Deciding between Chemo and Targeted Therapies for Recurrence

I've been a longtime follower of this community and I'm hoping that others here can help me cut through all the information I'm being given to make some decisions for my husband.

Background
My husband was diagnosed at age 34 in October 2018 after having neck pain for a few weeks and then a sudden onset of extreme disorientation. He had an emergency resection (97.8% debulked). His tumor was originally located in the left parietal lobe. His tumor is unmethylated, IDH wild-type. Initially he followed SOC. Radiation concurrent with TMZ, then Stupp protocol 5/23 with Optune.

In May 2019, he had progression, stopped TMZ and Optune in preparation for surgery. Second resection in June 2019. He got a pre-surgical infusion of Keytruda (Pembrolizumab). Second surgery was MRI assisted at Memorial Sloan Kettering. Resection was successful and he followed with a short course of photon radiation and Keytruda infusions every 3 weeks. Around this time we also stopped doing a strict Keto diet because he had dropped close to 40 pounds. We now follow it in moderation.

We used Store My Tumor to preserve a tissue sample from the second surgery and used that to create an autologous dendritic cell vaccine from whole tumor lysate at Thomas Nesselhut's clinic in Germany. He was primed with an oncolytic virus, also used adjuvants of Inter-leukin 2 and Aldara cream.

Fall 2019 we continued Keytruda infusions and his dendritic cell vaccine with Tetanus adjuvant. In October 2019 he had an adverse event (possible focal seizure or pressure wave). We discontinued Keytruda (had completed 7 rounds). Started on a course of Avastin infusions and 4 mg Dexamethasone to control inflammation. We made the decision to discontinue Optune at this time. It was a quality of life decision. It was really interfering with his enjoyment and activity (we have twin toddlers). I am 100% okay with that decision and won't force him to do something he hates.

In November 2019 he was accepted into the SurVaxM clinical trial via compassionate release. He completed a priming dose (4 rounds) of the peptide vaccine SurVaxM. His most recent dose was in April 2020. In January 2019, it looked like there was further progression in the corpus callosum. We decided to continue with Avastin infusions and dendritic cell treatment and did a course of Proton Beam radiation.
His first MRI post radiation showed a modest reduction in tumor. (March 2020).
His most recent MRI in May 2020 is showing new growth. The area that got proton beam radiation continues to shrink, but there is a new tumor measuring 2.9 X 1.7 cm within the posterior medial left temporal lobe. Thankfully he has remained largely asymptomatic and stable. He has issues with leg weakness from prolonged steroid usage and his right arm and hand have lost dexterity. He has never had a seizure. He has some memory issues and lately some issues with processing.
Now we are faced with a decision about what to do next and we are getting a lot of differing opinions.
His tumor has the following markers:

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We are deciding between adding a cytotoxic chemotherapy and a targeted therapy. One team of doctors is strongly recommending CCNU. Their other options would be Metronomic TMZ, Carboplatin, or Irinotecan.

Our vaccine team is very wary of cytotoxic chemo and believe it would negate the immunotherapies. They are okay with metronomic TMZ or metronomic Cytoxan.

A third doctor recommended Carboplatin and keeping Keytruda.

We have been offered the possibility of trying a targeted therapy to match his genetic markers. The choices there are Abemaciclib (CDK4/6 inhibitor) or Cabozantinib (MET fusion). I would like to get a PI3K/Mtor inhibitor or an MDMA inhibitor but there are next to none that are commercially available and I don't think we can get into any trials or want to wait that long. Piqray is one potential option in the PI3K/Mtor area. We don't know if we could combine them with chemo. I think we would have to see how he responds to one before adding them together.

Surgery and radiation seem unlikely though we are going to pursue consultations for surgery (we are based in NY) and gamma knife with Dr. Christopher Duma. I don't think these will pan out, but the consultations can't hurt.

I am really struggling with how to make these choices. His quality of life is fairly good. None of these options seem to have strong data behind them, but all have those small percentages of patients where things work and no one knows why.

I want to make a decision quickly. I am leaning towards Metronomic chemo (even though I know he is unmethylated and the chances of it working are small). But we can get it immediately and we know somewhat how he responds on chemo. He always tolerated it well, never had low counts and managed side effects with cannabis and IV fluids and colace. I think we could try chemo for one month and do another scan and see quickly if there is any impact.

We would have to get approval for the targeted therapies and I think perhaps it makes the most sense to hold those while we try something else.

He has been on his vaccine for almost one year and I have no idea if it has done anything, perhaps it's simply held things back.

I know this community has so much knowledge. I welcome any insight. He is 19 months past diagnosis and we have never had a long stretch of stability. We have thrown everything at this disease. Given how aggressive its been, I hope that all that we have done has given him more time than if we had just done SOC. I want to give him time, good time.

His genetic markers are:
TERT
CDKN2A
MDM2
CCND2
PTEN
FOXP1
TET2
YAP1
CCND2
BIRC3
PTPRZ1-Met Fusion

We completed EVA-PCD assay through Nagourney Cancer Institute. Tumor tissue sample allowed for testing of 5 agents. Results were:

• Dactolisib (PI3K/mTOR)--sensitive

• Palbociclib (CDK4/6)--sensitive

• Crizotinib (ALK/MET/ROS)--intermediate

• Carboplatin & Topotecan--intermediate

• Olaparib (PARP)--resistant

His medications are as follows:

Immunotherapy

Dendritic Cell Vaccine

SurVaxM vaccine

Keytruda

Tetantus adjuvant

Aldara adjuvant

Lion's Mane

Apoptosis/Autophagy 

Chloroquine 

Mebendazole 

Artemisinin 

Simvastatin 

Escozine 

Anti-Angiogenic

Avastin

EGCG 

Metabolic 

Metformin 

Anti-Inflammatory

Bromelain 

Curcumin 

Boswellia Serrata

Quercetin

Other 

Cymbalta 

Clonazepam

Valproic Acid

Melatonin

Turkey Tail

CBD (sublingual)

Cannabis (whole flower, vaporized as needed)

 

My father's GBM

 My father was diagnosed with GBM on 4/15 and he had a total resection surgery on 4/17.  I've been researching pretty much non-stop every since.  I watched the surviving terminal cancer movie, read Ben Williams book, have been scouring the internet gathering as much information as possible and this is how I ended up here.  

Here's all the information I have on my fathers tumor and the treatment and supplements he is on to date:

Genetic testing: MGMT was not detected (negative) unmethylated

IDH1 and IDH2 were not detected (negative) as well

It is EGFR amplified - which qualified him for ABT-414 clinical trial.

He is currently in the trial and has some symptoms which lead us to believe he is getting the actual drug and not the placebo.  

He finished up the standard treatment of Radiation and Chemotherapy a few weeks ago.

He is taking Keppra and a PPI daily

List of supplements: Cannabis oil, 20 mg melatonin, 800 mg curcubrain, reishi and coriolus mushroom supplement, 500 mg Boswellia extract, 400 mg green tea extract, 200 mg resveratrol, 200 mcg selenium, 10000 IU vitamin D3, Hemp seed and flax seed oil.

Also drinking fruit and veggie smoothies daily.

These are the off label drugs that I recently received and plan on having him start in a couple days.

Disulfiram-125 mg a day for the first week, then 250 mg daily

Chloroquine- 250 mg daily

Celebrex- 200 mg twice daily

Metformin- 500 mg once daily, titrating up to twice daily, then 3 times daily

Doxycycline 100 mg twice daily

Propranolol 60-80mg daily

Lipitor

DCA 5mg/kg per day, titrating up to 12-15mg/kg.

LDN (low dose naltrexone) start with 2mg nightly titrating up to 4.5mg

I have a few questions:

1.How does the dosing and schedule of the off label drugs look? Anything I should add or subtract? 

2. I know Disulfiram and DCA can cause neuropathy, should they not be taken together?

3. Should the green tea extract pills be avoided while on DCA?

4. The doxycycline I have is Dox T-SL (Doxycycline 100 mg / Lactic Acid 5 billion spores)  

It says "DOXT-SL contains Doxycycline along with 5 billion spores of lactobacillus sporogenes."

Would the lactic acid cause a problem?

5. Most of the research I've done says statins are beneficial, but I've also an article saying they should be avoided.  Should they be used or avoided? 

If he does take the Celebrex, any recommendations on dose?

6. The Naltrexone pills I have are 50 mg.  I've seen people dissolve them in 50mg of water and then use a syringe to suck up desired amount in mg.  Is this advisable?  Some people say this will cause inconsistent doses, but I don't know another way.

7. I've read that since his GBM is unmethylated and EGFR amplified that a metronomic chemo scheduling would be more beneficial than standard chemo treatment.  We meet with my fathers oncologist next week to take a scan and discuss the future game plan.  Does anyone have any recommendations on how to try and convince his dr. to prescribe the metronomic dosing schedule.

Any help or suggestions would be greatly appreciated.  Like I said, I've been doing a ton of research and sometimes it seems like the more I do, the more confused I get.  

Tom Wangerin - Cocktail Profile and Questions

Hi all,

Although this is my first post, I have been reading every minute of every day. Such an amazing wealth of information on here. I would appreciate any advice on our current course of action and opinions on our cocktail.

My dad was diagnosed with a grade IV GBM. He had surgery on 11/23/16 with 95% resected.

Lab Results:
MGMT Gene Promoter Methylation – Detected.
Percent of MGMT Methylation is 36.19%
IDH1/2 Mutation – Not detected
Positive for 1p Deletion

• Completed his first round of daily chemo/radiation on 1/19/17.
• Our first image was taken on 2/3/17. We had our first consultation with the UCSF Tumor Board (Dr. Butowski) on 2/7/17.
• Tumor had not seemed to grow in size any, but did morph into a new shape/area which is scary to see. Next image in 2 months.

Currently taking:
·       Dexamethasone (Decadron) – He is currently taking 4mg/day but we are doing what we can to wean him off. We have been told this will dictate whether we go on Avastin.
·       Eliquis – blood thinner - 5mg twice a day
·       Keppra – 500mg twice a day.
·       Bactrim (Antibiotic) – Original oncologist prescribed during chemo.

Supplements:
1:1 CBD/THC – Tincture drops in day, Oil at night.
Probiotics – Sibiotica (K-97)
Curcumin - Nutrivene Longvida 1000mg - 1x Morning 1x Night (1000-2000mg daily)
Fish Oil - Vital Nutrients - EPA-720mg, DHA-480mg per cap - 1x Morning
Boswellia Serrata Extract - Progena Meditrend – Currently taking (3) 333mg daily.
Melatonin - Vital Nutrients - 10mg/cap - 1x at Night (eventually will do 20mg)
Mushroom Extracts - Turkey Tail (Coriolus), Maitake D-faction, and Reishi each once a day.
Berberine - Vital Nutrients - 200mg/cap – starting with 1x day, soon 3/day.
Debating whether to add - Resveratrol and Green Tea Extract

Our NO was okay with all and suggested adding Cronaxal. I’ve struggled to find much convincing information out there, but I do trust our NO. Now the question is to use Cronaxal (expensive and high dosage) or get Sulfasalim (which Stephen ranked pretty high on his spreadsheet).
I read that this can benefit those that are NOT IDH mutated (which is us).

Genetic Testing
We are getting the tumor tested from Foundation One for more details – once we make sure there is enough tumor for them to test, and have some left for potential clinical trials. I’m keeping an eye out for EGFR, p53, VDR, HIF-1.
Any thoughts here?

Hoping for some advice in a selection of the following:

**Vitamin D3 – In some cases Vitamin D3 caused proliferation in some patients (Stephen W speaks of this: http://astrocytomaoptions.com/supplements/). Our NO was okay w/ Vitamin D3. Would checking his VDR receptor be of value for determining this, or is it safe (and potentially beneficial) to take 5,000-10,000iu daily regardless of tumor type?

I was very excited about a few of the prescription drugs below, but our NO was certain that none of them get past the blood brain barrier while taking doses safe for humans. We are still willing to give a few of them a shot, but I’m struggling to decide which combinations.

·       **Chloroquine Phosphate – (if overexpressing the EGFR protein or p53 status is unmutated) & **DCA - Sodium Dichloroacetate –(if HIF-1 is expressing) http://astrocytomaoptions.com/targeting-tumour-metabolism/
·      **Disulfiram – This drug looks like it has amazing potential.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=707

·       **Sildenafil & Celebrex: can work synergistically for both getting past blood brain barrier, anti-tumor qualities, and Celebrex potentially helping with a bit of edema.
http://onlinelibrary.wiley.com/doi/10.1002/jcp.24843/abstract

·      VT-122 (Etodolac & Propranolol) – with low dose daily TMZ schedule. This had great results. Any reason why more people aren’t doing this themselves?
(http://meetinglibrary.asco.org/content/151704-156)

·       CUSP9 – Looks like an amazing plan. I am yet to read of any results but I know many are starting to replicate this cocktail on their own.
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2408

Current Plan:

I.         TMZ Schedule – Because he is MGMT methylated it was an easy decision to go forward with the monthly TMZ cycles. All of our docs have insisted on the high dose 5days/month schedule rather than a metronomic schedule, regardless of whether EGFR is over expressed. Thoughts?
https://academic.oup.com/jnci/article/107/5/djv041/891259/EGFR-Amplified-and-Overexpressing-Glioblastomas

II.         Optune Machine – The UCSF board feels it’s not as beneficial as some of the studies make it out to be, and with it being such a pain to wear for the rest of your life… it’s not that easy of decision even with insurance coverage. I’m undecided here.

III.         Prescriptions with TMZ/Avastin - If you had to pick one prescription duo to take with TMZ and one prescription duo to take with Avastin to make them more effective which would you pick?

Thank you all for pitching in. This journey has been life changing, but manageable with the help you all bring.

Considering treatment options for high grade diffuse midline glioma H3k27m for my 8 year old daughter

Hi all,

Thanks so much to Stephen for your in depth reply to my questions about my 8 year old daughter and invitation to this blog. We moved to Norway in July and my daughter was diagnosed in early September with high grade diffuse midline glioma with H3K27m mutation after an extended biopsy, where it was determined that the tumor was not resectable. She underwent 3 further operations to have a double valve shunt put in to relieve hydrocephalus symptoms. She finished 6 weeks of radiation and Temodal about 10 days ago. The doctors want to start her on Temodal/Lomostine 4 weeks after radiation finished. If we follow this path, we could also have a full molecular analysis done and, upon recurrence, may possibly be able to access a trial using afatinib for BI1200.120, if applicable, or another targeted agent. I would also push for using repurposed drugs in the cocktail approach if possible and our conservative doctors could be convinced. 

We are trying to explore other options, and thanks to Stephen, learned about a new phase I peptide vaccine trial opening for paediatric glioma patients with mutation H3.3K27m based in San Fransisco. It is for patients who have completed 6 weeks of radiation and have not yet started chemo again, which is exactly where we are now. https://clinicaltrials.gov/ct2/show/NCT02960230

I am finding it so difficult to determine what would be the most promising, preferably least toxic option for my daughter. Any input on how promising a peptide vaccine targeted to this kind of mutation could be? Compared with temodar/lomostine/cocktail approach?

Many thanks in advance for your input.

Jeni

Advice on MGMT unmethylated tumor

Hi,

My father (67 years) was recently diagnosed with GBM in the cerebellum after a sub-total resection. The neurosurgeon said they were able to remove almost all of the tumor mass except for some minor residue.

There were two tumors, one in the middle of the cerebellum (vermis area) and one in the left hemisphere.

The result from the histopathology says:
* High staining of Ki67 marker.
* EGFR positive staining (but doesn't say how much nor whether EGFRvIII mutated or not)
* GFAP positive staining
* Vimentin positive staining
* Mainly cytoplasmic staining of MAP II.
* No staining of IDH1 R132H mutation.
* Only few cells show staining of p53 and NSE.
* No loss of 1p36 or 19q13.
* MGMT unmethylated (9% methylation as measured with pyro sequencing)

Father has just finished 6 weeks of radio+TMZ therapy and we're scheduled to meet the oncologist on Thursday to plan the next step. I recon she will order the standard 5/23 schedule TMZ chemotherapy per the Stupp protocol.

I have tried to read up on GBM and the treatment options available. However if I understand correctly, my father's unmethylated MGMT means the 5/23 TMZ schedule is likely not effective, but maybe a metronomic TMZ schedule would be.

I have put together a cocktail of supplements:
* Curcumin (Longvida) 1000 mg/day
* Zinc 30 mg/day
* Vitamin D3 5000 IU/day
* Silibinin 800 mg/day
* Berberine 1000 mg/day
* Garlic (AGE extract) 600 mg/day
* Lycopene 20 mg/day
* Selenium (as L-selenomethionine) 200 mcg/day

I'm also looking at adding PSK/PSP as well as Pterostilbene, but haven't yet found a good supplier that delivers to Sweden.

I'm thankful to any input or advice you can give me on how to proceed.

A few questions/thoughts:

1. Would you add or remove anything from the supplement cocktail, or change the dosage?
I read that some supplements could have both negative or positive effect depending on the dosage, i.e. Quercetin. Is there a list somewhere on known/suspected supplements to avoid?

2. My father is reluctant to do anything outside of the doctor's recommendation, so I have to try to keep the supplement cocktail as simple as possible. If I understand correctly curcumin and vitamin D are considered to be two of the most promising supplements. If I have to prioritize, which of the supplements should I keep (or exchange for something else)?

3. I've noticed that many of the supplement cocktails contain three different mushrooms - Reishi, Maitake, Corioulus versicolor. Are the mushrooms basically the same (i.e. source of PSK/PSP) or do they contain completely different agents?

4. When meeting the oncologist on Thursday, should I press for some alternative to the 5/23 TMZ schedule? I.e. addition of Keppra or some other MGMT "sensitizing" drugs or should I try to press for a metronomic TMZ schedule (or both)?

5. Should I try to press for additional meds (i.e Celebrex or others) when meeting the onc? Which ones would be most important?

6. Does the pathology report give any additional useful information to help treat this or meds that I should press for/supplements to add? I'm not able to make much out of it except for the MGMT status.

7. Should I ask for any additional (selective) gene testing done on the tumor sample? If I understand the pathological report correctly, the sample is a paraffin fixed type (not frozen) so that makes it inelligible for immunovaccine samples.

8. Anything else I should think of or that you would do/recommend? As we live in Sweden, the possibility of entering trials may be limited, but I'll nevertheless ask the onc about Optune etc.

Thanks,
Peter

Partially metronomic TMZ schedule

Hi all!

I would be happy to hear your advice on metronomic TMZ administration. That has been widely discussed here already but I've got a specific question.

My dad's GBM is MGMT unmethylated (and there is some contrast enhancement after the radiochemotherapy). Our oncologist obviously doesn't have anything else to offer so she proposed cycles of monotherapy with 300 mg TMZ daily in the standard schedule 5/23, i.e. 3x100 mg TMZ capsules daily.

Is there any sense of switching to some "partial" metronomic schedule, i.e. he would take 1 capsule of 100 mg TMZ every day for 15 days. After 15 days we'll run out of TMZ (we've got 1500 mg in 100-mg-capsules for one cycle). The oncologist wouldn't agree to put him on full metronomic schedule as this is not allowed officially...
So to conclude, it would be 15 days on (100 mg daily), 13 days off.

High five from Poland!

Metronomic TMZ with adjunct supplements/chemo for recurrence

Hello,

Has anyone had good results after a recurrence of a high grade glioma using Temodar on a daily low dose in combination with another agent? I'm looking for an approach that might increase it's effect for my wife who had a recurrence (AA3). Her NS has made the suggestion (just the TMZ alone) and I would assume her oncologist will be advising the same. Given that it appears her tumor didn't respond to TMZ in the first place I'm questioning that it will be the same outcome as before. Perhaps CCNU might be the better choice, or combining them if she tolerates it.
Ray

Tamoxifen + TMZ + Avastin

i am taking a metronomic dose of TMZ (80 mg per day) and get Avastin every two weeks.
I have recently added Tamoxifen (currently 20 mg bid, will be increasing to 30 bid tomorrow)
Is it ok to take those three together?
Thank you

Metronomic TMZ

Hi, just posting this in order to know if someone else is on Metronomic TMZ too. My wife has started 2 weeks ago with this protocol (50mg/m2) also concurrent with Avastin 15 mg/Kg/21d. Since the first infusion she got improvements on her left side, she has to deal with some level of hemiparesia after surgery on Oct-19

Would like to know if someone else is experiencing fatigue, tiredness or lack energy  due to the accumulation of TMZ in this schedule, or maybe the window between Avastin's infusions is too big (21d) and she is not able to keep a stable level in blood and the effect goes off after 10/14 days.

Thanks,
Francisco.