, cimetidine may have significant drug-interactions with some common drugs, potentially including chloroquine, so you will need to
have a pharmacist clear its use with your entire drug regimen.  Cimetidine inhibits some of the common cytochrome P450 metabolizing enzymes.  It's mechanism is thought to be as an anti-proliferative.  See:

http://www.ncbi.nlm.nih.gov/pubmed/16596218

Cyclopamine.  Cyclopamine is an alkaloid of the lily Veratrum californicum which inhibits the "hedgehog" pathway, an important signaling pathway in cell formation, proliferation, and differentiation in multiple tissue types.  Separate research at Johns Hopkins, NYU, and Univ. of Geneva have produced similar, promising results in gliomas with low toxicity profiles.  The hedgehog pathway appears to be one of the critical pathways for tumor survival, which is why this discovery is so closely watched.  I believe a pharmaceutical company called Curis, in cooperation with Genentech, is working on a small-molecule derivative of cyclopamine for use as a chemo drug.  It may be possible to get it without a doctor's prescription.  I'm not aware of any patient who has tried this drug off-label, so patient case studies are nonexistent.  But I am very excited about the potential of this drug and look forward to someone trying it.  Acquiring cyclopamine may require the help of someone familiar with chemistry.  See:

http://www.ncbi.nlm.nih.gov/pubmed/15652709
http://www.ncbi.nlm.nih.gov/pubmed/17628016
http://www.ncbi.nlm.nih.gov/pubmed/17196391

Sulfasalazine.  An anti-inflammatory currently approved for inflammatory bowel disease, sulfasalazine has shown promise in gliomas by inhibiting nuclear factor kappaB (NF-kappaB), reducing glutathione levels, inhibiting cystine uptake, and inhibiting the glutamate release from glioma cells which is thought to help proliferate tumor cells.  Neurobiologist Harald Sontheimer from Univ. of Alabama is the primary U.S. researcher on this, but studies have been published by Belgian and German researchers as well.  It's possible that there may be synergy with an over-the-counter drug called dextromethorphan, which is a non-toxic ingredient of many cough medicines.  There may be theoretical potential for sulfasalazine to be synergistic with Avastin in limiting the long-term effects of use.  See:

http://www.ncbi.nlm.nih.gov/pubmed/15328202
http://www.ncbi.nlm.nih.gov/pubmed/16079392

Alfacalcidol.  Alfacalcidol is an analogue of Vitamin D used in the treatment of low calcium levels in the blood.  In several small studies, alfacalcidol has produced remarkable results for such a low-cost, non-toxic substance.  While virtually all forms of Vitamin D have shown anti-tumor and chemopreventive properties, the common forms may become toxic in high doses by raising plasma calcium levels too high.  Alfacalcidol is easy to administer (oral pill form) and appears to be less likely to produce toxic effects.  To avoid hypercalcemia, you should have your calcium levels regularly checked when using high doses of alfacalcidol.  See:

http://www.ncbi.nlm.nih.gov/pubmed/11349882

Clinical Trials

For 2009, I would be especially interested in the following clinical trials:

--Novo-TTF (NovoCure)
http://www.eurekalert.org/pub_releases/2008-11/epr-ssn112408.php

--Neuradiab
http://www.glassarttrial.com

--UCLA, DCVax Brain vaccine trial, under Dr. Linda Liau
http://www.neurosurgery.ucla.edu/body.cfm?id=32

--Oncophage (heat shock protein vaccine) at UCSF (e.g. see update
http://www.sciencedaily.com/releases/2007/04/070416101218.htm)

--Tumor lysate-pulsed Dendritic Cell Immunotherapy at Cedars Sinai
http://www.cedars-sinai.edu/1119.html

--Celldex CDX-110 EFGRviii immunotherapy
http://www.celldextherapeutics.com/wt/page/pr_1162508352

--Dendritic Cell Immunotherapy at Univ. of Pittsburgh
http://www.virtualtrials.com/vaccine.cfm
This trial uses concomitant Poly ICLC, incidentally, and does not require resected tumor tissue. It just recently opened up an arm for pediatric patients.

--ICT-121 (a new vaccine drug which does not require tumor resection)
http://www.businesswire.com/portal/site/google/?ndmViewId=news_view&newsId=20081\
223005131&newsLang=en

--Any multi-tyrosine kinase inhibitor, especially if combined with a cytotoxic agent like TMZ

Vitamins, Minerals, and Herbal supplements

This is a whole subject unto itself.  There are many books and websites on the topic of treating cancer with evidence-based dietary substances and other supplements.  I recommend consulting with an expert, such as
Jeanne Wallace or Donald Yance.  I have begun to compile a list of supplements at:

http://www.treatingglioblastoma.com/supplements_alphabetical.htm

Diet

Eating a good diet is important for keeping the rest of your body healthy.  Many foods provide anti-cancer benefits and entire books have been written on the subject.  Interestingly, however, eating higher than average quantities of fruits and vegetables has NOT shown to help reduce tumor recurrences in a wide variety of cancers, but it is likely still important to eat a balanced, nutritionally sound diet.  It may prove to be more important to avoid ingesting carcinogens which exacerbate the environment in which malignancies form.  For this reason, I suggest organic foods whenever possible, avoid cooking foods in plastics, avoid heating most oils, and avoid burned foods. Diet goals should also include maintaining or increasing weight and muscle tone, which have numerous benefits during treatments.  Alcohol further disrupts the blood-brain barrier and should be completely avoided.

Some common foods with noted cancer-fighting properties:

--Japanese green tea
--Brussels sprouts, bok choy, Chinese cabbage, broccoli, and cauliflower
--Celery
--Garlic, onions, leeks, shallots, chives
--Hot peppers
--Many spices: tumeric (curcumin), ginger, cinnamon, licorice, garlic
--Whole soy products (make sure you avoid added MSG)
--Unsaturated fats (olive, canola, or flaxseed oils)
--Fatty acids (fish, flax, walnuts, almonds)
--Berries, especially raspberry and blueberry
--Pomegranates
--Pinneapples
--Citrus fruits, especially tangerines, lemons and limes
--Dark chocolate (70% cocoa or higher)
--Low glycemic foods

A book I find particular helpful in this area is Dr. Russell Blaylock's "Natural Strategies for Cancer Patients".  Dr. Blaylock is a neurosurgeon, so many of his suggestions have brain cancer patients in mind.

Exercise

It's critical to continue keeping the rest of the body healthy, because this will also help a patient's mental well-being.  Again, maintaining or increasing weight and muscle tone is important to the overall treatment of the disease.

Mental Well-Being

This touchy-feely stuff can actually make a difference.  Numerous studies have shown that depression and negative attitudes can negatively influence disease.  If you are religious, prayer can help improve mental well-being so long as the patient is praying for herself or is aware of someone else praying on her behalf.  Empirical studies show that the patient must be aware that someone is praying for them, in order to produce measurable results (intercessory prayer shows no clinical benefit).  Similarly, yoga and meditation provide measurable improvements in fighting cancer and the mechanisms are beginning to be defined.  Prayer, yoga and meditation all provide benefits through a well-defined "relaxation response" in which blood pressure and heart rate are lowered.

In addition, scientists at MIT recently found that rats who are raised in a low-stress environment produce more HDAC inhibitors in their brains than rats in a high-stress environment.  HDAC inhibitors are known radiosensitizing and therapeutic agents against brain tumors.  Interestingly, several antidepressant drugs also show efficacy against high-grade tumors, namely clomipramine and valproic acid, so it may be possible to get a win-win by using an antidepressant which treats both clinical depression and the tumor.  For an interesting study from Johns Hopkins regarding how depression affects outcome in brain tumors, see:

http://www.ncbi.nlm.nih.gov/pubmed/18786716

Living Environment

Brain tumor patients need to be in a very supportive environment, balancing the needs to be close to family, friends, and good medical care.  Patients need to understand as soon as possible, if they don't already, that they should let go of some aspects of life which are better suited to be done by other people.  The big ones here are
treatment research/decisions and financial matters.  Brain cancer patients have a unique disease in which their judgment can easily be affected without their knowing.  So I encourage patients to place the important decisions and treatment direction as much as possible in the hands of someone (or a team) they and their family trust to have their best interests at heart.  This doesn't mean that patients should be removed from any decision-making, but it does mean that patients need to realize that their judgment, initiative, attitude, and personality are often impaired by the disease, and they may not be able to notice the impairment.

Other environmental issues which are important to high-grade treatment are getting enough sleep, and staying warm.  Several studies have shown that localized hyperthermia (raising the body temperature above normal) helps preferentially kill glioma cells, and that hyperthermia has a chemosensitizing effect (it makes chemo more effective).  Of course patients should not risk hyperthermia without a doctor's care, but if you doctor allows, perhaps long, hot showers/baths, saunas, and hot tubs would not hurt.  For some interesting hyperthermia studies, see:

http://cat.inist.fr/?aModele=afficheN&cpsidt=14135909
http://www.springerlink.com/content/tgw7ekuujxwv194a
http://www.biomedklinik.de/pdf/Glioma-ASCO.pdf
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Please feel free to send comments or suggestions to me (braintmr@gmail.com).

Cheers,
John
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Ashland, Oregon
Volunteer Brain Tumor Patient Advocate
www.TreatingGlioblastoma.com
In memory of my father, Dave Williams