Need advice....IDH1+, (maybe) unmethylated GBM..MANY conflicting opinions

I have been reading this message board for years and been impressed with the knowledge of many of the participants.  I was hoping I would never need to post...

As posted by Stephen previously,  my now 25 y/o son was diagnosed in 2011 with OA Grade 2 (now felt to be AA3) and treated with surgery and then surgery to get "leftover" in 2012.  He was found to be IDH1+. Because of the infiltrative nature of tumor on path, he then entered into a clinical trial on the cognitive effects of proton therapy, which he completed 11/12.  No chemo was given.  (No apparent cognitive effects in his case either...did very well in college and is/was in med. school.)  On routine MRI 12/17, he was found to have a 6-7 mm area of enhancement in the middle of his resection cavity (tumor never enhanced before).  Advice was to watch for 2-3 months, but we moved up the surgery.  Note that his tumor grew about 1 mm in each dimension in 6 weeks.  He had a very generous GTR 2/15 and has had a pretty easy recovery--no apparent deficits.
Unfortunately, the path showed GBM IDH1+ unmethylated.  They also looked at his tumor from 2012 and it was also unmethylated.    Foundation One is not back yet.  We have been looking at different options and consulted physicians from several different areas.  Many have been very generous with their time and there is no consensus.  Opinions below...

(he didn't qualify for TOCA due to small tumor size and no prev. treatment)
--Local neuro-onc:  olaparib + Temodar + more proton.  Wasn't really certain of dosing.  (PARADIGM2 could provide that)
--Tumor board at Mass. General....some said NO treatment, some said Temodar.  Told to wait on radiation as scans might be too difficult to interpret
--Physician who is expert on IDH1....feels that IDH1+ GBM shouldn't be considered as really a GBM.  Rec. no radiation and PC(noV) since it has been shown to work.
--Physician at another institution who is involved with IDH1 studies...PCV.  He said to delay radiation because of  "better things coming" and it will probably take radiation + chemo to really eradicate tumor
--Second Opinion from well-regarded cancer institute....PCV has not been shown to work.  Use Temodar and radiation, though consider immunotherapy.
--UCLA...IDH1+ more indolent, possibly PARP + Temodar...perhaps immunotherapy depending on mutation burden.  Not good luck with olaparib, though don't know about mutant status of those patients. Told that IDH1+ SHOULD  be methylated and that test not very accurate.

So....he just missed a slot on the BGB-290(pamiparib) + Temodar (but without radiation) trial...expansion cohort likely opening in 4 weeks.   Evidently fairly well tolerated.  He strongly wants to return to school in August, which seems somewhat unrealistic, but not impossible.  Waiting 4 weeks for treatment doesn't seem like a great idea, unless one accepts the idea that this is a more indolent tumor.

Would really appreciate advice in this matter!  Thanks,   Marcia
(And thank you so much, Stephen!)

P53 loss questions

Hi all,

I'm in the middle of determining what my next steps will be following my AA3 (previously thought to be an Oligo 2) diagnoses.

The tumour is listed as having P53 loss (or truncated mutation), which I know is more unusual in this type of tumour. While doing research on a ketogenic diet I repeatedly came across brief descriptions of p53 playing a role in metobolism...so I decided to look into it more. Below are a few links to different papers I've read. It's seems like you can exploit this loss in a number of different ways.

Firstly, there is evidence that it has some role in fatty acid oxidation and glutathione oxidation (I do not have a mutation to the MYC gene - which also plays a role in glutathione oxidation). According to these papers, these tumours (with p53 loss) are highly vulnerable to glucose restriction, they allow the PPP to become unchecked - which is a pathway that metabolises glucose. (I have read that p53 loss may prevent gene mutations (I think I was understanding that right), which maybe why I do not have an MYC mutation (the mutations I do have are listed in my post called Pathology Report from a few weeks ago).

It also regulates ROS homeostatsis, either through pro or anti-oxidant means (would loss of p53 mean that ROS was unchecked and how would this impact IDH1 mutant gliomas where ROS is already significantly altered, right?) In general, I'm questioning how IDH1 mutation works with loss of p53? IDH mutation metabolises glutamate at high rates, correct? So if p53 is lost (therefore the tumour would not generate GLS2 (at least through P53) and I do not have an MYC mutation (which allows the tumour to uptake large amounts of GLS1 - both GLS1 and 2 metabolise glutathione, then what others ways what the cells use glutathione?

I'm also questioning whether a ketogenic diet would be useful if I am able to use Proton therapy. I believe all radiation therapy uses ROS as one mechanism, proton therapy using more. A ketogenic diet has been said to limit ROS (sort of like antioxidants) but if it will limited it in standard therapy will more be better in Proton therapy? And then, the P53 in relationship to ROS question also comes in here.

I have read that keto may not be good for an IDH mutant tumour because of NAD+. Can someone elaborate more on that?

Just some more info - I had a gross total resection (surgeon said 99.9%). I'm considering Proton Therapy (do people have a hard time getting that covered by insurance), CBD/THC is try to block glutathione uptake during radiation, ketogenic diet to block glucose with attention to glutamate and methionine intake and DHC fatty acids, if needed boswellia and celebrex to prevent need for steroids, Stephen has recommended disulfiram, which I will look into and I'm going to look into metformin (seems to have a special interest with P53 loss), curcumin ( I was taking it before surgery) and I'm considering not taking any chemo at this time.

I apologize that I'm not as organized as I could be in asking these questions. I am experiencing aphasia following surgery.

Here are the links:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135642/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763495/
http://www.pnas.org/content/107/16/7117.full
http://www.sciencedirect.com/science/article/pii/S0005272809000115
https://www.ncbi.nlm.nih.gov/m/pubmed/21336310/

Thank you all.

Maria

CCNU+TMZ - impressive outcomes for MGMT-methylated GBM

A reader of this blog kindly directed my attention to this breaking news, the first results of the phase III NOA-9 trial in Germany testing the combination of TMZ with CCNU (lomustine) for newly diagnosed MGMT-methylated glioblastoma.

"The mean median survival time in patients receiving CCNU was 46.9 months compared to 30.4 months in the control group with monochemotherapy."

The "mean" in the Google translation of the German language news report actually refers to the median (mittlere), as confirmed at the SNO 2017 presentation.

Although this was small for a phase 3 trial (only ~140 patients), a gain in median survival of over 16 months is unprecendented.

This will undoubtedly become the new standard of care for MGMT-methylated GBM.

https://clinicaltrials.gov/ct2/show/NCT01149109

https://forum.hirntumorhilfe.de/neuroonkologie/breaking-news-fortschritte-in-der-glioblastombehandlung-12606.html   (news article in German)

PCV vs Temodar in IDH1 mutated unmethylated astrocytoma

There must be a lot of people who have already dealt with this issue but I didn't see any discussions on it.

I'm 47 years old with a recurrent grade 2 Astrocytoma previously treated with surgeries. Just over 12 years ago it was also treated with radiation, but not with chemotherapy. It's IDH1 mutated, unmethylated and 1p/19q are intact. I'm deciding between radiation followed by PCV or radiation with Temodar and adjuvant Temodar.

The results of RTOG 9802 make PCV appear to be a reasonable option, but RTOG 0424  Temodar results are just as good. My doctor's say Temodar will be as effective as PCV and more tolerable. The advantages of PCV are: the RTOG 9802 survival plot for IDH1 mutations looks good, it's a multi-agent treatment, the methylation status isn't a factor, and there seems to be less risk of hypermutation.

Has anyone with similar tumor characteristics chosen PCV over Temodar, if so what influenced your decision and how did it work out?

Hi,

I'm updating this discussion for anyone in the future who might be interested.

I've had the 3 opinions below.

UCSF:

They didn't give me any new information about hypermutation. Results of trials will be released in 3 or 4 years.

They confirmed my diagnosis and recommended SOC with 6 cycles. They said there was no information more cycles or a different dose schedule provided any benefit. I wasn't eligible for the Everolimus or the other 2 trials for low-grade tumors.

UCLA:

This is where the recurrence was initially diagnosed.

They recommended SOC. With the following expected response rates for patients similar to me

50% without radiation.

75% response rate with radiation.

I didn't get a definition of response, but I think it means either shrinkage or cessation of growth.

Said there's no data to indicate the ketogenic diet helps, but it won't hurt

UCSD:

Confirmed diagnosis.

Said preliminary study results indicate Temodar works about as well as PCV.

10 or 15 % experience hypermutation.

12 cycles recommended.

Most tumors cease growing and about 15% of patients see a reduction in tumor size.

MGMT is less important in low-grade tumors than high-grade tumors.

IDH1 mutated tumors are more chemosensitive.

Treatment: I decided to go with proton radiation + Temodar. I can always change my mind after radiation if new information indicates switching chemo is best. I'm also taking various supplements and started the ketogenic diet.

I had my first proton and Temodar yesterday and woke up surprised by how much it affected me. Symptoms included: fatigue, headache, and I threw up after only 3 sips of coffee. An extra Ondanestron cleared up the nausea after about 1/2 hour.

Questions about Celebrex and Tamoxifen

Hi,


I am new to agents of GBM. I have following questions


1) Is it necessary or beneficial to take Celebrex in the periods between chemotherapy(TMZ) cycles?


2) We also want to add Tamoxifen to my mother's cocktail list, But we are not sure if it will be effective.


3)One study article tells me that adding folic acid will be helpful to change MGMT from unmethylated status to methylated status, Is that correct?


It would be greatly appreciated if you could share your knowledge or information about these questions.


Stephen, Would you like to help me?


Best Regards
James Zhou

Hi Stephen,
Could I check if my interpretation of the G34r mutation of GBM is correct.
Does this mutation mean that only a small part of the tumour is methylated?

Stephen W added the following image from the study Hotspot Mutations in H3F3A
and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Hypermutation Risks of Temodar

Hi all,
I've found great value in this blog and am posting for the first time.

I was diagnosed in march 2016 with grade 2 oligo.  Its a somewhat larger tumor, about 7x6x5cm and unlike most oligo's is not in the frontal lobe, but is left parietal and overlapping motor, sensory and speech areas and nearing midline crossover.  Because of all that it was considered a high risk surgery zone and so I have so far only had a biopsy and have been doing chemo.   I'm IDH1 mt, mgmt meth, 1p19q codel, ATRX normal, p53 normal.

So the broad plan was chemo then RT.  The hope was to shrink the tumor to be able to reduce the RT zone. So far 6 rounds of Temodar but I have now switched over and done 1 round of CCNU after having learned more about hypermutation risks with TMZ.

I've dug thru what published data there is and its all clear as mud.  On the one hand the 2014 Science paper (Johnson et al from the Costello UCSF lab) that seems to have really launched this topic found very clear and scary linkages showing hypermutation and upgrading at recurrance to GBM in about half of the patients treated with TMZ vs none with only RT, on the other hand it was a very small data set, had mixed genetics, was clearly a selected dataset and not randomized, and only looked at TMZ alone or RT alone, not the more common RT+TMZ.  The few other studies I have found add some implications that mutations in TP53 and mismatch repair genes  increase the risk, though some data also shows TMZ driving mutations of TP53 and MSHx which then creates the path to hypermutation.

In simplified terms if chemo mutates the cancer to a point where the 'self check' mechanisms during cell division stop working then the next time the cell gets hit with chemo it will go ahead and replicate in spite of the genetic damage from chemo and create new set of mutations.

To further complicate the picture most of the historical data looking at different chemo options is comparing PCV to TMZ, but procarbazine is a monoalkylating agent that is quite similar to TMZ.  So I've gotten some input from Doc's that CCNU alone may be less mutagenic because it is a bi-alkylating agent and will more effectively stop DNA replication thru double strand breaks.

So Steven or others who are into the science side of cancer, do you have any thoughts on how to unravel all this?  Recommendations on other approaches to consider, or ways to enhance effectiveness of chemo for low grade cases?

Thanks,
Bryan

SW edited this post to include the image below, from a presentation at the 2016 SNO conference in Phoenix Arizona:

Avastin alone vs. Avastin & chemo

To those of you battling with recurrent GBM (or grade 3 tumors): Are you being treated with Avastin alone or Avastin plus chemo? 

My wife is being treated with Avastin + lomustine (CCNU). Yet I have just seen that a recently completed phase 3 study concludes that combining Avastin and CCNU does not improve survival. http://www.cancernetwork.com/sno-2015/lomustine-bevacizumab-fails-improve-survival-recurrent-glioblastoma The prior phase 2 study indicated prolonged PFS for MGMT methylated patients receiving the combination, but the 9 months overall survival was precisely the same (67 %) for MGMT methylated patient receiving the combination vs. those receiving Avastin alone.

The obvious question is: Is it worthwhile enduring the extra toxicity events that the chemo causes when it is so questionable if anything is gained by it? 

Would it not be better to stick to Avastin alone (and combine it with DCA, Chloroquine, CBD, and Honokiol, as recommended by Stepehen)?

What about no mutant idh1?

There seems to be quite abit of information out there for tumors that are idh1 positive.
However is there any options if a Tumor was idh1 negative and also I read on Stephen webpage that nearly all tumors that are idh1 positive are mgmt methylated aswell dose this mean that if a Tumor is idh1 negative that the mgmt would be unmethylated?
Many thanks
Dayle

Lomustine, Carboplatin, Irinotecin... which would you pick?

All -

Dad's oncologist believes that given his decline while on Temodar we should try another option for our next round of chemo in a few weeks.  She said that the choices are Lomustine, Carboplatin, and Irinotecin.  Dad is also taking Avastin (started last week).  Our full cocktail is posted to this blog.

If you had the option to 'pick', which would you push for?  We don't have any genetic testing.  Dad's tumor had a biopsy but no surgical resection.  I've been trying to obtain his MGMT methylation status but it has been nearly impossible to request the test.  Lots of back and forth with nothing.

I'm now beginning to research these three options but want your opinions as well.

Thanks as always..
Annie

Why doctors don't offer lomustin?

Everybody is taking temozolomide and after that avastin. When I spoke to few doctors none of them offered lomustin. Is there a reason why doctors don't offer it? Is it because of side effects? We know that it worked very well for Benn in combination with verapamil.

Help on Accutane/PCV interaction

Hi All,
This is my first post so far, thanks to all for the knowledge shared especially to Stephen for the time he spends on this.

My wife was diagnosed 2 months ago with a GBM (mutated IDH1 / no MGNT) , It evolved from 2 full resection (201203-AAG3 / 201504-AAG3). Due to the internal capsule in compromised, there is a high risk of hemiplegia, so NO decided to apply PCV protocol in order to produce some regression that may help the work of the NS in a future surgery, decreasing the chance of collateral damage. Her tumour growth was fast in the last 3 months, but after the first PCV it has been stabilized. At that time we found Ben Williams story, Astrocytoma Options web, so we decided to follow cocktail aproach to create sinergy. She is now in the 2nd PCV cycle and we added Tamoxifen, Verapamil, Celebrex, Metformin and a bunch of suplements like Curcumine, Boswellia, Resveratrol, Fish Oil and a couple more. So now we want to add Accutane but we want to be aware of any possible interactions with PCV and avoid them.

PCV Protocol:

• Day 1 - Lomustine.
• Day 8 till 21 Procarbazine.
• Day 8 and 29 Vincristine.
• 2 weeks off.

Any advice on when she should take Accutane?

Thanks in advance.
Francisco.

Disulfiram and copper

Steven

Do you know what dose of copper would be used with disulfiram?  Being copper seems to be involved in cancer growth if not initation, it seems that the lowest dose of copper should be used.

Also, I am of the belief that it is the copper that is beneficial, not the gluconate component (the study specified CU gluconate)  Typically we see various chelated forms of minerals have different bioavailabitly, but it is the mineral with the therapeutic effect.  In the disulfiram/copper combination I suspect this is the case as well.  Do you know if there is something special about this particular copper preparation that gives it synergy with disulfiram?

Sertraline vs Fluoxetine

Steven and others…

I have been considering switching from Sertraline to Prozac.  I would appreciate your thoughts:   

Heres what I know based on what Steven has written on his web site.

·           

• When sertraline was added to doxorubicin it resulted in increased chemosensitive over fluoxetine and doxorubicin.  This is apparently due to sertraline’s ability to impact efflux pumps better than fluoxetine.  I do not know if TMZ and doxorubicin are comparable with regards to benefits brought about by inhibiting efflux pumps.

•    Prozac inhibits MGMT activity, sertraline does not

•     Disulfiram inhibits MGMT activity

Then from CUSP9*:

•  Sertraline blocks multiple survival pathways.  No mention of this is made with fluoxetine

So here are my questions:

• If sertraline inhibits efflux pumps as does disulfiram, how important are PPI’s likely to be if both sertraline and disulfiram are already being utilized?

• Since disulfiram already inhibits MGMT activity, in theory fluoxetine would not need to be used for this (ignoring the possibility of synergy for now).  And since both sertraline and fluoxetine inhibit efflux pumps, it seems sertraline might be better combined with disulfiram rather than fluoxetine and disulfiram because sertraline has the added benefit of blocking multiple survival pathways.  Do you agree with my thinking on this?

• Fluoxetine does inhibit MGMT as does disulfiram and I suspect the synergy between the two could be beneficial, but since we are dealing with an IDH1 mutation, presumably most of the cells are MGMT methylated.  There would of course be other cells that are not methylated that could benefit from MGMT inhibition, but with disulfiram in the mix already, do I need to prioritize fluoxetine over sertraline because of this?  Or would the added benefit of blocking survival pathways be of more importance?  I realize there is no known answer to this and I am asking you to offer input lacking any data, but I am wondering if based on what you have read, this makes sense.

• Jeremy is not willing to add a PDE5 inhibitor to his cocktail.  I think he has had his fill of drugs and supplements.  Does sertraline seem to improve BBB penetration? 

Thanks for the input!