On another thread on this blog, the topic came up of PD-1 agents causing brain edema (on the Gamma Delta T-cell thread). As it wasn't directly applicable to that thread, I thought a new thread might be useful, for the consideration by others who might be considering anti-PD-1 agents (in this case, nivolumab/Opdivo). Stephen W and I have been unable to find much published information on the incidence of brain edema with such agents, so I'm here publishing an individual experience that might be useful to others.
On my wife's research protocol, nivolumab was started simultaneously with the initial radiation Tx (so, standard /Stupp protocol+experimental nivolumab). This might make sense in theory, but it made it difficult to distinguish whether her neurologic symptoms were from the PD-1 agent or the radiation.
Over the six-week period of radiation (daily M-F) she had very gradual worsening of neurologic function. Since there didn't seem to be any obvious exacerbations around the time of her infustions (every 2 weeks), I attributed the changes to the radiation, and presumed she was more sensitive to radiation effects than most. In retrospect, I was wrong, and the deterioration in function was mostly from brain edema from nivolumab.
The tumor was in the left parietal lobe, close enough to the speech center to cause some language difficulty at initial presentation. The radiation Tx was "IMRT" meaning heavier radiation near the tumor bed than elsewhere, though no part of her brain was totally free from radiation. She lost hair over about 60 percent of her scalp, more than I expected.
She developed a gradually worsening R visual field defect, and gradually developed R-sided neglect. Also, gradually progressive unstable gait, and gradually worsening short-term memory, gradually worsening word-finding, gradually worsening confusion. The overall picture was similar to early- to mid-course Alzheimer's.
The first post-tx MRI was a month after conclusion of radiation (with Opdivo infusions continuing every 2 weeks). I was becoming alarmed that she didn't seem to be bouncing back after radiation stopped.
The MRI showed *severe* brain edema, all on the left side (tumor side). There was uncal herniation, the kind of thing you might see shortly after severe head trauma. The NO seemed shocked that she could still walk and talk and do reasonably well on a cursory neurologic exam.
A couple of infusions were skipped, and most of her symptoms gradualy improved. However, focal motor seizures didn't improve. These were very subtle in the first few weeks, but have become more obvious over time and required increasing Vimpat doses to control.
After skipping a couple of infusions in light of brain edema, she got more opdivo about a week or so ago, and all those symptoms got worse again after about 48 hours post-infusion. MRI then showed edema similar to to the last MRI, but I'm quite sure edema had improved then worsened again.
So we're out of the study.
Trying to interpret the pattern of edema (all L-sided) is challenging. It's possible the edema is from nivolumab doing it's job, killing off glioma cells in the left-side of the brain that hasn't showed up on any MRI. But I don't think so. I suspect she's having an auto-immune generalized brain effect, and that the edema is all L-sided because the radiation mostly impaired the blood-brain barrier throughout the left brain, allowing higher levels of the nivolumab antibody in all the tissues of the L brain. It's impossible to know for sure, though.
Possibly, in retrospect, a lesson here might be that nivolumab should be started after the conclusion of radiation, and not concurrently. Possibly a dose lower then 3mg/kq q 2 weeks would be better. Nobody will know for sure until there's a lot more research and experience.
For the time being, there's no definite residual tumor tissue at all. Realistically, she's rather likely to have recurrence at some point in the future. So we're scoping out other clinical trials to pursue if/when that happens.
At the moment, we're interested in:
https://clinicaltrials.gov/ct2/show/NCT01454596
"CAR T Cell Receptor Immunotherapy Targeting EGFRvIII for Patients With Malignant Gliomas Expressing EGFRvIII"
This is, in part, because NIH/NCI is close to us in Maryland. We're not yet sure her tumor does express EGFR, but we're pursuing that question. We're also looking for other promising trials applicable to first recurrence after experimental nivolumab tx, even if geographically distant. Suggestions welcome. With any luck, we may have a lot of time before we need to enroll in another study. Extensive cocktail continues.
Best wishes to the whole community,
Steve
stevemdfp at gmail dot com.
Steve, thanks for this post and sharing that information.
ReplyDeleteAnother trial recruiting at Johns Hopkins is Toca 511 for recurrent high grade glioma, however this trial is randomized between a Toca 511 arm and a standard treatment arm (either CCNU, TMZ, or Avastin).
Did her original pathology report say anything about EGFR amplification? EGFRvIII positive GBM is pretty much invariably also EGFR amplified.
This may be stating the obvious, but other interesting trials for recurrent GBM include the polio-rhinovirus trial at Duke, and DNX-2401 adenovirus in Columbus Ohio. I agree it's wise to start looking at clinical trials now and formulating a plan/s.
https://www.clinicaltrials.gov/ct2/show/NCT02197169
https://clinicaltrials.gov/show/NCT01491893
Hello Steve,
ReplyDeleteI interprete that as a combination of pseudoprogression together with immunemodulation of an antitumoral immune response that might have existed before start treatment or might have been induced by the radiochemotherapy. Nivolumab does not kill tumor cells in the first place. It blocks PDL1 - PD1 interaction thereby allowing that immune cells can kill tumor cells instead of being killed by the tumor cells. Checkpoint blockers will not work if there is no T cell that attacks the tumor. That is why checkpoint blockers sometimes fail in brain cancer, or (opposite) why they work better in lung cancer of smokers in comparison to lung cancer of non-smokers (the former having more immune reactivity than the latter). I would first try to boost further the ongoing immune reactivity without taking away too strong the internal control mechanisms. By the way, the CAR T cells are also active in a rather uncontrolled way so one should consider also eventual edema reactions.
Steve -
ReplyDeleteYour wife's situation illustrates the dilemma that PD-1 blockers seem to pose. If they are effective, they are frequently (always?) accompanied by edema or unacceptable levels of inflammation. This is all so new that doctors don't know how to recognize what is happening or how it can be controlled. It sounds like the two of you have been through hell with this.
My husband's clincial results have also been ambiguous. He started a trial of a different PD-1 blocker in March (REGN2810). In June, his MRI showed an "area of enhancement" and MRIs were subsequently taken at 4-wk intervals. The enhancement area grew slightly for the next three months until the 10/14 MRI, which showed growth of least 70%, prompting his removal from the trial. I think acupuncture was limiting the inflammation before then.
We are now waiting for another resection, and he he will try for the Toca 511 trial. If he is not selected, off-label Keytruda is possible. He is ineligible for the Poliovirus trial and his unmethylated tumor does not express EGFR, so there aren't many options available. However, I am not seeing major deficits and suspect that his MRIs are showing edema or inflammation, rather than tumor regrowth. In the meantime, he is using Optune to err on the side of caution.
Has your wife had another resection? I am wondering how you know she has edema and no tumor tissue. Our doctors tell us that opening up my husband is the only way to find out with certainty what is going on.
Best wishes to you,
Margaret
SVG -- you're right. I was speaking loosely when speaking of nivolumab killing glioma cells. It acts by facilitating killing by immune cells.
ReplyDeleteThe scans showed edema in parts of the brain that showed no sign of tumor, so I doubt the reaction is all related to tumor-killing effects. But we certainly hope that some tumor-killing was taking place.
Stephen -- We don't yet know her EGFR status; we'll get the frozen specimen tested, at cost to us if needed, but perhaps gratis by Hopkins or NIH, as it would be done to qualify for an NIH trial.
Margaret -- we don't know that there's no tumor. The area of enhancement is around the walls of the tumor resection cavity, with no clear specific focus of particularly suspicious enhancement.
I think it would be naive to presume there are no malignant cells present somewhere, but so far, the scans are encouraging.
She's in the initial round of treatment, full gross resection, radiation and temozolomide course, now on cycles of TMZ. However, the tumor is unmethylated, so the TMZ is probably not being very effective.
Our plan now is to prepare for the (statistically likely) day that recurrence is found, by going straight to a pre-chosen trial. An advantage of the NIH CAR T-cell trial is that craniotomy would not be needed.
Otherwise, I wonder about the feasibility of using a different PD-1 agent in conjunction with stereotactic radiation. Perhaps the presence of killed tumor cells would prompt an immune response, boosted by the PD-1 agent.
In all, I wish it had been possible to remain in the nivolumab trial, but at a greatly reduced dose, titrated to degree of edema. But when in a trial, that kind of flexibility is just not allowed by the protocols.
Hi Steve,
ReplyDeleteThis is my first post on this site (usually on Inspire). My husband had GTR on Sept. 30 2015, and just like your wife we started Nivo trial a week before radiation. So we are ahead of Margert's husband by about 5 months. Incidentally there is another Margaret and her husband has been on Nivo as well with similar path as ours, and he husband is about 4-5 months ahead of us. All unmethylated and IDH1 negative. So from what I read here, your wife is closely following our path.
Radiation causes a LOT of inflammation. Radiation effects are cumulative, get worse towards the end and even worse a month after radiation. Our MRI showed the huge radiation effects as well, but we could see the pattern was exactly like the radiation intensity pattern (we used VMAT). So I'm sure it was not Nivolumab causing the the problems in the myelin of the brain and causing leaky vessels by damaging the BBB.
Our MRI in March started showing the enhancement around the resection cavity (bright ring that was slowly getting larger). I believe this was due to Nivo. Cancer cells are mostly left over around the resection cavity, even when you have GTR.
In May, there was a big section on one side of the resection cavity that grew over a month, which started also to be symptomatic. We had a second surgery and they could NOT find any cancer cells. Only the immune system scavenger cells. We started Nivo again (2 more infusions + 6th Temodar cycle) and the same area came back in a month even bigger. No one knows if this is immune activity (inflammatory response to kill cancer cells) or Nivo Toxicity. I think it may be both. I also think the dosage of Nivo was decided based on recurrent cases and may be as you mentioned too much for the newly diagnosed. Anyway, we stopped Nivo after 18 infusions, and the MRI was very stable for a month.
Both TOCA 511 (if you need surgery, which Margaret's husband is going for) or VB-111 + Avastin (which we started in August) have shown very promising results. But honestly in our case I think even though we qualified for the VB-111 trial as a recurrence based on RANO criteria, it was all or mostly "treatment effects".
You should note that ALL the bright ring and most of the enhancement due to the original radiation when away immediately after Avastin use. My husband started having some right side weakness after the VB-111 and Avastin, which I believe happened because Avastin cut the blood supply to the leaky and damaged vessels and cells by the "radiation". My husband had focal seizure once, some tingling and numbness in his hand and leg, after the radiation. All this went away and got replaced with the weakness. Other than that he could not have felt better. Avastin allowed us to stop steroids, and honestly I think we should have used it concurrently when the inflammation and radiation effects showed up.
Anyway, at the end we had a very bad scare because they thought my husband is having a recurrence due to the MRI showing low diffusion in some areas of a cyst that had formed after VB-111 and Avastin. The neurosurgeon disagreed and said it is the same gelatinous junk they removed in the second surgery and the low diffusion areas are nothing but some proteins and dead cells. The MR Spectroscopy confirmed this. Now radiologists say it is probably residual tumor, but since my husband is improving and we know radiologists tend to be the most conservative, we are off all treatments and will just see the next MRI which will be about 2 months after Avastin use, and we will use 7Tesla MRI for better resolution and contrast, to get better information on the cystic content.
I also looked at NIH CAR T-cell (when we were told we have a recurrence), and since my nephew works there, I had him contact them. Unfortunately they are remodeling their facility and this trial is not accepting any new patients.
Anyway hope all this helps. You can look up my posts on Inspire as Minsha.
All the best Steve,
M
Dear Minsha, Welcome, I'm sure you'll find btcocktails a welcoming community, Stephen Western is incredible and we're lucky to have such a wonderful caring resource.
ReplyDeleteGood luck,
AGM (Fiatgal)
Hi,
ReplyDeletewhat about edema related to the monthly 5/23 TMZ schedule?
Google didn't reveal anything useful on the topic.
My father is on the 5/23 TMZ schedule and the same pattern is repeating every round. One day or a few after the last TMZ capsule is taken, dad gets problems with vertigo when lying down in the bed. About 5 - 6 days later the problem clears by itself, which I suspect is due to edema building up during the TMZ?
Now, is this a good or bad thing happening?
The last two MRI:s show successive partial shrinkage of the residual tumor since resection and RT (9.5mm -> 6.5mm -> 5mm). The tumor is unmethylated (9% methylation).
Apart from the TMZ he is taking: Vitamin D, Pterostilbene, Resveratrol, Curcumin, aged garlic extract, milk thistle, melatonin, berberine.
My wife has been doing quite well since I wrote the post above.
ReplyDeleteI just wanted to follow-up in regards to the literature.
A dramatic case of cerebral edema after nivolumab has been reported:
Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report.
https://www.ncbi.nlm.nih.gov/pubmed/27858578
In this case, it was fatal brain edema.
I'm rather shocked that after severe reactions from the first and second infusions, they went on and gave her a third. I suppose they felt there weren't any other treatment options.
In my wife's case, they also went ahead even after significant edema was found, at our request. The eighth and final dose caused prompt worsening of symptoms (gait, memory, coordination, speech). As mentioned above, in our case Avastin/bevacizumab reversed the edema very promptly. We're now very gradually reducing the frequency of Avastin infusions. Her remaining deficits are now subtle. Cocktail continues.