Questions about our cocktail and radiation (at 2nd recurrence)

I posted earlier this year, after my partner had his second gross total resection (his first resection was in Jan 2017).  We did pembrolizumab and CCNU along with a relatively small cocktail of supplements (vitamin D, curcumin, PSK, bosellia, melatonin).  We tried Celebrex and my partner immediately developed colitis, which made me gun-shy about introducing more treatments.  At that point his MRIs were improving, anyway, so it seemed better not to introduce new complexity.

Then, in June and July, he had a couple grand mal seizures and his MRIs worsened.  By early August the doctors concluded that there was actively growing tumor, so were officially at second recurrence.  We stopped pembro and CCNU, and began Avastin.  I also finally introduced metformin and simvastatin, apparently without any side effects.

A scan last week was a little worse but not dramatically.  There had been significantly more progression in the 4 weeks between the July and August scans than in the 6 weeks between the August and September scans. 

I’ve gotten our oncologist to agree to let us add telmisartan and mebendazole, although we haven’t started either yet.  My partner still needs 4-6mg dexamethasone daily to control cerebral edema, even with Avastin, and I’m hoping telmisartan will help us reduce that.  I’m still not sure what to think about mebendazole.  I share Stephen W.’s worry that the mega-doses could interfere with other treatments and I’m skeptical of Care Onocology’s profit motive (they patented their 4 drug combo and threaten to sue violators).

We’re also trying to get VAL-083 through expanded access, although that’s taking a while.  My partner is not a good candidate for treatments requiring another surgery, like vaccines.  He lost significant brain function in the second surgery and also suffered major complications from seizures and blood clots.  He's very clear that he does not want a lot of suffering from here on out.

I have two questions for anyone who wants to weigh in:

1. Is there anything we should strongly consider adding to this cocktail?  My partner’s tumor is MGMT unmethylated and IDH wildtype.  Tempus showed NF1 and RB1 as the only potentially actionable mutations (I've ruled out everolimus after the study indicating it worsened OS).
2. Our neuro-oncologist had us consult with our radiation oncologist, who recommended a short course (10 treatments) of lower intensity radiation than my partner had last year, when he did the standard Stupp protocol (plus Optune after radiation).  The RO thought it might help slow the growth down a bit and provide a little symptom relief but probably wouldn’t increase life expectancy much (if at all).  We’re really torn about whether to go through with it or not, and I don't know how to gather data on it effectively.  Unfortunately, we need to make the decision fairly quickly.

Thanks in advance for your help.

Medications and supplements during treatment !

Hi All



My mother was diagnosed about a month and a half ago with GBM the surgery was performed and the tumor was completely removed ,now she treated TMZ and Radiation

I purchased supplements that were taken before starting chemotherapy and radiation, such as resveratrol, green tea, mushrooms, pozzalia, turmeric, omega-3, flaxseed oil, melatonin, broccoli sprouts etc
But  we stopped it during treatment, is it better to stop eating supplements during treatment or take it during treatment??

What do you suggest to take medicines and supplements during (and after) chemotherapy and radiotherapy??
My mother is 49 years old and has no other health problems at all

Thanks in advance

Muddar

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 

Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy.

https://www.ncbi.nlm.nih.gov/pubmed/28842551

Any opinions on this study? Dosage in humans?

Interesting article reflecting on IDH1/2 mutations and treatment targets...

http://cgp.iiarjournals.org/content/15/5/421.full#T2

BR
TroelsR

DNX-2401

Does anyone have any information on the trial using DNX-2401?  We are trying to decide if the risks outweigh the benefit or vice versa. Its great for the 20% that had extended life but what they won't tell us is how those people were living. Did there side effects continue where even thought they lived three more years they were miserable? If anyone has any information to shed some light on this that would be great. Thank you!

Reviewing my mom's cocktail after 1 year progression free survival

Hi folks/Stephen,

We had my mom's MRI just a week back, and her last MRI showed no growth of the disease, had no choline elevation(in the spectroscopy report) and didn't show perfusion either. :)

She has completed her radiotherapy, 3 cycles of temozolomide and 3 cycles of lomustine+temozolomide. We moved to the Lomustine + Temozolomide protocol because her disease was methylated.

This group, especially Stephan have been extremely supportive so far in this tough journey. I wish to run through you all my mom's cocktail, and wanted to ask specific questions on her cocktail. Would really appreciate your help! My questions on my mom's cocktail are as follows:

1. Should I consider adding anything, or updating anything in the current cocktail?

2. Because my mom's choline elevation has constantly been coming down in the past three MRIs, my oncologist suggests we do three more cycles of lomustine + temozolomide. However, my mom's WBCs never come up beyond 1500 after the chemotherapy. The oncologist supplements with Iron and Folic Acid for WBC support, post which the count reaches 4000, both of which from what I've aware are negative prognostic factors for GBM. He says the effect of the chemo overpowers the negative prognostic factor of Iron/Folic Acid. Do you think that it is the right approach to go about things, or should I consider stopping the chemo and not supplement with Iron/Folic Acid?

Is there anything specific that you have tried and has worked well for your patient for WBC support?

3. Are there any clinical trials/additional treatments that you would suggest doing beyond the current line of treatment that we currently are on? For now, we plan to do three more cycles of chemo along with the supplements mentioned below.

Following are the details from her biopsy

IDH1 and IDH2: Not detected
CHR 1p and CHR 19q: Negative for CHR 1p and CHR 19q codeletion
Methylation: Detected
Ki67 labelling index is 15-20%

Following is her FoundationOne report:

Genomic Alterations Identified
EGFR A289V – subclonal, amplification, EGFRvIII
PTEN I67T
CDKN2A/B loss
TERT promoter -124C>T

Additional Findings
Microsatellite status MS-Stable
Tumor Mutational Burden TMB-Low; 3 Muts/Mb

Additional Disease-relevant Genes with No Reportable Alterations Identified†
IDH1
PDGFRA

Following is the diet and supplements that my mom is taking:

Diet: Ketogenic Diet/Low Carb high fat diet

Supplements

Supplement	Cap count
Boswellia Serratta 500 mg	8
Keppra 500 mg	2
Curcumin + Piperine 1 g	4
Longvida 400 mg	2
Metformin 500 mg	3
Quercetin 865 mg	4
Resveratrol 200 mg	2
Bromelain 500 mg	6
TMG 1 g	3
Reishi 1g	2
Mebendezole 100 mg for 3 months + Doxycycline 100 mg for 1 month (We have skipped the statins from the care oncology protocol fearing it might be too heavy on her liver)	1
Artimisia 1 g	2
Ashwagandha 500 mg	1
Selinium 200 mcg	1
Vitamin A + D + K2 - 5000 IU	1
Molybdenum Glycenate 1g	1
Celebrex 200 mg	2
Green tea extract 500 mg 40% EGCG	2
Marrow Plus	6
Echinisea 500 mg	3
Astragalus tea 3g	1
Juice from 5g of Ginger	1
Garlic 2 cloves	3

I look forward to hear from you all!

Hi everyone, hi Stephen,

what do you think about this study?
It`s little but still very impressive:

https://www.spandidos-publications.com/10.3892/ol.2018.9397

All the best,

ersti

When should certain GBM tumor profiles preclude THC use?

I am evaluating whether I should incorporate THC into my cocktail regimen. I have come across some studies showing that some genes expressed in tumors can either negate the anti-cancer effects of THC or even accelerate the proliferation of the cancer because of the THC. https://www.sciencedirect.com/science/article/pii/S0278584615001190. This article discusses growth factor midkine (MDK), the anaplastic lymphoma receptor tyrosine kinase (ALK), and epidermal growth factor receptor (EGFR).

Does anyone know how conclusive these studies are on which pathways glioblastomas may proliferate because of THC? More specifically, is anyone aware of any updates since this paper or other research that shows different results? I am EGFR amplified and obviously don't want to pour gasoline on the fire.

Cocktail for chemoradiation

Hi all,

Thank you so much to Stephen, Ben, and all of you folks for sharing your insights and information as we navigate through this. I had emergency surgery a few weeks ago and was diagnosed with GBM wild type. The tumor was 7 cm, right parietal lobe, full resection, MGMT methylated, IDH1 negative. My pathology report shows high CBL mutation frequency, high TP53, and my PDGFRA mutations and amplification appear frighteningly off the charts, but that's a whole other question :/

I've put together a cocktail for my six-week chemoradiation term, into which I'm eight days. I would appreciate any recommendations on what I might add, remove, revise. Thank you! 

 

Medication	DailyDose
Temozolomide	100 mg
Celebrex	400 mg
Chloroquine	250 mg
Naltrexone	4.5 ml
Melatonin	20 mg
Noscapine*	60 mg
CBD/THC	1 g
Progesterone**	300 mg

 

Supplement	Daily Dose
Boswellia	5 g
Berberine	1 g
Curcumin	5 g
Flaxseed Oil	43 g
Garlic Extract
GLA	3 g
Magnesium	200 mg
Probiotics
PSP	3 g
Sulfurphane	120 mg
Milk Thistle	1 g
Zinc	25 mg

  

(I'm holding off on antioxidants until after radiation.)

*Noscapine: One of my doctors recommended it. I haven't seen it mentioned here, and I'm wondering if its inclusion is truly beneficial or should be removed.  Here are some links:

Noscapine inhibits tumor growth in TMZ-resistant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/21925789

Synergistic suppression of noscapine and conventional chemotherapeutics on human glioblastoma cell growth
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002615/

But this thesis contends it's effective on its own for glioma cells but is not synergistic with TMZ.  http://digitallibrary.usc.edu/cdm/ref/collection/p15799coll127/id/269936 

**Progesterone
I had already been taking this before my diagnosis, and I increased the dose after having read some promising studies.

Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling
https://www.ncbi.nlm.nih.gov/pubmed/24787660

Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131441

But then I came across this:

Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266854/ 

Does the latter study imply it's instead dangerous for me to be on progesterone at all?

Thank you, and strength, peace, and healing to you all!

5-azacytidine + temozolomide improves survival in IDH1 mutant mouse model

Demethylation and epigenetic modification with 5-Azacytidine reduces IDH1 mutant glioma growth in combination with Temozolomide.

https://www.ncbi.nlm.nih.gov/pubmed/30184215  (pubmed abstract)

click here for full study via sci-hub

In a mouse model of IDH1-mutant brain tumors, 5-azacytidine alone improved mouse survival, and the addition of 5-azacytidine to temozolomide significantly improved survival compared to temozolomide alone.

5-azacytidine is a hypomethylating (or demethylating) agent approved and commonly used to treat acute myeloid leukemia and myelodysplastic syndrome.

Bevacizumab and re-irradiation for recurrent GBM

2018 Sep 4. https://www.ncbi.nlm.nih.gov/pubmed/30182159

Full article:
http://sci-hub.tw/http://link.springer.com/10.1007/s11060-018-2989-z

PURPOSE/OBJECTIVES:
We report the outcomes of the largest cohort to date of patients receiving both bevacizumab (BEV) and fractionated stereotactic radiotherapy (FSRT) for progressive or recurrent high grade glioma (HGG). Furthermore, the sequence of these two treatment regimens was analyzed to determine an optimal treatment paradigm for recurrent HGG.

RESULTS:
A total of 118 patients with recurrent/progressive HGG (GBM = 87, AA = 31) had received both BEV and FSRT (fractionated stereotactic radiotherapy). Patient characteristics were as follows: median KPS at recurrence was 80 (range 50-100); median age at recurrence was 57 years; median time to radiographic recurrence/progression was 10.8 months (mo) and 33.1% of patients had surgery for recurrence. The median time from the start of BEV to FSRT was 6.4 months and from FSRT to the start of BEV was 5.1 months.

For the entire cohort, median overall survival (OS) was 26.7 months and median survival time (MST) from recurrence was 13.8 months (24.4 months and 11.9 months for GBM only).

In patients that received BEV prior to FSRT (n = 50), median OS and MST from recurrence were 25.2 and 13.3 months respectively.

In patients receiving FSRT first (n = 56), median OS and MST from recurrence were 28.8 months and 13.9 months, respectively.

Sequencing of BEV and FSRT at recurrence was not significantly associated with OS (p = 0.08) or median survival from recurrence (p = 0.75).

 

CONCLUSIONS:
The combination of FSRT and BEV for recurrent/progressive HGG provides promising results in terms of overall survival and survival from recurrence. Combining these treatment modalities appears to improve upon the historic outcomes of either treatment alone. The outcomes data from this study support the ongoing RTOG trial exploring the combination of BEV and FSRT for recurrent HGG.

The gross tumor volume (GTV) was defined as peripherally enhancing tissue on T1 post-contrast MRI. Surrounding edema was not purposely included in the treatment volume. The planning target volume (PTV) was the GTV with no margin. The PTV was treated to a median dose of 35 Gy delivered in 10 fractions (Supplemental Fig. 1). The constraints for normal critical structures include: brainstem max dose<30 Gy; optic nerve max dose<25 Gy, chiasm max dose<25 Gy for patients previously irradiated near critical structures and max doses less than 35 Gy for patients not previously irradiated near critical organs at risk.

Baseline corticosteroids reduce activity of PD-L1 blockade

https://www.ncbi.nlm.nih.gov/pubmed/30125216 
Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer

http://sci-hub.tw/https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30666-1/fulltext  (summary of study published in the Lancet)

"Baseline corticosteroid use was associated with decreased overall response, and shorter median progression-free survival and overall survival in patients who received the equivalent to 10 mg prednisone or more per day at the start of the PD-L1 blockade."

10 mg of prednisone is equivalent to only 1.6 mg of dexamethasone.

http://clincalc.com/corticosteroids/

Cocktail approach during radiation

I am about to start radiation and temozolomide for the next 6 weeks and I'm not sure which specific drugs can be combined with TMZ during this stage. Can someone point me to a reference or if you have the knowledge on hand? I couldn't immediately find such a reference specifically for the radiation phase. 

My neurooncologist told me that I should be very careful about taking additional drugs during this radiation as different combinations don't have proven efficacy (TMZ may decrease in efficacy) and the toxicity of combinations can also be unknown. So I've looked into this, but I would appreciate any feedback. 

I understand that a different blog post (Rich cocktail), which might be a bit dated (3 years ago), is focused on treatment in general and not specifically for the phase of during radiation. 

Here is the list that I would like to try out during radiation. Is there anything you would add/modify? 

• Valproic acid (because I'm currently on Keppra, I may have to switch off of Keppra to take Valproic acid since I may not need multiple anti-seizure medications?)
• Metformin
• CBD Oil
• Iron supplement
• PSK 
• Alkylglycerols (possible liver side effects)
• Green tea
• selenium
• magnesium
• Boswellia serrata 
• Chloroquine phosphate

I'm MGMT unmethylated so I believe the TMZ efficacy doesn't seem as concerning. 

TMZ on morning or evening?

Hello all dear friends. I know that TMZ should be taken on an empty stomach. I know that Rich took TMZ on morning. How about Ben.W?I am really confused and I do not trust my oncologist.
Dear Stephen W maybe you are able to help me on that.
Thanks in advance.