I. Epidemiology
Metastatic liver cancer is extremely common in clinical practice. In western countries, the ratio of metastatic liver cancer to primary liver cancer is about 20:1, and in China, the probability of occurrence of both is similar.
Pathophysiology
There are four metastatic pathways.
① Trans-portal vein: it is the most important route of intrahepatic metastasis, which is 7 times more than the other routes causing liver metastasis.
② Transhepatic artery: lung cancer and the cancer embolus formed in the lung can enter the body circulation and form metastasis in the liver via hepatic artery blood flow.
③Translymphatic tract: This route is rare, and gallbladder cancer may extend into the liver along the lymphatic vessels of the gallbladder fossa.
Liver metastatic nodules are usually located on the surface of the liver and vary in size. The central part of the nodule may appear umbilical-like depression due to necrosis. In addition to the nodular type, liver metastases may occasionally present as a diffuse infiltrative type. Most metastases are oligometastatic tumors, and only 4-7% are blood-rich. Calcifications are seen in colorectal cancer, ovary, breast, lung, etc., especially in colorectal mucinous adenocarcinoma.
Gastrointestinal malignancies are the most common primary lesions of liver metastases, and colorectal cancer is the most common among them. Colorectal metastases most often occur within two years after resection of the primary site and are usually asymptomatic; a few patients may have vague pain in the upper abdomen. Although patients with lymph node metastases are more likely to develop liver metastases, liver metastases can occur in all stages of colorectal cancer, and 40-50% of surgically resected colorectal cancer cases eventually develop liver metastases. About 20-25% of new colorectal cancer cases have liver metastasis.
III. Diagnosis
The diagnosis of liver metastasis involves many ancillary tests, including laboratory tests, imaging tests and even laparoscopy. Laboratory tests are mainly used for follow-up monitoring and differentiation from primary liver cancer, as well as to assess the patient’s liver function level and reserve status. Serial testing of carcinoembryonic antigen (CEA) levels in many colorectal cancer patients is effective in detecting tumor recurrence during follow-up.
Confirmation of metastatic hepatocellular carcinoma relies on imaging, with ultrasound, CT, and MRI providing more reliable information. In typical cases, the lesions are often multiple, and CT shows a flat scan with low density, while MR shows a long T1 and long T2 signal, with ring-shaped enhancement in the arterial phase and no enlargement in the portal phase on enhancement scan. Some lesions may show the bull’s-eye sign, i.e., the central hypodense necrotic area of the lesion is surrounded by ring reinforcement, and another ring of hypodensity is seen outside the ring. Pathologically, the ring reinforcement is the tumor tissue, and outside is the compressed hepatocytes and hepatic sinusoids.
After the diagnosis of metastatic hepatocellular carcinoma is made, other related examinations such as gastrointestinal endoscopy, chest CT or positron emission tomography (PET) are needed to find the primary lesion and to confirm the presence of metastasis in other areas to provide the basis for the next treatment.
IV. Treatment
It is generally considered that when liver metastases occur, the disease is already advanced, and chemotherapy is the main form of comprehensive treatment. However, for colorectal liver metastases (CLM), surgery is currently the only possible cure. The operative mortality rate of curative hepatectomy is 1%-2.8% and the 5-year survival rate is 34%-38%, but only 10%-25% of patients with liver metastases from colorectal cancer are suitable for surgical resection when diagnosed.
The treatment of colorectal cancer liver metastases should adhere to the individualized treatment based on standardized treatment. First of all, the classification of CLM should be clarified. European scholars classify CLM into: stage M1a, which means liver metastases are resectable; stage M1b, which means liver metastases are potentially resectable, which means metastases are large, multiple or closely related to large blood vessels, making direct resection difficult. The 2009 edition of the NCCN guidelines also classifies unresectable liver metastases as potentially resectable or unresectable. For resectable liver metastases, the goal of treatment is to prolong TTP and OS through a combination of therapies; the key to potentially resectable is translational therapy to convert some of them to resectable.
Indications for surgical resection.
(1) Complete resection of the primary colorectal cancer (Ro).
(2) According to the anatomical basis of the liver and the scope of the lesion, the liver metastases can be completely resected. And sufficient liver function is required to be preserved. The residual volume of the liver is greater than or equal to 30% (heterochronic liver metastases) or 50% (simultaneous resection of liver metastases and colorectal primary foci for simultaneous liver metastases).
(3) The patient’s general condition such as cardiopulmonary function allows, and there are no unresectable extrahepatic lesions.
Contraindications include.
(1) Insufficient postoperative residual liver volume.
(2) Inability to obtain R0 resection of the primary colorectal cancer site.
(3) The patient’s physical condition, such as cardiopulmonary function, cannot tolerate surgery.
(4) The presence of extensive extrahepatic metastases.
Several common important issues of surgical resection.
1, the issue of cutting edge: At present, it is believed that as long as the cutting edge is guaranteed to be negative, it does not need to be 1 cm away from the tumor.
There is no clear correlation between the number of tumors and resectability. As long as sufficient liver function can be preserved, the number and location of tumors do not affect resectability.
3.Whether resectable liver metastases are treated with neoadjuvant chemotherapy: EORTC 40983 trial proved that neoadjuvant chemotherapy can reduce postoperative recurrence and prolong disease-free survival.
4.Simultaneous and staged resection of concurrent liver metastases: There is no definite conclusion, and NCCN guidelines consider both as optional modalities. The advantage of simultaneous resection is to complete the surgery in one stage and avoid the psychological and physical burden of secondary surgery: the disadvantage is that the risk of surgery is significantly increased. Concurrent resection should be performed first for liver metastases and then for the primary site, which is more consistent with the principles of asepsis and anaplasia. Staged resection, on the other hand, is suitable for those whose primary and metastatic foci are not in the same surgical area, and for those who are elderly and have comorbidities.
The role of chemotherapy in the treatment of CLM is reflected in several aspects, neoadjuvant and postoperative adjuvant therapy for resectable CLM, conversion therapy for potentially resectable CLM, and palliative therapy for unresectable CLM.
Several important issues related to chemotherapy.
1, translational therapy regimen for potentially resectable CLM, for patients with K-ras wild type take FOLFOX or FOLFIRI or FOLFOXIRI combined with targeted therapy as far as possible, through translational therapy, it is possible to convert 10% unresectable CLM to resectable.
2. Timing of surgery after neoadjuvant therapy: liver metastases can be operated when they shrink to resectable, and resectability can be assessed at least once every 2 months during chemotherapy.
3. Complete remission on imaging after neoadjuvant chemotherapy does not mean complete remission of pathology. Surgical resection is still necessary for this group of patients.
The other part of patients who are still unresectable are suitable for palliative treatment by various modalities including systemic intravenous chemotherapy, mediator therapy and local treatment of liver metastases (radiofrequency ablation, laser ablation, anhydrous alcohol injection and cryosurgery).