1. Background
Colorectal cancer has become the third most common malignancy and it causes the fourth highest number of deaths from cancer.
20C25% of colorectal cancer patients are stage IV at the time of initial diagnosis, and 15C25% have concurrent liver metastases (CRCLM), of which 70C80 % are confined to the liver only;
Surgical resection is the most effective method to treat CRCLM, but only a small number of patients are suitable for direct surgery;
The proportion of concurrent liver metastases undergoing curative surgery (6,3%) is much lower than that of heterochronic liver metastases (16,9%) [ 7 ]. The prognosis of patients who do not receive treatment is poor, with less than 30% of patients surviving beyond 1 year and a 5-year survival rate of less than 5%; the 5-year survival rate of simultaneous liver metastases (3,3%) is worse than that of heterochronous liver metastases (6,1%);
With the development of diagnostic imaging technology, more and more lesions can be detected at an early stage, so the proportion of simultaneous liver metastases is gradually increasing compared with heterochronic liver metastases.
2. Multidisciplinary team composition
Experts in the treatment of colorectal cancer liver metastases from the United States, Europe and Asia.
1 coordinator
5 oncologists (including 2 gastroenterologists)
5 hepatic surgeons
1 colorectal surgeon
2 imaging physicians
1 pathologist
1 gastrointestinal molecular oncologist
3. Definition of concurrent liver metastases
The biological behavior and prognosis of concurrent liver metastases are worse than those of heterochronic liver metastases, especially when compared with delayed liver metastases.
Concurrent liver metastases should be considered as “concurrently detected liver metastases”. This refers to liver metastases found at or before the time of diagnosis of the primary site.
Liver metastases found within 12 months after the diagnosis of the primary site or surgery are early heterochronous liver metastases.
Liver metastases found after 12 months after the diagnosis of the primary focus or surgery are late heterochronous liver metastases.
4. Guidelines for diagnosis and comprehensive treatment of liver metastases from colorectal cancer in China
(V2013)(Chinese Journal of Practical Surgery,2013,33(8):635-44,)
Concurrent liver metastasis: liver metastasis found at the time of diagnosis of colorectal cancer, or within 6 months after radical resection of the primary site of colorectal cancer;
Heterochronic liver metastasis: liver metastasis occurring 6 months after radical resection of colorectal cancer.
5. The status of imaging in the detection of simultaneous liver metastases
The status of imaging in the detection of simultaneous liver metastases is mainly used to detect and differentiate liver nodules and to evaluate the resectability of tumors.
The best assessment tools are CT and MRI, while combined thoracoabdominal CT is the best choice for initial tumor staging.
MRI is more sensitive than CT for the detection of lesions smaller than 25 px after neoadjuvant chemotherapy; MRI should be performed when lesions are difficult to distinguish (small liver nodules, both metastatic and benign lesions) or in the presence of a fatty liver.
If concurrent CRCLM is initially resectable, depending on the experience and expertise of the host hospital, liver MRI can be added to high-quality CT.
PET-CT can be used for the detection of extrahepatic metastases, especially in patients with recurrence or high tumor load (multiple nodes and/or large metastases), or in patients who are scheduled for complex liver resection.
6. The role of imaging in assessing tumor response to preoperative therapy
Ø The following information for assessing tumor response to treatment based on CT imaging needs to be provided by the imaging physician.
Response of tumor size ;
Response of tumor morphology;
Assessment of fatty liver and portal hypertension;
Preoperative assessment of the remaining volume of the liver.
MRI of the liver is indicated in the presence of hepatic steatosis and in patients with indistinguishable liver lesions, but the value of routine use of MRI to evaluate tumor response is unclear.
7. Pathology and molecular biology
The pathological response rate of tumor to chemotherapy is a surrogate marker to determine the effectiveness of chemotherapy, tumor biological behavior as well as recurrence and survival outcome.
Standard pathology reports should include: tumor size and margins; chemotherapy toxicity to non-tumor liver tissue; micrometastases; and a “danger halo” (which may indicate poor tumor biologic behavior).
Safe margins remain the ultimate goal of treatment; a minimum margin of 1 mm is recommended to be effective.
No definitive tumor marker has been shown to distinguish the biological behavior and prognosis of concurrent and heterochronic liver metastases.
Molecular detection of liver metastases is increasingly important in evaluating the biological behavior of CRCLM, and RAS (RAS and KRAS) mutations have been shown to be associated with poorer disease-free and overall survival after surgery for CRCLM, with or without the application of anti-EGFR therapy.
8. Chemotherapy regimen for concurrent unresectable liver metastases
Chemotherapy for metastatic colorectal cancer can achieve a high response rate of >50% and a median survival of 30 months. All first-line chemotherapy regimens for advanced colorectal cancer can be used for concurrent liver metastases.
Best first-line chemotherapy is recommended for potentially resectable concurrent liver metastases by all but one expert panel member.
Optimal chemotherapy regimens for concurrent liver metastases include two-drug (e.g., FOLFOX, FOLFIRI) combined with targeted (e.g., bevacizumab, cetuximab, panitumumab, selected according to RAS status), three-drug (FOLFOXIRI), and three-drug combined with targeted. For resectable concurrent liver metastases, experts agree that chemotherapy alone can be administered without targeted agents because there is no evidence for the use of biologic agents.
Concurrent liver metastases should be given at least 4 cycles of first-line chemotherapy, and if first-line treatment progresses or SD remains after 4 months, second-line chemotherapy should be used if conversion of junctional resectable or unresectable to resectable is still desired at this time.
9. Chemotherapy regimen for concurrent unresectable liver metastases
Those who do not respond to first-line chemotherapy can choose sequential therapy (such as adding a third drug on top of the two drugs).
Every 2 months is the best time to evaluate the efficacy of chemotherapy.
These recommendations are consistent with ESMO recommendations for metastatic colorectal cancer (e.g., two cytotoxic agents in combination with targeted therapy are recommended for patients with potentially resectable and unresectable metastatic colorectal cancer) and ICE guidelines in England and Wales.
The recommended total perioperative chemotherapy duration is 6 months (preoperative and postoperative adjuvant).
10. Primary site surgery
Colorectal surgery should be performed by a colorectal specialist.
Laparoscopic colorectal surgery is practicable and the results are similar to open surgery, but it will be more difficult if the tumor invades adjacent organs or penetrates the visceral peritoneum (T4).
For low and intermediate rectal cancer combined with simultaneous liver metastasis, preoperative radiotherapy is recommended for the primary site, and chemotherapy should be given for liver metastasis.
When both primary tumor and liver metastasis can be resected and the surgery is not complicated, simultaneous resection can be performed if only limited liver resection is needed. (If extensive hepatic resection (3 and more liver segments) or complicated rectal surgery with significantly increased postoperative complications and mortality is required, simultaneous resection is not recommended.)
When concurrent liver metastases are unresectable, resection of the asymptomatic primary site may be beneficial.
11. Liver surgery
If the primary focus is asymptomatic, especially for rectal cancer requiring neoadjuvant radiotherapy, liver-first surgery can be used (reversed approach). If rectal cancer requires radiotherapy and liver metastasis requires chemotherapy at the same time, a short course of radiotherapy (5×5) followed by chemotherapy is recommended.
If both primary and metastatic foci can be resected and only limited surgery is required, both primary and metastatic foci can be removed at the same time.
Preoperative chemotherapy is recommended to control metastases and reduce the size of the lesions to facilitate surgery.
If the liver metastases are still large after preoperative chemotherapy and are not suitable for simultaneous resection with the primary foci, an inversion model (priority liver surgery) can be used.
Those who undergo optimal chemotherapy and evaluate SD should still undergo liver resection as long as the residual liver volume is adequate and there is blood flow into and out of the liver. Resectability can be increased by some special means. (e.g. PVE or staged hepatectomy)
12. Recommendations for various clinical scenarios of concurrent liver metastases
In clinical practice, the main decision of treatment is the status of the primary and metastatic foci, more precisely, it should be whether the primary foci need emergency surgery and the resectability of the primary and metastatic foci.
(1) Consensus recommendations for asymptomatic CRC with concurrent resectable liver metastases
Preoperative chemotherapy with 4-6 cycles is unanimously recommended. However, the LiverMetSrvey data suggest that 5-year survival is not better for those with priority chemotherapy than for those with primary foci resected first. However, the extent of the lesion was smaller in those with priority resection of the primary lesion compared to those with priority chemotherapy.
Those with low to intermediate rectal cancer as the primary site often require radiotherapy, and concurrent surgery should not be chosen in this case. Concurrent surgery is also not recommended for those whose primary focus is colon or high-grade rectum, if the colon tumor surgery is complicated, or for high-risk patients, or if extensive liver resection (≥3 liver segments) is required.
The summary recommendation is to prioritize chemotherapy, combined with or without concurrent radiotherapy as appropriate, followed by concurrent surgery (for minor hepatic resection and easily resectable primary foci) or staged surgery (for other patients). However, there is no strong evidence that experts recommend chemotherapy first as opposed to resection of the colon first.
(2) Consensus recommendation for asymptomatic CRC combined with concurrent unresectable liver metastases
The expert panel agreed that chemotherapy should be administered first with the goal of converting liver metastases to resectable. For potentially resectable patients, all supported the optimal chemotherapy regimen: two-drug combined with biologics or three-drug combined with biologics.
Try not to operate at the same time. If liver metastases are converted to resectable, the upside-down strategy (i.e., liver first) is the recommended choice. (The 5-year survival rate for the upside-down model is 42%, 33% for those who remove the colon first versus 28% for those who remove it concurrently)
For rectal cancer, one approach is to administer a short course of radiotherapy to control the primary site followed by chemotherapy to shrink liver metastases, and the other approach is to administer optimal chemotherapy followed by radiotherapy and resect liver metastases during the interval of waiting for rectal surgery after radiotherapy.
(3) Consensus recommendation for symptomatic CRC combined with concurrent resectable liver metastases
The symptoms of CRC are mainly hemorrhage, obstruction or perforation. Bleeding can often be controlled with blood transfusions, and with chemotherapy, bleeding usually stops. The majority of experts (75%) agree that preoperative chemotherapy can be administered in CRC with bleeding, while others (25%) believe that the primary site should be removed first.
Surgery is required when perforation is present, and resection is an option if the tumor is easier to remove. Stoma is feasible when surgery is more complicated . The panel agreed that the primary site should be resected first in this case, if possible .
Stenting is a method of relieving obstruction but is generally effective and is considered by the group to be only indicated for easily resectable tumors, especially in elderly patients, and not for those with right hemicolectomy, rectum or on anti-angiogenic drugs. If there is clear clinical or imaging evidence suggesting complete obstruction, the panel agreed that surgical resection of the primary site should be preferred, with 9/11 (82%) advocating concomitant fistula and 2/11 (18%) advocating stenting.
Surgical resection of the primary focus is recommended for those with combined perforation or obstruction (surgery is not recommended for anemia due to bleeding), followed by chemotherapy and resection of liver metastases.
(4) Consensus recommendation for symptomatic CRC combined with concurrent unresectable liver metastases
The expert group believes that the goal of treatment for this group of patients is to convert liver metastases to resectable. Stenting is not recommended to avoid complications such as perforation, displaced bleeding, and pain. As mentioned previously, if combined with perforation or obstruction, the primary site should be resected, and the choice of systemic chemotherapy may also refer to the previous clinical scenarios.
In conclusion, in case of combined perforation or obstruction, resection of the primary focus is recommended first, followed by chemotherapy and then hepatic resection after the liver metastases have shrunk. In the case of combined anemia due to bleeding, the choice of induction chemotherapy is recommended to shrink the primary focus and metastases, followed by priority resection of the larger tumor load (usually liver first, i.e., reversed mode).
In conclusion
Concurrent liver metastases should be specifically referred to as “concurrently detected liver metastases”, i.e. the detection of liver metastases is prior to or concurrent with the diagnosis of the primary site. Concurrent liver metastases have a poor biological behavior and a shorter survival expectancy than heterochronic liver metastases. Initial high-dose abdominal enhancement CT is recommended to determine whether liver metastases are resectable.
① For asymptomatic CRC combined with simultaneous resectable liver metastases, chemotherapy is recommended as the first choice, followed by concurrent (small hepatectomy and easily resectable primary foci) or staged surgery (other patients), depending on whether concurrent radiotherapy is indicated. There is no stronger evidence for recommending preferred chemotherapy, as there is for preferred resection of the primary site, and clinical studies in this area are ongoing.
(ii) For asymptomatic CRC combined with concurrent unresectable liver metastases, the recommended first choice of optimal chemotherapy is to convert the liver metastases to resectable. The liver metastases and the primary site are then resected.
③For symptomatic CRC combined with concurrent resectable liver metastases, resection of the primary site is recommended if combined with perforation or obstruction (not recommended for combined anemia due to bleeding), followed by chemotherapy and hepatic resection.
④For symptomatic CRC combined with concurrent unresectable liver metastases, if combined with perforation or obstruction, resection of the primary focus followed by chemotherapy is recommended, followed by hepatic resection after the liver metastases have shrunk. In case of combined bleeding leading to anemia, induction chemotherapy is recommended as an option to shrink the primary site and metastases, followed by priority resection of the larger tumor load (usually liver first, i.e., reversed mode).
⑤ For potentially resectable liver metastases, a minimum of 4 cycles of first-line optimal regimen chemotherapy (two-drug combined with targeted or three-drug or three-drug combined with targeted) is recommended, with efficacy evaluated every 2 months for a total of 6 months of chemotherapy (preoperative plus postoperative). Transarterial infusion chemotherapy also has a high response rate and may be a treatment option.