Although this is my first post, I have been reading every minute of every day. Such an amazing wealth of information on here. I would appreciate any advice on our current course of action and opinions on our cocktail.
My dad was diagnosed with a grade IV GBM. He had surgery on 11/23/16 with 95% resected.
Lab Results:
MGMT Gene Promoter Methylation – Detected.
Percent of MGMT Methylation is 36.19%
IDH1/2 Mutation – Not detected
Positive for 1p Deletion
- Completed his first round of daily chemo/radiation on 1/19/17.
- Our first image was taken on 2/3/17. We had our first consultation with the UCSF Tumor Board (Dr. Butowski) on 2/7/17.
- Tumor had not seemed to grow in size any, but did morph into a new shape/area which is scary to see. Next image in 2 months.
Currently taking:
· Dexamethasone (Decadron) – He is currently taking 4mg/day but we are doing what we can to wean him off. We have been told this will dictate whether we go on Avastin.
· Eliquis – blood thinner - 5mg twice a day
· Keppra – 500mg twice a day.
· Bactrim (Antibiotic) – Original oncologist prescribed during chemo.
Supplements:
1:1 CBD/THC – Tincture drops in day, Oil at night.
Probiotics – Sibiotica (K-97)
Curcumin - Nutrivene Longvida 1000mg - 1x Morning 1x Night (1000-2000mg daily)
Fish Oil - Vital Nutrients - EPA-720mg, DHA-480mg per cap - 1x Morning
Boswellia Serrata Extract - Progena Meditrend – Currently taking (3) 333mg daily.
Melatonin - Vital Nutrients - 10mg/cap - 1x at Night (eventually will do 20mg)
Mushroom Extracts - Turkey Tail (Coriolus), Maitake D-faction, and Reishi each once a day.
Berberine - Vital Nutrients - 200mg/cap – starting with 1x day, soon 3/day.
Debating whether to add - Resveratrol and Green Tea Extract
Our NO was okay with all and suggested adding Cronaxal. I’ve struggled to find much convincing information out there, but I do trust our NO. Now the question is to use Cronaxal (expensive and high dosage) or get Sulfasalim (which Stephen ranked pretty high on his spreadsheet).
I read that this can benefit those that are NOT IDH mutated (which is us).
Genetic Testing
We are getting the tumor tested from Foundation One for more details – once we make sure there is enough tumor for them to test, and have some left for potential clinical trials. I’m keeping an eye out for EGFR, p53, VDR, HIF-1.
Any thoughts here?
Hoping for some advice in a selection of the following:
**Vitamin D3 – In some cases Vitamin D3 caused proliferation in some patients (Stephen W speaks of this: http://astrocytomaoptions.com/supplements/). Our NO was okay w/ Vitamin D3. Would checking his VDR receptor be of value for determining this, or is it safe (and potentially beneficial) to take 5,000-10,000iu daily regardless of tumor type?
I was very excited about a few of the prescription drugs below, but our NO was certain that none of them get past the blood brain barrier while taking doses safe for humans. We are still willing to give a few of them a shot, but I’m struggling to decide which combinations.
· **Chloroquine Phosphate – (if overexpressing the EGFR protein or p53 status is unmutated) & **DCA - Sodium Dichloroacetate –(if HIF-1 is expressing) http://astrocytomaoptions.com/targeting-tumour-metabolism/
· **Disulfiram – This drug looks like it has amazing potential.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=707
· **Sildenafil & Celebrex: can work synergistically for both getting past blood brain barrier, anti-tumor qualities, and Celebrex potentially helping with a bit of edema.
http://onlinelibrary.wiley.com/doi/10.1002/jcp.24843/abstract
· VT-122 (Etodolac & Propranolol) – with low dose daily TMZ schedule. This had great results. Any reason why more people aren’t doing this themselves?
(http://meetinglibrary.asco.org/content/151704-156)
· CUSP9 – Looks like an amazing plan. I am yet to read of any results but I know many are starting to replicate this cocktail on their own.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2408
Current Plan:
I. TMZ Schedule – Because he is MGMT methylated it was an easy decision to go forward with the monthly TMZ cycles. All of our docs have insisted on the high dose 5days/month schedule rather than a metronomic schedule, regardless of whether EGFR is over expressed. Thoughts?
https://academic.oup.com/jnci/article/107/5/djv041/891259/EGFR-Amplified-and-Overexpressing-Glioblastomas
II. Optune Machine – The UCSF board feels it’s not as beneficial as some of the studies make it out to be, and with it being such a pain to wear for the rest of your life… it’s not that easy of decision even with insurance coverage. I’m undecided here.
III. Prescriptions with TMZ/Avastin - If you had to pick one prescription duo to take with TMZ and one prescription duo to take with Avastin to make them more effective which would you pick?
Thank you all for pitching in. This journey has been life changing, but manageable with the help you all bring.
Welcome Ari,
ReplyDeleteYour post covers a lot of ground, and I'm probably going to respond in multiple installments.
Looks like you're on the right track, and have lots of good supplements in place already. There's no way of knowing how sulfasalazine would compare in efficacy with CROnaxal, and they would work by different mechanisms to control the glutamate levels around the tumor. You could always hedge your bets and do both. Sulfasalazine is so cheap the expense would be negligible. According to current data maybe 50-60% of GBMs overexpress the transporter (System XC) that is responsible for the harmful glutamate levels around a GBM tumor, and both CRONaxal and sulfasalazine could help attenuate those high glutamate levels. (In contrast, IDH1 mutant tumors probably take in, rather than release glutamate and convert it to 2-hydroxyglutarate, which can build up around the tumor and be problematic in a similar way that glutamate is in IDH non-mutant GBM).
The Foundation One report, which is a great thing to do if insurance will cover the cost (it's quite expensive), will tell you what mutations or gene amplifications and deletions - which all involve changes in the DNA code - there are in the tumor. It won't tell you about over- or underexpression of genes, like VDR or HIF1a. It will only tell you which genes are mutated.
Installment 2 coming tomorrow :)
On the subject of vitamin D, the study I referenced on the Supplements page was an in vitro study, showing that the hormonally active form of vitamin D (calcitriol) caused increased proliferation in one or two GBM cell lines but inhibited proliferation in other GBM cell lines. This is difficult to interpret, since the assay used in the study was a viability assay that only estimates the number of viable cells, but doesn't say anything about qualitative changes in the cells. For example, calcitriol is known to cause cell differentiation, and in other cell types (myeloid leukemia cells for example) the cells undergo a burst of proliferation before they undergo terminal differentiation after treatment with differentiating agents. One way to detect cell differentiation would be through flow cytometry, but this was not used in the vitamin D study referenced.
ReplyDeleteI've not seen any in vivo rodent model or human study where vitamin D supplementation worsened tumor progression. I suppose there's a chance of that happening, but I've not seen any documentation of it. On the contrary, in one study that retrospectively looked at the influence of various supplements on survival with GBM, vitamin D was the only supplement that had a statistically significant positive influence on survival.
https://academic.oup.com/nop/article/2/3/122/1036239/Complementary-therapy-and-survival-in-glioblastoma
It seems to me the weight of evidence is still in favor of vitamin D, but I can't say with 100% certainty that the outcome would always be beneficial, unfortunately. Testing the tumor sample for vitamin D receptor (VDR) by immunohistochemistry is possible but you'd have to find a lab able to do this testing. This is by no means a standard test for GBM.
Chloroquine is high on my list for GBM, and I'm especially intrigued by the potential of the chloroquine (or hydroxychloroquine) combination with rapamycin (aka sirolimus) as used in this case series and now in clinical trial:
https://www.omicsgroup.org/journals/sirolimus-and-hydroxychloroquine-as-an-addon-to-standard-therapy-for-glioblastoma-multiforme-case-report-2167-7956-1000141.php?aid=73417
https://clinicaltrials.gov/ct2/show/NCT03008148
I'm less thrilled about the use of sildenafil (aka Viagra), a PDE5 inhibitor, after this study was published:
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14656
The etodolac + propranol trial looks impressive on the surface, but would be more (or possibly less) impressive if the full details were published - there is lots of missing data in the abstract. Still, there is good evidence for the use of propranolol in other cancers. Etodolac is a COX-2 inhibitor (like Celebrex) and I'd consider it to be an alternative to Celebrex, but I wouldn't necessarily recommend taking both.
The study on metronomic TMZ and EGFR amplification is interesting, though there may have been some selection bias contributing to the results. It doesn't say anywhere in the study why some of the patients were selected for the metronomic schedule, and this was a retrospective study, not a randomized trial. I'd go along with the standard schedule if MGMT is methylated. On the other hand, if MGMT status was unmethylated and EGFR status was amplified I would be more inclined to fight for a metronomic schedule (but every oncologist that I know of is going to want to prescribe the standard of care).
ReplyDeleteIf they are inclined to doubt the positive results of a well-designed phase 3 trial of Optune for newly diagnosed glioblastoma, I hope they're willing to provide reasons for this skepticism. Sure, Optune probably won't help every patient, but neither does chemotherapy. The most any therapy can offer is to increase the odds of survival, and to me, Optune does increase the odds. To my thinking, if it leads to several extra years of survival it will have been well worth the trouble. A review of this study would be worthwhile, showing several patients seeming to have long-term benefit from Optune, even though it was discontinued after 12-18 months.
https://www.ncbi.nlm.nih.gov/pubmed/23095807
With such a dire diagnosis as GBM, I don't see the logic in not considering all tools at ones disposal (this is directed to oncologists who are still not making Optune available or educating patients about it), especially so if the "tool" is one of the very few approved for that indication, and has no systemic toxicity the way that chemotherapy does. Of course, as with any treatment, it should ultimately be up to the patient.
Many things have been tested in preclinical work in combination with TMZ, and have shown benefit, so it's hard to narrow it down to a couple choices.
ReplyDeleteIt's easier for Avastin, as only a couple widely available drugs have been tried in combination with Avastin in rodent studies and shown benefit, namely chloroquine and dichloroacetate (also cannabidiol, but that study has only been published in abstract form).
Stephen thank you so much for this all inclusive response.
ReplyDeleteWe have decided to move forward with 5,000IU/day of Pure Encapsulations Vitamin D3. I'm currently in the hunt for the best source/price for CROnaxal and will then make the decision on it VS. Sulfasalazine or both.
Chrloroquine is now high on my list for further research. I'm working to put what I feel is the most convincing data in front of our NO(s) and see why or whether they still combat it. Fortunately our docs are very helpful and willing to prescribe most of these prescriptions, I can just tell they have no belief in them whatsoever.
Thanks again for everything and stay tuned!
Hi Ari,
ReplyDeleteSorry to hear about your dad, but take some encouragement that you are doing the work needed to improve his outcomes over the typical standard of care.
While I only have oligo and not GBM, I have looked into the tradeoffs of different chemo choices a bit and so will add in my 2 cents.
One possible route is to consider being more aggressive with chemo than the typical SOC once you get thru RT. TMZ is the SOC over PCV mainly because it proved to have similar efficacy without nearly the risks of blood count complications. But a number of studies have either looked at combining CCNU and TMZ, or TMZ and procarb for cases of recurrent GBM with some success and a few have done it upfront with encouraging results.
CCNU is the harshest of the 3 and CCNU is also quite similar to TMZ. Procarb is also an akylating agent but also is suspected to have additional mechanisms where it interferes with RNA and enzyme synthesis (though its not well understood). So one strategy could be to ramp up intensity -- start with TMZ for 1-2 rounds and see how his counts do. Then add procarb if safe. Then maybe do CCNU alone, then CCNU + TMZ. There are partial studies looking at this but it would likely take a very willing NO to do this and it might also really reduce QOL so please, please take this with a grain of salt. Also with my oligo I am IDH1 mutated and so all of this may not apply as well.
So probably Stephen can weigh in with better input on this.
One other side item on your supplement list. Be cautious about hindering the impact of RT and to a lesser extent CT. In a simplified sense you don't want to add anti-oxidents on top of RT/CT. So Green tea might be very suspect, and to a lesser extent D3 and circumin.
Bryan
The issue of supplements during radiation is actually complex. Curcumin and Vitamin D, among others, is probably a *good* thing to be taking during radiation:
DeleteRelationship and interactions of curcumin with radiation therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896895/
A switch between cytoprotective and cytotoxic autophagy in the radio sensitization of breast tumor cells by chloroquine and vitamin D
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277402/
"These studies support the potential utility of vitamin D for improving the impact of radiation for breast cancer therapy. . ."
Curcumin, as well a a number of other agents, protects normal tissues from radiation, but sensitizes glioma cells.
I delved into this literature on such dual-action among available supplements when my wife was undergoing radiation. I don't have time today to re-review what I read. But I came to the conclusion that the only common supplement to definitely avoid during radiation was vitamin E.
It's standard advice among radiation oncologists to avoid taking anti-oxidants, to avoid protecting the malignant cells. That makes sense theoretically, but as demonstrated with curcumin, the actual effects don't match what one would assume.
I agree it is very complex and problematic, especially with some studies showing bimodal responses where moderately increasing levels are bad and greatly increases supplement levels is beneficial.
DeleteI found vit D a little worrying because of how variable the final result was -- D3 supplement into 25OHD into 1.25OH2D with many side metabolites and big variation in conversion rates. Looking at the cell culture study you referenced they tested 100 nmol/L of 1.25OH2D, which doesn't sound like much, but the standard patient level is closer to 100 pmol/L. So they tested a 1000x increase.
So personally I've been a bit cautious with some of the supplements but everyone certainly should weigh their own tradeoffs.