Prevalent Pseudoprogression and Pseudoresidue in Patients With Rectal Cancer Treated With Neoadjuvant Immune Checkpoint Inhibitors
Background: Immune checkpoint inhibitor (ICI) treatment in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) tumors holds promise in reshaping organ preservation in rectal cancer. However, the benefits are accompanied by distinctive patterns of response, introducing a dilemma in the response evaluation for clinical decision-making. Patients and Methods: Patients with locally advanced rectal cancer with MSI-H/dMMR tumors receiving neoadjuvant ICI (nICI) treatment (n=13) and matched patients receiving neoadjuvant chemoradiotherapy (nCRT; n=13) were included to compare clinical response and histopathologic features. Results: Among the 13 patients receiving nICI treatment, in the final radiologic evaluation prior to surgery (at a median of 103 days after initiation of therapy), progressive disease (n=3), stable disease (n=1), partial response (n=7), and complete response (n=2) were observed. However, these patients were later confirmed as having pathologic complete response, resulting in pseudoprogression and pseudoresidue with incidences of 23.1% (n=3) and 76.9% (n=10), respectively, whereas no pseudoprogression was found in the 13 patients receiving nCRT. We further revealed the histopathologic basis underlying the pseudoprogression and pseudoresidue by discovering the distinctive immune-related regression features after nICI treatment, including fibrogenesis, dense lymphocytes, and plasma cell infiltration. Conclusions: Pseudoprogression and pseudoresidue were unique and prevalent response patterns in MSI-H/dMMR rectal cancer after nICI treatment. Our findings highlight the importance of developing specific strategies for response evaluation in neoadjuvant immunotherapy to identify patients with a good response in whom sphincter/organ-preserving or watch-and-wait strategies may be considered.
Submitted June 10, 2022; final revision received August 23, 2022; accepted for publication August 23, 2022.
Author contributions: Conceptualization: M. Huang, Yu, Luo. Data acquisition: Lin, Zhang, X. Wang, P. Wang, Wu, Y. Huang, G. Liu, Meng. Data analysis and interpretation: Xie, Lin, Zhang, X. Wang, P. Wang, Peng, Li, Wu, Y. Huang, Zhuang, Shen, Zhu, G. Liu, Meng. Investigation: Xie, Lin, Zhang. Methodology: Xie, Lin, Zhang, X. Wang, X. Liu, G. Liu, Meng, M. Huang, Yu, Luo. Study administration: G. Liu, Meng, M. Huang, Yu, Luo. Writing—original draft: Xie, Lin, Zhang. Writing—review and editing: Xie, Lin, Zhang, X. Wang, X. Liu, G. Liu, Meng, M. Huang, Yu, Luo. Final approval of manuscript: X. Liu, G. Liu, Meng, Yu, Luo.
Data availability statement: Data are available upon reasonable request from the corresponding authors.
Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This study was supported by the National Natural Science Foundation of China under award numbers 82173067 and 81972245 (Y. Luo), and 81902877 (H. Yu); the Natural Science Foundation of Guangdong Province under award numbers 2022A1515012656 (H. Yu), 2021A1515010134 (M. Huang), and 2020A1515010036 (X. Liu); the Sun Yat-sen University Clinical Research 5010 Program under award number 2018026 (Y. Luo); the “Five Five” Talent Team Construction Project of the Sixth Affiliated Hospital of Sun Yat-sen University under award number P20150227202010251 (Y. Luo); the Excellent Talent Training Project of the Sixth Affiliated Hospital of Sun Yat-sen University under award number R2021217202512965 (Y. Luo); the Sixth Affiliated Hospital of Sun Yat-sen University Clinical Research-‘1010’ Program (M. Huang); the Program of Introducing Talents of Discipline to Universities (Y. Luo); and National Key Clinical Discipline (2012).
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