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 the revised Guidelines were released in 2010. 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 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). 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 a stratified analysis of the data 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, January versus 25, June, P=O, 011), while in patients with any RAS gene mutation, median overall survival was comparable in both groups (20, March versus 20, June, P=0, 600).
Similar results were obtained in the study 20050181, where patients with double wild type of 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 mutation, with or without the application of panitumumab The differences in their overall survival (11, August versus 11, January, P=0, 345) and progression-free survival (4, August versus 4, 0 months, P=0, 144) were not statistically significant.
These studies suggest that NRAS testing enriches more 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: their liver metastases are unresectable but are expected to turn out to be Ro resectable with certain treatment, and their systemic condition is able to accept resection surgery and intense treatment of the metastases. 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 were 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 can 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 radical resection of the primary site (mainly rectal cancer) is followed by some treatment. 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 of 20% and 1%, respectively, and finally 89 patients (74%) had the primary colorectal cancer removed, with postoperative complications and mortality 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 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.
The results of 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.
VI. Development of molecularly targeted drugs
The effectiveness of adding molecularly targeted drugs to the treatment of patients with unresectable colorectal cancer with liver metastases has been widely demonstrated. Currently, it is believed that chemotherapy combined with the application of molecular targeted drugs is the most promising treatment method to improve the resection rate of liver metastases.
In multiple randomized controlled studies of patients with liver metastases from colorectal cancer only, cetuximab combined with chemotherapy was found to have better translational resection rates. A meta-analysis including 484 patients with KRAS wild-type and initially unresectable metastatic colorectal cancer showed that the combination of cetuximab or panitumumab significantly increased the overall response rate (RR: 1, 67, p<0, 01), ro resection rate from 11% to 18% (rr: 1, 59, p=0, 04), and progression-free survival compared to chemotherapy alone prolonged (rr: 0, 68, p<0, 01), while overall survival was not significantly improved (p=0, 42). < p="">
The results of a randomized study at Zhongshan Hospital, Fudan University, which included 138 patients with translational resection rate as the primary objective, showed that chemotherapy with mFOLFOX6 or FOLFIRI plus cetuximab significantly improved the Ro resection rate compared with mFOLFOX6 or FOLFIRI chemotherapy alone (25,7% versus 7,4%, p<0,01) and significantly improved tumor response rate, overall survival and progression-free survival in patients. < p="">
Further analysis of patients grouped according to whether early tumor regression, i.e., tumor shrinkage of 20% or more at 8 weeks of chemotherapy or targeted therapy, showed that combined targeted therapy increased the chance of patients achieving early tumor regression compared with chemotherapy alone and that patients with early tumor regression had significantly better survival than those without early tumor regression.
A 2013 European Congress of Oncology meta-analysis on chemotherapy plus cetuximab for translational therapy, which included a total of four randomized controlled studies of colorectal cancer patients with liver metastases only, found that the R. resection rate was significantly higher in the group with the addition of cetuximab in three of the studies (CRYSTAL study, 5,6% vs. 13,2%; OPUS study, 4,3% vs. 16,0 0%: NCT01564810 study, 7,4% vs. 25,7%), but the difference was not statistically significant in the remaining l studies (COIN study, 13,2% vs. 14,9%, P>0,05).
Therefore, the Guidelines recommend translational therapy, with cetuximab in combination with chemotherapy preferred for patients with KRAS wild type.
In recent years, several studies on bevacizumab have shown that bevacizumab in combination with multiple chemotherapy regimens can improve survival in patients with metastatic colorectal cancer.The BEAT study included 1914 patients with unresectable metastatic colorectal cancer treated with chemotherapy in combination with bevacizumab, with chemotherapy regimens including FOLFOX (29%), FOLFIRI (26%), XELOX ( 18%) and fluorouracil monotherapy ( 16%), with their median progression-free survival and overall survival reaching 10, 8 months and 22, 7 months, respectively.
The ML18147 study evaluated the impact of KRAS gene status on bevacizumab treatment and showed that KRAS mutation status had no effect on the efficacy of bevacizumab in combination with FOLFOX or FOIFIRI.
The results of the CAIRO3 study showed that in cases without progression after chemotherapy combined with bevacizumab induction therapy, comparing capecitabine combined with bevacizumab maintenance therapy (maintenance therapy group) with observation follow-up (observation follow-up group) and waiting for progression before receiving chemotherapy combined with bevacizumab until 2nd progression, showed that the maintenance therapy group significantly prolonged first progression-free survival (7, April compared to 4 , 1 month, P
Moreover, among them, patients with resected primary foci of concurrent liver metastases benefited significantly from maintenance therapy, with median overall survival times of 18, 0 months (observation follow-up group) and 25, 0 months (maintenance therapy group), respectively (p<0, 01). < p="">
The multicenter randomized controlled trial TML study, which included patients with metastatic colorectal cancer who had first disease progression after bevacizumab combined with first-line chemotherapy and were randomized to receive treatment with or without bevacizumab in combination with second-line chemotherapy, showed that continued combination bevacizumab treatment prolonged overall patient survival (calculated from the randomization group after white disease progression, 11, 2 months compared with 9, 8 months, P=0, 0062), with a significant risk of death. 0062), with a significant 19% reduction in the risk of death, and also prolonged progression-free survival (calculated from the randomization group, May, July versus April, January, P<0, 0001), with a 32% reduction in the risk of disease progression; thus suggesting that bevacizumab cross-line therapy may provide a definite survival benefit to patients. < p="">
This shows that bevacizumab can be used in first-line therapy, second-line therapy, maintenance therapy and cross-line therapy in metastatic colorectal cancer, and is independent of KRAS gene.
VII. Research progress of local treatment of liver metastases
For patients with unresectable liver metastases, systemic chemotherapy, ablative destruction and hepatic artery infusion chemotherapy are needed to improve patient prognosis after multidisciplinary team discussion. However, there is no clinical conclusion as to which treatment is preferred.
The status of radiofrequency ablation in the treatment of liver metastases from colorectal cancer remains controversial. Available data suggest that the survival rate of patients with liver metastases treated with radiofrequency ablation alone is only slightly higher than that of those treated with other non-surgical treatments, so it is currently used only as a treatment option after ineffective chemotherapy or for the recurrence of liver metastases after surgery. The results of a review including 18 studies suggest that radiofrequency ablation significantly improves progression-free survival in patients, while overall survival is inconclusive.
Microwave ablation refers to the fact that microwaves above 900 MHz cause water molecules in the tissue to vibrate and frictionally heat up thus causing localized tissue coagulation and necrosis, with higher power microwaves producing a coagulation-ablation zone of about 2 cm within l min. Microwave ablation has certain technical advantages over radiofrequency ablation, such as microwave conduction is not limited by the dryness and carbonization of the tissue, so that the tumor internal temperature is higher and the ablation zone is larger in a shorter period of time, and the necrosis of tumor cells is more complete.
Combining microwave ablation with selected patients with unresectable colorectal cancer liver metastases can improve survival rates more effectively than chemotherapy alone. A retrospective large-scale study reported that the incidence of major complications of microwave ablation was only 2,6%.
In addition, cryotherapy, in which liquid nitrogen or argon is applied to rapidly lower the temperature of the tumor tissue to -18°C, will cause mechanical damage to the ice crystals formed within the cells and necrosis of the cells at the edge of the ablation zone due to dehydration or occlusion of the surrounding small blood vessels. However, the complication rate of cryotherapy is as high as approximately 30%, including bleeding, biliary tract infection, and liver abscess, and it is because of the high local recurrence and complication rate that the use of cryotherapy has now decreased.
A pooled study of 10 randomized controlled trials comparing the efficacy of hepatic arterial infusion of fluoropyrimidine with systemic chemotherapy for unresectable colorectal cancer liver metastases found a higher tumor response rate with hepatic arterial infusion chemotherapy alone (42,9% versus 18,4%, p<0,01), but no significant advantage in median overall survival time (15,9 months versus 12,4 months, p=0,24). Therefore, it is concluded that current clinical data do not support the use of fluoropyrimidine alone for hepatic arterial infusion chemotherapy in this patient population. < p="">
It has also been suggested that hepatic artery infusion chemotherapy with or without systemic chemotherapy is associated with higher tumor response rates and prolonged progression-free survival in liver metastases compared with systemic chemotherapy in patients with unresectable metastatic colorectal cancer, but there is no definitive advantage in terms of overall survival.
In recent years, several new local treatments have emerged. Selective internal radiotherapy (SIRT) involves the intrahepatic injection of millions of radioactive microspheres through the hepatic artery via a catheter, which selectively targets metastatic liver cancer tissue with up to 40 times the dose of conventional radiotherapy, while protecting healthy liver tissue.
A US multicenter retrospective study enrolling 548 chemotherapy-naïve patients with metastatic colorectal cancer treated with SIR-Spheres microspheres found that patients who had received one, two, or three or more prior chemotherapeutic agents had median survival of 13, 0, 9, 0, and 8, 1 months, respectively. Drug-eluting beads (DEB) for arterial infusion chemotherapy i.e. hepatic artery infusion of eluting beads carrying chemotherapeutic drugs.
In a study that included 70 patients with liver metastases from colorectal cancer, it was found that triple therapy with FOLFOX, bevacizumab combined with irinotecan drug-eluting beads significantly improved remission rates compared with FOLFOXl combined with bevacizumab (79% vs. 54% at February; 83% vs. 64% at June; 50% vs. 24% at December), without a significant improvement in progression-free survival (12 months versus 15 months, P=0,18), showing that combination drug-eluting bead therapy is safe, does not lead to chemotherapy delay, and does not increase chemotherapy toxicity.