Saturday, 30 December 2017

Treatment options post-RT/TMZ phase for IDH1 mutated, MGMT unmethylated GBM

Hi all,

I was diagnosed in late September with a GBM (frontal, left, with large cyst, IDH1 mutated, MGMT unmethylated), which was subsequently successfully operated (gross total resection) at the end of September. I guess as many/most here, I eventually stumbled across Ben William's book, the Glioblastoma Treatment options guide and ultimately this invaluable blog and community, which I have been studying and following closely since. I recently concluded the first phase of my treatment, following standard Stupp Protocol (6 weeks concomitant RT/TMZ) and am currently planning next steps (plus waiting for first post-RT MRI next week...).

While I did not get 'smart' in time to save my tumor material from being paraffined post-OP (unbelievably, this is still standard practice here in Germany in most hospitals), I did actively supplement my first phase of treatment with what I think is a reasonably aggressive 'cocktail' approach, including the following components:


- Chloroquine, 1x 250mg
- Celebrex, 2x 200mg
- Disulfiram, 1x 250mg - 500mg (+4mg copper)
- Sativex (THC/CBD spray), ca. 3-4 sprays (approx. 15-20mg)

In general, I tolerated these medications without any major problems or side effects, with a few exceptions. Notably, towards the end of the treatment I developed some peripheral neuropathy in my left foot, which has now almost recovered, however (took around 3-4 weeks to recover). Nevertheless, it cause me to cease the Chloroquine and Disulfiram shortly before the end of my RT treatment phase. In addition, I found it a little hard to tolerate Sativex as I wasn't too keen on the psychoactive effect, which gave me some anxiety / mild panic attacks from time to time at night. As a result, I took it only for around 3 weeks or so.

- Berberine: 1000mg
- Boswellia Serrata: up to 4400mg (gradually increased dosage over course of RT to protect from Edema)
- CBD oil (8%), 5 drops (started after ceasing to take Sativex)
- PSP, 2100mg
- Curcumin (Longvida), 2000mg, increased to 3000mg towards end of treatment
- Green Tea Extract, 3625mg
- Lycopene, 20mg
- Matiake D-Fraction Pro, 65mg (3x 23 drops)
- Melatonin, 20mg
- Omega 3 DHA/EPA, 3528mg
- Probiotics, ca. 40bn units
- Pterstilbene, 250mg
- Resveratrol, 500mg
- Selenium, 200ug
- Silymarin, 1500mg
- Soy extract, 3750mg
- Vitamin D, 9000IU

In general, all of the above were well tolerated without side effects. I'd also like to mention I was able to avoid any kind of Edema / Cortisone use during my RT therapy, which I believe may have been at least in part facilitated by Boswellia in combination with Celebrex.

- Ketogenic diet, max 40 g Carbs per day; generally constant medium to high Ketone bodies when measuring. Started 1 week before RT, and continued to last day
- Caloric restriction, lost ca. 8 kilos in 6.5 weeks of RT, which I think equates approx. 600kcal or so in daily caloric restriction
- Daily morning smoothie, with variety of hopefully beneficial things like berries, broccoli sprouts, spirulina, tumeric powder, Matcha green tea, cocoa powder,  etc.
- Daily walks of ca. 1 hour to combat radiotherapy fatigue and keep fit

Ketogenic diet was somewhat difficult to maintain psychologically, but possible due to my partner's kind help in continuously seeking out new and often tasty dishes to keep things interesting. Caloric restriction much easier, since Temodal anyway caused me lack of appetite. I believe daily walks were very helpful to avoid RT fatigue, which affected me only in very minor way and much less than I expected.



I am currently considering next steps, and having talked to various NOs and other Brain Tumor specialists, I am still not entirely convinced what the right way forward is. As expected, most doctors do not want to deviate from the Stupp Protocol (i.e. follow up the RT/TMZ phase with 6 months of 5/23 TMZ cycles). However, I am not convinced such a treatment would necessarily add much benefit in my case, since my tumor is MGMT unmethylated.

One of the leading specialists in Germany told me that the unmethylated MGMT status is irrelevant in the case of IDH1 mutated tumors like mine, since a study (NOA-4) showed that there was no significant difference in responsiveness  between MGMT methylated or unmethylated IDH1 tumors.

However, upon further research I stumbled across the following interesting study from China, which seems to suggest that IDH1 mutated tumors might in fact be particularly resistant to TMZ (3-10x more resistant in cell culture test). The study also notes that in China they observed relatively little additional benefit of TMZ cycles for the IDH1 mutated group of patients compared to RT alone, and the authors argue that survival benefits for IDH1 mutated tumors may simply be the result of a less invasive / more benign type of tumor relative to wildtype. It makes me wonder if the fact that MGMT doesn't seemingly play as big a role for IDH1 mutated tumors is simply the result of the fact that neither responds well to TMZ...:

I'm therefore a bit hesitant to simply go ahead with TMZ therapy hoping for the best, and would like to consider other options.
One approach I am considering is Immunotherapy at the IOZK clinic in Cologne, which is not far from my house. However, because I don't have frozen tumor material, they would have to make a personalized vaccine using a liquid biopsy approach. This, in turn, could make the treatment even more unproven than vaccines anyway are even when made from tumor lysate. An additional option which could possible materialize down the road (but not yet, as no trials are running here presently to my knowledge) is to try to get hold of an IDH1 vaccine on a compassionate use basis.

My immediate next step is to see the MRI results next week, but I'd be very grateful for any advice on how to proceed from here. Especially, I'd like to try and resolve the following questions:

1. Would it be unwise to not do any additional TMZ cycles? Are there any obvious chemotherapy alternatives perhaps?

2. Would the immunotherapy using liquid biopsy at IOZK clinic be a good alternative for ongoing chemotherapy cycles? Would it be advisable to start this right away (i.e. without any additional TMZ cycles), or should I do some TMZ cycles first just to hedge my bets?

3. Any other recommendations in terms of maintenance strategies. E.g. what medication(s) could make a good maintenance therapy, without concurrent chemotherapy?

Thanks in advance for any comments, and wish you all a very happy and most importantly healthy 2018!



  1. Thinking out loud:
    a) Maybe check into CeTeg trial results, which combined CCNU & TMZ, if you will continue chemo.
    b) We already talked about it on this blog - there is some evidence that IDH1 mutation is immunosuppresive, it might be worth combining IDH1 mutant inhibitor with immunotherapy from IOZK ? Althought entering IDH1mut inhibitor trial probably wouldn't allow that.
    c) Toca 511 had really nice outcomes for IDH1mut. Obviously after surgery, the option would be the intravenous administration. There was a trial opened in France (don't remember the drug's names), *similar* to Toca.

    Though I don't know if experimenting with these trials (before any recurrence happens) excludes you from future trials.

    You have a lot of useful information on which medication should work for specific target / mutation on Google drive (Pharma and non-pharma list and ranking for GBM, Matching drugs to targets). I had Oligo 2 removed and am currently taking immune-boosting supplements, which you are already using (plus metformin and low dose naltrexone with aged garlic extract).
    Everything I have mentioned was talked about on this blog, but I don't have time to dig it up now.

    PS: Happy and healthy new years guys!

    1. Thank you for your comments and suggestions, Matjaz. I've been following the board closely and also studied the Google Drive fairly extensively already. Unfortunately, I don't really think it's realistic for me at this stage to gain access to things like IDH1 mutant inhibitors or the TOCA 511.... I think I will have to make do with a more basic and accessible approach for now. CCNU + TMZ indeed looks promising for MGMT methylated patients - however, since I am not methylated, I don't really want to particularly place my bets on an intensified chemotherapy. I'd pursue it without doubt if I was MGMT methylated though.

    2. Hi Matjaz/John,

      My mother was diagnosed with GBM in late September too. She is IDH1 -ve and methylated. She is going through her 5/23 temodar cycles. I've read quite a bit about the CCNU+Temozolomide combination, but have still not been able to find any 'oncologist' who can prescribe me with this chemotherapy regime. Would be great if you can help me out with an oncologist who can help me here.

    3. our doctors in Russia also knew nothing about the CeTeg trial, until I showed them a printout of the study.
      then only they agreed to appoint this protocol.

    4. Hello Sahil,

      where are you being treated? Maybe someone from your country will see your message here and can suggest a good oncologist. As Semyon said, try printing out the CeTeg study and trial results and show them to your NO. It seems that it will take some time for TMZ+CCNU to become new standard of care.

    5. Hi Matjaz,

      My mom is being treated in India, and no oncolgist has a clue about TMZ+CCNU protocol.

      The research paper that you're talking about talks of a TMZ+CCNU combination while on radiotherapy. I've shared the link above.

      However, my mom has already completed her radiotherapy and her first 5/23 temozolomide cycle. I read somewhere about the 5/42 temolzomide+ccnu cycles for methylated cancers, but haven't found any research/oncolgist to help me out with such cycles. Would be great if you could help here.


      Unfortunately I don't have any other material on CeTeg, besides what you posted and what Stephen posted in his SNO summary. There are Stephen's photos of presentation slides on Google Drive, maybe that could help.

      "Phase III trial of CCNU/temozolomide (TMZ) combination therapy vs. standard TMZ therapy for newly diagnosed MGMT-methylated glioblastoma patients: the CeTeG/NOA-09 trial presented by Ulrich Herrlinger for the Neurooncology Working Group (NOA) of the German Cancer Society."...maybe try contacting Ulrich Herrlinger, probably he can help the most.

    7. Thanks Matjaz! Yes, I'll get in touch with Ulrich Herrlinger :)

  2. Hi John,
    My husband is IDH wildtype and unmethylated. He only did 2 adjuvant cycles of TMZ and we decided to stop because he was having extreme dizziness and fatigue. He did great for the 2 months after he stopped but then had recurrence and symptoms at the 8 month mark. From the beginning he took most of the supplements and meds that you are taking. He stopped chloroquine early on as we think he was having hallucinations and he also took Metformin for 9 months but stopped because of nausea. He has been taking cannabis oil, anywhere from 10-70 mg of thc a day and varying amounts of cbd, from the beginning as well. The most promising chemo for unmethylated tumors is Val-083 and we did travel to Houston to check out the trial but we cannot wait the 2-3 weeks for the re-test of his methylation status and so by default he did start on CCNU which will disqualify him from the trial. There is an option of getting Val-083 with expanded access and we have asked our NO to start the process. Good luck. Dianne

  3. RE: "One of the leading specialists in Germany told me that the unmethylated MGMT status is irrelevant in the case of IDH1 mutated tumors like mine, since a study (NOA-4) showed that there was no significant difference in responsiveness between MGMT methylated or unmethylated IDH1 tumors."

    If we look at this paper:
    it shows in Table 2, for IDH1 mutant anaplastic gliomas, median PFS with chemotherapy alone (PCV or TMZ) was 44.7 months in the MGMT methylated group (n=47) versus 28.1 months in the MGMT unmethylated group (n=15).

    Then in the Supplementary Table 2 of this paper:
    it shows that in the IDH mutant group treated with chemotherapy (PCV or TMZ), median PFS was 3.63 years in the MGMT methylated group and 1.51 years in the MGMT unmethylated group. This difference did not reach statistical significance (p value 0.624). However the lack of statistical significance could be due to the fact that there were so few IDH mutant patients who were also MGMT unmethylated. Median PFS with chemotherapy for IDH-mutant MGMT methylated tumors was 1-2 years longer than for those IDH-mutant MGMT unmethylated tumors.

    Personally I would not forego TMZ treatment on the basis of your tumor being MGMT unmethylated, because tumors can have very heterogenous MGMT methylation status: some parts of the tumor can show high methylation and other parts of the same tumor can be unmethylated for MGMT. MGMT methylation status can be complicated and is not so simple as a binary 0/1, either/or.

  4. RE: "The study also notes that in China they observed relatively little additional benefit of TMZ cycles for the IDH1 mutated group of patients compared to RT alone, and the authors argue that survival benefits for IDH1 mutated tumors may simply be the result of a less invasive / more benign type of tumor relative to wildtype."

    Similarly to my previous comment, if you look at figure 3B of the Yang et al. study, the survival curve for the IDH1 mutant patients is superior with combined RT+TMZ versus RT alone after the 2 year mark. The lack of statistical significance (p=0.22) is probably due to the low numbers of IDHmut patients treated with RT alone in this study (around 5). You would need a lot more than 5 patients to make any kind of valid comparison.

    Despite the cell culture study included in this paper, IDHmut tumors are not particularly resistant to TMZ. Cell culture studies that express a mutant form of IDH1 on top of genetic background of primary GBM (in this case the U87 cell line) don't reflect the real situation very well.

    I review literature showing increased response to combined RT + TMZ in IDH1-mutant GBM versus IDH1 wild type.

    In the same article I review studies showing increased response to TMZ treatment in IDH1 mutant grade 2 astrocytomas versus IDH1 wild-type.

  5. "1. Would it be unwise to not do any additional TMZ cycles? Are there any obvious chemotherapy alternatives perhaps?"

    As I mentioned above, the unmethylated MGMT status does not necessarily mean TMZ won't be effective, as the tumor may have heterogenous MGMT status, and some parts of the tumor may have low levels of MGMT experession.

    VAL-083 could also be a good chemotherapy alternative for MGMT unmethylated tumors, and is available in an expanded access protocol, at least in the US. It just received fast track designation in the US for recurrent GBM.

    Combining TMZ with a PARP inhibitor like olaparib could also over-ride MGMT, because it could sensitize the cells to TMZ-induced lesions other than the O6 lesion that is repaired by MGMT. This combination (TMZ + PARP inhibitor) would likely increase the toxicity of TMZ to bone marrow/healthy blood as a side effect.

    "2. Would the immunotherapy using liquid biopsy at IOZK clinic be a good alternative for ongoing chemotherapy cycles? Would it be advisable to start this right away (i.e. without any additional TMZ cycles), or should I do some TMZ cycles first just to hedge my bets?"

    Unfortunately there is little data showing efficacy of immune therapies specifically for newly diagnosed IDH1-mutant gliomas. There is some evidence showing an immunosuppressive effect of the 2-hydroxyglutarate produced by these tumors, which may render immune therapy less effective. Some form of hedging your bets is advisable, but that doesn't necessarily mean chemo must come first.

    "3. Any other recommendations in terms of maintenance strategies. E.g. what medication(s) could make a good maintenance therapy, without concurrent chemotherapy?"

    Borrowing from Ben Williams' playbook (his tumor was also IDH1-mutant), you could consider isotretinoin (Accutane). I believe this is also being used at IOZK as a means of reversing the immunosuppressive effects of myeloid-derived suppressor cells. It could additionally have direct differentiating effects on the tumor cells. I think of this drug as a maintenance therapy not to use concurrently with chemotherapy, given that at least one clinical trial showed worse survival with Accutane + TMZ versus TMZ alone.
    I suspect it may be interfering with the chemo by causing fewer cells to be in the active stages of cell division at the time chemotherapy is applied.

  6. Hi John,

    I was thinking about your anxiety/panic with the Sativex (THC/CBD spray). I don't know much about this particular spray, however I learned that in the THC there are two parts: Indica and Sativa. If you get straight THC/Indica, then you can get the sedative psychoactive (great for sleep). With the THC/Sativa, some people feel more pep or anxious with the psycoactive. Thus, these symptoms can occur if the THC has both strains. However, it also comes separate (just Indica or just Sativa). As for the CBD part you can get that separated out too and take only during the day. Just a thought. My husband, has found it helpful to separate the THC(with Indika) for sleep at night which is working very well and we are now going to try out the CBD (for day use) and see how that goes.

    If someone out there understands this better than me, then please chime in!

    By the way, Impressed by ALL you are doing for yourself!

    Blessings and Healing to You!


    1. For the sake of clarity, indica and sativa are two strains of the cannabis plant. THC is THC. Any difference in the effects of these two strains would be the result of different mixes or ratios of cannabinoids (including THC) and other active ingredients of the cannabis plant, rather than there being two different kinds of THC.

      Thanks for your comment though, it's important to realize that different strains of cannabis will have different psychological effects.

  7. Thanks a lot for all the comments and tips, which were extremely helpful. I've been rushing from medical appointment to medical appointment, and didn't have a chance to respond earlier. In the meantime I've also had my first post-concurrent RT/TMZ treatment MRI, which showed a little bit of contrast enhancement in the radiated area (but thankfully no contrast in any other areas of the brain). My NO is cautiously optimistic, but I will have to wait more time to confirm if it's a pseudo progression, so will have to be patient...

    I've also had a lot of discussions on the various treatment options (again, the views and ideas expressed here were helpful in asking the right questions, so thanks!), and after a lot of back and forth I've decided to probably (final confirmation next week) start with an immunotherapy. I figured it would be better to do this sooner rather than later, given the likely effect the chemotherapy would have on my immune system. I also thought that to optimize each approach (immune vs chemo), e.g. with the right off-label meds, supplements, dietary interventions etc., would ultimately lead to quite different strategies, meaning it's probably easier and more effective to focus on one giving it full attention. However, it probably does make sense to hedge bets a bit and I may later on do TMZ still, depending how things go.

    I'm therefore now reading up on immune support strategies, like low-dose TMZ, low-dose Naltrexone, Celebrex, fasting / caloric restriction etc. Thankfully the Astrocytoma Options page has quite a bit of material on it.

    Thanks a lot again, all!


  8. It is indeed so that the IDH mutated GBM tumors are more "immune cold" as compared eg to the mesenchymal GBM tumors. Indeed more inherent immunosuppressive mechanisms are playing a role, as Stephen mentioned. That is why for these tumors, a real INDUCTION of an antitumoral immune response is the issue, while in the mesenchymal it is more a matter of boosting up a potential inherent but failing immune response. In the INDUCTION of the antitumoral immune response, one can try to use an indirect mechanims over oncolytic virus therapy.

    1. Thank you. Also of interest is this recent paper:
      Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma.

      The IDH1 status of most of these samples was unknown, but the authors discuss how adding an IDH1 R132H peptide to this peptide cocktail would be reasonable in this lower grade glioma population.

    2. Thanks a lot. I wonder how easy it would be to access such an IDH1 R132H peptide, outside of clinical trials (as are being currently run in Mannheim, Heidelberg, etc.).

  9. Isn't there also something about tumor escape in above article? And to theoretically prevent that, one should use multiple peptide vaccine, not just IDH1. John, you're going to IOZK? Maybe ask about adding IDH1 peptide to the mix. Some time ago I saw there was a community about home made peptide vaccines for cancer, they practically just ordered peptides from pharma companies (example: So if normal people can get that stuff, probably IOZK can too. Just wondering..

    1. Thanks, Matjaz! I will look into it, though I'm not so sure about a DIY version ;)

    2. One of the authors of the DIY guide is a friend of mine. I can put you in touch with him if you're interested.

    3. I was not promoting or advertising DIY version! I was just saying that if normal person can acquire access to these peptides (eg. IDH1), probably an institution like IOZK can too.

    4. Thanks, Stephen and Matjaz. It could definitely be a good option to look into, but probably not immediately now as part of the treatment at IOZK. Maybe something to consider afterwards as a further treatment complement. I actually met one of the researchers in Germany who was involved in the recent & ongoing IDH1 peptide trials, and it sounded like a promising treatment angle.

    5. From my understanding, it is usually better to target as many pathways as possible to try to prevent tumor escape (hence cocktail approaches). Probably wouldn't hurt to ask Van Gool at IOZK what he thinks about adding IDH1 peptide to the mix.
      Anyway, I wish you good luck with treatment. Please keep us updated :)

    6. Thanks, Matjaz! I'll check in for an update in due course for sure. Getting my first round of vaccination tomorrow.