Two cases of falsely diagnosed massive progression post ICI treatment

[Olga]

Concealed complete response in melanoma patients under therapy with immune checkpoint inhibitors: two case reports
The assessment of tumor size by RECIST using CT scans and MRIs is considered to be standard of care for staging cancer patients. Despite radiologic evidence of widespread disease, we document for the first time that patients were completely free of viable tumor.
https://jitc.biomedcentral.com/articles ... 017-0309-3
the histopathologic examination of progressive metastases shortly after imaging proved them to be totally free of viable tumor cells.
Currently, tumor response is evaluated based on tumor size on CT and MR scans [7, 8]. FDG-PET-CT provides greater sensitivity than CT and also specificity since it can detect early changes in metabolism which might precede morphological changes [9]. This has been shown, e.g. in gastrointestinal stromal tumors treated with imatinib where response on PET was associated with PFS and preceded tumor shrinkage by several weeks [10]. Successful checkpoint inhibitor therapy can induce immune cell infiltration with a subsequent increase in tumor volume [11], i.e. pseudoprogression, which can be followed by a partial or complete response. This observation led to the development of the immune-related response criteria (irRC, 7) which define progression as an increase of tumor burden of at least 25% at 2 different time points with an interval of at least 4 weeks [7]. Both patients had progressive disease in the CT scans shortly before pathologic examinations revealed scarred, tumor-free metastases even when applying immune-related response criteria.

The concealed response was seen just 6 weeks after initiation of checkpoint inhibitor treatment in patient #2, whereas patient #1 had progressive nodes more than a year after start of and response to therapy. This demonstrates that concealed regression of metastases can be induced very early under immune checkpoint inhibitor therapy and (pseudo-)progression in imaging studies can occur as late as 15 months after start of treatment despite histologically confirmed response. In case #2, vital tumor manifestations at other sites could not be excluded since only abdominal and bone tumors were pathologically assessed. Concealed responses in patients that show stable or progressive tumors on radiologic staging may be much more common than expected and identified under immunotherapy with checkpoint inhibitors. Importantly, there have been two cases of radiologic pseudoprogression of brain metastases in patients treated with PD1-antibodies [12, 13]. Pathologic similarities with necrotic tissue and no vital tumor were reported in a lung carcinoma patient who underwent radiotherapy more than 2 years before anti-PD1 treatment [12]. In contrast, vital tumor with treatment-related CD45+ and CD68+ infiltrates was seen in a BRAFV600E-mutant melanoma patient with multiple small brain metastases after a single application of pembrolizumab [13].

In order to spare patients potential toxicity of unnecessary treatment or (even worse) change of an effective therapy in responding patients innovative methods for the detection of viable tumor tissue are desperately needed. FDG-PET/CT in melanoma could be valuable at least in sclerosed lesions but not in lesions heavily infiltrated by immune cells which due to their metabolism will be FDG-PET positive [14].

A prospective study with histologic assessment of ‘metastases’ under treatment with checkpoint inhibitors should be considered to confirm our findings. In tumor patients treated with immune checkpoint inhibitors progressive tumor manifestations may represent a concealed response without viable tumor. If suspected only histology can solve the diagnostic challenge.

[D.ap]

Olga
Very important information .
All to often we are operating under the unknown ..
Scans with out biopsies and the usage of a new frontier of immunotherapies without the understanding of their results .

Great supporting articles that could again keep someone from being bumped from an all important trial/ off label life saving immunotherapy .

Thanks once again , for advocating for our rare ASPS , cause . : )

Love

[Olga]

There is a problem with the biopsies as well. I am wondering if the frequent biopsies during the trials might be one of the reasons that the clinical trials with ASPS in ICI drugs seem to have a bit inferior results than the reports from our patients or doctors we know (such as Dr.Razak - he said that all of his ASPS patients responded to ICI some after he added SBRT to primary or other mets). I would say that the immunological aspects of the inflammation caused by the biopsies or other invasive procedure/their timing in connection to ICI cycles might be either overlooked or disregarded as they prioritize the research targets.

[D.ap]

Olga
A seeding issue?
If ASPS is “encased”
If a needle is introduced , then it becomes possibly circulated if not contained , sterilized in affect ?

Trying to connect the dots ..

[Olga]

I was mostly talking about the immunological adverse effects caused by the incisional biopsy when the Tregs are introduced into the tumors, but you rise a very good point too - multiple biopsies would carry a risk of seeding, growth factors elevated etc. They are pros there and try not to seed the tumors, needles are not reused, but things happen.

[D.ap]

Olga
Also , 25 % is seen as a reason to axe the Med ?
I would venture to say it would depend on where the tumor was found and how big it was, in proportion to the area/ organ it is residing in ,when it grew . Also how it is and or could affect the function of that organ .

In alveolar soft part sarcoma , we know it’s highly unusual that a tumor progression happens at a rate of 25% immediately . Maybe more like 1mm a month and aggressively at 2 when it reaches that stage ?Am I thinking correctly ?

I guess some trials perform scans at 6 weeks ? And maybe catch the tumor (s) at their most inflamed looking state .
So the assessment measurement is documented as a given exponentially larger size then the tumor actually is.

And or a scan maybe is needed as a patient is having issues that need to be investigated through scans and again the tumor is discovered inflamed and reported as progressing by a radiologist , with out regard to knowning if it’s inflammation or progression .

Thus the “progression “ is viewed as an exponential increase and dcd just because of the scan reading and or the patient ( or medical teams) feels the need to stop?

[D.ap]

There is a problem with the biopsies as well. I am wondering if the frequent biopsies during the trials might be one of the reasons that the clinical trials with ASPS in ICI drugs seem to have a bit inferior results than the reports from our patients or doctors we know (such as Dr.Razak - he said that all of his ASPS patients responded to ICI some after he added SBRT to primary or other mets). I would say that the immunological aspects of the inflammation caused by the biopsies or other invasive procedure/their timing in connection to ICI cycles might be either overlooked or disregarded as they prioritize the research targets.

Hi Olga,
You mentioned biopsies/procedures being scheduled in the infusion cycle , as maybe being inflammatory and possibly giving a false radiological report as progression ?
When is the best time to perform say a biopsy in an ICI cycle ?

[D.ap]

There is a problem with the biopsies as well. I am wondering if the frequent biopsies during the trials might be one of the reasons that the clinical trials with ASPS in ICI drugs seem to have a bit inferior results than the reports from our patients or doctors we know (such as Dr.Razak - he said that all of his ASPS patients responded to ICI some after he added SBRT to primary or other mets). I would say that the immunological aspects of the inflammation caused by the biopsies or other invasive procedure/their timing in connection to ICI cycles might be either overlooked or disregarded as they prioritize the research targets.

Hi Olga,
You mentioned biopsies/procedures being scheduled in the infusion cycle , as maybe being inflammatory and possibly giving a false radiological report as progression ?
When is the best time to perform say a biopsy in an ICI cycle ?

I would speculate that timing the biopsy soon after a infusion might be the better schedule?

[Olga]

My thoughts were about the biopsy skewing the immune response. I would avoid any interventions in the middle or end of the cycle between the infusions and to move them all toward the infusion */- few days, in that way the inflammation from the biopsy itself may attract the immune cells to a tumor and they would suddenly able to recognize the tumor due to the breaks unblocked by the ICI. In the middle of the cycle, as the time goes there are different immune cells come to a play the ones that we do not want to set free as they are pro-timor growth (a very weak level of evidence to what I posted here, just a some vague feeling on what I have seen from the case studies and patients reports)

[D.ap]

My thoughts were about the biopsy skewing the immune response. I would avoid any interventions in the middle or end of the cycle between the infusions and to move them all toward the infusion */- few days, in that way the inflammation from the biopsy itself may attract the immune cells to a tumor and they would suddenly able to recognize the tumor due to the breaks unblocked by the ICI. In the middle of the cycle, as the time goes there are different immune cells come to a play the ones that we do not want to set free as they are pro-timor growth (a very weak level of evidence to what I posted here, just a some vague feeling on what I have seen from the case studies and patients reports)

Thank you Olga
I feel that’s accurate as well , to utilize the immune check point inhibitors peak time in the infusion schedule to combat the possibility of the tumor, to progress rather than be attacked by the immune system, to get a piece of the tumor . Consequently creating an immune recognition rather than a progression, that inflammation can and will cause , through needle and or incision
biopsies.

Found a link to your pro-tumor growth cycles


“What Is Pro-Tumor Inflammation (PTI)? Pro-Tumor Inflammation (PTI) refers to a type of unregulated inflammation that may have many possible downstream consequences, such as facilitating tumor growth, tumor survival, and the development of metastasis in certain cancers.”

https://www.protumorinflammation.com/what-is-pti/