Bevacizumab: Is the lower the better for glioblastoma patients in progression?

A very interesting study confirming previous reports on the possibility of using low doses of bevacizumab. A dose of 1 mg / kg / 2 weeks looks very strange. However, to the surprise, the authors report a similar effect with other doses and less toxicity! Your opinion?

http://sci-hub.tw/https://linkinghub.elsevier.com/retrieve/pii/S0007455118302315

https://www.ncbi.nlm.nih.gov/pubmed/30301554

METHODS:

From September 2013 to August 2016, we recruited patients with progressive glioblastoma, whatever the previous treatments. We compared a routine control group (CG) of ten mg/kg, to a low dose group (LDG) composed of 5 subgroups: G5: five mg/kg, G4: four mg/kg, G3: three mg/kg, G2: two mg/kg, G1: one mg/kg; each patient was treated with the same dose every two weeks.

RESULTS:

Fifty-three patients were treated: 20 women and 33 men, 24 in the CG and 29 in the LDG. The median age at diagnosis was 62 years [35.0-77.0]. No statistical difference was found in overall survival either for the CG or the LDG (P=0.086) or among groups (P=0.251), with even a trend toward improvement for LDG: 62 weeks [20-145] versus 73 weeks [18-178]. The median progression free survival was comparable: 19.5 weeks [6.0-54.0] for the CG and 15.0 weeks [0.0-134.0] for the LDG (P=0.221). Bevacizumab was stopped either due to progression (45.1%) or toxicity (52.9%), without significant differences between doses but maybe less toxicities in the LDG (16.7% for toxicity in G1).

DISCUSSION:

Use of bevacizumab at progression at lower than usual doses seems to give the same results as the standard dose without giving additional toxicity.

 

Semyon's mom's profile.

My mother had an operation (in Germany, Frankfurt am Main) - removal of the tumor by 99%, and then - the rapid growth of the tumor to its former size (for 3 weeks)! The doctors were in shock.
(Glioblastoma, MGMT methylated)
10 days after chemoradiotherapy, MRI still showed tumor growth. The doctors decided that TMZ did not work in our case and suggested urgently switching to Avastin and Irinotecan.

Thinking, we decided to use a low dose of Avastin + CCNU.
I also decided to add 5 days of low TMZ after every day of CCNU.

The OncoDeep report showed the likely effect of Sirolimus, Olaparib and Trametinib.
I flew to Delhi (India) and bought at low price LYNPARZA Olaparib (1 bottle of 112 capsules of 50 mg) and MEKINIST Trametinib (1 bottle of 30 2 mg tablets).

Unfortunately, it is very difficult to interpret MRI. 3 doctors who watch my mom's MRI say sometimes the opposite conclusion!

Comments:

1. Suppression of T4 is very slow. We spent 3.5 months to reduce T4 from 12.4 to 3.3pmol / l. Also, T3 has fallen dramatically, although we take synthetic T3. Because of this, drowsiness and lack of appetite.

When suppressing T4, you can not take selenium, since it increases the production of the hormone T4! We started taking selenium and the hormone T4 took off from 3.3 to 5.14! Now with great difficulty again we need to knock it down((

2. For all treatment, my mother lost a lot of weight. From 65 kg (in January) to 52 kg (now). However, I do not see anything that we could refuse.

3. We bought a special meter and ketone strips to check that the mother is ketosis.

4. I ordered Mebendazole chewable tablets from Thailand for 500 mg / tablet. Maybe we will try to take large doses: 2-3 grams per day.

5. We use a higher dose of perillyl alcohol than Dr. Dr. Clóvis Orlando: 30 drops instead of 21. No unpleasant sensations! We plan to increase the dose to 40 drops. Dr. Clóvis Orlando wrote that they use perillic alcohol of 96% from Sigma Aldrich and that the other perillyl alcohol will not have an effect on GBM.

MRI-1: https://drive.google.com/open?id=1tPKrQgjIZzBgefhkknxNlQKbaC04XMI_

MRI-2: https://drive.google.com/open?id=1t3SgxGgJFi19i9qIwc47JucsV6ZCbLFa

MRI-3: https://drive.google.com/open?id=1JbRYk3DCUK87ndeRQK-Q7V7130oObiMV

MRI-4: https://drive.google.com/open?id=1Q6WFd9qtFAd18czkd5ouKYloIVBKuFS1

MRI-5: https://drive.google.com/open?id=1L-O1BgoVMohI7eXxH35qN__rNBDy3hrM

MRI-6: https://drive.google.com/open?id=1xWYd5_UsrAYb-c4wv49DSWTeJEN8Dl_F

MRI-7: https://drive.google.com/open?id=1MCpzZxPnl7eI1iigzJVWrOo2o4s8hKWz

MRI-8: https://drive.google.com/open?id=1De95kb-iZ30X7scIbZkeXxFq4KV5fgdT

11C-methionine PET 17.05.2018:
https://drive.google.com/open?id=18AaVybu5nvBH_cAe5QIfzO-efiwsUfkc

OncoDEEP report: https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc
http://btcocktails.blogspot.ru/2018/02/our-report-oncodeep-what-do-you.html

 

Our cocktail and report "OncoDeep". What do you recommend to pay attention to?

Since the tumor after surgery (removed 99%) increased again in the same size (3.5 x 5 x 5 cm) in 3 weeks and the tumor did not decrease after radiotherapy + TMZ, we probably have a very unusual cocktail for the first line:
- cycle 42 days: Avastin (3mg/kg/week) + CCNU (1 day 75mg/m2) + TMZ (5 days 90mg/m2),
- disulfiram 500mg (+Copper 5mg + DHA) and verapamil 200mg only on the days of TMZ + CCNU administration, and 2 days before and after.  I'm not sure, maybe it's advisable to take Disulfiram every day? Otherwise, disulfiram may not start to influence so quickly?
- every day: cloroquine phosphate 250mg, telmisartan 80mg, alfacalcidol 2mcg, oxaloacetate 100mg,  melatonin 20mg, curcumin longvida 2000mg,  Berberine 1000mg, DHA/EPA 1000mg, PSK / PSP 1800mg, Methimazole + T3, R-lipoic acid + hydroxycitrate + ketogenic diet, omeprazole 20mg + DCA 20mg/kg (10mg/kg/BID) + caffeine (2 cups of coffee and 5 cups of black tea) + vitamin B1 200mg

My mother has been responding well to taking DCA + caffeine for a week in the form of black tea and coffee. However, my mom's pulse increased to 90-95 after sleep or rest. To reduce it, we now take 10 mg of propranolol per day. An increase in the pulse may also be caused by the intake of the hormone T3.

Also I consider the addition of a low dose of naltrexone before bed.
We also ordered perillyl alcohol at www.sigmaaldrich.com and expect it soon.

Today we received a report from OncoDNA. The last 3 months I read and search for any information about glioblastoma, but unfortunately I find it difficult to understand this report. Doctors in Russia do not order such reports at all! Our doctor in Germany said that unfortunately, such reports will not help us in any way.

Maybe you can tell me what to look for in this report? Any comments?

For example, I can not understand, is there overexpression (amplification) of EGFR?
"Damaging TP53" = mutation of TP53? Not understanding this, I can not draw conclusions from this review (http://astrocytomaoptions.com/exploring-strategies-for-tp53-mutated-gliomas/) and other studies.
"Damaging PTEN" = loss or mutation PTEN? An interesting article in this case: http://btcocktails.blogspot.ru/2018/01/parp-inhibitors-for-pten-mutant-cancer.html
Which of the drugs on the list of potential clinical benefits to pay attention to ?

Here is a link to the report itself and some pictures of him:
https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc

 

 

A difficult choice of treatment for a large progressive GBM after chemoradiotherapy

From some studies it follows that:
- Avastin in the first line increases the quality of life and survival for partially resected GBM;
- combination of CCNU + Avastin is more advantageous than just Avastin for MGMT-methylated GBM;
- I can not also not use TMZ immediately after chemoradiotherapy, especially after CeTeg results for MGMT-methylated GBM;
- low Avastin dose (<3.6 mg / kg / week) with Telmisartan, is more beneficial than the Avastin standard dose and will not be so toxic for use with CCNU + TMZ.

As a result, after sleepless nights, I decided to try this combination:

The cycle of 42 days:

0 day - Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg
1 day - Avastin 6.5 mg / kg
1 day - Lomustine 75 mg /m2 (+ Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg)

2-6 days - Temozolomide 90 mg/m2 (+ Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg, Curcumin 2000mg)

7-41 days - Telmisartan 40-80mg, Disulfiram 300mg, Copper 2mg, DHA 900mg)

15 day - Avastin 6.5mg / kg
29 day - Avastin 6.5mg / kg
42 day - Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg

+ every day Melatonin/Agomelatin, Berberin, Shark Oil, Oxaloacetate, Honokiol...
If possible, DCA will be added 6mg / kg / twice every day.
If possible, the doses of CCNU and TMZ in the next cycle will be increased.

Angiotensin system inhibitors + low dose Avastin

This June a study was published by Victor Levin et al. of Kaiser Permanente Hospital, Redwood City, which follows up on a previous study on the use of Avastin doses lower than the standard dose.

https://www.ncbi.nlm.nih.gov/pubmed/28631191  (I've uploaded the full study to the Brain Tumor Library -> Folder 1. Therapies - Human Studies -> Angiotensin System Inhibitors)

The current study looked at the use of angiotensin system inhibitors, including both ACE inhibitors (benzapril, captopril, etc.) and angiotensin II receptor blockers (losartan, telmisartan, etc.) used for hypertension simultaneously with chemotherapy and/or Avastin in newly diagnosed and recurrent glioma patients.

In a very large cohort of 1186 infiltrative glioma cases (grades 2-4), use of an angiotensin system inhibitor (ASI) was significantly associated with better survival (hazard ratio 0.82), in a multivariate analysis adjusted for other variables such as age, extent of resection, GBM versus other grade, use of Avastin, etc.  This advantage of ASI treatment was even more significant in patients who were also treated with Avastin (HR 0.75).

A previously published cohort of 181 recurrent GBM patients treated with various doses of Avastin was examined with regard to their use of ASI drugs (for hypertension).  The previous study had shown trend toward longer survival in the group treated with lower-dose Avastin, and this study has been summarized elsewhere.
http://virtualtrials.com/pdf2016/benwilliamsTreatmentOptionsUpdate2016.pdf   (Page 90)

Remarkably, of the 89 patients treated with doses of Avastin lower than 3.6 mg/kg/week (the standard dose amounts to 5 mg/kg/week),  the 47 patients also using an ASI drug had a very impressive median survival of 99 weeks (22.8 months) versus 55.6 months (12.8 months) for the 42 patients receiving low dose Avastin without ASI drugs.

99 week (nearly 23 month) median survival (from treatment for recurrence) for a sizeable (n=47) group of recurrent glioblastoma patients in virtually unheard of.  Although all the usual caveats apply because of the retrospective, non-randomized nature of this study,  the outcomes are too impressive to ignore.

As Levin et al. conclude "Prospective clinical trials combining ASIs with low-dose BEV in GBM patients are now needed to confirm whether ASIs can enhance the efficacy of VEGF-targeted therapies and thereby improve clinical outcome."

As a side note, Victor Levin is the founder of the Society for Neuro-Oncology (SNO) and often described as the "father of neuro-oncology", at least in America.