Recent advances in treatment for colorectal liver metastasis

Abstract A major challenge for the management of colorectal liver metastasis (CRLM) is the multidisciplinary approach including surgery. Resection is the most important treatment strategy to prolong the survival of patients with colorectal cancer (CRC). Even when resection is not possible as a primary treatment, it may still be carried out for curative intent after effective chemotherapy. Therefore, resection should always be considered when conducting chemotherapy for CRLM. Neoadjuvant anti‐epidermal growth factor receptor (EGFR) antibody has shown a high response rate for RAS wild CRC. However, whether anti‐EGFR antibody is superior to antivascular endothelial growth factor antibody for all types of CRLM is yet to be determined. Recently, several randomized control trials of first‐line therapy for advanced CRC have been conducted, and some of them are ongoing. The optimal chemotherapy regimen and tumor biology indicated for neoadjuvant chemotherapy as well as conversion surgery are expected to be determined in the near future.

metastases depend on their resectability. 6 Similar guidelines are applicable for metachronous cancers. However, if the metastases are assessed as resectable, surgery is carried out, whereas systemic chemotherapy followed by evaluations for resectability every 2 months is recommended for unresectable liver metastases.
Even cases with multiple metastases can now be cured after resection as a result of recent advances in operative methods and chemotherapy. [7][8][9] Herein, we review and summarize the treatment options for CRLM. We also discuss recent advances in biomarker research for treatment decisions for liver metastasis.

| CATEGORIE S AND GUIDELINES FOR COLORECTAL LIVER METASTASIS
Japanese Society for Cancer of the Colon and Rectum has proposed a classification scheme for CRLM that combines findings of the presence or absence of liver metastases and number and size of metastases.
Analysis of registry cases using this classification scheme shows that the proportion of patients undergoing liver resection in categories H2 and H3 are smaller and that the prognoses are poorer than those in H1. 10 According to the JSCCR guidelines for the treatment of CRC, curative liver resection is recommended if the liver can be resected without leaving residual metastases, if the primary tumor is controlled or can be controlled, if there are no extrahepatic metastases or they can be controlled, and if remnant liver function can be preserved after resection. 11 NCCN guidelines 12 indicate that the treatment options for liver or lung-limited synchronous metastases depend on their resectability. Similar guidelines are applicable for metachronous cancers. The European Society for Medical Oncology guidelines 13 propose that treatment selection should be guided by the treatment intensity deemed necessary in advanced or recurrent CRC. In cases of wild-type liveronly disease, two-drug combination chemotherapy plus bevacizumab (Bmab) or cetuximab (Cmab) is recommended. Moreover, if the metastases are found to be resectable, resection is advised.
In Europe, Nordlinger et al 14  Not optimally resectable is defined as "difficult to resect for technical reasons (proximity to hepatic vein and portal vein branches)" or "technically possible to resect, but oncologically problematic (number of liver metastases greater than four, maximum diameter 5 cm or more, synchronous liver metastases, primary lymph node metastasis positive, and high levels of tumor markers)." Chemotherapy in combination with molecular targeted drugs is recommended, followed by curative resection if a response is achieved.

| LIVER RESECTION FOR CRLM
No standard rules for liver resection after chemotherapy have been established. If the metastasis is technically resectable, then liver resection is usually carried out regardless of the number of tumors.
Patient treatment varies substantially among institutions. However, many observational studies reported that resection of liver metastases yielded good long-term prognosis. [15][16][17][18] The Japanese Society of Hepato-Biliary-Pancreatic Surgery assessed perioperative factors in 727 hepatectomized patients with CRLM between 2000 and 2004 at 11 institutions. They reported 3-, 5-, and 10-year disease-free survival (DFS) and overall survival (OS) rates of 31.2% and 63.8%, 27.2% and 47.7%, and 24.7% and 38.5%, respectively. They created a nomogram that included six preoperative factors such as synchronous metastases, primary lymph node metastasis, number of tumors, extrahepatic metastasis at hepatectomy, and preoperative tumor marker level to predict the prognosis of patients with CRLM. 19 Meanwhile, Adam et al 3 reported that the 5-year survival rate was higher at 33% in patients who underwent chemotherapy followed by liver resection after an initial assessment of unresectable metastases than in patients who did not undergo liver resection at near 0%. In a clinical study in patients with either liver-only metastases from CRC or advanced or recurrent CRC, Folprecht et al 4 found that response rate was strongly associated with resection rate for metastases (liver-only metastases from CRC, respectively. This result showed that 50% of patients survived more than 5 years after conversion surgery. Thus, conversion surgery is considered to contribute to prolonged survival in this patient population. To improve the resection rate of liver metastasis, portal vein thrombosis, two-step surgery, and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) have been conducted. 23 ALPPS is a unique two-step hepatectomy technique for obtaining adequate but short-term parenchymal hypertrophy in oncological patients requiring extended right hepatic resection with limited functional reserve. 24 ALPPS improves the resectability of CRLM compared with conventional two-stage hepatectomy. However, ALPPS is still being developed and is associated with high morbidity and mortality. Moreover, the oncological long-term outcome remains ambiguous. Another study showed that stimulation of liver hypertrophy could accelerate tumor progression. 25 An observational study on ALPPS 26 aimed to compare the outcomes of ALPPS in patients with otherwise unresectable colorectal liver metastases and in matched historical controls treated with palliative systemic treatment. In this analysis, unresectable patients who required ALPPS were determined according to at least two of the following criteria: ≥6 metastases, ≥2 future remnant liver metastases, and ≥6 involved segments excluding segment 1. The authors concluded that ALPPS was not superior to systemic treatment with palliative intent. One reason for this result is that the short interval (median 11 days) between stages 1 and 2 of ALPPS does not allow sufficient time for detection of disease progression. Therefore, ALPPS can be used in limited cases only, and two-stage hepatectomy remains the standard treatment option for multiple liver metastasis.

| ABLATION THERAPY FOR CRLM
Although surgical resection is considered the gold standard for treatment of CRLM, only 10% to 20% of patients with liver metastases are deemed resectable. Metastasis is sometimes contraindicated for surgery because of anatomical reasons. Moreover, patients sometimes have comorbidities or liver dysfunction. In these cases, the patient is ineligible for major surgery. Instead, radiofrequency ablation (RFA) is often applied; however, the role of RFA in the management of CRLM is yet to be elucidated. The CLOCC trial randomized 119 patients with unresectable CRLM between RFA with FOLFOX (AEbevacizumab) vs FOLFOX (AEbevacizumab) alone. 27 The authors reported the superiority of RFA with FOLFOX (HR = 0.58, 95% CI: 0.38-0.88, P = .01). Other recent observational studies also showed the superiority of RFA combined with chemotherapy or surgery in terms of prognosis. [27][28][29] However, some studies have reported the risk of dissemination or incomplete ablation of RFA; therefore, the role of RFA for CRLM is controversial. In general, RFA should be considered in patients who are ineligible for resection as a result of anatomically unresectable lesions, functional insufficiency of hepatic reserve, medical comorbidities, and extrahepatic metastases.

| FOLFOX OR FOLFIRI FOR CRLM
According to previous clinical studies, the resection rate for liver metastasis is higher than that in other sites ( Table 1). Selection of chemotherapy regimen is important for CRLM because some unresectable cases can become resectable after chemotherapy. However, the optimal chemotherapy regimen for CRLM is yet to be determined. Whether FOLFOX is better than FOLFIRI or vice versa as a baseline regimen remains unclear. A study conducted by Tournigand et al 30 to compare the usefulness of FOLFIRI vs FOLFIRI followed by FOLFOX as second-line therapy in advanced or recurrent CRC after first-line FOLFOX chemotherapy showed that the rate of liver resection in the FOLFIRI-first group was 9% vs 22% in the FOLFOX-first group (P = .02). Therefore, FOLFOX is often preferred for CRLM.
Neoadjuvant chemotherapy is sometimes associated with pathological changes of the liver parenchyma, leading to concerns about toxicity to the remnant liver. There are two types of liver injury: the first involves vascular changes caused by oxaliplatin-based chemotherapy (sinusoidal dilatation with engorgement of red blood cells associated with sinusoidal obstruction syndrome such as that seen in perisinusoidal fibrosis or venous obstruction), 31 and the other is steatohepatitis (with severe steatosis, lobular inflammation, or hepatocyte ballooning) caused by irinotecan-based chemotherapy.
Steatohepatitis as a result of irinotecan-based chemotherapy possibly increasing the 90-day mortality rate (14.7%) is a cause for concern. 32 In combination with chemotherapy, the antiangiogenic drug bevacizumab protects against pathological changes of the liver parenchyma caused by chemotherapy, and its pathological benefits suggest that it could potentially improve prognosis.  In the clinical studies that target unresectable CRC, the resection rate of liver metastasis is 4% to 15% [38][39][40]44,45 (Table 1). However, in these trials, the patient with liver metastasis was not an allocation factor; thus, exact evaluation of the effect of chemotherapy for liver metastasis is difficult.
In clinical studies that targeted liver-only metastasis (Table 2), the anti-epidermal growth factor receptor (EGFR) antibody cetuximab excellently improved the response rate and yield of curative liver resection, for which it has attracted attention. However, the definitions of unresectable liver metastasis in each clinical study for liver-only metastases from CRC varied among these studies (Table 3).
Folprecht et al 46 reported the results of a randomized phase II study of FOLFOX/FOLFIRI plus cetuximab in patients with liver-only metastases from CRC. Among the 106 patients evaluated, the response and R0 resection rates were 68% and 38%, respectively, in the 53 patients receiving FOLFOX plus cetuximab, whereas they were 70% and 33%, respectively, in the 67 patients with KRAS wild-type status.
Addition of irinotecan in the 5-fluorouracil/folinic acid, oxaliplatin, irinotecan (FOLFOXIRI) regimen is effective for tumor shrinkage in CRLM. 47 The OLIVIA trial assessed the efficacy of bevacizumab plus modified FOLFOX-6 or FOLFOXIRI for patients with initially unresectable CRLM. Overall tumor response rate of the FOLFOXIRI arm was 81% (95% CI: 65%-91%), and the overall resection rate was 61% (95% CI: 45%-76%). 47 FOLFOXIRI + BV is also Regarding anti-EGFR antibody, panitumumab is effective for increasing the overall response rate (ORR) and resection rate. 48,49 However, when determining the optimal multidisciplinary treatment strategy for KRAS wild-type liver-limited, initially unresectable CRC, no unequivocal evidence shows that molecular targeted therapy in combination with chemotherapy is better with either anti-VEGF antibody or anti-EGFR antibody despite the presence of data suggesting that "liver resection rate," "improvement of response rate," and "pathological improvement" improve prognosis.   Tumor biology should be further studied for precise treatment of CRLM.
F I G U R E 1 Treatment flow for colorectal cancer liver metastasis. EGFR, epidermal growth factor receptor; 5-FU/LV, fluorouracil/leucovorin In the process of liver resection, the liver surgeon first determines whether or not a liver metastasis is resectable; one to three liver metastases within 5 cm can be resectable, but the judgment of the liver surgeon is necessary because factors such as location of the liver metastasis, liver function, and patient condition should be considered carefully Figure 1 shows CRLM treatment.
Liver metastases are classified into three types as follows: resectable, resectable but not suitable; and unresectable. The resectable cases should undergo resection first but chemotherapy should be given after resection. The resectable but not suitable cases and the unresectable cases should be given chemotherapy, but the choice of chemotherapy depends on tumor location and RAS and BRAF mutation status. In the case of RAS mutant, FOLFOXIRI + BV is highly recommended, but FOLFOX + BV is another choice. In the case of BRAF mutant, FOLFOXIRI + BV is strongly recommended. In the case of RAS wild and right-side CRLM, FOLFOX + anti-EGFR antibody is recommended in terms of response rate, but FOLFOX/FOLFIRI + anti-EGFR antibody should not be used for long periods without confirmation of tumor response. If tumor reduction is less than 30% 8 weeks after the start of treatment, the regimen should be changed to FOLFOXIRI + Bmab or FOLFOX/FOLFIRI + Bmab.
In the case of RAS wild and left-side CRLM, FOLFOX and anti-EGFR antibody are recommended.
In all cases, the liver metastasis should be re-evaluated at the eighth week of treatment. Resection should always be considered, and the chance for resection should not be overlooked, particularly in the resectable but not suitable cases.

| CONCLUSION
Because many agents have been developed in this decade, a proportion of CRLM cases have changed to curative disease. Patients with CRLM are considered to have stage IV disease, but they are always potential candidates for curative resection, if the metastases are limited within the liver. Therefore, the goal of chemotherapy is conversion surgery for curative intent. In these situations, optimal multimodality treatment option that includes chemotherapy, surgery, and radiology is essential.