Tuesday, 21 February 2017

Avastin & Lomustine Combo

We are considering adding Lomustine to Avastin for recurrent GBM.

Does anyone have experience with this regimen?

Thank you!

4 comments:

  1. In general if you have a new tumor sample and can post biopsy results that is very helpful to frame discussions.

    CCNU (lomustine) vs Temodar have fairly similar function and during initial treatment not that different. Some studies ongoing though to understand hypermutation and if CCNU vs TMZ is much different. Probably not relevant for recurrent GBM though.

    There is some increased logic to switch to CCNU if TMZ was already used. They are both alkylating chemo's which are mainly suppossed to work by attaching to DNA and causing replication failure, though they also have side functions that hurt the cancer too. TMZ though is a mono-alkylate and so the cell enters replication and does replication but then finds errors and so is suppossed to commit suicide (apoptosis). CCNU is or at least can be a bi-alkylate that links across the dna strands and so causes full double strand breaks when the cell tries to initiate dna replication and is only sometimes repaired by a different function (NHEJ).

    BUT both types of chemo can be removed from the dna before replication (like from MGMT enzyme) and so one path of resistance is increased repair function. So CCNU can already be weakened from previous TMZ treatment. But if the cell does start to replicate with CCNU attached then the double strand break will be a 'new' failure mode for the cancer and so CCNU is likely to be at least somewhat more effective than TMZ at rechallenge.

    The cost though is that CCNU is WAY harder on blood counts.

    I would say though that looking into methods to enhance the activity of either TMZ or CCNU would make good sense. In particular either suppressing MGMT or drugs that 'use up' some of the produced MGMT to give the chemo a chance to work (benzyl guanine type compounds). This is into clinical trial territory or at least a VERY flexible NO. But some of the 'cocktail' suggestions on this forum do have potential to help reduce MGMT over-expression.

    Hope that helps, and hopefully others can fill in many gaps and correct some of the mistakes I made (I mean really, give me some slack, I do have brain cancer after all ;)

    Bryan

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  2. Thank you for the detailed comment, Bryan. Do you have any references for the detailed mechanism of action for CCNU as compared to TMZ?

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  3. It is a very complicated area and I am by no means an expert and have just combined reading papers with a few consults with a Doc who did development on CCNU. But here is one of the papers on it that is a good overview:
    https://www.hindawi.com/journals/jna/2010/543531/

    But I'd say this paper didn't provide much info in terms of describing which mechanisms are most prominent and so makes it hard to draw much of a conclusion in terms of what is most relevant.

    From what I could figure out, TMZ mainly works by mismatch repair trying to fix the akylation damage after dna replication has occurred and CCNU mainly works at the beginning of replication by causing a double strand break when the 2 strands attempt to separate when it starts trying to replicate. Both drugs though can be removed from the DNA though during other phases of the cell cycle. So the question of rechallenge is basically did the cancer either mutate or upregulate any functions in response to TMZ and become resistent, and then does switching to CCNU bypass any of those mechanisms. Unfortunately I think the answer is 'it depends'.

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  4. Thank you for the detailed explanation, Bryan!

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