Liver metastases occur in at least 50% of cases of colorectal cancer (CRC), and at least 900,000 people worldwide are estimated to have colorectal cancer liver metastases (CRCLM). There has been much discussion among surgeons and medical oncologists on the management of CRCLM. It wasn’t until the 1980s that surgical excision became a recognized treatment option for liver metastases of colon cancer. About 15%–20% of liver metastases discovered at the time of diagnosis may be removed, and a sizable portion will recur after surgery. The complicated nature of CRCLM cannot be adequately treated by surgery alone. Over the last 20 years, there has been a substantial improvement in surgical skill and systemic therapeutic effectiveness, which has improved the prognosis for CRCLM. More patients are achieving the goal of having no evidence of disease (NED); nonetheless, selecting the appropriate treatment for the appropriate patient still requires work. An overview of CRCLM therapeutic options is provided in this review to help guide future research.

We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) for full-text articles from 2017 to May 31, 2023, using the keywords colon, liver, metastasis, surgery, neoadjuvant. The full-text articles found were carefully examined. In addition, all abstracts presented at international conferences between January 2020 and October 2023 were examined.

Pretreatment patients’ assessment

Locoregional treatment for enhanced colorectal cancer liver metastases

First proposed in 1995, the term “oligometastasis” appears in several guidelines and clinical trials. The term “oligometastasis” refers to a stage of the tumor where standard computerized tomography (TAC) scan, possitron emission tomography (PET), or magnetic resonance imaging (MRI) detects only a small number of isolated secondary metastases, usually fewer than 5. The concept was initially introduced in the 2015 guidelines for the management of CRC published by European Society of Medical Oncology (ESMO). It was utilized to differentiate between two forms of metastatic colorectal cancer (mCRC): diffuse disease, which includes lung and liver metastases, and oligometastatic disease. Individuals who are categorized as oligometastatic are seen to be a group with a strong chance of long-term survival. On the other hand, widespread illness is more widely distributed throughout the body. The main objective in each case is to reach a tumor-free condition with the intention of curing the disease and no detectable signs of it (NED). The main idea behind the treatment is to emphasize locoregional care that is founded on efficient systemic therapy. However, technically resectable liver metastases are no longer only oligometastases due to technological developments.

Treatment for intrahepatic lesions involves not just surgical resection but also a combination of surgical resection, ablation, and radiation therapy. Conceptually, it has also evolved from R0 resection to NED, meaning that current clinical exams no longer show any indication of a tumor. The NED criteria for locoregional therapy of CRCLM merely specify that all lesions must be completely removed by various procedures, the patient’s general condition must be able to resist surgery, and the residual liver volume must be larger than thirty to forty percent. There are no longer any rigorous limitations on the number and size of lesions. Segmentectomy and lobectomy are two traditional anatomical hepatectomy procedures that have mostly been superseded by parenchyma-sparing hepatectomy.

With a few exceptions, intrahepatic lesions should be treated: (1) the tumor is positioned in a way that makes it difficult to ensure the inflow or outflow of the liver (e.g., invasion of large blood vessels); (2) the tumor surgery is unable to achieve NED status; (3) the postoperative residual liver volume is insufficient; and (4) the patient's overall health makes the procedure intolerable. As followed initial liver cancer treatment approaches, liver metastases have been treated with arterial chemoembolization, local chemotherapy, and selective internal radiation therapy (SIRT). The role of these technologies has not been substantiated by high-level evidence. The continuous progress in surgical techniques has often breached the boundaries of the restricted zone of liver resection. Practitioners are currently looking into liver transplantation, the most advanced surgical method for treating CRCLM.¹ In the prospective investigation SECA-II, patients with nonresectable CRCLM had a 100%, 83%, and 83% survival rate following liver transplantation at 1, 3, and 5 years, respectively. Patients undergoing palliative care, on the other hand, had a about 10% 5-year overall survival (OS). At 1, 2, and 3 years, the disease-free survival (DFS) rates were 53%, 44%, and 35%, respectively. For patients who are carefully selected, liver transplantation results in the longest OS.² The association of liver partition and portal vein ligation for phased hepatectomy (ALPPS) is another state-of-the-art liver surgery procedure. The first long-term oncologic outcomes of ALPPS in 510 CRCLM patients showed a median OS of 39 months, a recurrence-free survival of 15 months, and a 90-day death rate of 4.9%. Positive long-term results were observed in individuals treated with ALPPS for CRCLM, which was primarily incurable.³

An effective treatment plan is based primarily on biological behaviour

Prior to starting a combination treatment for patients with colon cancer and liver metastases, a physical examination, a staging TAC scan total body with contrast, and a nuclear MRI of the liver with liver-specific contrast must be performed.

To rule out extrahepatic metastases, bone tests, brain MRIs, and PET/CT scans are optional extras.

The biological behavior criterion must be satisfied in order to determine whether surgery is required. After surgery for liver metastases, the oncological prognosis of patients is more affected by the tumor’s biological behavior. The most popular method for assessing tumor biology is the clinical risk factor (CRS) score system, which Fong et al⁴ established in 1999. However, there isn’t a single, accepted gold standard for this method. It consists of five indicators: (1) more than one liver metastasis; (2) a 12-month interval between the main tumor excision and metastasis; (3) the largest metastases are larger than 5 cm; (4) the carcinoembryonic antigen (CEA) level is greater than 200 ng/mL. The first indicator is a positive primary tumor lymph node. The 5-year survival rate for patients with a CRS score of 0 was up to 60%, whereas that of patients with a score of 5 was only 14%. Every point was recorded as one. The CRS scoring system is still the most important prognostic scoring technique in use, notwithstanding its flaws. Additionally, a prior retrospective study by Adam found that the prognosis following surgical resection is also impacted by the patient's responsiveness to preoperative chemotherapy. After liver metastasectomy, the patient’s recurrence is more common when the response to neo adjuvant chemotherapy is poor. Following surgical resection, the 5-year survival rate for patients who progressed on preoperative chemotherapy was only 8%, while the rates for patients who had partial response (PR) and stable disease (SD) were 37% and 30%, respectively. However, it should be noted in this research that tumor formation after treatment is not always strictly prohibited.⁵ The genetic nature of the tumor also affects the prognosis after surgical excision; the majority of research has focused on the RAS and BRAF genes.^6–8 Additional indicators of biological activity include tumor growth pattern, molecular subtypes, and pathological grading of tumor regression after treatment. It is clear that a number of variables affecting how people with CRCLM behave biologically may need to be combined. In a recent study,⁹ a novel scoring method known as Genetic and Morphological Evaluation (GAME) was presented. Six risk variables were identified by combining the genotyping of CRCLM with clinical characteristics: a high tumor burden (determined by the greatest diameter and number of metastases), extrahepatic metastases present, positive primary tumor lymph nodes, and a CEA level ≥ 20 ng/mg. The study validated the GAME and CRS scores in two large CRCLM populations at New York Memorial Hospital and Johns Hopkins Hospital. Additionally, it proved that GAME scores were eventually more likely to replace CRS scores. This illustrates how challenging and opaque assessing tumor biology may be. To be explicit, in the discussion that follows, we categorized CRCLM into two groups: “patients initially NED-eligible” and “patients initial non-NED-eligible” based on the technical feasibility of locoregional therapy to achieve the goal of NED. Systemic therapy administered to CRCLM patients who are initially NED-eligible before to surgery, or who are not initially NED-eligible prior to potential locoregional treatment, is known as neoadjuvant therapy (described below).

Strategies of treatment in resectable patients

For CRCLM who are initially eligible for NED, everyone agrees that effective systemic therapy and local treatment are critical. The EPOC study was the first phase III randomised controlled trial (RCT) to demonstrate that liver resection plus perioperative chemotherapy increased survival compared to surgery alone in patients with resectable CRCLM. Following perioperative chemotherapy, the 3-year DFS rose from 33.2% to 42.2%.^10,11 It is possible to resect CRCLM, and FOLFOX and CAPEOX are the recommended neoadjuvant treatments. According to 2021 National Comprehensive Cancer Network (NCCN) guidelines,¹² it is also possible to conduct primary CRC resection followed by chemotherapy and liver resection, with adjuvant treatment advised postoperatively. Creating a treatment plan for a specific patient involves numerous factors, the first of which is figuring out which patients require neoadjuvant therapy.

Patients with resectable liver metastasis and good biological behavior

There are advantages and disadvantages to neoadjuvant therapy. Determining whether patients are most suitable for neoadjuvant chemotherapy or a surgery-first strategy is critical. A multicenter retrospective investigation of 364 patients with resectable CRCLM was carried out in 2015 by Ayez et al.¹³ The group with a high CRS score (3–5) showed a substantial increase in survival after receiving neoadjuvant chemotherapy, whereas those with a low CRS score (0–2) showed no improvement in survival. The Annals of Surgery released the first prospective RCT on surgical sequencing in 2021. The results showed that the simultaneous removal of the primary and metastatic lesions was superior to the colon-first method. It’s crucial to remember that while more than 41.2% of patients in this study had only one liver lesion, 27% of patients in this study had two.¹⁴ Somewhat well, the tumors in these people behave biologically. Consequently, it is acceptable that surgery be done first, followed by adjuvant chemotherapy, for patients with a low CRS score (0–2) who are technically simple to resect.

Neoadjuvant treatment in patients with high-risk characteristics

Reddy et al¹⁵ performed a retrospective review on 499 CRCLM cases that were originally treatable at three US medical centers in 2009. The 202 patients who had surgery initially had a median OS of 76 months, compared to the 297 that were addressed to neoadjuvant patients. The neoadjuvant group tended to have a higher proportion of combined radiofrequency, more difficult liver resections, more liver metastases, and more positive lymph nodes. Nevertheless, there was a evident bias in the treatment selection procedure. Similar results were obtained in a 2012 study by Pinto Marques et al¹⁶ that looked at data from 676 CRCLM with hepatic metastases reectable d’emblee. In a survey done by Professor Adam’s,¹⁷ observed that neoadjuvant therapy was observed to offer a survival advantage when the diameter was higher than 5 cm or the metastatic number was greater than 3.

An expert agreement from Europe in 2009¹⁸ offered more complete instructions, stating that if the patient had a CRS score of > 2, neoadjuvant chemotherapy with surgical resection was recommended. Surgery should only be performed first for CRCLM that is initially resectable if there is a single metastasis that is less than 2 cm in size, according to the 2012 ESMO recommendations.¹⁹ The 2016 ESMO recommendations²⁰ state that consideration should be given to the tumor's biological behavior and the surgical technique for tumor removal when making the first decisions regarding CRCLM. In this case, neoadjuvant therapy is recommended for patients exhibiting poor prognostic indicators or technical challenges.

FOLFOX as gold standard regimen of chemotherapy in neoadjuvant setting

The only neoadjuvant chemotherapy that has been RCT-validated for resectable CRCLM is FOLFOX, which was used in the EPOC study and is now considered standard of care in this setting. Because the CAPOX regimen has been shown to be just as well as FOLFOX in treating advanced CRC, it is also commonly used in clinical practice. The combination of targeted therapy is more debateable. There are differences between the NCCN guidelines and the ESMO recommendations. In addition, the outcomes of the only noteworthy, randomized phase III trial in this area, NEW EPOC,²¹ led to modifications in both ESMO and NCCN guidelines. The NEW EPOC trial was conducted to investigate whether three months of preoperative FOLFOX plus Cetuximab (Cet) was more effective than FOLFOX alone in treating initially resectable CRCLM. In the experimental arm median progression-free survival (PFS) was 14.8 months, while in the control arm was 24.2 months. In the Cet arm the PFS was significantly shorter. In the context of neoadjuvant therapy, a phase III RCT has not yet been conducted on bevacizumab (Bev), another targeted drug that affects neo angiogenesis. The only phase II studies that show good objective response rates (ORR) when Bev is coupled with FOLFXIRI or FOLFOX/CAPOX are currently available in the literature. However, in 2017, the NCCN guidelines edition removed all targeted therapies from the neoadjuvant setting for in resectable CRCLM because of the unfavorable outcomes of NEW EPOC. In 2016, however, the ESMO recommendations²⁰ did not exclude targeted agents, stating that there is still disagreement about the best preoperative treatment for CRCLM that is technically resectable but associated with one or more poor prognostic variables. When these patients have a significantly lower chance of recovery, a more intensive treatment may be considered, such as doublet cytotoxic chemotherapy plus a targeted therapy or FOLFOXIRI triplet chemotherapy alone or in combination with Bev. Although the ESMO panel gave this suggestion a level of evidence of V, the panel consensus was more than 75%, indicating that clinical practice has come to a broad consensus on this issue. In addition, we need to be aware of the criteria for resectable liver metastases in RCTs and clinical practice. Only 53% of patients in the NEW EPOC study had a maximum lesion larger than three centimeters, and only 25% had a CEA greater than 30 ng/mL. Seventy-seven percent of patients had one to three intrahepatic metastases. It was discovered that the majority of CRCLM included in the NEW EPOC study had a good tumor biology and were technically simple to resect. Because of this, we do not, in our experience, recommend targeted therapy for patients who meet the inclusion criteria of the NEW EPOC study. That being said, targeted therapy should not be eliminated in situations involving complex surgical resection and poor tumor biological behavior (e.g., more than five metastases or a high risk of CRS score). RCT, however, must provide more robust trials.

Treatment for patients not resectable

In addition to targeted therapy, patients who are either potentially resectable or not a candidate for surgery should undergo chemotherapy, according to NCCN recommendations. The disease’s state would be assessed every two months, and locoregional therapy might be used if it was found to be NED-eligible; postoperative adjuvant therapy is also required.¹² Additionally, the guidelines highly recommend routine testing for the existence of the RAS, BRAF gene mutation in individuals with mCRC. When used as neoadjuvant therapy, triplet chemotherapy regimens have been demonstrated to yield better results in multiple clinical trials; additionally, the use of targeted therapy may enhance the effects. As demonstrated by the findings of GONO, a phase III RCT,²² the FOLFOXIRI regimen enhanced the conversion rate of R0 resection in CRCLM patients when compared to the FOLFIRI regimen: 36% versus 12%. It also extended median OS: 23.4 versus 16.7 months. The TRIBE study compared FOLFOXIRI with Bev with FOLFIRI and Bev in the first-line therapy of patients with CRCLM.²³ In the experimental arm, the median OS was 29.8 months, while in the control arm it was 25 months.

Bev + FOLFOXIRI was compared to mFOLFOX6 plus Bev in the OLIVIA study, a phase II randomized controlled experiment. The FOLFOXIRI Bev group, with similar median PFSs of 18.6 months and 11.5 months,²⁴ had greater rates of resection and R0 resection (61% against 49% and 49% versus 23%). The TRIBE2 investigation from 2020 reported a similar result.²⁵ As a result, the triplet regimen provides improved oncological outcomes: improved OS, improved PFS, and improved ORR. These improvements would increase the chance of conversion when used in conjunction with targeted therapy or chemotherapy alone. It is currently accepted that adding a targeted therapy will raise the conversion rate. The CRYSTAL study²⁶ found that in patients with KRAS wild type, FOLFIRI with Cet led to better results than FOLFIRI alone. While several studies have offered conflicting views on the most effective targeted medication, some have suggested Cet.²⁷ However, other research did not discover a statistically significant distinction between them.²⁸ Multidisciplinary team (MDT) should reevaluate liver metastases for NED eligibility two months after initiating systemic medication, and should promptly offer locoregional treatment, including surgical removal, if appropriate. If NED is not obtained after 6–8 months of chemotherapy, it is recommended to adjust the regimen in an attempt to try conversion again. Palliative care is recommended for patients who are intolerable, resistant to changing their course of therapy, or who show no improvement with palliative care. In the clinical context, we sometimes see patients whose intrahepatic metastases were diffuse at diagnosis; however, after neo adjuvant systemic chemotherapy, the majority of the metastases disappeared, enabling the patient to get locoregional therapy and eventually become NED (Fig. 1).

Figure 1. Flowchart of treatment of colorectal cancer patients with liver metastases. NED, no evidence of disease; MDT, multidisciplinary team.

Individualized treatment is an important focus in the future

With the increasing number of patients that can be brought to the operating table and the shrinking boundaries of liver surgery, the MDT surgeon not only needs to possess special technical skills but also needs to be aware of the various biological features of each case that is presented for liver surgery.

Surgical oncology is based on the same basic ideas as oncology. Currently, intrahepatic lesions failing to reach NED and residual liver volume less than 30% are considered absolute contraindications for liver surgery. The associated contraindications include intrahepatic lesions that require complex techniques to change in order to accomplish R0 surgical resection.

According to Adam et al,²⁹ extrahepatic metastases and tumor numbers greater than five, tumor development following therapy, and technically resectable but assessed to be at high risk of recurrence after resection are all considered relative contraindications. Based on the biology of each patient's disease, we should choose the optimal course of action for each while pursuing technical breakthroughs and adhering to current statements. A large number of carefully designed trials that show clinical management are still needed to explore the limit of surgical NED.

To summarize, patients with liver metastases and colon cancer exhibit significant variability. Patients that meet both the technical and physiological requirements for NED are typically the ones who benefit from locoregional treatment. When selecting neoadjuvant therapy or postoperative adjuvant therapy, the patient's risk factors are taken into account. In order to provide the best possible outcome for each patient, the MDT must integrate locoregional treatment with systemic treatment. Numerous publications have shown that a multidisciplinary approach to tumor treatment can lead to statistically significant improvements in outcomes when compared to an individual approach.

None.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.