Affluent blood supply of colorectal cancer liver metastases. (a) Female, 52-year-old patients with liver metastasis of colon cancer; enhanced arterial lesions advanced the top right lobe diaphragm. (b) Hepatic artery angiography showed the lesion with affluent blood supply. (c) Lipiodol chemoembolization epirubicin emulsion; the lipiodol deposited well. (d) Postoperative CT scan shows lipiodol deposition
18.1.2 Indications and Contraindications
Unresectable colorectal cancer liver metastases
Neoadjuvant chemotherapy before surgical procedures for colorectal cancer liver metastases
Prevention of colorectal cancer recurrence after liver metastasis surgery
Rupture of colorectal cancer liver metastases
Contraindications for vascular imaging.
Tumor/liver ratio is greater than 75 %.
Liver and kidney dysfunction.
Severe bone marrow suppression.
Uncontrolled severe infection.
18.1.3 Preoperative Preparation
126.96.36.199 Preoperative Check
During 3 days before intervention surgery, examinations should be taken including blood/urine/stool routine test, liver and kidney function test, coagulation function, electrolyte test, and tumor markers (CEA). Liver MRI or CT scanning should be carried on within 2 weeks before surgery. If being accompanied with other distant metastasis, the appropriate imaging should also be carried on.
188.8.131.52 Patient Preparation
Inform patients and their families of the surgery process, postoperative reaction, and possible complications. Let the patients sign the consent and fast 4 h before surgery. Administer 10 mg intramuscular injection of diazepam 30 min before surgery. Prepare the skin puncture site.
184.108.40.206 Drug Preparation
Conventional drugs include local anesthetics (such as 1 % lidocaine), heparin, saline, nonionic contrast agent, and so on.
Operating rooms for interventional procedure should be equipped with emergency rescue drugs such as epinephrine, atropine, nikethamide, dopamine, hydrocortisone, dexamethasone, nitroglycerin, cedilanid, and so on.
Drugs in TAI treatment are commonly used as floxuridine (FUDR)/fluorouracil (5-FU), cisplatin/carboplatin/oxaliplatin, irinotecan, epirubicin (EADM)/pirarubicin (THP), mitomycin C (MMC), and so on. Usually two to three kinds of drugs are combined to carry on perfusion. For hypervascular lesions, part of the drugs and lipiodol are mixed into emulsion to carry on transcatheter arterial chemoembolization (TACE).
Lipiodol: Peripheral embolic agent having a special affinity with tumor. The tumor tissue cannot easily remove it. It is a commonly used embolization agent for the hypervascular tumor. In general, the mechanism of lipiodol “orientation” thrombosis is that the tumor tissues are rich of new vessels, with great blood flow, and the lipiodol can flow to tumors due to the syphonage. The tumor vessel is distorted and irregular, lacking muscular and elastic layers and neural regulation. So the blood flow out is slow, which cannot effectively flush the attached lipiodol. Also, the tumor tissue lacks reticuloendothelial system which can remove the lipiodol. The lipiodol and chemotherapeutic agents are often mixed into emulsion to carry on embolization chemotherapy, which can not only make the tumor ischemia and hypoxia but also slowly release the chemotherapy drugs to kill the tumor continuously.
Gelatin sponge: Safe, nontoxic, low cost, and most commonly used as embolic agent in TAE. It can be cut into different sizes of strips or granulars according to the need and adds the contrast agent to carry on injections. When used in the embolization of part of vascular cavity, it can be absorbed completely within 7–12 days. Then the blood vessel will reopen. The complete embolization can lead to permanent embolism, which is commonly used in the reduction of tumor blood supply or tumor hemorrhage.
Other embolics: stainless steel rings, beads, glue, and Baiji, which are less used.
220.127.116.11 Equipment Preparation
18G needle, 4F or 5F vascular sheath, 0.035 or 0.038 smooth guide wire, 4F or 5F varieties of preforming catheter, such as the celiac artery, hepatic artery, and left gastric artery catheters, the 3F microcatheter, etc. (cobra, RH, RLG, Simmons I, Simmons II, multipurpose, etc.).
18.1.4 Treatment Method
The Seldinger method is used to puncture the femoral artery and place the intravascular sheath. Usually RH catheter is selected to selectively enter into the hepatic artery for angiography, which can make sure the metastatic lesion’s number, size, location, blood supply, arteriovenous fistula, and so on. If there is hepatic artery variation or other arteries (superior mesenteric artery, left gastric artery, inferior phrenic artery) taking part in the liver blood supply, the corresponding catheter should be chosen to selectively enter into these arteries to carry on angiography. The catheter tip is placed in the hepatic artery and dilutes the chemotherapy drug to carry on perfusion. There are two drug administration methods: once-shock perfusion and continuous perfusion. The former fits for the nonspecific cell period chemotherapy drug administration. After perfusion, the catheter and vascular sheath are removed; the operation is relatively convenient. The latter fits for specific cell period chemotherapy drug administration, which needs indwelling catheters and vascular sheath. The patients had to stay in bed for several days, which will increase the incidence of thrombosis and other complications. For the metastases of rich blood supply, some of the chemotherapy drugs and lipiodol are mixed into the emulsion to carry on embolization. If you can carry on superselective catheterization, make the catheter tip as close as possible to lesions to reduce the damage to normal liver tissue. It should be noted before embolization to avoid the right gastric artery, cystic artery, and other feeding arteries of the hollow organs to prevent ectopic embolism. The whole embolization process should be completed under the fluoroscopic monitoring, which can not only observe the deposition of lipiodol in the lesion but also detect lipiodol reflux in time. After using the lipiodol emulsion to carry on chemotherapy embolization, if the blood flow of the lesion’s blood supply artery is still fast, use thin strips or particles of gelatin sponge to enhance the embolization according to the circumstances to further reduce the tumor blood supply. Use the cases of the lipiodol emulsion chemotherapy embolization; the liver area plain film is shot to record lipiodol deposition.
18.1.5 Postoperative Management
The patient is supine, with the puncture side limb braking for at least 6 h to observe bleeding and hematoma formation at the puncture site, dorsalis pedis arterial pulse, body skin color, temperature, feeling, and so on.
Monitor the vital signs; ECG monitoring is used for high-risk patients.
In 3–5 days after liver surgery, carry on liver protection, acid suppression, antiemetics, antibiotics, and symptomatic and supportive treatments.
The embolism syndrome is a common reaction after TAE, including a series of clinical syndromes such as nausea, vomiting, upper abdominal pain, gastrointestinal motility decrease, and liver dysfunction, mostly transient. The fever is often led by the metabolites of tumor necrosis affecting body temperature regulation center and can last for several days to several weeks. The nonsteroidal anti-inflammatory drugs can be used to carry on symptomatic treatment. Abdominal pain is often caused by visceral ischemia after embolization, the tumor near the liver capsule and other factors. The treatment objectives of modern medicine for cancer pain or pain associated with cancer are to sustainably and effectively eliminate the pain and maximally improve the patient’s life quality. Therefore, we should correctly grasp the principle of three-step analgesic to relieve pain in patients in a timely manner. But during the treatment process, we should pay attention to identify the acute abdominal pain. Gastrointestinal motility decrease should be properly administrated with gastrointestinal motility drugs. Encourage patients to get out of bed and carry on eating.
In 3–5 days after the surgery, review the liver and kidney function and blood routine to decide whether to continue to carry on liver protection and support and symptomatic treatment. In 6–8 weeks, carry on follow-up with CT/MRI and CEA to observe the healing effects.
18.1.6 Healing Effect
18.104.22.168 Unresectable Colorectal Cancer Liver Metastases
Similar to the history of intravenous chemotherapy for colorectal cancer liver metastasis, 5-FU/FUDR + LV is the most widely and deeply studied drug in the arterial treatment. Since the 1980s, many institutions have carried on a large number of random control studies on 5-FU/FUDR + LV through arterial and intravenous administration. Some scholars [5, 6] summarized seven groups of the classic studies. The results showed that the effective rates of arterial and intravenous administrations were 41 and 14 %, with a significant difference, but the survival terms of the two had no significant difference. They thought the reason that the survival terms of the two were similar was that some patients in the intravenous administration group crossed over to the arterial treatment group after lesion progress, while some patients in the arterial administration group crossed over to the intravenous administration group due to port catheter system (PCS) implantation failure or complications or other factors. The arterial administration group’s extrahepatic metastasis lesion has not been well controlled. Kemeny et al.  randomly divided 135 patients with colorectal cancer liver metastasis into two groups, arterially and intravenously administered with FUDR and LV. The effective rate of the arterial administration group was 47 %, significantly higher than 24 % of the intravenous group (P = 0.012). The former’s median survival term (P = 0.0034) and median progress time (P = 0.034) were significantly longer than the latter.
In the 1990s, the appearance of oxaliplatin and irinotecan makes the colorectal cancer chemotherapy embark on a new level and makes the effective rate of the colorectal cancer liver metastasis remarkably increased, and the survival term is significantly prolonged. Many scholars studied the two drugs’ arterial administration. Dzodica et al.  studied the arterial and intravenous administration of oxaliplatin in VX2 rabbit model. The peripheral peak concentration of arterial administration was significantly lower than that of intravenous administration, which indicated that the arterial administration had a relatively higher therapeutic index. Irinotecan is a kind of prodrug, which must be catalyzed into active product 7-ethyl-10-hydroxycamptothecin (SN-38) by the carboxylesterase in the human body to play a pharmacological effect. Because the liver carboxylesterase concentration was higher than that in other organs, the conversion rate of SN-38 by the hepatic artery administration was significantly higher than that by intravenous administration (P = 0.015) so that the former’s hepatic SN-38 concentration was higher than that of the latter . Irinotecan, oxaliplatin, and FUDR all have good effects on the colorectal cancer liver metastases, and the action mechanisms and dose-limiting toxicities of three chemotherapy drugs are different, which makes the combination of three drugs have theoretical basis. Currently, a number of in vitro drug sensitivity tests have confirmed that these three drugs have synergistic effect between each other, for example, oxaliplatin and irinotecan active metabolite SN-38 could synergistically inhibit human HT29 colon cancer cell lines. Oxaliplatin and fluorouracil could synergistically inhibit human LoVo colon cancer cell lines. SN-38 and 5-FU could synergistically inhibit varieties of human colon cancer cell lines. Falcone et al.  reported the random control study results of irinotecan, oxaliplatin, and FUDR’s FOLFOXIRI program and FOLFOX program, which approved that the effective rate of FOLFOXIRI group was significantly higher than that of the latter. The median survival term and median progress time were significantly longer than the latter. Therefore, FOLFOXIRI program becomes a hot spot in colorectal cancer chemotherapy study. Intervention Division, Zhongshan Hospital, used irinotecan, oxaliplatin, and FUDR as first-line or second-line program to treat 32 patients through arterial perfusion with unresectable colorectal cancer liver metastases. The total efficiency rate was 46.9 %, median survival term was 17.7 months, and it achieved good results (Fig. 18.2).
Irinotecan, oxaliplatin, and FUDR combined arterial treatment for colorectal cancer liver metastases. (a) Female, 74-year-old patients with liver metastasis of colon cancer. (b) Adopt irinotecan, oxaliplatin,, and FUDR programs; carry on TAI and TAE. (c) After two treatments, the lesion was significantly reduced to PR
22.214.171.124 The Adjuvant Treatment of Colorectal Cancer Liver Metastases
After resection of liver lesions, implementation of TAI can not only control the small undiscovered intrahepatic metastasis lesions but also prevent intrahepatic recurrence. Kermeny et al.  carried on a control study between the patients who received arterial perfusion chemotherapy after the operation of colorectal cancer liver metastases and the patients who do not receive the treatment. The 4-year intrahepatic recurrence free rates were 67 % and 43 %, respectively, with a significant difference. In another study, 156 patients who received the colorectal cancer liver metastasis resection were randomly divided into two groups : one was given arterial administration of FUDR and intravenous administration of 5-FU and LV; the other was given intravenous administration of 5-FU And LV. Both treatment periods were six cycles. The 2-year survival rates of intravenous administration group and the artery and vein combined administration group were 72 and 86 % (P = 0.03). The two groups’ median survival term was 62.7 and 72.2 months. The death risk of the intravenous administration group was 2.34 times of the artery and vein combined administration group.
126.96.36.199 The Neoadjuvant Treatment of Colorectal Cancer Liver Metastases
The advantages of arterial neoadjuvant treatment are as follows: (1) control and reduce intrahepatic metastasis lesions, decrease tumor stage, make the unresectable tumor resectable, improve the curative resection rate, and reduce the relapse rate; (2) control preoperatively existing small lesions and reduce the postoperative recurrence; (3) prevent postoperative changes in tumor blood supply and influence the effects of chemotherapy; (4) prevent the tumor proliferation stimulation induced by the primary tumors and control the iatrogenic transfer; (5) as a chemotherapy-sensitive test, rationally select the sensitive drug and help to determine prognosis; and (6) screen the patients who cannot receive the surgical treatment.
There are a lot of reports about radical resection of inoperable colorectal cancer after receiving intravenous chemotherapy , but there is still less experience in the arterial neoadjuvant therapy of the colorectal cancer liver metastases. Zelek et al.  treated 31 patients with unresectable liver metastases of colorectal cancer, among which 11 patients received the radical resection through the method of intravenous administration of irinotecan and 5-FU, combining with artery epirubicin.
188.8.131.52 Puncture- and Catheterization-Related Complications
Puncture site hematoma and pseudoaneurysm formation
Poor blood coagulation and improper hemostasis can cause puncture site bleeding, hematoma, or even formation of pseudoaneurysm. After the formation of hematoma, it should be noted whether there is expansion of the scope of hematoma or local swelling throb. If there is progressive expansion of the hematoma, it is needed to carry on repressure dressing and use hemostatic. In early hematoma formation period, we can puncture with a big syringe needle into the thick hematoma to carry on the aspiration to relieve the congestion as much as possible. If there is local swelling throb near the puncture site, the color Doppler imaging should be carried on to make clear whether there is pseudoaneurysm formation. If pseudoaneurysm is found, mark the position of the orificium fistulae by the color Doppler imaging and carry on pressure dressing. If these measures are ineffective, according to the situation, inject the prothrombin complex under the guidance of the ultrasound or carry on surgical intervention.
This is caused by entering into the arterial intima through the guide wire or catheter and lifting the intima. It is common in the cases with the basis of atherosclerosis or tortuous blood vessels. The symptom is that the blood flow cannot reach the remote artery, and local contrast agent takes on stasis strip. Try to use soft head leaned over the guide wire sandwich. But in most cases the intervention operation must be terminated.
It is related with the stimulation of the catheter, guide wire, and chemotherapy drugs on the arterial wall. It often occurs in cases with fine and tortuous-shaped arteries. Minor seizures generally do not affect further operations. More severe spasm makes the artery canal narrower, apparently decreasing the blood flowing into the spastic distal segment, which will affect the follow-up treatment. In the operation, gently operate the guide wire and catheter and slowly perfuse the chemotherapy drugs. The micro-catheters are used for patients with arterial spasm to avoid the incidence of this complication. In case of spasm, immediately stop the guide wire and catheter manipulation and slowly inject with 2 % lidocaine. If it’s void, we can dilute 30 mg papaverine with 10 ml normal saline to inject slowly. If all above treatment methods are ineffective to severe spasm, the operation should be terminated.
Arterial injury or perforation
If the guide wire operation injures the arterial wall or the contrast agent rate is too large, it will lead to the arterial wall perforation, which shows as contrast agent extravasation. The minor injury can be treated with local and systemic hemostatic agents. Serious injury and perforation require gelatin sponge, stainless steel embolization, or even surgical repair.
This may be related with the guide wire and catheter’s stimulation of the receptors on artery walls. The heart rate and blood pressure decrease at the same time. In severe cases, loss of consciousness occurs. Intravenous injection of atropine must be carried on immediately. If necessary, repeat the injection. And at the same time, give other treatments accordingly.
Bend or rupture of the guide wire and catheter
This may be related with vascular distortion, unskilled surgeon operation, operation not under the fluoroscopic monitoring, or other factors. The guide wire bend can be taken out carefully through the catheter under the fluoroscopic monitoring. The catheter bend segment should be withdrawn within the blood vessels with wider diameter (such as abdominal aorta). After probing with the guide wire soft head, take it out under the fluoroscopic monitoring. Guide wire and catheter’s rupture should be firstly disposed with the capture device. If not successful, the surgery is needed.
184.108.40.206 Drug-Related Complications
During arterial perfusion chemotherapy and chemoembolization, the liver and gastrointestinal blood concentrations are significantly higher than peripheral blood drug concentrations. So the liver and upper gastrointestinal local adverse reactions are obvious. The incidence rates of the bone marrow suppression, alopecia, diarrhea, and other systemic adverse reactions are lower than those in the intravenous chemotherapy. In addition to chemotherapy drug adverse reactions, the common complications are as follows:
Poor liver function reservation and portal vein involvement are high-risk factors for postoperative liver failure. This complication can be prevented by a comprehensive assessment of preoperative liver function of patients, attention for intraoperative superselective catheterization, and reduction in the high-risk cases.
Renal failure is not only related with renal toxicity of chemotherapy drugs but also related with the metabolite injury and renal tubular blockage caused by the necrosis of a large number of tumor cells in short term after the chemotherapy embolization. Preventive measures can be taken by avoiding using chemotherapy drugs with greater renal toxicity as possible as you can and full hydration and alkalinization of urine after surgery.
Ectopic embolization generally refers to the liquid embolic agent flowing back into the cystic artery, right gastric artery, and gastroduodenal artery during TAE, causing damage or perforation of the gallbladder or stomach. During the surgery, the catheter head should avoid the abovementioned artery, and avoidance of regurgitation during the chemotherapy embolization can play a preventive role.
Bile duct sclerosis and biloma
Because the blood supply of bile duct system is from the liver artery, hepatic artery administration can cause bile duct complications. There are many reports about bile duct sclerosis in western countries, which mostly appears in cases with FUDR administration through the artery. The occurrence rate is up to 3–26 %; the clinical symptoms are similar to primary sclerosing cholangitis. At the same time of the administration, the arterial administration of dexamethasone or switch to 5-FU can reduce the incidence rate of this complication. Biloma formation may be related to bile leakage after the local bile duct wall ischemic necrosis. Small-volume bile tumor need not be treated. If the volume is great and produces symptoms of oppression, puncture and drainage can be carried on.
The biliary tract surgery history is the high-risk factor for the formation of liver abscess after TAI or TAE. The biliary tract surgery can lead to intestinal bacteria retrograding into the liver. The cytotoxic effect of chemotherapy drug and liver tissue local ischemia after the embolization can both cause decrease of anti-infection immunity and lead to liver abscess. After the formation of abscess, the combination administration of sensitive antibiotics is needed, and puncture and drainage should be carried on after the abscess grows mature.
In recent years, the targeted therapy drug develops very fast and has achieved good clinical healing effects. The colorectal cancer targeted therapy drugs with clear healing effects are cetuximab targeting epidermal growth factor receptor and bevacizumab targeting vascular endothelial growth factor [15, 16]. Therefore, it is a new direction of the treatment of colorectal cancer liver metastases to combine the molecular biology and the traditional chemotherapy drugs. TAI can increase the tumor’s local blood drug concentrations and reduce the side effects of drugs on the systematic circulation, playing a role in organ targeting. In this way, TAI can enhance the efficacy of molecular targeted drugs, and it is worthy of further study.
18.2 Percutaneous Port Catheter System Implantation
Port catheter system (PCS) implantation is to percutaneously make the indwelling catheter into the target vessel. Its end is connected with the kit indwelled under the skin to establish the long-term intravascular drug delivery pathway involvement technology. PCS implantation has the following advantages: it is a simple delivery method through an operation; it can establish a long-term use vascular access for the TAI to avoid repeated intubation; it can, with just a puncture into the kit, administer drugs; it can be carried on at outpatient service; and it can decrease the average cost of treatment. In 1981, percutaneous PCS implantation appeared in the United States. The first Chinese percutaneous PCS implantation via subclavian artery was reported in 1994. And then it is carried on in the domestic field extensively. Comparing with the surgical implantation, the percutaneous PCS implantation has less damage and fewer complications, no destruction of the arterial anatomy, and long patency . If necessary, PCS can be adjusted or removed . PCS only provides a therapeutic method with no tumor treatment effect itself. The main effects of TAI through PCS are related with the chemotherapy regimens, tumor differentiation degree, catheter indwelling position, patient’s physical conditions, and other factors [19, 20].
18.2.1 Indications and Contraindications
The metastasis lesions needing multiple TAI administrations.
The hepatic artery as the only blood supply artery for the hepatic lesion. If there are other visceral arteries participating in the blood supply, embolization on these vessels should be carried on.
220.127.116.11 Contraindications: In Addition to TAI and TAE Contraindications, There Are
The kit implementation site may be carried on hyperthermia or radiotherapy.
There is infection or scarring or swelling lymph nodes in PCS kit implantation site.
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18.2.2 Preoperative Preparation
During 3 days before intervention surgery, examinations should be taken including blood/urine/stool routine test, liver and kidney function test, coagulation function, electrolyte test, and tumor markers (CEA). Liver MRI or CT scanning should be carried on within 1 week before surgery. If being accompanied with other distant metastasis, the appropriate imaging should also be carried on.
Inform patients and their families of the surgery process, postoperative reaction, and possible complications. Let the patients sign the consent. In addition, patients should be informed of the implanted chemotherapy kit’s size, shape, implant position, influence on the daily life, and nursing kit, so that patients can have adequate psychological preparation.
The same as “Section I.”
Conventional interventional devices
These include 21G puncture kit (including the 21G puncture needle, 0.018 in. thin guide wire, and 4F trocar) or 18G puncture needle, 180 cm long and 0.035 or 0.038 in. smooth guide wire, and 4F or 5F catheter various preformed catheter (cobra and RH are the most commonly used).
Port catheter system
This is composed of the kit, interface nut, indwelling catheter, and tunnel needle. PCS kit shell is made by hard plastics or metal. Puncture membrane is made by the high-density silicone, which is located in the upper shell, can bear hundreds of puncture, and will not leak. In one side of the kit, there is OD 0.038 in. stainless steel pipe. After setting into the indwelling tube, screw the interface nut on and fix the indwelling catheter and the shell closely. The indwelling catheter’s outer diameter is usually 5F, and the inner diameter can pass the 0.038 in. guide wire.
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