Saturday, 29 July 2017

GBM treatment options with a moderate budget

My 29 years old husband was diagnosed on 3/26 with a multifocal, thalamic GBM. We are from Hungary. He has undergone surgery on the 5th of April. 80% of the walnut-sized tumor was resected from his thalamus. His other, frontomediobasal tumor seems to be inactive (although it's pretty big, too) so the surgeon didn't resect it and it didn't received radiation either. He has completed SOC and currently is on his first cycle of 5/23 TMZ monotherapy. He has no EGFR amplification. His tumor is IDH negative and indeed very aggressive. Only 3 weeks after surgery he was hospitalized because of edema which was caused by tumor regrowth. So now he has quite a few smaller tumors around his thalamus besides the remaining 20% piece. 

His first post-radiation MR is scheduled for the middle of August. Since I've not yet received the information regarding his MGMT methylation status (long story) I'm constantly worrying and seeking for opportunities in case of tumor progression since in my country there's no protocol for recurrent glioblastoma other than Avastin. I mean no PCV or other chemos, no immunotherapy, no clinical trials, no Optune device (I requested an offer from Germany and it turns out that it costs 30 000 € /months and you need a technical and medical support at home).

I'm aware that we need to manage our finances cleverly in this situation. If you had up to 20,000-30,000 USD which option or options would you go for?

- Immunotherapy in Germany (It seems to me that only Nesselhut Clinic fits into our budget but reviews are not so convincing as nothing in the world of GBM.) 

- Keytruda / Opdivo immunotherapy + TMZ 
In Hungary it's not part of the protocol but hopefully we can find a doctor who will prescribe it at our own expense. As I can see Opdivo has kind of failed; is Keytruda. better? Do we need PD-L1 testing to get it?

- We have gamma knife in Hungary and it can be paid through National Insurance (so patients who qualify don't need to pay for it) but doctors are reluctant to let GBM patients to choose this option. It's usually used for small and simple tumors and for brain metastases. If our NO will advise against it or will be not so eager to help maybe I can search for other European gamma knife possibilities although I can't find too many comments on gamma knife and GBM.

- Neuroblate Laser Ablation. As far as I know it's exactly for problematic tumors, like thalamic ones. I'm planning to send them an inquiry but I have concerns about whether it is an adequate alternative to surgery for inoperable tumors. Can it prolong life or is it just a palliative treatment? How much would be the estimated cost? Has anybody personal experiences with it? Is laser ablation superior to gamma knife? 

Our NO said my husband's thalamic tumor is no accessible for surgery anymore and considering his bad reaction to the first surgery maybe laser ablation or gamma knife wouldn't be the best option for him. What are your thoughts on it? 

- SPMF treatment in India. It's quite cheap but no statistics are available and it's so hard to believe for me that the same effect is achievable with 1-2 hours of treatment for 28 days as with the Optune cap which you need to wear almost all day long up until it works. I've read about a young patient with thalamic tumor on Inspire who had Optune and it didn't do any good for him because of the location. I suppose that the same applies for SPMF, too. 

- I sent an inquiry to Duke's polio virus trial.
My clinical trial applications have been ignored from all over the world so I was tricky enough to mention that "I'm aware that non-U.S. citizens should cover their costs on their own in case of qualifying for a clinical trial and I hope I can manage it with the help of my family. "
I got this answer from doctor Friedman personally "We would not have a trial for you at this time since the surgery was so long ago and the tumor is not growing If it ever does regrow please let us know"

Maybe it was just a polite "no" or maybe this possibility is truly open for us in case of a recurrence but the truth is that I have no idea how much a treatment like this could cost in one of the world's best institutions for cancer. Anybody has any idea about their fees?

- Ask the Brazilian doctor to come to Hungary and teach us to administer Perillyl Alcohol. I've read that the brave persons who tried to make it themselves found it unbearable to use.

Any and all help is very much appreciated. Thank you in advance and sorry for my grammar mistakes.


  1. Ildi,
    I did not see this post until now (after I answered the second one). I didn't realize it is a thalamic glioma. In this case, the most likely genetic mutation is an H3 K27M mutation (the name of the gene is H3F3A, which encodes the histone 3.3 and the mutation is K27M). Please see other posts and discussion on this blog under the labels "ONC201" and "H3K27M_mutation".

    See also my article "Genetic Overview of Brainstem and Thalamic Gliomas" under "Adult Thalamic Gliomas". 8 out of 10 adult thalamic gliomas had the H3 K27M mutation.

    If there is tumor tissue available, it would be a good idea to confirm if the tumor cells have this mutation or not. It is possible to determine the H3 K27M mutation by immunohistochemistry using an antibody on preserved tumor tissue.

    There is reason to believe the new drug ONC201 may be effective for this tumor type. There's an expanded access study to get access to this drug, but you'd have to confirm whether the tumor has the mutation first.

    1. Wow, this is excellent news! I actually read the post here about ONC201 but I didn't realize that this was applicable to thalamic gliomas, too. We'll definitely give it a try. Many thanks, Stephen!

  2. I'm surprised Friedman did not just tell you "no" since the Poliovirus trials and some of the other interesting trials at Duke do not allow multifocal tumors.

    It's probably worth reaching out to the Gamma Knife clinic and centers using NeuroBlate directly to get their opinion on its suitability in your husband's case. Cleveland Clinic is the most prominent center using NeuroBlate in the USA. Gamma knife is generally used for small tumors under 4 cm diameter.

    When considering vaccines it's important to know how much tumor tissue is still available and in what condition? If there is no tissue preserved suitably to make a lysate-pulsed dendritic cell vaccine, it could still be possible to create a synthetic peptide vaccine based on the mutations discovered in the tumor cells by genetic sequencing.

    I've never been that excited about PD-1 or other checkpoint inhibitors as standalone therapies. They will likely be more useful when combined with vaccines or other therapies that arouse an effective immune response. Think of the effective immune response as being a fire, and PD-1/PD-L1 being like the rain that wants to extinguish the fire, and PD-1 inhibitors being like the roof placed over the fire to keep the rain off. If there is no fire to begin with, the roof will not help.

    1. Hi Stephen,

      in the exclusion criteria they refer to "actively growing multi-focal tumor". I wrote dr. Friedman that according to his neuro-oncologist the frontomediobasal tumor isn't actively growing and isn't going to cause issues in the near future and it seems to be a low grade glioma. We'll see in August...

      Actually I don't understand it; if it's multifocal then how could the thalamic one be a grade IV and how could the other one be a low grade tumor but that's exactly what he said. So maybe that's why he didn't say no directly.

      We have no frozen tissue so this is another reason why Nesselhut Clinic might be our only choice. (besides the budget limits)

      Thank you for shedding some light on checkpoint inhibitors, it's more clear now.

  3. IOZK can create DC vaccines for thalamic glioma without tumor tissue, as they can load the DCs with Newcastle Disease Virus + modulated electrohyperthermia - induced serum-derived antigenic microparticles.

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  5. Oh my gosh, according to this study, a Neuroblate surgery costs $91,356 so this is totally out of our reach.

  6. Hi Stephen, I'd like to share with you a little update on my husband's situation. We had our first post-radiation MRI (3 weeks after completing the first 5/23 TMZ cycle) on Monday and we'll see our NO on next Monday to evaluate the results.

    We got the analysis of the scans written in medical hieroglyphics but I can clearly see that it mentions a new enhancement with extensive perifocal edema, a new spot with non-enhancing "malignant" signaling, moderate increase of the necrotic tissues at the thalamic residual tumor and the frontomediobasal tumor also became active (increased signaling). I'm sorry that I haven't mastered the terminology yet.

    He is on 16 mg Medrol (equal to 3 mg dex as you mentioned) which we naively halved 5 days before the MRI, plus metformin since May, plus Celebrex since a month (which are considered to have anti-edema properties, too) so I'm quite shocked about the news. He was very sleepy in the 6-7 weeks following RT but for the past few days he has been really well again physically and mentally, just like before diagnosis and now THIS....

    After the seemingly devastating news I've just got the pathology report that says that my husband is MGMT negative, that is hypermethylated. What does it mean exactly? So is he simply MGMT methylated or is it something even better? As far as I know, in case of a hypermethylation even radiation therapy should have been more efficient on his tumor but I don't really see the results of it...

    Should we continue on with taking fluoxetine if he is methylated? Can it cause MGMT demethylation like disulfiram in theory? Is there any chance that his tumor had been MGMT methylated at the time of the resection (5th of April) and now it isn't anymore?

    It turns out that he has no H3K27M mutation so ONC201 is not an option for him although it was my favorite plan B.

    He has 5% positivity to PD-L1. Can you tell me what this means when it comes to applying for a checkpoint inhibitor therapy?

    Thank you for your help, this is simply priceless.

  7. Hi Ildi, I'm sorry you have received such seemingly bad news. It's odd that his clinical state doesn't match with the radiology findings, as you say he's feeling well again like before diagnosis. Probably best not to draw too many conclusions until speaking with the NO. Are his doctors aware of the change in the Medrol dose 5 days before MRI?

    What exactly is the phrasing of the MGMT results? "MGMT negative" is meaningless unless we know what kind of testing was being done. "Hypermethylated" in this context means the same as methylated. Methylated/unmethylated are relative terms. MGMT is an enzyme that removes alkyl groups from the O6 position of guanine within DNA. As such, it removes the methyl groups from O6 following temozolomide treatment, or the chloroethyl groups following nitrosourea treamtent (for example, CCNU, BCNU etc.). There may be some kind of association between MGMT status and radiation response, but there would be no direct causal link, because radiation is not an alkylating agent (it does not cause the kind of damage that is fixable by MGMT).

    Before I discuss fluoxetine and disulfiram I'd like to clarify that the DNA methylation caused by temozolomide, at specific locations leading to DNA damage, is a completely different process from the methylation of gene promoters that leads to silencing of gene expression. This can be confusing because we use the term "methylation" for both of these processes.

    As far as I'm aware, fluoxetine doesn't have DNA demethylating effects.

    As for disulfiram, there was a clinical trial studying it as a DNA demethylating agent for prostate cancer. However only "a minority of patients had transient global PBMC [peripheral blood mononuclear cell] demethylation changes". So it a rather weak demethylating agent, and I've never seen it linked to decreased MGMT methylation specifically, or increased MGMT gene expression.

    In my view, disulfiram as an inhibitor of MGMT protein levels/activity, as seen in mouse studies, is more persuasive than its role as a demethylating agent, which is purely hypothetical when it comes to MGMT specifically.

    The influence of fluoxetine on MGMT expression is only one possible mechanism. There have been other studies showing therapeutic effects (in mice bearing xenografted brain tumors) by completely different mechanisms.

    Some tumors can have variable methylation status for MGMT. It's possible to have strong MGMT methylation in one part of the tumor, and little methylation in other parts of the tumor, so the result of testing can be influenced by which part of the tumor the sample was taken from. This isn't true for all tumors, as some have more homogenous MGMT methylation status. It's possible that treatment with TMZ could selectively deplete the parts of a tumor with higher MGMT methylation/less MGMT enzyme activity, leaving more cells behind with less MGMT methylation/more MGMT enzyme activity. But this probably wouldn't happen spontaneously.

    Was the K27M testing done by DNA sequencing, or by immunohistochemistry (IHC)? If his tumor doesn't carry this mutation, that can be seen as a good thing, since that type of tumor is typically quite aggressive. Was any more testing carried out to try to identify the driver genetic alterations? I'm not aware of what kind of testing is available in Hungary.

    1. Hello Stephen, I can't thank you enough for your detailed explanations, it is such a great help.

      Oh, somehow I thought that hypermethylation means something excessive, like 100% methylation.

      The thing is that we worked with a molecular diagnostic company who made the sequencing of 600 genes of which they identified only one as a driver: SETD2-K1711 (in 37% of the genes). Their analysis was pretty pricey and the information they provided didn't seem very valuable. So I contacted the pathologist lady that was making the original pathology report which was ordered by the doctor right after surgery and this very nice and helpful lady made for us 3 additional tests that I asked for. (MGMT, PD-L1, H3K27M). I think the testing was done by immunohistochemistry. Since it was a kind gesture I didn't want to bombard her with further questions after our long correspondence since May. So I don't know if he has a low or high methylation.

      The NO said that he has a very aggressive tumor (it was actively growing only 3 weeks after surgery) but now that we know that he is methylated he can't be H3 mutant at the same time so I think the tests have been done properly for sure.

      Now the private company wants to do some additional testing for us: MSI, PIK3CA, MET, ROS1 FISH. Based on your knowledge are these relevant tests? I simply don't trust this company and I've been wanting to get rid of them since months but they pushing me with sugar-coated messages that they don't give up on my husband...

      Based on these studies these tests seem to me to be pretty irrelevant:
      (PIK3CA mutations were identified in 17% of adult samples -> there was an 80% chance that he would have H3K27M mutation but he did not... I also haven't been able to find any drug targeting this mutation.)
      MSI - I can't find any matching drug in case of MSI. With regard to MET at least there's a drug called crizotinib but it's 8632 USD, I think there are several more proven drugs than that.

      Please advise, do we really need these tests?

      Thank you and I'll let you know how the appointment went with the NO.

    2. I'd be interested to see the report from the diagnostics company if you have it. If they tested 600 genes it's a mystery why PIK3CA wasn't included in the original testing.

      Did the report from this company identify other mutations besides the one in SETD2? I'm more familiar with FoundationOne reports where "variants of unknown significance" are included in the appendix. SETD2 depletion can cause microsatellite instability (MSI) and increased mutation load, but I would expect this to be reflected in the number of mutations observed in the 600 genes sequenced. So it's important to determine how many total mutations were observed in those 600 genes, not just the ones with known significance or "driver" status. If there was an elevated number of mutations, that could translate to increased responsiveness to PD-1/PD-L1 antibodies.

      The SETD2 mutation is an interesting finding and could guide therapeutic strategies:

      Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

      If ineligible for these trials he could potentially apply for access to the drug on Compassionate Use protocol.

  8. I'm not sure what 5% PD-L1 positivity means in terms of response to PD-1/PD-L1 antibody therapy, but according to one study that would put him at about the 62nd percentile for PD-L1 expression, as only 38% of tumors had PD-L1 expression of 5% or greater. Median expression of PD-L1 in GBMs when measured by immunohistochemistry was only 2.77%. On the other end of the scale, about 5% of GBMs had 50% or greater positivity for PD-L1.

    I've not yet seen studies identifying a % of PD-L1 expression that is predictive for response to anti PD-1/PD-L1 therapy.

    I hope that answers your questions. Let us know what the NO has to say about the scan results.