Jussi from Finland - Dx 2008 - 30.3.1991 - 23.8.2019 R.I.P.

[Olga]

Jussi -
re. radiation therapy timing and technique.
I do not know if Nivolumab pharmacokinetics is different from the pembrolizumab, you will have to find and read it, but with Keytruda (pembrolizumab) the max effect of immune checkpoint inhibition is reached at 72 hours post infusion. So there is no need to have it few hours between one and another - a radiation increases of PD-L1 expression in the tumor tissue and it attracts the immune cells to it, and it has to overlap with the window of opportunity when the immune cells brakes are released by the ICI drug of choice (there are also other points as how it could work as the dying cells signaling etc). Stereotactic radiation unit allows you to avoid irradiating the skin and I would try to avoid damaging it as the skin is the home of very active immune Langerhans cells, plus you do not need to have an active inflammation site at the burn wound - it may disturb the immunological response redistributing the lymphocytes to the burned site. Although if this met location is very subcutaneous, you won't avoid the damage on any unit.
Perhaps, you have incorrectly picked the target, as far as I remember the radiation burns are very immunespressive. If this is the met that you feel is already responding, there is no need to irradiate it, the immune system found it. I would suspend the plan for now, you have to be careful as any intervention can work in 3 ways - help, do nothing or interfere with the main treatment.
With the irradiation to the heart met - it would work the same way, there is an idea that when a patient is currently under ICI drugs treatment, the dose can be sub-optimal, i.e. an incomplete irradiation and the immune system will finish what the radiation could not. George from China had an incomplete cryoablation to his heart tumor located on the outer part of heart (similar to yours) with the Keytruda started later. Two years ago, doing fine now.
And yes, as Deb figured it correctly, I was thinking re. NLR number, if it changed since your first ICI treatment attempt.

[arojussi]

As I understtood radiation and immunological medication is valid combination. Not yet well understood, but it seems promising. And based in current evidence to achieve abscopal effect you need 3-5 high dose fractions like 6-10 gy. Trying to irradiate heart met with suboptimal dose and hope immunesystem clears the rest sounds even more experimental and lot more dangerous.

Yes radiation burns can intervine with immunotherapy, but I think scientific evidence supporting radiation and immunotherapy combination is stronger, than scientivig evidence saying that radiation burns destroy effects of immunological medication. Subcutaneous met is the safest target we can find, so we have to use it. Of course this is not save, but in long term I believe my changes of being alive 2 years from now are higher, than if we abort plan with radiation. Olga I have enormous respect for your ideas, but at this point I trust my own judgement more. So if you cant provide puplications to support your thoughts I am going ahead with the radiation as 8 gy in 3 fractions. Idea isnt to destroy subcutaneous met, but to create abscopal effect. As asps mutates very slowly heart met is most likely identical to subcutaneous met.

[Olga]

Jussi - trying to irradiate heart met with the sub-optimal dose is not a suggestion, but just a discussion - our radiation oncologists mentioned that it could be tried if nothing worked, in the future.
Re. irradiating the sub-cutaneous met - I am not saying to drop this idea, but may be just postpone it till the next round trying to find the more advanced unit, able to spare the skin and make the burnt area smaller with more conformity to a tumor shape. You basically do not have to rush. Immune system is a very gentle instrument to play with.
Also you did not answer - is this the same subcutaneous met that you feel is already responding? If it is already responding, I would not irradiate it by the same reason you said - its make up is likely close to the one in the heart, and the tumor specific immune response is already forming there if immune system started to eat it, and they are going into circulation, and targeting it now you will destroy these cells. The point of the radiosurgery is to attract the immune cells into the tumor, but if it is already able to recognize it, what is the point? You just need more of the same.
I do not think that I am going to start reading/posting on the immunological effects of the skin burns to give you supporting articles - it is a big, a very specific task, perhaps you can do it yourself, and share with us what you found.

[arojussi]

I been in pubmed all night and I still want to go ahead with 8 gy in 3 fractions starting next week. Basically adding radiation to immunotherapy synergises so well together, that I cant resist change to try it. Adding radiation increases my changes of complete or near complete response significally. As doses: one fraction with 8 gy is definitely too little. 2 fractions might be too little and 3 fractions can cause skin damage. Based on data in pubmed I cant say if two or 3 fractions is petter, but knowing Ivan`s case I am considering 3 to be better. My dad is very scared that 3 fractions will cause severe skin damage that can only be managed with systemic antibiotics and steroids eliminating immunotherapies benefits and it is possible, but I dont believe it is likely. I believe skin damage can be managed with local treatments. I need to look more into that and discuss with my doctor, but overall having radiation is worth the risks for me at least. (for hospital risks are lot bigger as if something goes wrong expaining this combination of treatments is difficult.) As skin damage is real concern I take break from cediranib for now. As cediranib has very short half-life It will be almost completely out of my system by thusday, when radiation is planned to start. subcutaneous lesion is too close to skin surface so radiation will have to be traditional. Still I believe it is the safest target and yes it is the same lesion that has shrunk and yes tumors can continue to shrink without radiation, but radiation increases changes of radical response, so I am willing to risk skin damage.

Thanks for helping me with this very difficult decision.

[Olga]

You are completely missing my point. You are planning to irradiate the met that is already having a tumor specific response in it, destroying the immune specific cells that are at work there. The cells that could teach your immune system to recognize the tumor elsewhere. If you read Brittany Sullivan blog, she was also having a response in subcutaneous met under arm (go way back to 2015) and then her heart responded, she did not have any target radiation added, she did however have a WBRT for her brain mets low dose 30 days before of the trial start
http://johnandbrittanysullivan.blogspot.com/

[Ivan]

As I understtood radiation and immunological medication is valid combination. Not yet well understood, but it seems promising. And based in current evidence to achieve abscopal effect you need 3-5 high dose fractions like 6-10 gy. Trying to irradiate heart met with suboptimal dose and hope immunesystem clears the rest sounds even more experimental and lot more dangerous.

Yes radiation burns can intervine with immunotherapy, but I think scientific evidence supporting radiation and immunotherapy combination is stronger, than scientivig evidence saying that radiation burns destroy effects of immunological medication. Subcutaneous met is the safest target we can find, so we have to use it. Of course this is not save, but in long term I believe my changes of being alive 2 years from now are higher, than if we abort plan with radiation. Olga I have enormous respect for your ideas, but at this point I trust my own judgement more. So if you cant provide puplications to support your thoughts I am going ahead with the radiation as 8 gy in 3 fractions. Idea isnt to destroy subcutaneous met, but to create abscopal effect. As asps mutates very slowly heart met is most likely identical to subcutaneous met.

So if what you say is true - that subcutaneous met is the same as the heart - it means that the heart met is likely also responding rapidly, right?

The thing with radiation - and I'm not suggesting one way or the other - is that you can do it on any cycle of the drug at any point. I.e. you can do the radiation at any point, but you can't ever undo it. So if the radiation oncologists believe that the healthy tissue could be burned significantly, I would think long and hard in that case. If immunotherapy doesn't work, then you can always try radiation. But if immunotherapy works and you try radiation and it is counter-productive, you cannot un-try the radiation.

The irradiated tissue is not killed by the radiation itself, it's actually killed by immune system cells. If your immune system cells are already currently attacking the tumors aggressively, they could be distracted to the healthy damaged tissue. If you think that you have had an improvement in heart-related symptoms, I would see it as a strong indicator of response. I personally felt a quick relief, which I was worried to be a placebo effect. But it was real.

I support radiation, but perhaps waiting one cycle and finding a place where more advanced radiation techniques are offered which would not damage healthy tissue would be advantageous? Even if the timing is a day off or something, I don't think it would make much of a difference. Most of the radiation damage develops and unfolds over weeks, not over hours. This could be the best of both worlds.

[arojussi]

In melanoma study. 6 out of 18 patients achieved abscopal effect, when radiation was combined with immunotherapy. 3 complete responses. And there were no severe adverse effects caused by radiation. Most common radiation schedule was 24 gy in 3 fractions. In asps radical abscopal effects are also common.

I am already trying immunotherapy second time, if I develop disease progression changes of hospital allowing me to continue immunotherapy are low. Skin damage would be even bigger as lesion grows.

I had 59 brain mets radiated from my brains and all the sudden we cant radiate subcutaneous lesion, because it is too dangerous. To me that doesn't make any sense. My nature hasn't changed, so I still use the most aggressive treatments possible. My dad would be against radiation if we could prove, that immunotherapy is working already, but we cant prove that as we don't even have echo done before I started imunotherapy. We are making decisions based on very limited information here, but I still feel adding radiation is best. For radiation I stopped cediranib, to allow my skin to heal better. Changing cediranib to radiation will definitely improve my quality of life. And I believe radiation immunotherapy is safer, than immunotherapy cediranib combination.

[Ivan]

Jussi, is there no better radiation technique to minimize adverse side effects? A machine with more advance targeting? Even in Heidelberg. I want the best of both worlds for you

[D.ap]

Jussi
I’ve been watching and reading and I believe the bottom line is like Ivan has said prior to my post , can you find a machine that won’t produce a burn ? Or is the cyst entirely too close to the upper layers of your skin?
Burns are an entirely different and very prolonged healing process for any person .

My niece is a wound nurse and all articles say that it can take a year to scar up , all the while using antibotical tropical ointments , you are involving treating outer layers
(burning )verses concentrating on inner layers ?
Wouldn’t that mean your antibodies ,immune system ,would be doing the same? And the antigens would be damaged ?

[arojussi]

Yes it is too close to surface for strereotactic treatment. Yes radiation burns are nasty, that is why I stopped cediranib. If I need to use systemic antibiotics, before my immunesystemlearns to reconice cancer I simply die, I am willing to accept that risk as if we gain abscopal effect I can achieve radical long lasting partial response.

[Ivan]

Yes it is too close to surface for strereotactic treatment. Yes radiation burns are nasty, that is why I stopped cediranib. If I need to use systemic antibiotics, before my immunesystemlearns to reconice cancer I simply die, I am willing to accept that risk as if we gain abscopal effect I can achieve radical long lasting partial response.

Did the radiation oncologist tell you what dosage the healthy tissue would receive exactly?

[arojussi]

If we want stereotactic treatment we would have to target one of the few lung mets I have left. That is possible, but we would have to start planning from the start again. And my instinct tells me that targeting subcutaneous lesion is still little safer. Radiation wont be sub mm accurate, but I would imagine: skin damage is easier to manage than lung damage. 8 gy in 2 fractions equals 40 gy in standard fraction radiation, so 8 gy in 3 fraction is most likely somewehere between 50-60 gy. After reading studies I concluded that adding radiation to immunotherapy is justified and 8 gy in 3 fractions is best dosing. So question is if we should target lung met or subcutaneous met. From start I stated that my left arm is sacrificable and there seems to be only educated quesses, saying that radiation burns will effect to immunotherapy. So I will ask if doctor believes, that radiation damage can be managed without systemic antibiotics and if he believes so, then I will go ahead with radiation. I will also ask what kind of dose will healthy tissue get. Antibiotic ointment shouldnt hurt gut microbiome a lot.

[arojussi]

Radiation doses of 60-70 gy are used in melanoma. As my biological dose is less than 60 gy I consider it save enough. In good case I will just have slight redness in my skin. In worst case Iwill have severe radiation burn. I dont think severe burn is likely. Using smaler dose is less likely to achieve abscopal effet. So initially I would like to have 3 fractions, but if I develop severe skin damage after 2 fractions, we either stop or use 6 gy fraction in third time.

[arojussi]

Basically if we want to make radiation less risky for the skin, we could do planning of radiation again to smaller field as tumor has shrunk and for abscopal effect maybe targeting the whole tumor isnt vital, it might be nobody knows what is truly important here. This is medically reasonable, but still experimental approach.

[D.ap]

Jussi
Is the cyst being treated like a cancerous lescion ? With the radiation treatments?