Dear Stephen, dear all!
I want to apologize in advance for
the mistakes, because I have not practiced English for a long time.
Some
history:
My mom’s tumor was found on MRI in
2011, doctors did not operate it because it was inconveniently located. One of
the best Russian surgery said that we just have to watch it and do MRI each
year. Seven years it did not interfere, but gradually grew and changed
boundaries, in 2018 epileptic seizures started and appeared contrast on MRI.
07/17/2018 85% of the tumor was
removed.
Three courses of TMZ (5/23) and 6 courses of Avastin. After
the first course of TMZ and Avastin, MRI showed a reduction in the tumor and a
decrease in contrast. Doctors said that radiation therapy should not be done
because of the location of the tumor.
Histology
results:
- glioblastoma;
- MGMT methylated;
- no mutation was detected in 599-601 codons of the BRAF gene;
- diffuse expression of GFAP;
- p53 (norm);
- Ki-67 index - 25%;
- expression of synaptophysin;
- IDH1, NF, CD34 (in the tumor endothelium) was not detected in the tumor cells;
- mutations in 4 exogenes of the IDH11 and IDH2 genes were not detected;
- the deletion of the 19q13 locus was not found (the ratio of the number of signals 19q: 19p is 1.34);
- a deletion of the 1p36 locus was detected (the ratio of the number of signals to 1p: 1q is 0.70;
- in the nuclei of tumor cells a tri-, tetrasomy 19 chromosome is detected;
- microsatellite instability by markers NR-21, BAT-25, NR-24, NR-27 was not detected (tumor phenotype with a stable repair system - MSS);
- PD-L1 expression is not determined;
- Ki-67 index - 25%;
- expression of synaptophysin;
- IDH1, NF, CD34 (in the tumor endothelium) was not detected in the tumor cells;
- mutations in 4 exogenes of the IDH11 and IDH2 genes were not detected;
- the deletion of the 19q13 locus was not found (the ratio of the number of signals 19q: 19p is 1.34);
- a deletion of the 1p36 locus was detected (the ratio of the number of signals to 1p: 1q is 0.70;
- in the nuclei of tumor cells a tri-, tetrasomy 19 chromosome is detected;
- microsatellite instability by markers NR-21, BAT-25, NR-24, NR-27 was not detected (tumor phenotype with a stable repair system - MSS);
- PD-L1 expression is not determined;
- BRCA1, BRCA2, CHEK2 not found.
My mom's cocktail (weight 63 kg, height 172 cm):
Coriolus versicolor
|
3150 mg. Better take on empty stomach
or with meal?
|
Nexium (esomeprazole)
|
60 mg 2
times a day. Two days before chemo, one day after
chemo. Or she should take it constantly?
|
DCA
|
12 / mg per kilogram 2 times a day and than increasing (ordered but not
arrived yet)
|
Hydroxycitrate (Garcinia cambogia extract) + Lipoic acid + Low Dose
Naltrexone (protocol METABLOC)
|
Hydroxycitrate: 500 mg thrice daily; Sodium R Lipoate: 800 mg twice daily
+ 5mg before bed time
|
ECGC and Sulfofran
|
Could you please advice on dosage of ECGC? And should she take ECGC and sulfofran
only during 5 days of TMZ or all course of TMZ?
|
Boswellia (wokvel)
|
Should be taken only during radiation? If my mom doesn't have radiation
can boswellia affect the tumor positively, or it just reduce edema and that
is all?
|
Ashwagandha
|
What dosage and best trade mark?
|
Aged Garlic
|
What dosage?
|
Maitake
|
Mom takes this mushroom supplement: https://ru.iherb.com/pr/Fungi-Perfecti-Host-Defense-MyCommunity-120-Veggie-Caps/21448
(Maitake (Grifola frondosa) mycelium - 142 mg)
Is it enough or I better buy Maitake D-fraction?
|
Perillyl alcohol
|
I understand that my mom's cocktail is very far from the ideal, but I'm trying to improve it every day.
Questions:
1. Which mutations do we still need to pass to choose the
most effective treatment tactics and select the optimal cocktail? I read on the
forum about EGFR, EGFR III and many other mutations, but I have never heard
about it from mom’s oncologist.
2. What drugs should I add to my mom’s
cocktail that will be maximum effective
in her case (Actuante during 23 days off TMZ, disulfiram with copper during 5
days of TMZ, Artemether during 5 days of TMZ, Captopril, Tagamet, Celebrex, Minocycline
or other)?
I got a bit
confused in such a huge amount of drugs in the Stephen’s library, because in
Russia there was absolutely no one to consult on this topic, 3 chemotherapists
refused to even listen about such methods.
3. My mom also takes Valproic
acid against epilepsy after surgery, but she doesn’t have radiation. Probably
we should change it on Keppra, because she is still on TMZ? Or there is no
need, because her MGMT is methylated?
4. Are there any drugs - MGMT
inhibitors, that can possibly change the status of MGMT methylated to unmethylated?
5. How do you think, should we go from only TMZ to TMZ +
lomustine? And make 12 courses (3 TMZ have already done)?
6. Do I understand correctly that
I should limit mom’s protein intake to 0.83 grams protein per kilogram body
weight?
I want to thank Stephen for the blog! I can’t even
express how useful this resource is!
I wish all of you and your loved ones good health!
Irina
Dear Irina,
ReplyDeleteI could comment on two your questions, which may be verified by someone else.
Ad. Colriolus versicolor and Maitake schedule: I found recommendations to take the mushrooms on empty stomach with vitamin C, to enhance bioviability, as recommended by the mushrooms suppliers. Also, in a few hours interval around the mushrooms application, one should avoid milk products.
Ad. TMZ+CCNU: since your mother is methylated, adding CCNU may be highly beneficial, given the results of CeTeG clinical trial, https://clinicaltrials.gov/ct2/show/NCT01149109. However, the combo is highly toxic for blood platelets and neutrophiles, which must be closely monitored. It is much more toxic than the TMZ alone. Therefore the standard 4-weeks TMZ cycles must be extended to 6-weeks, or to intervals, after which the platelets counts are larger than 100,000 and white cels >2000 (see the CeTeG information in the link provided). You may found many posts on this subject in this blog, also regarding the cycles number. It may be not possible to continue TMZ+CCNU with standard does proscribed in the CeTeG trial, for as many as 12 cycles, given the cumulative toxic effects of both agents, but of course different people react differently, and the doses may be lowered, if the standard ones cannot be tolerated.
In our case, we could not continue TMZ_CCNU (standard doses) treatment beyond 4 cycles due to the toxic effects, in spite of extending the cycles to 8 weeks, when the treatment schedule starts to be problematic. But people here report standard schedule of 6 cycles without problems. Please consult these posts closely, since I am not a doctor (click label CCNU_lomustine on the right).
Best wishes,
Stefan Sobieski
Answering your questions Irina:
ReplyDelete1. Which mutations do we still need to pass to choose the most effective treatment tactics and select the optimal cocktail? I read on the forum about EGFR, EGFR III and many other mutations, but I have never heard about it from mom’s oncologist.
You need to get a FoundationOne or Caris test done for your tumor to be able to know mutations like these. You can go for targeted therapies/clinical trials basis the mutations. Please note that the mutations of the disease keep changing with time and treatment, but the knowing the tumor mutations is a great start.
For instance, tumors with EGFR, EGFR vIII+ have had significantly improved survivals with chloroquine. There cane be other examples.
2. What drugs should I add to my mom’s cocktail that will be maximum effective in her case (Actuante during 23 days off TMZ, disulfiram with copper during 5 days of TMZ, Artemether during 5 days of TMZ, Captopril, Tagamet, Celebrex, Minocycline or other)?
Would suggest adding Accutane after her chemotherapy because that is when the trials have seen improved survival rates. You can add Celebrex immediately at a dosage of 400-600 mg.
I got a bit confused in such a huge amount of drugs in the Stephen’s library, because in Russia there was absolutely no one to consult on this topic, 3 chemotherapists refused to even listen about such methods.
Yes, almost all oncologists wouldn't agree to alternative treatments. You'll have to do your own research work. Blogs like these/Facebook groups are a great start, and look for researches that have statistically significant data.
Consult Naturopath oncologists like Patrice Surley that can help you with lot of good supplements that are great adjuvants to the chemotherapy.
3. My mom also takes Valproic acid against epilepsy after surgery, but she doesn’t have radiation. Probably we should change it on Keppra, because she is still on TMZ? Or there is no need, because her MGMT is methylated?
Would suggest adding Keppra because keppra helps in improving the methylation of the tumor, which is a good thing for the chemotherapy.
4. Are there any drugs - MGMT inhibitors, that can possibly change the status of MGMT methylated to unmethylated?
(Don't know the answer to this)
5. How do you think, should we go from only TMZ to TMZ + lomustine? And make 12 courses (3 TMZ have already done)?
My mom was at exactly at the same point as yours. Switch to TMZ + Lomustine, and try to do 6 cycles of this combination(a total of 9 cycles, that is). The TMZ+Lomustine combination has seen significantly improved survival for methylated tumors.
Please take note that this a way more toxic treatment than TMZ alone, so do only has many cycles as her blood work/body allows. Something that Stefan has already spoken of.
6. Do I understand correctly that I should limit mom’s protein intake to 0.83 grams protein per kilogram body weight?
Yes. Would suggest you keep it between 0.6-0.8g of protein in her diet, because the cancer cells can feed on protein too. Definitely wouldn't suggest supplementing with whey protein, which I see a lot of patients do.
Good luck!
As Sahil mentioned, working with a practitioner specializing in brain cancer for advice on nutrition and supplements could be useful for you.
ReplyDeletehttp://www.patricesurley.com/
1) It's not clear from her pathology what exact type of tumor this is. The fact she went 7 years with observation only suggest this is not the typical type of adult GBM and may not have the same common mutations as the typical adult GBM. Most adult GBMs have gains of chromosome 7, a loss of chromosome 10, and mutations in the TERT promoter. If her tumor doesn't have these alterations, then her tumor is probably a different class of GBM. EGFR is the most targetable of the commonly altered genes in GBM so having EGFR testing (EGFR amplification, or also expression of the EGFR protein by immunohistochemistry) could be useful. Larger-scale genetic testing by companies such as Foundation Medicine (USA), or Caris, or OncoDNA (Belgium) is expensive (several thousand dollars), and may or may not lead to actionable treatment options, but they may help clarify what type of tumor it is.
2) The cocktail approach is highly experimental, which is why oncologist's refuse to comment on it. Nobody knows what combination is optimal, because every tumor is different. I have given an approximate ranking in the drug/supplement spreadsheet (A,B,C,D) based on my own research, ease of access, and my subjective opinion, and the things higher on the ranking are the things I would focus on. But that is just my own system and not definitive. As Sahil mentioned, I would not use Accutane until chemotherapy cycles are completed, because it could interfere with the efficacy of chemotherapy.
3. Keppra doesn't change MGMT methylation status, but in a small group (n=4) there was less MGMT protein in the tumor after starting Keppra compared to before starting Keppra. There is some evidence from Korea that patients taking Keppra while on TMZ do better, and to prove this they are conducting a prospective clinical trial, but we don't know if the benefit (if there is any) is due to effects on MGMT expression or some other mechanism. In North America Keppra is generally used as the most common anti-seizure drug for GBM.
4. There are drugs that have an influence on MGMT expression in the lab (rodent studies) such as fluoxetine (Prozac) and these could be especially helpful for tumors with unmethylated MGMT [unmethylated MGMT gene promoter -> higher expression of MGMT protein; methylated MGMT promoter -> lower expression of MGMT protein]. For your mother, because her tumor has methylated MGMT (leading to lower expression of MGMT protein), MGMT inhibitors are not as important for her.
On the other hand, if you're worried about inadvertently shifting MGMT status from methylated to unmethylated, I'm not aware of any of the common cocktail drugs that are proven to have such an activity. Hypomethylating agents such as 5-azacytidine and decitabine could have this kind of activity, but these drugs aren't commonly used in GBM.
5) This really depends on the tolerability of the combination regimen for her. Also it is hard to implement the combination regimen without an oncologist's co-operation, because TMZ alone is a 4 week cycle, and CCNU + TMZ is a 6 week cycle. We've discussed this on the blog recently:
http://btcocktails.blogspot.com/2018/10/lomustinetemozolomide-combination-for.html#comment-form
6) There is no clinical evidence stating that limiting protein intake has a survival benefit for GBM, but there are mouse studies showing this in other types of tumors. The ketogenic diet limits protein intake because the body can convert protein into glucose so it can be hard to get into ketosis if protein intake is high. When the body is healing from surgery or chemo, the requirement for protein goes up. This would be something to discuss with a cancer-focused nutritionist.
Standard temozolomide 5/23 dosing at 200mg/m2 for a 2m2 man is 5 x 400mg = 2000 mg / 28 days.
ReplyDeleteWith the CCNU+TMZ schedule it is 200mg CCNU followed by 5 doses of 100mg/m2 = 1000 mg / 42 days (6 weeks). Therefore comparative TMZ dose is 1000 * 28 / 42 = 667 mg / 28 days.
I can see that with CCNU the TMZ dose is much less (667 mg vs 2000 mg) but we have added 200mg of lomustine on day 1 / 40.
Can we then attribute the increased toxic effects to the single 200 mg of lomustine ?
I would say yes that is correct. The 100 mg/m2 dose of lomustine is only slightly less than the standard 110 mg/m2 dose when used by itself or within the PCV protocol. 100 mg/m2 lomustine is still in the upper dosing range. Combined with Avastin they go down to 90 mg/m2, but even that is not always sustainable for more than a few cycles.
DeleteSo yes I would say adding the single dose of lomustine on top of TMZ is going to lead to increased toxic side-effects.