Dear Stephen and all,
My 15 year old has been diagnosed with GBM in March 2019. We live in Tokyo, Japan and she is being treated by the hospital famous for treating most of the GBM patients in Japan. I would like to get some advice and insight regarding my daughter's GBM, treatment option, etc. Here is some background information about my daughter:
Initial diagnosis: She was admitted to the hospital after having a facial seizure on the left-hand side. She had a CT and MRI scan, which showed a brain tumor.
Location of the GBM: Right Frontal Lobe, near the Temporal Lobe (near the "surface" of the brain). Size was 2cm.
Result of the Pathology Report (Only received information verbally. Seems to be normal in Japan):
Primary GBM
Negative for IDH 1 / IDH 2
Negative for 1q / 19q deletion
MDMT Methylation: Unknown at this time (although the Neurosurgeon told us that we can get this tested if necessary)
Rx Drug: Keppra 500mg twice a day
My daughter had surgery in March, and she had complete resection. Neurosurgeon told us that 95% or more was resected and everything seen by "eye" was taken out. As of now, she has been recovering without any problems with paralysis or seizures.
Currently she is going to school everyday and getting the Radiation / Temodal (100mg) treatment on an outpatient basis. Thereafter, we have been told that she will be on the 12 cycle Temodal treatment. In addition to this, she is also getting the autologous formalin-fixed tumor vaccine (immunotherapy) for 6 weeks. This is a personally made vaccine using my daughter's tumor that was resected from the surgery. This is not a standard treatment in Japan and the neurosurgeon has told us that there is no guarantee that this will "cure" my daughter but there has been studies done where there has been a prolonged PFS time for some GBM patients who received this treatment. Although this is an expensive treatment, we took a chance because we wanted to try everything we can for our daughter.
Having said that, I would like to get some advice regarding my daughter's GBM:
1) The neurosurgeon team at the current hospital and the former hospital where she was at both told us that my daughter had a lower grade brain tumor (most likely Grade 2, maybe 1 and very unlikely that it would be 3). We were shocked that the actual pathology report came out as Grade 4 / GBM. In addition, the tumor size did not change much from the time of the initial diagnosis in December and when she had surgery in March. Has anyone had experience with this kind of a turnout?
2) Having read many research or studies on GBM, I have been told that being young and being a female seems to have a better prognosis but are there any young adults or adolescents with GBM who can relate to this? GBM seems to be rare in young people so I don't see a lot of researches or studies in this area.
3) Has anyone heard or experienced the autologous formalin-fixed tumor vaccine? I'm wondering if this is just available in Japan. In addition to this, I am thinking of having my daughter participate in the Peptide vaccine clinical trial that is being done at a university hospital here. This is if my daughter meets their criteria and the HLA status, but has anyone had the Peptide vaccine treatment? If so, do you have any feedback?
4) I am thinking of putting her on the cocktail regimen but I haven't found any recipe for adolescents. I'm also not sure if our neurosurgeon will be supportive in my daughter taking supplements. Is there any advice on the supplements that she might be able take at her age? If I want her to take a minimal amount, what supplements should we prioritize?
5) If there are any young adult / adolescent GBM survivors, have you had any difficulties from the side effects of radiation therapy? Our radiation oncologist told us that she will most likely suffer from brain function deterioration and memory issues, which I have been freaked out about. She is a HS student and she would like to go to college. I would like to hear of any experiences from long-term survivors and any advices if possible.
6) After getting the surgery, my daughter seems to be more emotional and seems to get angry easily. She has a hard time controlling her anger. She is a teenager and an adolescent so that may add to this, but she is more short tempered than she was before the surgery. Has anyone had any experience with this kind of issue? If so, is this something that we need to live with, or does it get better?
I have accepted the reality and the GBM survival rate data, but I have lots of hope for my daughter. I would like to do everything possible for her to live a happy life. Any kind of help would be appreciated.
Thank you for your help.
Sorry to hear of this diagnosis at so young an age.
ReplyDeleteAre you able to request an actual copy of the pathology report (hard copy or digital copy). Here in Canada we have to specifically request all documents, otherwise we get nothing.
Information on MGMT methylation status could be valuable and affect future decisions, as well as clinical trial eligibility.
Do you have a link to additional information on the vaccine treatment, or have they published anything in international journals? There are many different types of cancer vaccine. Tumor lysate vaccines usually require fresh frozen tissue (not formalin-fixed paraffin embedded) so perhaps this is a different type of vaccine. I can't comment on the vaccine without more details.
1) This seems like an unusual case: A tumor that looks and behaves like a low grade tumor (not growing in a three month period), being diagnosed as a GBM based on histopathology. You may need to have some genetic testing done to clarify exactly what you're dealing with.
2) GBM (if it truly is a GBM and not a misdiagnosis) usually has a different genetic background in children and adolescents, compared to GBM in middle aged people. Pediatric low grade tumors often have BRAF mutations, and adolescent GBMs in the cerebral lobes often have H3F3A G34 mutation (or H3 G34 for short). Prognosis really depends on the specific subtype of tumor, more than on gender and age.
3) There are all different kinds of peptide vaccines. I would need links to the actual studies before I could comment on a specific vaccine. Although if the links are in Japanese this will be a barrier for me.
4) Again I don't think of age being as important as knowing the specific genetic subtype of tumor. Does the tumor have BRAF mutation, H3F3A mutation, or some other driver... It's possible BRAF was already tested for the V600E mutation with immunohistochemical techniques (IHC). Another reason to ask for a copy of the pathology report.
5) Are they applying standard photon radiation, or non-standard proton radiation? Proton is often used for pediatric cases due to less collateral damage to surrounding brain tissue with this technique.
I don't feel like there is enough information to actually have a good idea of expected prognosis. This may turn out to behave more like a low grade tumor in spite of the histopathological diagnosis of GBM, and I feel like more testing is required.
My son was diagnosed with GBM at age 19, 38 months ago. He has since graduated from college and working full time. He had surgery and chemo/radiation, plus all kinds of re-purposed medication, supplement and CBD/THC. None of these treatments caused any major issue for him. We think the cocktail approach is very important. Best wishes for your daughter.
ReplyDeleteHi Holly8, thank you so much for your encouraging response. It gives me lots of hope that there is a young adult survivor who graduated from college and working full time. I realize that the cocktail approach is helpful to a lot of the GBM survivors. If I may ask, do you happen to have a list of supplements that your son took? Did you use the same kind of supplements that adults take? Thank you very much for your help!
DeleteThis comment has been removed by the author.
ReplyDeleteI'm deeply sorry for you and your family to be going through something so terrifying and painful. Surgery and/or radiation treatment could lead to increased irritability and disinhibition (angry outbursts). Steroids/dexamethasone and its discontinuation could also cause increased anger. And as the mom of a teenage daughter, it could be adolescence. I strongly encourage you to discuss with your neuro-oncologist. It's possible that medication (SSRI, lithium, different anti-seizure med) could be of benefit. Wishing you the best of luck!
ReplyDeleteHi SJ67, thank you so much for giving me information on irritability and disinhibition. I did in fact discuss this with our neurosurgeon (this is what we call in Japan) but he told me this should be controlled in about a year, and that this is something that should be expected considering the surgery that my daughter went through. This is probably somewhat cultural; I think a lot of doctors in Japan opt not to use medication as much as possible unless the patient exhibits a severe psychiatric episode. Its helpful to know that my daughter's outbursts may be from the surgery and/or radiation. Thank you for your insight.
DeleteHi Stephen, thank you very much for your response. I will talk to the neurosurgeon and see if I can get a formal pathology report. I will also ask about the possibility of getting genetic testing done, as this seems critical in finding out what my daughter's tumor consists of.
ReplyDeleteIn regards to the vaccine that my daughter is being treated, following is the study that was published on Journal of Neurosurgery: https://thejns.org/view/journals/j-neurosurg/121/3/article-p543.xml It sounds like there are many different types of vaccines available, but in general, have you heard of any promising results from cancer vaccines?
Also in regards to the peptide vaccines, I wasn't aware that there are different types of peptide vaccines as well. I found the following study in Journal of Clinical Medicine, which is in relation to the peptide vaccine that I mentioned about: https://www.mdpi.com/2077-0383/8/2/263/htm I am not sure how the peptide vaccine works, but any information will be helpful.
For the radiation, my daughter is receiving the standard radiation, which I assume is the photon radiation, which is called IMRT in Japan.
Thank you so much for your help!
Thanks for the link. A different publication describes the actual vaccine manufacturing procedure.
Deletehttps://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1349-7006.2007.00518.x
Briefly, formalin-fixed and/or paraffin-embedded preserved tumor are deparaffinized and fragmented, then an alcohol extract is added, the "pellet" is washed with saline, and suspended in a solution containing tuberculin microparticles. The resulting vaccine is injected into the arm periodically.
This is quite different from the methods I'm familiar with, and different from autologous tumor/ dendritic cell vaccines such as DCVax which require fresh frozen tissue (not formalin-fixed paraffin-embedded), and then a lysate is made from the tissue and mixed with autologous dendritic cells from the patient.
So, I'm not familiar with this kind of vaccine, but the paper reports a 3-year survival rate of 38%, which compares favorably to most large GBM trials. For example Optune + TMZ led to 3-year survival from randomization of 26% in the EF-14 trial. Small trials do often report more favorable outcomes than larger trials though, probably due to some form of patient selection.
And yes, there have been very good clinical trial results (usually early phase) with vaccines for GBM. The phase 3 DCVax trial published very preliminary data, before unblinding, so overall survival results for the entire trial were published (nobody yet knew which patients got vaccine upfront and which got placebo). Still, there were more long-term survivors than one would expect for newly diagnosed GBM. We're still waiting for the full, unblinded data to be published.
Deletehttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
As a generalization I would say that at the current level of technology, vaccines work really well for only a minority of patients, but when they do work for an individual, the results can be very good indeed. Combination treatments (for example vaccine + checkpoint inhibitor) will probably be needed to bring the benefits of vaccines to a larger patient base. Trials are now starting to test such combinations.
Peptide vaccines are different in that they do not use autologous tumor tissue, but instead are based on synthetic peptides (essentially, short proteins) that match proteins that tend to be overexpressed in tumors (tumor-associated antigens), or mutated proteins that are found only in the tumor (tumor-specific antigens). There are a virtually unlimited number of peptide vaccines possible, because of the wide range of tumor-associated antigens and tumor-specific antigens, and a peptide vaccine can consist of any combination of these, and may contain only one peptide or a cocktail of many peptides. Some peptide vaccines are adapted to the individual based on whole exome sequencing of the tumor and identification of immunogenic antigens for each individual tumor.
So it's hard to make any general statement about efficacy of peptide vaccines as there is so much variety in terms of which peptides are used.
Hi Stephen, thank you so much for you detailed explanation on the vaccines. I learned a lot from your information. My daughter is in fact getting the autologous formalin-fixed tumor vaccine right now. We have been told that in general, there is only a need to do one round of shots (1 shot every week for 3 weeks), but because they were able to provide 2 rounds to shots, we have opted to get 2 rounds of this vaccine. This is not covered by the health insurance, so we had to pay out-of-pocket for this treatment. Our doctor had told us pretty much the same thing you said--for patients that have a good response from this treatment, the overall survival rate is good. But this doesn't mean that this works for everyone. We took a chance because we wanted to try anything that would be best for our daughter.
DeleteWe are continuing to search for any other treatments available, including clinical trials and cocktail approach.
Hi Tiara, is the vaccine made by Daichi Sankyo and the University of Tokyo ? They now show very promising results for the Delta 47 modified Herpes virus or at DUKE using the polio virus
ReplyDeleteHi Tiara,
ReplyDeleteMy son is currently using the Care Oncology metabolic 4 cocktail (Metformin, strostatin, Mebendazole, Doxycycline). He has taken Low dose Naltrexone, chloroquine, Disulfiram, Celecoxib, Dichloroacetate (DCA), Valganciclovir (Valcyte) for 6-12 months by various rotation and combination. You can search all these medication online and find literature associating them with clinical benefit for GBM. We have an oncology consultant that prescribe most these medication.
Hi Holly8, thank you for sharing the names of the actual medications. This is very helpful!
DeleteHi Tiara, since you're in Japan have you ever considered the Daichi Sankyo Oncolytic Virus ?
ReplyDeletehttps://translate.google.com/translate?hl=en&sl=auto&tl=en&u=https%3A%2F%2Fwww.amed.go.jp%2Fnews%2Frelease_20190213.html%3Ffbclid%3DIwAR3rLbU6z4MYkAoqr9trLuXQNMwKG9eLYRJd7v8YJiK-Urfex3on7zGtRtE
Stephen and all, I would like to get some insight or advice on one of the supplements listed for the cocktail approach. I've been doing some research in Japan and found out that some people here are using CBD oil. As THC seems to be illegal in Japan, I believe the option we have here is purchasing the CBD oil. I would like to find out the benefit of taking CBD oil for GBM. Also, for people who have been taking the CBD oil, is it worth trying and how are you
ReplyDeletetaking them? Is the taste tolerable?
Thank you for your help!
Hi Tiara - I'm very sorry to hear about your daughter's GBM diagnosis. I was diagnosed with GBM in Sep 2017 myself, and so far thankfully have remained progression free. I am also living in Japan by the way, near Osaka.
DeleteI am using CBD oil and would personally recommend it due to complete lack for side effects (I tried Sativex with THC before, but the psychoactive effect gave me panic attacks sometimes.... just not for me). I am roughly following the below approach, namely medical grade CBD oil from pharmacy of which I currently take around 5-10mg in the morning and around 10mg in the evening, on roughly a 3-day-on 3-day-off schedule as below:
http://ar.iiarjournals.org/content/38/10/5831.long
http://btcocktails.blogspot.com/search/label/cannabinoids_THC_CBD
Obviously, with the cocktail approach you can never be sure what works for you and in which combination. But the CBD oil really has no disadvantage in my opinion, so I would add it if you can.
I am also following the care oncology protocol (Metformin 1500mg + Doxycycycline 100mg + Mebendazol 100mg... minus the Atorvastatin, as it made my liver readings rise). In addition, I am taking Celebrex (2x200mg), which may be a worthwhile addition in particular with immunotherapy (see below info site):
http://astrocytomaoptions.com/immunotherapy/
The above cocktail of off-label meds is completely side effect free for me by now, barring the occasional very minor bout of nausea.
I am also currently doing an immunotherapy at IOZK in Cologne, with a multimodal approach including local hyperthermia, virotherapy with NDV virus, and a vaccine produced via liquid biopsy (via blood). I am very happy with the treatment at IOZK, though it can be a bit of a logistical challenge from Asia as on-site presence is required in Germany roughly every 6 weeks or so.
As to supplements, I would imagine the majority most of us take would not be too harmful really. Given the immunotherapy your dauhgter is doing, I would make sure to include mushrooms (e.g. PSK or PSP), Maitake D-Fraction, maybe Reishii... I would also strongly recommend Curcuma (e.g. Longvida), Green Tea catechins (especially EGCG, which you can buy in pill form or get by drinking a lot of good quality matcha or sencha tea.... in Japan, I often buy the little strong cold green tea bottles which have 540mg catechins ("Healthya"), plus I drink a cup of matcha first thing every morning with vitamin c to enhance bioavailability). Furthermore, I suggest you add sulforaphane as well (e.g. by sprouting broccoli sprouts or even simpler by buying broccoli sprout seeds and putting a few teaspoons in a smoothie). You can also buy sulforaphane in pill form, but I think sprouts / seeds are probably a safer bet to get actual sulforaphane as it's a very unstable compound).
Obviously, there are many more things which you should consider adding (e.g. probiotics, Vitamin D, Fish Oil, anti-oxidants....). Many of these may also have benefit for immunotherapies, while additionally acting as chemosensitizers.
I wish your daughter all the best with her treatment, and wish you lots of strength and luck for this difficult journey.
Best,
John
Hi John,
DeleteThank you so much for your response and encouragement. All of the information that you provided is very helpful, especially because you refer to products that can be purchased in Japan. I will definitely look into these. BTW, while you are in Japan, are you actually being followed by a NO in Japan or do you get checked when you go back home?
Thank you for your help!
Hi Tiara - sorry for the late response, as I was travelling in Europe. I am currently not being followed by an NO in Japan, but it is something I may consider in the medium term. For the time being my doctor teams are all in Germany.
DeleteBy the way, I am not sure how you are planning to get the supplements, but one website I am using for delivery to Japan is the following:
https://jp.iherb.com/
I have never had any problems with this, the only caveat being that each individual order cannot be more than something like 14,000 JPY. So I just order several at the same time usually.
Best,
John
Hi John,
DeleteThank you very much for your response. And thank you for sharing the iherb.com website. In fact, I had actually checked this website out when investigating supplements for my daughter. I will probably use this website as recommended by you.
Sincerely,
Tiara
Hi Tiara, have you considered the Delta 47 modified Herpes Virus researched by the University of Tokyo and Daichi Sankyo ? Results seems very promising and it is a few steps from commercialization
ReplyDeleteHope this helps,
Lilpause
Hi Lilpause,
DeleteThank you so much for your comment on Delta 47. Yes, I am aware of this new treatment as this was introduced in a Japanese TV show as well. The results certainly seems promising for GBM patients. As they stopped registering new patients for this clinical trial, I will wait for this to be approved and provided in the market. Thank you for your help!
Hi Tiara,
ReplyDeleteOne of the researchers involved told me that it might take 4/6 months for the government to approve its commercialisation and 2/3 more for them the set a price. From what I've researched at the IOZK they inject the ND virus intra venously, in Japan they solved the blood brain barrier issue by injecting directly into the tumor site though a catheter, showing a much greater results, and that is I why I intend to go there and get the treatment myself hoping I won't get a recurrence before that.
I also heard amazing things about the use of Valganciclovir from various researchers around the globe.
Let me know if you need the email address of the people involved from University of Tokyo.
lilpause73@gmail.com.
Best wishes to your daughter.
Lilpause
Hi Lilpause,
DeleteThank you so much for your message. I will send you a message directly to your e-mail.
Sincerely,
Tiara
I recently also inquired about the G47 Delta treatment option. Indeed, it seems very promising. However, my impression was that it may be a bit longer off than you think (possibly well into the first Half of 2020) as the formal application has not yet even begun. Another thing to consider especially for non-Japan residents is that it seems the treatment requires a one-week stay at hospital each month, for at least 6 months. So it might be a bit of a logistical challenge, depending on circumstances.
DeleteHower, that being said, the initial survival data is extremely encouraging with over >90% 1-year survival rates. Certainly a space to watch~and a possibly good option in future!
Best,
John
Dear Tiara,
ReplyDeleteAs we are also learning new stuff every day, in relation to my brother's GBM, I might say that among other tests, MGMT test could help on searching for additional therapy options (in addition to its prognostic value, which is less important in my opinion, since it does not actually change the treatment).
We happen to find this clinical trials, regarding combined treatment option with TMZ+CCNU, instead on mono-therapy with TMZ only, in relation to methylated MGMT (positive) test result.
Remark - CCNU (Lomustine) is an old known chimo drug, used before TMZ became the standard treatment and it is still an available off-the-shelf drug. Both TMZ & CCNU are alkylating agents with quite similar mechanism of action.
So, in case of methylated MGMT result and good enough KPS factor (the ability for normal/ regular daily functionality, which i'm happy to hear in your daughter case is very good), you may approach the oncologist and convince him to try TMZ+CCNU, based on the following clinical trials.
Yes, they will probably tell you that these are relatively small trials for stage 2 and 3, but I already understood that unfortunately it is all about funds and money. When there is no drug company that support and push the trial, then it is only university fund and ends with a smaller trial that has much smaller chances to become a standard treatment even when it is very successful.
Read these articles well and if it is relevant (methylated MGMT result) I think it worth trying under the regular proper monitoring (blood counts etc.).
We got tentative approval for this combined treatment for my brother and we hope he will have good enough blood counts next month, to be able to start the combined treatment.
Best wishes and health for your daughter,
Regards,
Nissim
The clinical trials:
Phase 2 study - concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma
Full report - https://academic.oup.com/neuro-oncology/article/18/10/1442/2222621
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Phase 2 study - Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide
Summary - https://www.ncbi.nlm.nih.gov/pubmed/19188676
Full report - https://ascopubs.org/doi/full/10.1200/JCO.2008.19.2195?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
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Phase 3 study - Lomustine-temozolomide combination therapy vs. standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter
Summary - https://www.ncbi.nlm.nih.gov/pubmed/30782343?dopt=Abstract
Full report - https://clinicaltrials.gov/ct2/show/NCT01149109
Remark - we also got additional information about the results and its application from Prof. Dr. Herrlinger from Bonn university, who conducted this trial (he was very kind and answered our questions with much details). He said that patients with methylated MGMT GBM and very high KPS (90% and higher) are suggested to have the combined CCNU+TMZ treatment as private trial/ treatment during the initial or adjuvant chimo treatment.
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