Prevalent Pseudoprogression and Pseudoresidue in Patients With Rectal Cancer Treated With Neoadjuvant Immune Checkpoint Inhibitors

Abstract

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.

Evaluation of transrectal ultrasound-guided tru-cut biopsy as a complementary method for predicting pathological complete response in rectal cancer after neoadjuvant treatment: a phase II prospective and diagnostic trial

“…Beyond superficial biopsies, TRUS-TCB provides comprehensive whole-layer pathological insights. Combined with superficial biopsies, TRUS-TCB aids clinicians in “watch-and-wait” determinations for suspicious post-immunotherapy lesions, contributing to sphincter preservation 28 . A trial participant in our study receiving immunotherapy echoed previous findings—TRUS-TCB predicted pCR accurately, while MRI indicated residue.…”

A novel neoadjuvant regimen of chemo-immuno-embolization with transcatheter rectal arterial intervention in locally advanced rectal cancer: a study protocol for a phase II trial (CIETAI-R)

“…Nevertheless, it should be noted that preoperative imaging examinations may not accurately assess tumor volume in patients receiving ICIs due to potential signs of tumor pseudoprogression resulting from immune activation. Combining circulating tumor DNA and blood-based tumor markers is an alternative approach to re ect the true response to ICIs treatment (35). On the other hand, the watch-and-wait (WW) strategy under close surveillance is considered an alternative for patients achieving cCR.…”

Neoadjuvant immunotherapy based on PD-1/L1 inhibitors for gastrointestinal tumors: a review of the rationale and clinical advances

“…Xie et al . 78 revealed that pseudoprogression and pseudoresidue were present in three CRC patients (23.1%) and 10 CRC patients (76.9%), respectively.…”