Wednesday 10 August 2016

T4 Suppression

Because T4 suppression therapy looks promising for GBM’s and other cancers based on a small observational study, I thought I would post my sons response to this treatment over time.  The study can be found in Stevens Brain Tumor Library, Therapies - human Studies. 

For those not familiar with my sons story, here it is.  Originally diagnosed with a large Oligo 2 in 2007.  It was located in the left parietal region.  Received radiation and TMZ.  There was no evidence of tumor until October 2014 when a GBM was diagnosed after personality changes.  This was treated with TMZ, radiation and Optune.  In Feb 2016 he experienced his first recurrence, three areas in the occipital lobe.  Treated with SRS and TMZ and was started on Nivo.  All 3 areas resolved within two months.  Then in June an area of enhancement showed up in the pons and one month later a recurrence in the occipital lobe and in the area of the 2007 resection cavity.  TMZ and Optune were discontinued.  The small enhancing area in the resection cavity was treated with SRS in an attempt to enhance the possibility of an immune response in conjunction with Nivo.  CCNU and Avastin were recommended.  Concerns over Avastin are the increased migration and invasive nature of GBM’s once exposed to it.  CCNU is myelosuppressive and we are trying to obtain an immune response from Nivo so we are not too excited about that. 

Which brings us to the T4 suppression therapy.  This was started yesterday.  We will see if a response occurs and if not, or if neurologic symptoms become worse, we will continue T4 suppression and add CCNU and Avastin.  The BELOB trial showed a relatively small benefit with CCNU and Avastin, with the exception of IDH-1 mutated tumors where the response was significant.  My son’s tumor is IDH-1 mutated.  At least the original GBM was, and I am told recurrent tumors maintain that mutation.  So maybe CCNU and Avastin will prove significantly beneficial.  For now, we are holding on the CCNU and Avastin.  That could change quickly.

Jeremy has been on a repurposed drug and supplement cocktail throughout his GBM treatment.  Both NO’s he sees have been supportive of the cocktail approach because they believe he is responding better than the typical IDH-1 mutated GBM patient.


I will keep you up to date.  If the T4 suppression approach is effective, it might be worth looking into as an additional treatment for those in our group.  I have contacted Dr. Hercbergs, the primary investigator in the Observational study on T4 suppression.  He provided me with additional information and target FT4 levels if anyone needs this information.

29 comments:

  1. My husband followed the hypothyroid protocol under the direction of Dr. Hercbergs. He achieved the desired FT4 level and sustained it, but did not see a result anything like described in the observational study. Read the paper carefully and you will see there were patients that did not remain on the protocol. I believe those to be patients for whom it was not effective. I know another patient for whom it was not successful. It is a relatively gentle treatment so worth a try, but I don't think the response rate will be what was presented. If you are a responder it's great though so worth trying. My husband's NO at Duke was even supportive of him trying it, so saw potential.

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  2. May I ask why you didn't stick with the Optune? We're still early on it and are hoping for good things with it.

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  3. For reference, the paper Mike mentioned is called "Medically Induced Euthyroid Hypothyroxinemia May Extend Survival in Compassionate Need Cancer Patients:An Observational Study" by Hercbergs et al.
    http://www.ncbi.nlm.nih.gov/pubmed/25410096

    For discussions of this therapy on this blog see the labels "methimazole_plus_cytomel" and "thyroid hormones"

    "T4" refers to the thyroid hormone thyroxine. Cytomel is a synthetic version of T3 thyroid hormone, used in this study to prevent clinical hypothyroidism.

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  4. Logan Lo

    With the initial recurrence Optune was continued and then the pontine enhancement developed and Optune was continued, but after two more areas of enchantment developed a month later his NO said it was no long appropriate to use Optune as it had failed as a treatment.

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    1. Michael - Apologies for the super late response. I only noticed this reply now. Thanks so much for the information. Catching up on all this great information now.

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    2. Stephen, is there some option that we can be notified about replies to our posts?
      Thank you. (Great work in maintaining this blog)

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    3. Apart from monitoring the Recent comments on the sidebar, you can also check the "notify me" box underneath the comments box. Clicking in that box is like a subscription to the thread and you should receive notification of new comments sent to your email.

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    4. The "notify me" box is right underneath the box where you would type a comment.

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  5. Email from Dr. Hercbergs you might find interesting

    Dear Michael
    Actually this study which took 6 years to do, gathering data from numerous internet and personal contacts. It has attracted quite a bit of interest from individuals on the Internet [USA ,Spain,Ireland,Australia,New Zealand,Italy, Argentina ,Canada,Norway etc.] seeking help, invitations from medical journals and hundreds of Research Gate 'hits'. Physicians have been aware of this research for years but frequently refused to give it even as compassionate care.

    I have been asked the same question multiple times , and my answer is : there is no pharmaceutical funding[$$$] for repurposed drugs. So I decided to offer this treatment directly to folks with any types of cancer who needed it . This treatment is being regularly prescribed the last 4 years by oncologists in Hadassah Ein Karem and Tel Aviv and of course here in the US privately, but the results have not as yet been published . I published my first study on recurrent glioma in 2003 using the drug propyltiouracil with excellent results, but again there was no funding from any source, including the NCI, here in the US.The interest from that study [as of now]was crushed by the advent of Avastin and with the drug industry pouring in money to physicians and clinics to finance studies trying the drug which helps in the short term but does not prolong life.My study introduced the drug Cytomel based on the 2009 discovery that T3 was much less stimulating for cancer than thyroxine and avoided the dreaded fatigue of hypothyroidism -its all in my paper.
    T3 also alone may induce indirectly hypothyroxinemia and certainly should replace L-T4 in a patient with active cancer. Recently, leading endocrinologists from the ATA are beginning to adopt this approach . I am continuing to prescribe the treatment for various cancers with comparable outcomes and now have interested co-investigators in Israel and Europe but it will take 2-3 more years to gather data.
    In answer to your question :the methimazol can be given together with the Cytomel
    Best regards
    Dr.Hercbergs

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  6. Mike,
    Thanks for posting Dr Hercberg's response, we have been in contact with him but as yet not gone ahead with the treatment. Did Jeremy discontinue Chloroquine while taking Nivo?

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  7. Linda

    We dropped chloroquine not as a result of Nivo, but because there is evidence, or at least it is suspected that part of the action of artemisinin and its analogs is via autophagy. Since Jeremy had progression while on chloroquine it seems like a good idea to drop it and turn to the various artemisinin compounds.

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  8. More from Dr. Hercbergs

    Yes cytotoxic and radiaiton therapy usually work better in the hypothyroxinemic state .I have no insight into the IDH-1 status .Avastin also might work better but reducing blood thyroxine alone may have comparable therapeutic efficacy to Avastin [on edema] based on a small number of such patients. My working hypothesis these years has been that thyroxine depletion positively and favorably affects[down regulates ] many of the genes that support GBM viability. This has in part been confirmed by microarray anaysis using the analog of thyroxine —triac acting via a non-genomic mechanism through the avbeta 3 integrin.
    Regards
    AH

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  9. The majority of patients referenced in the paper were also receiving some other treatment, which is not made clear. My husband did show a strong response to Avastin but not to the hypothyroid protocol. Good to try it because it could work but not sure I would try just that because once these tumors get ahead of treatment, it's hard to get it under control again.

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  10. Michael did you maybe consider clinical trials with checkpoint inhibitors and DC vaccines ?

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  11. Sorry, I missed the question. Jeremy has completed 4 months of Nivo which had no apparent impact on tumor growth. It did however impact glucose levels. At least thats the speculation. After short course of Dex (4 days, then 4 days tapering) his glucose was 636 (non fasting) The assumption was once the Dex cleared his system, BS would return to normal. Weeks later it remains high, typically mid 250's fasting, and mid 400's during the day. His NO believes this is the result of the Nivo. He is now using insulin until his BS returns to normal. As far as DC vaccines, we have no tumor to create one and due to the nature of his tumors (multiple focci and in both hemispheres) he does not qualify for a trial.

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  12. Update on T4 suppression. For those following Jeremys response, labs after the first 4-5 weeks of methimazole, cytomel and Cholestyramine showed a significant reduction in FT4 (baseline was 1.18 and now 0.64 which makes him hypothyroid. TSH has decreased significantly as well (sorry, don't have the labs in front of me so don't recall the specifics). No symptoms of hypothyrodism. Will continue to suppress FT4 to get as close to 0 as possible. We are adding LDN and CBD/THC oil as well as verapamil around the time of CCNU. I was asked why I continue to use the repurposed drugs and in response to my answer Dr. Hercbergs said "I understand the approach to blocking as many signaling pathways as possible— Thyroxine depletion probably gets most of them." Next MRI is in a few weeks. Be interesting to see what is occurring. Might take lower thyroxine levels to start making a difference.

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  13. One other response from D. Hercbergs.
    "There is usually a ‘LAG” period where imaging changes may take 3-6 weeks to become apparent..A drop of > 40 % from the baseline FT4 has been associated with tumor response ,and increase PFS"

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  14. For those following Jeremy response to thyroxine suppression, here is an update. About 5 or so weeks ago his GBM took off like wildfire with enhancing areasshowing up in both sides of the brain, in the pons and elsewhere. Surprisingly steroids have not been necessary. Shortly thereafter he was started on the T4 suppression therapy with methimazole and cytomel. He also started Avastin and CCNU. He has received 3 Avastin infusions and one CCNU dose. His recent thyroid labs show him to be responding well to thyroxine suppression with his FT4 well into the hypothyroid range at 0.64. TSH was low and FT3 was midrange. The goal is to get FT4 as close to 0 as possible. Yesterdays MRI shows resolution of multiple enhancing areas, reduction in others and stability in the pontine enhancement. How much of this is from Avastin/CCNU, or FT4 suppression or the combination is of course unknown. We have been told the Avastin and CCNU should be more effective when FT4 is suppressed so hopefully with the next few Avastin infusions and CCNU (along with verapamil which we are adding for the first time this round of CCNU), we will see an even better response. Will keep you all informed

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  15. Great to hear some good news.

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  16. Jeremy thyroxine suppression update. Jeremy recent had another MRI. He has been on the T4 suppression therapy for a couple months and he is nicely hypothyroid. He is taking 60 mg methimazole and 25 mcg cytomel. His MRI has improved dramatically in most areas. Whether this is due to thyroxine suppression, avastin/ CCNU is anyones guess. Probably the result of the combination. Dr. Hercbergs has told me once the thyroid is suppressed, chemo will be more effective.

    Here is a summery of the MRI report. I left out specifics.

    1) All but one of the multiple enhancing lesions in the brain have significantly reduced in size and enhancement or disappeared. The single enlarging lesion has mild increase in size and enhancement, being located just inferior to the pons.

    I believe there was about 6 enhancing areas.

    Dr. Hercbergs (a radiation oncologist for those that are unfamiliar with him) when presented with Jeremys recent labs and MRI stated "The FT4 is very satisfactory and is reflected in the impressive radiological response in multiple sites.I suggest to keep going with the the current doses of everything [except Questran] In a month or so perhaps the the pons lesions will also show response. The FT4 is down extremely well but may still have more of a downside...I have a patient with a brain stem glioma now over 5 years on methimazole and Cytomel-the FT4 appears to be stable last 2 years at <3.3 [Maccabi Israel lab.

    So not sure what is responsible for the positive changes. We have also started LDN and CBD/THC, but neither has been used long enough (I believe)to be a variable responsible for the improvement.

    I do wish we would have started the thyroxine suppression at first recurrence. One of the tumors has effected the 7 and 8 cranial nerves on the left from the "nuclei to the internal auditory canal area" which has resulted in balance problems and deafness in the left ear.

    We will know more in about 5 weeks when the next MRI is completed, or clinical presentation improves or declines.

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    1. That's terrific news and I hope this improvement is long lasting!

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    2. great news Michael!
      Jeremy is fortunate with you, :)
      God bless!

      Melinda

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  17. Hi Michael,

    So glad to hear the favorable news and thank you very much for the continued sharing of this information with us. I regularly contemplate starting thyroxine suppression myself- Would you happen to know if Dr. Hercbergs is a proponent of initiating thyroxine suppression prior to a first recurrence, or is it just recommended upon recurrence? Also to clarify, is Jeremy still taking Nivo or was that discontinued back in August 2016 after the elevated glucose levels occurred?

    Thanks,
    Mike B.

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  18. Mike

    I do not know what Dr. Hercbergs feelings are regarding use prior to recurrence. He is passionate about the treatment. I suspect he would be for it, but can't speak for him. Based on what he has told me (chemo and radiation are more effective with thyroxine suppression, and tumor growth is altered - slowed, stopped or regression) with thyroxine suppression, I would think the sooner it is started the better. If we had to do it all over again I would give serious consideration to upfront use and at the very least, at the first recurrence. We waited too long for optimum benefit since there had been so much tumor migration prior to starting the treatment. Delaying the treatment may ultimately result in less disease control and a poorer outcome than if we had started much sooner. Nivo has not been resumed since his glucose levels became erratic. He remains on insulin and metformin and another oral diabetic med (can't think of the name)and his glucose remains erratic. Looks like the only thing gained from Nivo was glucose control issues. No indication of benefit. In fact it was two months after starting Nivo that all hell broke loose with multiple foci. Not the fault of Nivo, but just no benefit.

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  19. Jeremy Update. Jeremys 10 year battle came to an end yesterday morning. His passing was for the most part peaceful. His passing is of course heartbreaking. Losing a child is horrible. Losing any loved one is horrible. Jeremy put up a good fight and I could not be more proud of him. He was braver, more determined than I would have been if I was the one with a GBM. He leaves behind his wife and two children, 19 months and 4 1/2 years. When things settle down (that does happen doesn't it?) I will pass along my thoughts on what we might have done differently. Maybe the information will be helpful to you. You have all been extremely helpful and it is an honor being part of this intrepid family. Wishing all of you strength and courage in your fight. By the way, there is one positive to all this and it may sound a little strange, but finally, the tumor within Jeremys brain, the one that surely came from the pits of hell, is now dead.

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    1. Mike, I wish I could offer something more meaningful than, "I'm so sorry."

      You were amazing for Jeremy and an example of someone that would do anything to save a loved one.

      I wish you and your family some peace during this time.

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    2. God rest him in peace!
      I am so sorry, Mike!
      Condoleances, and be strong!
      Melinda

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  20. very strange my business name was posted rather than my name. I wonder how that happened. I no longer seem to have the ability to post as Mike. Strange

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  21. Mike, you were a wonderful father to the end. We all appreciated your detailed entries so you didn't just help your son, you helped us as well. Many thanks and know that we will be saying a prayer for you and yours. He is waiting for you and you will see him when it is your turn to cross over.

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