In July 2018 I was diagnosed with grade II astrocytoma in right precentral gyrus. I had a subtotal resection in October 2018, leaving some tumor tissue that was too close to corticospinal tract. Basic immunohistochemistry tests revealed the presence of GFAP and IDH (R132H), p53, ATRX mutations in resected tumor tissue.
My oncologist considers my tumor to be "high-risk" because of subtotal resection, me being close to 40 years old and, most importantly, the tumor tissue consisting of about 10% gemistocytic astrocytes. Because of this, we decided to start adjuvant therapy as soon as possible.
I should be starting radiotherapy in about a month (PCV chemo will be done later, separately).
I did a lot of research and this blog was a precious resource. I recently decided on a cocktail of medications and supplements to take during radiotherapy and would greatly appreciate any comments and suggestions on what else to include or what to exclude from the list.
This is a cocktail I intend to use during radiotherapy. I plan to use different cocktail later with chemo.
Important note: some of the points in "Reasoning" column may be based on weak evidence or may be speculative claims extracted from different sources. I didn't have time to compile all the sources of the information but if there are any specific questions in comments I'll be happy to post any additional links or papers.
List of Rx drugs:
| Name | Reasoning | Note |
|---|---|---|
| Acetazolamide | possible radiosensitizer; carbonic anhydrase II (CAII) inhibitor. |
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| Alfacalcidol | promotes redifferentiation; hedgehog pathway inhibitor. |
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| Auranofin | increases ROS; inhibition of PI3K/AKT/mTOR axis; inhibition/reduction of TNF, IL-6, CRP;,inhibiton of phosphofructokinase. |
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| Celecoxib | edema control; COX-2 inhibitor; PGE2 inhibitor; carbonic anhydrase 9 (CAIX, CA9) inhibitor; suppresses Wnt/β-catenin signaling. |
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| Metformin | ||
| Minocycline | PARP inhibitor; inhibits MMP-2 and MMP-9; modulates phenotype of microglia; disrupts CCL2 chemokine signaling; STAT3 inhibitor; NF-κB inhibitor; MAPK pathway inhibitor; hypoxia inducible factor 1 alpha (HIF-1α) inhibitor; Akt/mTOR pathway inhibitor. |
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| Sodium phenylbutyrate | Histone deacetylase inhibitor (HDACi); c-myc inhibitor; urokinase inhibitor. |
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| Disulfiram | increases ROS; possibly synergistic with Auranofin?; proteasome inhibitor; NF-κB inhibitor. |
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| Memantine | possible reduction of radiation-induced neurocognitive decline ? | |
| Perillyl alcohol | direct cytotoxicity; possibly reduces endothelial-tomesenchymal transition; mTOR inhibitor; Ras inhibitor; G1 cell cycle arrest ? |
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| Prazosin | limited evidence of direct cytotoxicity to glioma initiating cells; | |
| Tamoxifen | Still just considering use during radiotherapy. May be rendered useless by Celecoxib, a potent CYP2D6 inhibitor; Will be used during and after PCV. |
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| Ibudilast (MN-166) | Just considering; No concrete evidence for use during radiotherapy. Limited evidence of benefits when used with chemo. | |
| Itraconazole | Hedgehog pathway inhibitor | Not high on the list because of CYP450 interactions. |
| Mebendazole | Will probably skip this one for now because of no evidence of benefits in combination with RT, also low bioavalibility. |
List of supplements:
| Name | Reasoning | Note |
|---|---|---|
| Boswellic acids | edema control | Downside: non-selective inhibitor of the major drug metabolising CYP enzymes 1A2/2C8/2C9/2C19/2D6 and 3A4 in vitro. |
| Glucans / PSK / mushroom extracts | ||
| Guduchi (Tinospora cordifolia) extract | limited evidence of guduchi as differentiation agent and radiosensitizer | |
| Honokiol (Magnolia bark, Houpu) | autophagy promotor; enhances ROS production; |
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| Omega 3 / DHA | High DHA/EPA ratio | |
| Pterostilbene | possible radiosensitizer | |
| Sulforaphane | possible radiosensitizer | |
| Tetrandrine (from Stephania Tetrandra) | Wnt/β-catenin inhibitor; possible radiosensitizer. |
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| Cannabis | possible radiosensitizer | |
| Epigallocatechin-3-gallate (EGCG) [from green tea extract] | possible radiosensitizer | |
| Garlic | increases ROS; NF-κB inhibitor; HDAC inhibitor at high doses; |
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| Luteolin | increases ROS; NF-κB inhibitor; |
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| Melatonin | ||
| Propolis | ||
| Silibinin (active component of silymarin from milk thistle) | low dose during radiotherapy - could reduce ROS? |
Thanks for including so many details.
ReplyDeleteAcetazolamide. I've seen this more in relation to chemosensitizing than radiosensitizing, and that is how its being used in clinical trial for GBM. But yes, there is also some lab evidence it could also act as a radio sensitizer.
https://www.ncbi.nlm.nih.gov/pubmed/21676479
Auranofin is good in theory (and included in CUSP9) but I'm not sure how much would get into the brain tumor.
Celebrex (or other COX-2 inhibitors such as etodolac), I would definitely recommend in combination with and after radiation, given one of the tumor responses to radiation is to increase prostaglandin E2 production.
Sodium phenylbutyrate would have to be given in high doses, and would be very expensive (at least in North America, not sure about other countries). I once calculated it would cost $3300 USD per month for even a generic brand, at a dose of 9 grams per day.
See recent post and comments on ibudilast. Not sure how you would even access this as it doesn't appear to be fully approved yet. It has "orphan status" which basically means it is being given priority status through the clinical trial process, but still has to successfully complete clinical trials before full approval.
https://btcocktails.blogspot.com/2019/03/ibudilast-for-cocktail.html#comment-form
Lots of things are found to inhibit CYP enzymes when tested at various concentrations in vitro. I take it for granted that many of these would not have significant interactions with CYP enzymes clinically. I would always want to see clinical evidence of drug interactions, and not exclude something just on the basis of in vitro data.
Long chain omega 3 fatty acids are most likely radio sensitizers, given their instability and high degree of unsaturation. And unlike gamma-linolenic acid, EPA and DHA actually do get into the brain.
A general comment is that this is a very ambitious cocktail, on the same scope as CUSP9. In CUSP9 they start all drugs at a reduced (half) dose, introduce one new drug every few days, and then increase to full dose one by one. Patients are monitored in hospital for the entire ramping up period which takes about a month. I would also advise this kind of cautious approach when using so many different drugs and supplements, so you may want to start before the start of radiation, just to have time to ramp up your cocktail.
You could also run your drug list through the drugs interaction checker at drugs.com, to see if anything is red flagged.
Valproic acid in the form of Depakote could be a more financially viable alternative to sodium phenylbutyrate. See my review of some of the evidence here:
Deletehttp://astrocytomaoptions.com/radiation/
Keep in mind though that this evidence is from glioblastoma studies, not low grade IDH-mutant astrocytomas, which are a biologically distinct tumor type.
Thank you, Stephen. I really appreciate your comments. I was afraid no one would read this lengthy post :) .
ReplyDeleteI know this is a very ambitious cocktail and I'm not taking it lightly. The final cocktail will not include some of the drugs/supplements. For example, I decided to start Tamoxifen a couple of weeks before chemo and I'll probably skip Phenylbutyrate because of the cost (it's very expensive in Europe too and virtually impossible to get off-label). This would have been much longer post if I included all the execution plans like starting doses and expected interactions/side effects. I did thorough interactions check on drugs.com and will be consulting a pharmacologist, tracking all the relevant blood markers, etc.
Great points on CYP interactions, Omega-3, Acetazolamide, Auranofin, and Celebrex. Do you think switching from Celebrex to Aspirin during chemo would produce comparable PGE2 suppression (disregarding possible GI issues)? Preventing high-dose Tamoxifen induced blood clots is the main reason I'd like to switch.
I know Valproate can be used as HDACi but most of the in vitro studies I've read so far have shown VP has the greatest effects on cell lines with wild-type p53. There is also one study associating use of VP in grade II and III gliomas with an increased risk of tumor progression or death. https://www.ncbi.nlm.nih.gov/pubmed/26830093
Granted it's a retrospective study and there are other studies showing good outcomes in patients with LGGs taking Valproate.
On the other hand (possibly unrelated to its HDACi activity) Phenylbutyrate seems to have the strongest effect on cell lines harboring p53 mutations, like T98G and U251:
https://www.ncbi.nlm.nih.gov/pubmed/9524087
https://www.ncbi.nlm.nih.gov/pubmed/17707275
I'm not claiming this is (conclusive) evidence, it's a bit of a stretch and I would appreciate hearing your thoughts on this.
Thank you,
Mislav
Excellent Mislav, I'm glad you're being cautious and doing the proper research before implementing.
DeleteI doubt aspirin would provide comparable PGE2 suppression because it is more selective for COX-1 than COX-2.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1742-7843.2008.00332.x
(see figure 1 A and B)
Perhaps an NSAID with roughly equal COX-1 and COX-2 suppression would be the best compromise. Ibuprofen for example is slightly more selective for COX-1 but also has significant activity against COX-2.
Your comments on valproate are a perfect example of why all gliomas can't be lumped together, and I believe IDH1 status places a tumor in a different category altogether. Fortunately IDH-mutants are officially treated as a separate category as of 2016. Unfortunately most of the existing data is from pre-2016 when IDH-mutants and IDH wild-type was lumped together in most studies.
Studies in grade 2 and 3 gliomas are very difficult to interpret properly without relatively complete data on IDH1 status, and the value of old studies pre-IDH testing is limited in that way. I haven't given as much weight to the valproic acid study for LGG you linked to, because data on IDH1 was only available for 16 of the 46 patients who used valproic acid. What if complete data for IDH1 showed the valproic acid group had a higher % of IDH wild-type than the no valproic acid group? And that would influence survival more than anything else. We just don't know.
Moving forward, every trial in lower grade gliomas will have nearly complete info on IDH status, and this will improve the interpretation of these studies immensely.
There is some intriguing info with phenybutyrate. For example there was a complete response in 1 out of 4 anaplastic astrocytomas patients using it in an early phase 1 study. Of course there was no info on IDH1 status at that time.
https://www.ncbi.nlm.nih.gov/pubmed/12241121
I would love to see another clinical trial with phenylbutyrate done in lower grade glioma, now that we could stratify by IDH1 status.
Looking forward to hearing more from you as you gain experience with your cocktail and its implementation.
I don't fully understand the mechanisms behind this, but apparently COX-1 activity leads more to downstream production of thromboxane, while COX-2 activity preferentially leads to production of PGE2.
DeleteRegarding Ibudilast, it is possible to obtain it. As already mentioned in the Ibudilast post, the drug has been marketed in Japan and Korea since 1989 to treat post-stroke complications and bronchial asthma.
ReplyDeleteIt's still sold in Japan under trade name Ketas. I've been able to obtain it through an agency that specializes in providing access to medications from foreign markets. I don't want to advertise it but, @Stephen W, I can send you the link and you can decide if it's something worth sharing as a resource.
My mistake, I forgot it had been approved in those countries, thanks for the correction.
DeleteGood luck with your wonderful plan.
DeleteI wonder whether the agency you mentioned could also provide drugs such as valcyte?
Thank you Stephen, there is so much useful information here! It made me read a couple of Wikipedia entries and 4 papers (so far) I haven't read before :). Researching such complex topics can turn in to a never-ending quest. It may sound odd but I do kind of enjoy it.
DeleteSahel, thank you very much. To be honest I'm scared of taking so many drugs but I decided to take the risk anyway. There is no Valcyte/Valganciclovir in their catalog but I believe they accept custom orders. If you leave me your email address I can send you the link privately or share it here with Stephens permission. I may be making too big of a deal out of this but I don't feel comfortable posting something that might be consider as an ad without Stephens permission.
Please email me the link and I'll have a look.
Delete