Wednesday 14 February 2018

Need recommendations for consulting for CCNU+Temozolomide for my mom

Hi folks,

My mother is a GBM patient who was diagnosed in September. Her GBM is IDH1/IDH2 -ve, is methylated and she almost had a complete resection. She has completed her 6 weeks of radio/chemotherapy and has complete 2 cycles of 5/23 temozolomide. The following study about using a combination of CCNU(Lomustine) + Temozolomide for methylated GBMs has had me interested for quite a while now:

http://btcocktails.blogspot.in/2017/11/sno-summary-episode-1-ceteg-trial-ccnu.html

I wish to switch to the CCNU + Temozolomide cycles for my mom since this protocol, I see it brings about a significant improvement in life expectancy for methylated GBM patients.

However, when I brought this up to my oncologist, I received quite some discouragement on doing this protocol because he said it wasn't global standard of care, which is why I began with the usual temozolomide cycles. I recently got to know that this is almost standard treatment given by oncologists in Germany with methylated GBMs.

I reached out to several oncologists in Germany to consult on this protocol via skype/call, but they refused to do so since it is a toxic therapy and they don't want to do it from distance.

I'm stuck. I probably know this protocol will definitely help improve my mom's life expectancy but I don't have an oncologist to do this protocol under.

My questions

 - Can somebody with a good oncologist/hospital in/outside Germany which can consult me on skype/call for this chemotherapy protocol? It shall be of great help for me.

- If you don't know of one, would you recommend switching to the Lomustine+Temozolomide cycles by myself? I don't really want to self medicate since I don't know the answers to the following questions:

a. Whether it is okay to switch from temozolomide to temozolomide+lomustine cycles
b. What are the possible side effects that can happen with this chemotherapy regime and how to tackle them(Low blood counts, nausea, weakness, headache etc)
c. How many more cycles of Lomustine+Temozolomide cycles should I really do, and how should I dose them.
d. Reactions with the supplements that my mom already is on.

I really look forward to your response.
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22 comments:

  1. Stefan14 February 2018 at 16:50

    Hi Sahil,

    our history is very similar to your's, we are now under the TMZ+Lomoustine treatment. After radiation +TMZ, our oncologist decided to try the first cycle with TMZ alone, and then we switched to a second cycle with the CCNU. So it may answer also your question.

    Unfortunately, I may confirm that the drug is very toxic, since the platelets dropped down to 50,000 and it's the 4th week after the first day of the chemo cycle. During all the TMZ therapy so far they were never smaller than 120-130,000.

    I may also confirm that it causes severe fatigue. Our doctor says that we must monitor the blood, and if the tendency continues we must be back in the hospital. I do not know, how to prevent the platelets drop, so if someone of you has an idea, what can be that prevented, I would be very grateful to hear. Btw. besides the fatigue, there is no other strong side effects (at least so far).

    The CCNU is prescribed at the first day at 6-week cycle with 5 days TMZ. I do not remember the exact dosage of Lomustine, likely 75mg/m^2, I am pretty sure that our young adult person takes ~110-120mg. I will check tomorrow and let you know.

    I do not know yet for how long the mix is prescribed, I suppose that for 6 cycles.

    My primary concern is also supplements, since our doctor does not want to prescribe any drugs besides the official combo + some anti-vomitting and anti-seizure drugs; as Semyon wrote in one of his messages, we are on our own and must decide whether or not take additional drugs.

    Regards,
    Stefan

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    1. Stephen W14 February 2018 at 17:23

      Dosing and scheduling details here:
      https://clinicaltrials.gov/ct2/show/NCT01149109

      CCNU dose is 100 mg/m2 and TMZ at also at 100 mg/m2 with provisions for stepwise increase of TMZ dose up to 200 mg/m2. It also specifies 6 cycles of treatment for both arms (TMZ + CCNU or TMZ alone).

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    2. Stephen W14 February 2018 at 17:40

      Melatonin could potentially help with platelets. There are studies on its use to treat idiopathic thrombocytopenic purpura.

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    3. Sahil Pruthi14 February 2018 at 23:09

      Hi Stephan,

      Thank you for sharing your journey with this treatment protocol so far. Is it possible for you to refer your oncologist to me, so that I can ask him/her if they can help me take this treatment protocol from distance?

      As far as platelets are concerned, I have a lot of good ideas that have worked for my mom. You can use one/all of the following:

      1. Papaya leave tea - 2 to 3 times a day
      2. Giloy - 400 mg twice a day
      3. Tahini
      4. Marrow plus - 6 tablets a day(Haven't used this, but have read a lot of positive feedback for this product)

      Hope this helps.

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    4. Stefan15 February 2018 at 16:50

      Hi Sahil,

      thanks so much for your response and advise.

      Our oncologist is extremely busy in a pediatric hospital in which she works, and I have no direct contact, besides a kind of emergency phone - something wrong happens, we are permitted or should call her.

      If you could wait for ~10 days, we will see her personally during the next visit in the hospital, and then I shall try to ask. But frankly speaking, she likely will refuse to advise by distance since doctors here are very restrictive regarding procedures and would need to see the patient first. Since your mum is an adult person, it may be an another obstacle. Also, in our case the TMZ+CCNU therapy is somehow experimental but we are "safe" in the sense that if something wrong happens then we are able to reach our hospital within a few hours, and the oncologist knows what to do.

      I am really very sorry that I cannot help you at the moment, I understand your dilemma and the problem.

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    5. Sahil Pruthi17 February 2018 at 10:15

      Oh alright Stephan. I understand that consulting on this protocol from distance might be an issue, but there's no harm in trying. I'm okay waiting for 10 days, would be great if you could ask your oncologist and let me know if she could be of help. I shall wait to hear from you on this thread itself :)

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    6. Stefan25 February 2018 at 14:00

      Hi Sahil, unfortunately our tomorrow visit was postponed since the platelets dropped down to 53,000 and for a preceding week the number did not change; we must test the blood at Tuesday. It seems that the CCNU is toxic much beyond my imagination a week ago. The doctor did not find time to speak with me by phone, so I must wait. But I saw in a post below that you fortunately found a doctor who could help you, this is good news.

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    7. Stefan6 March 2018 at 13:19

      Hi Sahil,

      after my today's visit in the hospital I am really upset. Sadly, the doctor did not find time to speak with me. I asked a few questions on supplements and supportive treatment by e-mail, but I have got only answer that none works. That is it. I am sorry, I think that we are slowly going to be on our own, and so I cannot really help with the on-line consultation.

      Actually, one important thing that I learned in this thread is the proper CCNU+TMZ schedule. Our first round was CCNU+TMZ on the first day, and then 2-5 days of TMZ. I think that the toxic effect of CCNU could be doubled. We start the next round but I am afraid from much worse level.

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  2. Stephen W14 February 2018 at 17:36

    Any oncologist could prescribe this regimen given that both of these are approved drugs for brain tumors. The challenge is finding one that is willing to prescribe something that isn't "global standard of care". There is unfortunately a universal shortage of these. I'd be willing to wager there are a few in India, but I don't know any by name. It's never ideal to self-medicate chemotherapy, it would be much better to have someone overseeing the process, and you would probably need an oncologist to write the lomustine prescription anyway.

    To view photos I took of the slides from this presentation at SNO, go to the Brain Tumor Library -> Conference Slides and Abstracts folder -> 2017 SNO -> ACTR-58.

    The combination led to increased rates of neutropenia, thrombocytopenia (low platelets), nausea (but not vomiting), brain edema, and low grade alopecia. See the slides labeled adverse events 1 and adverse events 2.

    The CeTeG trial specified six courses of CCNU + TMZ, but it would of course depend on how well it's working and how well it's tolerated.

    Drug interaction databases don't typically include non-pharmaceutical supplements/nutraceuticals, so it's hard to say anything about interactions. The Gleostine FDA label doesn't list any contraindications with it.
    https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017588s043lbl.pdf

    Lower doses of lomustine (75-90 mg/m2) could be used if 100 mg/m2 is too hard on the blood counts. 90 mg/m2 is the standard dose of lomustine when combined with Avastin, and I've seen trials even going down to 75 mg/m2.

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    1. Sahil Pruthi14 February 2018 at 23:37

      Thank you so much for sharing all the information and the insights on the possible side effects of using this combination.

      I've spoken to over 15 oncologists here, not one is willing to deviate from the global standard of care, because they tell me they don't have experience with using this combination :(

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    2. Sahil Pruthi17 February 2018 at 12:52

      Hi Stephen,

      One important question on the CCNU+TMZ combination. Trying to connect the dots here and put forth my question.

      In Ben Williams' book, I'd read various researches on 6/12/24 cycles of TMZ and their correlation with life expectancy.

      The research on CCNU+TMZ compares 6 cycles of TMZ with 6 cycles of TMZ. Since my mom is already done with 2 cycles of TMZ alone and will very likely start her CCNU/TMZ combination in her 3rd cycle, how many cycles of CCNU/TMZ should I really be asking for? Should the *total* number of cycles be 6, or should the just the CCNU+TMZ cycles be 6, making it a total of 8 chemotherapy cycles? I'm not quite sure how the life expectancy be affected in both these cases.

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    3. Stephen W17 February 2018 at 16:04

      There is no convincing data that says 6 cycles of TMZ (or TMZ + CCNU) is the optimal number of cycles. Many centers in the US use 12 TMZ cycles as the standard.

      To my knowledge there has only been one randomized clinical trial seeking to answer this question that has published results (6 versus 12 cycles of TMZ).
      https://www.ncbi.nlm.nih.gov/pubmed/28658891
      Comparative Study of Adjuvant Temozolomide Six Cycles Versus Extended 12 Cycles in Newly Diagnosed Glioblastoma Multiforme

      This was a smaller trial (20 patients in each of the two arms), but it did show a significant survival advantage for 12 versus 6 cycles of TMZ. Unbelievably, no data on the MGMT status of the patients was collected, a rather serious limitation for this study.

      Given that up to 12 cycles of TMZ may be better than stopping at 6, but also the fact that TMZ+CCNU is harder on the blood and less likely to be tolerated for >6 cycles, my sense would be to aim for 6 cycles of TMZ/CCNU (making a total of 8 chemo cycles), keeping in mind this number may be limited by hematological toxicity before reaching the 6th cycle.

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    4. Sahil Pruthi20 February 2018 at 11:18

      Thank you Stephen! I finally found one oncologist who agreed to do this protocol in India. This blog and your inputs have been really helpful, hoping it works well for my mom :)

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    5. John20 February 2018 at 11:21

      Well done, Sahil - looks like your determination paid off. Hope the cocktail and treatments work out well for your mom. Good luck!

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    6. Sahil Pruthi20 February 2018 at 11:49

      Thank you so much John! :)

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  3. Stefan14 February 2018 at 18:56

    Thank you, Stephen.

    Perhaps it's out of scope but I immediately found this paper
    https://www.researchgate.net/publication/286207894_Experimental_data_about_melatonin_effects_on_platelet_count_and_functional_activity
    and many other sources. However, I found also this article
    https://www.ehealthme.com/ds/melatonin/low-platelet-count/
    showing that some people report the opposite effect but I think it should be relatively safe on short basis (up to 6 month) or unless an interaction with chemo drugs is present.

    We introduced small doses of 5mg/day just after the TMZ ended; I am afraid to increase the dose to 15-20mg as seen in many coctails, since a neurologist with whom I consulted this did not recommend that due to seizures danger when taking Depakine (Valproic acid, 800mg/day). He also warned me that is it may be risky to change the Depakine drug after taking it a few months to Keppra (levetiracetam), which also appears in coctails - I thought that switching it to Keppra could be the best option as it enhances the sensitivity of GBM to TMZ.

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    1. Semyon15 February 2018 at 00:07

      Stefan, my mom takes every morning Depakine 500mg and Melatonin 20mg before going to bed. Mom also drank a whole month instead of Melatonin Agomelatin 50 mg before bedtime! There were no side effects. Moreover, during the first Melatonin administration, sleep improved. Now mom takes sustained release melatonin 20 mg in bed.

      A month ago, my mother took 120 mg of Lomustine + 5 days of Temozolomide for 140 mg. This is less than in CeTeg. Thrombocytes are normal! Mom also takes a lot of nutritional supplements.

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    2. Semyon15 February 2018 at 00:12

      Stefan, dear, you are not alone, I imagine in what psychological hell you are because of the need to make decisions.

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    3. Stefan15 February 2018 at 16:11

      Thank you, Semyon, I am very grateful for your comments. Yes, this disease is a real hell.

      We will try to increase the melatonin dose in steps.

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  4. Semyon24 February 2018 at 23:19

    Another interesting question is how to take Lomustine and Temozolomide.

    Our doctor recommended taking Lomustine before bedtime.
    Next, you need to wake up at 4 am, take temozolomid and go to bed further.
    The question is, to take Temozolomide the same night, before which Lomustin or the next?

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    1. Stephen W24 February 2018 at 23:33

      I wouldn't take TMZ at 4 in the morning after having taken lomustine the night before. I would probably take the TMZ at the same time of day as the lomustine (before bed). That is, lomustine at bedtime on day 1, TMZ at bedtime on day 2-6. I'm not sure how they did it in the trials, but that's what makes the most sense to me.

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    2. Stephen W24 February 2018 at 23:37

      Or if you want to take TMZ at 4 in the morning for circadian reasons, I would take the lomustine that way as well (lomustine at 4 am on day 1, TMZ at 4 am on day 2-6).

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