by Suzanne Bissonnette BSc MBA
In the field of immuno-oncology, differentiating between pseudoprogression and true disease progression poses a significant clinical challenge. Pseudoprogression is characterized by the apparent growth of tumors on imaging scans due to immune cell infiltration, rather than actual tumor growth. True progression, on the other hand, reflects the genuine advancement of cancer. As immunotherapies are increasingly used, understanding the nuances of these response patterns becomes critical.
Imaging and Serial Scans
Imaging techniques such as PET/CT play a central role in distinguishing pseudoprogression from true progression. Oncologists use serial imaging to track changes over time; continuous tumor growth or new lesions on successive scans point to true progression, while stabilization or shrinkage indicates pseudoprogression1. Emerging imaging technologies and tools such as CD8 ImmunoPET are being studied in various settings and may help assess irAEs 22 and perhaps discern pseudo from true progression.
Clinical Assessment and Tumor Flare
In some cases of pseudoprogression, patients may experience a phenomenon known as "tumor flare," where clinical symptoms initially worsen, mimicking true disease progression. This flare is caused by immune cells infiltrating the tumor, leading to inflammation and swelling, which can be mistaken for tumor growth. Signs and symptoms such as increased lymph node size, fever, and pain may suggest progression. Flare-ups may be observed with checkpoint inhibitors, CAR-T therapies, or other immunomodulators, where immune activation against tumor cells leads to temporary worsening before improvement. Despite apparent progression on imaging, continued treatment may often precede a favorable therapeutic response to immunotherapy.3, 4
Biopsy and Biomarker Analysis
Biopsies can help clarify ambiguous cases by identifying whether an increased mass consists of tumor cells or immune cells such as lymphocytes and macrophages. Biomarker analysis, like measuring lactate dehydrogenase (LDH) levels, offers further insight, with elevated levels typically correlating with true progression and stable or reduced levels suggesting pseudoprogression. 2
New Technologies and Evolving Response Criteria
Newer technologies, such as liquid biopsies for circulating tumor DNA, are proving valuable in distinguishing between pseudoprogression and true progression. Radiomics—advanced imaging data analysis—shows promise in identifying subtle differences between pseudoprogression and actual tumor growth.5Traditional cancer response criteria like RECIST have been modified for immunotherapy to account for atypical response patterns. irRC and iRECIST 6, allow treatment continuation even if early scans suggest progression, avoiding premature therapy cessation.
Distinguishing pseudoprogression from true progression in immunotherapy-treated patients is complex and relies on a multimodal approach combining imaging, clinical evaluation, biopsy, and biomarker analysis. New tools such as ImmunoPET technology may be useful to clinicians, to assess the whole-body immune response in real time thereby potentially facilitating clinical decision making about continuing or discontinuing therapy.
References :
1. Mönch, S., Heimer, M.M., Winkelmann, M. et al. Patterns of pseudoprogression across different cancer entities treated with immune checkpoint inhibitors. Cancer Imaging 23, 58 (2023). https://doi.org/10.1186/s40644-023-00580-9
2. Amaral et al. Early detection of side-effects in patients with metastatice melanoma receiving immune checkpoint inhibitors by investigation of CD8+ immune infiltrate with [89Zr] crefmirlimab berdoxam PET. JCO 2024, 42, 16 suppl. https://doi.org/10.1200/JCO.2024.42.16_suppl.TPS9601
3. Imataki, O., Uemura, M., Fujita, H. et al. Pathological landscape of tumor flare reaction to epcoritamab treatment. Int J Hematol 120, 467–471 (2024). https://doi.org/10.1007/s12185-024-03833-w
4. Le Fèvre, Clara, et al. "Pseudoprogression versus true progression in glioblastoma patients: A multiapproach literature review: Part 1–Molecular, morphological and clinical features." Critical Reviews in Oncology/Hematology 157 (2021): 103188.
5. Alizadeh, M.; Broomand Lomer, N.; Azami, M.; Khalafi, M.; Shobeiri, P.; Arab Bafrani, M.; Sotoudeh, H. Radiomics: The New Promise for Differentiating Progression, Recurrence, Pseudoprogression, and Radionecrosis in Glioma and Glioblastoma Multiforme. Cancers 2023, 15, 4429. https://doi.org/10.3390/cancers15184429
6. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143–52. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30074-8/abstract
