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.
Francisco,
ReplyDeleteBen Williams' cocktail would be a decent model to base your strategy on, since your wife has the same tumor type that he had (IDH1-mutant secondary glioblastoma).
Ben also did PCV chemo, alternating with BCNU: Between the first and second round of chemotherapy, Ben began taking oral Accutane (13-cis retinoic acid) at a dose of 160mg per day on a two week on/ one week off schedule. Accutane was not taken on the days of chemotherapy. I'm not sure how this was integrated into the PCV schedule which is more complicated than the BCNU schedule. Anyhow,
Ben was careful not to take Accutane during the days of chemo, and this turned out to be a wise decision, as a more recent trial found that Accutane combined with TMZ led to worse survival than TMZ alone.
If you go to the alphabetical label section of the blog (found along the right-hand panel, underneath the Blog Archive), and click on the label "Ben Williams", you'll find my short summary of what Ben did during his conventional treatments.
http://btcocktails.blogspot.ca/2015/08/ben-williams-cocktail-profile.html
Accutane is often dosed in glioma trials according to body surface area, for example the trial above used "isotretinoin dose was 40 mg/m 2 orally
twice daily". You can calculate her body surface area here:
http://halls.md/body-surface-area/bsa.htm
Also note the recent study showing that the drug thalidomide was synergistic with Accutane (13-cis retinoic acid) in a mouse model.
http://btcocktails.blogspot.ca/2015/09/13-cis-retinoic-acid-accutane-and.html
What is the dose of high-dose tamoxifen she'll be taking?
Another thing to consider is that if her MGMT status is unmethylated, it will be good to make the CCNU (lomustine) component more effective by adding drugs that inhibit MGMT, such as fluoxetine (Prozac), Keppra (levetiracetam), valproic acid (Depakote), disulfiram (Antabuse). If she's had a history of seizures she may have already been prescribed the Keppra and/or Depakote.
Good luck, and let us know how everything goes.
Thank so much Stephen!!!
ReplyDeleteShe is taking 160 mg daily of Tamoxifen (body surface 1.74). I saw Ben's cocktail profile , but like you mentioned, the schedule of PCV is a little more complicated than BCNU, maybe we can include it in the 2 weeks off before the beginning of the new cycle, also my sister in law found the synergic effect adding thalidomide, thanks for the advice.
She has never had any seizure, but anyway after the first surgery started to take Keppra by doctor's prescription, now she is taking 2500 mg per day.
We can get Fluoxetine and Disulfiram easily, so will add both to my wife's cocktail. Will take a look around the blog to find the proper dosage and any possible interactions with the rest.
Again. thanks for the input!
I will contact Ben and ask him how he scheduled the Accutane during the PCV cycle.
ReplyDeleteDrugs.com warns against combining procarbazine (the P component of PCV) with SSRI antidepressants (like fluoxetine) due to increased risk of serotonin syndrome, as procarbazine has monoamine oxidase inhibiting activity:
ReplyDelete"CONTRAINDICATED: By inhibiting serotonin metabolism, monoamine oxidase inhibitors (MAOIs) may potentiate the pharmacologic activity of selective serotonin reuptake inhibitors (SSRIs) and increase the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition..."
"In general, SSRIs should not be used concurrently with MAOIs or other agents that possess MAOI activity (e.g., furazolidone, procarbazine). At least 14 days should elapse between discontinuation of MAOI therapy and initiation of treatment with SSRIs, and vice versa. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, a washout period of 5 weeks minimum is recommended when switching from fluoxetine to an MAOI. Similarly, a washout period of 3 weeks is recommended when switching from vortioxetine to an MAOI."
On the other hand a retrospective study found no cases of serotonin syndrome in 26 lymphoma patients taking both procarbazine and antidepressants (mostly SSRIs).
http://www.ncbi.nlm.nih.gov/pubmed/24038727
Dear stephen..
ReplyDeleteis the 40mg/m2 dose similar to what Ben did..??
When i calculated the dose for my husband it was almost half of Ben's dose: 160mg/day..
what should we do??
The 40 mg/m2 is TWICE daily. So yes that is similar to what Ben did, assuming his body surface was around 2 m2.
DeleteAH..okay that makes sence thx stephen :)
DeleteI found the same about Procarbazine interaction with Prozac so for now only adding Disulfuram with copper.
ReplyDeleteI think Ben's input will be so helpfull, thanks for taking time to contact him, I appreciate it.
Ben's reply:
ReplyDelete"I avoided taking accutane concurrently with either BCNU or CCNU, but otherwise used a schedule of 2 weeks,on-one week off. I also used a smaller dose than that used in the clinical trials, namely 120 mg/day. Note there is good evidence that accutane is synergistic with vitamin D."
My biggest question is should it be taken with Procarbazine, which is taken for 14 days of a PCV cycle?
DeletePersonally I wouldn't combine it with procarbazine. Procarbazine has a mechanism very similar to TMZ, they are in fact both metabolized to the methyldiazonium ion (this is definitely true of TMZ and very likely true of procarbazine). Studies in GBM actually showed worse survival when Accutane was combined with TMZ compared to TMZ alone. My hypothesis is that Accutane causes fewer cells to be dividing when TMZ is applied, reducing the number of cells killed by TMZ.
Deletehttps://www.ncbi.nlm.nih.gov/pubmed/25239666
I know Ben was taking Accutane during the six week chemo cycles, but I would hesitate even on that. I primarily think of Accutane as something to do as a maintenance therapy after completion of chemo.
Thanks. I was considering the same thing. It may be that isotretinoin causes cell cycle arrest, at least temporary (think I read somewhere that retinoids fail to induce terminal redifferentiation, unfortunately, I can't find the article now). Hope high-dose alfacalcidol won't interfere with chemo in a similar manner.
DeleteI was wondering the same thing about vitamin D, but there is this study showing co-operation with vitamin D and TMZ, though only in rodents, so not 100% reliable:
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888049/
Ben also advises dropping the vincristine from the PCV protocol, as there is little evidence of its usefulness for brain tumors and Ben still has neuropathy from using it 20 years ago.
ReplyDeleteFor those reasons, I'm planning to replace Vincristine with a really high dose of Mebendazole, up to 18g divided into 3 equal doses and *only on two days of the cycle when Vincristine would be taken* (otherwise it would be too expensive and risk of leukopenia/anemia would be greater).
DeleteI got the idea from this article
https://www.ncbi.nlm.nih.gov/pubmed/28386621 .
The article may have been mentioned here before.
I'll take such high doses because of low bioavailability and I'll try to mix it with some sunflower or olive oil to achieve better gastrointestinal absorption.
After I try it I'll post an update as a separate article. Probably just about tolerability and some general results because there will be no way to measure if it had any effect.
As of 2015, researchers at Johns Hopkins doing the mebendazole trials in high grade glioma have recommended a mebendazole dose of 100 mg/kg/day (5 grams per 50 kg), though I think they started at 500 mg three times daily in the beginning. I have seen studies where children with hydatid disease were treated with up to 200 mg/kg/day.
DeleteI like your idea of doing high doses only on certain days.
My wife suffered some tingling on the fingers this week after Vincristine application, it lasted 2 days approx, think is a good advice to drop it according to the effectiveness showed. She is already taking 10000 IU of D3 daily, now with the addition of Accutane, Disulfiram+copper and Thalidomide think is a good combination and probably we can generate synergic effect with CCNU.
ReplyDeleteAgain, thanks to you and if you can tell Ben we all appreciate his wisdom and courage.
I've seen retrospective studies in oligodendroglioma where PC (no vincristine) was roughly as effective as PCV.
ReplyDeleteKeep in mind disulfiram (esp in combination with copper) can also cause peripheral neuropathy (numbness or tingling/pins and needles) in hands and feet, something to monitor closely.
More from Ben:
ReplyDeleteHe told me that he started the Accutane at a higher dose (160 mg per day as stated on virtualtrials.com?), but later reduced it to 120 mg per day.
His exact words on vincristine were "My advice to anyone using PCV is to drop the vincristine. It is a nasty drug and there is no real evidence it contributes anything. I still have neuropathy caused by the drug despite using a reduced dose." (I asked permission to quote him)
I noticed the difference in dosage, thanks for clarify that.
ReplyDeleteRegarding Vincristine...wow, that's very surprising. I really don't know how the Oncologists still prescribing this kind of drugs, knowing about effectiveness. I'm looking for some papers about it to show our Oncologist. I hope he won't put too much resistance since he always highlighted CCNU how the important drug in the PCV protocol.
Thanks again Stephen!
There was a retrospective study comparing PCV and PC (without the V) in olidogdendroglioma. The conclusion was that "Findings support the hypothesis that PC may be as effective as PCV chemotherapy, while avoiding the additonal risks of vincristine."
Deletehttp://www.biomedcentral.com/1471-2377/9/33
Now she is suffering jaw pain, this is her 2 cycle, dont want to imagine after 6 rounds how this could get worse.
DeleteGuess we are going to have a long talk with NO to drop VCR.
Thanks Stephen!