Dear Stephen and blog visitors,
I've posted multiple times about my husband's case but this is his disease history in a nutshell:
He is IDH negative wild type, MGMT methylated.
2017/03/27 Diagnosed with multifocal GBM IV (walnut sized thalamic tumor + possibly lower grade frontal lobe mass in an area measuring 51 mm x 38 mm x 11 mm)
2017/04/05 surgery only on the thalamic site where 80% of the tumor was removed. He had a diffuse early progression with edema 3 weeks after the surgery throughout the surgical cavity and beyond. He received the traditional chemoradiation protocol for 6 weeks only in the thalamic area. 3 months after that, the first MRI showed slight progression on both tumor sites (despite the fact that the other mass wasn't even radiated so I guess there's some signaling between the two area)
After starting the maintenance Temodal courses, both tumor sites gradually reduced in size for almost a year.
2018/June The frontal lobe area stopped shrinking.
2018/ October scan: Thalamic area also stopped shrinking.
2019/ January scan: Both sites were stable.
2019/ April 30 Thalamic site is still stable, the oncologist is very satisfied with this area but the frontal lobe area started to invading towards the temple (temporal lobe?) so he decided to send him to radiation therapy. He said surgery is not an option at this stage because thanks to the chemo this is not a mass anymore. So not a solid tumor with clear margins, "just" infiltrating signaling (the report said: we can't state for sure that it became malignant). Sorry, my vocabulary is not enough to define it correctly. I'm worried that this frontal lobe thing is currently going through some transition to be an actual GBM. In the past 1 week he also started having complex partial seizures. During the 2 years of journey his only seizure case was a long and scary grand mal a year after diagnosis while the scans were great. Nothing else prior or after that, up until now. Is it a bad sign, right?
Stephen, do you think RT is the right path? Don't you think that treating the frontal area aggressively will make the thalamic tumor "irritated"? My husband just finished his 24th and last TMZ cycle last week and we'll have an appointment on Thrusday to schedule the date of the first treatment so we don't have much time to weigh our options and actually we don't have too many of them.
Also, I asked the NO about lomustine but he said that this should be our 3rd "plan B". First thing we need to do is RT. Then Avastin if RT won't work and last chance is lomustine because it's very hard to obtain in our country. Last time it took him 3 months to get it for another patient. I said that I can put it on his desk within 2 weeks on my expense in its generic form but he said "We need to spare it for later."
My radiation cocktail plan is the following:
* ketogenic diet
* Metformin (reducing the dose to 2x 500 mg because of the ketogenic diet)
* Minocycline 200 mg
* Valproic Acid (25 mg/kg)
* chloroquine (250 mg)
* continuing with DCA (10-12 mg/kg x 2)
* Sulforaphane (Jarrow Formulas, 2 capsules)
* EGCG (600 mg)
* melatonin 20 mg
* steroid-sparing plans to avoid swelling (Boswellia, 3 capsules of the Wokvel brand + Celebrex 400 mg - is it enough?)
* memantine 20 mg
* D,L methadone 1,75 ml x 2
* Perillyl Alcohol
Would you change anything?
# I have a concern with Minocycline. Considering that they're in the same class of drugs, would this apply to Minocycline, too? The publication concludes that radiosensitization doesn't neccesarily enlengthens the life span and causes skin damage.
# IV C therapy. Maybe we could do this here in Hungary with a naturopathic doctor based on the protocol in the clinical trials. But the only thing that the NO was clearly advised against in the beginning was anything that involves his veins because as he said "we need to spare them for Avastin." Also, there's a line in the current IV C trial for GBM among the exclusions that: "Patients who are on the following drugs and cannot have a drug substitution: warfarin, flecainide, methadone..." And he is still taking D,L methadone, although that is low dose compared to what addicts take.
Does IV C have an importance as a maintenance therapy, without chemo and radiation? Because that seems to me the most complicated option and I'd rather spare it for later if there's rationale behind using it in itself because I feel that with all this cocktail meds, the 3 infusions weekly and the POH inhalations every 6 hours we would overdo it a bit...
# Finally I found a source to get both Sativex and cannabis oil, although they're very expensive. Do you recommend to change methadon to cannabis? I know the evidence is quite anecdotal for both of them but considering that he progressed while taking it, I don't think that methadone is effective for him anymore.
# My keto concerns: almost all of his meds contain artificial sweeteners, the low quality types like sorbit and sacharins. Is it likely that this will take him out of ketosis?
Just for other patient's information, we also tried the CLOVA cocktail without olanzapine from this January until now but I don't think it worked for him. We increased the dose a little bit because we have different packaging here: lithium 500 mg, cimetidine 900 mg, Valproic acid 900 mg.
We made some changes in the cocktail (dropped Celebrex because it increases lithium's concentration and also fluoxetine because we were afraid to use two antidepressants at the same time) but I don't think this is the reason behind the progression.
I thought he could do some break with all the antidepressants during RT. Or do you know something that can be useful especially during this period? We talked to doctor Pilkington just before we got the bad news and we decided to start clomipramine. But now, with this new seizure activity I don't have the courage to give him clomipramine as it reduces the seizure threshold, just like chloroquine and memantin.
Sorry for my long text of wall.
Hi Ildi,
ReplyDeleteThe frontal-temporal tumor could very well be progressing to a GBM, but hard to know for sure without a surgery. As this part of the brain did not have radiation previously, the plan to radiate the tumor there does seem reasonable to me.
The higher dose valproic acid (25 mg/kg per day) was well tolerated when combined with chemoradiation in the phase 2 trial I've discussed before. However in a cocktail with so many other drugs you might run into more dose limiting side-effects like nausea. In the valproic acid trial they started at a dose of 10 -15 mg/kg/day one week before the start of radiation and escalated to 25 mg/kg/day by the start of radiation. I believe the total daily doses were divided into two daily half doses (12.5 mg/kg twice daily).
I've heard from other people that minocycline is one of the lesser tolerable drugs they've tried, and the study with doxycycline you linked to increases those concerns. I definitely wouldn't start at 200 mg of minocycline, but 50 mg twice daily as they do in CUSP9 as a starting dose.
Steroid-sparing drugs do not necessarily eliminate the need for dexamethasone. They may simply allow for a lower dose to be used. Every case is different and the need for dex should be evaluated for every individual case. Celebrex 200 mg twice daily is fairly standard, and I wouldn't go higher than that to begin with.
The reason for avoiding methadone while taking high dose vitamin C is likely due to pharmacokinetic interactions.
https://academic.oup.com/painmedicine/article/9/3/315/1925903 (See the miscellaneous section under pH)
Vitamin C/ascorbate is a bit tricky because large intravenous doses are required to generate hydrogen peroxide that can work well with radiation.
https://www.pnas.org/content/104/21/8749
Vitamin C at some doses could actually interfere with radiation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266032/
To the extent that high dose intravenous vitamin C can generate hydrogen peroxide, it could act on its own as a pro-oxidant therapy. However combining it with other pro-oxidant therapies (radiation being the major example), creates the possibility for synergy that you don't get with single agents. I do have some reservations about iv C, as mentioned above, just in the sense that it has to be dosed properly.
As far as substituting cannabis for methadone, this makes sense, if he is progressing while on methadone. I don't know of any therapy that is effective for everyone, and he may be one of the ones that doesn't respond to methadone.
Most recommendations for staying in ketosis say to limit total daily carb intake to no more than 20 - 50 grams daily.
Saccharin is actually a sugar substitute that is 0 on the glycemic index. Sorbitol is very low on the glycemic index (9). Even if you were consuming 5 grams worth of pills daily, I doubt the carb value would be of any significance compared to food.
There is some clinical trial evidence supporting valproic acid and chloroquine during radiation. I would also suggest a COX-2 inhibitor (like Celebrex) during and after radiation. See my summary of this evidence here:
http://astrocytomaoptions.com/radiation/
Doctors often recommend to stay away from NSAIDs if the patient is on dexamethasone, out of concern for adverse gastrointestinal events. However this is probably less of a concern with selective COX-2 inhibitors like Celebrex and more of a concern with non-selective COX-1/2 inhibitors like ibuprofen and aspirin.
Hi Stephen,
DeleteI'm very grateful for your guidance, thank you! Unfortunately it's very likely that the lower grade tumor is progressing to GBM because now he has a seizure almost every day despite the fact that his oncologist increased his valproic acid dose. (18.5 mg/kg). I have one more question if you don't mind. I know that multifocal disease is quite rare so you might not have experience on that matter but we were shocked that the radiologist prescribed again the 140 mg daily TMZ together with the radiation therapy. When redirecting us to the radiologist, the oncologist never mentioned that he has to take TMZ again after finishing the 24th 5/23 cycle just last week and he clearly stated that TMZ is not effective for that frontal tumor anymore. Do you find it reasonable to go with the standard radiochemo after such a long pre-treatment with TMZ? His radiologist is a very distant person, way above 70 years old so we're better not to ask questions...
With metronomic (daily) TMZ, one can always argue that it has anti-angiogenic activity, even if the tumor itself is completely resistant to it.
DeleteMy biggest concern in your situation is that after 24 cycles of TMZ, there has been ample opportunity for a sub-clone to arise with mismatch repair defects/hypermutation that would be completely resistant to TMZ (but not to lomustine or carmustine).
Without any further information, I would favour lomustine chemotherapy over any further rounds of high dose TMZ, though I might consider doing a lower metronomic dose of TMZ during radiation for the potential anti-angiogenic effects. Even less than 140 mg daily could have benefits (I assume 140 mg is the standard 75 mg/m2 dosing. 50 mg/m2 is another common metronomic dosing for TMZ in recurrent GBM).
Thank you, Stephen! What is the reason behind using a lower dose? Reducing the risk of hypermutation or is it "just" more tolerable for his body? It's 100% that the radiologist would not prescribe a lower dose but maybe I can make "new capsules" with our jewelry scale that we use to measure DCA.
DeleteWhen I said a "lower metronomic dose", I just meant the standard 75 mg/m2 dose which is half as much as in the 5/23 monthly schedule. I probably wouldn't go to the trouble of trying to persuade the doctor to change the dose or change the dose yourself, without a good reason for it.
DeleteI only mentioned the 50 mg/m2 dose just to make the point that lower doses can still provide therapeutic benefit, but the 75 mg/m2 dose is almost always the dose used during radiation.
I see, thank you!
DeleteDear Ildi,
ReplyDeleteI am not an expert at all...I just know that my father's partial seizure could not be stop with valproic acid and that is why they add keppra. He is now taking 750 mg/day keppra with 500 valporic (which I think we would emit soon) and he is doing ok, seizure wise. Also I've heard vampit works for many...
My suggestion is to find a good neurologist and consult with him...NO and Neurosurgeon in our experience were not so much helpful in this regard. and try to find a younger neurologist who does not prescribe Phenytoin only :)
Good luck!
Dear Sahel, thank you so much for your input! I'll ask his doctors about Keppra, although I've heard a lot of bad things about this medicine. (aggression, mood swings, extreme fatigue etc.) The concerning thing for me is not the seizures themselves, rather the underlying issue which is the progression, out of the blue. I know it's typical with GBM but you can't prepare for that... If these seizures can't cause permanent damage, we're OK with them happening here and there, I just want to kill this stupid tumor in the first place :(
Delete