Download PDF
Review  |  Open Access  |  6 Jul 2024

Hepatic arterial infusion chemotherapy: a review with technical notes

Views: 89 |  Downloads: 19 |  Cited:  0
Hepatoma Res 2024;10:28.
10.20517/2394-5079.2024.06 |  © The Author(s) 2024.
Author Information
Article Notes
Cite This Article


Combined hepatic artery infusion (HAI) and systemic chemotherapy have demonstrated its clinical efficacy in prolonging overall survival in unresectable intrahepatic cholangiocarcinoma and as a conversion to treatment strategy in a small proportion of patients. The utilization of HAI chemotherapy is restricted by the scarcity of surgeons and oncologists who are well-experienced in its use. This represents a significant drawback of this treatment method. In recent years, a solid push to expand its use, mainly in the United States and recently also in Europe, has been made possible by the HAI Consortium Research Network. Results of ongoing Clinical Trials are eagerly awaited to give the basis for further expansion of this technique and oncological treatment outside of historically established centers. In this technical note review, we aim to give a brief historical description of the origins and evolution of intra-arterial chemotherapy for unresectable intrahepatic cholangiocarcinoma. We will, therefore, discuss the surgical technique by providing some tips and tricks without neglecting the difficulties that may be encountered.


Hepatic artery infusion, pump chemotherapy, intrahepatic cholangiocarcinoma, unresectable cholangiocarcinoma, conversion therapy


First described in 1840 by Durand-Fardel, cholangiocarcinoma (CCA) encompasses a diverse group of cancers derived from the epithelial cells lining the biliary tree, exhibiting characteristics of cholangiocyte differentiation[1]. The tumor develops from the canals of Hering to the main bile duct[2]. The different types of cholangiocarcinoma (CCA) are classified based on their location within the liver - intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). CCA represents a significant portion of gastrointestinal and liver malignancies, accounting for approximately 3% of all gastrointestinal tumors and comprising around 15% of primary liver cancers, making it the second most common primary liver cancer[3-5]. By 2040, liver cancers, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are projected to be the third leading cause of cancer deaths, after lung and pancreatic cancer, exceeding colorectal cancer[6].

While there have been recent improvements in surgical treatments for cholangiocarcinoma, the outlook for patients remains poor, with less than 5% surviving beyond five years. The average survival time for intrahepatic cholangiocarcinoma (iCCA) ranges from 18 to 30 months, but this drops to only 6 months if the tumor cannot be surgically removed. Surgery is currently the sole curative option for early-stage disease. Unfortunately, most patients are diagnosed at later stages when the cancer is metastatic, unresectable, or locally advanced, and only a quarter of them qualify for surgical resection[5,7]. For those unresectable, hepatic arterial infusion (HAI) of high-dose chemotherapy may provide some benefits[8].

Since the 80s, Nancy Kemeny has devoted her career to the treatment of patients with unresectable metastatic colorectal cancer and intrahepatic cholangiocarcinoma. She has established a critical role for regional Hepatic Artery Infusion (HAI) chemotherapy in both adjuvant and advanced settings. This therapy was initially not widely accepted outside of Memorial Sloan Kettering Cancer Center (MSKCC) in New York. However, its efficacy has since been demonstrated and is now widely used throughout America, Asia, and Europe.


The latest version of the NCCN clinical practice guideline for hepatobiliary cancers (v. 3.2023) specifies the criteria for selecting patients eligible for arterially directed therapies, which include TARE, TACE, DEBTACE, and HAI. Initially developed for the treatment of metastatic colorectal cancer, nowadays, the role of HAI chemotherapy has been found effective for patients suffering from advanced unresectable intrahepatic CCA that is confined to the liver[8-15] [Table 1].

Table 1

Summary of studies. HAI +/- SYS chemotherapy treatments for unresectable iCCA.

StudyNumber and Type of PatientsTreatment RegimenPFSOS
Jarnagin et al., 2009[9]34 PLC
•26 iCCA
•8 HCC
4-week cycle
HAI: FUDR (0.16 mg/kg × 20/pump flow rate) and DEXA 25 mg on day 1 for 14 days of each cycle
7.4 months29.5 months
Kemeny et al., 2011[10]22 PLC
•18 iCCA
•4 HCC
4-week cycle
HAI: FUDR (0.16 mg/kg × 30/pump flow rate) and DEXA 25 mg on day 1 for 14 days of each cycle
SYS: bevacizumab 5 mg/kg every other week.
8.45 months (CI 5.53-11.05)31.1 months (CI 14.14-33.59)
Inaba et al., 2011[11]13 iCCA4-week cycle
HAI: GEM 1000 mg/m2 30-min infusion on days 1, 8, and 15 for 5 cycles
-389 days (CI 158-620)
Ghiringhelli et al., 2013[12]12 iCCASecond-line treatment
2-week cycle
GEM (1000 mg/m2 given over 30 min) followed by OX (100 mg/m2 given over 2 h)
9.2 months (CI 2.1-29.4)20.3 months (CI 13.2-49.7)
Massani et al., 2015[13]11 iCCA2-week cycle
Day 1: 100 mg/mq of OX
Day 2: 5 FU 7 mg/kg at 2 mL/h in CI for 48 h
-17.6 months
Konstantinidis et al., 2016[14]104 iCCA
•26 SYS
4-week cycle
HAI: FUDR (0.16 mg/kg × 20/pump flow rate) and DEXA 25 mg on day 1 for 14 days of each cycle
SYS: mostly GEM-based
HAI/SYS 12 months
SYS 7 months
HAI/SYS 30.8 months
SYS 18.4 months
Higaki et al., 2018[15]12 iCCA42-day cycle
HAI: CIS 65 mg/m2 2 mL/min on Day 1
SYS: S-1 60 mg/m2 per day 1-28
-10.1 months (CI 3.6-23.2)
Cercek A, et al., 2020[8]38 iCCA4-week cycle
HAI: FUDR (0.12 mg/kg × 30/pump flow rate) and DEXA 30 mg/pump on day 1 for 14 days of each cycle
SYS: GEM (800 mg/m2) with OX (85 mg/m2) on Day 1 or 15, every 2 weeks
11.8 months (1-sided 90% CI, 11.1)25.0 months (95%CI: 20.6-not reached)

In 2009, a study by Jarnagin et al. showed promising results for unresectable liver cancer treatment using HAI with floxuridine and dexamethasone, achieving a 47.1% response rate and a median survival of 29.5 months[9].

A 2011 trial by Kemeny et al. investigated the addition of systemic bevacizumab to HAI chemotherapy, resulting in a median overall survival of 31.1 months[10].

A phase I/II study published in 2011 by the Japan Interventional Radiology in Oncology Study Group explored HAI using gemcitabine, with a response rate of 7.7% and a median overall survival of 389 days[11].

In 2014, a retrospective study by Ghiringhelli et al. examined HAI of GEM followed by systemic oxaliplatin as second-line treatment in patients with unresectable iCCA, reporting a median PFS of 9.2 months and a median OS of 9.1 months[12].

Massani et al. published a retrospective analysis of HAI treatment alone (fluorouracil and oxaliplatin) in unresectable iCCA patients, revealing a median OS of 17.6 months[13].

An analysis by Konstantidinis et al. of patients with locally advanced intrahepatic CCA demonstrated improved OS in those receiving combined HAI and systemic chemotherapy compared to systemic chemotherapy alone (30.8 vs. 18.4 months)[14].

A 2018 Japanese pilot study compared HAI of cisplatin plus oral S-1 to conventional therapies in patients with unresectable iCCA, showing a median OS of 10.1 months in the combined treatment group[15].

In 2020, a phase II trial by Cercek et al. investigated HAI FUDR chemotherapy combined with systemic gemcitabine and oxaliplatin in unresectable ICC patients, reporting a median PFS of 11.8 months, a median OS of 25.0 months, and a 1-year OS rate of 89.5%[8].

The NCCN panel recommends locoregional therapy for unresectable or metastatic cholangiocarcinoma without extrahepatic disease, but HAI chemotherapy is only recommended for clinical trials or tertiary referral centers[16].


Novel methods for regional chemotherapy with nitrogen mustard were described independently by Calvin T. Klopp and Howard R. Bierman in the late 1950s[17,18]. After the publication of these findings, the use of chemotherapy via arterial administration was explored for several types of cancer, including liver cancer. In 1964, Sullivan et al. first described the method of chemotherapy by continuous hepatic arterial infusion and reported “significant tumor regression”[19]. Other investigators have demonstrated the clinical benefit of HAI with tumor response rates up to 73%. Unfortunately, the high morbidity rate related to pump port and catheter placement and the not negligible mortality rate have at first prevented the widespread use of infusion chemotherapy[20-23]. During the 1970s, the usage of the technique was given a boost due to the advancement of technology which led to the development of an implantable subcutaneous pump that made it feasible to safely administer arterial infusions to outpatients[24,25]. In 1980, this device was successfully experimented with by infusing fluorodeoxyuridine (FUDR) into the hepatic artery[26].

Sigurdson et al. established the scientific basis for arterial infusion in 1987. They demonstrated that drugs delivery to the tumor is significantly greater with hepatic artery infusion than with portal vein infusion. The mean level of tumor FUDR after HAI was 12.4 ± 12.2 nmol/g, which was much higher than the mean level of tumor FUDR after portal vein infusion, which was 0.8 ± 0.7 nmol/g, P < 0.01[27]. Drug selection needed a rational basis, including agents with short half-lives and evidence of antitumoral activity. The liver has a unique dual blood supply system that enables the targeted delivery of chemotherapy drugs to tumor cells via the arterial blood supply while preserving the healthy liver tissue by utilizing the portal blood flow. FUDR was demonstrated to have a half-life of less than 10 min and an estimated increased hepatic exposure by HAI (based on hepatic extraction, total body drug clearance, and hepatic arterial blood flow) of 100- to 400-fold[28]. Due to hepatic extraction and first-pass metabolism, systemic exposure and toxic effects are decreased by up to 99%, while also achieving higher and more targeted drug concentrations in the tumor compared to systemic administration[8,28]. Considering these assumptions and the positive outcomes of initial smaller studies in the 1970s and 1980s, delivering chemotherapy directly to the liver through a surgically implanted pump under the skin gained widespread adoption[29-31].

Over the last thirty years, the implementation of potential randomized controlled trials has provided more substantial proof of enhanced response rates and survival rates over systemic therapy in specific patients. Following the publication of the first randomized trial on HAI in MSKCC in 1987[32], more than 100 publications from the center have showcased the effectiveness of regional chemotherapy on liver neoplasms[33-35].


Hepatic arterial anatomy variations

The evaluation of hepatic vascular anatomy before surgery is vital and should involve an arterial phase CT. A normal hepatic arterial anatomy is characterized by the common hepatic artery originating from the celiac axis and the gastroduodenal artery (GDA) arising from the common hepatic artery before the bifurcation of the right and left hepatic arteries. However, 30% to 50% of patients exhibit anatomical variations in the hepatic arterial supply, which can be in the form of accessory or replaced hepatic arteries[36,37]. The most common are aberrant origin of the GDA from either the right and left hepatic artery or as a trifurcation (6% to 11% of patients), accessory left hepatic artery (2% to 10%), accessory right hepatic artery (4% to 16%), replaced left hepatic artery with no native left (4% to 16%), and replaced right hepatic artery with no native right (6% to 16%).

Crossover liver perfusion has first been described by Redman[38] and Koehler[39]. Koehler demonstrated cross-perfusion on a small consecutive series of patients treated with hepatic artery ligation for otherwise uncontrolled bleeding. After the ligation, collateral vessels that supply arterial flow to the liver start developing as early as four hours. These collaterals come from different sources such as the replaced or accessory hepatic artery, interlobar liver collaterals, phrenic artery, gastroduodenal artery through arterial branches in the pancreas duodenum and omentum, collateral branches of the GDA as they pass into the porta hepatis, and recanalization of the ligated hepatic artery. Over the next six months, these collateral vessels continue to grow in size and number[39]. Rayner et al.[40] in 1986 and Cohen et al.[41] in 1987 provided additional evidence illustrating that hepatic lobar arteries do not function as end arteries. Their research also revealed the rapid restoration of blood flow to the contralateral hepatic lobe through collateral vessels following the occlusion of a variant vessel. During the placement of a hepatic arterial pump, technical difficulties may arise in the presence of anomalies. In the case of unusual anatomy, it is recommended to insert the catheter into the GDA and tie off any accessory or replaced vessels while depending on cross-perfusion[31]. Collateral blood flow to the hypoperfused lobe of the liver typically develops within two to four weeks in almost all patients when there is incomplete liver perfusion following ligation of a replaced or accessory artery[36,42].

Pump placement technique

The surgical procedure typically starts by dissecting the porta hepatis and performing a cholecystectomy. This action helps to clear the operative area and identify the common bile duct. In addition, it reduces the likelihood of chemotherapy-related cholecystitis, which can affect 20%-30% of patients otherwise. The dissection of the hepatic artery commences medially to the common bile duct and then continues to the artery's proximal end. Afterwards, it proceeds onto the common hepatic artery for a distance of roughly 1 cm and onto the gastroduodenal artery for approximately 2 cm. Finally, the gastroduodenal artery segment and the hepatic artery's proximal and distal sections are dissected free of surrounding tissue with the ligation of all the small arterial branches encountered. A GDA occlusion test is routinely performed before proceeding with surgical maneuvers to verify the persistence of flow of the proper hepatic artery. Artery occlusion can be temporarily accomplished with the use of a bulldog clamp. The suprapyloric arterial branches and the right gastric artery are cut and tied off. This process of gastroduodenal devascularization is necessary in order to minimize the chances of incorrect blood supply to the stomach and duodenum, which can cause gastritis, duodenitis, and gastroduodenal ulceration when undergoing HAI chemotherapy[36,43].

The GDA is tied off 2 cm from where it branches off, and a small cut is made before the ligature. It is important to be careful not to create a tear in the inner lining if the lumen is gently widened. A "flute-shaped" catheter is inserted and positioned at the junction where the hepatic and gastroduodenal arteries meet to prevent any turbulence that could harm the catheter or the cannulated artery's long-term viability[36].

The catheter is secured in place with ties above and below the insertion point, ensuring a firm hold without obstructing the catheter's flow. However, complications like catheter tip movement into the hepatic artery, GDA, or complete dislodgement can occur. These may lead to vessel or catheter blockage, aneurysm, GDA rupture, or bleeding. To verify liver-only pump perfusion, a dye solution (methylene blue or fluorescein) is injected into the pump and its distribution is observed. The Codman 3,000 pump (Intera Oncology, Boston, USA), which was used in hepatic artery infusion (HAI) procedures, was discontinued in 2018. As a result, there was no FDA-approved HAI device available until the Synchromed II infusion pump was approved (Medtronic, Minneapolis, Minnesota, USA). The pump has a 20cc capacity and a flow rate of 1.0 ml/die; it is MRI compatible (1,5 to 3,0 Tesla magnetic field) and is designed to last 6.5 years. Subcutaneous placement of the positioning lodge is carried out in the lower left abdomen, as per the technique recommended by the Memorial Sloan Kettering Cancer Center (MSKCC)[37] [Figure 1]. Contraindications are the presence of a stoma, an inflammatory/infectious process, or a distance from the skin greater than 2,5 cm.

Hepatic arterial infusion chemotherapy: a review with technical notes

Figure 1. Placement location for hepatic arterial infusion chemotherapy pump. The catheter tip is placed at the origin of the gastroduodenal artery (GDA).


As a routine procedure, locoregional lymphadenectomy is performed on the hepatic artery, hepatoduodenal, portocaval, and peripancreatic stations (8, 12, and 13). It has a dual function to provide a clear operative field and good exposure and to determine nodal staging[30,40].

The effectiveness of routine lymphadenectomy for intrahepatic cholangiocarcinoma remains a topic of debate[44]. While there is no conclusive evidence regarding the necessary extent of lymphadenectomy for accurate staging and its prognostic value, it has been observed that it can provide significant benefits in unresectable patients. Specifically, it can help alleviate portal tumor burden and prolong survival[45]. To ensure adequate nodal staging, the American Joint Committee on Cancer's eighth edition requires at least six harvested lymph nodes[46], while the National Comprehensive Cancer Network recommends hilar lymphadenectomy[16]. Additionally, an expert panel sponsored by the American Hepato-Pancreato-Biliary Association recommends lymphadenectomy as a part of the standard surgical therapy for iCCA[47].


High-volume centers report low mortality rates (under 1%) for pump placement procedures, with overall patient morbidity ranging from 12% to 41%[37,42,48-51] [Table 2]. In 2005, the MSKCC study group conducted a large retrospective study on 544 patients who were treated between 1986 and 2001. The study's findings on the long-term durability of the pumps were encouraging, with low failure rates of 5%, 9%, and 16% at six months, one year, and two years post-implantation, respectively. These results indicate that the pumps tested are a durable and reliable treatment choice for patients[37].

Table 2

Hepatic Artery Pump-Related Complications

Pump Pocket-Related
Pump migration
< 1%
< 1%
< 0.5%
< 5%
Transaminases, Bilirubin, Alkaline Phosphatases elevation
Biliary Sclerosis


Complications that may occur after pump therapy can be categorized as related to the pump/pocket, catheter, vascular, or biliary systems. These complications may arise early in the postoperative period or after the initiation of pump therapy. It is important to identify, assess, and treat such complications promptly to save the infusion pump, as up to 45% of these complications can be resolved with early and aggressive treatment[52]. Complications that occur within the first 30 days are more likely to be successfully treated compared to those that occur later, with salvage rates of 70% and 30%, respectively[37].

Pump pocket infections are uncommon, up to 2%, but care must be taken intra- and postoperatively to avoid any source of contamination. Early identification of infection symptoms is crucial in managing cellulitis associated with infusion pumps. Conservative antibiotic therapy may be effective in treating mild cellulitis, but true infections may necessitate the relocation of the infusion pump. This process involves the removal of the pump, catheter isolation, and rerouting to a new site, after which a new pump is connected to the catheter.

Additionally, pump migration should be suspected if clinical signs such as skin erosion or ulceration, blistering, or pump displacement are observed. In the case of skin erosion or ulceration, the pump should be considered contaminated and removed and re-sited. Moreover, the pump can rotate or flip, especially in obese patients, where it is helpful to consider the placement in the chest wall routinely. In this case, re-siting in the same pocket may be possible. In < 5% of cases, complications are related to pump malfunction.

In less than 1% of patients, postoperative bleeding may occur. Conservative therapy is sufficient for managing minor bleeding into the pump pocket. However, in the event of a significant pump pocket hematoma that expands, surgical revision and evacuation of the clot are necessary, even if a compressive dressing has been applied. An arterial dissection can be manifest intra-operatively during catheter placement because of difficulty passing into the lumen of the GDA. In the context of a dye perfusion study, the presence of dye in the arterial wall may be observed. When this occurs, it is usually advisable to refrain from performing surgical maneuvers that could compromise the integrity of the hepatic artery. Instead, leaving the catheter in place and assessing the situation through postoperative angiography is often a more prudent course of action[52].

Arterial pseudoaneurysm is a rare condition that affects less than 5% of patients. It can be asymptomatic and found incidentally during restaging or can cause sudden, severe symptoms such as acute abdominal pain, anemia, and shock. Effective management of this condition requires angiography and either stenting or embolization.

In the early postoperative course, a clot in the catheter can be treated with a gentle heparin flush or lytic therapies through the pump catheter. However, if there is a delayed thrombosis or occlusion due to the presence of an extensive fibrin sheath within the catheter lumen, it can lead to high pump failure rates and pose significant challenges. In case the thrombosis extends into the hepatic artery, one should avoid catheter-directed therapy as it may result in the formation of pseudoaneurysm and result in bleeding.

Catheter migration or dislodgement can occur in 5% to 18% of patients. The severity of the issue depends on the timing and location of the displacement. In rare cases, the catheter may erode into the abdominal viscera, particularly around the site of insertion, such as the duodenum, or even in a distant area. When necessary, surgical revision is required[52-53].

Toxicity caused by hepatic arterial infusion chemotherapy can lead to a range of adverse effects, including chemical hepatitis, gastritis, peptic ulcer, and biliary sclerosis (BS). The occurrence of BS is especially concerning due to the possible requirement for a biliary stent and the potential for long-term liver damage[54]. It was first described by Hohn et al. in 1986[40] and further confirmed by Kemeny et al. in 1985[55] and in a randomized trial in 1992[56] and in 2012 by Ito et al.[54] on 475 consecutive patients who received HAI chemotherapy. Patients who received floxuridine-based chemotherapy had a BS incidence between 0.9% and 26%[32,43,48,57-63]. Regular monitoring of biochemical parameters is essential when signs of BS are observed, as indicated by increased levels of serum alkaline phosphatase and/or total bilirubin. In the event of abnormal liver function tests, HAI can be interrupted or conducted at lower doses but with a watchful eye on the blood chemistry trend. Intra-arterial steroids, specifically dexamethasone 4 mg, are commonly used during hepatic artery infusion (HAI) chemotherapy to mitigate or prevent the occurrence of biliary sclerosis (BS).


The combination of hepatic artery infusion and systemic chemotherapy has demonstrated clinical efficacy in extending overall survival in unresectable intrahepatic cholangiocarcinoma, and has served as a conversion to treatment strategy in a minority of patients. A noteworthy limitation of HAI chemotherapy is the restricted availability of experienced surgeons and oncologists. Recent efforts have been made to broaden its application, particularly in the United States and, more recently, in Europe, facilitated by the HAI Consortium Research Network. Anticipated results from ongoing clinical trials are poised to provide the foundation for the expanded utilization of this technique and oncological treatment beyond traditionally established centers.


Authors’ contributions

Made substantial contributions to conception, manuscript drafting and revision: Stecca T, Massani M

Performed manuscript drafting and revision: Greco A, Brollo P

Financial support and sponsorship


Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.


© The Author(s) 2024.


1. Ilyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013;145:1215-29.

2. Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European network for the study of cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016;13:261-80.

3. Alvaro D, Bragazzi MC, Benedetti A, et al. AISF “Cholangiocarcinoma” committee. Cholangiocarcinoma in Italy: a national survey on clinical characteristics, diagnostic modalities and treatment. results from the "cholangiocarcinoma" committee of the italian association for the study of liver disease. Dig Liver Dis 2011;43:60-5.

4. Khan SA, Davidson BR, Goldin RD, et al. British Society of Gastroenterology. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 2012;61:1657-69.

5. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020;17:557-88.

6. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated projection of US Cancer incidence and death to 2040. JAMA Netw Open 2021;4:e214708.

7. Mosconi S, Beretta GD, Labianca R, Zampino MG, Gatta G, Heinemann V. Cholangiocarcinoma. Crit Rev Oncol Hematol 2009;69:259-70.

8. Cercek A, Boerner T, Tan BR, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol 2020;6:60-7.

9. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol 2009;20:1589-95.

10. Kemeny NE, Schwartz L, Gönen M, et al. Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results? Oncology 2011;80:153-9.

11. Inaba Y, Arai Y, Yamaura H, et al. Japan Interventional Radiology in Oncology Study Group (JIVROSG). Phase I/II study of hepatic arterial infusion chemotherapy with gemcitabine in patients with unresectable intrahepatic cholangiocarcinoma (JIVROSG-0301). Am J Clin Oncol 2011;34:58-62.

12. Ghiringhelli F, Lorgis V, Vincent J, Ladoire S, Guiu B. Hepatic arterial infusion of gemcitabine plus oxaliplatin as second-line treatment for locally advanced intrahepatic cholangiocarcinoma: preliminary experience. Chemotherapy 2013;59:354-60.

13. Massani M, Nistri C, Ruffolo C, et al. Intrahepatic chemotherapy for unresectable cholangiocarcinoma: review of literature and personal experience. Updates Surg 2015;67:389-400.

14. Konstantinidis IT, Groot Koerkamp B, Do RK, et al. Unresectable intrahepatic cholangiocarcinoma: Systemic plus hepatic arterial infusion chemotherapy is associated with longer survival in comparison with systemic chemotherapy alone. Cancer 2016;122:758-65.

15. Higaki T, Aramaki O, Moriguchi M, Nakayama H, Midorikawa Y, Takayama T. Arterial infusion of cisplatin plus S-1 against unresectable intrahepatic cholangiocarcinoma. Biosci Trends 2018;12:73-8.

16. NCCN Guidelines Panel Members. Biliary Tract Cancers Version 2. Available from: [Last accessed on 11 May 2024].

17. Klopp CT, Alford TC, Bateman J, Berry GN, Winship T. Fractionated intra-arterial cancer; chemotherapy with methyl bis amine hydrochloride; a preliminary report. Ann Surg 1950;132:811-32.

18. Bierman HR, Byron RL Jr, Miller ER, Shimkin MB. Effects of intra-arterial administration of nitrogen mustard. Am J Med 1950;8:535.

19. Sullivan RD, Norcross JW, Watkins E Jr. Chemotherapy of metastatic liver cancer by prolonged hepatic-artery infusion. N Engl J Med 1964;270:321-7.

20. Narsete T, Ansfield F, Wirtanen G, Ramirez G, Wolberg W, Jarrett F. Gastric ulceration in patients receiving intrahepatic infusion of 5-fluorouracil. Ann Surg 1977;186:734-6.

21. Taylor I. Cytotoxic perfusion for colorectal liver metastases. Br J Surg 1978;65:109-14.

22. Dahl EP, Frelund PE, Tylén U, Bengmark S. Transient hepatic dearterialization followed by regional intra-arterial 5-fluorouracil infusion as treatment for liver tumors. Ann Surg 1981;193:82-8.

23. Patt YZ, Mavligit GM, Chuang VP, et al. Percutaneous hepatic arterial infusion (HAI) of mitomycin C and floxuridine (FUDR): An effective treatment for metastatic colorectal carcinoma in the liver. Cancer 1980;46:261-5.

24. Blackshear PJ, Dorman FD, Blackshear PLJ, Varco RL, Buchwald H. A permanently implantable self-recycling low flow constant rate multipurpose infusion pump of simple design. Surg Forum 1970;21:136-7.

25. Blackshear PJ, Dorman FD, Blackshear PLJ, Varco RL, Buchwald H. The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 1972;134:51-6.

26. Buchwald H, Grage TB, Vassilopoulos PP, Rohde TD, Varco RL, Blackshear PJ. Intraarterial infusion chemotherapy for hepatic carcinoma using a totally implantable infusion pump. Cancer 1980;45:866-9.

27. Sigurdson ER, Ridge JA, Kemeny N, Daly JM. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Oncol 1987;5:1836-40.

28. Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 1983;10:176-82.

29. Johnson LP, Rivkin SE. The implanted pump in metastatic colorectal cancer of the liver. Risk versus benefit. Am J Surg 1985;149:595-8.

30. Weiss GR, Garnick MB, Osteen RT, et al. Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastases using an implantable infusion pump. J Clin Oncol 1983;1:337-44.

31. Thiels CA, D'Angelica MI. Hepatic artery infusion pumps. J Surg Oncol 2020;122:70-7.

32. Kemeny N, Daly J, Reichman B, Geller N, Botet J, Oderman P. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 1987;107:459-65.

33. Datta J, Narayan RR, Kemeny NE, D'Angelica MI. Role of hepatic artery infusion chemotherapy in treatment of initially unresectable colorectal liver metastases: a review. JAMA Surg 2019;154:768-76.

34. Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005;352:734-5.

35. Kemeny N, Fata F. Hepatic-arterial chemotherapy. Lancet Oncol 2001;2:418-28.

36. Allen PJ, Stojadinovic A, Ben-Porat L, et al. The management of variant arterial anatomy during hepatic arterial infusion pump placement. Ann Surg Oncol 2002;9:875-80.

37. Allen PJ, Nissan A, Picon AI, et al. Technical complications and durability of hepatic artery infusion pumps for unresectable colorectal liver metastases: an institutional experience of 544 consecutive cases. J Am Coll Surg 2005;201:57-65.

38. Redman HC, Reuter SR. Arterial collaterals in the liver hilus. Radiology 1970;94:575-9.

39. Koehler RE, Korobkin M, Lewis F. Arteriographic demonstration of collateral arterial supply to the liver after hepatic artery ligation. Radiology 1975;117:49-54.

40. Rayner AA, Kerlan RK, Stagg RJ, Price DC, Hohn DC. Total hepatic arterial perfusion after occlusion of variant lobar vessels: implications for hepatic arterial chemotherapy. Surgery 1986;99:708-15.

41. Cohen AM, Higgins J, Waltman AC, Athanasoulis C, McKusick K. Effect of ligation of variant hepatic arterial structures on the completeness of regional chemotherapy infusion. Am J Surg 1987;153:378-80.

42. Curley SA, Chase JL, Roh MS, Hohn DC. Technical considerations and complications associated with the placement of 180 implantable hepatic arterial infusion devices. Surgery 1993;114:928-35.

43. Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: long-term results of a prospective randomized trial. J Clin Oncol 1992;10:1112-8.

44. Aziz H, Pawlik TM. We asked the experts: role of lymphadenectomy in surgical management of intrahepatic cholangiocarcinoma. World J Surg 2023;47:1530-2.

45. Bartsch F, Hahn F, Müller L, et al. Relevance of suspicious lymph nodes in preoperative imaging for resectability, recurrence and survival of intrahepatic cholangiocarcinoma. BMC Surg 2020;20:75.

46. Zhou R, Lu D, Li W, et al. Is lymph node dissection necessary for resectable intrahepatic cholangiocarcinoma? A systematic review and meta-analysi. HPB (Oxford) 2019;21:784-92.

47. Weber SM, Ribero D, O'Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB (Oxford) 2015;17:669-80.

48. Daly JM, Kemeny N, Oderman P, Botet J. Long-term hepatic arterial infusion chemotherapy. Anatomic considerations, operative technique, and treatment morbidity. Arch Surg 1984;119:936-41.

49. Heinrich S, Petrowsky H, Schwinnen I, et al. Technical complications of continuous intra-arterial chemotherapy with 5-fluorodeoxyuridine and 5-fluorouracil for colorectal liver metastases. Surgery 2003;133:40-8.

50. Creasy JM, Napier KJ, Reed SA, et al. Implementation of a hepatic artery infusion program: initial patient selection and perioperative outcomes of concurrent hepatic artery infusion and systemic chemotherapy for colorectal liver metastases. Ann Surg Oncol 2020;27:5086-95.

51. Janczewski LM, Ellis RJ, Lidsky ME, D'Angelica MI, Merkow RP. Hepatic artery infusion chemotherapy: a quality framework. Ann Surg Oncol 2024;31:701-4.

52. Sharib JM, Creasy JM, Wildman-Tobriner B, et al. Hepatic artery infusion pumps: a surgical toolkit for intraoperative decision-making and management of hepatic artery infusion-specific complications. Ann Surg 2022;276:943-56.

53. Kerr DJ, McArdle CS, Ledermann J, et al. Medical Research Council's colorectal cancer study group; European Organisation for Research and Treatment of Cancer colorectal cancer study group. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003;361:368-73.

54. Ito K, Ito H, Kemeny NE, et al. Biliary sclerosis after hepatic arterial infusion pump chemotherapy for patients with colorectal cancer liver metastasis: incidence, clinical features, and risk factors. Ann Surg Oncol 2012;19:1609-17.

55. Kemeny MM, Battifora H, Blayney DW, et al. Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 1985;202:176-81.

56. Kemeny N, Seiter K, Niedzwiecki D, et al. A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasoneversus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer 1992;69:327-34.

57. Kemeny NE, Niedzwiecki D, Hollis DR, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 2006;24:1395-403.

58. Chang AE, Schneider PD, Sugarbaker PH, Simpson C, Culnane M, Steinberg SM. A prospective randomized trial of regional versus systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987;206:685-93.

59. Hohn DC, Stagg RJ, Friedman MA, et al. A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California oncology group trial. J Clin Oncol 1989;7:1646-54.

60. Martin JK Jr, O'Connell MJ, Wieand HS, et al. Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 1990;125:1022-7.

61. Lorenz M, Müller HH. Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion versus fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 2000;18:243-54.

62. Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol 2002;20:1499-505.

63. Martin RC, Edwards MJ, McMasters KM. Morbidity of adjuvant hepatic arterial infusion pump chemotherapy in the management of colorectal cancer metastatic to the liver. Am J Surg 2004;188:714-21.

Cite This Article

Export citation file: BibTeX | EndNote | RIS

OAE Style

Stecca T, Greco A, Brollo PP, Massani M. Hepatic arterial infusion chemotherapy: a review with technical notes. Hepatoma Res 2024;10:28.

AMA Style

Stecca T, Greco A, Brollo PP, Massani M. Hepatic arterial infusion chemotherapy: a review with technical notes. Hepatoma Research. 2024; 10: 28.

Chicago/Turabian Style

Tommaso Stecca, Alessandra Greco, Pier Paolo Brollo, Marco Massani. 2024. "Hepatic arterial infusion chemotherapy: a review with technical notes" Hepatoma Research. 10: 28.

ACS Style

Stecca, T.; Greco A.; Brollo PP.; Massani M. Hepatic arterial infusion chemotherapy: a review with technical notes. Hepatoma. Res. 2024, 10, 28.

About This Article

Special Issue

© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (, which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Data & Comments




Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at

Download PDF
Share This Article
Scan the QR code for reading!
See Updates
Hepatoma Research
ISSN 2454-2520 (Online) 2394-5079 (Print)


All published articles are preserved here permanently:


All published articles are preserved here permanently: