The treatment of colorectal cancer with synchronous liver metastases requires resection of both the colorectal cancer and liver metastases. The symptoms and position of the primary lesion and resectability of the liver metastases must be taken into consideration. In addition, whether and when radiotherapy should be administered need to be considered for advanced middle and low rectal cancer. Therefore, there are no uniform standards for the clinical treatment of colorectal cancer with synchronous liver metastases.
Whether simultaneous resection is equally as safe as staged resection is a matter of debate. Along with the progression of surgical technology, selective simultaneous resection is becoming increasingly applied. It has been reported that simultaneous resection does not necessarily increase the incidence of postoperative complications compared with staged resection. 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 difficulty of hepatic metastasis resection, especially those requiring extensive liver resection and/or Miles surgery for rectal cancer[22, 23]. There have been no prospective, randomized, controlled studies to answer this question definitely. At the first visit, the treatment centre and expertise of physicians in the treatment of liver metastases vary, and 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 show that after screening, the overall incidence of postoperative complications and the incidence of severe complications were still higher in patients undergoing simultaneous resection than those undergoing staged resection. Apparently, if all patients underwent simultaneous dissection without screening and discrimination, more severe complications or even perioperative death might have occurred. Therefore, the staged resection strategy does have the benefit of avoiding the superposition of complications and severe complications.
Typically, patients with synchronous colorectal liver metastases are treated with initial primary colorectal cancer resection followed by 2-3 months of chemotherapy. After which, resection of the liver metastases will be performed only for those patients without interval disease progression. A previous review pointed out that this paradigm should be reconsidered since it may be not suitable for all patients. Several studies showed that there was no significant difference regarding survival between patients receiving simultaneous resections and staged resections[10, 25]. This was also identified in a recent study. In this study, the OS and RFS of patients undergoing simultaneous resection and staged resection did not differ significantly, and the OS was superior to that reported in those receiving palliative chemotherapy. This indicates that either strategy is reasonable and effective. However, not all patients are fit for simultaneous resection concerning the safety of simultaneous colorectal resection and major hepatic resection we mentioned above. Therefore, a staged resection strategy remains an important choice. For the staged resection, the traditional procedure is to remove the primary colorectal cancer first, and then liver metastasis will be resected in a second surgery. Nowadays, the emergence of the new “liver first” strategy appears without comprising survival results. However, regardless of the strategy, whether chemotherapy should be administered between the two sequential surgeries is under debate. The survival results of patients receiving delayed resection strategy have been reported in a few studies[14, 27]. However, the sample sizes were relatively small, and the survival of patients receiving delayed resection compared to sequential resection were not involved. So, this still needs to be investigated further. A published international expert consensus noted that for colorectal cancer with synchronous liver metastases without acute symptoms related to the primary lesion, systemic chemotherapy is recommended as the preferred choice. At present, an increasing number of patients receive chemotherapy before resection of either the 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 group (41/49) had received initial chemotherapy, and some were even treated by molecularly targeted agents. Patients who did not receive initial chemotherapy were those who had no heavy tumour burden and a poor tolerance or refused initial chemotherapy. However, the survival analysis indicated that the median OS of patients undergoing sequential resection was lower than that of those undergoing delayed resection. Much to our surprise, according to the multivariate survival analysis, whether initial chemotherapy was administered did not affect OS, while chemotherapy administered between the two surgeries was an independent risk factor. In the baseline comparison, the 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 [28, 29]. For these patients, the staged strategy of resected liver metastases first and the primary rectal cancer second can be adopted. If chemotherapy is given between the two surgeries, the waiting period may be too long for second-stage resection. Oedema caused by radiotherapy may make resection of the rectal cancer very difficult, and sequential resection seems to be the only choice left. However, multivariate survival analysis using the Cox model indicated that the position of the primary tumour did not affect OS either. Although there were some imbalanced factors in the baseline data and treatment regimens between the two groups, the median OS in the SeR group was still lower than that in the DeR group after correcting for biasing factors. Another major concern is whether the tumour will progress after the first-stage surgery with the administration of chemotherapy instead of immediate second-stage surgery, which makes further surgery impossible. In the present study, after excluding patients with an initially unresectable tumour or failed to conversion chemotherapy, 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 for excessive concern regarding tumour progression. We believe that regardless of whether initial chemotherapy is administered, it is preferable to add chemotherapy after the first-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 second-stage surgery and that the incidence of postoperative complications does not increase.
The survival benefits of delayed resection were higher than those of sequential resection, probably because of the following advantages of administering chemotherapy between the two surgeries: (1) the inflammation caused by the first-stage surgery may promote the spread of tumour cells, and chemotherapy between the two surgeries can control potential micro-metastases; (2) chemotherapy can cause further shrinkage and necrosis of the tumour, thus achieving tumour regression and improving the prognosis; (3) patients are screened based on biological behaviour[32, 33] and observed for some time after chemotherapy to determine the best timing for second-stage surgery after the lesion stabilizes. This is conducive to avoiding early postoperative recurrence. The poor prognosis of patients undergoing sequential resection may also be attributed to the longer interval between resection of the primary colorectal cancer and liver metastases. Resection of either the primary colorectal cancer or liver metastases is highly traumatic. It usually takes approximately 3 to 4 weeks before the patient’s physical strength is sufficiently improved for the next surgery. However, the patient may need to wait for the arrangement of the next surgery without the protection of chemotherapy. Since the present study adopted a retrospective design, there was the problem of mismatching baseline information. Given differences in the physical status, local symptoms due to the primary lesion, referral system and level of the first visited centre, not all patients could receive treatment based on high-level multidisciplinary team (MDT) decisions. Therefore, there were no uniform standards for the choice of initial treatment. In addition, some patients were treated in the Department of Medical Oncology or in other centres, so complete, detailed records of specific adverse events or chemotherapy-induced liver injury pathological scores cannot be obtained. Moreover, the small sample size would influence the results. In the future, a prospective, randomized, controlled study will be performed to obtain more reliable conclusions.