Number of cases
First year (%)
Third year (%)
Fifth year (%)
Site of intersection of the rectum and sigmoid colon
Ulcer fungiform or ulcer infiltration type
19.2 Prevention of Postoperative Liver Metastasis of Colorectal Cancer by Neoadjuvant Therapy (Preoperative Interventional Chemotherapy)
19.2.1 Advantages of Neoadjuvant Therapy
The neoadjuvant chemotherapy is a systematic chemotherapy applied for the treatment of cancer, before radical surgery or radiotherapy, also known as preoperative chemotherapy. Since 1982, Frei firstly proposed the concept of neoadjuvant chemotherapy, and thereafter its clinic effect and value were recognized gradually. According to the theory of first-order kinetics of Skipper , administration of a certain amount of anticancer drugs can only kill a certain percentage of cancer cells, which is not associated with the number of cancer cells existing in the treatment, that is, it is not a fixed number of cells, which provided the basis for the preoperative chemotherapy. Therefore, administration of sufficient large dose of anticancer drugs within the tolerance range of the patients is allowed. The proportion of the proliferating cells among the tumor cell is called growth fraction (GF). During the early stage, there are fewer tumor cells, GF is greater, and the time of growth is short, relatively sensitive to the cell-cycle-specific drugs. And in the advanced tumor, the number of the tumor cells increases, GF decreases, and the time of growth extends, which reduces the sensitivity to the cell-cycle-specific drugs, but at this time, the use of a large dose of cell-cycle-specific drugs may reduce the volume of the tumor cells and promote the increase of the GF, and the sensitivity of the cell-cycle-specific drugs will increase. Therefore, before resection of primary foci of the tumor, administration of chemotherapy drugs is sensitive and effective to the treatment of small cancer foci; besides, it also has killing effect on the primary focus. Therefore, theoretically the earlier the chemotherapy is given, the less the drug-resistant cell strains. Moreover, many animal model tests showed that after the tumor resection, the stimulating factors to promote the cancer cell growth would be induced to accelerate the metastasis focus growth, inducing the cancer cells to form the clones with the anti-chemotherapy drug characteristics. In addition, through the preoperative chemotherapy, the number of the tumor cells reduces, thus inhibiting the production of such growth-stimulating factor and slowing down the growth of the metastasis foci. Compared with postoperative chemotherapy, the advantages of the neoadjuvant chemotherapy are as follows:
Prevent the change of the postoperative tumor blood supply from affecting the chemotherapeutic effect. After the surgery, the vascularity of the primary lesions is changed, and the scar and the changed vascularity cannot achieve an effective concentration of residual lesions after chemotherapy. But preoperative chemotherapy has no such problems. Schuhmacher CP et al. discovered that  the patients who have complete remission from the neoadjuvant chemotherapy have a significant improvement on the survival rate. And it is believed that the preoperative chemotherapy can realize the cytotoxic drugs to access to the tumor through the complete tumor blood vessels, thus avoiding the reduction of the concentration of chemotherapeutic drugs in the residual tumor tissues due to the destruction of tumor blood vessels after surgery.
Control and kill the small clinical or subclinical metastases and reduce the postoperative recurrence and metastasis .
Most of the preoperative patients can tolerate the higher doses of chemotherapeutic drugs, and the acute toxicity reactions can be reduced.
Reduce the clinical staging, shrink the primary focus, and increase the surgery opportunity.
The observation of the pathological results of the surgical specimens can help to understand the sensitivity of the tumor on the chemotherapeutic drugs and help the selection of the postoperative chemotherapy drugs.
Rule out the patients that are not suitable for surgery. Some tumors of poor biological actions advance rapidly and during the chemotherapy period, the wide local infiltration and remote metastasis may occur. For such patients, even if surgical resections are conducted, they can relapse rapidly.
For the patients of non-metastases of colorectal cancer, whether or not they should accept the neoadjuvant chemotherapy, the “guidelines of diagnosis and comprehensive treatment of liver metastases of colorectal cancer draft” (2009 edition) specifies that “generally, the stage III preoperative patients, if they have no bleeding, obstruction or perforation, etc., can accept the neoadjuvant chemotherapy, with the regimens of FOLFOX, capecitabine alone or 5-FU/LV and the recommended time is 1–3 months before the surgery” [4, 5].
However, there are no EBM evidences for the patients of non-metastases of colorectal cancer for whether or not to accept the neoadjuvant chemotherapy (intravenous chemotherapy). But as recommended by the NCCN Guidelines of Colon Cancer in 2010, these patients are not applicable to accept the neoadjuvant chemotherapy (intravenous chemotherapy), but directly accept the surgery.
Since the higher recurrence rate and demanding for continuing the physiological functions after radical resection of rectal cancer, the neoadjuvant therapy of rectal cancer mainly focuses on the combined therapy of preoperative local radiotherapy and chemotherapy, to enhance the R0 operative resection rate and reduce the local recurrence rate. But there is no great significance of improving the patients’ overall survival [6–9].
19.3 Local Artery Infusion Chemotherapy (Interventional Chemotherapy) Can Enhance the Local Drug Concentration, and the Drugs Flowing Back to the Liver Can Reduce the Incidence of Liver Metastasis
How to further improve the efficacy and targeting of neoadjuvant chemotherapy is an urgent issue to be solved. The traditional intravenous injection was applied earlier, easy to do but with great side effect, and the effective concentration cannot be met in the local part of the tumor and easy to produce drug resistance. Therefore, people try to find more effective chemotherapy drugs and better chemotherapy regimen to enhance the effect of the intravenous chemotherapy. With the progress of the interventional radiology techniques, the chemotherapy drugs can be delivered to the major feeding arteries of the primary tumor or tumor metastases directly through the selective arterial cannula, that is, preoperative interventional chemotherapy, which is featured by strong selection, centralized drug administration, and high concentration of drug in the foci as well as small systematic toxicity reaction. Clinically, the femoral artery puncture (Seldinger method) is generally adopted for the preoperative intervention. The chemotherapy drugs are injected to the major feeding arteries through the superselective arterial catheterization. For patients whose tumor’s nutrition blood vessels cannot be judged directly, the tumor staining method can be adopted to judge the sources of the major blood supply and then superselective arterial catheterization is adopted. In addition, intraperitoneal chemotherapy is a highly selective local drug treatment method, with significant pharmacokinetic advantages compared with the venous chemotherapy. The high concentration of chemotherapy drugs in the enterocoelia is absorbed through the peritoneum, after through the portal vein system and the retroperitoneal lymphatic system, that involves the blood circulation, which consists of the blood dissemination and lymphatic metastasis paths of the digestive tumors. The preoperative intraperitoneal chemotherapy can improve the concentration and the action time of the chemotherapy drugs of the peritoneum, tumor tissue, and the related lymph nodes, which can help to reduce the intraoperative iatrogenic cancer cell dissemination, eliminate the subclinical or small peritoneal metastases, and has better curative effect of control over the postoperative peritoneal recurrence, lymph node metastasis, and reduction of liver metastasis .
Compared with traditional intravenous chemotherapy drug application, the intervention chemotherapy can realize the onetime administration of drugs through the major nutrition artery of the tumors, and over two thirds of the drugs will produce effect in the local tumors. The pharmacokinetic studies have shown that there is obvious dose-effect relationship between the drugs and the toxicity of tumor cells, that is, concentration dependence. When the local concentration of the chemotherapeutic drugs increases by one time, the killing effect on the tumor cells can be increased by ten times. Therefore, under the same drug doses, the killing effect of the intervention chemotherapy on tumor cells can be increased significantly. In addition, the arterial injection of chemotherapy drugs can enter the systemic circulation again, which have certain effect on the systematic clinical or subclinical metastases, and flow back to the tumor site through the venous return to realize the secondary chemotherapy . Studies have shown that after intervention chemotherapy, the tumor necrosis foci are mainly at the tumor center surrounding the blood vessels, with the necrotic rate up to 80 %, medium to severe necrosis rate of 60 %, while after the systematic intravenous injection of drugs, the tumor necrosis is mainly located at the shallow layer of the tumor with the necrosis rate of about 40 %, mostly mild to moderate necrosis. After the intervention chemotherapy, varying degree of vascular inflammation and microvascular thrombosis will occur for the tumor-feeding vessels, which also delayed the growth of tumors to a certain degree .
In addition, due to the particularity of colorectal blood supply, the arterial infusion of chemotherapy drugs can flow back to the liver through the portal vein system, which also has an “infusion chemotherapy” effect on the micrometastasis in the liver.
19.3.1 Reasons for the Hepatic Artery Administration of Drugs
The injection of the chemotherapy drugs in the hepatic artery for preoperative interventional therapy is mainly based on the following: (1) the multiplication rate of the tumors – for the patients with delayed liver metastasis after the radical operation, their livers have the “small metastasis” that cannot be discovered through the existing imaging techniques before operation; after surgical removal of primary foci, the inhibited factor of blood vessels are removed, which activates the growth of the dormant micrometastatic tumor and causes the occurrence of distant metastasis [13, 14]; (2) the blood supply of the micrometastasis with the diameter of 0.5–3 mm in the liver is mainly from the hepatic artery, and this micrometastasis is just the target of preoperative intervention therapy .
19.3.2 Why Choose the Stage III Colorectal Cancer Patients
Sadahiro from the University of Tokyo firstly reported the randomized controlled trial of preoperative preventative hepatic artery intervention therapy of colorectal cancer in 2004. There were 305 cases of stage II and stage III colorectal cancer patients involved in this study, and no preoperative liver metastasis has been discovered for the patients. The 305 patients were divided into two groups randomly: 119 cases of preoperative hepatic artery intervention group (3-week perioperative 5-FU continuous observation of hepatic artery chemotherapy) and 186 cases of surgery alone group. The results showed that, for the stage III patients, the preoperative intervention therapy can reduce the postoperative recurrence rate by 60 % (95 % CI 0.24–0.64; P = 0.0002), mortality rate 63 % (95 % CI 0.21–0.67; P = 0.0009), and liver metastasis rate 62 % (95 % CI 0.22–0.66; P = 0.0005), but no effect for the metastasis of other organs. There is no curative effect for the stage II patients .
The General Surgery Department, Zhongshan Hospital affiliated to Fudan University firstly carried out the clinical study of prophylactic hepatic and regional arterial infusion chemotherapy (PHRAIC) in China and obtained the preliminary results. The PHRAIC group of patients were firstly subject to the prophylactic hepatic and regional arterial infusion chemotherapy: infusion of the fluorodeoxyuridine 500 mg, MMC 10 mg, and oxaliplatin 50 mg, respectively, to the hepatic artery and the major feeding arteries of the tumor; after 7 days of chemotherapy, the patients accepted the radical surgery of colorectal cancer; the control group of patients were directly accepted of the radical resection of colorectal cancer. The results showed that in stage III patients, PHRAIC group was significantly better than the control group in 3-year liver metastasis rate (12.7 % vs. 28.3 %, P = 0.001), 3-year tumor-free survival rate (82.3 % vs. 58.7 %, P = 0.0096), overall survival rate (87.7 % vs. 75.7 %, P = 0.002), and median survival time (40.1 vs. 36.3 months, P = 0.03). The preoperative intervention would not increase the incidence of the postoperative complications. These clinical results were published in Annals of Surgery in 2007 (IF=7.678) . For the patients of stage II, there was no significant difference between the two groups.