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).
(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-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
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
Hi Semyon,
ReplyDeleteSorry to hear that things are not going as well as hoped for your mom. This is such a tough disease.
A couple of thoughts:
1. On the mri's I'm not sure if there is some miscommunications, or if you should get another opinion on reading them, but if there is disagreement between tumor growth and treatment effects then it really complicates decisions on next treatment steps. Also the 'sudden regrowth' of the tumor may be not quite what it seems. From the surgery the resection cavity would be listed as zero tumor given 99% removal, but then the region around the resection cavity got a ring of enhancement and that thin ring would be listed as the dimensions of the resection, making it seem like it regrew 100%. The later MRI's actually show very large reductions in T2 flair, less swelling, far less midline shift, etc, but she is also taking Avastin which has big effects. But overall another opinion on the mri's might help.
2. Most glioma studies on a ketogenic diet seem to show that simply being in ketosis without calorie restriction does not have much effect. Seems to lean more towards indication that glucose levels have to be suppressed quite low (say below 65-70mg/dl) and total protein be limited. Its a pretty challenging regimen to implement.
3. Olaparib has shown some success with TMZ but with significantly increased toxicity (see the oparatic trial). To do CCNU+TMZ+Oliparib seems dangerous and should definitely be something her doctors know about.
4. If there is concern that TMZ didn't do much, then CCNU + procarbazine may be a sensible alternate to TMZ + CCNU. As an aside, 50mg/m2 is the lower range for dosing but is still considered to have an effect.
Thank you for your responses!
Delete1. As I understand it, if there was no rapid growth of the tumor after resection of 99%, then the contrast enhancement would disappear after a few months. But it still exists ...
2. The ketogenic diet did not reduce the fasting glucose level, but the addition of Metformin immediately lowered the glucose to the levels indicated by you!
By the way, how about the theory that when the brain is in a state of ketosis, then it works on ketones, and not on glucose?
1. The rapid increase in contrast after surgery is cancer growth. But continued contrast enhancement after RT/TMZ can just be vasculature damage, especially if it is stable. Contrast enhancement is more a measure of BBB disruption and is not a direct measure of cancer cells. Your NO and radiologists would have to determine what is going on, which is why I was saying that if there is disagreement then to get another opinion. Seeing that the enhancing region is fairly stable now is at least a good sign.
Delete2. In terms of Keto, it is extremely complicated. The more I read about it the more frustrated I get. Not only is it very hard for researchers to study something as complicated as Keto and cancer metabolism, the tools (ie mouse models, cell cultures, etc) don't translate well at all. Mice and rats have dramatically lower capability of utilizing ketone bodies than humans for instance. If you look up literature from RE Strowd you get a fairly balanced view, vs someone like Seyfried who is a bit of a zealot, or even farther out would be D'Agostino or Mercola. The general overview though seems to be : brain cancers vary a great deal in whether they can use ketones, its been shown that they can adapt over time, and that the body actively protects the brain from starvation and so the brain gets priority for any available glucose and thus so does the cancer. In theory reducing glucose levels below 70mg/dl (and keeping it there most of the day) has an effect and the effect in theory is greater the lower you go, though below 45 or 50 can be dangerous. Also note that home glucose/ketone meters are not nearly as accurate as professional blood work, so testing via both methods is best. On top of this some studies show protein must also be kept on the low end. Roughly the proposed 'recipe' is glucose around 60mg/dl, ketones over 3mmol/L, protein around .7g/kgm . Metformin is likely most useful for blocking some glucose uptake and for slowing the conversion of proteins back into glucose by the liver (gluconeogenesis). Probably still means you have to raise ketones sufficiently and control protein, just possibly easier to do that with Metformin. And this is just for the simple model of ketone metabolism vs glycolysis. From there is the huge area of what impact it has on cell signalling or the immune system. So its a pretty difficult treatment to sort out.
I don't think increase in contrast after almost complete resection necessarily means cancer growth. Is this new area of contrast enhancement around resection cavity or increase of enhancement which was already there before surgery and wasn't removed?
DeleteI also had a contrast enhancement show up on one part of resection cavity on MRI, 3 months after complete resection of grade 2 oligodendroglioma. On pre-op scans there was no contrast enhancement and glioma didn't change in size before surgery. Now (28 months later), that area is still there, but no change in size - and every radiologist so far thinks it is fibrotic change / gliosis. One radiologist told me that it is indeed very hard to separate between gliosis and recurrence if the area is small/thin. Gliosis (brain scarring) can be going on for few years. If they suspect it might be recurrence, MR spectroscopy and perfusion may help in giving the answer.
I definitely agree with Matjaz that enhancement from surgery is not definitive indication of growth and also that during RT enhancement changes are also not a sure thing.
DeleteOn Semyon Mom's MRI though the enhancement is not minor ring enhancement but is at the back of the resection cavity and is 2.5cm wide and a full 1cm deep. So while its possible its reactive gliosis or vascular leakage, its seems less likely given the size. MR spec would be a great tool if its possible for them to get it done.
Thank you very much for your thoughts and time!
DeleteTo understand what exactly is happening, what in your opinion will be more accurate and informative?
Magnetic resonance spectroscopy (MRS) or FET PET? Or is it better to do both?
Unfortunately neither are without problems. FET PET is pretty reliable IF the tumor is aggressively using glucose. Most GBMs do, but not all.
DeleteMRS is probably better at differentiating between tumor, treatment effects and healthy cells but it is not terribly accurate as a 1 time scan and could be skewed quite a bit by a keto diet plus all the cocktail stuff.
I'd say either one is mostly an add on to other clinical indicators (mri, seizure rate, blood work) and most useful when deciding on a change in treatment plan. IE in your case it may have helped in the beginning of january when you had to decide on what treatment path to take. Doing it now probably won't change much, but if it is available to you at reasonable cost and the NO agrees then either one is at least informative and may help later on.
I think you're thinking of FDG-PET which is a glucose-based tracer. FET PET used an amino acid tracer (FET is based on tyrosine) and works better for brain tumors than FDG-PET.
DeleteGood catch stephen, yep I had them backwards in my head.
DeleteBottom line is that any advanced scans are most useful when you have more than one so that an A-B comparison can be made. A lot of it comes down to what you can get approved by the NO or covered by insurance.
Hello!
ReplyDeleteI understand that every case is unique, but in the case of my mother-in-law, switching from TMZ to CCNU+Avastin seems to help, at least for now.
She was diagnosed with GBM in February 2017, underwent total resection in March 2017 with clean MRI after surgery. Her tumor was found to be MGMT-methylated, IDH-wildtype.
Standard Stupp protocol followed. 42 days of radiation+TMZ. In May 2017 the MRI has shown the contrast enhancement autour the resection cavity. Doctors encouraged us this could be due to surgical damage repair processes. 6 cycles of TMZ followed but at a reduced dosage of 240 mg/m2 due to low thrombocytes. Unfortunately the MRIs in July and September have shown the slow growth of contrast enhanced areas. We have performed the PET in October which has shown that the contrast enhancement is associated with the tumor growth, and not with vascular repair processes. Still our NO kept kept her at TMZ saying the growth is slow and TMZ might still help.
The next MRI in December 2017 has shown the things got much worse and the tumor growth has sped up. Our NO has recommended her to switch to Avastin+Irinotecan, which seems to be a common practice in Russia, but at the time I have read here a lot about the success of the CeTeG trial for MGMT-methylated tumors. We were able to convince our NO to let her try CCNU+Avastin. The regimen is as follows. 40mg CCNU at 1st, 8th, and 15th day of a six week cycle. 400 mg Avastin at 1st, 15th and 29th day, e.g. once in two weeks (patient's height 160 cm, weight 60 kg). Due to intricasies of Russian healthcare system she is taking infusions of original Avastin, and its locally produced substitute (Avegra) following each other. The MRI in February 2018 has shown the major reduction of contrast enhanced areas, so the regimen was continued. The next MRI is planned at the end of May.
KYA, thanks for your message. Very interesting.
DeleteI first hear about taking Lomustin in your schedule. Usually a full dose of Lomustine is taken once every 6 weeks.
Perhaps, there are some advantages with this division of the dose? Any thoughts?
I'm just planning to take only Lomustine in the next cycle + Trametinib.
Also: Veramapil + EGCG (which is also reported to be an inhibitor of P-glycoprotein).
As far as I understood, the splitting of Lomustine dose is done to smear its devastating effect on thrombocytes.
DeleteAs for the reasoning behind the Lomustine+Avastin combo versus Lomustine alone, it comes from the BELOB trial. Lomustin damages tumor cells and Avastin hinders the tumor's blood supply by inhibiting the vascular growth (excuse me, if I'm writing obvious things here).
This comment has been removed by the author.
ReplyDeleteI decided to do the 3rd cycle:
ReplyDelete1 day: Lomustine 90 mg / m2
(90mg * 1.5m2 = 135mg The doctor said that Lomustin is taken in a smaller direction, so the dose will be 120mg.)
2 day and the next 30 days: Trametinib 2 mg / day + Verapamil (dose is not yet clear).
After this cycle, I will do an MRI to see if there was an effect.
Also 3 days prior to taking Lomustin, my mom already takes Verapamil (400mg per day, 40mg / hr), EGCG, Silimarin (which probably also are inhibitors of P-glycoprotein) and DHA (from omega-3), which is reportedly interacting with Lomustine. The same will be taken within 3 days after Lomustin. Then the dose of P-glycoprotein inhibitors will be reduced.
The next, the 4th cycle will probably be Temozolomide + Olaparib. So I can alternate CCNU and TMZ, reduce the blood load, test Trametinib and Olaparib and possibly slow the adaptation of the tumor to chemotherapy.
I'm very concerned about Trametinib - its side effects and its interaction with other medications from our heavy cocktail - low dose Avastin, sirolimus, chloroquine, depakin, metorphine, methimazole, hydroxy-citrate and alpha-lipoic acid. It's probably crazy to mix everything at once ... However, without Trametinib, there were no significant side effects.
I also worry that in studies with brain cancer, Trametinib was used together with Dabrafenib. It is unclear will Trametinib work alone (or with Lomustine)?
Yesterday, instead of oral sodium R-lipoate, we decided to start doing 10 days of Alpha-lipoic acid droppers at 600 mg per infusion. Yesterday we made the first dropper - the level of glucose in the blood did not fall. We bought ready-made solutions of 50 ml containing 600 mg of alpha-lipoic acid. The duration of the dropper is 30 minutes.
You are probably right, it may well be a bit "crazy" to mix all these medications and supplements. However, given the seriousness of the condition I think it makes complete sense to push a bit, at least within reason. As long as there are no complete red flags... just my opinion.
DeleteI think you've done an amazing job putting this treatment plan together, and I really hope it works for your mother. Wish you and your mom the best of luck, which is something we all also need beyond the cocktail alone!
- John
Thank you for your kind words, John!
DeleteThis is an invaluable blog with wonderful people and all this gives at least a small bit of hope. Although I understand that all this cocktail of medicines and all our persistence can be in vain.
11C-methionine PET showed that another tumor site with a diameter of 12 mm appeared:
ReplyDeletehttps://drive.google.com/open?id=18AaVybu5nvBH_cAe5QIfzO-efiwsUfkc
At the last MRT, the size of the new tumor was 7mm and it was unclear what it was.
Does this mean that Avastin stops working? What does the second tumor site mean?
By the way, the price of 11C-methionine PET in Russia is $ 420.