Compare of Sequential, Delayed and Simultaneous Resection Strategies for Synchronous Colorectal Liver Metastases


 Background: The present study aimed to compare perioperative safety and long-term survival of patients with synchronous colorectal liver metastases receiving sequential resection (SeR), delayed resection (DeR) and simultaneous resection (SiR).
Methods: From January 2007 to December 2016, data of patients receiving surgery at Peking University Cancer Hospital for synchronous colorectal liver metastases were retrospectively collected. The above three different surgical strategies were compared.
Results: A total of 233 cases were included, with 49 in the SeR group, 98 in the DeR group and 86 in the SiR group. The incidence of severe complications was 26.7% in the SiR group, higher than that in the DeR group (11.2%, p=0.007) and the SeR group (16.3%, p=0.166). Overall survival at 1-year and 3-year in the SeR group (93.9% and 50.1%) was lower than the DeR group (94.9% and 64.8%, p=0.019), but not statistically different compared with the SiR group (93.0% and 55.2%, p=0.378). Recurrence-free survival at 1-year and 3-year in the SeR group (22.4% and 18.4%) was lower than the DeR group (43.9% and 24.2%, p=0.033), but not statistically different compared with the SiR group (31.4% and 19.6%, p=0.275). Cox multivariate analysis indicated that T4, lymph node positive primary tumor, liver metastases>30mm and selective sequential resection (compared with delayed resection) were correlated with poor prognosis. 
Conclusion: Simultaneous resection has a relatively higher incidence of severe complication, and when staged resection strategy was made, the prognosis of delayed resection was better than that of sequential resection.


Background
Liver is the most common target organ of metastases from colorectal cancer. Almost 50% of the colorectal patients will develop liver metastases during the course, and 15-25% of the patients already have liver metastases upon diagnosis of primary colorectal cancer (synchronous liver metastases) [1,2].
Surgery is still the best treatment to achieve long-term survival or even cure in patients with colorectal liver metastases, and the 5-year survival after surgery is about 30-50% [3,4].
Compared with metachronous liver metastases, synchronous liver metastases usually have poorer biological behaviors and the treatment is also more complicated. Moreover, surgery for synchronous liver metastases has to deal with both primary and metastatic lesions, and can be divided into two major categories, simultaneous and staged resection. Generally, a higher proportion of patients receive selective staged resection of colorectal cancer and liver metastases [5,6]. Along with the progress in surgical technique, the proportion of patients receiving simultaneous resection increases over time [7,8]. However, simultaneous resection causes surgical trauma at two sites at the same time, which may increase the risk (e.g., intraperitoneal infection, anastomotic stula and hepatic insu ciency). As a result, the incidence of complications and mortality are higher for simultaneous resection than staged resection [9,10]. So, not all patients are t for simultaneous resection, and staged resection remains an important choice.
Conventionally, the primary colorectal cancer lesion is rst resected, and then the liver metastases. Later the "liver rst" surgical strategy appeared [11], that is, the liver metastasis is rst resected, and then the primary colorectal cancer lesion. But whatever the strategy, chemotherapy between two surgeries is selective and not mandatory [12][13][14], for fear of chemotherapy-associated liver injury and the missing of best timing for surgery due to post-chemotherapy progression. Nowadays, more and more patients start chemotherapy before the resection of primary colorectal cancer and liver metastases [15]. However, for selective staged resection, especially those who have received initial chemotherapy, no consensus has been reached as to whether rst-stage surgery should be sequentially followed by second-stage surgery or by interval chemotherapy then second-stage surgery. Comparisons of the safety and long-term survival bene ts between these two strategies and simultaneous resection are still unknown.
The purpose of the present study was to compare perioperative safety and long-term survival of three different strategies, namely, selective sequential resection, delayed resection or simultaneous resection in colorectal cancer with synchronous liver metastases.

Study design, selection of patients and grouping
From January 2007 to December 2016, patients receiving surgery at the department of hepatobiliary surgery at Peking University Cancer Hospital for colorectal cancer with synchronous liver metastases were retrospectively collected and reviewed. Synchronous liver metastasis was de ned as the occurrence of liver metastases synchronous with or before the con rmed diagnosis of colorectal cancer. Inclusion criteria: resection of primary colorectal cancer and liver metastases was performed with curative intent, and the patients completed the treatment; the combined extrahepatic metastases were also resected. Among patients with initially unresectable colorectal liver metastases, those who did not receive secondstage surgery due to failed conversional chemotherapy after the rst-stage surgery were thus excluded.
The treatment strategy was determined based on multidisciplinary discussion attended by colorectal surgeons, hepatic surgeons, medical oncologists, radiation oncologist and radiologists. The informed consent was obtained from the patients before the treatment began. The patients were divided into three groups based on surgical treatment strategies: sequential resection (SeR, sequential staged resection of colorectal cancer and liver metastases, without interval chemotherapy); delayed resection (DeR, staged resection of colorectal cancer and liver metastases, with interval chemotherapy); simultaneous resection (SiR, one-stage resection of primary colorectal cancer and liver metastases simultaneously). Simultaneous resection is more often used in patients that the tumor disease burden is not heavy, or the primary lesion is located in the right colon with heavy tumor burden but can be resected through one incision. Staged resection is mainly used in patients with severe symptoms of the primary lesion, or with heavy tumor burden, or with tumors located in the rectum requiring preoperative radiochemotherapy. After the rst surgery, patients with resectable liver metastases were treated with sequential resection or neoadjuvant chemotherapy, and patients with unresectable liver metastases were treated with conversional chemotherapy, then evaluated for the next surgery.
The protocol was approved by the ethics committee of Peking University Cancer Hospital and con rmed to the Declaration of Helsinki. The informed consent was harvested from all patients.

Initial assessment
Before initial treatment, all patients received contrast-enhanced MRI of the liver, contrast-enhanced CT of the abdominopelvic cavity or contrast-enhanced MRI of the pelvic cavity (only for rectal cancer patients) and plain CT scan of the chest. If the primary colorectal cancer had already been resected at other centers, the operation note, pathology report and postoperative complications were kept and recorded in details. Radiological assessment was performed to exclude any signs of residual lesions.

Surgery
The tumor number and position were determined by preoperative imaging, intraoperative ultrasound and palpation. The resected scope of liver was determined based on the tumor number and position. For lesions that were located deep in the liver parenchyma and smaller than 2cm in diameter, combined radiofrequency ablation was selectively performed to avoid excessive loss of liver volume. The liver resection margin was usually larger than 5mm, and the margin of 1mm (R1 margin status) for some lesions was acceptable as long as the chemotherapy was effective. Major liver resection was de ned as the resection of 3 hepatic segments and above.

Perioperative chemotherapy
Based on the consensus, initial chemotherapy was usually recommended for patients with asymptomatic primary lesions in our center, except for patients' refusal. Systemic chemotherapy regimens were oxaliplatin and/or irinotecan based regimens in combination with uorouracil and leucovorin (folfox/fol ri/folfoxiri). Combined molecular targeted agents were selectively used according to the resectability of liver metastases and clinical risk scores. Assessment was performed after 2 or 4 cycles of initial chemotherapy, and those t for surgery received surgery as soon as possible. For advanced middle and low rectal cancer (T3/T4 and/or N+), combined radiotherapy was given based on local staging. For staged resection, the chemotherapy regimen given between two surgeries was usually the same as the initial chemotherapy, or folfox/capox/fol ri plus or not molecular targeted agents in the absence of initial chemotherapy. Adjuvant chemotherapy was recommended regularly if the patients' conditions allowed after surgery.

Perioperative safety
Postoperative complications were assessed by Clavien-Dindo grading system [18]. For staged resection, overall incidence of complications was the sum of incidence of complications after two surgeries, and the highest grade of complications after either surgery was taken as the nal grade of complications. Severe complications were de ned as those of Clavien-Dindo grade 3 or above.

Postoperative follow-up and survival analysis
Radiological assessment was given within 1 month after resection of both colorectal cancer and liver metastases. Later the patients received reexaminations once every 3 months. Overall survival (OS) was de ned as the interval from the start of the initial treatment (surgery or chemotherapy) to the last followup or death. Recurrence-free survival (RFS) was de ned as the interval from resection of both colorectal cancer and liver metastases to the time of the rst recurrence. The time of the last follow-up was December 2018 for all cases.

Statistical analysis
Statistical analysis was performed using SPSS 22.0 software. Continuous variables were described by ranges, and intergroup comparisons were conducted using t-test or U test. Categorical variables were expressed as frequencies or percentages. Intragroup comparisons were performed by using chi-square test. Kaplan-Meier survival analysis was performed, and the survival curves were compared by using the log-rank test. Univariate and multivariate analyses were performed using Cox model to identify the prognostic factors. P<0.05 indicated signi cant difference.

Comparison of baseline data between the three groups
A total of 233 consecutive cases conformed to the inclusion criteria, with 49 cases in the SeR group, 98 cases in the DeR group and 86 cases in the SiR group. The comparison of baseline data between the three groups is shown in Table 1. In the SeR group, the proportion of patients with primary lesions in the rectum was signi cantly higher than that of the other two groups (P<0.05). Moreover, the median number of liver metastases in the SiR group was lower than that in the SeR group (P=0.011). Besides, the three groups of patients showed no signi cant difference in gender, age, T stage and N stage of primary lesions, diameter of liver metastatic lesions, or distribution in single or double lobes. The proportion of combined extrahepatic metastases was low in all groups, and there was no signi cant difference among the three groups.
2. Comparison of chemotherapy regimen, surgical strategies and postoperative complications between the three groups The comparison of chemotherapy regimen and surgical strategies among the three groups is shown in Table 2. Compared with the DeR group, a higher proportion of patients received initial chemotherapy in the SeR and SiR groups (P<0.05). It was as high as 83.7% in the SeR group. In addition, the proportion of patients receiving initial chemotherapy with molecular targeted agents was also higher in the SeR group (P<0.05). In the DeR group, the median number of chemotherapy cycles between the two surgeries was 4 (1, 25), and the median interval was 20.7 (10.1, 77.2) week. In the SeR group, the median interval was 5.7 (3.4, 14) week between the two surgeries. There was no signi cant difference in the proportion of patients receiving adjuvant chemotherapy among the three groups. Except for the higher proportion of portal occlusion in the SeR group, the three groups showed no signi cant difference in the use of extensive liver resection and combined radiofrequency ablation, intraoperative blood loss and postoperative status of resection margin.
As to postoperative safety, the perioperative mortality was 0 in all groups. The incidence of overall complications was 48.8% in the SiR group, higher than that in the DeR group (31.6%, p=0.017) and the SeR group (40.8%, p=0.369). The incidence of severe postoperative complications was 26.7% in the SiR group, which was higher than that of the DeR group (11.2%, p=0.007), and also higher but not signi cantly than that of the SeR group (16.3%, p=0.166). The SeR group and DeR group showed no signi cant difference in the overall incidence of postoperative complications and incidence of severe complications.

Survival analysis
There was no signi cant difference in the median OS (45 vs. 43 months, p=0.887) and RFS (9 vs. 8 months, p=0.714) between patients receiving simultaneous resection and staged resection (Fig. 1) Table 3). The results showed that T stage and N stage of primary lesions, diameter of liver metastatic lesions, resection strategies and adjuvant chemotherapy were correlated with OS. Other imbalanced factors in baseline and treatment such as position of primary lesions, number of liver metastases, whether receiving initial chemotherapy or not, or the use of molecular target drugs did not affect OS. Cox multivariate analysis indicated that T4, lymph node positive primary tumor, tumor size>30mm and selective sequential resection (relative to delayed resection) were correlated with poor prognosis (Table  4).

Discussion
Treatment of colorectal cancer with synchronous liver metastases requires resection of both colorectal cancer and liver metastases. Symptoms and position of primary lesions and the resectability of liver metastases must be taken into consideration. In addition, whether and when radiotherapy should be given are also needs to be considered for advanced middle and low rectal cancer. So, there is no uniform standard for clinical treatment of colorectal cancer with synchronous liver metastases.
Whether simultaneous resection is equally safe as staged resection is a topic of dispute [19]. Along with the progress in surgical technology, selective simultaneous resection is increasingly applied. It has been reported that simultaneous resection does not necessarily increase postoperative complications compared with staged resection [20]. However, it should be noted that most of the patients who underwent simultaneous resection were screened for the location of the primary lesion and/or the extent and di culty of hepatic metastasis resection, especially for those requiring extensive liver resection and/or Miles surgery for rectal cancer [21,22]. There are no prospective randomized controlled studies to answer this question de nitely. Upon the rst visit, the treatment center and expertise of physicians in the treatment of liver metastases vary and the coordination between colorectal and hepatic surgeons is usually needed for simultaneous resection. For this reason, not all patients will be chosen for simultaneous resection. In our retrospective study, patient screening was also performed to ensure postoperative safety and recovery, and selection bias did exist. However, the results showed that after screening, the overall incidence of postoperative complications and incidence of severe complications were still higher in patients receiving simultaneous resection than those receiving staged resection.
Apparently, if all patients received simultaneous dissection without screening and discrimination, more severe complications or even perioperative death might have occurred. Therefore, the staged resection strategy does have the bene ts of avoiding superimposition of complications and severe complications.
In this study, OS and RFS of patients receiving simultaneous resection and staged resection did not differ signi cantly, and OS was superior to that reported in those receiving palliative chemotherapy. This indicated that either strategy is reasonable and effective. As not all patients are t for simultaneous resection, staged resection remains a favorable choice. Generally, in staged resection, the primary colorectal cancer is rst resected, followed by 2-3 cycles of chemotherapy. Resection of liver metastases will be performed after liver metastases are stabilized. The "liver rst" strategy also appears latter. But whatever the strategy, whether chemotherapy should be given between two surgeries is still debated. A published international expert consensus [15] pointed out that for colorectal cancer with synchronous liver metastases without acute symptoms related to the primary lesions, systemic chemotherapy is recommended as the preferred choice. At present, more and more patients receive chemotherapy before the resection of either primary colorectal cancer or liver metastases. For those who have already received chemotherapy and are scheduled for staged resection, whether chemotherapy should be given between the two surgeries is our major concern. In the present study, most of the patients in SeR (41/49) had received initial chemotherapy and some were even treated by molecular target agents. Patients who did not receive initial chemotherapy were those who had no heavy tumor burden and poor tolerance or refused initial chemotherapy. However, survival analysis indicated that the median OS of patients receiving sequential resection was lower compared to those receiving delayed resection. Much to our surprise, according to multivariate survival analysis, whether receiving initial chemotherapy or not did not affect OS, while chemotherapy between the two surgeries was an independent risk factor. In baseline comparison, SeR group had the highest proportion of patients with rectal cancer. This is because middle and low rectal cancer usually needs to be treated by synchronous radiotherapy and the interval between the end of radiotherapy and rectal surgery is 6-8 weeks [23,24]. For these patients, the strategy of rststage resection of liver metastases and second-stage resection of primary rectal cancer can be adopted. If chemotherapy is given between the two surgeries, the waiting time may be too long for second-stage resection. Edema caused by radiotherapy may make the resection of rectal cancer very di cult, and sequential resection seems to be the only choice left. However, multivariate survival analysis using Cox model indicated that the position of primary tumors did not affect OS either. Although there were some imbalanced factors in baseline and treatment regimen between the two groups, the median OS of the SeR group was still lower than that of DeR group after the correction of biased factors. Another major worry is that whether the tumor will progress after the rst-stage surgery as chemotherapy is given instead of immediate second-stage surgery, which makes further surgery impossible. In the present study, after excluding the patients with initially unresectable tumors and failed to conversion therapy, only 2 patients in the DeR group progressed during chemotherapy between the two surgeries, which made second-stage surgery impossible (2/100). Therefore, there is no need to be too worried about tumor progression. We believe that no matter whether initial chemotherapy is given or not, it is preferable to add chemotherapy after the rst-stage surgery in selective staged resection. Although it may increase the risk of chemotherapy-associated liver injury, cautious evaluation indicates that the risk is controllable for the second-stage surgery and the incidence of postoperative complications does not increase.
The survival bene ts of delayed resection were higher than those of sequential resection, probably because of the following advantages of chemotherapy between the two surgeries: (1) In ammation caused by the rst-stage surgery may promote the spread of tumor cells [25], and chemotherapy between the two surgeries can control potential micro-metastases; (2) chemotherapy can cause further shrinkage and necrosis of tumors, thus achieving tumor regression[26] and improving the prognosis; (3) The patients are screened based on biological behavior[27, 28] and observed for some time after chemotherapy to determine the best timing for second-stage surgery after the lesions are stabilized. This is conducive to avoid early postoperative recurrence. Poor prognosis of patient receiving sequential resection may be also attributed to the longer interval between the resection of primary colorectal cancer and liver metastases. The resection of either primary colorectal cancer or liver metastases is highly traumatic. It usually takes about 3 to 4 week before the patients' physical strength is improved for the next surgery. However, the patients may need to wait for the arrangement of the next surgery without chemotherapy protection.
Since the present study adopted a retrospective design, there was the problem of mismatch of baseline information. Given the difference in physical status, local symptoms of primary lesions, referral system and levels of the rst visit center, not all patients can receive treatment based on high-level multidisciplinary team (MDT) decisions. Therefore, there is no uniform standard for the choice of initial treatment. Moreover, a small sample size would also in uence the results. In the future, prospective randomized controlled study will be performed to obtain more reliable conclusions.

Conclusions
Simultaneous resection has a relatively higher incidence of severe complication, and when staged resection strategy was made, the prognosis of delayed resection was better than that of sequential resection.
Abbreviations CRLM: Colorectal liver metastases; SeR: sequential staged resection of colorectal cancer and liver metastases, without interval chemotherapy; DeR: staged resection of colorectal cancer and liver metastases, with interval chemotherapy);SiR: one-stage resection of primary colorectal cancer and liver metastases simultaneously; CI: Con dence interval; OS: Overall survival; RFS: Recurrence free survival; MDT: multidisciplinary team.