Xinyu Qin, Jianmin Xu and Yunshi Zhong (eds.)Multidisciplinary Management of Liver Metastases in Colorectal Cancer10.1007/978-94-017-7755-1_17

17. Targeted Therapy of Colorectal Cancer Liver Metastasis

Jun Zhou¹ and Lin Shen¹

(1)

Department of Gastroenterology, Beijing Cancer Hospital, Peking University School of Oncology, Beijing, China

Lin Shen

Email: lin100@medmail.com.cn

17.1 Introduction

The liver metastasis is the main death cause of the colorectal cancer. About 20 % of patients at first diagnosis have liver metastasis; besides, in the follow-up after colorectal cancer operation, there will be 20–45 % of patients with liver metastasis. This means that at least half of patients with colorectal cancer will have liver metastasis during the development of the colorectal cancer.

Surgical removal is the only radical means to completely treat the colorectal cancer liver metastasis. However, in patients who are first discovered with colorectal liver metastasis, only 20 % can accept liver surgery whose aim is completely treatment. There are some patients who belong to potential liver metastasis cutoff group. These patients can be carried on with the preoperative rational treatment to possibly achieve the removal purpose. Of course, there are some patients that had already lost the opportunity of radical resection surgery when founded, but if the drugs or other means can achieve apparent effects, then there is still 7–14 % who can transfer to liver metastasis which can be carried on with radical resection surgery.

For the patients with inoperable liver metastasis, the median survival is less than 20 months; the 5-year survival rate is less than 5 %. In contrast, according to current literature reports, the 5-year survival rate of the patients with resectable colorectal cancer liver metastases is up to 20–58 %. And, for the initial unresectable patients, if the adoption of new adjuvant therapy can achieve the resectable aim, then the 5-year survival rate of these patients can be close to that of the initial survival of resectable patients with the same level.

Therefore, the opportunity to access to curative liver resection is the most influential factor whether the patients with liver metastasis of colorectal cancer can be long-term survival. This aim has not only become a main problem in the comprehensive treatment of liver metastases of colorectal cancer but also is one of the major pursuing goals of neoadjuvant chemotherapy or targeted therapy.

17.2 The Neoadjuvant Chemotherapy of Colorectal Cancer Liver Metastasis

The meaning of neoadjuvant chemotherapy is that for colorectal cancer liver metastases which can be removed, we can reduce the metastatic tumor burden and liver damage, prevent recurrence, and prolong the disease-free survival term. The initial state of inoperable colorectal cancer liver metastasis and the drug treatment before surgery can make some patients access the opportunity of surgery treatment and obtain long-term disease-free survival. Recent studies indicate that the higher the chemotherapy remission rate in patients with colorectal liver metastases, the higher the cut rate. In 2005, Folprecht et al. published an important review in Annals of Oncology. In the paper, the researchers conclude many period II/III clinical studies on the new adjuvant treatment of unresectable liver metastases. The results show that the remission rate and the cutoff rate of the unresectable liver metastasis of patients are significantly positively correlated (r = 0.96, P = 0.002). Not only that, the study also shows that even for patients with liver metastases without the initial choice, the remission rate and the cut off rate are also clearly related (r = 0.74, P < 0.001).

Therefore, a reasonable choice of neoadjuvant chemotherapy and the achievement of the chemotherapy remission rate as far as possible in a short time have become important therapeutic targets of the potentially resectable or unresectable liver metastasis of colorectal cancer. Combination of three drugs in the program, FOLFOXIRI program (5-FU + oxaliplatin + irinotecan), has higher performance and higher operation resection rate in the treatment of colorectal liver metastasis than those of two-drug combination rate but higher side effects, so that people have some worries about their clinical application. So what kind of programs can further improve the remission rate on the base of the existing chemotherapy?

In recent years, targeted drugs are generally the epidermal growth factor receptor (EGFR) monoclonal antibody and vascular endothelial growth factor monoclonal antibody and chemotherapy, which are used in advanced colorectal cancer and significantly improve the patient’s chemotherapy benefit. At the same time, because the adverse effects of EGFR monoclonal antibody are particular mild, this accordingly makes the drugs in combination of two targeted chemotherapy drugs becomes a new direction in new adjuvant treatment of colorectal cancer liver metastases.

17.3 Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody

Currently, the recommended EGFR monoclonal antibodies for advanced colorectal cancer include cetuximab and Jesper monoclonal antibodies. A large number of clinical studies approve that only the KRAS wild-type tumor tissue patient can benefit from the EGFR monoclonal antibody treatment. Currently, it is only recommended for this type of patients. Among all kinds of treatments, the efficiency of combination of the antibody with the chemotherapy is 10 % higher than that of the chemotherapy alone. Especially the efficiency of the first-line treatment with the chemotherapy can reach 65 % and efficacy in patients with liver metastasis is up to 77 %. It is reasonable to expect such a high remission rate in patients with colorectal cancer can bring high removal rate.

17.3.1 Cetuximab Monoclonal Antibody

17.3.1.1 The Study on the Irinotecan Combination

In 2005, Peeters et al. published a clinical study result. In forty-two cases of unselected patients with advanced colorectal cancer who received FOLFIRI + cetuximab combined chemotherapy, the effective rate is 45 %, eight of them received R0 resection of liver metastasis after chemotherapy, and the resection rate is19 % [3].

In 2006, Folprecht et al. published a phase I/II clinical study result. In twenty-one unselected advanced colorectal cancer (liver metastasis or extrahepatic metastasis) patients who received irinotecan weekly programs (AIO) + cetuximab combined chemotherapy, the effective rate was 67 % (14/21), four of them received R0 resection of liver metastasis, and the resection rate is 24 % [2].

In 2007, Min et al. published a phase II clinical study result. In twenty-three patients with initial unresectable liver metastasis of colorectal cancer who received FOLFIRI + cetuximab combined chemotherapy, the effective rate is 39.1 % (9/23), seven of them received radical resection of liver metastasis, and the resection rate is 30.4 % [1].

CRYSTAL study is a phase III clinical experiment aiming to the first-line treatment for advanced colorectal cancer. The results are published in the New England Journal of Medicine in April of 2009. 1217 patients with positive expression of EGFR who have lost opportunities for radical surgery were randomly enrolled into the FOLFIRI + cetuximab combined chemotherapy group or FOLFIRI chemotherapy-alone group. The proportion of patients receiving follow-up surgery after chemotherapy in united targeted drug group and the chemotherapy group are 6 % and 2.5 %, respectively. And the difference between R0 resection rate is three times (4.3 % and 1.5 %). Further analysis revealed that among the K-ras wild-type-alone liver metastasis patients, the efficiency of the combined targeting drug therapy group can be up to 77 %, far higher than 50 % of the chemotherapy-alone group. And the joint targeting group’s R0 resection rate of liver metastasis is 9.8 %, while the resection rate of the chemotherapy-alone group is only 4.5 % [4]. CRYSTAL study is a phase III randomized controlled clinical study; from a more advanced level of proven evidence-based medicine, it is approved that improvement of the remission rate of tumor can increase the resection rate; even in the patients whose initial judge is unresectable, we also should make each effort to get re-excision opportunities for patients.

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