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

Levetiracetam (Keppra) + standard of care, single-arm phase 2

A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
https://meetinglibrary.asco.org/record/189964/abstract

This was reported at the recent ASCO virtual conference.

• Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2
• The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation
• Forty-six patients were enrolled between August 2016 and January 2019
• Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months

This was a single arm trial, with outcomes compared to a historical control group. A median overall survival of 30 months and median progression-free survival of 15 months does seem to be an improvement on historical results. 

For comparison, the unblinded results of the phase 3 DCVax trial (preliminary report based on 331 patients) had a median overall survival of 23.1 months from surgery. The historical control group used by the Korean team that conducted this levetiracetam trial had median OS of 17.5 months.

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.

Background:

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)

Suggestions

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.

Ryan.

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?

Results of Ivosidenib (inhibitor of mutant IDH1) for nonenhancing IDH1 mutant gliomas

Just published in the Journal of Clinical Oncology

Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
https://sci-hub.tw/10.1200/JCO.19.03327

• out of 35 patients with nonenhancing glioma, objective response rate was 2.9% with one partial response
• of these same patients, 30/35 (85.7%) had stabilization of their disease.
• for these same 35 patients, median progression-free survival was 13.6 months.
• the drug was well-tolerated with no dose-limiting toxicities reported.

As seen here, many of the patients with non-enhancing glioma have had disease stabilization for three years or more.  Not bad for a drug that is so well tolerated and with no dose-limited toxicities.

Lomustine questions

Hi all

I'm posting on behalf of my sister with some questions about her treatment plan.

First, some background history:

2009: Initial diagnosis with full resection and biopsy diagnosed with grade 2 astrocytoma, resulting in watch and wait approach with no radiation / chemo and regular MRIs

2019: 10 yr MRI scan revealed recurrence of tumor in same location; partial resection and biopsy showed very localized portion of tumor had increased proliferation index resulting in grade 3 astrocytoma finding. She completed the IMRT and temodar (TMZ) regimen and has been on TMZ since last summer. She's being treated at Duke's Preston center.

She is IDH1 positive and no 1p/19q co-deletion

Due to COVID-19, her March scan was not conducted by Duke but rather by a local rural center and the scan showed evidence of progression in one area. She has a follow up scan next week at Duke.

Duke is recommending she 1) switch to lumostine (CCNU) or 2) enroll in the STELLAR trial in hopes to be randomized to the CCNU+eflornithine arm. 

Questions for the group:

1) If she gets randomized to the lomustine alone arm, is there any real clinical or prognostic value to in staying in the STELLAR trial given that her non-trial treatment option is lumostine anyway and she would have fewer restrictions not in the trial

2) I am recommending she also take papaya leaf extract given the suggestion that it can help with platelet counts which is a known side effect of lumostine. Duke did not want her to take it because it has "antioxidant properties" which doesn't make sense. Does anyone understand this concern?

Thanks for the feedback and the resource of this group!!