Monday 29 June 2020

Grade II Astrocytoma (IDH1 Mutant) treatment plan

Hi Stephen and all,

Thank you for allowing me to create this thread. I am a 31 years old male from Australia.

I recently got diagnosed with a Grade II Astrocytoma with histopathology report as follow;

Clinical Notes: Incidentally found left Insular region glioma
Mitoses: 0/HPF


Immunohistochemical Stains: Block 1

Ki67: 1%
How estimated: Visually and IDH1, Ki67 dual stain
IDH1 R132H: Positive
ATRX:  Lost
P53:  10%(moderate/strong staining)
EGFR:  Negative
Other Positive:  GFAP, PHH3 highlights 2 mitotic figures, however, it remains possible that these cells are not tumor cells hence it shouldn't be used in grading

MGMT promoter Methylation: If clinically indicated. Block 1 Tumor 60%. Patient Agreement required.

I had Gross Total Resection and according to my neurosurgeon, there is no residual tumor left. Size upon diagnosis was around (14mm x 13mm x 10mm).

I had a few questions regarding Histopathology, wondering if you all can help, please?

1) Should I push for a more thorough genetic study on this tumor? Is it worth it at this point in time to get PTEN, MGMT (as it looks like they haven't performed this test) & Ip/19q codeletions? I know it is unlikely for it to be 1p/19q codeleted since it has p53 staining & ATRX loss.
  
2) Why does it mention mitotic figure: 0/10HPF, then goes on to mention PHH3 highlights 2 mitotic figures but 'possibly' nontumor cells? How do they know that they were nontumor cells?

3) Does Ki67 index & P53 values mean much?


My neurosurgeon has advised holding off any chemo/radiation for the time being and adopt a 'watch and wait' approach. I am happy to hold off chemo/radiation too but I do want to start taking supplements and other medication to possibly delay the recurrence. I plan on taking the following supplements and medication (Please tell if I am mental for doing it).

Supplements:

Curcumin (Longvida)
Vit D (4000IU)
Fish Oil
Vit C (4g)
Magnesium
Resveratrol
Green Tea Extract
Selenium
Milk Thistle
Sulforaphane (From broccoli sprouts)
ZINC: Should I add this? I read on this forum somewhere that it is not really beneficial for people who have enough Zinc levels in their blood. 

Medication:

Aspirin daily 100mg daily (COX 2 Inhibitor) or should I consider Celebrex?
Melatonin (10g - 15g daily)
Metformin 1000mg daily (Keeping the blood sugar level down)

I am thinking of using;

Metformin 1000mg daily (Keeping the blood sugar level down)
Betablocker (Propanolol)
Low dose Mebendazole (Cycle off every after a month use)
Angiogenesis Receptor blocker
DCA
Clomipramine

Thank you for pointing out Isosidenib and Vorasidenib Steph!

- I am really worried about my glioma acquiring hypermutation, is it possible that Agios inhibitors can turn IDH1 into Wildtype by how they operate? 

- I know no one knows for sure, but is it normal to adopt watch and wait approach for Grade II astrocytoma? 

- Are there any clinical trials I should consider? I can't seem to find any trials on LGGs at the moment.

Thank you so much for taking out the time to read this.

Regards

Ruki


















9 comments:

  1. Hi Ruki,
    The good news is that the tumor is IDH1 mutant (better prognosis and response to treatments).

    1) In my opinion further genetic testing isn't necessary - this type of tumor has only three common mutations early in its evolution (IDH1, TP53, and ATRX). It is exceedingly rare to see a truly mixed oligoastrocytoma, with both 1p/19q codeletion, as well as TP53 and ATRX mutations. It is a fairly safe assumption that your tumor is a true astrocytoma (not 1p/19q codeleted).

    2) It's fairly straightforward to identify tumor cells versus normal astrocytes in your type of tumor - virtually all the tumor cells will stain positive for the IDH1 R132H mutant protein.

    It's not clear to me whether MGMT methylation testing was done - what does the 60% refer to? Was it tested and found to be 60% methylated on some kind of methylation index? Maybe it's possible to clarify that with your oncologist. MGMT methylation testing would be worthwhile especially if it's covered under your medical insurance.

    Ki-67 is simply a measure of how many cells are in the active stages of the cell cycle. 1% is very low - so that is good!

    The P53 testing measures how many cells (and how strongly) stain positive for the p53 protein. Many of the common mutations in the TP53 gene lead to a mutant p53 protein that resists breakdown, so often mutant TP53 cells will have elevated levels of mutant p53 protein. But the association is not clearcut - you can't really determine if TP53 is mutated just by measuring the expression of p53 protein. It is possible to have TP53 mutations that don't lead to a buildup of mutant p53 protein, and some kinds of TP53 mutations also lead to truncated p53 proteins that can't be recognized by immunohistochemical tests (they appear to be p53 negative).
    That said, in your type of tumor (low grade IDH1 mutant astroctyoma), 99% of the cases will have a TP53 mutation. 77% will have an ATRX mutation leading to loss of ATRX expression. Other mutations are rare in this type of tumor. For example PTEN will only be mutated in 1% of cases and EGFR in less than 1%.

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  2. Your supplement list looks fine to me. I'm especially in favor of curcumin, vitamin D, and fish oil containing omega 3 fatty acids.
    I wrote an article on my first website (Astrocytoma Options) that summarized some evidence in favor of zinc supplementation for certain TP53 mutations.
    http://astrocytomaoptions.com/exploring-strategies-for-tp53-mutated-gliomas/
    However these studies were done in isolated cells and mice, not in humans, so it is of course uncertain whether this would translate, but zinc supplementation is not likely to be harmful in any case.

    Compared to high grade glioblastoma type tumors, low grade IDH1-mutant astrocytomas have a low expression of the COX-2 gene (the gene's actual name is PTGS2). So Celebrex (a COX-2 inhibitor) might not be necessary.

    Metformin is usually well tolerated at 1000 mg, but it's a good idea to start at a lower dose (say 500 mg) and then increase after a week or so. If you go too high too quickly with metformin, you could experience nausea and other gastrointestinal upset.

    The other drugs you're considering have more evidence (of whatever kind, anecdotal, lab studies etc.) in glioblastoma as opposed to low grade IDH1-mutant tumors. Instead of these, I would consider Accutane (13-cis retinoic acid) as a maintenance drug, if you are not going to go immediately into chemotherapy. Accutane was one of the drugs in Ben William's cocktail (Ben is a long-term survivor of an IDH1-mutant glioblastoma, and spiritual father of this blog), and there is some theoretical evidence that IDH1-mutant gliomas have a dysfunctional retinoic acid pathway.
    https://pubmed.ncbi.nlm.nih.gov/22945948/

    As with most drugs, there are potential side effects of high-dose Accutane, so doing some preliminary research is always important.

    Your tumor will almost certainly not acquire hypermutation unless you are treated with temozolomide. As your team is advocating a "watch and wait" approach, that is not an immediate concern.

    The Agios IDH1 inhibitors (ivosidenib and vorasidenib) will not cause hypermutation. These drugs simply inhibit the functioning of the mutant IDH1 enzyme, and will not change a mutant gene into a wild type gene. The reason they seem to work well for lower grade gliomas is that early in the evolution of these tumors, the mutant IDH1 enzyme is critical to their progression and tumor-like behaviour. Later on, moving up to grade 3 and especially grade 4 tumors, other driver mutations are gained and the IDH1 mutation is no longer necessary for their rapid progression (and the IDH1 inhibitor drugs are no longer that useful). Rarely, the IDH1 mutation might be lost due to deletion of the mutant allele. But in my opinion, if ivosidenib is available in Australia, and you can somehow get insurance to pay for it, that is probably your current best option. Vorasidenib (AG-881) is in a phase 3 trial, recruiting only in the USA. https://clinicaltrials.gov/ct2/show/NCT04164901

    Watch and wait is common for low-risk, grade 2 tumors. Your successful surgery (gross resection) probably puts you in the lower risk category. But if ivosidenib is available (both legally and financially), the side effects are minimal compared to chemotherapy, and I would try to reserve conventional chemotherapy options for later. And I can't recommend any clinical trials recruiting for grade 2 astrocytoma that would be a better option. Low grade glioma trials are much less common that high grade glioma trials, and even more rare in Australia, I'm sure.

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  3. Hi Steph,

    Thanks for the detailed explaination of histopathology report, it makes heaps more sense now. I will ask my neuro about MGMT Methylation status when i see him next.

    Accutune sounds like a good idea, i will add this to my maintenance after researching a safe dose for myself. There are reports that SSRI have an effect on Glioblastoma, do you think adding SSRI into my daily routine might have some impact on a low grade tumour?

    I am trying to find out if Ivosidenib is available in Australia but it seems like we don't have this drug in Australia. I was looking at the price if i can order it from overseas but it seems beyond my reach. Do you know if there is any other way to access this medicine (Compassionate grounds etc.)?

    One more thing question about chemotherapy, do you know PCV is effective against IDH1 Mutant low grade gliomas or is it only TMZ?

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    1. There have been a number of clinical trials with Accutane for high grade gliomas (in the scientific literature it is called 13-cis-retinoic acid, or isotretinoin). Most of these trials combined it with chemotherapy, which we now know is probably not a good idea - one trial showed better outcomes with TMZ alone than with TMZ + Accutane. However when used alone for recurrent gliomas (1996 study) about 40% of the grade 3 patients had at least disease stabilization.
      https://clincancerres.aacrjournals.org/content/2/12/1931.full-text.pdf

      The dosing used in these trials is typically high - 100 mg per square meter of body surface area per day divided into two daily doses, on days 1 - 21 of a 28 day cycle. (Body surface area calculator here: http://halls.md/body-surface-area/bsa.htm
      However I would probably start at a lower dose to see what your reaction is before ramping up to the higher doses.
      This could be a longer term maintenance therapy if you find it to be tolerable (some people struggle with side effects), and if you can get a doctor to write a prescription - easier for men than for women as it is contraindicated during pregnancy. The on label use of this drug is actually for acne.

      Given your total resection, the odds are that you have a number of years before you might see a recurrence, and perhaps by then ivosidenib and more likely vorasidenib could be the new standard of care for your type of tumor. The estimated study completion date of the phase 3 vorasidenib trial is 2028. It is feasible that vorasidenib could become standard of care for non-enhancing, lower grade IDH1-mutant gliomas sometime during the course of your disease.

      The evidence for SSRI antidepressants in glioblastoma is interesting but scanty (restrospective observational studies rather than clinical trials, plus rodent studies). It is even more of a stretch to apply for a different biological subtype (IDH1-mutant gliomas).

      Unfortunately, as of June 2018 when I contacted Agios, "Particular to your request, unfortunately, our program in solid tumors does not provide access to unapproved investigational medicines outside of our clinical trials. This is informed in part by the early stage of development (phase 1), limited safety data, and limited understanding of efficacy."

      Perhaps their policy has changed since 2018, and it would be worth reaching out to the company to ask about options for you in a country where there are no clinical trials for these drugs. Also, ivosidenib was approved by the FDA in July 2018 for use in IDH1-mutant leukemia, though perhaps it has not yet been approved in Australia. The Australian drug regulatory authority is most likely at least looking at approval for this indication given that it is now available in other countries (USA for sure).

      PCV would likely be just as effective as TMZ for your tumor. However, if it were me I would drop the P (procarbazine) and the V (vincristine) and just take the C (CCNU, or lomustine). Fortunately CCNU has a different mechanism than TMZ (though they are both alkylating agents) and does not create a selective pressure towards mismatch repair defects and then hypermutation. On the other hand, it is typically not as well tolerated as TMZ at standard doses (my friend has been able to tolerate it better at below standard doses).

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  4. cheers for including Accutane dose calculator. Mine works around to 200mg/day so I will slowly build up to that quantity.

    I hope that it stays low grade until we have SOC for low grade gliomas which doesn't hypermutate them and keeps them at bay for longer. I will refrain from using SSRIs if there is no documented effect on low grade tumors. Glad to know that CCNU is effective on low grade gliomas and does have a different function than TMZ.

    I will talk to my neurosurgeon & email Agios to find out if i can access Vorasidenib or atleast isovidenib. I will report back for the benefit of other forum users either they will allow me to have it or not.

    Thank you so much for your help Steph!

    Cheers

    Ruki

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    1. Please keep us posted, and best of luck!

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  5. Agios replied that Ivosidenib and Vorasidenib is not available outside of clinical trials for gliomas.

    Do you think i should ask for CDKN2A/B test on my tumor or is it rare to homozygous deletions in Grade II astros? Cheers Steph

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    1. The Agios response is what I expected, but good to confirm it nevertheless.

      CDKN2A/B deletion is something I would expect in a grade 4 tumour rather than a grade 2. It is one of the mutations that can contribute to a lower grade tumour transforming into a higher grade.
      This is backed up by a 2019 study
      https://pubmed.ncbi.nlm.nih.gov/31832685/
      which states in the abstract "CDKN2A homozygous deletion was not recorded in grade II gliomas."
      Then later in the main body of the text:
      "We did not observe any CDKN2A homozygous deletion among the 40 grade II IDH-mutant gliomas of our additional series including 20 diffuse astrocytoma IDH mutant and 20 oligodendrogliomas IDH mutant + 1p/19q codeleted"

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    2. Copy that. Does sound like bit of an overkill then.

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