Liver metastasis is one of the most common metastases of colorectal cancer and a major factor affecting patients’ prognosis. Without treatment, the natural survival of most patients does not exceed 12 months, while the median survival of those who receive systemic chemotherapy is less than 24 months, and the overall 5-year survival rate is less than 8%. It has been found that among patients with liver metastases from colorectal cancer, about 20%-35% of metastases are confined to the liver, and for these patients, complete surgical resection of liver metastases can increase their 5-year survival rate to about 40%, but only 15%-20% of patients are suitable for surgical resection, and nearly 2/3 of patients have recurrent metastases after surgery. Therefore, how to improve the surgical resection rate and how to prolong the disease-free survival after surgery has become one of the focuses of clinical attention.
Colorectal cancer liver metastases can be divided into two categories: resectable and unresectable, but it is difficult to strictly distinguish between the two in clinical practice. At present, it is considered resectable as long as all the lesions visible to the naked eye can be removed, the margins are negative and sufficient liver function can be preserved, and the number and size of metastases are no longer the main factors affecting surgery.
Neoadjuvant chemotherapy
For patients with liver metastases from colorectal cancer, neoadjuvant chemotherapy (i.e. preoperative chemotherapy) may have the following advantages.
(i) It shrinks the tumor, increases the surgical resection rate and reduces the risk of surgery;
② Suggest the sensitivity of chemotherapeutic drugs, and if the postoperative pathology shows necrosis of tumor tissue, it suggests that preoperative chemotherapy is effective, thus providing help for the selection of postoperative chemotherapy regimen;
③Kill micro-metastases and improve the eradication rate.
Resectable liver metastases
In patients with resectable liver metastases, several phase II clinical studies have shown that preoperative neoadjuvant chemotherapy does not increase surgery-related mortality.The EORTC prospective phase III study showed no significant difference in surgical resection rates, no increase in perioperative mortality, and a significant increase in 3-year disease-free survival in patients who received 6 cycles of FOLFOX4 chemotherapy before and after surgery compared with those who received surgery alone ( 42.4% versus 33.2%, P=0.025). This suggests that perioperative chemotherapy may provide a survival advantage for patients with liver metastases from colon cancer.
Nevertheless, neoadjuvant chemotherapy may result in partial or total disappearance of intrahepatic lesions, making it difficult to find the lesions intraoperatively for radical resection. Benoist et al. found that 83% of liver metastases in complete remission (CR) after chemotherapy did not achieve complete pathological remission and were bound to recur within one year, so surgical resection was required for lesions that had achieved CR on imaging, but it was difficult to achieve R0 resection because the lesions had disappeared. It can be seen that neoadjuvant chemotherapy should be stopped when it is appropriate, and surgery can be performed when the conditions for surgery are reached, but clinically it is difficult to grasp this timing, and doctors need to continuously summarize their experience and gradually improve their ability to grasp it.
For patients with liver metastases, the current preference is that neoadjuvant chemotherapy should not exceed 6 cycles. This is because according to clinical experience, the peak of chemotherapeutic efficacy is reached after 5-6 cycles of chemotherapy. If the number of chemotherapy cycles continues to increase, on the one hand, it will affect the patient’s physical condition, and on the other hand, the possibility of tumor progression will also increase. Of course, some scholars believe that chemotherapy will lead to postponement of surgery, and a small number of patients may lose the chance of surgery due to tumor progression during chemotherapy, so it is necessary to review the efficacy periodically. Therefore, regular review and evaluation is necessary. Generally, the evaluation is done once every 2~3 cycles, and if tumor progression is suspected, it should be reviewed at any time to avoid delaying surgery due to ineffective chemotherapy.
Unresectable liver metastases
For patients with inoperable liver metastases, neoadjuvant chemotherapy can shrink or disappear the liver tumor in a significant proportion of patients, transforming it from unresectable to resectable, thus increasing the surgical resection rate.
Most studies have shown that for patients with inoperable resectable liver metastases, the liver resection rate after treatment with oxaliplatin or irinotecan-based chemotherapy regimens reaches 10%-40%, and the 5-year survival rate can reach 30%-40%, confirming that neoadjuvant chemotherapy can improve the surgical resection rate of colorectal cancer liver metastases. However, more than 70% of patients will have intrahepatic recurrence after surgery, and this ratio is significantly higher than those who were resectable at the time of primary treatment. It can be seen that for unresectable liver metastases, neoadjuvant chemotherapy can give some patients a second chance for surgery and prolong survival, but it is difficult to achieve complete cure.
Surgical treatment
Surgical resection is the only treatment for patients with liver metastases from colorectal cancer that may lead to long-term survival. There are two main approaches to surgery for resectable simultaneous liver metastases – simultaneous resection or staged resection.
A 2009 study by Martin et al. concluded that there was no significant difference in the incidence of surgical complications between simultaneous resection of liver metastases and the primary site compared with staged resection, but the length of hospital stay was shorter. There is insufficient evidence to prove the superiority of the two surgical approaches in terms of their impact on patient survival, so the choice of surgical approach needs to be based on the status of the liver metastases (number, size, and distribution of metastases), the patient’s condition (physical status, presence of underlying disease, etc.), and the surgeon’s experience. For patients in whom simultaneous resection is difficult, the primary foci can be removed first, followed by chemotherapy, and then metastases can be resected 2-3 months later.
For heterochronous liver metastases, if they occur during or within a short time after postoperative adjuvant chemotherapy, then neoadjuvant chemotherapy is equivalent to second-line treatment, and the efficiency of second-line treatment for advanced and metastatic colorectal cancer is significantly lower than that of first-line treatment, which is only about 20%, so the possibility of benefiting from neoadjuvant chemotherapy for these patients is significantly reduced, and for such patients, if they can be surgically resected, they can be directly For such patients, if surgical resection is possible, surgical resection can be performed directly.
Postoperative adjuvant chemotherapy
Patients with colorectal cancer liver metastases still face a high risk of recurrence even after radical resection. In 2008, Mitry et al. analyzed two phase III studies and showed that the postoperative adjuvant chemotherapy group had an advantage over the surgery-only group in terms of median progression-free time (PFS, 27.9 months versus 18.8 months) and median overall survival (OS, 62.2 months versus 47.3 months). And multifactorial analysis showed that adjuvant chemotherapy was an independent influencing factor for PFS and OS, affirming the role of adjuvant chemotherapy.
The most commonly used adjuvant chemotherapies include fluorouracil, oxaliplatin, irinotecan, etc. The fluorouracil-based combination regimen is currently the most commonly used chemotherapy regimen. The choice of specific regimen can be based on the efficacy of preoperative neoadjuvant chemotherapy, the patient’s physical condition and genotyping, etc.
Radiofrequency therapy
In recent years, radiofrequency therapy has been more and more widely used in the treatment of liver tumors. In colorectal cancer liver metastases, some studies have concluded that for lesions with a tumor diameter of less than 3 cm, radiofrequency therapy can achieve long-term efficacy similar to that of surgical treatment, and the adverse effects are relatively mild; while for patients with larger tumor diameter, the local recurrence rate after radiofrequency therapy is higher than that of surgery, but still better than that of those without local treatment, suggesting that For patients with small lesions or poor physical condition who can hardly tolerate surgery, radiofrequency therapy is an alternative treatment modality.
With the in-depth research, multidisciplinary comprehensive treatment mainly based on surgery has become the main treatment for colorectal cancer liver metastasis, and this progress has changed the previous concept that malignant tumors lose the chance of surgery once distant metastasis occurs. The adoption of neoadjuvant chemotherapy and adjuvant chemotherapy can shrink the tumor, improve the R0 resection rate and reduce the postoperative recurrence rate, thus prolonging the survival of patients. Before formulating the treatment plan, the patient’s own characteristics and previous treatment history should be fully considered, and multidisciplinary doctors such as surgical oncology, internal medicine and imaging department should work together to develop the best treatment plan for the patient.