Friday 8 March 2019

Advices before radiation therapy

Dear Stephen, dear all!

My mother had an operation (summer of 2018), not completely removed. There was no radiation therapy. Then she took TMZ 5/23 and Avastin, after 7 courses the tumor began to grow.

Next week Mom starts radiation therapy.
In this connection, I have a number of questions.

1) If TMZ ​​5/23 does not work, can we try the metronome scheme for the period of the radiation? Or is it better to change the medicine? The tumor is methylated.

2) What do you think about platinum drugs with TMZ?

3) Has anyone heard of Vidaza? Our doctor says that in Germany they use it in protocols with glioblastoma.

4) How long before radiation therapy should she take thc/cbd oil so that it works as a sensitizer? How much ml? Or we should devide it into 2 doses?

5) Which of the following is better not to include in a cocktail during radiation therapy: (and what is better to add?)

  • Coriolus versicolor
  • Maitake D-fraction
  • Selenium
  • Chloroquine 
  • Celebrex 
  • LDN 
  • Aged garlic (What is the dosage of garlic???)
  • Omega 3 
  • Zinc 
  • Prozak
  • DCA – 25 mg/kg х 2 times
  • Milk Thistle 
  • Dandelion 
  • Wobenzim
  • Berberine 
  • Boswellia WokVel 
  • Pterostilbene 
  • Metformine
  • Depakine chrono 
  • Probiotics
  • THC/CBD


Please help me! Thank you!

15 comments:

  1. 1) A metronomic TMZ schedule at a dose of 75 mg per square meter of body surface per day is the standard way to give TMZ during radiation.

    2) I would sooner add a drug like lomustine before I would add a platinum drug (like carboplatin), given her tumor is MGMT methylated. You could also consider the chemo protocol used in the CeTeG trial, which published results recently.

    https://btcocktails.blogspot.com/2019/02/ccnu-tmz-ceteg-noa-09-phase-3-trial.html

    In the combination arm receiving CCNU + TMZ, cycles were 6 weeks in length, with 100 mg/m2 oral CCNU given on day 1 of each cycle and TMZ on days 2-6 of each cycle, with a starting TMZ dose of 100 mg/m2 and possible escalation up to 200 mg/m2 in later cycles. Cycle 1 starts at the same time as radiation.

    3) Yes Vidaza is the brand name for 5-azacytidine, a demethylating/hypomethylating drug commonly used in myelodysplastic syndrome and acute myeloid leukemia. I've not heard of any study reporting that it's effective in GBM, although there are papers that show it could be particularly helpful in IDH-mutant gliomas, which have pathological levels of DNA methylation. There's even a trial being planned in France specifically for IDH mutant gliomas.
    https://clinicaltrials.gov/ct2/show/NCT03666559
    I don't have a much confidence in this drug for non IDH-mutant gliomas.

    4) I can't answer that with any confidence, as there's been no human trials studying cannabis as a radio sensitizer.

    Some things that have either human or lab evidence as being effective in combination with radiation are summarized in an article I wrote here:
    http://astrocytomaoptions.com/radiation/

    Chloroquine was also used throughout radiation therapy in the Mexican trials such as
    https://www.ncbi.nlm.nih.gov/pubmed/16520474

    Some other people on the blog have tried various combos during radiation with some success, so hopefully others will comment. All the best.

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    Replies
    1. Stephen, thank you so much for you help!!!
      Our first radiation therapy day is the day after tomorrow. I pray for sucsess!

      Please, help me with a few more questions 🙏

      1) How do you think, is it possible to modify scheme CCNU + TMZ next way: give CCNU 100 mg/m2 for the first day of radiation therapy and then give TMZ 75 mg/m2 not just for 5 days but for all radiation therapy period?
      Could it be more effective? Or it will be very toxic?

      2) If tmz 5/23 has already failed could it be diffrent in combination with lomustin?

      3) our doctor want to do not 60 Gr radiation therapy but 45 Gr (15 days for 3 Gr each). He says that it is more effective. What do you think? I’ve never heard about such tactic in case of gbm.

      4) Stephen, have you herd something about allogeneic stem cells transplantation (from donor) in case of gliomas? Our doctor offered such idea. And also he adviced to add cord blood stem cells through spinal canal.

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    2. And one more question. I want to add 25mg/kg * 2 times daily of DCA during 15 days of radiation therapy. Is it good idea? We have nothing to loose.

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    3. 1) I don't know, I've never heard of anyone doing that. It could be too toxic.

      2) There was a trial published in 2010 testing metronomic TMZ for recurrent GBM, divided into three groups based on the timing of first progression/recurrence: (B1) patients who progressed during the first 6 cycles of TMZ, (B2) patients who progressed during TMZ cycles beyond the 6th one, and (B3) those who progressed at least 2 months after completing TMZ treatment. In group B2 (initial progression during late TMZ cycles), metronomic TMZ had very limited benefit.
      http://ascopubs.org/doi/pdf/10.1200/JCO.2009.26.5520

      Just for clarification, did he complete 7 full cycles of TMZ before progression?

      If his tumor progressed while on TMZ, I might be inclined to try Lomustine + Avastin instead of continued TMZ. Lomustine alone can be hard on blood counts, and adding TMZ will be even harder, and might not be worth that risk if the tumor has a resistance to TMZ.

      One way an MGMT-methylated tumor can become resistant to TMZ is by acquiring mismatch repair defects (for example, mutations in MSH6 or one of the other mismatch repair genes). If that is the case, TMZ will not only be ineffective, but can lead to "hypermutation" and a more aggressive tumor, due to the acquisition of new driver mutations. (Although these hypermutated tumors may be more likely to respond to immunotherapy).

      My opinion is that lomustine is a better choice for recurrent MGMT-methylated tumors that progressed on TMZ. Cell studies have shown that mismatch repair defects can make the cells more sensitive to lomustine (CCNU) and BCNU, but resistant to TMZ and procarbazine.

      3) This would be called a "hypo fractionated" regimen, which means larger single doses, but fewer fractions. These hypo fractionated radiation regimens are more commonly used for re-irradiation of recurrent GBM. There are a number of reviews online, for example
      https://academic.oup.com/neurosurgery/article-abstract/82/1/24/3866410



      Hypofractionated radiation (40 Gy in 15 fractions = 2.67 Gy per fraction) has also been used in older populations (over 65).
      https://www.nejm.org/doi/full/10.1056/NEJMoa1611977

      4) I'm not sure exactly what is being offered. Do they want to try intensive high-dose chemo and then repopulate the blood and bone marrow with stem cells? As for example
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219984/

      25 mg/kg twice daily of DCA is fairly high dose. In the clinical study published in 2010, they started patients at half that dose, and if that was tolerated they went up to 25 mg/kg twice daily.

      "We treated patients with a starting dose of 12.5 mg/kg orally twice a day for 1 month, at which point the dose was increased to 25 mg/kg orally twice a day."

      What he has to lose from too high a DCA dose is quality of life, especially peripheral neuropathy and also central nervous system side effects. See a review of side effects under "Safety" on this page:
      https://medicorcancer.com/dca-therapy/

      Neuropathy can take some time to develop though (weeks to months) so he might not have those side effects if treatment lasts for only 15 days, but I would still keep a close watch for early symptoms of DCA toxicity.





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    4. Dear Stephen! Thank you very much for your reply!
      1) it is difficult for me to say when TMZ failed and whether it had worked at all because we startet avastin along with tmz from the very beginning. MRI was at the end of November, where the tumor was stable, it was my mom’s 4 course of tmz. Since the beginning of November, we did Avastin once every 3 weeks, and then we had to take a break for a month due to an adverse reaction. On February 7th (it was the end of 6 course) MRI showed that the tumor had grown strongly. We immediately continued to take Avastin, increased it to 600 mg.
      2) today is the first day of radiation therapy (15 days, 3 Gr). I thought for a long time and decided that we would try Lomustine 160 mg and tmz for 5 days 240 mg (my mother is 170 cm and 56 kg). We also continue Avastin 600 mg. But today our doctor said that we should take only lomustin for 4 weeks (40 mg for the first day of each week), 160 mg at all. Than 2 weeks break
      How do you think, is it right decision and right schedule?
      3) Stephen, what do you think about val-083 in our case?
      4) we were offered therapy with dendritic cells, but there are different options:
      - by blood test
      - on the card file of other tumors (because we don’t have frozen tumor)
      Does this make sense?
      5) there are so many ways to act, viruses, dendritic cells, stem cells therapy, heat shock proteins. I want to try any chance, but how to choose...? 🙏

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    5. Hi Irina,
      I've not heard of lomustine given on any other schedule than once every 6-8 weeks. I have no comment on a once weekly schedule because I've not seen this used before. I would at least ask why he or she wants to use a 40 mg/week schedule rather than a 160 mg/6 week cycle schedule. The cumulative dose will be the same. Perhaps her doctor has experience that this schedule is better tolerated than the standard schedule? There must be some reason for her doctor choosing a non-standard schedule.

      VAL-083 will be more difficult to obtain than lomustine, as it isn't yet approved. VAL-083 is a good choice of chemotherapy for MGMT-unmethylated tumors because it has a mechanism of action that is independent of MGMT. For MGMT-methylated tumors there isn't a strong rationale to use VAL-083 instead of TMZ or lomustine.

      Who offered therapy with dendritic cells? I would have to know more specifics or have a link with further info before I could comment.

      Almost all of the clinical trials I would recommend are in North America or Europe, and I don't know any in Russia I could recommend. But if you are able to travel to Europe for a clinical trial I could suggest some trials ongoing there.

      Has her tumor been tested for EGFR status? (EGFR mutation or amplification).

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    6. Stephen, thank you so much for your answer!
      Our doctor prescribed once weekly schedule because he is afraid of drammatically blood counts drop. But at the end we decided to take 160 mg once.

      We have some medical universities and clinics in Russia, offering dendritic cells. Methodology is diffrent:
      - vaccine on the basis of your tumor
      - vaccine on the basis of a blood test (supposedly the tumor cells can be removed from the blood)
      - vaccine based on other tumors catalog
      Don’t know, which type is morre effective? We are looking at dc vax, but it is so expensive and there ia a big turn. Probably you could advise some good dendritic cells vacsines?

      We are availiable to travel! Could you please reccomend us the best trials?🙏

      We don’t have enough tumor material to test EGFR status.

      We are also looking forward optune trials, because we cann’t afford this devise without trial... how do you think, is it worth trying? For excample this: https://clinicaltrials.gov/ct2/show/NCT02893137?term=Optune&cond=Glioblastoma&rank=3 ?

      Thank you for your time and help!

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    7. Sorry for the delay Irina.
      Vaccines made from a tumor lysate usually require frozen (in liquid nitrogen) tumor tissue. This is the method used by DCVax for example. The standard FFPE preserved tumor tissue can't usually be used, or is of inferior quality for this purpose.

      Sometimes if there's no frozen tumor tissue available, tumor antigens can be extracted from the blood, but this method isn't as preferable because tumor cells/ DNA in the blood is very limited compared to using the tumor itself where cells are very plentiful.

      There are also peptide vaccines which use antigens predicted to be over expressed in GBM, but this "off the shelf" method isn't as individualized as an "autologous" vaccine custom-made for each individual patient, as in the first method above.

      As far as I know, DCVax in only available in the United Kingdom through their Specials program and the waiting list is long. I know people who had to wait a couple years. In Germany, IOZK offers vaccines of comparable quality, and they also use Newcastle Disease Virus and hyperthermia to complement the vaccine. They can extract tumor antigens from blood where no properly preserved tissue is available as in this case:
      https://btcocktails.blogspot.com/2018/01/total-resection-followed-by-multimodal.html

      The biggest barrier to vaccine treatment outside clinical trials is often the expense.

      What regions are you able to travel to? Europe only, or North America as well?

      Optune has proven benefit in both newly diagnosed and recurrent GBM, having had two phase 3 clinical trials completed, and has full FDA approval in the USA. The last therapy to achieve this level of evidence in GBM was temozolomide back in 2005. So yes it is worth trying.

      I would reach out to the company (Novocure) directly to find out about availability in Russia or any neighbouring countries.

      "Please email internationalinfo@novocure.com for all inquiries to other countries."

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    8. Dear Stephen! Thank you very much for your reply!

      1. We are ready to go for clinical studies anywhere! The main thing is to choose the most effective for us. Please advise such research!

      2. What do you think about MDNA55 https://clinicaltrials.gov/ct2/show/NCT02858895?term=MDNA55&rank=1 ?

      3. What do you think about experimental therapy (in Russia) on the introduction of dendritic cells with the addition of several viruses (alternately, such as: smallpox, new casle, Hyundai, coxsackie, poliovirus)?

      4. Do you know anything about tetanus vaccine and glioblastoma?

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  2. Stephen, help me please!🙏

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    Replies
    1. Sorry, I must have missed your comment above, will try to answer by the end of the day.

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  3. Dear Stephen! Thank you very much for your reply!

    1. We are ready to go for clinical studies anywhere! The main thing is to choose the most effective for us. Please advise such clinical trial!

    2. What do you think about MDNA55 https://clinicaltrials.gov/ct2/show/NCT02858895?term=MDNA55&rank=1 ?

    3. What do you think about experimental therapy (in Russia) on the introduction of dendritic cells with the addition of several viruses (alternately, such as: smallpox, new casle, Hyundai, coxsackie, poliovirus)?

    4. Do you know anything about tetanus vaccine and glioblastoma?

    Thank you!

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    Replies
    1. Some clinical trial ideas to look into:

      Pembrolizumab in Association With the IMA950/Poly-ICLC for Relapsing Glioblastoma (IMA950-106) in Geneva Switzerland
      https://clinicaltrials.gov/ct2/show/NCT03665545

      Safety and Efficacy of the ONCOlytic VIRus Armed for Local Chemotherapy, TG6002/5-FC, in Recurrent Glioblastoma Patients (ONCOVIRAC) in France. This is a phase 1/2 dose finding trial and I don't know if they've found the recommended phase 2 dose yet, so this is still early-stage without much evidence yet.
      https://clinicaltrials.gov/ct2/show/NCT03294486

      I like the MDNA55 trial, but recent data shows it to be mostly effective in tumors with positive expression of IL4R (interleukin 4 receptor), and they will likely test IL4R expression in the tumor as part of the trial, but you won't know this at the time of entry (unless you get an outside lab to do the testing which would also require a tissue sample).
      https://www.prnewswire.com/news-releases/medicenna-presents-promising-clinical-data-from-phase-2b-recurrent-glioblastoma-trial-of-mdna55-300791451.html

      3) The key word here is "experimental". I haven't seen much evidence for these except for some limited published data from IOZK in Germany on the use of Newcastle disease Virus in combination with vaccines, and the modified poliovirus trial at Duke University. Have the clinics in Russia published any data?

      4) Yes, in some clinical trials at Duke, and at University of Florida they are using tetanus/diptheria injections as a way to increase the efficacy of dendritic cell vaccines. The idea is that the tetanus shot will improve dendritic cell trafficking to lymph nodes, and they've had good results with this. See for example.
      https://www.ncbi.nlm.nih.gov/pubmed/25762141

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  4. Dear, Stephen! Thank you so much for help!

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  5. Irina - My husband was in the phase II of the MDNA55 in Nov '18. 2 1/2 days post surgery he experienced extreme inflamation that left his right arm immobile, a skuffle in his right leg (left frontal tumor). He can't talk much since the trial. Just a few random words that nearly form a sentence, but mostly he is silent now. He had nearly 1/2 the brain filled with inflamation and he was on 24 mg of dexamethasone for about 2 weeks, then we started weening down the dose week by slow week. He had regrowth in March and had a second resection on April 28th (the doctor said it was 60% necrosis/40% tumor removed). Just 3 weeks post surgery the resection showed that the tumor was already growing back around the edges of the resection sight. My husband started CCNU + ADD Rapamyacin trial. He is doing Optune too. His MRI yesterday showed lots of inflamation/no growth of tumor at all. The doctor believes ( but we're all just guessing as there isn't good data yet) that the residual drug from the MDNA55 is causing the cell death (Yay). There is a small area of concern, but it isn't growing. Summary: Major, no joke Inflamation!! You might need a helper to get through the first few weeks. My husband needs some help physically now, but I'm so thankful that the MDNA55 is still in there with the other things we are doing, but I believe that there is a hostile environment from the inflamation/dexamethasone that is making things easier on the cancer to grow back. He is on 2mg a day of dexamethasone at this point (also Diamox, celebrex, boswellia). I'm adding new things to the cocktail all the time and haven't got a good list to post yet. I'll get my act together. Using most of the "A" list cocktail drugs/supplements from Stephen's list except THC at this point. PS - I read a book from a lady who did a good job documenting her medications for cervical cancer. She did tons of research and I feel it's got both helpful information as well as a bit of education on cancer in general: How to Starve Cancer by Jane McLelland. I feel more empowered and knowledgeable when reading this most of all. I wish you a healthy and happiness!! Above all things I've read, Stephen and this site have been my absolute resource on everything. Thank you Stephen, thank you fellow users of this site for all your input. You remain my team and my support network and I'm routing for you always!!

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