Two cases of falsely diagnosed massive progression post ICI treatment
Posted: Tue Sep 10, 2019 1:13 pm
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.
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.