Colorectal cancer is one of the most common malignant tumors, accounting for
approximately 10% of new cancer cases and cancer-related deaths worldwide each year. In
recent years, with the development of industrialization and urbanization, the increase in
the number of elderly patients, and changes in dietary structure and lifestyle habits,
the incidence and mortality rates of colorectal cancer in China have risen significantly.
Some patients are already in locally advanced or late stages at the time of diagnosis,
making treatment more difficult. Among them, patients with MSI-H/dMMR colorectal cancer
account for about 10% to 15% of the total.
Neoadjuvant therapy for rectal cancer primarily targets resectable mid-to-low rectal
cancer patients with T3/4 and any N stage. Currently, neoadjuvant therapy for rectal
cancer mainly involves chemoradiotherapy, while patients with a low risk of recurrence
may opt for neoadjuvant chemotherapy. For patients with mid-to-low locally advanced
rectal cancer, intensified systemic chemotherapy can be chosen before and after
preoperative radiotherapy. For patients with technical difficulties in sphincter
preservation but a strong desire to preserve the sphincter, higher intensity treatments
can be considered, such as the CinClare protocol of concurrent chemoradiotherapy with
capecitabine and irinotecan, the FOWARC protocol of concurrent radiotherapy with FOLFOX,
or interval chemotherapy, including total neoadjuvant therapy. However, for MSI-H/dMMR
patients, neoadjuvant chemoradiotherapy is less effective. Xu Ruihua from the Sun Yat-sen
University Cancer Center evaluated the clinical response and safety of four cycles of
neoadjuvant treatment with sintilimab in dMMR or MSI-H colorectal cancer. In this study,
16 patients underwent at least one response evaluation. All six patients who underwent
radical surgery achieved R0 resection. Tumor shrinkage was observed in 15 patients (94%)
at the first evaluation after treatment. Among the 16 evaluable patients, 3 (19%)
underwent radical surgery and achieved pCR, 9 (56%) achieved cCR and opted for a
watch-and-wait strategy, 3 (19%) did not achieve cCR and underwent radical surgery with
residual tumor found in the pathological specimens. One patient (6%) discontinued
treatment due to a severe adverse event (grade 3 encephalitis), did not achieve cCR, and
refused surgery. The results of immunotherapy in patients with MSI-H/dMMR metastatic
colorectal cancer have greatly encouraged researchers to explore its application in
neoadjuvant therapy. The NICHE study, the world's first neoadjuvant immunotherapy study
in non-metastatic colon cancer, showed a 100% MPR and a 69% pCR rate after neoadjuvant
immunotherapy in 32 patients with dMMR colon cancer. Based on this study, the larger
NICHE-2 study was conducted, enrolling a total of 112 patients with non-metastatic dMMR
colon cancer. These patients received one dose of ipilimumab (1 mg/kg) combined with
nivolumab (3 mg/kg) followed by one dose of nivolumab (3 mg/kg) monotherapy within 6
weeks before surgery. The short-term efficacy results showed an MPR of 95% and a pCR rate
of 67%, consistent with previous results, with good tolerability and only 4% experiencing
grade 3-4 adverse events.
Sintilimab targets the same molecule as nivolumab and pembrolizumab but has a different
amino acid sequence. Multiple preclinical in vitro studies have validated the effect of
sintilimab in blocking the PD-1 pathway. Completed preclinical pharmacodynamics, animal
pharmacokinetics, and toxicology studies have shown that sintilimab has clear targets,
reliable cell line sources, good drug stability, and has demonstrated good activity in
completed preclinical studies.
Based on multiple previous studies, the optimal cycle for neoadjuvant immunotherapy has
not yet been determined. However, different treatment cycles result in significant
differences in pCR, which may be related to the number of treatment cycles. This study
aims to explore the postoperative pathological complete response rate of 8 cycles versus
4 cycles of neoadjuvant sintilimab treatment in dMMR/MSI-H locally advanced colon cancer.
