Tuesday, 16 June 2020

Quite urgently seeking Suggestions

Hi Everyone,

I have been a long-time reader of this amazing blog that Stephen created and regularly check it for any posts about new treatments or therapies. I am really happy to see that Stephen still occasionally posts new studies and answers some questions. 

I am quite urgently seeking advice on next steps in relation to treatment for my partner (of 18 years), who is a very physically active person and despite everything that has occurred, remains very positive. She is 40 years old.


We are based in Australia and she was diagnosed in December 2011 (2 days before Christmas!) with a low grade Astrocytoma in the left Temporal Lobe. 

2012 (February): She underwent craniotomy that resulted in a subtotal resection – it was an awake craniotomy owing to the tumour’s location near important speech areas.
Histopathology of the sample was unfortunately not very detailed and only confirmed a Low Grade Astrocytoma with a very low KI67 of < 1%

2015 (February): The lesion increased in size over the years (pretty much doubled) to 55 x 34 x 49mm – so a second surgery was performed that again resulted in subtotal resection.

Histopathology results showed – Low Grade Astrocytoma, IDH1 Mutated.
A retrospective FoundationOne profile was obtained on this sample in 2017 and only showed 2 mutations: IDH1 (R132H) mutated and TP53 (R175H).

2017 (September): The tumour continued to grow and extended into the frontotemporal region and insula. Another Surgery was conducted in two sessions due to expected length, and a large portion of tumour from the temporal and frontotemporal regions was removed, as well as a small portion from the insula.
Histopathology results showed – IDH1, 1p/19q co-deletion, ATRX lost, TP53 Mutated, KI67 of 2%

A Caris profile was also obtained which also showed that the tumour was not MGMT methylated – although after asking Stephen about this at the time, he said that MGMT was a bit of a hit and miss due to the heterogeneity found in tumours – so we remained hopeful that MGMT may still be methylated in most of the tumour given it is typical of low grade gliomas.
* The Caris report conflicted with the histopathology and showed ATRX intact.

2018 (January): Managed to get Bayer to sponsor my partner to take part in their IDH1 Inhibitor trial (BAY1436032), went to L.A and got knocked down at the last minute due to not completely satisfying their RANO requirements!
(September) Sought out the top neurooncologist + radio oncologist team in Sydney and she started IMRT then moved on to a round of TMZ which finished in early 2019.

2019 : MRI’s showed decent shrinkage in the tumour volume for the first 6 months then stable.

2020 (January) : MRI showed slight enhancement in the original temporal lobe resection cavity + strangely an enhancing nodule on the right ventricle. These were determined by the neuro and radio oncologists to be late radiation treatment effect and thought that they would resolve.

(Late February) MRI showed the enhancing nodule in right ventricle shrinking a bit, but enhancing area in temporal lobe cavity growing a bit. Still determined to be late treatment effect.

(June) : MRI – ALL HELL HAS BROKEN LOOSE. There are now another 3 large enhancing lesions – one in the right Frontal lobe, with a small one behind it, one in the Left ventricle (looks like a cherry sitting on the ventricle wall) and a much larger enhancement of in the original temporal resection cavity.

Needle Biopsy – a needle biopsy has just (yesterday) been performed on the right frontal lesion to get a better understanding of the makeup of the new lesions. We are currently awaiting the results and will also hopefully be getting a Caris or FoundationOne genetic testing on the sample.

The surgeon mentioned that he could already see an increase in size since her last last (less that 1 week prior). So this is a very fast growing tumour/s.

Proposed Initial Treatment

Her neuro-oncologist and radio-oncologist have suggested that she begin (as soon as possible) with CCNU + Procarbazine – and possibly Avastin for the swelling.

 Current Medications (all anti-epileptics):

- Epilim (Sodium valproate)
- Fycompa (Perampanel)
- Lamictal (Lamotrigine)
- Briviact (Brivaracetam)
- Frisium (Clobazam)


I would be extremely grateful if anyone can:

- provide their thoughts on the proposed treatment
- make any other treatment suggestions
- suggest anything that could possibly increase the effectiveness of the   
   suggested treatment
- point out any pitfalls or things to be aware/weary of whilst on the treatment
- suggest any promising potential trials or treatments anywhere in the world
- suggest any cokctails that they have used with this treatment that have 
  resulted in better outcomes + better tolerability

The rapid change from a fairly stable low grade astrocytoma really did catch us (and her doctors) off-guard and I would be very appreciative of any advice or suggestions that anyone could kindly offer.

Thanks to you all.

New Note:

Just today my partner was told that she has extremely low levels of Vitamin D. Strangely enough, she has been really craving oily fish for the last 3 months and has been eating smoked trout and smoked salmon almost daily - obviously not enough to build up sufficient levels. The 3 month craving of Vitamin D strangely coincided with the new lesions showing up and their extremely fast growth.

I wonder if dramatically increasing her Vitamin D level may slow the progression? She has started taking 4000 IU and intends to keep it up every day.

Can anyone comment on this level of Vitamin D, would you up it even further? And are there any caveats with regards to Vitamin D supplementation.

Also, it there a particular way to rapidly raise the levels in the blood?


  1. Stephen put together a website http://astrocytomaoptions.com/radiation/ Have you checked it out? Stephen left useful links in this blog on one of the tabs. For drug interactions enter your partners list into drugs.com interaction checker. Obviously avoid major drug interactions if possible. I am not familar with all of the drugs you mention. As for treatment options my dad has a GBM and i put up his cocktail list on this blog back in January. His main treatment currently is avastin and TMZ. He combines this with a cocktail which you can check out in my post.

  2. The main page to Stephens website is http://astrocytomaoptions.com/ My post in January "good news tumor shrinkage..." has links also which i found useful.

  3. Hi Ryan, I'm sorry to hear that the situation has taken a turn for the worse. When you say she did a "round" of TMZ, do you mean a single 5 day course, or multiple courses (6 or more)? If she did multiple monthly courses of TMZ in 2018, there is a possibility that the new rapid growth you're seeing is a hypermutated secondary GBM. FoundationOne I believe now routinely tests for mutational burden (TMB) which will tell you if the tumor is hypermutated or not, and Caris also tests for this if requested.

    It is important to know if the new tumor growth is hypermutated (caused by DNA mismatch repair defects often due to mutations in mismatch repair genes such as MLH1, MSH6, MSH2, and PMS2). If hypermutated, further TMZ will not likely be effective and could be counterproductive, while CCNU is what I would advise in this situation. I would not advise procarbazine for a mismatch repair defective tumor, hypermutated glioma - its mechanism is very similar to TMZ and lab studies from the late 1990s showed that mismatch repair defective glioma cells were resistant to methylating agents such as TMZ and procarbazine, but had heightened sensitivity to agents like CCNU and BCNU.

    In the absence of knowledge on hypermutation status, my choice would be to proceed with CCNU (lomustine) chemotherapy. This is based both on theory as well as seeing my friend's response to CCNU for her hypermutated (prior TMZ treated) secondary GBM. She was treated with 5 cycles of CCNU in 2018, and is now on round three of CCNU for her second recurrence. We are currently seeing tumor shrinkage on CCNU, even though her tumor was treated with it a couple years ago. There was also a more recent study showing CCNU as effective in these types of tumors.

    Avastin may or may not be helpful. My friend was treated with both Avastin and CCNU in 2018, and we suspected the CCNU was helping more than the Avastin. She was not even able to reduce her dose of dexamethasone even on Avastin. But you could try Avastin for one or two cycles and see if it helps with swelling/edema. I would consider CCNU to be the main part of her therapy at this point, and especially if the tumor pathology reports show it to be a hypermutated, mismatch repair defective recurrence.

    I can't speak for Australians, but I know here in Canada most people can tolerate 10,000 IU daily of vitamin D3 quite safely. This is the dose my friend has been taking.

    There was a small study done a number of years ago using alfacalcidol as a treatment for GBM. But this is a prescription drug so you would need to speak to a doctor about this, and it would likely increase active vitamin D levels in the blood, and could potentially act as a differentiating agent on the tumor cells.

    A caveat to this is that another trial showed 13-cis retinoic acid (Accutane) counterproductive when combined with temozolomide). There is no proven explanation for this but one possible explanation is that the Accutane (a differentiating agent) caused more cells to be in a non-dividing state and so reduced the percentage of cells sensitive to the chemo. So you could aim to get her vitamin D levels back into the normal range. And then a more intensive cell differentiating strategy (alfacalcidol and/or Accutane) could be used as a maintenance therapy when chemotherapy is completed.

  4. Here is a sci-hub link to the recent major Nature paper on hypermutated gliomas, which also discusses CCNU sensitivity.

  5. Hi Stephen and Rhubarb,
    Thank you both very much for replying to my post.

    It really was both very informative and also a warm blanket in terms of know that both your respective friend and father are doing well on their treatments – I really hope for both of you that that carries on well into the future.

    Rhubarb, I did actually check out Stephen’s Astrocytomaoptions Radiation page – she actually did 6 weeks of radiation just before the chemo. It is unfortunately she couldn’t be on Keppra whilst on radiation as a radiosensitiser as she had a petty bad reaction to Keppra in the past. I was hoping that since she was on Briviact (Brivaracetam - and analog of Keppra) that it may help, but couldn’t find any information in that regard.

    That is also a good point to keep an eye on the drug interactions (drugs.com), particularly when heading onto chemo. I have also read through your dad’s cocktail on the link that you provided and will begin putting together a cocktail over the next few days and trying to source everything. Thanks for sharing that. It really does sound like you have a great healthcare system over there in Ireland – my partner actually holds an EU passport too, so hopefully could access in existing or future trials in the EU – currently AU does not have any relevant trials by the looks of it.

    Stephen, with regards to your question about the TMZ that my partner received – sorry that I was not very clear on that. What I meant by a round was what I thought was a standard course of TMZ, so she received 6 months of 5 days on TMZ and 23 days off, per month.

    We visited my partners neuro-oncologist today and she found your suggestions very interesting an is in agreement with regards to dropping the Procarbazine, but would like to try at least a few rounds of the Avastin at least at first to see if she gets any benefit out of it.

    I was wondering – and asked her during the meeting – about whether there was perhaps a conflict between using Avastin, which (to my limited knowledge of it) restricts blood vessel growth, and the need to deliver the CCNU to the tumour – i.e. restricting the very thing that you need to the CCNU to the tumour. The oncologist said that it is not entirely clear exactly how Avastin worked but that it may actually increase the blood flow in existing blood vessels. I wonder if you have any thoughts on this?

    Thank you also for all the information regarding the TMZ induced hypermutation. I definitely plan on trying to get the Caris testing done on the sample ASAP and have contacted them – I had some concern that the sample obtained from the biopsy might not be of sufficient size for the testing, but confirmed today that the neurosurgeon took numerous samples, so fingers crossed. I am really grateful for the research that you have included in your answers and particularly in relation to not needing to include Procarbazine with the CCNU – this definitely would make it easier on her body and I would hate to have found out later that it was unnecessary or possibly even counterproductive.

    I have noted your thoughts on Vitamin D and also the caveat and agree that it is probably better to err on the side of caution and just keep it at normal levels (we will be keeping a close eye on the levels now) and then once off CCNU, aim for ~ 10,000 IU.

    Have you by any chance shared the current supplement cocktail that your friend is on? It gives us a lot of optimism to hear how well she has done considering the hypermutated tumour and also that the second recurrence is also responding to CCNU!

    My partner has also asked me to thank you both very much for your valuable advice.

  6. Glad to be of assistance. Just a few further comments.
    I consider valproic acid (Depakote) to be more of a potential radiosensitizer and Keppra (levetiracetam) to be more of a possible chemosensitizer, given its potential to modify MGMT expression. I've also not seen research on brivaracetam in this respect.

    Clinical trials in GBM don't show a conflict between Avastin and CCNU. The randomized phase 2 BELOB trial in 2014 showed generally better outcomes (PFS-6, OS-9) with the combination over each drug singly, even for MGMT unmethylated patients.

    I would agree with trying Avastin a couple times to see if it helps her, and if not you can stop.

    If I recall, the Caris testing for Total Mutational Load, and the immunohistochemistry tests for mismatch repair deficiency were optional, so I would double check to make sure those are going to be included for you.

    My understanding is that both temozolomide and procarbazine are broken down in the body to the same active agent (methyldiazonium ion). So obviously these drugs can be helpful in gliomas that have not evolved resistance to them, but as I mentioned I would not recommend them for a mismatch repair defective/ hypermutated tumor.

    I can share with you my friend's supplement cocktail that she was using during her CCNU + Avastin regimen in 2018. Please note that the dose of CCNU when combined with Avastin is lower than the dose used when not combined. The actual doses of CCNU she took in 2018 were between 160 and 120 mg, dropping down to about 100 mg by the fifth cycle because of low platelet counts. This time around she started with 200 mg, but this was quite hard on her, and she dropped down to 150 mg and 120 mg for subsequent cycles.

    Her supplement routine in 2018 was:
    a pre-prepared curcumin + EGCG (from green tea) + sulforophane capsule
    Echinacea tincture (for immune support)
    vitamin D3 (10 drops per day = 10,000 IU)
    Celebrex (400 mg per day)
    fish oil containing EPA and DHA (2 gel caps per day)
    small dose of dexamethasone (1 mg or lower)

    she was also using Gravol and cannabis oil (now legal in Canada) for anti-nausea support

    This time around I believe she's trying to follow a similar approach.

    Not sure what the status of Optune is in Australia and if it is available there? This can be a good compliment to chemo.

    I am glad to be able to give you and your wife important information during such a difficult time. Please keep us posted on the outcome of the genetic testing.

  7. Hey Stephen,

    Thank you for your further advice and also for pointing out that I had mixed up radiosensitizers and chemosensitizers! :)

    If you don’t mind, I just have a couple of questions in relation to your last post:

    With regards to your comment that trials in GBM don’t show a conflict between CCNU + Avastin and actually showed generally better outcomes, this was for recurrent GBM (or at least in the trial that you listed). Would my partner’s case be considered recurrent GMB, even though it is indeed recurrent tumour, but it is recurring from a lower grade?

    Also, is it your understanding that recurrent TMZ induced hypermutated tumours usually occur as secondary GBM’s with their IDH1 mutation still present? We are still waiting for the pathology on this, due today – so fingers crossed.

    How would one determine if the Avastin is not working? For instance, with your friend – who had shrinkage when she first tried CCNU + Avastin, how was the decision made that the Avastin was not making a difference and all the shrinkage was due to CCNU? It would be good to know these criteria so we can know when to get rid of it during my partners treatment.

    With the tumour epigenetic testing, we actually ended up going for a local company that I was not aware of which the oncologist suggested because it would be easier for her to communicate with a locally based lab. I am not sure if you have heard of them (Genomics for Life). We have ordered the NGS sequencing panel which includes all the mismatch repair deficiency genes that you previously referred to, as well as mutational burden. We also ordered the transciptome analysis – which measures mRNA expression of 20809 genes, including ones to see cannabinoids may be useful. We should have the results of this in approximately 10 days.

    Luckily AU now has access to medicinal cannabis + cbd, but there is still a bit of red tape – unlike you guys in CA (thanks to Trudeau) – I will be getting on to my partners general practitioner tomorrow and getting her to start the application, it can’t hurt to have it handy if not for therapeutic means, at least as a potential anti-nausea option as is the case with your friend.

    With Optune, unfortunately it is not available in AU, which really sucks as my partner would be more than happy to wear it 24/7.

    Thank you very much for sharing your friends cocktail, we will try to replicate it as closely as possible.

    Thanks again from both of us.

  8. Half of the histopathology is in - it is crazy how long this has taken!

    The tumour has been confirmed to be GBM, TP53 mutated, ATRX mutated KI67 30%

    We will know the IDh1 and MGMT status in the next few days and then the epigenectic testing results hopefully at the end of next week.

    I am REALLY hoping that IDH1 mutation has been retained.

    With the first occurrence of a GBM that has occurred from a lower grade glioma, are they to be taken/viewed as first occurrence GBM's and not second recurrence GBM's ?

    Sorry to bombard you with posts/questions.

  9. Hi Ryan,
    In my opinion, the term "glioblastoma" should be reserved for those with typical GBM genetic characteristics (gains of chromosome 7, loss of chromosome 11, and commonly EGFR mutation or amplification). IDH1 mutant, TP53 mutated tumors such as your partners should be termed "astrocytoma, IDH1 mutant" throughout their evolution. So if it was up to me, your partner's current tumor would be a recurrent astrocytoma (IDH1 mut), grade 4. But historically, tumor classificiation was based on histology, not genetics, leaving us with a more confused terminology. The distinction between newly diagnosed / recurrent has a lot to do with prior treatment, so I would call it recurrent grade IV astrocytoma, but others would call it recurrent secondary glioblastoma.

    Yes, in the case of lower grade astrocytomas, the hypermutated recurrences almost always present as "secondary glioblastoma" and still retain the IDH1 mutation, TP53, and ATRX mutations, plus hundreds of new subclonal mutations not found in the original tumor. Often there is a new mutation in one of the mismatch repair genes.

    In my friend's case, she had significant edema and was dependent on higher doses of dexamethasone to control this. After starting Avastin, there was no changes to her quality of life (with regard to the edema) and she also had difficulty lowering the dose of dex. Often when Avastin is "working" there is fairly quick reduction in edema, and improvements in quality of life due to that. There is no way we can prove the tumor control was due to CCNU alone and not Avastin, and she did continue Avastin for about 6 months, but from the above clues we theorized that Avastin was not helping as much. There is also some retrospective clinical evidence that Avastin is not as helpful in secondary IDH1 mutant "glioblastoma" as compared to primary glioblastoma (which are actually two distinct types of tumors). The oncologist originally wanted to treat her with Avastin alone, but I was doubtful that this would be the optimal treatment and advocated for adding CCNU to her regimen. If there is a reduction of edema and/or improved quality of life with Avastin treatment then it could be considered to be "working". Avastin can mask what is actually going on with the tumor in MRIs due to its changes to tumor blood vessels (pseudoresponse), but using it to treat edema and/or reduce the dose of dex is valuable in itself. For the current recurrence, my friend has used CCNU alone (and no Avastin), and we are still seeing positive results, comparable to the last time around.

  10. The local company for genomic testing should be fine, so long as they are sequencing enough genes to get a decent estimate of mutational burden (so you can tell if the tumor is hypermutated or not). It sounds fine to me.

    There is some evidence that cannabinoids can be useful in treating the tumor itself and not only symptoms. see for example

    I am always somewhat hesistant to extrapolate results for primary glioblastoma to IDH1-mutant astrocytoma, given their distinct evolution and biology. However, given that far more clinical trials for different agents have been carried out for primary GBM, I think its wise to look at this data, with the caveat that the results will not necessarily be the same for IDH1 mutant gliomas. In some cases, agents will be more effective in the latter category (for example conventional chemo and radiation), and in some cases less effective (Avastin MAY be an example of this).

    There is a very, very high probability the IDH1 mutation has been retained. What is more uncertain is whether the tumor is hypermutated or not - as low grade astrocytomas can and do evolve to grade IV without hypermutation occurring. If not hypermutated (implying mismatch repair is still functional), alkylating agents that add methyl groups to DNA (temozolomide and procarbazine) could still play a role.

    Again I would call this a recurrence of secondary GBM (the term "secondary" clarifies an evolution from a previously diagnosed and treated astrocytoma).

    Happy to answer questions, as your partner's experience mirrors that of my friend in many ways.
    Let us know the outcomes of the NGS testing when it arrives.


  11. Hey Stephen,
    Unbelievably we are STILL waiting on the IDH1 and MGMT status from the original histopathology – it must be down to all the COVID-19 testing they are doing. We have fingers crossed. The NGS testing will be ready some time this week as well.
    In the meantime, we have all of the supplements that your friend is on and are just trying to work out doses etc. We have managed to get my partners vitamin D3 back to normal range, so scaled her does back down from 6000 IU’s to 3000 IU’s per day until we confirm the IDH1 status – then we could increase it again?

    She is also taking 1200 mg of the Longvida optimized curcumin – should this be increased at all?

    When searching for the correct dose of Sulforaphane, I came across a recent study that suggests that it may not be good for all GBM subtypes. The study - Sulforaphane Potentiates Anticancer Effects of Doxorubicin and Cisplatin and Mitigates Their Toxic Effects - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207042/ - mentions that,

    "in later stages of cancer, Nrf2 and Keap1 are mutated and Nrf2 activity increased. This means that inhibitors of Nrf2 could be better than activators of Nrf2 in the later stages of the disease. Thus, cancer stage should be taken into account for the usage of specific Nrf2 activators or inhibitors during cancer therapy"

    And another study, https://www.nature.com/articles/s41388-019-0956-6 ( https://sci-hub.tw/https://www.nature.com/articles/s41388-019-0956-6 ) mentions that,

    “We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype..” and;
    “Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition.”

    I could be reading the studies incorrectly, so just wanted to grab your thoughts - if you don’t mind – on using Sulforaphane (given all the positive studies showing improved survival), even though the above studies seem to suggest it could promote proliferation and transition to the mesenchymal subtype? And what dose of Sulforaphane would you recommend? We had intended on using both capsules and fresh sprouts.

    One last question on your friend’s supplements, is ECGC extract dose and the fish oil dose – our fish oil capsules each contain:

    Omega-3 marine Triglycerides : 900mg
    EPA: 540mg
    DHA: 360mg

    Thanks so much Stephen.

  12. Hi Ryan, I hope you get the pathology and NGS reports back soon.
    The problem with cell culture (in vitro) studies, especially for nutraceutical compounds like sulforaphane, is that in most cases the scientists choose to test drug concentrations that are way too high, and way beyond the levels that could be achieved in the blood plasma following oral dosing. To be honest, I rarely even take the time to read through such studies - though I feel like I wasted a lot of time reading these when I was starting out as a researcher. The minimum level of evidence I would want to see is rodent evidence - at least there the scientists have the limitation of showing that a drug/compound can have effects at levels that don't kill the animal from unwanted side effects. In cell culture studies there is no limit on the concentration that they can test. But even rodent evidence tends to be unreliable as far as translating to humans, given the 65 million years of evolution that separates rodents from primates (different metabolism, immune system. etc), and the artificial techniques used to generate experimental brain tumors in animals. Human evidence is vastly preferable to preclinical lab evidence.

    My friend used the curcumin/sulforaphane/EGCG supplement due to research done in Brent Reynolds' lab (University of Florida).
    He called this mixture "epidiferphane". I believe the first clinical trials using it are testing it to prevent some of the side effects of chemotherapy such as peripheral neuropathy.
    Then United Cannabis Corporation gained the rights to sell the product, but I'm not sure if it currently being marketed.

    1000 - 2000 mg of Longvida is probably what I would aim for.
    The list of supplements I shared with you was from 2018. She is probably currently not taking the "epidiferphane = curcumin/sulforaphane/egcg" as she probably ran out. Of these three items the one with the most research in brain tumors is curcumin, and there is even some clinical data (I once saw an abstract on this online, but am unable to locate it right now).
    But in answer to your question, she was taking these three supplements combined in one capsule (4 capsules per day), and I'm unsure of the weight of the individual ingredients.

    I've read that when taking omega-3 fish oils, a therapeutic dose would be three grams per day of EPA + DHA, or in other words, at least three of your capsules per day (2700 mg).

  13. Thanks a lot for getting back to me with the dosages and info Stephen.

    I seem to remember you mentioning previously that you give very little weight to invitro studies – I will definitely bear this in mind when I come across them in future.. So I guess when it comes to the Sulforaphane we will go with the much larger body of evidence that points to a definite benefit.

    It is a shame that epidiferphane is not accessible - it looks as though it could be very beneficial.

    I saw your post regarding the substantially better results of a ketogenic diet and fasting during re-irradiation – is re-irradiation something to consider in the scenario of a secondary hypermutated gbm? Or is that mainly dependent of the location of the tumour/s?

    I know, as you mention above, that you don’t even put too much wight into rodent studies but I came across this one - https://www.sciencedaily.com/releases/2020/05/200501184255.htm - regarding adding the schizophrenia drug trifluoperazine during radiation and the results were remarkable, it tripled the survival of the rodents:

    “Combining radiation treatment with trifluoperazine extended survival in 100% of the mice to more than 200 days, compared to 67.7 days in the control group receiving only radiation.”

    They mention they are hoping to start a clinical trial this year.

    I will post those NGS results soon.

    1. I recall that the new marketers of epidiferphane had branded it as "uTHRIVE". I used to be able to view info on it here: https://nutrimedhealth.com/product/uthrive/
      Now my browser tells me "THIS CONNECTION IS NOT PRIVATE" and wants me to change my Certificate Trust Settings in order to view this page, which I have not done.

      Repeat radiation to the same spot isn't very common. I think the location and size of the tumor and is important so you'd have to discuss with her team whether this would be a recommended treatment.

      Thanks for the article on trifluoperazine. You can get the full study from sci-hub
      This is indeed interesting, but I have learned a certain degree of scepticism when it comes to results of mouse studies translating into humans. For one there is publication bias - typically only those studies with notable or impressive results see publication. How many studies have you seen where the drug failed to do anything interesting? (as opposed to clinical trials, where even negative results often get published). I recall a study showing ketogenic diet + radiation gave unbelievably good results in mice - probably leading to the clinical trial we've just been discussing on the blog. There appeared to be some activity in humans, but not the same phenomenal results we saw in mice. Another issue is that mice are often injected intraperitoneally with some drug that humans take orally, so the mice are probably getting much higher levels in the blood than humans can expect. Mouse studies also often use a single tumor model (it is more expensive to use multiple models) and so we never know if any positive results are relevant to a specific model or have a more general application (for example, IDH1 mutant tumors have a specific pathobiology, compared to non IDH-mutant GBM). When experimenting with the cocktail approach, it really comes down to what level of evidence and how much experimentation each person is comfortable with.

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  15. Hey Stephen,

    We finally got the NGS sequencing and transcriptome analysis back – the reports are quite extensive (incorporating recommended trials/therapies etc…). I am detailing he main comments below. I really don’t have a clue about some of the mutations that they are talking about, but from what I understand, it is a bit of a mixed bag – some proneural subtype features and some mesenchymal ones. It also has a low mutational burden, so likely not TMZ induced hypermutation in this case?

    I would be really grateful if you wouldn’t mind offering your thoughts after looking at the results and whether you would possibly add anything to my partners treatment – like procarbazine?

    Comments from the testing:

    The molecular changes are consistent with a diagnosis of a Glioblastoma, IDH1-Mutant Type, Grade IV with a TP53 mutation and a PTPRZ1-MET fusion. An ATRX variant was identified in the tumour.

    • There is a low tumour mutation load present within the tumour. This is associated with a low response to single agent immune checkpoint inhibitors. Microsatellite testing shows the tumour is microsatellite stable.

    • PTPRZ1-MET fusion has been reported in 15.0% of secondary glioblastomas (3/20), and tumours from patients harbouring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates.
    • The VAF% for the TP53 c.524G>A; p.(R175H) and ATRX c.6217+5G>T; intron 26 variants is consistent with somatic loss-of heterozygosity.
    • TML results have been incorporated into this report. No pathogenic variants were identified in KRAS, PIK3CA, PTEN, JAK1, JAK2, KEAP1 or STK11.
    • Chr1p/19q co-deletion was not identified.
    • The TP53 c.524G>A; p.(R175H) variant is most likely a somatic variant, however a germline variant is included in the differential diagnosis. Clinicopathological correlation is required
    • There is a low estimated CD8+ T-cell abundance and low estimated B-cell abundance with a low tumour mutational burden.
    o Low estimated CD8+ T-cell abundance and low estimated B-cell abundance are associated with a low response to single
    agent PD-1/PD-L1 blockade.
    • There is low expression of CD274 with neutral expression of PDCD1LG2, PDCD1, CTLA4 and IFNG with an increase in expression of CXCL9.
    • The proneural subclass of GBM is associated with mutations in isocitrate dehydrogenase 1 (IDH1), however the gene expression profile shows increased expression of a number of mesenchymal genes including CHI3L1 and VIM.
    • There is increased expression of MKI67 (Ki67) and increased expression of PTPRZ1 consistent with the gene fusion.
    • There is increased expression of PDGFRA and KIT consistent with the gene amplification.
    • There is an increase in gene expression associated with cell cycle regulation, NOTCH signalling and DNA damage response pathway.
    • There is no increase in EGFR signalling.
    • There were 8271 differentially expressed genes with 3597 (43.49%) genes down-regulated compared to the normal tissue reference sample and 4674 (56.51%) genes up-regulated.

    Thanks Stephen..

    1. Thanks for sharing this.
      The summary mentions IDH1, TP53, and ATRX mutations which is standard in this type of tumor.
      New mutations are PTPRZ1-MET fusion and a possible PDGFRA/KIT amplification. The other genes mentioned are not mutations, they are simply measuring the expression level of these genes (in terms of RNA).
      CD274 is another name for PD-L1. Low expression of this, plus low CD8 T-cell abundance says to me that PD-1 or PD-L1 immune checkpoint inhibitors would not be particularly effective.

      Given that the tumor isn't hypermutated, temozolomide and procarbazine could still be considered. One thing to consider is that the PCV regimen was developed before temozolomide was available. Temozolomide is now the standard drug for GBM, while procarbazine is rarely if ever used as a single agent for GBM. Why?
      Instead of procarbazine I would look into regimens that combine CCNU + TMZ (there is phase 3 trial evidence for this combination, and you can find discussion of it on this blog). OR I've often thought CCNU and TMZ could be used in alternate cycles (a 6 week cycle of CCNU followed by a 4 week cycle of TMZ), to interfere with the tumor's ability to evolve resistance, but I've not heard of anyone trying this, as it is unconventional so few oncologists would want to experiment outside of a clinical trial.

      I've not seen the research showing that "PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy" but that would be something else to look into. Given that TMZ and procarbazine are both alkylating agents that methylate DNA, and have a similar/same mechanism of action, these fusions might confer resistance to procarbazine as well??

  16. I found a study specifically focused on IDHmut and NRF2 blockade, suggesting increased dependency of NRF2 in IDH-mutant cells.
    Targeting IDH1-Mutated Malignancies With NRF2 Blockade

    My question concerning sulforaphane were mainly about what is the mechanism of action in animals and humans, versus at high concentrations in cell culture studies. Apparently there is some in vivo and clinical data linking sulforaphane to NRF2 induction.

    This could be assembled into an argument against using sulforaphane in IDH-mutant tumors, although there is no direct evidence.

  17. Thank you very much for offering your interpretation of the results Stephen – it was very helpful!

    Your comments regarding the use of TMZ instead of procarbazine definitely make sense. I will keep looking to see if I can find any trial/study that showed that MET fusions are resistant to TMZ, as they suggest – as yet I haven’t been able to find one. I may also contact the sequencing company and ask them to refer me to the literature that lead them to making that determination.

    I managed to find the relevant post on this blog that that you referred to, about the combined CCNU + TMZ phase 3 trial (http://btcocktails.blogspot.com/2017/09/ccnutmz-incredible-outcomes-for-mgmt.html?showComment=1506456873395#c1762216509132126048), thanks for pointing that out… that is a really big improvement over TMZ alone. I will definitely be showing it to the oncologist and also mentioning your suggestion of alternating CCNU and TMZ cycles to target the tumours' ability to gain resistance.

    I know that you have mentioned before that the IDH1 mutation plays more of a role in the earlier stages of tumour progression that the later stages, but do you think an IDH1 inhibitor such as AG120 or AG881 may still play a role?
    It is really unfortunate that my partner had to be one of the 15% of sGBM patients that have the MET fusion – what I have read on this mutation doesn’t make for pleasant reading, but everyone is different, so hopefully she will have a much better outcome! We are considering blockading the MET fusion with Crizotinib at some stage during her treatment the NGS report cites a couple of decent responses to it:

    "Tumour testing on a patient glioblastoma (GBM), WHO grade 4 showed MET gene amplification with MGMT promoter methylation. The patient progressed on a clinical trial for patients with newly diagnosed GBM that combined the standard regimen of concurrent radiation and temozolomide followed by monthly temozolomide with cediranib, an oral small-molecule pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. The patient was enrolled in a Phase I trial of crizotinib and experienced rapid and durable clinical improvement (Chi, Batchelor et al. 2012)."

    "Two patients with an unmethylated MGMT promoter and IDH1 (R132H) wild-type recurrent glioblastoma were treated with crizotinib. Prolonged stabilization of the disease (17 months) was achieved in the first case. Anaplastic lymphoma kinase (ALK) expression and c-MET protein overexpression was observed.

    Conversely, no response to crizotinib was obtained in the second case with MET protein overexpression and c-MET amplification but no ALK expression or ALK gene amplification (Le Rhun, Chamberlain et al. 2015)"

    Crizotinib definitely seems quite promising, but is not covered here by the Govt or insurance for brain tumours, so at a $6k per month price tag, we have to try and negotiate a bit with Pfizer :)

    We are also looking into perhaps blockading PDGFRA.

    Although we would like to throw everything at it right now, the oncologist has advised to proceed more slowly and to prevent destroying the blood counts We may stick with that approach for the near future - she begins Avastin next week – unless the MRI’s indicate otherwise.

    I have also had a little more time to sift through the reports – I wish they would include a trimmed down, to-the-point version, instead of trying to bulk it up to 160 pages! For the sake of completeness, I am listing all of the detected amplifications, variants and deletions below:

    Somatic gene amplifications
    - PDGFRA
    - KIT
    - KDR
    Somatic gene deletions
    - CDKN2A
    - TERT
    - CTNND2
    - SDHA
    - PRDM9
    - CDH10
    somatic variants
    - IDH1 (Exon 4)
    - TP53 (Exon 5)
    - ATRX (Intron 26)

    Probable germline variants
    - PTPRT (Exon 26)
    - KMT2B (Exon 26)
    - MTA1 (Exon 13)
    - PALB2 (Exon 4)
    - BORCS8-MEF2B (Exon 3)
    - FGFR4 (Exon 9)

    A somatic PTPRZ1(1) - MET(2) (chr7:121513611 - chr7:116339125)
    gene fusion was identified in the tumour

    1. I may have found the relevant study concerning TMZ resistance:


      Tumour exosomes from cells harbouring PTPRZ1-MET fusion contribute to a malignant phenotype and temozolomide chemoresistance in glioblastoma

    2. The full results of the TMZ + CCNU for MGMT methylated GBM trial was published in full in The Lancet in 2019:

      "Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial"

      The actual results were maybe a bit less impressive than they originally appeared. If you look at figure 3, survival at 3 and 4 years was significantly better, but then at 5 years the gap narrowed down. There was a trend towards better progression-free survival but the difference wasn't statistically significant.

      There was also a study on the health-related quality of life from that same trial published in The Lancet.

    3. My sense is that by the time a tumor has evolved to grade 4, mutant IDH1 is no longer necessary - I've seen rare cases in the literature where a formerly IDH1-mutant tumor lost the mutant allele through deletion when they recurred as secondary GBM, and the tumors grew just fine regardless. I don't think the Agios drugs would be effective. In the phase 3 trial of AG-881 they are recruiting only grade 2 gliomas with no contrast enhancement (implying they are slower growing, and don't yet have a leaky blood-brain barrier in the tumor as most GBMs do).

      Yes crizotinib could be worth a try if you can access it (in spite of the expense), and as part of a multi-drug regimen. I wouldn't rely on it alone.

      Imatinib is BCR-ABL inhibitor that also inhibits PDGFRA and is approved for certain types of leukemia. Fortunately the patent ran out and it is now approved as a generic in Australia, so you might be able to get this more affordably than a drug that is still on patent.

      Imatinib hasn't been generally successful in GBM, but perhaps in patients with specific biomarkers such as amplified PDGFRA it could have a use.

      In her type of tumor (secondary IDH1 mutated GBM) I've seen more than one study showing conventional chemo (such as CCNU) as being more effective than Avastin. Avastin could help with some of the edema related side-effects but I would be more confident with CCNU as an actual anti-tumor therapy, and there are multiple trials that have combined these two drugs in a single regimen. As related, in my friend's case when her tumor recurred as a secondary GBM, the oncologist advised Avastin alone, which I was not comfortable with in terms of efficacy, and I advocated in favour of adding CCNU, which she did. In fact, she did one dose of Avastin and then three weeks later she started CCNU + Avastin, but this confused things with the assisting nurses, because CCNU was started halfway through the 6 week Avastin cycle and this wasn't typical protocol according to the books. It would have been less confusing to the assisting team if she was considered to have done a "half cycle" of Avastin, and then started a new full cycle three weeks later when CCNU was added.

  18. Thanks once again for your replies to my questions Stephen, I did read them when they were posted but have only just now got the time to respond.

    That is great that you found the article about MET fusions and TMZ resistance – I couldn’t find any reference articles when I previously searched for it.

    After looking at figure 3 of the CCNU + TMZ study, as you suggested, the results don’t look as fantastic.

    Even if she did not have the MET fusion and likely resultant TMZ resistance, my partner probably wouldn’t be able to add the TMZ at this stage as she has unfortunately had her platelet count come down quite sharply over the last week (from 198 to 98), which is a bit of a worry. She did have a menstruation cycle at the time of testing and also has probably pushed the vitamin D levels a bit too high - around 100 ng/mL at the prior blood test and probably higher in the one with the rapid drop in platelets (it wasn’t measured that time around). I have seen a few studies ( https://pubmed.ncbi.nlm.nih.gov/28486836/ ) that suggest platelet counts and volumes are indirectly proportional to each other, so maybe these factors contributed to the sudden drop in platelets… we have now reduced the vitamin D to 1000 IU daily for the time being.

    If a person with a MET fusion did want to try the ccnu + tmz, I wonder if the TMZ resistance could be overcome if using a MET fusion blockade … such as with Crizotinib?

    Thanks also for posting that study on Imatinib – although, as you pointed out, it wasn’t generally effective with GBM, the couple of outstanding responders were amazing – for example the 60-month survival of a 32-year-old patient after only 1 TMZ treatment at recurrence! I know that you don’t place much stock in invitro studies, but in relation to the effectiveness of Imatinib on GBM’s, the NGS report did mention a study which showed that it actually increased invasion invitro at therapeutic levels similar to real life,
    “tyrosine kinase inhibitors imatinib and nilotinib produces a rapid and striking increase in tyrosine phosphorylation of p130Cas, FAK and PXN, key signalling molecules required for cell motility 20,24. These effects were induced at concentrations similar to clinically relevant drug concentrations.”

    The study is here: https://sci-hub.tw/10.1038/srep27378

    And it concludes, “The results presented here suggest a potential adverse effect of the use of imatinib and nilotinib treatment in GBM tumours, which is dependent on augmented adherent tumour cell motility.”

    She will definitely only be using any of the blockade drugs as part of the treatment regimen and not as a single agent.

    I note your comments regarding Avastin and we will always opt for CCNU over Avastin if it becomes a choice. She has just had her first MRI since starting CCNU to get a baseline before starting the Avastin – we have yet to have a consultation but from the images it “appears” as though 2 of the tumor’s are the same or similar size, but the 3rd one definitely seems bigger, we are hoping that maybe it will be pseudo-progression. This is only the not quite at the end of the first round of CCNU, so would you ordinarily expect to see results as early as that?

    1. In the imatinib study, they state that " Because the peak plasma/serum concentrations of imatinib and nilotinib, are approximately 5 μM and 4 μM, respectively", and proceed to test the drugs at 10 μM (micromolar).

      This is referring to the total levels of drug found in the blood plasma. But in fact, 95% of imatinib and 98.4% of imatinib is bound to plasma proteins and therefore not likely available for target binding, according to the free drug hypothesis. I would consider several hundred nanomolar of these drugs to be realistic in vitro, not 10 micromolar. This is another example of why I distrust in vitro reports of drug mechanisms. Even when they say they used realistic drug concentrations, they are often basing that on total plasma levels, rather than free/unbound plasma levels. And then even less gets across the blood-brain barrier.

      I didn't realize she was already starting CCNU. CCNU could have immediate effects, but it can also have longer term effects in sensitive tumors. I've seen reports where lower grade gliomas continued shrinking for months after stopping CCNU. I would give it at least another cycle and MRI before saying anything definitive (it is working or not working).

  19. Thanks Stephen.

    I really see what you mean now about not having faith in the in vitro reports. It is quite crazy, you would think, especially if they make the claim “concentrations similar to clinically relevant drug concentrations”, that they would calculate the actual plasma levels! There is obviously very poor peer oversight when it comes to publishing these studies. We will keep Imatinib as a potential option.

    With the CCNU, that is good to know that effects aren’t always immediate. We have been looking over previous scans from 10 June (when we first experienced the significant growth and multiple foci) and the preoperative scan that was taken 15 June before the biopsy and measured a growth rate of one of the tumors as 1.1% daily… quite incredible that you would clearly notice a change in 5 days. However, the size as of this latest scan on 20 July is only bigger by approximately 10%, which would correlate almost exactly, when using the 1.1% growth rate, the timespan between the biopsy to when CCNU started. So, we are hoping that the majority of the growth took place prior CCNU starting and that CCNU may have slowed or halted the growth at least. The other tumors seem to be more or less the same size.

    Would you expect if the CCNU is actually having an effect by either slowing/halting growth or by shrinking the tumors, that there would always be associated edema? Because there was no mention of edema from the Dr’s or radiologist. We have made the decision to hold off on the Avastin that was to have begun yesterday, so that we can try and get one more MRI in just before the start of the second CCNU cycle and get a more accurate picture – as you mentioned and I have read elsewhere on the forum that Avastin can mask the true picture of what’s going.

    I don’t suppose you have any statistics on the percentage of GBM’s/sGBM’s that do respond to CCNU? And is that dependant on MGMT methylation as with TMZ? Laughably, we are still, 5 weeks later, waiting on MGMT status…
    Fingers crossed that the CCNU works, but in the worst case if it does not, would you have any other suggestions for a chemo to try?

    The great news is that her blood counts have shot back up nicely within a week!

    Sorry for always bombarding you with so many questions, I just place a lot of stock in your knowledge and advice, which has been of tremendous help..

    1. I think the problem with those sorts of statements is overspecialization. Scientists working only in the lab on isolated cells do not necessarily talk with clinicians or have a detailed understanding of human pharmacokinetics - what happens to drugs once they are ingested or injected into the body. But yeah sometimes I read things and wonder how they got passed peer review. It is extremely common to quote total plasma levels (regardless of plasma protein binding of the drug) and then reference those total levels as being "clinically relevant" to in vitro drug/cell studies.

      Your second paragraph echoes my thoughts exactly. The tumor could have grown after the previous scan but before the treatment started, which could confound the interpretation. You really need two post-treatment scans (or one immediately prior to the start of treatment) to get a more accurate idea of how the treatment is affecting growth kinetics.

      I am not a doctor, but my understanding was that radiation was more of a cause of edema than chemotherapy. Edema occurs even without treatment in brain tumors when the tumor quickly grows blood vessels in a chaotic way - those blood vessels are leaky and allow fluid to leak out in the the surrounding tissue. Radiation can also damage the blood vessels. Chemotherapy could cause inflammation, but to my understanding it does not necessarily create new edema. I am no expert on this type of topic though.

      The standard treatment for cerebral edema in brain tumor patients is dexamethasone or similar corticosteroids, so if she was having significant edema they would have probably put her on that.

      Avastin can definitely complicate the interpretation of MRIs. It can create a "pseudo response", where it looks like the tumor is shrinking on contrast-enhanced MRIs, when actually it might just be reducing the amount of contrast agent leakage from the blood vessels, while the tumor grows unchecked. This is not always the case, and I do believe Avastin can prolong lives where the tumor is highly angiogenic and VEGF-A driven. But it can definitely complicate MRI interpretation, and I wouldn't disagree with your strategy of holding off on Avastin until after the next MRI. I don't have much faith in Avastin for this subtype of tumor anyway.

      Response to CCNU depends on MGMT status, just as with TMZ. So response rates in tumors that are MGMT methylated will be higher than MGMT unmethylated tumors. The MGMT enzyme can remove the methyl groups from DNA after temozolomide treatment, or the chloroethyl groups from DNA after CCNU, BCNU etc.

      But, I can say that IDH1 mutant gliomas as a group have higher levels of DNA methylation, and are more likely to be MGMT methylated.

    2. Unfortunately I don't have statistics for % of IDH1-mutant GBM/ secondary GBM that respond to CCNU after prior treatment with TMZ.

      There have been trials testing CCNU for recurrent primary glioblastoma. In the BELOB trial (reporting in 2014), the PFS-6 rate with CCNU alone for the MGMT methylated group was 26%. In other words 26% of the MGMT-methylated patients were still without disease progression 6 months after starting CCNU treatment. In the EORTC26101 trial reporting in 2017, the PFS-6 was 30% in the MGMT methylated group, after CCNU alone.

      But as we know, IDH1-mutant tumors have a different pathology and biology and so there might be a higher chance of benefit.

      Unfortunately, apart from TMZ and CCNU/BCNU, I don't have much faith in other chemotherapies for GBM/glioma. There is a reason most other chemotherapies aren't considered as first or second-line treatment - they don't tend to work. A big part of this is the failure to adequately penetrate the blood-brain barrier. I would rank re-irradiation as more likely to work than trying third line chemotherapy, perhaps proton radiation, but this would be a question to take to the doctors, whether re-irradiation could happen without overt risk to critical brain structures.

      Another idea would be to rechallenge with TMZ, perhaps on a metronomic schedule. You could also attempt to increase sensitivity to TMZ by combining it with a PARP inhibitor. There has been much laboratory investigation recently of combining TMZ with a PARP inhibitor in hypermutated gliomas that have lost sensitivity to TMZ alone. Unfortunately many of the approved PARP inhibitors such as olaparib have less than ideal blood-brain barrier penetration. There is a PARP inhibitor called BGB-290 that has better BBB crossing, and is in clinical trials for brain tumors in the USA.

      If you were in a location where Optune was available, I would suggest that as a fallback as well.

      - metronomic TMZ, or TMZ + PARP inhibitor?

      Glad to hear her blood counts improved! Hope I can be of further help.

  20. Hi Stephen,

    It has been a while since my last post/update of my partners’ progress – we have been keeping really busy camping + generally keeping active.
    She is just about due to start her 4th round of CCNU (220mg).

    She has been having MRI’s approximately once every 6 weeks or so, prior to the start of the each CCNU cycle. Since my last post and up until and including her last MRI a few days ago, the multiple (3) tumours that that had previously sprung up in the ventricles have continued to shrink to the point of almost disappearing, which is really good news.

    In August, one of the ventricle tumours actually had an intra-tumoral haemorrhage which burst and caused quite severe headaches for a few weeks – but this too resolved. This is a very good result, particularly considering these tumours were growing at an extremely fast rate (~ 1.1% per day).

    During this time, the original temporal/insula tumour had also shrunk a little and had largely remained non-enhancing, however during the previous scan in September, a couple of circular enhancing regions appeared within the tumour. This, at the time, was thought to possibly be treatment related effect (by her radiooncologist – who we still use to interpret the scans, as he is very knowledgeable and works solely with brain tumours), however this last scan has shown significant increases in numbers of enhancing regions and encroachment into other surrounding structures.

    This development really has everyone baffled, given how successful the CCNU has been with the other foci that had stemmed from the temporal tumour. It has only been a couple of days since the scan and they are still trying to come up with an answer as to what is happening – we personally are hoping somehow that it is perhaps delayed radiation necrosis and have asked the radiooncologist to check these scans with the Radiotherapy Field treatment location. She also, just prior to the new enhancements showing up, had a fall off her mountain bike – going down a black run  - and took quite a serious knock to the head, resulting in a hospital visit! So maybe that is involved somehow.

    Going forward, the neurooncologist wants her to keep on the CCNU (which we totally agree with) and also wanted her to start Avastin – however the radiooncologist has said to hold off on the Avastin until we know what is going on – as it may preclude her from any potential trials.

    Other options that we also still have available would be to try the Crizotinib with the CCNU (with or without the Avastin) - but not sure how this would go toxicity wise.

    She seems to have pretty robust bone marrow and her blood counts have so far been bouncing back well after the nadir, which is really helpful.

    Another option – and this is really thanks in very large part to you having posted the results of the Duke University CMV – Dendric Cell Vaccine trials (http://btcocktails.blogspot.com/2020/08/cmv-cytomegalovirus-specific-dendritic.html). After seeing those amazing results, I did a search to see if by any chance there was a similar trial in Australia and to my amazement, there actually was a similar trial that had been conducted in Brisbane (where we live) – but it had unfortunately concluded and they were not accepting new patients. I contacted the professor in charge of the research/trial and he advised that they would begin a new one next year and that they were just about to publish their results – which can now be found here:


    It was only a small trial but as you can see, they had pretty spectacular results for a subset of patients. We could potentially access this therapy via the Special Access Scheme (similar to the Right to Try act in the US).

    I am wondering if I could trouble you for your opinion with regards to what you think may be going on with the tumour – I know it is very difficult to say, particularly with not seeing scans (I am happy to send through some screenshots)? Have you ever heard of one region having almost total response, while another not responding at all?

  21. Hi Ryan, I'm sorry to hear of this troubling development. In honesty, when the question is about the interpretation of radiology this is my least knowledgeable area of brain tumour research as I have not focused on it. I hope they are able to give you some answers to make sense of it.

    The way you describe her recurrence reminds me of the way a tumor can "blow up" when a hypermutated subclone develops after TMZ treatment, which is then completely resistant to TMZ. I am less familiar about resistance mechanisms for CCNU. If the new enhancements are true tumor progression, then clearly some resistance mechanism to CCNU has evolved. If there is a chance to do more genetic testing with some of the new tissue it might give some insights as to what is happening.

    Thanks for the link to the CMV-specific T-cell trial. I had been aware of that trial for years but hadn't seen the results. If there is any way you can access this in Australia through Special Access it would be worth a try.

    Anyhow, I hope you get some answers from the doctors soon!

  22. Thank you very much for your reply and insights Stephen.

    Yes, I really do hope that they can shed some light as to what is going on - perhaps I will push for a FDG PET scan to try and see if they can distinguish if it is true progression.

    I really hope that it not a "blow up" case, but if it is a CCNU blow up - then maybe we should be adding TMZ right away. Only problem with adding the TMZ is that she has just last night taken a high dose of CCNU (220mg) - which would be to high to then add TMZ on top would it not?

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  24. Just further to my question above in relation to adding TMZ to the CCNU, as you have mentioned before in other posts, CCNU can re-sensitize TM-resistant tumours to TMZ – but do you think the opposite is also true – that adding TMZ to CCNU can re-sensitise a CCNU-resistant tumour to CCNU? I can’t find any literature regarding this.

    Also, I am assuming you would think adding TMZ to CCNU is preferable to adding Avastin because you mentioned before that you suspect Avastin was mainly only helping with the swelling?

    1. I don't think of it as CCNU resensitizing a tumour to TMZ. I think of it more as a case of CCNU making it harder for the tumor to evolve resistance to TMZ when the two drugs are combined (MGMT methylated tumors have a tendency to evolve resistance to TMZ via mismatch repair defects leading to hypermutation - but such cells are actually more sensitive to CCNU, at least according to in vitro work). On the other hand I think of a PARP inhibitor (olaparib etc.) as something that could help resensitize to TMZ in cases where resistance is mediated by mismatch repair defects such as mutations in MSH6.

      https://sci-hub.st/10.1158/1078-0432.CCR-19-2000 (same study as download from sci-hub)

      In the CeTeG trial they gave 100 mg/m2 of CCNU on day 1 and also 100 mg/m2 of TMZ on days two to six. This CCNU dose is somewhat reduced from the standard dose of 110 mg/m2 which is probably the dose your partner received (assuming body surface of 2 metres squared). I know from my friend's experience that even reduced doses like 150 mg (total) CCNU can be too much after several cycles. So yes it does seem like it might be too much to add TMZ immediately after a full dose of CCNU.

      If I'm recalling correctly (correct me if I'm wrong), she was treated with a course of TMZ (2018-2019), and then after the grade 4 recurrence this year the genetic analysis did not show evidence of hypermutation, but there was evidence of a PTPRZ1-MET fusion which may promote increased resistance to TMZ.

      Given the fact that TMZ did seem to work initially, and the absence of hypermutation in the last genetic analysis, it may be worth another try if all this activity on the scan is indeed new tumor progression. Really in a scenario like this I would not take Avastin off the table either. When there are so few options I think it's best to make use of whatever therapies exist (including Avastin) and by close observation try to figure out what is working and what isn't. I think Avastin does work for some people (at least in the short-term). But I have less confidence in it being effective for IDH1-mutant GBM as opposed to the more common type of GBM, and would certainly not rely on it alone.

      I hope her team is able to find some answers soon.