Early recurrence in patients undergoing curative resection of colorectal liver oligometastases: identification of its clinical characteristics, risk factors, and prognosis

Colorectal cancer (CRC) has become a leading cause of cancer-related death both in China and worldwide (Chen et al. 2016; Torre et al. 2015). The liver is the most frequent site of metastatic disease. At the time of diagnosis, 20–25% of patients present with synchronous metastases, and approximately half of these patients develop metachronous disease after primary tumor resection (O’Reilly and Poston 2006; Van Cutsem et al. 2010). Despite improvements in the comprehensive treatment and management of patients with colorectal liver metastases (CRLM) in recent years, liver resection remains the most effective treatment, offering the possibility of a cure for CRLM patients (Gallinger et al. 2013; Kanas et al. 2012). Complete liver resection can achieve long-term survival in 46.0% of patients, with a 5-year survival rate of up to 60% (Chan et al. 2014; Kulik et al. 2013). Nevertheless, approximately 60% of patients who first undergo liver resection experience recurrence during follow-up (Chan et al. 2014; Cucchetti et al. 2015). Therefore, identification of different risk subgroups based on the severity of metastatic disease and tumor biological aggressiveness will help establish and optimize therapeutic strategies.

The traditional clinicopathologic factors are inadequate to define the underlying biology of CRLM. In the latest version of the European Society for Medical Oncology (ESMO) Consensus Guidelines, the clinical value of oligometastatic disease (OMD) was highlighted, and metastatic CRC was divided into OMD and widespread systemic disease (Van Cutsem et al. 2016). The concept of OMD emerged 2 decades ago and is typically defined as a state of metastatic disease that is limited in total disease burden, according to the limited number of clinically evident or radiographic sites (Engels et al. 2012; Van den Begin et al. 2014). OMD represents a disease state that exists in a transitional zone between localized and widespread systemic diseases, which shows a genuine potential for cure when patients receive complete R0 resection of their metastases (Reyes and Pienta 2015; Weiser et al. 2013).

It is well known that disease recurrence after liver resection is common and negatively impacts patient survival (Leung et al. 2016; Nordlinger et al. 2008). Early recurrence after liver resection is one of the most important factors for prognosis and quality of life in patients with CRLM. Approximately 10–30% of patients develop early recurrence after liver resection, which is associated with the poorest survival outcome (Imai et al. 2016; Malik et al. 2007; Vigano et al. 2014). To date, few studies have highlighted the clinical implication of early recurrence in colorectal liver oligometastases (CLOM) patients who undergo curative resection. Thus, the aim of this study was to investigate the clinical characteristics, risk factors, and prognoses related to early recurrence after liver resection for patients with CLOM.

Accumulating evidence has shown that fewer liver metastases are significantly associated with less recurrence, thus translating to better survival after R0 hepatic resection for CRLM patients (Chan et al. 2014; Fong et al. 1999; Sasaki et al. 2016; Zhang et al. 2010). Characterized by liver-only metastases with a limited number of lesions (≤ 5 metastases), liver oligometastases have been correspondingly identified to indicate low-risk CLRM patients, who may achieve a favorable survival outcome after curative liver metastasis treatment (Lu et al. 2016; Takeda et al. 2016; Weiser et al. 2013). The previous studies have reported that the 3-year OS rate in patients with unresectable and widespread systemic CRLM was lower than 50% (Chafai et al. 2005; Folprecht et al. 2014; Li et al. 2014), while the current study showed that the 3-year OS rate was 68.7%, with a 3-year RFS rate of 42.5%, in CLOM patients undergoing complete resection of total lesions.

Despite these excellent outcomes, recurrence remains an intractable problem for treating CLOM patients. Our previous study found that even when the primary and metastatic tumors were resected, up to 50% of patients with CLOM experienced disease recurrence postoperatively. However, the high-risk event, early recurrence, was not definitively identified and investigated in that study (Lu et al. 2016). Herein, our current study showed that 16.0% (49/307) of patients with CLOM developed early recurrence after liver resection. Among them, approximately 50% of the recurrences occurred within 3 months postoperatively. In addition, intrahepatic recurrence was the most common recurrence pattern in early recurrence.

Early recurrence was identified as an independent risk factor for poor long-term survival and was recognized as the leading cause of death within 5 years of curative resection of CRLM (Kaibori et al. 2012; Vigano et al. 2014; Yamashita et al. 2011). In the current investigation, we focused on early recurrence and its influence on prognosis in CLOM patients. Although CLOM represents a relatively non-aggressive tumor biology with limited widespread metastatic capacity (Reyes and Pienta 2015), our study revealed that patients with early recurrence faced a poor outcome. Hence, the identification of risk factors and methods to screen out high-risk subgroups for early recurrence are urgently needed to guide individual treatment.

In CRLM patients undergoing liver resection, early recurrence has been confirmed to be associated with more aggressive diseases, such as synchronous, multiple and large-mass metastases, advanced T and N staging of primary tumors, inadequate surgical resection, and failure of systemic therapy (Bhogal et al. 2015; Imai et al. 2016; Jung et al. 2016; Malik et al. 2007; Vigano et al. 2014. For the first time, our study demonstrated that in CLOM patients undergoing curative liver resection, the independent risk factors for early recurrence were node-positive primary tumors and a metastasis diameter > 3 cm. Unlike the results of the studies by Malik et al. (2007) and Yamashita et al. (2011), the number of liver metastases was not identified as a risk factor in these selected patients. We considered that the actual predictive effect of the number of liver metastases for early recurrence might not be easily determined in CLOM patients with complete tumor resection because of the limited burden of metastatic tumors. Based on these results, detailed preoperative comprehensive measurement of the disease is urgently needed, as this may help oncologists select patients with different risks of early recurrence. Once patients are diagnosed with CLOM with advanced N staging of the primary tumor and large-mass liver metastases, the limited benefit of surgery and high risk of early recurrence in this cohort of patients should be carefully taken into consideration. For these patients, intensive chemotherapy has been proposed to increase the control of micrometastatic disease and, more importantly, to provide a test for chemo responsiveness, which could further identify aggressive disease and select good candidates for subsequent surgery (Allen et al. 2003; Power and Kemeny 2010). On the other hand, a non-surgical strategy might be an effective alternative to immediate surgery as the first-line treatment. For instance, RFA has been proposed as an effective ablative technology to provide survival benefits comparable to surgical resection for patients with resectable CRLM (Ko et al. 2014; Otto et al. 2010). Taken together, we suggest the combination of intensive chemotherapy and local ablation as the first-line treatment for these high-risk patients.

It has been noted that subsequent treatment might be a crucial factor to prolong the survival of patients with early recurrence (Lan et al. 2014; Vigano et al. 2014). Although salvage resection could prolong long-term survival for patients with liver recurrence, the secondary resection rate was significantly lower in patients with early recurrence than in those with late recurrence (Imai et al. 2016). Similarly, in our study, less than 5% of patients with early recurrence were able to receive salvage liver resection, and the resection rate was significantly lower for patients with early recurrence than for those with later recurrence (4.1 vs. 19.7%, P = 0.010). Within a shorter postoperative period, several factors could impede the performance of surgical resection, including worsened condition status, potential surgical complications, and development of unresectable metastases. As a result, the low probability of salvage liver resection for early recurrence disease could contribute to the poorer long-term survival for these patients. Nevertheless, early recurrence should not be considered a hopeless situation. Early engagement and communication among members of an MDT that includes surgeons, medical oncologists, radiation oncologists, and other specialists are needed to combine local ablative and systemic treatment to optimize the chance for a cure (Weiser et al. 2013).

Some limitations of this study should be acknowledged. First, this retrospective study included an uncontrolled methodology and a limited number of patients from a single institution. Therefore, the findings need to be validated in a larger prospective cohort of patients. Second, the short duration of follow-up time was insufficient to evaluate 5-year survival outcomes and exactly determine which patients experienced late disease recurrence. In addition, the impact of chemotherapy on early recurrence was difficult to evaluate in this retrospective study. Moreover, preoperative treatment selectively given to patients with more advanced disease might interfere with its real therapeutic effect. At the same time, the regimen and administration duration of perioperative chemotherapy might be related to the occurrence of early recurrence, which was not analyzed in the current study. Moreover, the data for molecular biomarkers such as KRAS, NRAS, BRAF, and PIK3CA mutations and microsatellite instability (MSI) status were not available for the majority of patients in this study. Thus, future studies should include an evaluation of these molecular biomarkers.

Early recurrence occurred in 16.0% of CLOM patients, even those undergoing curative liver resection, and was identified as the independent predictor of poor prognosis. The risk factors for predicting early recurrence included the presence of a node-positive primary tumor and metastases diameter > 3 cm. Our study results suggest that early recurrence should be investigated in the routine treatment of CLOM patients before liver resection. Detailed preoperative comprehensive measurements might be needed to stratify high-risk patients, and non-surgical treatment for early recurrence might represent an effective alternative.