Liver metastases from colorectal cancer are common in clinical practice. About 25% of patients with stage IV colorectal cancer have concurrent liver metastases, and about 50% of patients will eventually develop liver metastases. 85% of patients with liver metastases are considered unresectable at the time of diagnosis, and the 10-year survival rate for unresectable patients is less than 10%. Currently, surgical resection is still considered the only means of cure for patients with liver metastases from colorectal cancer, even though treatments such as radiofrequency ablation have been shown to be more effective under certain conditions!
A combination of medical and surgical oncology (OncoSurge) is now routinely applied in the management of liver metastases. By turning unresectable liver metastases into resectable lesions through systemic chemotherapy, it is possible to change the treatment goal of patients from palliative to curative, and systemic chemotherapy in this case is generally called “conversion chemotherapy”; while systemic chemotherapy for resectable liver metastases is generally called “neoadjuvant chemotherapy”. “neoadjuvant chemotherapy”.
As a surgeon, how to deal with colorectal cancer liver metastases requires consideration of many factors, which often determine our treatment strategy.
1. Primary tumor stage. The later the stage, the worse the treatment effect of liver metastasis, and lymph node metastasis is an independent negative prognostic factor for OS and DFS.
2. Preoperative CEA level. Generally, the higher the CEA value, the worse the prognosis, and some studies consider CEA>200ng/mL as a poor prognostic factor.
3.Number and size of liver metastases. The higher the number (>4) and the larger the diameter (>5CM), the heavier the tumor load is predicted to be, and the worse its treatment effect is, but the number and size of tumor cannot be used as the judgment standard of whether complete resection can be performed! As long as R0 resection can be performed, patients can still benefit.
4. Concurrent metastasis and disease-free interval. Concurrent metastasis is worse than heterochronic metastasis, and the time interval between resection of primary tumor and appearance of liver metastasis is less than 12 months predicts higher tumor aggressiveness.
5. Extrahepatic metastasis. Traditionally, extrahepatic metastasis (EHD) is a contraindication to hepatic resection. However, current technical improvements have benefited some highly selective patients, such as combined pulmonary solitary metastases.
6.Surgical margins. R0 resection is the guarantee of obtaining efficacy, but with recent advances in chemotherapy, residual (R1) resection of marginal micrometastases or treatment with radiofrequency and other means have little impact on overall survival (OS), although the local recurrence rate is likely to be increased.
7. Intraoperative and postoperative factors. Intraoperative bleeding and postoperative surgical complications may affect the immune system of the body or delay the use of postoperative chemotherapy, making the treatment effect poor.
8. Evaluation of imaging and pathological response of tumor to preoperative chemotherapy. Tumor shrinkage after chemotherapy, RECIST evaluation is the criterion for judging, especially patients who get transformed after shrinkage have more benefit; however, it should be noted that when bevacizumab combined with chemotherapy, because of the anti-angiogenic effect of bevacizumab, its performance is not in the volume change of tumor, so RECIST criterion is not suitable for the evaluation of this situation, and the evaluation of other detection metabolism and other imaging will be more accurate.
Complete remission on imaging (rCR) is possible after treatment of liver metastases, and this is a good outcome for some patients. However, given that complete remission on imaging is not equal to complete remission on pathology (PCR), it is still advocated to remove the original tumor site as much as possible R0 and parallel postoperative adjuvant chemotherapy. The tumor regression grading (TRG) of postoperative specimens also predicts the response of tumor to treatment, and complete remission of tumor predicts a better outcome.
9. Some other molecular biological indicators. For example, KRAS, BRAF, circulating tumor cells (CTC), etc. may also be associated with prognosis.
There are also many factors influencing the determination of whether liver metastases can be resected. For patients who are unresectable or potentially resectable, a comprehensive evaluation is needed. The MDT team of colorectal cancer at Sun Yat-sen University Cancer Hospital performs comprehensive analysis and evaluation for such patients. Given that MRI has a higher detection rate than CT for lesions smaller than 1 CM, imaging evaluation of liver metastases for metastases is currently performed by MRI. A primary site that can be or has been radically resected, a systemic condition that permits, and the absence of unresectable extrahepatic metastases are prerequisites for hepatic resection surgery. The liver metastases are judged for R0 resection based on the anatomical basis of the liver and the extent of the lesion, preserving sufficient liver function to achieve a residual liver volume (FLR) of 30% or more with the presence of two contiguous liver segments, if possible. Although there are relative criteria for judging resection, it is difficult to achieve a uniform standard in practice, which is one of the important reasons for the wide variation in the results of current clinical studies in this area. For example, metastases located in the hilar region, although few and small in number and size, may be defined as unresectable and may be successfully converted after chemotherapy with a 10% reduction even if PR is not achieved. Bilobar multiple and bulky tumors considered as contraindications to surgery in the past have also become resectable indications with the development of surgical techniques and chemotherapy. Of course technically resectable does not necessarily lead to survival benefit, for example, patients with higher number of metastases or larger tumors also have more aggressive tumor biology, which we call biologically unresectable.
To better achieve R0 hepatic resection, in addition to systemic chemotherapy, several strategies are used for preoperative treatment: including portal vein embolization (PVE), staged hepatic resection, staged hepatic resection combined with portal vein ligation (PVL) liver division (ALPPS) in situ isolation technique, radiofrequency for liver metastases (RFA), and hepatic artery perfusion (HAI), all of which can improve the conversion rate.
1, PVE can be used as a preoperative treatment to increase surgical safety in patients with borderline FLR. Contraindications to PVE include tumor invasion of the portal vein, portal vein thrombosis, and severe portal hypertension, and imaging is required every 3-6 weeks to evaluate the possibility of resection. Staged liver resection requires first a minor surgery to remove all metastases preserving the FLR liver segment, followed by 4 to 6 cycles of chemotherapy or waiting, during which time PVE may need to be introduced and imaging evaluation followed by secondary surgery, which can make some unresectable or become resectable, and this approach requires attention to improve the rate of secondary surgery, because a simple non-radical primary surgical resection is not helpful for survival. is not helpful.
2. ALPPS is a new alternative to PVE for increasing FLR. ALPPS is a faster way to increase FLR than PVE and can be attempted even after PVE has failed, with some literature suggesting that an average 63% volume increase in 3 days can be achieved using the in situ liver transection technique.
3. RFA utilizes thermal injury to kill tumor cells and can achieve better liver preservation while being percutaneous, lumpectomy or intraoperative. It is effective for perioperative chemotherapy, with less than or equal to 3 metastases, tumor diameter less than or equal to 3CM, and lower CEA level is a predictor of benefit from RFA treatment.
HAI can be used in combination with full-dose systemic chemotherapy or RFA to achieve response rates of over 90% and conversion resection rates of 24%-47%.
The current rationale for neoadjuvant chemotherapy in resectable patients is derived from the EORTC 40983 study, in which perioperative FOLFOX regimens improved PFS but did not meaningfully improve final OS, so currently chemotherapy needs to be administered with caution in resectable patients, especially in the case of single metastases. The recent New EPOC study of cetuximab in combination with chemotherapy suggests that the use of targeted agents may have negative effects in resectable patients, so the use of targeted agents in resectable patients needs to be considered in a comprehensive manner, including whether they are resectable or potentially resectable.
For unresectable patients, the goal of chemotherapy is downstage. In the Adam study in France, chemotherapy was used to change 12.5% of patients from initially unresectable to resectable. The CELIM study combined with cetuximab chemotherapy yielded an R0 resection rate of 34%. The application of systemic chemotherapy is aimed at transformation, making unresectable lesions resectable rather than a complete response of the lesion. At least 4 cycles of chemotherapy are mandatory, and surgical resection should be performed as soon as resectable conditions are identified at bi-monthly reviews, and if the lesion progresses after 4 months of chemotherapy, a switch to a second-line chemotherapy regimen may be considered. Currently, regimens including FOLFOX, FOLFIRI, FOLFOXIRI and combination with bevacizumab and cetuximab can be considered. Adjuvant chemotherapy after radical resection is still recommended, and completion of 6 months of chemotherapy in the perioperative period (preoperative and adjuvant) is recommended.
Bevacizumab is a humanized monoclonal antibody against VEGF, and some studies have shown that bevacizumab plus chemotherapy improves liver resection and response rates in metastatic colorectal cancer (ORR 78%, conversion rate 40%). A colorectal cancer MDT team summarized the treatment of patients with colorectal cancer confined to liver metastases at our institution in recent years. Patients were divided into groups receiving and non-receiving bevacizumab and received three chemotherapy regimens, XELOX, FOLFOX and FOLFIRI. Divided into bevacizumab and chemotherapy alone groups, PR and SD were 59.4%, 40.6% and 38.6%, 50% in the two groups, respectively, and we found that platinum-containing chemotherapy regimens combined with bevacizumab had a higher rate of resection of liver metastases than non-platinum-containing chemotherapy regimens (80% vs. 50%, P=0.08). In terms of safety, the bevacizumab group showed acceptable adverse effects (12.5%).
As surgeons facing liver metastases from colorectal cancer, their decision making needs to be backed by the support of a multidisciplinary team (MDT). Specialists related to colorectal cancer such as surgical oncology, internal medicine, radiotherapy, imaging, pathology and other stomatologists and nutritionists form a colorectal cancer treatment team to make decisions based on a comprehensive patient-centered assessment so that patients receive the best treatment plan.