Friday, 14 July 2017

My father's GBM

 My father was diagnosed with GBM on 4/15 and he had a total resection surgery on 4/17.  I've been researching pretty much non-stop every since.  I watched the surviving terminal cancer movie, read Ben Williams book, have been scouring the internet gathering as much information as possible and this is how I ended up here.  

Here's all the information I have on my fathers tumor and the treatment and supplements he is on to date:
Genetic testing: MGMT was not detected (negative) unmethylated
IDH1 and IDH2 were not detected (negative) as well
It is EGFR amplified - which qualified him for ABT-414 clinical trial.
He is currently in the trial and has some symptoms which lead us to believe he is getting the actual drug and not the placebo.  
He finished up the standard treatment of Radiation and Chemotherapy a few weeks ago.
He is taking Keppra and a PPI daily

List of supplements: Cannabis oil, 20 mg melatonin, 800 mg curcubrain, reishi and coriolus mushroom supplement, 500 mg Boswellia extract, 400 mg green tea extract, 200 mg resveratrol, 200 mcg selenium, 10000 IU vitamin D3, Hemp seed and flax seed oil.
Also drinking fruit and veggie smoothies daily.

These are the off label drugs that I recently received and plan on having him start in a couple days.
Disulfiram-125 mg a day for the first week, then 250 mg daily
Chloroquine- 250 mg daily
Celebrex- 200 mg twice daily
Metformin- 500 mg once daily, titrating up to twice daily, then 3 times daily
Doxycycline 100 mg twice daily
Propranolol 60-80mg daily
Lipitor
DCA 5mg/kg per day, titrating up to 12-15mg/kg.
LDN (low dose naltrexone) start with 2mg nightly titrating up to 4.5mg

I have a few questions:
1.How does the dosing and schedule of the off label drugs look? Anything I should add or subtract? 
2. I know Disulfiram and DCA can cause neuropathy, should they not be taken together?
3. Should the green tea extract pills be avoided while on DCA?
4. The doxycycline I have is Dox T-SL (Doxycycline 100 mg / Lactic Acid 5 billion spores)  
It says "DOXT-SL contains Doxycycline along with 5 billion spores of lactobacillus sporogenes."
Would the lactic acid cause a problem?
5. Most of the research I've done says statins are beneficial, but I've also an article saying they should be avoided.  Should they be used or avoided? 
If he does take the Celebrex, any recommendations on dose?
6. The Naltrexone pills I have are 50 mg.  I've seen people dissolve them in 50mg of water and then use a syringe to suck up desired amount in mg.  Is this advisable?  Some people say this will cause inconsistent doses, but I don't know another way.
7. I've read that since his GBM is unmethylated and EGFR amplified that a metronomic chemo scheduling would be more beneficial than standard chemo treatment.  We meet with my fathers oncologist next week to take a scan and discuss the future game plan.  Does anyone have any recommendations on how to try and convince his dr. to prescribe the metronomic dosing schedule.

Any help or suggestions would be greatly appreciated.  Like I said, I've been doing a ton of research and sometimes it seems like the more I do, the more confused I get.  

19 comments:

  1. Just a few comments for starters.
    Atorvastatin (Lipitor) is in a clinical trial in Saudi Arabia for GBM, though I'm not sure why this statin was chosen above other statins. The research that I've seen shows other statins such as simvastatin have much higher potential to cross the BBB. In any case I consider the evidence for statins a GBM therapy to be still fairly marginal, though perhaps no more marginal than many other commonly used agents.
    https://clinicaltrials.gov/ct2/show/NCT02029573
    https://www.ncbi.nlm.nih.gov/pubmed/21098985

    Combining two agents that can cause peripheral nerve damage may increase the risk of this occurring. That's not to say that it shouldn't be attempted, but I would be on close watch for the early signs of neuropathy and either taper off on the dose or drop one of the drugs if symptoms start to occur.

    I wouldn't worry about green tea extract + DCA combination. There may be something to the reported risk of combining DCA with caffeine, there is very limited information on this. But in that case you can purchase green tea extract brands that contain little or no caffeine.
    http://www.thedcasite.com/DCA_protocol/Brain_cancer_risks.html
    https://www.caffeineinformer.com/caffeine-content/green-tea-extract

    Lactobacteria are a normal part of the gut microbiome. I would encourage the use of priobiotics. The lactic acid they produce in the gut does not impact the acidity of the brain tumor microenvironment -- GBM tumors are prolific producers of lactic acid, and this is independent of the gut microbiome. Short answer - don't worry about the lactobacillus added to the doxycycline, it's there for a good reason.

    In my opinion 200 mg Celebrex twice daily would be reasonable, and is about a middle of the road dosing.

    Dissolving 50 mg tablets of naltrexone was discussed in the comments of this blog at one point. Low dose naltrexone can be purchased online, but if for whatever reason the standard 50 mg is what is most available to you, I would probably go the route of dissolving in a solution to facilitate the lower doses.

    https://www.buyldn.com/
    http://btcocktails.blogspot.com/2016/09/low-dose-naltrexone.html#comment-form

    The idea that metronomic medium dose TMZ is a better idea for GBM with unmethylated MGMT status and EGFR amplification comes mainly from a single study. This study was retrospective, and there may have been some selection bias (were healthier patients more likely to be put on the metronomic schedule? We don't know...). In any case I would just present this study to the doctor as the best piece of evidence. His oncologist will still likely want to proceed with standard dosing, all oncologists are very resistant to deviate from the currently accepted standard of care.

    https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djv041

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    Replies
    1. Stephen,
      Thank you so much for your quick reply. The information you provide is such a valuable resource for patients and caregivers that are dealing with the horrible disease. I will do my best to try and contribute to these forums any information and knowledge that I gain along the way, and hopefully one day we'll figure out a way to beat this monster.

      I had a typo earlier, I meant to ask about dosing suggestions for Lipitor, not Celebrex.
      Also, any suggestions on DCA dosing schedule?
      I know some people do 1 day on, one day off.
      Others do 5 days on, 2 days off.
      Some people use 2 weeks on, one week off.

      Thanks again for all your help!

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    2. With the caveats about statins already stated in my comment above, if using Lipitor as a GBM therapy it is probably reasonable to follow the dosing used in the only clinical trial testing atorvastatin for GBM. In this trial the dosing is 40 mg per day for three weeks, at which point the dose is increased to 80 mg per day.

      http://academic.oup.com.ololo.sci-hub.cc/annonc/article-abstract/doi/10.1093/annonc/mdw367.32/2799093/Phase-II-study-of-atorvastatin-in-combination-with

      I've never heard of a 1 day on, one day off DCA schedule. The clincial trials for glioma carried out to date have used a twice a day schedule and didn't appear to incorporate rest days or periods. Medicor Cancer Center in Toronto use/used a 2 week on, 1 week off schedule and they treated lots of patients and gathered lots of data on this schedule. There is relatively little data on other schedules that I've seen.

      The schedule is probably less important than the individual's metabolism of the drug. A fast metabolizer can withstand higher doses and might not need any rest period at a dose where a slow metabolizer might need more rest periods to avoid side-effects. Proper DCA dosing is tricky because of these differences between individuals.

      http://btcocktails.blogspot.is/p/w-hat-has-come-to-be-known-as-drug.html

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    3. Thanks again Stephen for all of your help!

      Like you predicted, his oncologist wants to stick to the standard 5/28 chemo dosing schedule. This also has to be the case because right now he's enrolled in the ABT-414 clinical trial.
      In your opinion, would it be worth it to really fight for the metronomic schedule? That means he would have to quit the trial. At that point I would push for the Optune, which he cannot use concurrently while in the trial either.
      Also, if we do stick with the current standard 5/28 schedule, do you see any supplements/off label drugs that I have in my regimen above that he should avoid during the 5 days on chemo?

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    4. I'm not so convinced of the metronomic schedule for EGFR amplified tumors that I would drop out of a clinical trial to pursue it. There may have been significant selection bias in the retrospective study cited earlier, which could be partially responsible for the outcomes. The Cominelli et al. study (2015) did show that the metronomic schedule decreased the percentage of EGFR-amplified cells and decreased EGFR intensity in the tumors, but it could be that ABT-414 targets EGFR-expressing cells even more effectively. If it were me, I would stay in the trial, and continue using Keppra and other cocktail ingredients that might help reduce MGMT activity (disulfiram and fluoxetine, ie Prozac, are two others that have some preclinical evidence in this regard).

      None of the individual ingredients stands out to me as a red flag, although this is a fairly aggressive cocktail, so cumulative toxicity could become an issue. We already touched on the risks of DCA + disulfiram in terms of neuropathy.

      The daily DCA doses you mentioned are conservative, as clinical trials have used the same single doses, but TWICE daily. In one clinical trial, "slow metabolizers" (ie. those who would be most likely to achieve high plasma levels of DCA leading to toxicity) were given 4 mg/kg every 12 hours, that is, 8 mg/kg per 24 hours. For a fast metabolizer that dose may be ineffective.

      https://www.ncbi.nlm.nih.gov/pubmed/24297161

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    5. Seeing how it is an aggressive cocktail, is there anything I should be looking out for, aside from the neuropathy? Should I be doing any additional tests at home or something I should be asking his doctors to check? I.e. additional things to look for in his blood work?

      He'll be starting the Disulfiram and the LDN tomorrow. I'll wait and see how well he is handling the Disulfiram before adding the DCA. Should I be slowly introducing the other drugs every few days and checking for any reactions?
      I have not ordered the DCA yet because I wanted to make sure that I find a high quality product. They now sell DCA on Amazon and it looks like a good deal. It's from DCA-LAB, it says it's 99.9% pure. I couldn't really find too much information on it, but it looks legit to me. Do you know anything about this company, do you think it's high quality?

      Thanks again for all your help!

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    6. One of the things typically included in blood work is liver enzymes. When there is liver toxicity, the liver starts leaking certain enzymes, so their level in the blood is increased.
      http://www.mayoclinic.org/symptoms/elevated-liver-enzymes/basics/definition/sym-20050830

      CUSP9, as an approved trial recruiting patients, could be used as a model for how to implement a multi-drug cocktail. In this trial most of the drugs are started at reduced (half) doses, and new drugs are added one at a time, every other day. Then the drugs are later increased to their final doses.

      I've not done searches for DCA recently. This DCA-LAB product does look legit to me too. Many people on this blog are using pharma-dca.com, but this dcalab.com brand looks like it could be a competitor.

      https://pharma-dca.com/
      https://www.dcalab.com/our-lab

      There was some good discussion of DCA on the old cancer compass cocktails thread. I'm going to create a single post here on the blog to consolidate that info.

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    7. Stephen,
      Do you believe that any antioxidants should be off limits during chemotherapy, or is this a dated way of thinking?
      I'm going to add ip-6 with inositol and was just wondering what your thoughts were on antioxidants during treatment. His oncologist gave us a paper with things to avoid during chemo and radiation. We've ignored a lot of these recommendations because a lot of the information I found recommends most antioxidants during therapy. There seems to be people on both sides of the fence in this argument and I was just wondering where you stand. Is it possible to take too many antioxidant supplements, should certain one's be avoided?

      Thanks again for all of your help!

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    8. I do feel that the idea that "all antioxidants should be avoided during radiation/chemotherapy" is not useful. Instead I think each different compound should be evaluated individually and not lumped together with every other compound that has antioxidant properties - they can be very different from one another. Some compounds with antioxidant properties, such as epigallocatechin gallate, or resveratrol, have added to to the therapeutic effects when combined with temozolomide in animal models. On the other hand there was also a mouse study in which intraperitoneal injections of ascorbate (vitamin C) interfered with the effects of radiation. In one study, vitamin E was associated with increased mortality although based on only 19 users of vitamin E.
      https://academic.oup.com/nop/article/2/3/122/1036239/Complementary-therapy-and-survival-in-glioblastoma

      A different study showed reduced risk with the highest level of vitamin E use, but only for grade 3 gliomas, and no significant effect for grade 2 or grade IV. This study also showed higher risk for GBM with high intake of vitamin C, genistein, and total antioxidant index. "Among all Grade IV cases, a number of antioxidants and other nutrients were significantly associated with poorer survival. These included high intake of
      the total Antioxidant Index, vitamin C, genistein..." Unfortunately there are some numerical errors in the corresponding tables, so .44 should be 1.44 in table 4 for vitamin C, third tertile, grade IV glioma, and 0.36 should be 1.36 in table 5, Antioxidant index, third tertile, grade IV glioma. [There are similar numerical errors elsewhere in the tables. When the Hazard Ratios (HR) look odd, or don't match up with what it says in the text, look at the 95% confidence interval (95% CI) in round brackets to the right of the HR number]

      https://www.ncbi.nlm.nih.gov/pubmed/20482871
      Daily intake of antioxidants in relation to survival among adult patients diagnosed with malignant glioma.

      In any case, yes I do believe it's possible to overdo antioxidants, but I also don't believe all antioxidants should be avoided. I believe they have to be evaluated on a case-by-case basis taking into account the available evidence.

      For a much more ambitious discussion of antioxidants and cancer therapy, see Ben Williams essay on the subject.

      http://virtualtrials.com/pdf/williamssupplements2014.pdf
      The Role of Supplements (including Anti-Oxidants) in Cancer Treatment

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    9. I read the article in the link above. Some very good info in there. From what I can tell, my list looks to be beneficial. In your opinion, does it look like I have too many antioxidants, or should any be avoided while taking chemo?
      Cannabis oil, 20 mg melatonin, 800 mg curcubrain, 500 mg Boswellia extract, 400 mg green tea extract, 200 mg resveratrol, 200 mcg selenium, 10000 IU vitamin D3, IP-6 & Inositol
      I just want to make sure that I'm not doing more harm than good.

      Also, I started my dad on disulfiram while he was taking chemo. We gave it to him at night, and the next day he was extremely nauseous/vomiting. At first I thought it may be from the chemo, but we stopped the disulfarim to make sure. He was a little queasy for a few days, but no vomiting. The more I thought about it, I was thinking maybe it was from the cannabis oil and the disulfiram. The oil is made using 99.9% pure isopropyl alcohol, and maybe there was still trace amounts left in the oil. Do you think that this would make him sick after only one dose of 250mg of disulfiram? I want to try to start him on it again, but don't want to make him sick. Did you say that prozac would work along the same lines as the disulfiram?

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    10. I'm not a chemist or a biochemist, but according to my understanding isopropanol shouldn't interact with disulfiram. Unlike ethanol, isopropanol doesn't depend on aldehyde dehydrogenase enzymes for its metabolism and excretion. The disulfiram-ethanol reaction occurs because disulfiram inhibits aldehyde dehydrogenase, causing a toxic buildup of the intermediate metabolite acetaldehyde.

      In contrast, isopropanol is converted to acetone by alcohol dehydrogenase, and the acetone is excreted by the kidneys. I've not seen that aldehyde dehydrogenase plays a role in isopropanol metabolism.

      http://www.ebmedicine.net/topics.php?paction=showTopicSeg&topic_id=38&seg_id=717

      Hard to say for sure whether the disulfiram was the main cause of the nausea/vomiting if he was also taking chemo at the time. But perhaps there is ethanol in something else he is ingesting?

      An Antabuse product information sheet has the following statement: Under all circumstances, patients receiving ANTABUSE Tablets must not take alcohol or alcohol-containing preparations, e.g. certain cough syrups, sauces, vinegar, tonics, foods prepared with wine, and even should avoid the use of after shave lotions and alcoholic back rubs."

      The main thing that disulfiram and Prozac have in common is preclinical evidence showing both might inhibit or downregulate MGMT. That's where the similarity ends, and both have many other non-overlapping potential mechanisms of action. I would not think of them as being interchangeable.

      My thinking around antioxidants is on a case by case basis. Many of those agents in your list have positive evidence as synergistic or at least additive with chemo. None of them have evidence as interfering with chemo that I've seen. Nothing jumps out as me as a red flag in that list.

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    11. "Isopropanol is a Secondary Alcohol Which is Metabolized by Alcohol Dehydrogenase Only to a Ketone (Namely, Acetone), Rather than to an Aldehyde: ketones cannot be oxidized to an aldehyde and therefore, only limited acidosis can result"
      http://mdnxs.com/topics-2/toxicology/isopropanol/

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    12. So, from your understanding, trace amounts of isopropanol shouldn't have any adverse reactions from the disulfiram? If that's the case, I'll have him take it again. I would just hate to make him extremely sick again, seems to take a few days to recover once he's been throwing up.
      I guess it could have just been from the Temodar. I just wasn't thinking this was the case because the doctors told us most people didn't get too sick from Temodar. If it was from he chemo, I think we may need to find my father a new anti-naseau medicine. Have you heard of the Sancuso (granisetron) patch? I was reading this may be a more effective anti-naesu med.

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  2. Roy, Good luck with your dad and you have done some great research.

    FYI, I am a 2+ year warrior and here are some of my dosing:

    Off label drugs I took during my post radiation standard of care (TMZ 5/28 day cycle) and Velipar trial (5/28 day)

    Celebrix - 200mg twice daily
    Metformin - 500mg twice daily

    Other supplements I took include:
    * Resveratrol - 200 once daily
    * Selenium Cruciferate - 200 once daily
    * Thymus - 1000mg once daily
    * Vitamin K2 - 160 twice daily
    * Molybdenum - 1000 once daily

    My Cannibis oils:
    * THC - RSO starting at titration level 3 30ml per day and now at titration level 6 10ml per day
    * CDB - RSO at 15ml twice per day

    Marc

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    Replies
    1. Marc,
      Thanks you so much for taking the time to show me your supplements/off label dosing. It's very encouraging to speak with people, such as yourself, that are fighting and beating the odds. Hopefully as more and more people share their success stories and what they are doing to combat this disease, eventually long term survivors will be the norm.
      I have a few more questions for you, if you don't mind.
      1. Did you have any genetic testing done on your tumor?
      2. Did you have total resection surgery?
      3. You were taking 30 ml of oil daily? That seems like a lot

      Thanks again for your reply. I hope all is well.

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    2. Roy,

      I did have Foundation and Guardian testing
      Yes, I did have a total resection. Done at Scripps Green Hospital (San Diego) with the highlighting dye.
      Yes, I take 30ml (3 pumps in the morning and 3 pumps in the evening) of the CDB only oil. It has basically no THC so no effects. the THC I can only take a night since it has a big impact and cannot go to work under the influence.

      Marc

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    3. Hi Marc,

      Can you advice what you are taking now from your list of drugs and supplements.


      Celebrix - 200mg twice daily
      Metformin - 500mg twice daily

      Other supplements I took include:
      * Resveratrol - 200 once daily
      * Selenium Cruciferate - 200 once daily
      * Thymus - 1000mg once daily
      * Vitamin K2 - 160 twice daily
      * Molybdenum - 1000 once daily

      My Cannibis oils:
      * THC - RSO starting at titration level 3 30ml per day and now at titration level 6 10ml per day
      * CDB - RSO at 15ml twice per day

      Thank you

      Luyeza

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  3. Good luck Roy and please keep us posted. BTW - who and where is your NO? I'm curious to know how he proceeds with your Dad.

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    Replies
    1. Thanks for your well wishes. I will definitely be posting updates. I really hope that all the information shared on this site will extend the lives of many people in the future.
      I am from the Chicagoland area. His oncologist is sticking with the standard of care for GBM. He already received radiation and chemo, he has been on a break, we just met with his doctors yesterday and they plan on continuing the 5/28 chemo treatment for the next year or so. I mentioned the cocktail approach to him and he seems to believe there's not much validity to it. He basically said that if we want to try it, go ahead, but he doesn't think it helps much. All the supplements and drugs I will be giving my father I have mostly procured from the internet. I also tried to convince him to do the metronomic schedule of chemo, but he thinks that there is no proof regarding it working better for unmethylated tumors or tumors with amplified EGFR. He said he doesn't believe this would be beneficial, and thinks it's more toxic.

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