Silibinin effective for brain metastases in lung cancer - 1294931

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daxys
Silibinin effective for brain metastases in lung cancer - 1294931

This seems to be an option for everyone with brain metastases (inform your doctor as it is quite new) ) Here are links to research done in Spain in 2017 where patients brain mets improved significantly by taking silibinin :
https://academic.oup.com/annonc/article/28/suppl_5/mdx366.035/4108588 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5077992/
The results show great improvement - threefold compared to normal situation. It was after WBRT , but it might work on its own according to theoretical part of the research. Dr. Barrera-the head of this research informed me that silibinin was effective on its own in a mice model.
Silibinin (also called silybin) is a major constituent of silymarin - milk thistle extract. In the research they used Legasil - a silibinin extract with increased bioavailability (through Eurosil 85 formulation). Bioavailability could be a problem with regular extracts.
Legasil also contains vitamin E, which according to Mr. Barrera does not probably play any role here.

JimC
Hi daxys,

Hi daxys,

Although this preliminary data indicates that this is a subject which warrants further study, as the authors point out there is a need for additional research before silibinin can be endorsed as an effective therapy. Many cancer treatments which seem effective in small trials, and especially in animal models, fail to deliver on their initial promise.

In addition, silibinin can have effects on the liver, as well as the absorption rate of certain drugs, so I would caution against beginning such therapy without consulting your oncologist. With that in mind, the portion of your post which recommends a beginning dose has been removed.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

daxys
This seems to be solid

This seems to be solid research backed by elaborated theoretical part published last month : https://www.nature.com/articles/s41591-018-0044-4
Some more information is also here :
https://www.cnio.es/ing/publicaciones/a-new-therapy-proves-effective-aga...
https://medicalxpress.com/news/2018-06-therapy-effective-brain-metastasi...
It has also provided consistent results in all phases so far : in vitro, animal models, case study with 2 patients and a trial with 18 patients.
A larger trial is needed, but since silibinin is a cheap natural compound, the large trial will not be financed by large pharmaceutical companies and it might take some time. Therefore I think people should be informed about this option now and of course they should discuss this with their oncologist first.

JimC
Hi daxys,

Hi daxys,

Please do not misunderstand my comments. I appreciate and applaud your desire to bring this possible treatment to the attention of GRACE members. I agree that silibinin has passed the early hurdles in the vetting process, which are more fully described in Dr. Weiss' post on How to vet a treatment idea But as Dr. Weiss states, many proposed treatments are based on solid scientific theory, work well in animal models and show promising results in small trials, only to fail when more rigorously tested in large, randomized trials. We would hope that this in not the case with silibinin, and that it becomes a valuable weapon in our fight against cancer. But that has not yet been proven.

I am pleased that you have added your recommendation that patients discuss possible treatment with silibinin with their oncologist. As you can see from this page from the Memorial Sloan Kettering Cancer Center, there are factors which should be considered by patients and physicians before beginning the use of this (or any other) supplement.

Also, regarding funding for clinical trials of easily available, inexpensive supplements vs. expensive drugs developed and marketed by pharmaceutical companies, while it is true that Big Pharma spends huge sums of money funding trials for drugs they hope will be big sellers, trials are also funded by the government and by private foundations, as Dr. Weiss points out. And many trial concepts are created by dedicated research oncologists whose only motivation is to find effective new treatments. A search of clinicaltrials.gov reveals 24 clinical trials of milk thistle-related treatments for various conditions, despite the lack of profit motivation.

Again, thank you for bringing this promising treatment to the attention of the GRACE community.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

onthemark
Hi daxys,

Hi daxys,

I'd also like to thank you for your informative posts and links on milk thistle related treatment for brain mets.

It certainly does seem promising and if I ever were to get brain mets it is something that I would definitely look into.

How is it working for you Mum? Is she on osimertinib and Silibinin?

daxys
Thanks to both of you for

Thanks to both of you for your comments and your concerns are valid of course. Maybe I should have formulated my post a little differently. People should discuss this with their doctors first and evaluate together the situation and whether it makes sense to incorporate this into their treatment at the moment. My mum has been 3 weeks on osimertinib and she is not taking silibinin with it. Her brain lesion that looked like a brain metastasis on a CT scan is considered rather to be a meningeom (bening tumor) after later MRI evaluation. Even if she had a brain metastasis, I guess it would be a better idea to start treating it with osimertinib alone. Before starting osimertinib my mum was for about 7 weeks without any treatment and in that time she was taking silibinin (her brain lesion was considered to be a metastasis in that time).
We are seeing the oncologist on Thursday. An X-ray will be done to see whether osimertinib is working.
I am afraid it might not be working (my mum does not have any side effects). Then I guess we will have to try chemo or go back to Afatinib. I would like to ask you or other here about the best strategy for possible Afatinib retreatment - I will do that in a separate thread.

Onthemark, I am in contact with a son of a patient who has been taking osimertinib and silibinin together for one year successfully. He said that adding silibinin seemed to reverse the trend of increasing CEA values for his mum. His mum does not have brain mets but he might have added silibinin to delay resistance I guess. There is also some research on silibinin as a potential agent for delaying resistance to TKIs.

onthemark
Hi daxys,

Hi daxys,

What a big relief to hear that your mum has a meningioma rather than a brain met from lung cancer. Your situation is rather complicated. Was thinking that lesion was cancer a factor in switching off of Afatinib or was that done for some other reasons.

There are clinical trials looking at alternating 1st generation TKI's with 3 rd generation. 1 month of one and then one month of the other etc. This is thought to control larger populations of cancer cells and at the same time reduce the odds of resistance developing. There are indications from animal studies that resistance may not develop at all.

I'll respond about my thoughts about silibinin. If it also increases the time to resistance developing then perhaps there is no harm that she had it for 7 weeks, whilst you were waiting for new treatment to start. There's been a surprising amount of research on silibinin over the years. I still have to look into it some more to understand even why it is supposed, theoretically, to be effective.

Are you following your mum's CEA? My oncologist also likes to measure these values and now I go in once a year for scans and blood tests. I have some long lasting side effects from cisplatin but my scans are all stable.

When was your mum's last two ct scans and when did she stop taking afatinib? I am not so sure an xray can measure effectiveness in all cases but it might give some information if the differences are big.

Keep us posted!

onthemark
ps. about the general

ps. about the general question of going back to a previous TKI after developing resistance. This is an evolutionary biology question. There's a population that can develop that is, again, susceptible to the TKI. The longer it has been the larger this population will be.

In one arm of the clinical trial the patients take 1st gen+ 3rd gen together. In the other arm they alternate 1 month 1st gen then 1 month 3rd gen. Of course Afatinib is 2nd gen but there is no reason to think similar principles don't apply.

daxys
Hi Onthemark,

Hi Onthemark,

I put the information on my mum's case into my profile. She stopped taking Afatinib at the end of March. The reason was that the oncologists here (Czech Rep.) can't prescribe TKI's anymore after a patient progresses on them. Which is quite limiting our treatment strategies. We will have to pay for it if we get back on it too.
The last two CT scans my mum had were at the end of February (smaller progression) and then mid June (60% progression).

I am starting to follow my mums CEA right now. The oncologist ordered one test in December 2017 (CEA 1,2 ug/l) another one on our last visit 3 weeks ago (we will learn the results at our visit this week). But the oncologist did not want to do the test regularly from now on, so I decided we will do them on our own. Yesterday my mum had the last CEA test done here in our local laboratory. I was really suprised how low my mums CEA still is. The result of yesterdays test is CEA 1,77 ug/l. So it gives us some hope that osimertinib might be working or at least it stopped the progression.

Thank you for mentioning the research involving alternating 1st generation TKI’s with 3 rd generation. I have not heard of that yet and will try to find more information.

Btw. the researchers who did silibinin trial for brain mets say that based on the mechanisms of its working silibinin could be effective this way for brain mets of any cancer. So this research is potentially a really ground-breaking thing.

onthemark
Hi daxys,

Hi daxys,

Thanks for sharing the information of silibinin and brain mets.

For people on TKI's who get a response, the key to long lasting treatment is preventing, delaying or possibly even reversing resistance. Whatever cancer cells grew since your mum stopped Afatanib in March 2018 did so without the selective pressure on Afatinib and not be under the selective pressure of resistance to it as the cells that caused small progression in the ct scan of Feb 2018.

I hope your mum gets a good result on the xray. When is her next ct scan? You can always add silibinin later if that makes sense to you and your doctor.

Here are three links on clinical trials with protocols for alternating TKI's:

https://clinicaltrials.gov/ct2/show/NCT03122717
https://www.jto.org/article/S1556-0864(17)32030-0/abstract

and also this is interesting.
https://www.frontiersin.org/articles/10.3389/fmed.2016.00076/full

There are a couple of other references regarding alternative TKI's that I have come across but am not finding them now.

onthemark
ps. Here is one of the

ps. Here is one of the articles I was looking for:

"Can We Prevent Resistance to Osimertinib? Combination or Sequential"

https://www.jto.org/article/S1556-0864(18)30625-7/fulltext

And about resensitizing to previous treatment as well as an excellent overall review see:
"Navigating the “No Man's Land” of TKI-Failed EGFR-Mutated Non–Small Cell Lung Cancer (NSCLC): A Review"

https://www.sciencedirect.com/science/article/pii/S1476558617304700

daxys
Thanks a lot for the links,

Thanks a lot for the links, Onthemark.
Actually the guy who I wrote about above (who added silibinin to osimertinib for his mum) also added gefitinib to osimertinib for her, so he kind of used similar combination strategy. His mum was on gefitinib originally. He is on Inspire.com as JunC . By adding gefitinib he stopped her small progression on osimertinib.
My mum's next CT scan will be either at the end of August or at the end of September. I will have to discuss it with mum's oncologist tomorrow. I guess the earlier term willbe better if the X-ray does not show visible improvement.

onthemark
Hi daxys,

Hi daxys,

Thank you for sharing JunC's experience. Since your mum responded to Afatinib there is a good chance it is still a medication that can work for her at the right time and in the right combination.

I hope you see terrific results on the xray tomorrow. Keep us posted!

onthemark
daxys,

daxys,

I would just rely on the xray to prove there is no very bad result or exceptionally good result, like NED. Indeed remarkable turnaround in metastatic lung cancer has been seen in case reports of TKIs and personal experiences one can read about on the web, although that is not the most common situation.

I thought it was an urban myth that those who get side effects from TKIs are more likely to respond, but then I found this 2013 paper: "Skin Rash could Predict the Response to EGFR Tyrosine Kinase Inhibitor and the Prognosis for Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis"

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055128

They were not studying Tagrisso though, which has a milder side effect profile. It seems there are similar types of published results for immunotherapies as well.

Did you mum also have no side effects on Afatinib? I think the fact your mum was stable on Afatinib for a long time is also important to factor in as a positive prognostic. But that is just my thinking.

daxys
My mum had pretty strong side

My mum had pretty strong side effects on Afatinib (just like most patients I guess). Then she had no side effects on pemetrexed (which did not work) Her no side effects on osimertinib might have been be effected by dexamethason she was taking along. It had constipation effect and also it is used to the treatment of rash.
I have read something similar on skin rash and TKI efficacy, anyway I think it does not apply for everyone.

onthemark
Hi daxys,

Hi daxys,

I hope the next ct scan shows a good result. Is your mum still on dex?

daxys
My mum weaned off dex 2

My mum weaned off dex 2 weeks ago.

daxys
I would like to focus this

I would like to focus this topic on silibinin as it still bothers me we are not 100% sure about the best product that would be safe and most effective. I feel rather frustrated and helpless after putting so much effort in communication with Rottapharm/Madaus here trying to get information on their products from Legalon family.

It would also be helpful if had some more information on the efficacy of silibinin products. From my research and information I got from the researches it seems that products with Eurosil 85 formulation are superior in bioavailability. The Spanish researchers used Legasil (with Eurosil 85 formulation). But Legasil contains also vitamin E, which might be problematic.

Silibinin phytosomes (that claim to have increased bioavailability) did not prove to have desired absorption e.g. in prostate cancer trial.

The best product then would be "Legalon Forte Madaus" from Germany. It should have Eurosil 85 formulation and it does not contain vitamin E as Legasil or Legalon E do. Legalon Forte Madaus should be easy to order from Germany.
Unfortunately, the communication with Madaus company has been quite difficult and I am still waiting for a 100% confirmation of the efficacy of the product in the form of some product documentation. The way their representatives here communicated with me does not assure me I can completely rely on their information.

I think it would help if more people tried to contact Rottapharm/Madaus company (from their locations, their local representatives) with the request for confirmation that "Legalon Forte Madaus" contains Eurosil 85 formulation. If we get their reliable confirmation then we will have a really effective silibinin product made in good (German) quality and with superior bioavailability.

onthemark
I'm sorry to hear you are

I'm sorry to hear you are having difficulties getting the specific information from the manufacturer in Germany. I believe the same product as Legalon Madaus is being sold in the US as Thisilyn. You might have better outcome contacting the US manufacturer of Thisilyn at: https://www.naturesway.com/Contact-Us

The ingredient's list does not indicate there is Vitamin E in the formulation.

The following article provides a decent background to the subject although it is a bit dated (2007):
Milk Thistle Nomenclature: Why It Matters in Cancer Research and Pharmacokinetic Studies
http://journals.sagepub.com/doi/pdf/10.1177/1534735407301825

daxys
There is a larger family of

There is a larger family of Legalon products. Most of them are still made using old formulation with lower bioavailability. As far as I know the increased bioavailability can be found in Legasil (sold in Spain), Legalon E (Italy) and probably in Legalon Madaus Forte (sold in Germany) too. There is no information on Thisilyn about its relation to Legalon products. I guess, even if Thisilyn was related to them, it would not be made using Eurosil patentation as it is probably only used in new products made in central locations. The information on Thisilyn does not also say anything about the silibinin content (does not probably have standardized content of silibinin as a percentage of silimarin)

There are many sylimarin products that "boast" with high efficacy, advanced delivery etc., but the highest bioavailability is the reason why Spanish researchers used Eurosil based product and did not choose another one - thats what the head of research (Mr. Bosch) said in his email.

onthemark
hi daxys,

hi daxys,

the research paper that I linked to in my previous post says that legalon is the same as thisilyn, but maybe it is outdated and that is no longer the case.

onthemark
ps my understanding from what

ps my understanding from what you have written is that one would require the Eurosil 85 formulation, irrespective of what the brand name is. I hope the manufacturer answers your questions but in the meantime the Legasil brand that was used in the brain mets studies is the one to go with. Have I understood what you are saying correctly?

daxys
Hi Onthemark,

Hi Onthemark,
Here is what the head of Spanish researcher said to my question about what silibinin extracts could be used:

Q: Should Legasil be preferably used or could it be other Silibinin extract product with high Silibinin content?
Does Vitamin E contained in Legasil play any important role here?

A: Legasil is the best current formulation of silibinin for humans and our clinical research has been done with this product. Legasil has a new formulation of silibinin called Eurosil85, which improves its absortion by our gut. Vitamin E is not providing any benefit for his activity on the brain (it is incorporated due its activity on liver function).

daxys
So if we want to be sure that

So if we want to be sure that we are using an effective product, we should use a product that has Eurosil 85 formulation - Legasil (Spain-contains vitamin E) or Legalon Madaus Forte (Germany-without vitamin E) or Legalon E (Italy-contains vitamin E).

From the results of the research, it seems using Legasil (containing vitamin E) should be without problems, Spanish researchers did not see any negative effect in their patients.

However - the role of vitamin E in lung cancer has been seen as potentially problematic. Vitamin E is an antioxidant and there was a debate about antioxidants and their role in lung cancer. I guess you are familiar with this - if not, here is a link : https://www.reuters.com/article/us-antioxidants-idUSBREA0S1QV20140129). The debate does not have clear results ( it seems antioxidants might be potentially harmful in smokers). Some say antioxidants are OK with lung cancer.

Another thing is that someone might want to try to take silibinin along with TKIs or chemotherapy. In such a case adding high doses of vitamin E could also be potentially unsafe (I guess). The more agents we add the higher risk that it could interfere with the therapy.

Therefore I think it would be safer to use a product that does not contain vitamin E. This product is "Legalon Madaus Forte".

JimC
Hi daxys,

Hi daxys,

I agree that it's good to be cautious in the use of supplements, especially when you are actively receiving anti-cancer treatment. There are so many supplements it's difficult to impossible to test for all interactions, and the industry is not particularly well-regulated. So I agree with your decision to avoid supplements with vitamin E and use a product for which you have been able to get detailed information on its specific formulation.

Good luck with silibinin, and please keep us updated.

JimC
Forum moderator

<p>I began visiting GRACE in July, 2008 when my wife Liz was diagnosed with lung cancer, and became a forum moderator in January, 2010. My beloved wife of 30 years passed away Nov. 4, 2011 after battling stage IV lung cancer for 3 years and 4 months</p>

onthemark
Hi daxys,

Hi daxys,

Are you certain that Legalon Madaus Forte uses the Eurosil 85 extraction? This information should be on the patent information leaflet. I have not been able to get an answer myself to this question.

daxys
Hi Onthemark,

Hi Onthemark,
On Friday I got a reply from the head of Spanish research team who said that also he was informed by Rottapharm/Madaus that Legalon Madaus Forte uses Eurosil 85. So I guess we can trust this information now.
It is rather confusing/weird that it is not specified anywhere in the product information leaflets, you are right.
What exactly is the patent information (link?) where it should be stated?

One more thing : there are more Legalon Forte kinds/producers and only "Legalon Forte Madaus" uses Eurosil 85 formulation.
Legalon forte from other producers such as EmraMed and others are not probably made in Germany and do not use Eurosil 85. I contacted some of these producers earlier and they were not familiar with Eurosil 85 and informed me that their products are imported to Germany. Here is a link to a product that does not use it :
https://www.idealo.de/preisvergleich/OffersOfProduct/4949294_-legalon-fo...