Tuesday, 18 September 2018

Drug Cocktail for Newly Diagnosed GBM


Hi Everyone,

I'm new to the blog and blogging in general. My brother is 3 weeks post op craniotomy for removal of 2cm brain tumor in left frontal lobe - complete resection was not possible but approximately 80% removed. Otherwise Joe is a healthy 35 yo male

Pathology report came back:
Grade IV Glioblastoma, wild type
Negative IDH1/2
Negative MGMT methylation
No amplification of EGFR gene

He will be part of a clinical trial with proton therapy radiation at MGH in Boston.  Joe is gripped by depression but committed to starting treatment - hopefully along with a drug cocktail. I've been helping him research and pull it together. When he starts radiation and chemo in a week or so I would like him to be on below meds / supplements


DrugDosage
Valproic Acid1000mg
Chloroquine250mg daily
Celebrex200-400mg daily
Fluoxetine40mg daily 


SupplementDose
CBD / THCgradually increasing dose
Boshwella 1000mg
Green Tea
Curcumin1000-2000mg +
Melatonin10-20mg
Maitake D 100mg
Fish Oil
Probiotic
Turkey Tail - ie PSK 3000mg
Vitamin D35000-10,000 UI
quercetin500mg
milk thistle 1000-2000mg
Reishi mushroom

This is not a complete outline as I'm using some supplements he purchased and some meds he is already on (valproic acid).  I would love to have any suggestions or thoughts.

I also have some questions for you all (I'm sure the first of many) 

1. How open are neuro oncologist to a cocktail approach? Joe is afraid of asking them about adding anything to the current standard of care 

2. Is it true that unmethylated MGMT tumors are not as responsive to TMZ? Should we ask about a metronomic everyday low dose? What is the current dosing of TMZ in standard of care?

3. Should we look into adding Antabuse, Metformin, or an ACE Inhibitor? 

Best, 

Jenna

*my apologies for any typos 

19 comments:

  1. 1. It depends. Most are not very open. Some are more open than others, and some are actively trying to push the envelope on drug repurposing, for example

    https://academic.oup.com/nop/article/3/3/154/1751853

    It would be good to at least know where his neuro-oncologist stands on this issue.

    2. Yes that is true. MGMT is an enzyme that undoes the work of alkyating chemotherapies such as TMZ, CCNU etc. "Unmethylated" MGMT means the gene can be actively expressed. "Methylated" MGMT means the gene is silenced.

    During radiation, TMZ is given daily in an intermediate dose (75 mg/m2). After radiation, it is given for 5 consecutive days of a 28 day cycle, for 6 to 12 or more cycles, usually at a dose double that given during radiation (150-200 mg/m2). Almost every institution uses this protocol, and most oncologists would resist giving any other schedule, outside of a clinical trial. There is a theory that daily TMZ at a dose of 40-50 mg/m2 (instead of the high dose 5 day schedule), would be more beneficial for MGMT unmethylated tumors due to anti-angiogenic effects, although this theory hasn't really been proven in clinical trials. An alternative strategy would be to use drugs with the intention of inhibiting MGMT activity, combined with the standard schedule. There is observational evidence that the common anti-seizure drug Keppra (levetiracetam) can lower expression of MGMT protein in tumors, although this was a small study with only 4 patients.

    https://www.ncbi.nlm.nih.gov/pubmed/20525765

    One strategy could be to focus on higher dose valproic acid (Depakote) as a radiosensitizer, and then possibly switch over to Keppra during monthly chemotherapy cycles. There is a prospective single arm clinical trial in Korea to test Keppra as a TMZ sensitizer.
    https://clinicaltrials.gov/ct2/show/NCT02815410

    The dose of Depakote used in the most successful clinical trial was higher than a typical anti-seizure dose.
    https://www.ncbi.nlm.nih.gov/pubmed/26194676

    It started at 10-15 mg per kilogram of body weight per day, one week before the start of radiation, and escalated to 25 mg/kg per day by the first day of radiation. These daily doses were divided into two (so 12.5 mg/kg twice daily). For a 60 kilogram adult, this would amount to 750 mg twice daily (1500 mg per day). One of the anti-cancer mechanisms of valproic acid is thought to be HDAC inhibition, and this higher dose might be required for consistent HDAC inhibition in the tumor.

    Multiple clinical trials are testing disulfiram/Antabuse in GBM. As a single drug combined with standard therapies, the outcomes weren't spectacular, but it may be more effective combined with copper, which is also being tested in trials. I like metformin because it not only can control glucose and insulin levels, but there is mouse evidence for beneficial immune effects of metformin, and it is very cheap. It is also well tolerated if you don't escalate the dose too rapidly.

    I like ACE inhibitors (CUSP9 chooses captopril, but there are others) as they might be able to target tumor-promoting macrophages.
    https://www.ncbi.nlm.nih.gov/pubmed/23333075





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  2. Thank you so much for the info. Valproic Acid then Keppra approach may be something his doctors can get behind.

    I was reading this anecdote about Captopril from the first article you linked
    "One important caveat about captopril is its ability as a sulfhydryl donor to scavenge free radicals this may lead to the reduction of oxidative stress. Captopril therefore might lessen the impact of chemotherapy and radiation therapy, which as described above rely to some degree on increased oxidative stress to kill cancer cells."
    Maybe something to add in after radiation and chemo?

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    Replies
    1. If you look at the picture of the captopril molecule on wikipedia, the "SH" represents the sulfhydryl group. Most other ACE inhibitors don't have this SH group, and aren't free radical scavengers. One study says that even non-sulfhydryl containing ACE inhibitors can inhibit lipid peroxidation, but the millimolar concentrations of the drug used in this study are highly unrealistic.

      https://www.ncbi.nlm.nih.gov/pubmed/1378110

      Free radical scavenging might not even be much of an issue, even for sulfhydryl contining ACE inhibitors like captopril. It would only be an issue if sufficient quantities of the drug were getting into the tumor. Whereas for inhibitory effects on tumor-promoting macrophages, it could work systemically and wouldn't necessarily have to cross the blood-brain barrier, according to the study already referenced.
      https://www.ncbi.nlm.nih.gov/pubmed/23333075

      In any case you one could seek one of the other ACE inhibitors that doesn't contain a sulfhydryl group. Or, a different class of drug, the angiotensin-II receptor blockers (ARBs, such as telmisartan) could be used instead for the same purpose. ACE inhibitors and ARBs have also been shown to reduce the requirement for corticosteroids in some studies.

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  3. I strongly recommend daily Temodar for your brother.

    My husband's tumor is also unmethylated and IDH negative. He went on a clinical trial after his 1/16 diagnosis that did not include Temodar. After an inoperative recurrence in 11/17, our doctor put him on Torisel (based on genetic testing) and daily Temodar, along with Celebrex, Prozac and Metformin. He continued using Optune (started in 12/2016).

    Since January 2018, every MRI has shown that the tumor is either stable or has shrunk. Based on this, I would fight for daily Temodar and Optune, if I were you. My husband was only expected to live a year, but he is now nearing three years and still rides his bike and works part-time.

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    Replies
    1. Fantastic! What was his daily dose of Temodar (in either total milligrams, or mg per square meter)?

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    2. Torisel, or temsirolimus, isn't a conventional chemo drug. It's drug targeted to mTOR, one of the proteins downstream in the PI3K-mTOR proliferative signaling pathway that is overactive in a majority of GBMs. It is a "rapalog" analogous to rapamycin (sirolimus), and everolimus. These drugs are also used as immunosuppressants for organ transplant patients, and their use is a little controversial - one recent randomized trial found that adding everolimus to standard treatments led to worse survival than standard treatments alone for unselected GBM.

      https://www.ncbi.nlm.nih.gov/pubmed/29126203
      https://www.ncbi.nlm.nih.gov/pubmed/29956084

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    3. What dose of prozac was prescribed by a doctor to your husband? And what is the weight of your husband?

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    4. I'm closely following the discussion of daily Temodar options. The data for newly diagnosed following six weeks of SOC is not terribly strong for metronomic schedule, but given some success in recurrent unmethylated, I plan to discuss with our NO. The Phase II trial of metronomic for recurrence (Neuro-Oncology 2010) substantially improved OS and PFS, but it was a retrospective study with potential problems in selection bias. An in vitro study on EGFR amplified and overexpressed GBMs showed a better response with metronomic TMZ. (2015 JNCI) A 2011 study (Experimental and Therapeutic Medicine) showed metronomic treatment of TMZ enhances the inhibition of angiogenesis accompanied by the down-regulation of MGMT expression in endothelial cells.
      Why haven't more large studies on metronomic dosing been done? Is it a valid consideration for unmethylated, EGFR overexpressed mutations as part of the SOC after 6 weeks of TMZ plus RT? Thank you for any insight!
      L

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    5. I meant to include that in the Musella Foundation Treatment Optionsi page 17, it states, "Although clinicians will likely resist any alternative to the standard TMZ schedule for newly diagnosed patients outside of clinical trials, a medium-dose metronomic schedule is worthy of consideration for patients with unmethylated MGMT status, and especially for those patients with unmethylated MGMT status and amplified EGFR." (which is our situation) Thanks.

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  4. Hi Jenna - not sure if it is useful for you, since you seem to already have quite a cocktail there, but I posted my RT cocktail & experience back in December last year:

    http://btcocktails.blogspot.com/2017/12/treatment-options-post-rttmz-phase-for.html

    Since you ask about Antabuse, I did take that for most of my RT, but I chose to abandon it in the end because it was giving me some peripheral neuropathy in my foot (which has since resolved). I saw on a drug interactions checker, that this effect might become a bit more likely when you take it with Chloroquine (see drug interactions checker on drugs.com, which assigns moderate risk for nerve damage for this combination). Since, as Stephen mentioned, the recent evidence for Disulfiram (ex-copper) hasn't been overwhelming, I'm not sure I would personally take it again if I had to do it again. On the other hand, I thought 400mg Celebrex with quite a high dosage up to 4g+ of Boswellia probably permitted me to avoid use of steroids during radiotherapy. I think steroids should definitely be avoided as much as possible (as long as it can be done safely...).

    I would personally consider adding Sulforaphane if you don't have it in the cocktail yet - just make sure it's the right one (with actual sulforaphane, and not just the precursor. E.g. a widely used one in USA is Broccomax, but there is a lot of innovation now on the supplement side with sulforaphane).

    Also, which Curcumin is your brother using? Over time, I really increased my curcuma intake in various ways, and I now take Longvida (to my knowledge, only one proven to penetrate BBB) + Theracurmin (to my knowledge, best proven overall bioavailability) + actual tumeric (twice a day... using home made golden paste which is basically tumeric + pepper + cocunut oil. You can make a delicious traditional milk drink with it). Maybe a bit overboard, but curcumin is a really good supplement. My CRP (inflammation) score is down to 0.4-0.5 range in my last few blood checks...

    Last but not least, I hope your brother's depression can hopefully improve over time - a healthy mind will certainly help along the difficult recovery path, both from a QoL and medical point of view. What helped me a lot in this regard was reading Ben William's book - "surviving terminal cancer" - which put my mind in an action mode and also led me to this blog ultimately. Another good one was "Radical Remission", which is a good read and provides a pretty intelligently researched perspective on factors that drive real remission stories. If anything certainly gave me some hope reading about other 'lost' cases achieving long term remission. Some supplements like Ashwaghanda (which also has anti-cancer properties) can also help with anxiety / stress quite a bit. I take 500mg Sensoril formulation daily, and I felt like it took the edge off a bit (could also be imagining it, but who knows with all this cocktail ;)

    https://www.amazon.com/Radical-Remission-Surviving-Cancer-Against/dp/0062268740/ref=sr_1_1?ie=UTF8&qid=1537373353&sr=8-1&keywords=radical+remission

    https://www.amazon.com/Surviving-Terminal-Cancer-Treatments-Oncologist/dp/1477496513/ref=sr_1_1?ie=UTF8&qid=1537373378&sr=8-1&keywords=surviving+terminal+cancer

    I wish your brother all the best on his cocktail and his treatment - very lucky to have you on his side for sure, to support his treatment!

    Best,
    John

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  5. My husband is 6' and 163 pounds and is getting 100 mg/day. Besides its increased efficacy, another advantage of daily dosing is diminished side effects. His appetite is completely normal. He is getting Torisel infusions because of a mutation in his tumor that is more common with renal cancer, which Torisel treats. He is taking 20 mg of Prozac 2x daily, but stopped Metformin because it caused weight loss.

    I cannot recommend Optune enough. I think chemo weakens the cells and then Optune delivers the coup de grace. or vice versa.

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  6. Jenna,

    do you perhaps know, which mutation Torisel targets? We are also dealing with (most likely) non IDH1/2 and non-MGMT methylated disease, and with other rare mutations identified. I am seeking treatment options, which might be more beneficial than the present ones.

    Regards,
    Stefan

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    Replies
    1. Torisel (temsirolimus), like everolimus and sirolimus (rapamycin) are mTOR inhibitors. mTOR isn't commonly mutated in GBM but is a downstream of PI3K in the PI3K/Akt/mTOR signaling pathway. Mutations in PI3K proteins such as PIK3CA and PIK3R1 are fairly common in GBM (about 11% each). Also PTEN is a negative regulator of PI3K signaling, and PTEN is mutated in about 30% of GBMs.

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    2. This paper discusses mutations in the MTOR gene itself in renal cell cancer, which isn't very common in GBM.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833135/

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    3. Thank you Stephen, I am very grateful for your help, patience, and the enormous time you share with all us.

      I am not sure if the mutations are/were present in the genetic profile made with Ilumina HiSeq1500 at ~2 months ago. Likely not. The tumor samples from surgery (early August 2017) were confronted with a blood sample. The following gene mutations are identified and described in the report

      H3F3A (G34)
      TP53
      ATRX
      PDGFRA
      TCF12
      IRF12

      TERT promoter (sequencing made with the Sanger method) - no changes in the most common hotspot areas (C228 and C250) characteristic for GBMs

      There are also described deletions in regions 4q, 13q, 16q and 17q.

      As far as I understood, the results imply one of pediatric GBM (K3 G34) types, with the last there mutations interpreted in the report as rare and non-well documented. Also, if I understand correctly, the tumor is non IDH1/2 mutated (since the K3 G34), and non-MGMT methylated, which is the consequence of the identified mutations.

      I am aware the that the genetic profile of the disease might changed after radiotherapy and four different cytostatic agents. We just finished the fourth round of Topotecan+DICT (dicarbazine) chemotherapy, due to apparent progression after prior radiotherapy and 4 cycles of TMZ+CCNU (the end of July).



      Many thanks,
      Stefan

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    4. Hi Stefan, the H3F3A G34 mutation (H3 G34 for short) is not strictly a pediatric type, but occurs most commonly in adolescent and early adulthood. The cases I've seen were in ages from 16 to 36, median 20.

      Yes this mutation is mutually exclusive with mutant IDH1, they are never found in the same tumors.

      I've seen studies that show H3 K27M diffuse midline gliomas are never (or virtually never) methylated for MGMT. But I have seen a few cases of H3 G34 mutant gliomas that were considered MGMT methylated so I wouldn't assume yours is unmethylated just because of the G34 mutation. In general though, the G34 mutant tumors have the lowest levels of overall DNA methylation of all the glioma subtypes. These is the opposite pattern compared to IDH1-mutants which have the highest levels of overall DNA methylation.

      The H3 G34 mutant tumors are also in a different genetic class from the typical adult type of GBM, which usually have TERT promoter mutation, no ATRX mutation, loss of one copy of chromosome 10, gains of chromosome 7.

      The PDGFRA mutation is interesting because it implies the tumor could respond to small molecule PDGFRA inhibitors, rather than EGFR inhibitors. Approved drugs that inhibit PDGFRA include imatinib (Gleevec). The problem with most of these targeted kinase inhibitors in terms of brain tumor therapy is that none of them were designed for central nervous system cancers and tend not to cross the blood-brain barrier very well. They might have a therapeutic effect in the contrast-enhancing parts of the tumor with a leaky BBB, but likely won't help much in parts of the tumor that are protected by an intact blood-brain barrier.

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    5. Thank you so much, Stephen.

      The patient has been diagnosed in age of 17, so almost at the peak...

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  7. Thank you Stephen and everyone for sharing your knowledge. I was curious about typical dosing of Chloroquine. I know it is thought to be a radiosensitizer - in typical clinical trials with chloroquine is taken at a specifi time prior to radiation?

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