Impact of endoscopic metallic stent placement and emergency surgery on detection of viable circulating tumor cells for acute malignant left-sided colonic obstruction

Colorectal cancer (CRC) is one of the most commonly diagnosed cancer worldwide. Up to 30% of patients with CRC suffered acute colonic obstruction [1‐3], at the time of the initial diagnosis [4]. Self-expanding metal stents (SEMS) serve as a bridge to surgery (BTS), which provide more opportunities to prepare for radical surgery. SEMS and conventional emergency surgery (ES) [3, 5, 6] have become two conventional treatments which widely utilized in malignant obstruction, especially left-sided colonic obstruction. However, the method of SEMS as a BTS may be associated with worse long-term prognosis and relapse of CRC patients.

Circulating tumor cells (CTCs) are potential substitutes for distant metastasis and promising novel biomarkers for tumors [7], which can gain access to the circulatory system and are detectable in the peripheral blood [8]. In our previous study [9], we found that compared with emergency surgery, SEMS are associated with more perineural invasion, a higher recurrence rate, and worse overall survival in patients. Nevertheless, the underlying mechanisms remain unresolved. Based on this, we doubt that CTCs were increased after SEMS placement in some way to influence the prognosis and recurrence.

In this study, we employed a novel method to capture CTCs with flow-cell system and analyzed the CTCs from a cohort of 32 colorectal cancer patients with obstruction. We examined the differences between the number of CTCs before and after the treatment of SEMS or ES in CRC patients to evaluate whether the treatment of SEMS will influence the CTC after stent insertion.

This prospective multicenter study was conducted at Shanghai Tongji Hospital and Ningbo First Hospital. We examined differences in the numbers of CTCs before and after SEMS or ES. We included the patients with primary CRC with acute left-sided colonic obstruction from March 2018 to January 2021. The study protocol was approved by the institutional review board of Tongji Hospital Affiliated to Tongji University (approved no. KYSB-2017-007). The clinical trial was registered (ChiCTR-OON-17010877). Written consent was obtained from all the participants before study.

This study is a multicenter trial that analyzed whether SEMS placement would cause an increase in the number of CTC. We employed a novel method to capture CTCs in 32 patients, 21 of these were treated with SEMS, and 11 were treated with ES. The results suggest that CTC counts obtained before and after placement did not differ significantly. Furthermore, we analyzed the CTC counts in the SEMS and ES group in different stages, but no statistical difference was observed also.

Since the concept of CTC came out, it has been considered as a poor prognostic characteristics and poor survival outcome [12]. Yang et al. found that [13, 14], for CTC-positive patients with CRC, despite of the sampling time, adjuvant therapy, and TNM stage, they revealed a shorter overall survival and disease-free survival in their meta-analysis. However, several scholars considered CTCs detected at different follow-up time points after surgery were of different prognostic impact [15] and the methods of detecting CTCs will influence the overcome [16]. Racila and colleagues [17] first described a novel method to detect the extremely rare CTCs in 1998, which is the gold standard nowadays [18]. They used an immunomagnetic enrichment technique to detect CTCs which based on epithelial cell adhesion molecule (EpCAM) [19]. Another important method to detect CTC is based on nucleic acid identification by PCR methods [20‐22]. Here, we used a microfluidic device to detect CTC based on crossflow filtration technology, then distinguishes CTCs by analyzing glucose uptake of fluorescent-labeled 2-NBDG [10]. This method based on 2-NBDG staining to identify metabolically active cells in blood; however, whether to claim that all 2-NBDG-positive cells are cancer cells is reasonable remains further exploration. Lu et al. also employed this method to detect CTC from lung cancer patient and concluded that CTCs can be served as a biomarker to assist the diagnosis and predict lung cancer metastasis [10]. Inclusive analysis these results, we found that this method could indeed help to explore more CTCs compared with other methods.

To date, some studies have demonstrated that stent insertion may result in tumor cell dissemination into the peripheral circulation and may induce distant metastases [16]. Nesteruk confirmed that CTC detection 7 days after surgery was of prognostic significance for the local recurrence, while 24 h not [23]. Shinya et al. [24] also found that an increase in the number of CTC after stent insertion and that the pressure exerted on the tumor during SEMS expansion result in a direct release of some cancer cell, which will induce recurrence despite R0 resection or adjuvant therapy. In our study, we did also collect blood samples 7 days after surgery. However, the CTC counts before and after surgery in the SEMS and ES groups did not show significant difference. Thus, we conclude that stent insertion may not result tumor cell dissemination and increase the CTC number. Thus, combined with previous study findings and other studies, we speculated that there are also other factors affecting patients’ prognosis, such as peripheral nerve invasion [25‐27] and the alteration of epigenetic [28].

The present study had several limitations. First, the study was a non-randomized study, so selection bias may exist in the choice of decompression method. Second, the volumes of clinical samples were limited and we did not carry out survival analysis due to immature survival data. Third, ctDNA may be both more sensitive and more accurately [29], which is widely used in clinic. In hence, ctDNA will be considered for later research.

In conclusion, our analysis of CTC counts which captured by the novel method of FlowCell system in this cohort of 32 patients suggested that the treatment of SEMS does not cause an increase in the number of CTC after stent insertion. Furthermore, there are may be other factors besides CTC to cause these poorer oncologic outcomes after SEMS placement.