Liver is the main target organ of colorectal cancer hematogenous metastasis, and liver metastasis is one of the key points and difficulties in the treatment of colorectal cancer. About 15%-25% of colorectal cancer patients have liver metastases at the time of diagnosis, and another 15%-25% of patients will have liver metastases after radical resection of the primary colorectal cancer site, and the majority (80%-90%) of these liver metastases cannot be radically resected. Liver metastases from colorectal cancer are also the leading cause of death in patients with colorectal cancer [1]. The median survival of patients with unresectable liver metastases is only 6.9 months, with a 5-year survival rate close to 0%, while the median survival of patients with radical resection of liver metastases is 35 months, with a 5-year survival rate of 30% to 50% [10-14]. Studies have shown that a proportion of patients with initially unresectable liver metastases can become resectable lesions after treatment [8]. Therefore, active and comprehensive treatment through multidisciplinary team (MDT) is expected to prevent the occurrence of colorectal cancer liver metastases, improve the surgical resection rate of liver metastases and the 5-year survival rate after surgery.
I. Diagnosis of colorectal cancer liver metastasis
(A) Definition of colorectal cancer liver metastasis
According to the international common classification method: Synchronous liver metastases are liver metastases found when colorectal cancer is diagnosed or occurring within 6 months after radical resection of the primary site of colorectal cancer; while liver metastases occurring after 6 months of radical resection of colorectal cancer are called metachronous liver metastases.
Since there are significant differences in the diagnosis and treatment of liver metastases at the time of diagnosis of colorectal cancer and liver metastases after radical resection of the primary site of colorectal cancer, this guideline is divided into two aspects: “liver metastases at the time of diagnosis of colorectal cancer” and “liver metastases after radical resection of colorectal cancer”. Therefore, this guideline is based on two aspects: “combined liver metastasis at diagnosis of colorectal cancer” and “liver metastasis after radical colorectal cancer surgery”.
(2) Diagnostic routine of liver metastasis at diagnosis of colorectal cancer
For patients with confirmed colorectal cancer, in addition to serum CEA and CA19-9 examination and pathological staging, liver ultrasound and/or enhanced CT imaging should be routinely performed to understand the occurrence of liver metastasis, and for patients suspected of liver metastasis, serum AFP and liver MRI can be added [17-18] (Class 1a evidence, Grade A recommendation). but may be used as appropriate when the condition warrants [19-20] (Class 2a evidence, Level B recommendation). Percutaneous needle biopsy of hepatic metastases should be used only when indicated (Class 4 evidence, Level C recommendation) [21].
The liver must be routinely explored during surgery for colorectal cancer to further exclude the possibility of liver metastases [22]. Intraoperative biopsy may be considered for suspicious liver nodules (Class 3a evidence, Grade B recommendation).
(iii) Follow-up after radical surgery for primary colorectal cancer
After radical surgery for colorectal cancer, patients should be followed up closely to understand the occurrence of liver metastasis.
1.History inquiry, physical examination and liver ultrasound examination should be conducted once every 3-6 months for 2 years, and then once every 6 months until 5 years.
2, Depending on the elevation of preoperative tumor markers, appropriate tumor markers such as CEA were tested every 3-6 months for 2 years and every 6 months thereafter until the completion of 5 years [23] (Class 1a evidence, Level A recommendation).
3, Patients with stage II and III colorectal cancer are recommended to have 1 thoracic/abdominal/pelvic enhancement CT scan every year for 3 to 5 years [24] (Class 1b evidence, Level A recommendation). Patients with suspected liver metastases should undergo additional MRI, and PET-CT scans are not routinely recommended.
4, e-colonoscopy should be performed within 1 year after surgery, and if abnormalities are found, they need to be reviewed within 1 year; otherwise, they should be reviewed within 3 years and every 5 years thereafter. If the patient’s age of onset is less than 50 years old, the frequency of e-colonoscopy should be increased appropriately. For patients who cannot undergo total colonoscopic colonization before radical colorectal cancer surgery due to obstruction or other reasons, the first e-colonoscopy should be completed within 3-6 months after surgery [25] (Class 1a evidence, Level A recommendation).
(iv) Follow-up after complete resection of liver metastases from colorectal cancer
After complete resection (R0) of liver metastases from colorectal cancer, patients should also be closely followed up to understand whether there is recurrence of liver metastases.
1.According to the elevation of preoperative tumor markers, it is recommended to follow up serum CEA and other appropriate tumor markers every 3 months for 2 years after surgery, and every 6 months for the next 3-5 years.
2, Thorax/abdomen/pelvis-enhanced CT scan every 3-6 months for 2 years after surgery and every 6-12 months thereafter for 5-7 years [24] (Class 1a evidence, Grade A recommendation).
3, Other follow-up contents and frequency were performed with reference to the follow-up after radical surgery of primary colorectal cancer.
II. Treatment of colorectal cancer liver metastases
(I) Radical resection of primary colorectal cancer
Radical surgery is by far the most effective cure for colorectal cancer [26]. It is also an important part of preventing the occurrence of liver metastasis.
The scope of radical surgery for colorectal cancer includes all the tumor and its two adequate intestinal segments and the surrounding tissues and organs that may be infiltrated, as well as the related membranes, main supply vessels and lymphatic drainage areas, and the specific surgery varies according to the tumor site.
2.The scope of radical surgery for rectal cancer should include all of the tumor, sufficient intestinal segments at both ends, surrounding tissues and organs that may be infiltrated, as well as the related mesentery and lymph nodes. Total mesorectal excision (TME) should be followed for tumors in the middle and lower rectum.
3. Intraoperative biopsy or resection should be performed if suspicious lymph nodes outside the resection area are found.
(2) Neoadjuvant treatment for colorectal cancer without liver metastasis at the time of diagnosis
Preoperative neoadjuvant therapy to kill microscopic metastases that cannot be detected by imaging can minimize distant metastases after radical surgery [27-28].
1. neoadjuvant treatment for low and middle-grade rectal cancer (Note: for high-grade rectal cancer, i.e., those whose lower edge of the tumor is more than 12 cm from the anal verge, its treatment is referred to colon cancer.)
(1) Combined radiotherapy or radiotherapy: rectum is an inter-peritoneal organ with relatively fixed location and narrow surrounding space, so radiotherapy can act on tumor tissues with less damage to surrounding normal tissues. It is recommended for rectal cancer with preoperative diagnosis of stage T3 and above or any T or lymph node positive, if it is not accompanied by bleeding, obstruction or perforation [29-32].
Combined radiotherapy: radiotherapy with a total dose of 45-54 Gy at a conventional split dose (usually 5 d per week for 5 weeks) and the application of chemotherapy based on 5-FU or capecitabine. Radical surgery for rectal cancer was performed 4 to 8 weeks after the end of radiotherapy treatment [31,33] (Class 1c evidence, Grade B recommendation). The combination of preoperative radiotherapy and chemotherapy can provide a better therapeutic effect by using the advantages of each. Radiotherapy works locally to reduce the tumor stage or even remission, while chemotherapy can kill the “micrometastases” preoperatively to prevent distant metastases. Preoperative radiotherapy can make TME surgery easier to perform, reduce the chance of distant metastasis, and achieve a better prognosis: for stage II rectal cancer patients with local infiltration, it can reduce T-stage, and for stage III patients, it can not only reduce T-stage, but also act on local lymph nodes to reduce N-stage [32,34-36].
Radiotherapy: short-course (5 d) radiotherapy with a total dose of 25 Gy at the tumor site and lymphatic drainage area of rectal cancer can also be considered [32,37-39], and radical surgery can be performed 1-7 d after radiotherapy. However, short-course radiotherapy cannot be downgraded and will also increase the difficulty of surgical operation and the chance of anastomotic leakage, which should be taken seriously [40] (Class 2b evidence, Level B recommendation).
(2) Combined perfusion chemotherapy in the hepatic artery and the regional tumor artery: preoperative stage III or above, without bleeding, obstruction or perforation, can be considered in units where available. 5-FU or 5-FU precursor drugs or combined with oxaliplatin are perfused via the hepatic artery and the regional tumor artery respectively, and radical resection is performed 7-10 d after chemotherapy. Preliminary results from current clinical trials have shown that this regimen is helpful in preventing liver metastases, although it does not significantly reduce the stage [41]. It can be followed in clinical studies and is not routinely recommended.
(3) Systemic chemotherapy: preoperative chemotherapy can also be applied in patients judged to be stage III preoperatively, if there is no bleeding, obstruction or perforation [28]. The available regimens are FOLFOX, capecitabine alone or 5-FU/LV, but there is no clear evidence-based medical evidence and it is not routinely recommended.
2.Neoadjuvant therapy for colon cancer
Neoadjuvant treatment for colorectal cancer has no clear evidence-based medical evidence and is not routinely recommended. Preoperative systemic chemotherapy, combined perfusion chemotherapy of hepatic artery and regional tumor artery should be further studied clinically.
(iii) Intraoperative portal vein chemotherapy and intraperitoneal chemotherapy for patients with metastasis-free colorectal cancer
The efficacy of this treatment plan lacks evidence-based medical data, so it is not recommended as a conventional means, and clinical research can be concerned.
(IV) Adjuvant therapy for patients with metastasis-free colorectal cancer after radical surgery
1. postoperative adjuvant chemotherapy can prolong 5-year disease-free survival and overall survival for patients with stage III or higher colon cancer, T3 or higher or any T, lymph node positive rectal cancer [42-43]. Therefore, patients with the above colorectal cancer should undergo 6 months of adjuvant chemotherapy after surgical treatment with the following treatment options: FOLFOX, CapeOX, 5-FU/LV, or capecitabine alone [43-46] (Class 1a evidence, Level A recommendation).
In stage II patients without risk factors for metastasis, postoperative adjuvant chemotherapy has not seen significant results in many clinical studies, so clinical observation and follow-up are recommended [47] (Class 1b evidence, Level A recommendation). However, adjuvant chemotherapy should be given to high-risk stage II patients (T4, poor tissue differentiation, peritumor lymphovascular nerve invasion, intestinal obstruction, or T3 with local perforation, indeterminate or positive cut margins, and fewer than 12 lymph node biopsies) with the same regimen as for stage III patients [43,48] (Class 2a evidence, Level B recommendation).
2, Patients with T3 and above and any T, lymph node positive low to intermediate rectal cancer who have not undergone radiotherapy preoperatively, postoperative adjuvant radiotherapy can improve 3-year disease-free survival and reduce local recurrence rate [49-50], but there are limited studies on whether it can reduce colorectal liver metastases, and the combination with adjuvant chemotherapy needs to be validated in more clinical trials. Patients who have received preoperative radiotherapy or combined radiotherapy should also receive adjuvant therapy postoperatively.