Liver metastases are extremely common in patients with colorectal cancer, and surgery remains the only curative means available. However, most of the liver metastases (80%-90%) cannot be resected radically at the initial stage, so liver metastases become the most important cause of death in colorectal cancer patients. In recent years, many advances have been made in the treatment of colorectal cancer liver metastases, and many new treatment methods have emerged, which have improved the treatment level of colorectal cancer liver metastases in China to a certain extent.
In order to standardize the diagnosis and comprehensive treatment of colorectal cancer liver metastasis in China, funded by the Clinical Key Discipline Project of the Ministry of Health, the Gastrointestinal Surgery Group and Colorectal Anorectal Surgery Group of the Chinese Society for Surgery and the Colorectal Cancer Specialty Committee of the Chinese Anti-Cancer Association initiated the joint preparation of the draft Guidelines for the Diagnosis and Comprehensive Treatment of Colorectal Cancer Liver Metastasis in 2008, and released the revised Guidelines in 2010 after the In 2013, the Guidelines were revised again by summarizing the advanced experience and latest progress at home and abroad. The new version of the Guidelines mainly emphasizes the following contents.
I. Emphasis on genetic testing related to liver metastasis of colorectal cancer
With the progress of molecular biology, more and more biomarkers related to colorectal cancer have been discovered. The addition of molecular targeted drugs to the treatment of metastatic colorectal cancer patients can benefit some patients and significantly increase the chance of cure of liver metastasis in this group of patients. Therefore, how to screen out this group of patients has become an important topic of great interest at present.
Mutations in the KRAS gene, which predicts resistance to anti-EGJFR therapy, are mostly located in codons 12 and 13 of exon 2, and are closely related to the KRAS gene status of the tumor tissue.
The PRIME study further examined exons 3 and 4 of the KRAS gene and exons 2, 3 and 4 of the NRAS gene in 639 patients with metastatic colorectal cancer without mutations in exon 2 of the KRAS gene, and the results showed that 17% of patients had other RAS gene mutations, and survival analysis showed that this group of patients did not benefit from anti-EGFR therapy (panitumumab). The results showed that 17% of patients had other RAS mutations and survival analysis showed that this group of patients did not benefit from anti-EGFR therapy (panitumumab).
The FIRE-3 study compared the efficacy of bevacizumab or cetuximab in combination with the FOLFIRI regimen in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer, and the results of the data from the stratified analysis showed that in patients with dual wild-type KRAS and NRAS genes, the median overall survival was significantly better in the cetuximab plus FOLFIRI group than in the bevacizumab plus FOLFIRl group ( 33.1 months versus 25.6 months, P=O.011), while in patients with any RAS gene mutation, median overall survival was comparable in both groups (20.3 months versus 20.6 months, P=0.600).
Similar results were obtained in the 20050181 study, where patients with double wild-type KRAS and NRAS genes could prolong overall survival (16.2 months versus 13.9 months, P=0.077) and progression-free survival (6.4 months versus 4.4 months, P=0.006) by adding treatment with panitumumab, while among patients with RAS gene mutations, with or without the application of panitumumab The differences in their overall survival (11.8 months vs. 11.1 months, P=0.345) and progression-free survival (4.8 months vs. 4.0 months, P=0.144) were not statistically significant.
These studies suggest that NRAS testing can more enrich the group of patients who are effective against EGFR therapy. Thus, KRAS and NRAS gene mutation status are now predictors of anti-EGFR therapy efficacy to guide individualized clinical treatment.
The current study also concluded that in patients with metastatic colorectal cancer with wild-type KRAS gene, BRAF gene mutation cannot be used as a predictor of efficacy and is associated with poor disease prognosis. Moreover, PI3KCA gene mutation and PTEN gene deletion can also be used as predictors of prognosis.
II. Emphasize the role of multidisciplinary team in the diagnosis and treatment of colorectal cancer liver metastasis
With the progressive understanding of malignant tumor treatment process, the traditional single-disciplinary treatment model has been changed to a comprehensive treatment model with the participation of multiple disciplines. Multi-disciplinary team (MDT) refers to the formation of a fixed team of physicians from multiple related disciplines to conduct regular and regular clinical discussions based on defined treatment guidelines or consensus opinions for a specific disease, and to formulate and implement standardized and individualized treatment plans for patients.
Currently, the Guidelines recommend that all patients with liver metastases from colorectal cancer should enter the MDT treatment model. The MDT for colorectal cancer is patient-centered and should include physicians from gastrointestinal surgery, liver surgery, medical oncology, radiotherapy, radiology imaging and other related specialties. Its important roles appear in: more accurate disease staging, less treatment confusion and delay, more personalized assessment system, better treatment articulation, improved quality of life, and optimal clinical and survival benefits.
MDT classifies patients with liver metastases from colorectal cancer into the following 4 different groups by conducting a comprehensive assessment of patients with different treatment goals.
1. Group 0 patients: their liver metastases are fully Ro resectable, and the goal of treatment for these patients is to make them curable. The appropriate neoadjuvant or (and) adjuvant therapy should be performed around surgical treatment to reduce the risk of recurrence after surgery.
2. Group 1 patients: whose liver metastases are unresectable but are expected to turn out to be Ro resectable with some treatment and whose systemic condition is capable of undergoing resection of the metastases and intense treatment. The aim of treatment for this group of patients is mainly to minimize the tumor or increase the volume of the residual liver, and the most aggressive and comprehensive treatment plan should be used.
For this group of patients, an intensive three-drug combination regimen is recommended to minimize the duration of treatment and thus obtain the best response rate of the tumor, followed by surgical resection. For specific regimen selection, cetuximab combined with FOLFOX or FOLFIRI regimen is recommended for KRAS wild-type patients; bevacizumab combined with two-drug chemotherapy or three-drug chemotherapy regimen is considered for KRAS mutant patients, and once the metastases are converted to resectable, they should be aggressively surgically resected.
3. Group 2 patients: whose liver metastases may remain unresectable while rapidly progressing (or at risk of rapid progression) and/or with associated symptoms, but whose systemic condition allows for higher intensity therapy. The aim of treatment for this group of patients is to shrink the tumor or at least control disease progression as soon as possible, and a more aggressive combination therapy regimen should be used.
4. Group 3 patients: whose liver metastases may remain unresectable and are asymptomatic or at risk of rapid progression, or with severe co-morbidities that preclude high-intensity treatment. Their treatment aims to stop further progression of the disease and should be maintained with a low-intensity and low toxicity regimen.
By grouping patients and clarifying the different treatment purposes of each group, patients are given the most reasonable examination and the most appropriate comprehensive treatment plan.
III. Selection of surgical timing for metastases in simultaneous liver metastases of colorectal cancer
Complete surgical resection of liver metastases is still the best method to cure liver metastases from colorectal cancer. The optimal surgical treatment strategy for colorectal cancer combined with liver metastases at the time of diagnosis is controversial. A meta-analysis including 14 studies with a total of 2204 patients found that simultaneous resection of primary and metastases in one stage and staged resection in two stages had similar operative time (p=0.16) and intraoperative bleeding (p=0.10); however, simultaneous resection in one stage had shorter hospital stay (p<0.01) and lower complication rate (p<0.01), and the difference in long-term survival between the two groups was was not statistically significant. < p="">
Another meta-analysis including 2880 patients also found that overall survival (p=0.64) and recurrence-free survival (p=0.79) were similar between one-stage simultaneous resection and two-stage staged resection, while one-stage simultaneous resection had a lower postoperative complication rate (p=0.0002), and the difference in 60-d postoperative morbidity and mortality between the two groups was not statistically significant. Therefore, in appropriately selected patients, one-stage simultaneous resection is safe and reliable and may be the treatment of choice.
Patients whose preoperative evaluation cannot meet the conditions for simultaneous resection in phase I can be surgically resected first for the primary colorectal cancer lesion and in phase II for the liver metastases. Currently, another staged resection model (resection of liver metastases followed by resection of the primary colorectal cancer, also known as the “inverse model” or liver first approach) has attracted much attention.
Resection of liver metastases first reduces the risk of liver metastasis progression and chemotherapy-related liver damage, while the primary site (mainly rectal cancer) is treated before radical resection. A study that included 121 patients in 3 observational studies and 1 retrospective cohort study found that 112 patients (93%) had liver metastases removed first, with postoperative liver complications and mortality rates of 20% and 1%, respectively, and finally 89 patients (74%) had primary colorectal cancer removed, with postoperative complications and mortality rates of 50% and 6%, respectively, and a median overall survival of 40 (19- 50) months, and the recurrence rate was 52%, which shows that this model is safe and feasible.
IV. Minimally invasive surgical treatment of colorectal cancer liver metastases is the future direction
Minimally invasive is the direction of future surgical development. At present, laparoscopic surgery has become the standard protocol for colorectal cancer surgery, which can accelerate the recovery of patients’ postoperative gastrointestinal tract function, shorten the hospitalization time, and not affect long-term survival compared with traditional open surgery. In a study that included more than 300 patients with liver metastases from colorectal cancer in four studies, the overall 5-year survival rate after laparoscopic hepatectomy was 46%-64%, which was comparable to that after open hepatectomy, and had the advantages of smaller incision, less pain, less anesthesia requirement and shorter hospital stay.
This also suggests that laparoscopic liver surgery is also safe and feasible. However, there are few reports on laparoscopic colorectal surgery combined with laparoscopic liver surgery, and for the limited data available, combined laparoscopic surgery appears to be safe and feasible. In recent years, the introduction of robotic surgical systems has revolutionized minimally invasive surgery. The technical advantages of this system in terms of greater intuition, precision, convenience and remote manipulation reflect the future trends in minimally invasive surgery.
A meta-analysis that included a total of 217 patients from 19 studies found that robotic liver surgery was most commonly performed for wedge resection and segmental resection of the liver, with an operative turn-over rate of 4.6%, a postoperative complication rate of 20.3%, most commonly peritoneal effusion, an operative time of 200-507 min, intraoperative bleeding of 50-660 ml, and an average postoperative hospital stay of 5.5- 11.7 d. The follow-up results showed that the disease-free survival of robotic surgery patients was comparable to that of laparoscopic surgery patients.
At present, the robotic surgery system has not yet demonstrated sufficient advantages compared with laparoscopic surgery, but with the accumulation of clinical data and the updating of robotic surgery systems, the future of robotic surgery systems is expected.
V. Whether to remove the primary foci in unresectable liver metastases is still inconclusive
For colorectal cancer patients with unresectable liver metastases, if there are no symptoms such as bleeding, perforation or obstruction in the primary foci, there is a big controversy whether direct chemotherapy or chemotherapy after surgical removal of the primary foci should be given.
The results of a prospective study that included 233 patients with unresectable colorectal cancer with metastases showed that after receiving first-line chemotherapy, only 16 patients (7%) required emergency surgery for primary tumor obstruction or perforation, and 10 patients (4%) required non-surgical interventions such as stenting or radiotherapy for symptoms related to the primary tumor, and the median survival of the whole group of patients reached 18 months, so it is considered that this group of patients The most appropriate treatment modality is chemotherapy without resection of the primary lesion.
It has also been suggested that with the combination of chemotherapeutic agents and targeted agents, the primary intestinal lesion would be well controlled and thus would not require surgical resection due to the development of symptoms in the primary lesion.
However, other studies support surgical resection of the primary colorectal cancer lesion first. A meta-analysis including eight retrospective studies with a total of 1062 patients showed that resection of the primary lesion prolonged patient survival by 6.0 months in patients with unresectable colorectal cancer who were asymptomatic or had mildly symptomatic liver metastases (P
A further systematic review that included 21 studies found that most showed that patients could benefit in survival from palliative resection of the primary lesion: a multifactorial analysis also showed that tumor load and patient physical status were the main independent prognostic factors. However, these studies were retrospective analyses and may be biased in terms of patient selection, so prospective, randomized controlled studies are still needed to assess the value of primary site surgery.