I am finding it tricky to decide the best times to give my 18yr old daughter her Cocktail medications and wonder if anyone could advise?
The NO has stopped her TMZ saying he thinks she has her first recurrence within the 6 months of TMZ after radiotherapy. It's in a different area to original tumour and NO thinks it extends to Brain Stem so we are waiting the date of a Perfusion Sequencing MRI Scan. Her GBM is Methylated. original Biopsy said ATRX lost, focal positivity for GFAP. EMA is negative as well as IDH1. Proliferation labelled Ki67 reached 40% focally. I've been told recurrence Biopsy if done would probably have different results.
I am keen therefore to get the maximum benefit from the medications she is on, which are:-
Celebrex 100mg x 2 x twice daily
Itraconazole 100mg x 1 x once a day
Keppra 750mg morning 1000mg evening
Metformin 500mg x 1 x twice daily
Omeprazole 20mg x1 x twice daily
Rantidine 150mg x1 x once a day
Dexamethasone 6mg x twice daily
Melatonin 10mg x 2 bedtime
Docusate 100mg if required for constipation.
Cyclizine 50mg x 1 up to 3 times daily if required for nausea.
PSK 16 1070mg x 3 once daily
Pure Fish Oil 1100mg x 2 once daily
Vitamin D3 x 2 1000unit tabs once daily.
Yesterday she also started Doxycycline 100mg x 1 once a day.
I read that Dexamethasone reduces the effectiveness of Itraconazole and some medications like
Doxycycline need to be taken two hours apart from indigestion remedies.
Any help as to how to optimize the use of these medications, and /or any recommended treatment advice would be greatly appreciated.
I'm aware that she needs to be on more Cocktail medications but these are proving difficult to get at the moment. Not sure if there any that would be of particular benefit to get right now?We are awaiting delivery of Boswellia and are hoping to get a prescription for Low Dose Naltrexone.
Regards
Jo
Hi Joanne,
ReplyDeleteIt's difficult to plan a strategy without knowing what specific kind of tumor you're dealing with. Because of her young age, and the loss of ATRX, it's almost certain this is one of 2 types: the tumor likely has a mutation in the H3F3A gene, or has an alternative IDH1 mutation (the standard test only tests for one variant - IDH1 R132H).
Did she have surgery initially, or biopsy only? If there is tissue left for testing it would well be worth asking about the possibility of testing for H3F3A mutations and genetic sequencing of IDH1 (to test for alternative IDH1 mutations).
Where was the initial tumor location? If in one of the cerebral lobes, it's possible the tumor has a H3F3A (G34) mutation.
The reason it's important to distinguish between H3F3A mutants and IDH1 mutants is that the one is characterized by DNA hypomethylation and the other by DNA hypermethylation, so different strategies would apply in each case.
Itraconazole is a tricky drug to incorporate into a cocktail, as it is a strong inhibitor of CYP3A4 (one of the most important drug metabolizing enzymes in the liver), so it interacts with many other drugs by inhibiting their metabolism, and thereby increasing the plasma levels of other drugs that are metabolised by the CYP3A4 enzyme.
One handy resource is the Interactions Checker at drugs.com - you can sign up and create your own personalized drug list, and the database will spit out all the potential interactions among those drugs.
I believe the problem with tetracyclines (like minocycline and doxycycline) and indigestion remedies applies mainly to antacids that contain the following metals:
"Antacids containing aluminium, calcium or magnesium and preparations containing iron impair absorption and should not be given to patients taking oral tetracycline"
This is because the tetracycline antibiotics have an affinity for binding with those metals.
Some optimization of the cocktail could be done for sure, but that would be an easier task if you can persuade the hospital to perform or send away for further testing for H3F3A and IDH1 mutations.
Lastly, whereabouts are you located? There are a number of very interesting clinical trials for recurrent GBM recruiting in the USA.
Thank you so much for replying Stephen. Your understanding of the Biopsy is a terrific help.
DeleteMy daughter had a 90% resection of her original tumour which was a left frontal parietal cystic tumour. The Biopsy Report said that a test was done for 'somatic mutations' of IDH1 and IDH2 genes, which investigated somatic mutations affecting amino acid position 132 of the IDH1 gene and position 172 of DH2 gene using pyrosequencing technology.
Gene assayed IDH1 and IDH2 the report shows same results for each -
Mutation status negative, change none.
Genotype G/G change quality.
Parameters edited no, change passed.
it says the tumour shows mutation of Histone 3, common in Paediatric high grade glioma. Loss of ATRX staining is consistant with mutation in this gene commonly seen in astrocytic tumour but not in adult glioma. I will ask for the tests you mention to be done. We are based in the UK. Which trials do you consider most interesting?
Kind Regards
Jo
Parameters edited
Hi Jo,
DeleteNo need to request the testing that I mentioned as from what you told me it has already been done.
DNA sequencing showed no mutations in IDH1 or IDH2, but a mutation in Histone 3 (aka H3F3A) was found, as I expected.
Does the pathology report say which specific mutation this is (for example H3F3A G34_, or sometimes also known as H3F3A G35_)? If it doesn't we can assume it is a G34 mutation as opposed to an H3F3A K27_ mutation, which is far more common in brainstem gliomas in young children. The fact that her tumor started in the cerebral lobes and that she is in her late teens suggest it is likely the G34 type.
Logans wife's tumor has that same mutation and I've commented on the H3F3A G34/G35 mutation in a previous comment:
http://btcocktails.blogspot.ca/2016/04/idh1idh2-status.html#comment-form
I will comment again on potential trials.
I should mention that my original NO - who is very conservative - prescribed us Depakote at 500mg for the G34 mutation. I would ask your NO for the same as he felt there was enough data out there to support it. Again, he was very, very conservative so I feel the evidence must have been pretty compelling.
DeleteHi Logan,
DeleteThank you for the Depakote information. I'll speak to the NO about it on Monday.
Has your wife had problems with oedema?
Regards
JO
On and off, yes. We continue with dexa and supplement with boswellia.
DeleteStephen, when you wrote above that:
Delete"The reason it's important to distinguish between H3F3A mutants and IDH1 mutants is that the one is characterized by DNA hypomethylation and the other by DNA hypermethylation, so different strategies would apply in each case."
That's made me wonder a few questions:
Is it possible to be both G34 and IDH1 mutated?
When you say that G34 mutants are hypOmethlated, do you mean that in relation to MGMT methylation, they are positive for it? Or something else entirely?
While I wouldn't go so far as to use the word "impossible" a tumor having both IDH1 and H3F3A (either G34 or K27) mutations is extremely unlikely. These are two very distinct types of tumor, and all existing literature says they are mutually exclusive.
DeleteIDH1 mutant tumors tend to have hypermethylated DNA throughout the genome (not just at the MGMT promoter).
The seminal paper on the distinction between methylation patterns in IDH1-mutant versus H3F3A-mutant gliomas is a 2012 paper called "Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma" (Sturm et al 2012)
From that paper:
"Of note, all mutations in H3F3A and IDH1 were mutually exclusive"
"patients in the G34 cluster were found mostly around the threshold between the adolescent and adult populations (median age 18 years, range 9–42 years)"
"Comparing the two H3F3A mutations, patients harboring G34-mutated tumors clearly had a longer OS than patients with tumors carrying the K27 mutation"
"In contrast, tumors in the G34 cluster specifically showed widespread hypomethylation across the whole genome, and especially in nonpromoter regions, when compared with all other subgroups (Figures 2A and 2B)."
If you look at figure 2 in the paper, it shows that IDH1-mutant gliomas have the highest degree of DNA methylation, while H3F3A G34 mutants have the lowest degree of DNA methylation, even lower than healthy controls. This refers to methylation throughout the genome (not specifically in the MGMT gene). The quote above says the absence of methylation in G34 type tumors is especially prevalent in non-promoter regions (whereas methylation of the MGMT promoter is what causes its silencing), and it is entirely possible for specific genes or gene promoters to be hypermethylated even in G34 type tumors. That is, the hypomethylation in H3F3A G34-mutant tumors (and the hypermethylation in IDH1-mutant tumors) is not homogenous across the entire genome.
The study is available as a free download:
http://www.cell.com/cancer-cell/fulltext/S1535-6108(12)00364-9#
Hi Stephen,
DeleteCould I ask for any suggestions you may have as to how to optimize the Cocktail now that I know my daughters tumour has the G34r mutation and EGFR is not amplified? I have added in the Valproic Acid but as she has a paediatric variant of GBM i'm not sure what else to introduce.
Joanne, this is a tricky question to answer as no clinical trial has specifically looked at H3F3A G34R mutated tumors, and there are few, if any cell lines or mouse models for this type of tumor. Some progress has been made with the discovery that MCYN is an important driver of this tumor subtype.
Deletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763966/
In addition to valproic acid, agents that can completely block mTOR, such as NVP-BEZ235, can destabilize MYCN. Other studies show rapamycin and the rapalog temsirolimus (which also inhibit mTOR) are particularly effective against MYCN-driven neuroblastoma tumors.
BEZ235 is an experimental drug still in clinical trials, while rapamycin and temsirolimus are both FDA approved. Rapamycin is the older and cheaper of the two, but still quite expensive. Rapamycin alone hasn't been super effective in general GBM trials, but perhaps would be more effective in selected subgroups. Crossing of blood-brain barrier is also likely an issue with all these drugs.
In short, there is very limited evidence that is helpful in specifically targeting the H3F3A (histone 3.3) G34R mutant subtype of GBM, but the general evidence for GBM could still be used to plan a cocktail. I keep lists of my top pharma and non-pharmaceutical picks in the Brain Tumor Library. Hope that helps.
Hi, Jo. I took the liberty of doing a ClinicalTrials.gov search. I doubt all UK clinical trials are included in this database, but many are. I found a few that might be applicable:
ReplyDeletehttps://clinicaltrials.gov/ct2/show/NCT02017717
https://clinicaltrials.gov/ct2/show/NCT02343406
https://clinicaltrials.gov/ct2/show/NCT01390571
https://clinicaltrials.gov/ct2/show/NCT02029690?term=glioma&recr=Open&cntry1=EU%3AGB&rank=7
My wife is enrolled in the first one. I hope this is of help.
Best wishes,
Steve
Thanks Steve,
DeleteUnfortunately the nivolumab vs bevacizumab trial is "active but not recruiting" in the UK. This often means those locations have already filled their recruitment quota.
The ABT-414 requires tumors with EGFR amplification.
Jo,
ReplyDeleteI was unable to find any trials for recurrent GBM in the UK that I would consider exciting or worthwhile. This isn't surprising considering there are only 5 or so currently recruiting trials for recurrent GBM in the UK listed on clinicaltrials.gov
As Steve mentioned there might be trials that aren't listed on that website, but this has been my primary resource for finding trials. Virtually all the trials I'd consider exciting for recurrent GBM are located in the USA.
If the tumor has EGFR amplification the ABT-414 trial would be a possibility. EGFR amplification is common in adult primary GBM, but I'm not aware of such a correlation in H3F3A-mutant GBMs of children and young adults.
Valproic acid (Depakote) could be an interesting therapy to look into, as in the lab it can downregulate MYCN levels (studies have shown a correlation with high levels of MYCN and H3F3A G34 mutant GBM), and decrease methylation of tumor suppressor genes.
http://www.ncbi.nlm.nih.gov/pubmed/22863973
Outside of clinical trials, there are several German immunotherapy clinics offering cancer vaccines, if $$$ is available. I'll share the Brain Tumor Library with you for information on these.
Hi Stephen,
ReplyDeleteThanks for the information I will have a look at it. Maybe the Valproic acid will be a possibility.
You certainly need plenty of $$$ for the German vaccines.
I'm not sure how it works with travelling to the USA for a trial.
Regards
Jo
I would absolutely look into it; the generic version of Depakote is quite inexpensive: https://www.northwestpharmacy.com/product/depakote-depakote-dr
DeleteHi Logan,
DeleteMy daughter is now on Valproic Acid for targeting of MYCN. Her NO has advised looking for worldwide trials targeting the G34r mutation, although as your probably aware there don't seem to be any at present. Looking into Checkpoint 1 inhibitors at the moment, though not sure how easy to get prescribed.
Can I just ask if you've found anything else to help your wife with this mutation?
This comment has been removed by the author.
DeleteHi Jo
Deletewe are woefully short of any promising trials in the UK and there is no sign of Optune becoming available any time soon. We do know of cases where the NHS has funded treatment in the USA and elsewhere if there are no options domestically. Given your daughter's age I would expect she would have a fighting chance at being eligible for this, although I understand it is by no means straightforward. You would need to make a case along with your oncologist and be ready to seek a second opinion if you don't get the help you need. You're probably aware already but just in case, Cancer Research UK has up to date info on trials. The Brain Tumour Charity and Brainstrust are also good resources for information and support. We're all of us here against our wishes, but it's particularly tough to hear of a teenager with GBM. Our thoughts and prayers are with you. Good luck and stay strong.
I agree the UK is awful for any promising trials. This has also been made more difficult as when my daughter was diagnosed she was 17 and they told us this put her a bit in limbo for trials etc as she was over 16 but under 18. To Make things more frustrating we have just had a second opinion only to be told she couldn't have the drugs as she has a paediatric variant tumour. We have been advised to search worldwide for trials for aimed at G34r mutation-don't think they exist.
DeleteKind regards
Wonderful - I too am looking at checkpoint inhibitors and the NY Times recently did a detailed report on them:
ReplyDeletehttp://www.nytimes.com/2016/07/31/health/harnessing-the-immune-system-to-fight-cancer.html
Looking deeper into the depakote, I think that for my wife's weight, a dose closer to 1gram a day would have been better - she's 40kg.
Note that for brain stem GBMs - which are deeply seated cancers like my wife's - the only thing that I know of that has passed Phase 1/2 clinical trials is Perillyl Alcohol; you can read more about it here:
http://www.cancertreatmentsresearch.com/?p=602
Finally, I feel that the Optune device is definitely helping her; do you have access to that where you are?
Optune isn't available in the UK yet, although, I think we may be able to get it via Germany.
DeleteIt is however out of our reach financially at around £15,000 per month to hire.
What makes you think that the Depakote dose would be better at 1gram?
Thank you for the links I will have a read.
My wife was taking 1 gram/day of depakote for about a year - she weighed around 45-48 kilos during that time. She is now taking 750 mg/day, and she weighs about 50 kilos. Her depakote levels are checked with her bloodwork every week, and when the levels started getting higher than our NO wanted, it was reduced to 750mg. I think this dosage is less than the dosing in the most relevant studies, but it's what our NO is comfortable with.
DeleteKendall, you don't know me, but I have been keeping up with you and your (now) wife since CC. Thrilled to see you post a comment and to hear that your wife is slightly heavier.
DeleteGetting weight onto my wife has been our focus for the past several months.
Logan, I hope that we have provided inspiration and hope for you, as others have for us. I haven't posted too much recently as we have been very busy (getting married!)
DeleteGaining weight can be very difficult, especially depending on the current treatment. By far the best tool for appetite issues is cannabis. It's best in the evening hours, as it stimulates appetite and helps with sleep as well. Other than that, try to keep your wife as active and as happy as you can, obviously working with whatever obstacles you have. Also, do your best to balance healthy foods with things she likes. I found on several occasions that she wouldn't be hungry, but I'd make something she liked and put it in front of her and some of it would disappear.
I wish I had more suggestions for you. My wife is a foodie, so I've had to elevate my cooking game to chef status!
Congrats on getting married! We have been using Remeron to help her gain weight, and that seems to be helping.
DeleteMay I ask how your wife is doing right now? She is roughly the same height and weight as my wife so whenever you posted, I always paid special attention to what you wrote.
Thanks! I'm glad something is helping.
ReplyDeleteShe is doing very well. She is about 20 months from original diagnosis, and has had stable scans for the past 8 months. At our NO appointment this week, we decided that she will not take any chemo for the next couple of months. She has done 18 maintenance cycles, and is sick of them, so she is on a "chemo holiday". We are going to spend the time traveling. After that, we will decide whether to start it up again, or rely on the cocktail alone.
I try to make sure that she always has something to look forward to that's within the next 2-3 months. I'd rather keep her mind occupied by fun things.
How is your wife doing?
It's hard to say; her scans have been stable but there's potentially new things developing. We're too close to our original dx to know for sure - plus we've been to the ER 9 times since this whole hell started.
DeleteUnlike your wife, we haven't been able to do any chemo since the initial chemo because her bloods have never bounced back. We keep hoping that this week will be different but it never is.
Is your wife still doing Optune?
Logan,
DeleteIs it white blood cell count, platelets, or both that are too low? What is your NO's threshold?
She actually never started Optune treatment. We first were looking into compassionate rindopepimut use (for EGFRvIII), but our NO basically told us that, while it may pretty effectively target the EGFRvIII cells, there really isn't a point if the other cells are left untreated. Turns out, about a year later, it was found that rindopepimut really didn't offer much benefit.
The main reason she hasn't used Optune is because she has giant cell GBM. The frequency of the device is set at a level that specifically targets cells that are of the average size of GBM cells. Again, a situation where we would be targeting a minority of the cells, rather than the majority.
Treatment so far has been SOC + cocktail + rather radical diet changes + anything I can do to keep her happy.
Best, Kendall.
Kendall - I realized that I wasn't notified as to your reply, apologies for the late comment.
DeleteOddly, her platelets were rubbish for months but everything was fine. Then she had a massive (12+ per day) amount of seizures due to an infection. Since then, her platelets have been fine but the WBCs have been rubbish.
Maddening. We've only had one single 5/23 maintenance dose in the past eight months.
Well, if it's working for her, that's all that really matters. I too am trying to do everything I can to keep my wife happy as well.
Hi Jo,
ReplyDeleteWe tried Low Dose Naltrexone, started around 1mg increasing to 4.5 when hubby had a clonic tonic seizure.I think he had only taken the Naltrexone for a week. Stoped the Low Dose Naltrexone and hasn't had a seizure since.
I know we all react differently to drugs but thought it was worth noting.
Best wishes
Thanks for that Linda, I still haven't managed to get hold of the Naltrexone yet, but when I was told about it they said you need to find the right dose without going too high. I must admit it makes me wary to use it if seizures are a risk.
Delete