Cure Alveolar Soft Part Sarcoma International (iCureASPS)

So Ivan started Keytruda yesterday, on Dec.23, 2017.
His first infusion went very smoothly, without any allergic reaction and no any side effects during the first day and 24 hours after, he celebrated this fact by going to a gym on an infusion day.

He is getting it trough the Merck associated oncologist who is able to prescribe it to a self paying patients (BC Cancer Agency is prohibited from prescribing drugs it can not pay, and they stated no funds despite the sarcoma board recommending the drug - only the drugs for the approved indications are founded and until in the US FDA approves pembrolizumab for ASPS, Canada will not even consider approving it - they just go after US).
Ivan's oncologist applied to Merck Canada to provide a patient's assistance. They declined. Ivan's Merck associated oncologist applied to Merck Canada to give us 20% discount - they denied it too. So we started self paying full price. And I am very happy with it, as the very option to get it now beats any negatives caused by the high price, at least we do not need to fly somewhere overseas trying to get it.
We will try to do something about the price, appeal to Cancer Agency and Merck Canada.
His infusion was done at the private infusion clinics, it is the only way to get a self founded drug infused, at the public hospitals they can not do it. It was a good experience, small 3 chairs infusion clinics with the nurse watching if the first acute side effects happens - the initial allergic reaction to a drug can be severe in rare people who can not have this drug at all (I read the up-to date side effects profile and management guide that was just recently posted on the PubMed https://www.ncbi.nlm.nih.gov/pmc/articl ... le_300.pdf)
The plan is to add a radiation of the soft tissue gluteal met on the next infusion date in 3 weeks from now, with the goal to increase the activity of the pembrolizumab by providing it a target on the surface of the irradiated met (can increase the PD-L1 expression on the surface of the irradiated met) so it can recognize the tumor better and hopefully the immune system will release the tumor-specific immune killing cells into systemic circulation. I found the article when the irradiation was used in the Keytruda treated and non-responding cases of metastatic tumors (melanoma) and there was a great systemic response after the irradiation of the gluteal met - i.e. it made the distant mets visible for the immune system. Fortunately we have a great radiation oncologist interested in this subject. Also Dr.Razak, the head of the sarcoma oncology board in Toronto PMH said that all of his ASPS patients responding to PD-1 and PD-L1 drugs has some kind of radiation before/during the treatment.
The next cardiac MRI is in Feb.2018 so we won't know if there is any signs of response till then.

Ivan had his second Keytruda infusion on Jan.12, combined with the first radiation treatment to his gluteus maximus muscle of the hip within few hours of each other. It is the largest and most superficial of the three gluteal muscles. The radiation treatment consists of 8 Grays given 4 times every other day, for the overall 32 in one week, with the stereotactic radiation unit used (Stereotactic radiotherapy (SBRT) gives radiotherapy from many different positions around the body. The beams meet at the tumour. So the tumour receives a high dose of radiation and the tissues around it only receive a low dose. This lowers the risk of side effects). They call it SABR here - stereotactic ablative radiotherapy.

The metastasis Ivan had there was completely asymptomatic and we decided to treat in an attempt to produce some abscopal effect (to provide an immune system with the dead tumor tissue to sniff on and to develop the systemic tumor specific response T-cells that would be able to find a recognize and kill the ASPS cells in other locations). We will not know if this approach works as in case of the response elsewhere there is no way to find out what caused the response - Keytruda itself or the combined approach. Dr.Razak, the head of sarcoma oncology in Toronto, recommended to have this combined treatment as out of all of his ASPS patients that had PD-1/PD-L1 drugs, the best response was obtained in cases when the radiation treatment was used on the close timing with the ICI drug, and because of the wide interest/discussion that is happening in the med. community now that the local metastasis treatment (radiation, cryo or other ablation) can provide the in situ tumor vaccine for the better tumor specific response that PD drugs are aimed unmask, but only if the timing/dose is right - these treatment can also interfere with the PD drugs and even produce a wrong type of response. There are numerous clinical trials going on to find the best combination, we had no time to wait - asked numerous oncologist leading the clinical trials, read the newer trials regimens chosen for the better expected effect based on what is known by now. So our current understanding is to schedule both, immunotherapy drug and the local ablative treatment in the close proximity to each other.

Ivan tolerated both very well, with minimal side effects that we can not even distinguish from the mild symptoms of cold he appears to be having recently. I would even say that he feels somehow better recently, more active, is often having both, cycling and gym session in one day if weather permitting. He is even playing a volleyball again. He works more too. It is hard to say what is helping, perhaps it is just his strong will took over and made him block the negative symptoms off, hard to say. The blood work is perfect as per his oncologist, the other tests are not done yet.
I was worried re. second Keytruda dose being more toxic with the radiation, but it looks pretty good by now, a week after the second doze.

Hi Ivan and Olga

I’m truly glad to hear of a good tolerance to the infusion of Keytruda and sbrt.
Will the sbrt be repeated if the scans show good results ?
The sbrt treated tumor is how big?

Is the Keytruda being administered at 2mg/ per Kg?/ 2 weeks . Is it over a 30 minute time frame ?

D.ap wrote:Hi Ivan and Olga

I’m truly glad to hear of a good tolerance to the infusion of Keytruda and sbrt.
Will the sbrt be repeated if the scans show good results ?
The sbrt treated tumor is how big?

Is the Keytruda being administered at 2mg/ per Kg?/ 2 weeks . Is it over a 30 minute time frame ?

First three doses were 150 mg. My body weight is 78 kg, so that's slightly below but very close to 2 mg / kg.

The fourth dose I just had (and moving forward) is now a flat dose of 200 mg.

Ivan

Great to know
You will be at max dose and moving forward !
Good to know .
I’ll review and let you know of questions .
How’s the gut response ?
Thanks for the input .
Till next time my friend
L
Debbie

D.ap wrote:Ivan

Great to know
You will be at max dose and moving forward !
Good to know .
I’ll review and let you know of questions .
How’s the gut response ?
Thanks for the input .
Till next time my friend
L
Debbie

I don't feel anything off with my stomach, if that's what you mean.

This is an update for 5 months of Ivan treatment with the single agent Keytruda+ SBRT - he started on Dec.22, 2017 and the latest set of scans were done at about 5 months later in May, 2018 - cardiac and pancreatic MRI with the contrast. They both have shown dramatic shrinkage of about 70-80% in volumetric size if compared to an initial pre-treatment scanning, in both locations, with smaller mets shrinking to a point of hard to measure size. Lung mets that were caught in the scanning field, are also noted much smaller or disappearing. The reduction in linear dimension - if we review the change in the largest dimension of the met - is also very significant.

The details of the case:

Ivan's metastatic Alveolar soft part sarcoma progressed in Nov.2017 to newly found then 2 cardiac: interventricular septum 31*37 (now 13*19) and basal anteriolateral wall 22*18 (now is hard to identify size) and 2 pancreatic metastases: uncinate process 16*13 (now 6*6) and central part 10*10 (now absent).

After numerous consultations with surgeons, interventional radiologists and oncologists, and acknowledging the excessive risks of the permanent damage that would be done by the surgeries and intriguing reports of success by the pembrolizumab in ASPS patients published on the Pubmed and this board, Ivan started Keytruda (pembrolizumab) on Dec.22, 2017, flat dose of 200 mg/every 3 weeks.
He was already having the symptoms of his heart metastases then.
In an attempt to improve the possibility of the response and elicit the abscopal effect, one of his occult metastases in the soft tissue was treated by the radiosurgery course concurrently with the second dose of Keytruda, starting on the day 1 and given every other day, 4*8Gray (this 20 mm met was accidentally found on the abdominal CT, and was located deep in a gluteus maximum).

We have also made an effort to improve his microbiome composition, adjusting his diet to increase the Akkermansia muciniphila and faecalibacterium praeusnitzii population as per recent publications suggesting the improved efficiency in the people with this microbiome variety abundance.
We do not know if any of it helped or he is just predisposed to have a good response to this drug. According to the Dr. Breelyn A. Wilky results of the trial posted at the ASCO 2018, one of the factors associated with the positive treatment outcome was circulating neutrophil:lymphocyte ratio < 4.1, Ivan's neutrophils to lymphocyte ratio was before of treatment (and still is) low, in 1.3 - 1.5 range.
His first sets of scans at 2 month has shown some response, his subjective well being improved around that time significantly. Now, at 5 months since the start, he does not have any limitations to his training routines and schedules such as competitive volleyball, cycling and weight lifting.
The side effects are getting more noticeable now - reduced salivary flow/dry mouth - probably caused by the immune system attacking the salivary glands. The dry mouth causes some other side effects downstream such as: some pretty significant inflammation of the tongue with uncertain reason - either a candidiasis or an immune reaction. And the WBC count got a bit lower than a norm.

I am finally realising the importance of diet for cut microbes.

Based on quick look into pubmed I believe, that crabe fruits and possibly soy isolate might be beneficial.

What kind of changes you did in your diet?

We actually did not modify his diet by that much - only added the probiotics. He always ate very healthy (well, at least the last 10 years), with tons of raspberry and blueberry consumed in a summer every year.
Instead of answering, I decided to post what we wrote about 6 month ago here:
http://www.cureasps.org/forum/viewtopic.php?f=90&t=1630
It was a big project for me and Ivan, to write it, but we abandoned it as the level of evidence is low and no conclusions could be done without a proper testing, but still something that you might find an interesting read.

We just have received 2 MRI result - abdominal MRI and heart MRI.
The abdominal MRI is done to watch two pancreas metastases - one in the uncinate process close to the pancreatic head and one in the middle. According to the report, they both are hard to visualize - almost not visible and not measurable anymore. We are very happy to hear that - after almost a year ago one that is close to the pancreatic head was considered as borderline unresectable unless most of the pancreas is taken out during the huge abdominal surgery.
The heart MRI is done to watch two heart metastases - in the interventricular septum and in the base of the heart. The one in the septum substantially decreased again and the one at the base is hard to visualize - it is not evident in the delayed enchacement.
There are no full written reports for both - heart and abdominal MRI - only preliminary ones, I will update it as we get them.
it really takes a long time here to get the reports finalized - more than 2 weeks passed.
Another interesting observation is the continued improvement in Ivan's lymphocytes count, it continues to slightly grow. The problem was that it constantly slowly declined since he started Keytruda at the count of 2 10*9 L and hit the lowest normal in June 2018 (the count was 1 with the normal values 1-4 10*9 L). I started to watch his absolute lymphocytes and neutrophils count and neutrophils-to-lymphocytes ratio (NLR) after absolute lymphocytes and NLR were found to reflect the immune system ability to produce the robust immune response after the breaks are released by the ICI (Keytruda, Opdivo, atezolizumab).
In June we modified his diet to include more elemental zinc containing foods - more lean protein like turkey, pumpkin seeds, eggs plus the minimal dose of the zinc chelate 25 mg - 1 pill a day - which is a minimal dose possible. I had the very low expectations that there is going to be any effect of this regimen as from what I read, it is pretty hard to increase the lymphocytes count without the use of the granulocyte colony stimulating factors (G-CSF) - that can also speed up the growth of cancers in patients. But our plan seems to be working as of now - a nearly linear increase in lymphocytes count since we started in June.

repost from the Personal Updates forum, posted by Ivan on Feb 22, 2020:

"I have discontinued PD-1 after 26 months with sustained response. If there's a recurrence, I intend to resume it. I'll keep getting brain / abdominal / cardiac MRI and chest CT every 3 months or so for now.

Presently, the main problem I have is adrenal insufficiency that has developed over the last year or so. I have to take cortisol & aldosterone replacement daily. Will monitor to see if this is autoimmune and whether it comes back, but otherwise I'll have to keep taking the replacement for the rest of my life.

Overall, I am feeling well and life is good."

To add more information why we decided to discontinue this treatment for now, voluntarily, after the last 4 scans showed stability (cardiac MRI, CT scan) or no signs of mets anymore (brain and abdominal MRI). Ivan was on Keytruda monotherapy for more than 2 years.

Basically the goal of the immunotherapy is to create the sustained immune system response with the specific tumor killing immune system memory cells reproducing themselves. After the immune system response and attack are registered and durably sustained for awhile with the good reduction in visible size and number of the mets, it is assumed that this tumor specific memory is created. The immune system is able to recognize and attack the tumors. When to stop is an open question now. Usually this treatment is only given for 2 years but Ivan was not limited by the insurance, they gave us the right to decide as there is no statistics to support either way.
why we decided to stop. Under the PD-1 inhibitors the immune system runs without the breaks, and if it is very active the attack on the tumors is great but it can also attack the healthy tissues in the body. People on immune checkpoint inhibitors get all kids of authoimmune attacks - rheumatic, colitis, pneumonitis. Ivan seems to get the adrenals and the salivary glands attacked. Will they recover off treatment? we do not know. The tumor board at the BC Cancer agency decided to support us and promised an option to resume the treatment in the future if needed.

Hello Olga
Great news on sustained and no growth !
Also it’s wonderful that the tumor board has agreed to make Keytruda available if need be in the future .
However I’m sure sorry to hear of the autoimmune issues .

Sending you and Ivan lots of hugs and sharing in the wonderful news .💕
Love ,