Neoadjuvant immunotherapy for colorectal cancer: Right regimens, right patients, right directions?

Abstract

Neoadjuvant chemoradiotherapy (NACRT) or chemotherapy (NACT) followed by radical resection and then adjuvant therapy is considered the optimal treatment model for locally advanced colorectal cancer (LACRC). A recent total neoadjuvant therapy (TNT) strategy further improved the tumour regression rate preoperatively and reduced local-regional recurrence in locally advanced rectal cancer (LARC). However, distant metastasis was still high, and little overall survival benefit was obtained from these preoperative treatment models. According to mismatch repair protein expression, MSI-H/dMMR and non-MSI-H/pMMR statuses were defined in colorectal cancer (CRC) patients. Due to the special features of biologics in MSI-H/dMMR CRC patients, this subgroup of patients achieved little treatment efficacy from chemoradiotherapy but benefited from immune checkpoint inhibitors (ICIs). The KEYNOTE-177 trial observed favourable survival outcomes in metastatic CRC patients treated with one-line pembrolizumab with tolerable toxicity. Given the better systemic immune function, increased antigenic exposure, and improved long-term memory induction before surgery, neoadjuvant ICI (NAICI) treatment was proposed. The NICHE trial pioneered the use of NAICI treatment in LACRC, and recent reports from several phase II studies demonstrated satisfactory tumour downsizing in CRC. Preclinical rationales and preliminary early-phase human trials reveal the feasibility of NAICI therapy and the therapeutic efficacy provided by this treatment model. Better tumour regression before surgery also increases the possibility of organ preservation for low LARC. However, the optimal treatment strategy and effective biomarker identification for beneficiary selection remain unknown, and potential pitfalls exist, including tumour progression during neoadjuvant treatment due to drug resistance and surgery delay. Given these foundations and questions, further phase II or III trials with large samples need to be conducted to explore the right regimens for the right patients.

Simvastatin inhibits PD-L1 via ILF3 to enhance CD8 + T cell-mediated ferroptosis in gastric cancer cells

“…GC patients who underwent preoperative neoadjuvant chemotherapy were divided into two groups treated with and without statins (≥ 6 months) (50 patients in each group). The Tumor Regression Grading (TRG) system (Table S1) is frequently employed to evaluate this treatment response of GC patients subjected to neoadjuvant therapies, typically chemotherapy or radiotherapy [30]. TRG grading of postoperative pathology were conducted between two groups of GC patients, which found that statins-treated groups exhibited more prominent tumor regression and were more sensitive to chemotherapy (Fig.…”

Complete mesocolic excision and extended lymphadenectomy: Where should we stand?

“…As such, perhaps a stronger consideration of CME + D3 dissection should be given to locally advanced right‐sided colon cancers since complete removal of the right‐sided tumor and its lymphovascular supply is arguably paramount in preventing what might become very difficult‐to‐treat disease. While a more detailed dive into genetic mutations and immunotherapy regimens is outside the scope of this review, interest in immune checkpoint inhibitors in the neoadjuvant setting has inspired several clinical trials, 34 the results of which may affect how multidisciplinary teams approach both resectable and unresectable CRCs.…”

“…31 Additionally, studies have demonstrated a correlation between elevated bile acid metabolites and an increased incidence of colon cancer, the former of which is present in greater concentrations in the right colon. Perhaps most important are the differences in genetics, as these can have significant therapeutic has inspired several clinical trials, 34 the results of which may affect how multidisciplinary teams approach both resectable and unresectable CRCs.…”

Clinical significance of metastasectomy and pathological response to pembrolizumab in mismatch repair-deficient metastatic colorectal cancer: A retrospective multi-institutional study

“…They demonstrated that pCR was con rmed in three of ve patients (60%) with an MSI-H tumor, and in 11 of 37 patients (30%) with a microsatellite stable tumor [22]. Although the survival bene ts of adjuvant immunotherapy are still not satisfactory, probably due to the signi cant decrease of neoantigens after surgery, neoadjuvant immunotherapy may have the potential to improve clinical outcomes in dMMR localized CRC [29].…”