There is still controversy in clinical practice regarding the appropriate surgery interval for SLM patients after NAC, and different guidelines recommend different timing for surgery. For example, the latest version of the National Comprehensive Cancer Network (NCCN) updated guidelines for the management of metastatic colorectal cancer recommends that the surgical interval after NAC be 5–12 weeks [16], while the "ESMO Guidelines" recommends that the optimal operation time is 6-8 weeks after NAC [17]. Apart from the ongoing controversy, these guidelines have a broad coverage of CRLM patient population, but fail to address the differences within the CRLM patient population, which inevitably leads to heterogeneity among the groups included in the studies. For example, synchronous liver metastasis (SLM) and metachronous liver metastasis (MLM) patients have different prognostic characteristics [4,5]. SLM patients have a worse prognosis. Therefore, the applicability of these guidelines for patients with SLM remains to be proven. Likewise, several studies have been devoted to the optimal timing of surgery for patients with CRLM after NAC. For example, Chen et al. found that patients with a longer time to surgery (TTS) were more likely to have adverse pathological responses, while those with a shorter TTS had significantly better PFS and OS [19]. Thomas L et al. found that compared with CRLM patients with time to resection (TTR) <2 months, patients with TTR ≥ 2 months had shorter RFS and OS [20]. Although these studies indicate that different surgical timings after NAC can affect patient outcomes, they also do not pay attention to the differences in prognosis among different subtypes of CRLM patients. In addition, these studies do not address the impact of different timing of surgery on postoperative complications in CRLM patients. Therefore, we conducted this study on initially resectable SLM patients to investigate the optimal timing of surgery and provide the greatest survival time for these patients.
In present study, SLM patients were divided into early resection subgroup (4≤TTS<6) and delayed resection subgroup (6≤TTS≤8) according to the TTS after NAC. Based on data from the current study, patients in the early surgical resection subgroup had better OS and DFS than the delayed surgery subgroup. In response to this finding, and in conjunction with previous studies in other malignancies, we can clarify that some of the following reasons may contribute to the worse prognosis of patients who delay underwent surgery. First of all, not all SLM patients receiving NAC can benefit from delayed surgical resection, and some patients with insignificant or enlarged lesions after NAC may cause further tumor growth and metastasis due to delayed resection [21]. Second, severe complications during NAC are a key factor in increasing TTS, and the low physical status of these patients may be directly related to poor prognosis [22]. More importantly , more studies have shown that more than 6 weeks after NAC leads to the regrowth of potentially resistant tumor cell populations while further reducing the efficacy of surgical treatment [23,24]. The present study matched the two groups of patients at baseline level after propensity score (including the progressive disease during NAC and the incidence of serious complications after NAC), therefore, we believe that this difference in prognosis may be more related to the biological characteristics of the tumor itself. Undergoing radical surgical resection within 4-6 weeks after NAC may be a better option.
Notably, among SLM patients who underwent radical resection earlier, there may still be some patients who have not recovered from the post-NAC neutropenic window, and premature surgery may theoretically lead to an increased rate of postoperative complications, especially those related to postoperative infection [25]. In addition, the liver damage caused by NAC cannot be fully recovered in a short time, and therapeutic liver resection at this time will further increase the burden on the liver [26]. Therefore, this study found that the incidence of postoperative jaundice in the 4≦TI<6 group was higher than that in the 6≦TI≦8 group. Meanwhile, the increase in the incidence of postoperative hemorrhage in the 4≦TI<6 group may also be related to the transient disorder of coagulation function caused by liver function decline.
Due to differences in postoperative complications between the two groups of patients, further investigation was conducted to explore the impact of postoperative complications on the prognosis of SLM patients undergoing simultaneous resection after NAC. Initially, we classified postoperative complications in both groups using the Clavien-Dindo Grade system and found that the main differences were concentrated in grade I complications. We further analyzed the factors related to postoperative complications using single-factor and multi-factor analyses, but found no correlation between postoperative complications and prognosis. This result further confirms the viewpoint that tumor biology, rather than postoperative course, strongly determines the probability of patient survival, as reported in previous studies [27,28]. In summary, patients with SLM may be a better choice for surgery within 4-6 weeks after receiving NAC.Although patients with SLM undergoing surgery 4–6 weeks after NAC has a higher rate of postoperative complications, radical surgery is still recommended for a better survival benefit.
Our study is the first to investigate the timing of surgery after NAC in resectable SLM patients. In addition to focusing on the prognosis (OS, DFS) of patients, we also paid attention to the short-term clinical outcomes of patients after surgery. Meanwhile, this study performed propensity score matching on the two groups of patients, minimizing the impact of retrospective study bias on the conclusions. This study can provide new evidence for clinical diagnosis and treatment. However, this study still has the following limitations. The first point to consider is that this study is a retrospective cohort study, which unavoidably introduces bias. Next, the relatively special population included in this study led to a small sample size. Thirdly, this study is a single-center cohort study, and the conclusions may not necessarily represent the situation in other countries and regions. Therefore, future randomized controlled studies and large-scale multicenter prospective cohort studies are needed for further verification.