With the continuing progress of ctDNA technology in targeting various malignancies, ctDNA technology has brought new ideas for tumor detection and treatment guidance after first reported in 1989 by Stroun et al . Although ctDNA detection method and detection time are still debatable,The importance of ctDNA technolog cannot be overlooked in clinical practice.
As far as we know, the effect of ctDNA on the prognosis of postoperative RFS in patients with NSCLC is still uncertain.In order to further demonstrate the role of ctDNA in NSCLC and its influence on postoperative prognosis of NSCLC patients. We performed a meta-analysis with 799 patients in 10 studies in our study. The results demonstrated that the ctDNA positive group had a higher predictive effect on postoperative NSCLC recurrence than the ctDNA negative group with the pooled RR = 3.75, P < 0.05. The RFS of NSCLC patients in the preoperative ctDNA positive group was lower than the preoperative ctDNA negative group (HR = 3.40, P < 0.05), according to data from four trials. The presence of ctDNA may be an independent predictive factor for postoperative NSCLC recurrence, according to the findings of this meta-analysis.
ctDNA is fragmented DNA obtained from tumors and circulated in the bloodstream, and it frequently carries mutations, deletions, insertions, copy number aberrations, methylation, and other gene mutation information. As a result, ctDNA has the potential to detect cancer that has gone undetected and to track tumor-specific alterations. The ease of plasma collection allows for continuous monitoring of the ctDNA level in order to anticipate the mutation state vertically and to assess the risk of recurrence. Therefore, ctDNA has become a widely used indicator of MRD.
The detection of ctDNA was compared to the traditional radiological monitoring method in seven trials from this meta-analysis, and the former was found to be 6.7 months ahead of the latter ( the longest 12.6 months, and the shortest 88 days ). Abbosh et al proposed a median lead time of 151 days for ctDNA in the TRACERx project, which was the first to report it. Despite the fact that the patients, clinical phases, and adjuvant treatment strategies in each study were all different, the final results showed that ctDNA technology beat radiography methods in diagnosing tumor recurrence. Because routine imaging cannot detect MRD and recurrence, and repeated CT scan can be harmful to the patient's health, the final decision of treatment is impacted by the physician's level of experience and subjective considerations. Based on the aforementioned, it is believed that ctDNA technology can be used in conjunction with radiographic techniques for tumor surveillance.
Although ctDNA technology can be used to monitor MRD after tumor surgery, the guidelines have recommended relevant ctDNA monitoring time for colon cancer, but there is no clear standard for postoperative ctDNA detection and follow-up time for NSCLC[12, 24]. The variable detection period may raise the risk of false positive results and lead to excessive adjuvant therapy. According to Chen et al's research, ctDNA decays rapidly after tumor excision, and ctDNA detection on the third day after resection can be utilized as the baseline value for postoperative NSCLC monitoring. Li et al used dynamic monitoring and discovered that the positive group had a obvious shorter RFS than the ctDNA negative patients. Different collection and follow-up time in this study are shown in Table 1.
According to the survey, even after surgical treatment, 5-year OS of NSCLC patients from 92% of stage Ia1 to 26% of stage IIIb. So, even in early conditions, the clinical requirement for adjuvant therapy is increasing in order to eradicate MRD. However, up to now, adjuvant chemotherapy in patients with NSCLC following surgery has given only 4–5 percent of the absolute survival benefits compared to observation or best supportive treatment. Because the present TNM staging paradigm may not effectively detect MRD, it may lead to erroneous postoperative treatment decisions. ctDNA samples from 330 perioperative patients were evaluated in Xia L et al study. The findings revealed that ctDNA-based MRD outperformed clinical pathological indicators like TNM stage in predicting RFS, and that ctDNA-based MRD positive patients would benefit from adjuvant therapy. The other two studies suggested that the state of ctDNA after adjuvant treatment was closely related to RFS, and adjuvant treatment had beneficial effects on postoperative ctDNA positive patients[16, 27], after comparing the benefits of adjuvant treatment in postoperative ctDNA positive and negative groups.
Our meta-analysis has some limitations that need to be addressed. first, the number of enrolled trials is tiny, as is the total sample size and the sample size gap in each study, both of which inevitably lead to some biases. Second, standardizing the detection of ctDNA, stratifying the recurrence risk of patients based on the results of ctDNA detection at different times, and formulating corresponding follow-up strategies for different patients to guide postoperative adjuvant therapy remain significant challenges in clinical practice. Finally, each study differs in terms of illness stages and ctDNA technique. This dilemma demonstrates that future research should focus on ctDNA detection technologies and risk classification of different patients in order to better understand the critical role of ctDNA monitoring in the prognosis of NSCLC and guide the management of following diseases.