"Pseudoresponse" on Cediranib by MRI

[Fictional]

FYI, I don't want to alarm anyone, but I'm starting to see more references to "pseudoresponses" to Cediranib in the medical literature.

Usually this seems to refer to Cediranib and brain mets when the MRI appearance normalizes quickly - it might be that the appearance improves on MRI, but the tumor is not being killed. Problems arise when the medication is withdrawn. This has NOT been observed with alveolar soft part sarcoma. I saw papers e.g. with glioblastoma multiforme. The reason for this is that Cediranib reduces tumor vasculature more than kills tumor.

It may be that pseudoresponses occur with all TKIs, too. I don't have a specific great article to link to, but if you are interested in learning more about the subject and want to follow developments, just put "pseudoresponse" and "cediranib" into Google.

[Bonni Hess]

Dear 'F',
This information of course raises concerns regarding the accuracy of the seeming significant tumor shrinkage and necrosis which we have observed thus far with ASPS patients receiving Cediranib treatment. The articles which I found related to this concern all seemed to address the issue of pseudoresponse for glioblastoma patients receiving treatment with anti-angiogenic TKI's such as Cediranib, so it is unclear whether this may also be an issue with ASPS. We will certainly discuss it with Brittany's radiation oncologist as well as her Clinical Trial oncologist, and I will update the Board with any information which we receive regarding this important and concerning issue. As always, we are deeply appreciative of your continued dedicated research and invaluable sharing of vitally important information.
With special caring thoughts and continued Hope,
Bonni

[Bonni Hess]

Dear ASPS Community Friends,
We received the following response from Dr. Sawyer (Brittany's extremely knowledgeable Clinical Trial oncologist in Edmonton) regarding our concerns about the issue of pseudoresponse with Cediranib as it relates to Brittany's very positive scan results:

I think the pseduoresponse is more relevant to glioblastoma multiforme (which we abbreviate as GBM). GBM causes a lot of swelling in the brain, there has been a thought/suspicion that these vascular acting drugs merely decrease the swelling caused by the cancer but did not act on the cancer itself. In GBM you see as much or more the swelling and edema from the reaction to the cancer as the cancer itself. I have seen some very convincing radiological studies that cediranib does more than just take the swelling down. These radiological studies have shown that the stretched and displaced neuronal tracts basically went back to their original normal configuration.
In these ASPS spots especially in the lungs there essentially little or very little edema around the metastasis, these are essentially solid chunks of cancer surrounded by air. When these things are getting smaller, it is not edema getting better; it is the cancer shrinking. There is no “pseudo” about the healthy lung and air that we are seeing where the tumor was.
Bottom line I do think these are real responses we are seeing. Nothing pseudo about these. I can see this being a bit of a problem in brain cancer but as well even there I have seen evidence from AZ studies that more than decreased swelling and edema is going on.

Hopefully Dr. Sawyer's excellent explanation and reassurance based on his extensive research and knowledge will help to alleviate concerns that may have been raised by the information which 'F' shared about the pseudoresponse issue. Take care everyone.
With special caring thoughts and continued Hope,
Bonni

[Olga]

Actually it seems that cediranib might improve the radiological response of the brain mets previously treated by the radiosurgery (Gamma Knife type on Brittany's case), reducing swelling around the necrotic tissue formed after the treatment shot and helping this necrosis to dissolve.

[Fictional]

I think the caution would be when the medication is stopped - and this is always the issue with any TKI.

I only thought mention it after Paul's experience.

Medication has to be stopped in order for other things to be done (surgery, gamma knife, switch to another drug, etc.) - and with the brain there is less tolerance for space if something like bleeding occurs.

Usually necrotic tissue is not a problem. But if there are residual cancer cells (became dormant) - that start growing again, the question arises what to do.

[Bonni Hess]

Dear Olga and 'F',
Thank you for your responses and valued perspectives and addtional input. It would be very helpful to have more information regarding what occurred in Paul's situation since at this point it is only conjecture, but cerebral hemorrhage is a known concern with TKI medications like Cediranib, and one which we are painfully aware of with Brittany's history of brain mets. The implications with Paul are certainly that he must have heartbreakingly developed resistance to the Cediranib and had either new brain mets or increased growth of his existing brain mets necessitating the surgery that tragically resulted in his death. Based on the information about pseudoresponses that you shared 'F', there is also the extremely concerning possibility that Paul's brain MRIs were showing a psuedoresponse when in actuality his existing brain mets were growing. Rebound and rapid disease progression if the TKI is discontinued for too long a period is a serious concern, but in Clare Clarke's situation she has been off of the Cediranib for a year and half and still thankfully has continued stable disease. Unfortunately, because Cediranib is such a relatively new medication and still in the Clinical Trial stage, there are still too many unknowns and not enough accumulated and documented available data to make any kind of definitive conclusions at this point. This is why it is so vitally important for those who are receiving Cediranib treatment to share their anecdotal treatment experiences and results on this Board, and Hopefully everyone will.
With special caring thoughts and continued Hope,
Bonni

[Fictional]

This is a cross-post that I added in 'K''s thread in response to Bonni's comments about Cediranib.

This paper talks about having a special MRI (diffusion weighted) showed that a glioblastoma was infiltrating and spreading - although contrast-enhanced MRI did not show it: http://neuro-oncology.oxfordjournals.or ... 6.abstract

Or from the Neuro-oncology Working Group: J Clin Oncol 28:1963-1972.

Pseudoresponses After Treatment With Antiangiogenic Therapies

"Antiangiogenic agents, especially those targeting vascular endothelial
growth factor (VEGF), such as bevacizumab, and the VEGF
receptor, such as cediranib, can produce marked decrease in contrast
enhancement as early as 1 to 2 days after initiation of therapy and
commonly result in high radiologic response rates of25%to 60%.43-46
These apparent responses to antiangiogenic therapy may be partly a
result of normalization of abnormally permeable tumor vessels and
not always necessarily indicative of a true antiglioma effect (Fig 4). As
a result, radiologic responses in studies with antiangiogenic agents
should be interpreted with caution. There is a disappointing disparity
between the unprecedented high response rates these agents produce
in recurrent glioblastoma and the modest survival benefits, if any, that
have been reported."

There is an emerging literature documenting MRI-based pseudoresponses in response to Cediranib specifically. Cediranib quickly affects blood vessels, and that affects swelling and contrast enhancement, but it can be misleading. So it may look as if the tumor disappears, but really, it is still there, alive and just can't be seen by MRI any more.

In Brittany's case, it seems clear that she has benefited from being on Cediranib. But it is also fair to recognize that MRI lesions that shrink or disappear are not the same as documented tumor death. Now if the MRI signal improves, it is nice people are not having to go to surgery and so you don't have a biopsy - but just so you know - it is not the same hard evidence - and more doctors than myself have noted that Cediranib does not always improve survival - and that it may be due to pseudoresponses that change the MRI appearance and not actually kill tumors.

I don't say this to induce fear - but to encourage vigilance. We celebrate with Brittany's excellent success - but there have been deaths and progression on or following Cediranib too. In the pediatric study, we heard of 2 children in the NCI study who weren't doing well on Cediranib, although granted they had severe disseminated disease and I was only told general information. Maybe that is why I have not heard of the ASPS pediatric study being expanded.

In terms of why Brittany may have had such a potent response to Cediranib - I wonder whether her having had so many surgeries may have elevated her VEGF levels - and that was why her tumors were growing so fast and even more VEGF-dependent - but perhaps also why they were so responsive to Cediranib. There are many individual factors that we just don't know about.

[Ivan]

That's very interesting info, 'F'. Certainly something to keep in mind, and keep an eye out for.

[Bonni Hess]

Dear 'F',
This is certainly information to be aware of, and yes, concerned about, and we will, as always, continue to be vigilant in following documented study results and anecdotal treatment outcomes. However, to at least partially alleviate the fear that your comments may have raised I'd like to note that the article which you have cited is talking about cediranib pseudoresponse in recurrent glioblastoma, NOT ASPS, and I also refer you and anyone reading this back to my March 7th entry on this thread in which I provided the following response to the Cediranib pseudoresponse concern from Brittany's extremely knowledgeable and highly respected Clinical Trial oncologist at Cross Cancer Institute, Dr. Michael Sawyer:
I think the pseduoresponse is more relevant to glioblastoma multiforme (which we abbreviate as GBM). GBM causes a lot of swelling in the brain, there has been a thought/suspicion that these vascular acting drugs merely decrease the swelling caused by the cancer but did not act on the cancer itself. In GBM you see as much or more the swelling and edema from the reaction to the cancer as the cancer itself. I have seen some very convincing radiological studies that cediranib does more than just take the swelling down. These radiological studies have shown that the stretched and displaced neuronal tracts basically went back to their original normal configuration.
In these ASPS spots especially in the lungs there essentially little or very little edema around the metastasis, these are essentially solid chunks of cancer surrounded by air. When these things are getting smaller, it is not edema getting better; it is the cancer shrinking. There is no “pseudo” about the healthy lung and air that we are seeing where the tumor was.
Bottom line I do think these are real responses we are seeing. Nothing pseudo about these. I can see this being a bit of a problem in brain cancer but as well even there I have seen evidence from AZ studies that more than decreased swelling and edema is going on.
We continue to hold very tight to Hope that the stabilization of disease and tumor shrinkage which ASPS patients have been experiencing with Cediranib is more than a pseudoresponse, and that study data and anecdotal evidence will confirm this.
With special caring and continued Hope,
Bonni