Levetiracetam (Keppra) + standard of care, single-arm phase 2

A pilot study of levetiracetam as a sensitizer of temozolomide for newly diagnosed glioblastoma: A prospective, open-label, phase II study (KBTS-1601 study).
https://meetinglibrary.asco.org/record/189964/abstract

This was reported at the recent ASCO virtual conference.

• Eligible patients were aged 18 years or older and had newly diagnosed glioblastoma with an ECOG performance status of 0-2
• The first dose of levetiracetam was given just after the surgery at 250mg orally twice a day and increased up to 500mg twice a day prior to radiation
• Forty-six patients were enrolled between August 2016 and January 2019
• Median overall survival (OS) was 30.0 months, and median PFS was 15.0 months

This was a single arm trial, with outcomes compared to a historical control group. A median overall survival of 30 months and median progression-free survival of 15 months does seem to be an improvement on historical results. 

For comparison, the unblinded results of the phase 3 DCVax trial (preliminary report based on 331 patients) had a median overall survival of 23.1 months from surgery. The historical control group used by the Korean team that conducted this levetiracetam trial had median OS of 17.5 months.

Good news from MRI scan. GBM Tumor shrinkage from 4.5cm to 2cm

Happy New Year everyone. I wanted to give a positive news update as it is great motivation when there only seems to be negative news regarding glioblastoma. My dad had his 3 month MRI scan follow up (since the last scan in September) today and it shows tumor shrinkage from 4.5cm (in addition to swelling) down to 2cm and no swelling. 

What was added since the previous MRI scan (September) was starting these drugs in October:

• 16 mg dexamethasone and then slowly reducing to 2mg now; 
• Biweekly IV Bevacizumab - avastin ; 9 rounds completed; 
• 2g daily Valaciclovir - valtrex (1g in the morning, 1g in the night);
• 100mg daily Artemisinin;
• 500mg daily Astragalus. 

I think the Bevacizumab - avastin and Valaciclovir - valtrex really helped.

I want to share his treatment as I know there is no one cocktail list and it can be difficult to know what to take and also where to get the drugs or supplements. We began by taking the list of "A" drugs from the table which Stephen shared with us after I emailed him directly. Stephen also provided a link to the Ben William's and Richard Gerber's cocktail list. Since my dad is unmethylated we tried to follow Richard Gerber's cocktail list as closely as possible. We printed out the BT Cocktail list Stephen shared with us, modified it to the "A" drugs and printed this as my dads list to show his oncologists and GP with the dosage he was taking. We were lucky some friends were able to get chloroquine phosphate, Celebrex and melatonin over the counter in Spain. This meant we could start slowly adding drugs one by one before getting the GP to prescribe these drugs to my dad. His oncologist was happy for my dad to try whatever he wanted once he did the treatment they suggest - he was free to add any supplements or drugs once we provided the oncologist and GP with the cocktail list, dosage, purpose (this info from the cocktail list Stephen shared) and the date we added the drug and only one by one with two weeks apart. For the likes of Valaciclovir - valtrex we named the researchers who carried out the study and the publication and then our GP was happy to prescribe these drugs from our local pharmacy.

We check his drug interactions using drugs.com website. It allows you to enter the list of drugs and says potential side effects or which drug combinations throughout the day to avoid. We also get the pharmacist to make up weekly blister packs and they put his drugs into morning, lunch, evening and night - this service really helps us keep organise. We keep a day example of how the pharmacist previously made up the blister pack and hand that in to the pharmacist the following month so they remember - as even for the pharmacist its alot in the cocktail to remember.

We are attending 2 hospitals because one is a general hospital to deal with his seizures and it is 10 mins drive away and his oncologist/neurologist hospital are 15 mins away from our house - we are very lucky with the excellent healthcare in Ireland and that it is all provided for (consultation, MRI scans, surgery, radiation, chemotherapy, Bevacizumab - Avastin, prescribed cocktail medication, social worker, counselling, hospital stays, blood tests, tumor analysis).

We were taking N-acetylcysteine early on (it is a Glutamate transporter 1 (GLT1)) but we stopped as we read it might enhance the tumor growth - we do not know if it is good or bad to take??? I think the seizure drugs blog glutamate transport?

We also obtained Disulfiram but never added this to our cocktail as we do not know if it interacts with the seizure drugs??

We also were taking Ranitidine (75mg daily) but stopped this after reading about side effects combined with Bevacizumab - avastin. Although my dad never had any issues. 

We are also interested in adding more to the cocktail perhaps similar to the CUSP9rv3 clinical trial cocktail such as ritonavir. We are also continuing to do research on HAART/HIV antriviral treatment as apparently HIV patients in Brazil/Mexico did not get GBM's over a 20 year period. 

My dad needed to take Duclox for constipation during chemo but is fine now.

My dad does not follow a ketogenic diet but we do encourage him to have a vegan diet as much as possible low in sugar. However if he wants to eat biscuits, bread, chocolate etc he does - he loves Latte's and dark mint chocolate. He does not have any alcohol due to the seizure medication.

BACKGROUND:

• My father was diagnosed with Grade 4 GBM after a grand mal seizure 24th Feb 2019. Located in the left temporal lobe, around 3cm.
• He had a successful craniotomy on the 7th of March 2019. About 95% removed, at least all visible tumor was removed.
• He completed the 30 sessions of radiation/310mg TMZ. 17th April 2019 to 30th May 2019
• He then did 3 months of 5/23 400mg TMZ chemo. July-September 
• TMZ was stopped and been doing Avastin every 2nd Monday since 23rd September 2019 - today 13th January 2020 still doing.
• Some notes to point out: he was swimming the evening before he had his 1st seizure. He couldn't finish a pint of guinness that night and had some pins and needles in his right arm before sleep - he had no other symptoms to indicate this tumor before 24th February 2019. He had the seizure in the middle of the night. 7th March Surgery went really well and was chatting away normally 1 hour afterwards. To this day he has never had any pain or headaches. He had no side effects during radiation and chemotherapy apart from the seizure 5 weeks after it finished. 

Side Effects:

• 30th June 2019: About 5 weeks after 30 sessions radiation/chemo and after having daily tingling, we spent the day walking around the countryside for many hours. We had a 2 hour car journey and he was 2 hours late taking his Keppra (at the time he was only on 1g total in the day, 500mg morning and 500mg evening). That night he had 4 multiple seizures. He came through after the 1st seizure but he seemed to have panicked when he saw the paramedics that he went into the 3 other multiple seizures. The hospital induced him into a coma for 24 hours which we were not expecting. His Keppra dosage was increased to 2.5g a day and they added phenytoin 300mg in the morning. They also restarted him in dexamethasone 2 weeks 4mg and then 2 weeks 2mg.
• 4th September 2019: He had been having foot twitching since 30th June every night when sleeping. From the end of August he was starting to mix up people's names and words due to aphasia resulting from the edema. Hospital increased the Keppra to 3g per day, added Clobazam 10mg x 2 and 16mg Dexamethasone daily - which we have been reducing since September until now (18th Jan) where he is on 2mg Dexamethasone. His speech has now returned to 100% and no seizures  after adding Phenytoin, Clobazam. There was alot of swelling/looked like the tumor was very active by MRI and due to MGMT unmethylation the hospital stopped the TMZ and have now been giving him Bevacizumab - Avastin on Mondays every 2 weeks, 9 rounds so far.  Bloods are all normal and within range.
• October 2019: My dad took Zovirax tablets and then switched to Valtrex as it apparently has better bioavailability. For 2 weeks when he started taking this we noticed he broke out in large cystic type spots around his face and neck - it almost looked like his body was trying to get rid of toxins??? These spots went away after about 2 weeks after starting the Acyclovir treatment.

Daily Routine: He carries around Midazolam injections in case he was ever to have a seizure

MORNING:

1. 8.30am: Ensomeprazole 40mg (One tablet a day). Stomach protector for steroid

After Porridge (with seeds):
9am: Following medication all prescribed by GP 

1. Dexamethasone 2mg (One tablet a day). Steroid to reduce swelling
2. Ramipril 5 mg (One tablet per day). ACE inhibitor, Lower Blood Pressure, Prevents accumulation of Tumor associated Macrophages) 
3. Phenytoin - Epanutin 300 mg - (3 x 100 mg tablets all taken at this time. Anti-seizure
4. Clobasam - Frisium 10 mg (twice a day, 10 mg in morning, 10 mg at night) Anti-seizure
5. Levetiracetam - Keppra 500mg x 3 (twice a day, 1.5g in morning, 1.5g at night) Anti-seizure
6. Metformin Hydrochloride 500 mg (twice a day, 500mg in morning, 500mg at night). Diabetes and Immune booster
7. Valaciclovir - Valtrex 500mg x 2 (twice a day, 1g in morning, 1g at night) Anti-viral, HSV, VZV, EBV, CMV. Guanosine binds to cancer cell DNA and converted by viral thymidine kinase and host cell kinases to aciclovir triphosphate (ACV-TP)
8. Chloroquine phosphate - Avloclor 250 mg. (One tablet per day, 155mg active chloroquine base). Malaria. Inhibition of late-stage autophagy
9. Minocyline 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Mebendazole instead). Targets macrophage/microglia. Anti-seizure
10. Mebendazole Vermox 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Minocycline instead). 

After omelette (with garlic):

10.00am: Supplements. Mainly obtained from iherb apart from Turkey tail which is difficult to get in Ireland and we get via evitamins.

1. Boswellia NOW 500mg tablet. (1 of 3 tablets per day) Reduces edema
2. ECG (green tea extract) . Now 400 mg. Sensitizer to TMZ by GRP78 inhibition
3. Maitake D Mushroom Wisdom (600 mg tablets – 1 tablet per day). Immune
4. Curcumin. Doctor's Best (1000mg tablets – 1 tablet once per day but give other brands of Curcumin later in the day as this is not Longvida and difficult to swallow) Immune; STAT3 inhibitor
5. Multivitamins. Optimum Nutrition, Opti-Men. (1 tablet once per day)
6. Vitamin D3.  NOW (10,000 IU tablets – 1 tablet once per day). Cell differentiation; Immune
7. Mushroom supplement mix from Fungi Perfecti Host Defense Stamets 7 (Royal Sun Blazei; Cordyceps; lions mane; Maitake; reishi; Chaga; Mesima); Immune
8. Artemisinin. Doctor's Best (100mg tablets – 1 tablet once per day) Malaria and Direct Cytotoxicity, apoptosis

LUNCH:

After snack:

1pm: Medication prescribed by GP 

1. Celecoxib - Celebrex (200mg tablet) Arthritis and COX-2 inhibitor, Immune (PGE2 inhibition),  reduces edema

1pm Supplements:

1. Astragalus NOW (500mg tablet) Immune

TEA: (meal followed by a glass of Kombucha or Kefir)
After snack:

5pm:

1. Omega 3-6-9  Now Foods, 1200 mg - 1 tablet per day) From Borage, Flax Seed & Fish Oils Increased oxidative stress in tumor cells
2. Milk Thistle, Silymarin Now Foods, (300 mg tablet) Immune and liver support
3. Berberine Natural Factors, WellBetX (500 mg tablet).Glucose metabolism and Induces senescence of  cells by down regulating the EGFR-MEK-ERK signalling pathway
4. Boswellia NOW 500mg tablet. (2 of 3 tablets per day) Reduces edema
5. Curcumin. Protocol for Life Balance, Curcumin SLCP Longvida 400 mg and  Advanced Orthomolecular Research (AOR) Curcuviva 400 mg (80 mg curcuminoids and Nordic Naturals Curcumin Gummies Mango 200mg Longvida. Prefers the Nordic Naturals gummies. Immune; STAT3 inhibitor

EVENING:

9pm: Medication prescribed by GP 

1. Clobasam - Frisium 10 mg (twice a day, 10 mg in morning, 10 mg at night) Anti-seizure
2. Levetiracetam - Keppra 500mg x 3 (twice a day, 1.5g in morning, 1.5g at night) Anti-seizure
3. Metformin Hydrochloride 500 mg (twice a day, 500mg in morning, 500mg at night). Diabetes and Immune booster
4. Valaciclovir - Valtrex 500mg x 2 (twice a day, 1g in morning, 1g at night) Anti-viral, HSV, VZV, EBV, CMV. Guanosine binds to cancer cell DNA and converted by viral thymidine kinase and host cell kinases to aciclovir triphosphate (ACV-TP)
5. Atorvastatin 20 mg (1 tablet a day) Manage Cholesterol
6. Minocyline 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Mebendazole instead). Targets macrophage/microglia. Anti-seizure
7. Mebendazole Vermox 100 mg (twice a day, 100mg morning, 100mg evening - one month on and switch one month off to use Minocycline instead). 

9pm Supplements:

1. Resveratrol Now Foods, 200 mg,
2. Soy Isoflavones with Vitamin B6. Holland and Barrett Contains active daidzin, genistin and other isoflavones, phyto-oestrogens
3. PSK or PSP (Turkey Tail Mushroom/Corilus versicolor/Trametes versicolor) NFH Hot-Water extract Immune 500mg (obtained from Walmart) have backup from evitamins from Mushroom Wisdom. 
4. Probiotics; Garden of Life, Dr. Formulated Probiotics, Mood+ ( 1 tablet once per day); 16 strains  50 Billion CFU¹ (203 mg)
5. Boswellia NOW 500mg tablet. (3 of 3 tablets per day) Reduces edema
6. Spirulina powder mixed in with green juice

NIGHT:

11pm: Medication prescribed by GP

1. Melatonin 20mg; 

Useful links we used:

Ben William's cocktail: https://btcocktails.blogspot.com/2015/08/ben-williams-cocktail-profile.html

Richard Gerber's MGMT unmethylated cocktail: https://btcocktails.blogspot.com/2015/10/rich-cocktail.html

CUSP9rv3 Cocktail list (Neurology consultant DR. Marc-Eric Halatsch) https://clinicaltrials.gov/ct2/show/NCT02770378

Positive correlation between HIV antiviral treatment and low occurrence of glioblastoma https://www.researchgate.net/publication/266011045_Gliomas_and_brain_lymphomas_in_HIV-1AIDS_patients_reflections_from_a_20-year_follow_up_in_Mexico_and_Brazil

https://virtualtrials.com/survive.cfm

https://virtualtrials.com/noteworth.cfm

http://www.anticanceralliance.com/cusp-nd/

https://www.survivingterminalcancer.com/

https://clinicaltrials.gov/ct2/show/NCT02770378

https://www.frontiersin.org/articles/10.3389/fphar.2018.00218/full

https://www.canceractive.com/article/repurposing-old-off-patent-drugs-as-new-and-effective-cancer-treatments

HAART Antivirals? Atorvastatin dosage?

My dad is on valtrex (valaciclovir/valacyclovir) daily and I noticed it is a guanosine analogue. I was wondering if anyone is taking HIV HAART treatment, such as tenofovir as well? It is a adenosine analogue and therefore I would imagine would work well to bind to Cytosine and Valtrex to Thymine in the cancer DNA? I would imagine antiviral drugs are limited if only 1 of 4 potential DNA base analogues is used? I know the CUSP9 protocol is using ritonavir but it is just used by itself - perhaps a cocktail of antivirals need to be used to combine with the cancer DNA?

Also we were wondering about Atorvastatin dosage as he is on 20mg a day but Care Oncology seem to recommend people are on 80mg a day? Do people get side effects on this dosage? Should we increase the dosage?

Background on my dad:

My father was diagnosed with Grade 4 GBM after a grand mal seizure 24th Feb 2019. Located in the left temporal lobe. 

He had a successful craniotomy on the 7th of March 2019

He completed the 30 sessions and then 3 months of 5/23 TMZ chemo. In September 2019, there was alot of swelling/looked like the tumor was very active by MRI and due to MGMT unmethylation the hospital stopped the TMZ and have now been giving him Avastin on Mondays every 2 weeks.  Bloods are all normal and within range.


He was having trouble with speach and twitching in September time but this is now gone and he is back to 100% after adding Phenytoin, Clobazam and Dexamethasone

Daily:

Seizure drugs: 1.5g x 2 Keppra ; Phenytoin; clobazam daily. 
He carries around Midazolam injections in case he was ever to have a seizure but has only had 2 occassions this year.

2 x 2 mg Dexamethasone daily

Experimental Drug Cocktail (Ben Williams):

1g x 2 Valtrex (valaciclovir/valacyclovir); Chloroquine (155mg active ingredient); Celebrex 200mg; metformin 500mg x 2; 20mg Atorvastatin; ramipril; ranitidine 75 mg;  melatonin 20mg; 100mg mebendazole (1 month on/1 month off); 100 mg x 2 minocycline (1 month on/1 month off);

Daily supplements of multivitamin; 16 strain Probiotics; PSK; Maitake D; ; Mushroom supplement mix for brain (lions mane 300mg; bacopa 250 mg; reishi 150 mg; gotu kola 130 mg; ginko 120 mg); curcumin (longvida); vitamin D; ECG; Milk Thistle; Berberine; Boswellia; Resveratrol; Omega 3-6-9; Soy Falvonoids (geinistein); Astragalus; Artemisinin

Low dose perampanel added to levetiracetam (Keppra)

Experience of Low Dose Perampanel to Add-on in Glioma Patients with Levetiracetam-uncontrollable Epilepsy

Abstract

After introduction of levetiracetam (LEV), treatment of seizures in patients with malignant brain tumors has prominently improved. On the other hand, we still experience some cases with LEV-uncontrollable epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptor antagonist that has recently been approved for treating focal epilepsy as a secondary drug of choice. Available literature reporting PER medication in patients with gliomas is still sparse. Here, we report our initial experience with glioma patients and report efficacy of adding low dose 2-4 mg PER to LEV in patients whose seizure were uncontrollable with LEV monotherapy. Clinical outcome data of 18 consecutive patients were reviewed. This included nine males and nine females aged 24-76 years (median, 48.5 years), treated for glioma between June 2009 to December 2018. We added PER to patients with LEV-uncontrollable epilepsy. Adverse effects, irritability occurred in two patients, but continuous administration was possible in all cases. Though epileptic seizures occurred in four cases receiving 2 mg PER, 17 cases achieved seizure freedom by dose increments; final dose, 2-4 mg PER added to LEV 500-3000 mg. Our study revealed anti-epileptic efficacy of low dose PER 2-4 mg as first add-on therapy to LEV in glioma patients who have failed or intolerable to LEV monotherapy. Low dose PER added on to LEV may have favorable efficacy with tolerable adverse effects in glioma patients with LEV-uncontrollable epilepsy.

https://www.ncbi.nlm.nih.gov/pubmed/31748440

Cocktail for Yara’s father / help with drug side effects / 30% PD-l1 expression

Hello my dear friends and partners!

I had many doubts and I still have them despite of reading much.
And I decided to ask for your help at least.

My father had surgery 4 month ago. Chemoradiation finished 1 month ago. Left side of brain was damaged. He has Glioblastoma.

He has problems with speech and memory now.
That is why it is too hard to establish the cause of some uncomfortable and bad feelings after taking medicines and CAMs… He can not describe it correctly and can not remember when it was started for example…

---------He has no mgmt/idh1/braf/msi
---------He has 30% PD-l1 expression.
---------MRI shows continued growth (mono TMZ was not effective).

This month we started:
avastin+TMZ (5+23, 400 mg)

It is risky because TMZ did not worked well before. But I found it can do other work: reduce PD-l1 expression. And decided to use PSP(PSK) Oriveda together (6 pills =5 days with TMZ, 2 pills other days).

!) MAIN QUESTION: is this mechanism can work or not?
https://www.ncbi.nlm.nih.gov/pubmed/30709339

!) SECOND QUESTION IS: he is getting shakes. What can it be?  (inside based like fever). But temperature is ok. Blood pressure is pretty normal. Pulse is ok.
Problem is – he can not remember when it was started (may be after avastin). It was more than 1 time. He is hiding his condition may be…
And he sleeps much.

These supplements was added (after radiation/before or together with new chemo):
avastin (1 in 2 weeks) +TMZ (5/23)
++++++ melatonin 20mg only 5 days (or need to use all time?)

---------1) alpha lipoic acid (2x300=600)
---------2) curcubrain (1x400=400)
---------3) PSP(PSK) Oriveda (2x350 = 700  or 6 at TMZ days)
---------4) Carvedilol for pulse (1/2)
---------5) started to change carbamazepine (200mg) to keppra (250mg) – TOGETHER 1 week. Then more keppra less carb.

PS – keppra for unmethylated MGMT (still risk if TMZ not working)

Help me to connect his fever/shake with suppliments.
I can guess 1) it is avastin 2) keppra together carbamazepine 3) may be PSK/PSP… But may be you know bwtter?

Also he is taking (from the beginning)

---------metformin (1500)
---------Boswellia (2000)
---------D3 (4000)
---------Omega3 (1500)
---------allopurinol
---------Losartan
---------Nifedipine
---------Aspirine low dose

He has diabetes 2 type/hypertonia/


-----------What can I add or remove? (may be malatonin all days not only 5)? may be lower dose TMZ/ methronomic or replace TMZ with Irinotecan? (to not risk with combinations).
------------Is my combinations effective (TMZ+melatonin+PSP+keppra) with our mutations? (add/remove?)
------------What can be the reason of weakness and shake/fever?
------------Do you have link for Japan protocols (psk/psp)?
Thank you!

Request for choosing a suitable cocktail

Hi everybody and many thanks to Stephen for adding me to
this wonderful blog.

I have some questions regarding my father situation and it’s
a bit embarrassing cause we don’t have detailed information about the tumor as
many of you have, so I wonder if someone could kindly help me to choose the
best probable cocktail for him while I know that it is just a shot in the dark.

He is 69 years old and last year (March 2018) during working
with probably toxic glue he suddenly fainted out and later he had problem in
his stomach. We went through lots of colonoscopy and other procedures during a
year and he lost more than 10 kg. Finally (at September 2018) we had a MRI that
said low grade glioma (in the LT temporal)
is the first possibility. (I guess since his HDL and LDL cholesterol were 41
and 77 mg/dl in July 2018 the tumor was not aggressive at that time). We’d been
told that because of tumor location it is better to do nothing and just wait.

(I am suspicious about
Finasteride pill that he took for 3 years for his prostate and we recently switched
to Terazosin)

Then in December we had
the second MRI which shows a “51*47*24 mm heterogeneous mass with surrounding edema
and extension to hippocampus region and mass effect on the LT with mild mid
line shift”.

Then we went through a
painful process to decide whether we should take the risk of surgery and
finally we decided not to (which I am still doubtful about it). After a stereotactic
biopsy which only says this:

•  Microscopy:

Sections reveal fragments
of tissue including an astrocytic neoplasm. The cellularity is high. The cytologic
atypia include unclear hyperchromatism and some pleomorphism with scattered
cells having larger more hyperchromatic nuclie, occasional multinucleated. There
is rather extensive necrosis with prominent vascular and endothelial
proliferation.

• Diagnosis:

Astrocytoma, anaplastic
with necrosis (glioblastoma multiforme), left temporal and basal ganglia involvement. 

We started the temodal (120)+ radiotherapy (30 sessions) recently and now he
is in his second week.

He is taking 1 sodium
valproate 500, had around 25 dexamethasone (finished now), 3 phenytoin 100, 2 ranitidine!,
and 1 Terazosin a day.

I am trying to persuade
his Drs: to change ranitidine to cimetidine and maybe adding metformin (since he
had lost many weight I don’t know if they accept this and as someone mentioned
here metformin and cimetidine does not go well together. Am I right? But cutting
his carbohydrate too much is quiet hard so I still like metformin)

Also maybe chloroquine if
they accept.

-        
So the first silly question is that, if he goes well with the first cycle
can we say his tumor is methylated?

-        
Do you think Turmeric curcumin NovaSol could work as a replacement for
Longvida? Because of his weak stomach I thought soft gels might work better.  (https://www.amazon.com/Turmeric-Curcumin-NovaSOL-Bioperine
Softgels/dp/B018GQJQHM/ref=sr_1_2_s_it?s=hpc&ie=UTF8&qid=1533759320&sr=1-2&keywords=NovaSol%C2%AE&dpID=61EqNrydTdL&preST=_SX300_QL70_&dpSrc=srch)

-        
What would you suggest for such a vague situation for a cocktail or other
therapy? (  Ttf and vaccine are not available here)

I know most of information I said are useless but I thought it might help for some better guess. 

Many thanks in advance,

Sahel

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

Drug	Dosage
Valproic Acid	1000mg
Chloroquine	250mg daily
Celebrex	200-400mg daily
Fluoxetine	40mg daily

Supplement	Dose
CBD / THC	gradually increasing dose
Boshwella	1000mg
Green Tea
Curcumin	1000-2000mg +
Melatonin	10-20mg
Maitake D	100mg
Fish Oil
Probiotic
Turkey Tail - ie PSK	3000mg
Vitamin D3	5000-10,000 UI
quercetin	500mg
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 

Agents for MGMT Unmethylated, PTEN Mutation, and PDGFRA Amplificayion

Hi,


My mother got the GBM surgery on Feb 6 this year. She is MGMT unmethylated, PTEN mutation, and PDGFRA amplification.


Does any one know effective agents for treating these disorders or symptoms?


Regards
James Zhou

Treatment questions

I have a few questions I've been thinking about and would love your opinions. Background first, my husband is fighting an AA3 right insular brain tumor. Surgery removed 80% of the tumor and then an emergency surgery three days later removed nearly his entire right temporal lobe.  His tumor was never tested for MGMT status but it is IDH1 mutated. Surgeries were in July 2016 with TMZ and radiation following in September and October.  He is currently finishing up his 5th cycle of TMZ, been wearing Optune since the end of November and will be receiving his 5th round of NDV infusions at the IOZK clinic this coming week.  Last MRI done in early January has shown no tumor change from his original surgery.  My questions are:

1. Research has shown that patients who complete 12 rounds of TMZ often have longer periods of PFS. However, vaccinations that would begin in May at the IOZK clinic require that he discontinue TMZ or else risk them not working. We are spending all our savings to do this treatment. What I'm wondering is if we should continue on as planned with 6 cycles of TMZ and then vaccinate or try to push back vaccinations to complete 12 rounds of TMZ and then do vaccinations?

2. Seizures endured during his two week hospital stay in July required 4 different medications to calm my husbands seizures. Before being discharged, his medical team were able to get that down to two medications: Keppra and Vimpat. He was prescribed his maximum dose at 3000mg and 400mg respectively. Since learning of this website and studying different supplements and such, with all the pills he is swallowing he's slowly weaned himself down to 2000mg and the occasional 200mg if he remembers his lunch medications. His NO has never been particularly interested in bringing any of his seizure medications down, probably because of his chart notes. At our last visit our NO was questioning his moods. Asking if he seemed more agitated than usual. I lied and said no because I was worried that she'd take him off of Keppra (the medication we were discussing). My understanding is that it helps with MGMT status. So finally my question is, should I try and keep him on Keppra for its benefits or let them change his seizure medication to Gabapentin?

Thank you for any insight in advance. I'm really wondering what others might do in our situation.

Anti seizure medications

Hi all,

Thanks to everyone for contributing to this amazing blog as always. Sorry I have been quiet for a while.

A quick update on Mum. She has been doing a cocktail with mainly natural supplements, Cbd oil and some repurposed drugs including Celebrex, Metformin and Mebendazole (Cimetadine on hold whilst she comes off Phenytoin). She has also been having treatment at the IOZK in Cologne. She completed 4 cycles of Temodar out of the standard regime in the UK of 6. She could not get onto her 5th round as her neutrophils have remained too low. She had her first Dendritic cell vaccine a few weeks ago after completing 6 cycles of Newcastle Disease virus and localised hyperthermia (which are given once a month and are planned out to time with the patients chemo rounds). They were not concerned that she was unable to complete chemo -it did not affect their treatment. The dendritic cell vaccine used Mums tumour tissue from her last operation in December and was cultured over 7 days immediately prior to the vaccine. They were able to produce 3.5million dendritic cells which they were happy with as a good vaccine contains 1 million apparently (not sure who counted them! :) .. )

Her scans have shown a tiny 6mm fleck that appeared in April but has remained unchanged since.

Her speech, reading and writing has been affected and her vision/balance slightly but she is doing really well right now in general.

Last week she had a series of partial seizures. Most of them occurred during the night and they did not last for too long but Dad took her to A & E for the first 3 of them. They got milder during the week and her last one was a week ago on Friday morning. Mum has been coming off Phenytoin which she was put on about 3 months ago when she had her last seizure. Not sure why they gave her that as it interacts with Cimetadine and has much worse side effects but for some reason it takes ages to come off safely. She is nearly completely off it and they have increased her Keppra to 1250mg twice a day. This seems a lot to me especially as her seizures have been fairly mild.

My question to the group is which anti seizure medication are you or your loved ones taking and what dosage?

I believe Keppra is the best in terms of less side effects but at that high a dosage perhaps it will cause some problems for Mum. I would like her to increase the dosage of Cbd oil too as this has anti seizure properties and she has been on a fairly consistent average dose for a while now.

Are there any other anti seizure medications that people are taking other than Keppra and has anyone been on a high dosage of this for a long period of time? If so, how have you/they found it?

Thanks all and warm wishes to everyone.

Alison

Hi Everyone,

Thank you to Stephen for adding me to the forum. We very much appreciate a place where we can discuss things with likeminded people. My father (Adrian; 58, UK) was diagnosed with GBM at the beginning of May this year. He had total resection and has had no detrimental effects so far from either the GBM or the surgery. He is currently in week 4 of chemoradiation and we have started him on a cocktail of drugs after reading through information on this page, Stephen's page, and reviewing the literature (we have a science but not a medical background). We wanted to post our list in part to introduce ourselves and also to get any advice you guys may have. Dad's tumour is IDH1 negative. I post below what Dad is taking and post a couple of questions below. His GP is open to prescribing drugs if we provide him with some evidence of effectiveness. Thanks for taking a look.

Adrian’s Daily Cocktail (updated 20/07/2016, last few days of chemoradiotherapy)

Prescription while on Radio and Chemo therapy for 30 days:

Hydrochloride Dihydrate - Anti-Sick (Ondansetron 8mg tablet) started 1x morning, reduced to 1/2x morning
                        - 20/07/0216 stopped after 25 days caused constipation and minimal sickness feelings
Temozolomide (Temodal - Merck Sharp & Dohme 140mg capsule, BMI based dosage) 1x morning
Co-Trimoxazole (Anti-Biotic 480mg tablet) 1x morning every other day
Levetiracetam (Keppra 500mg tablet) was 1x morning and 1x evening, reduced mid term to 1x morning, and a week later reduced to 1/2x morning, recommended to stop(?)
                        - 20/07/2016 stopped after 20 days (as no fitting experienced)

Prescription Chemo therapy after Radiotherapy (expected):

Temozolomide (Temodal - Merck Sharp & Dohme 140mg capsule, BMI based dosage) 2x morning for 5 consecutive days every month following Radiotherapy

Ongoing Prescription by special request:

Celebrex (Pfizer 100mg capsule)    1x evening
Chloroquine (Avloclor - Alliance Pharma 250mg tablet) 1/2 tablet twice a week in morning (available off prescription)
Cholecalciferol 800IU (Fultium D3 - MA Hodder Internis, equiv. to 20 micrograms Vitamin D),   1x capsule in morning (available off prescription under other brands)

Ongoing Supplements:

Cannabinoids (CBD Brothers CBD Oil Blue Edition)    2x drop morning, noon and evening
Turkey Tail (Immune Support 500mg capsule)     3x morning and 3x evening
Melotonin (Eurovital 10mg tablet)     1x evening
Fish Oil (Omega 3 - Solgar 950mg capsule)     1x morning and 1x evening
Boswellia (Solgar capsule)     1x morning and 1x evening
Curcumin (Super Bio-Curcumin - LifeExtension 400mg capsule)    1x morning
Optimized Resveratrol (LifeExtension 250mg capsule)    1x morning
Berberine (Swanson 400mg capsule)     1x morning and 1x evening
Milk Thistle Fruits (Silamarie - Bio-Health 450mg capsule)   1x morning and 1x evening
Ashwagandha (Solgar 400mg capsule)   1x morning and 1x evening
Senna (Senokot - Reckitt Benckiser, 154mg tablet),    1-2 as required, evening, to offset Anti-Sick tablet constipation.


1) Is there anything else we should be taking at the moment or anything we have currently that we should be taking at higher dose or specific times of the day? He is having radiation late afternoon, Monday-Friday. Not being a medical expert I am wondering if we are covering enough bases or doubling up unnecessarily? Would be great to get a basic understanding of the processes so can get a better feel of the literature.

2) Should we stop taking levetiracetam completely at the moment as oncologist recommends?  I read one paper Kil et al 2011, that this drug may be helpful in sensitising the cancer cells during chemoradiation. I see also that is useful as a sensitiser when he will be on the high dose chemotherapy.


Thank you

Sam & Adrian

Seizure and Brain Bleed

My 61-year-old, otherwise healthy, husband had a major seizure at 4:am Tuesday, think Grand Mal. This was the first time anything like this has happened, very frightening. Greg was rushed to our local hospital and released withing 4 hours. He had a CAT scan and it looks like he has a small brain bleed. Greg's neuro-onc didn't seem overly concerned. She has him back on Keppra 750mg twice a day. His short-term memory is even shorter if that's possible. His walk is even more hesitant.  We're waiting for the results of the second CAT scan, taken yesterday morning. We're back at UCLA next Wednesday for his routine MRI, blood and visit with neuro-onc. Has anyone had a similar experience? What does it mean to have a brain bleed, even a minor one? Do you recover from that or is the "new normal" reset?
Newest response from Greg's neuro-onc: "I don't think so.  These symptoms are quite typical of a bleed but as long as there is no worsening of the bleed, which sounds like there's not, he'll get better in about 3-6 months.  But he may feel better if we give a short burst of steroids for 4-5 days, 4 mg twice a day, before going back down to 4 mg."
Additional question: About a month ago, we stopped (cold turkey) almost all complementary meds, including chemo to give Greg a break. We also stopped cbd-thc sub-lingual spray. He continued to take curcumin+, metformin and just a couple of other meds but not the 25+ vitamins/supplements that have been part of his cocktail since September. Could that have something to do with the seizure/brain bleed? 

Keppra and Temozolomide

Hi Everyone!

I'm new to this blog. I've read many posts and this is a great help to me, as I'm a beginner in the drug coctail treatment.

Our story briefly:
1) My father, 55, was diagnosed with an unknown brain tumor in October 2015 (the biggest dimension 43 mm). Craniotomy was carried out 3 days after the diagnosis. Preliminary histopathology - astrocytoma III, final result - glioblastoma IV.
2) First MRI after the surgery in December, right before chemoradiation, showed still a big tumour. According to the oncologist - radical recurrence. According to another neurosurgeon (we consulted the MR image in another hospital) - first craniotomy improperly done (!!). I'm not sure who's right... the other neurosurgeon, specialized in gliomas, was very convincing.
3) We decided for another surgery (by another surgeon). The resection must have been deeper as afterwards my dad's sight is worse (he sees everything darker, has problems with reading, seeing details etc., however he's getting better, it's been 6.5 weeks since the surgery).
4) Now chemoradiation. First cycle of Temodal during radiation for 42 days on a daily basis.
5) Tumour unmethylated, IDH1 negative. Other genetical tests of a frozen sample in progress.

We are at the very beginning of the drug&supplements treatment. It's very difficult to collect all the prescribed drugs. We're located in Poland. Started like that:
Temodal (150 mg/day);
Depakine (valproic acid) 2x500mg/day- prescribed by the neurosurgeon to prevent seizures;
Keppra (will start tomorrow, 2x500 mg/day)- added in order to sensitize the tumour for TMZ (prescribed by our GP on request, she agreed);
Dexamethasone (2 mg/day);
Proton pump inhibitor (1x/day) - drug called IPP20 in Poland;
"Pheonix tears" with high THC and CBD (rectal application) - 2 ml/day
Curcumin (up to 3000mg/day)
Quercetin
Vitamin C (1000 mg/day)
Sugar-free diet and radical reduction of meat. Working on reduction of gluten.


I have one question and would be grateful if anyone could advise sth:
What would be the best scheme of taking Keppra to sensitize the tumour for TMZ. Does it matter, if the first doze (500mg) is taken with Temodal on an empty stomach or he can take it later, after his daily radiation (with a meal afterwards)?
Should we add Prozac and Disulfiram, apart from Keppra, for a better chance of TMZ working?


Cheers!
Piotr

Valproic Acid, Levetiracetam Do Not Improve Survival in Newly Diagnosed GBM

What was commented as being a certain fact before, now is not anymore! 

EDIT: as Stephen points out below, the time frame of this study differs from others, so its conclusions can´t be generalized.

LINK TO THE STUDY 

 

IDH Wild-Type GBM

I''ve copied over the addendum path report for my husbands tumor.  I haven't been able to find any promising treatment throughout my research for his tumor type and feeling quite desperate!  Any suggestions based on the additional information we have...I'm not liking what I've read so far and the outcome doesn't look good....

Comment This case was subjected to IDH1/2 mutation analysis performed at Moffitt. It was also sent for MGMT promoter methylation testing, for FISH testing of chromosomes 1 and 19, and of chromosome 10  (PTEN locus), as well as for EGFR vIII assessment. No IDH1 or IDH2 hotspot mutation was found by sequenom. MGMT testing was negative for methylation of the gene promoter. FISH testing was  negative for codeletion of chromosomes 1p/19q, but positive for monosomy of C10 at the PTEN locus.  The EGFR vIII deletion was negative. In addition oncogene testing by Next Generation Sequencing was  performed at Moffitt and reported separately; in summary, no mutation was found in the assessed  genetic 'hotspots'. The findings are characteristic of IDH-wildtype glioblastoma. The histopathologic  diagnosis and interpretation are unchangedAddendum Pathology Report
	RIGHT TEMPORAL TUMOR Addendum IDH1 AND IDH2 MUTATIONAL STATUS: - NEGATIVE FOR IDH1 AND IDH2 MUTATIONS BY SEQUENOM 1p/19q STATUS: - NEGATIVE FOR 1p/19q CODELETION BY FISH MGMT PROMOTER METHYLATION STATUS: - NEGATIVE FOR MGMT PROMOTER METHYLATION PTEN/CHROMOSOME 10 STATUS: - POSITIVE FOR PTEN/C10 LOSS BY FISH EGFR vIII STATUS: - NEGATIVE FOR EGFR vIII NGS TRUSIGHT HOTSPOT MUTATION ANALYSIS: - NEGATIVE FOR ACTIONABLE MUTATIONS Any help would be much appreciated!

Sertraline vs Fluoxetine

Steven and others…

I have been considering switching from Sertraline to Prozac.  I would appreciate your thoughts:   

Heres what I know based on what Steven has written on his web site.

·           

• When sertraline was added to doxorubicin it resulted in increased chemosensitive over fluoxetine and doxorubicin.  This is apparently due to sertraline’s ability to impact efflux pumps better than fluoxetine.  I do not know if TMZ and doxorubicin are comparable with regards to benefits brought about by inhibiting efflux pumps.

•    Prozac inhibits MGMT activity, sertraline does not

•     Disulfiram inhibits MGMT activity

Then from CUSP9*:

•  Sertraline blocks multiple survival pathways.  No mention of this is made with fluoxetine

So here are my questions:

• If sertraline inhibits efflux pumps as does disulfiram, how important are PPI’s likely to be if both sertraline and disulfiram are already being utilized?

• Since disulfiram already inhibits MGMT activity, in theory fluoxetine would not need to be used for this (ignoring the possibility of synergy for now).  And since both sertraline and fluoxetine inhibit efflux pumps, it seems sertraline might be better combined with disulfiram rather than fluoxetine and disulfiram because sertraline has the added benefit of blocking multiple survival pathways.  Do you agree with my thinking on this?

• Fluoxetine does inhibit MGMT as does disulfiram and I suspect the synergy between the two could be beneficial, but since we are dealing with an IDH1 mutation, presumably most of the cells are MGMT methylated.  There would of course be other cells that are not methylated that could benefit from MGMT inhibition, but with disulfiram in the mix already, do I need to prioritize fluoxetine over sertraline because of this?  Or would the added benefit of blocking survival pathways be of more importance?  I realize there is no known answer to this and I am asking you to offer input lacking any data, but I am wondering if based on what you have read, this makes sense.

• Jeremy is not willing to add a PDE5 inhibitor to his cocktail.  I think he has had his fill of drugs and supplements.  Does sertraline seem to improve BBB penetration? 

Thanks for the input!