Guidelines
Liver Cancer 2022;11:407–425
DOI: 10.1159/000524893

Received: June 27, 2021
Accepted: April 4, 2022
Published online: May 5, 2022

Clinical Practice Guidelines for Hepatic
Arterial Infusion Chemotherapy with a Port
System Proposed by the Japanese Society ofInterventional Radiology and Japanese Societyof Implantable Port Assisted Treatment
Kazuomi Ueshima a Atsushi Komemushi b Takeshi Aramaki c Hideki Iwamoto d
Shuntaro Obi e Yozo Sato f, g Toshihiro Tanaka h Kiyoshi Matsueda f
Michihisa Moriguchi i Hiroya Saito j Miyuki Sone l Takuji Yamagami k
Yoshitaka Inaba g Masatoshi Kudo a Yasuaki Arai l
aDepartment of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan;
bDepartment of Radiology, Kansai Medical University Medical Center, Osaka, Japan; cDivision of Interventional

Radiology, Shizuoka Cancer Center, Shizuoka, Japan; dDivision of Gastroenterology/Iwamoto Internal Medicine
Clinic, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan; eDepartment of Internal
Medicine, Teikyo University Chiba General Medical Center, Chiba, Japan; fDepartment of Diagnostic Ultrasound& Interventional Radiology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan;
gDepartment of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Aichi, Japan; hDepartmentof Radiology/IVR Center, Nara Medical University, Nara, Japan; iDepartment of Molecular Gastroenterology
and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan;
jImaging and IVR Center, Sapporo Higashi Tokushukai Hospital, Hokkaido, Japan; kDepartment of Diagnostic andInterventional Radiology, Kochi Medical School, Kochi, Japan; lDepartment of Diagnostic Radiology, National Cancer
Center Hospital, Tokyo, Japan

Keywords
Hepatic arterial infusion chemotherapy · Hepatic arterial
infusion chemotherapy with a port system · Liver cancer ·Hepatocellular carcinoma · Liver metastases

Abstract
Hepatocellular carcinoma is one of the leading causes ofcancer-related death both in Japan and globally. In the advanced stage, hepatic arterial infusion chemotherapy (HAIC)
is one of the most commonly used treatment options for liver cancer in Japan, and implantation of a catheter system(called a port system) in the body is a treatment method thathas evolved mainly in Japan. The Guideline Committee ofKarger@karger.com
www.karger.com/lic© 2022 The Author(s).
Published by S. Karger AG, BaselThis is an Open Access article licensed under the Creative Commons
Attribution-NonCommercial-4.0 International License (CC BY-NC)(http://www.karger.com/Services/OpenAccessLicense), applicable tothe online version of the article only. Usage and distribution for commercial purposes requires written permission.

the Japanese Society of Interventional Radiology and theJapanese Society of Implantable Port Assisted Treatment
jointly published clinical practice guidelines for HAIC with aport system to ensure its appropriate and safe performancein Japanese in 2018. We have written an updated English version of the guidelines with the aim of making this treatment
widely known to experts globally. In this article, the evidence, method, indication, treatment regimen, and maintenance of the system are summarized.
© 2022 The Author(s).
Published by S. Karger AG, BaselKazuomi Ueshima and Atsushi Komemushi contributed equally tothis work.

Correspondence to:Kazuomi Ueshima, kaz-ues @ med.kindai.ac.jp

Introduction

Hepatic arterial infusion chemotherapy (HAIC)
has been performed to treat liver cancer in many countries; however, it is less frequently performed in Western countries than in Asian countries because of thelack of evidence of a survival benefit. HAIC has been
adapted to the treatment algorithm in the Japan Society of Hepatology (JSH) practice guidelines for hepatocellular carcinoma (HCC) as well as Taiwaneseguidelines; conversely, this method has not been included in practice guidelines in other countries, suchas the American Association for the Study of Liver
Diseases (AASLD), European Association for the
Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) guidelines [1–5]. Also, it has not been included in practice guidelines
from the international society for medical oncology,
such as the American Society of Clinical Oncology(ASCO) or European Society for Medical Oncology(ESMO) [6, 7]. In Japan, HAIC is considered an effective treatment option for liver tumors, and it is widely
performed. In addition, the regimen of HAIC varies
by country; therefore, there is no uniform regimen
worldwide. Meanwhile, the literature describing thecurrent proper HAIC methodologies is insufficient.
This clinical practice guideline specific to HAIC witha port system was established by the Japanese Societyof Interventional Radiology (JSIR) and the JapaneseSociety of Implantable Port Assisted Treatment (JSIPAT) in collaboration with JSH to provide a consensus
statement on HAIC. The purposes of this document
were to provide a deep understanding of HAIC with aport system and to ensure the standardization andsafety of HAIC worldwide.
Target Audience
This guideline was established to ensure the appropriate and safe performance of HAIC with a port system by
medical professionals who treat liver cancer.
Method of Guideline Development

We first searched the literature on HAIC with a portsystem. On October 24, 2020, PubMed was searched using the terms “intra-arterial chemotherapy” and “hepatic
arterial infusion.” No publication date was specified in
the search, and 653 references were retrieved.

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DOI: 10.1159/000524893

The committee members performed a manual searchof the abstracts identified in PubMed as a primary screening in reference to the JSH “Clinical Practice Guidelines
for Hepatocellular Carcinoma 2017,” and 94 relevant papers were identified. Another search of studies written in
Japanese identified seven additional references. In total,
101 references were therefore reviewed in the development of these guidelines.
The strengths of the level of evidence and recommendations were stipulated according to the Gradingof Recommendations Assessment, Development, andEvaluation system recommended by “Minds Handbook
for Clinical Practice Guideline Development 2014” tofill the gap between evidence and clinical practice as follows [8, 9]: Strength of recommendation: strong, weak.
Summary of the level of evidence: A, strong; B, moderate; C, weak; D, very weak. For clinical questions thatlacked studies with a strong level of evidence and thatwere difficult to evaluate objectively, the recommendations were based on the consensus of the committee
members.
Key Clinical Questions
Key questions frequently faced in clinical settings were
proposed by the committee members, who are professionally engaged in the treatment of HAIC. The key clinical questions identified were as follows:
1. What is HAIC with a port system?
2. What are the indications for HAIC with a port system
in HCC?
3. What regimens should be used in HAIC with a portsystem for HCC?
4. What are the therapeutic outcomes of HAIC with aport system for HCC?
5. What therapies can be combined with HAIC with aport system for HCC?
6. What are the indications of HAIC with a port system
for liver metastases?
7. What regimens should be used in HAIC with a portsystem for metastatic liver cancer?
8. What are the therapeutic outcomes of HAIC with aport system for liver metastases?
9. What are the complications and treatments of HAIC
with a port system?
10.What is the appropriate method for implanting thecatheter and port system?
11.How should an implanted catheter and port system bemanaged after placement?
12.For which clinical conditions should HAIC with a portsystem be suspended or discontinued?
Ueshima et al.

1. What Is HAIC with a Port System?

Statements
HAIC with a port system is a treatment method forliver neoplasms, with the port system enabling the direct
injection of chemotherapeutic agents into target lesions
in the liver. The difference between HAIC and a one-shot
intra-arterial injection is that continuous administrationof time-dependent cytotoxic antitumor agents such as
5-fluorouracil can be performed easily and safely.
Commentary
The port system was developed to allow patients to receive repeated injections of chemotherapeutic agentssafely and easily without compromising their quality oflife. This port system is called a “reservoir” or “port.”
The system consists of a catheter and a port. Generally,
the port is a device defined according to the following
conditions: (1) it is connected to a catheter placed in a
vessel, and the catheter system is suitable for placementin the body over a long period; (2) it has an internal chamber that directly communicates with the internal lumenof the catheter, and after subcutaneous placement, it enables repeated puncture to inject a drug or drain body
fluid via percutaneous puncture; and (3) it does not havea pump function for continuous injection or drainage[10]. The port was developed in the United States and Japan and was first reported in 1982 in both countries [11–13].
HAIC with a port system uses the aforementioned features to administer treatments for liver neoplasms, withthe port system enabling the direct injection of chemotherapeutic agents into the target lesions in the liver
through the hepatic artery. The device used in HAIC witha port system was first reported by Arai et al. [11].
Another type of port system is System-I [14], whichenables a microcatheter to be repeatedly inserted into theartery via percutaneous puncture. The microcatheter inserted via System-I is guided to the feeding artery of thetarget lesion and is used to inject drugs or embolic agents.
HAIC without a port system has also been described.
It is used when administering concentration-dependent
anticancer drugs such as cisplatin and epirubicin, and it
is less invasive to patients. However, if repeated doses are
required, a port system may be used in consideration ofpatient convenience.
HAIC has the advantage of cost-effectiveness. For example, regarding HCC treatment in Japan as of December 2021, the cost of low-dose 5-fluorouracil and cisplatin (FP) therapy is JPY 53,488 (USD 465 converted at 115
Guidelines for Hepatic Arterial Infusion
Chemotherapy with a Port System

yen per USD) per course in patients with a body surface
area of 1.75 m2 (170 cm, 65 kg). Conversely, sorafenib,
lenvatinib, and atezolizumab plus bevacizumab carrycosts of JPY 533,568 (USD 4639), JPY 338,495 (USD2943), and JPY 898,235 (USD 7811), respectively. Therefore, HAIC is extremely inexpensive compared with other systemic chemotherapies (online suppl. Table S1; see
www.karger.com/doi/10.1159/000524893 for all online
suppl. material).
2. What Are the Indications for HAIC with a Port
System in HCC?

Recommendations
HAIC with a port system is generally indicated for patients with multiple intrahepatic lesions or vascular invasion. However, HAIC may also be an option even in patients with extrahepatic metastasis when intrahepatic lesions or vascular invasion determine the patient’s
prognosis. However, HAIC with a port system may be thebetter treatment option for patients with treatment-naïve
major vascular invasion because of its greater local control of vascular invasion. In addition, HAIC with a portsystem is the most suitable treatment option for patientswith poor liver function, such as Child–Pugh class B not
indicated for systemic chemotherapy (weak recommendation, level of evidence C; Fig. 1).
Commentary
HAIC with a port system is generally indicated forpatients with multiple intrahepatic lesions or vascularinvasion. However, HAIC may also be an option in patients with extrahepatic metastasis when intrahepaticlesions or vascular invasion influence the patient’s
prognosis. Thus, in such situations when patients haveChild–Pugh class A liver function, systemic chemotherapy such as atezolizumab plus bevacizumab [15],sorafenib [16], or lenvatinib [17] is ordinarily the firsttreatment choice [18]. In that sense, HAIC is indicatedfor patients who are refractory to standard systemic
chemotherapy. However, HAIC with a port system maybe the better candidate treatment option for patientswith treatment-naïve major vascular invasion becauseof its greater local control of vascular invasion. In addition, HAIC with a port system is the most suitable treatment option for patients with poor liver function, suchas Child–Pugh class B not indicated for systemic chemotherapy. Next, we will describe the tumor situations
in which HAIC is indicated and characterize them by
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Indication of Hepatic arterial infusion chemotherapy with a port system for hepatocellular carcinoma
Child-Pugh A

Child-Pugh B(Score 7–8)

× Not suitable(Molecular targeted agents preferred)

Good candidate○ Recommended

Good candidate

× Not suitable(Molecular targeted agents preferred)

Good candidate

Good candidate

Good candidate

StageIntermediate stage
Advanced stage
with macrovascular invasionNaïve case
TACE failure/refractoriness case
Advanced stage
with extrahepatic spread(If intrahepatic lesions or vascularinvasion influences the patient‘s prognosis)

Fig. 1. Indications of HAIC with a port system for HCC.

tumor factors, liver function, clinical characteristics,
and other factors.
1. Tumor size/tumor number and distribution
A maximum tumor size of ≥5 cm is reported to be associated with more rapid progression and poorer prognosis [19], although other studies reported no difference inprogression-free survival (PFS) compared with the findings in patients with tumor sizes of ≥10 cm [20–22]. However, most of the studies that found no difference in PFS
did not examine the outcomes of HAIC alone. A large
tumor size may lead to poor drug distribution and insufficient local drug concentrations inside the tumor. Therefore, careful consideration should be given to the use of
HAIC in patients with large tumors. It was reported thatthe objective response rate (ORR) and overall survival(OS) were lower in bilobar multiple HCC than in hemilobar HCC [20]; however, there is insufficient evidence tocomment on differences in the efficacy of HAIC according to the tumor distribution.
2. Tumor volume and tumor occupation rate
Patients with a tumor volume ≥400 mm3 were foundto have inferior OS (hazard ratio [HR] = 2.520, 95% confidence interval [CI] = 1.252–5.072, p = 0.01), but PFS andORR data were not reported [23]. When tumors occupied≥50% of the liver, HAIC was associated with poor ORR,
which affected OS [21]. In univariate analysis, an occupation rate ≥50% affected tumor progression and the ORR
of HAIC, although multivariate analysis did not identify
any significantly associated factors [19, 24]. Thus, it is difficult to reach any firm conclusions regarding the effects
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of the tumor occupation rate on the efficacy of, or indications for, HAIC.
3. Macroscopic growth pattern
No significant correlation was reported between themacroscopic growth pattern and the therapeutic effect of
HAIC with a port system using lipiodol in combination
with unspecified cytotoxic antitumor agents [20]. Furthermore, univariate analysis of HAIC for nodular andnon-nodular lesion types found a significant effect on OS,
although no difference was observed in multivariate analysis [19]. The authors did not discuss any relationshipwith a direct antitumor effect.
4. Patients with portal vein invasion
A phase III randomized controlled trial (RCT) was
conducted in Japan to verify the additional effect of
HAIC with a port system using low-dose FP (SILIUS trial). The results did not meet the primary endpoint, but a
sub-analysis suggested that HAIC with a port system had
an additional effect in patients with HCC and main portal invasion [25]. Another phase III study from China
reported that combining sorafenib with HAIC using oxaliplatin + 5-fluorouracil + leucovorin improved OS versus sorafenib alone in patients with portal vein invasion[22]. Furthermore, retrospective studies recorded positive outcomes for HAIC in comparison with sorafenib,suggesting that HAIC may have provided a survival benefit in patients with HCC and portal vein invasion [19,26, 27].
The pathological condition of portal vein invasion can
be classified into two patterns: portal vein invasion caused
Ueshima et al.

by the ineffectiveness of transcatheter arterial chemoembolization (TACE) and treatment-naïve portal vein invasion. It has been reported that the OS in patients withportal vein invasion caused by TACE is much shorter
than that in patients with treatment-naïve portal vein invasion (7 months vs. 13.4 months), and the ORR is also
lower in patients with portal vein invasion caused by
TACE (18% vs. 39%). This means that HAIC with an implanted port system is suitable for cases of treatment-naïve portal invasion.
However, a number of new regimens for HCC haverecently been approved. Lenvatinib was linked to a higher ORR than sorafenib as well as non-inferior OS [17]. A
phase III trial of lenvatinib excluded patients with main
portal invasion and an intrahepatic tumor occupation
rate ≥50%, meaning that its efficacy and safety have notbeen verified for these tumor conditions. However, inclinical settings, lenvatinib is widely used for advanced
HCC with portal vein invasion. Atezolizumab plus bevacizumab produced a survival benefit compared withsorafenib alone in the IMbrave150 trial [15]. In thisstudy, approximately 40% of patients had major portal
invasion, and atezolizumab plus bevacizumab is currently the first treatment option for patients with portal veininvasion. Because the number of available treatment options has increased, it is necessary to thoroughly consider whether HAIC or systemic therapy should be used inpatients with Child–Pugh class A HCC and portal veininvasion, for which molecular targeted agents are indicated, although HAIC with a port system is indicated forpatients with Child–Pugh class B HCC and portal veininvasion.
5. Patients with hepatic vein invasion
In cases of HCC with hepatic vein invasion, an intrahepatic lesion response to HAIC with a port system incombination with radiation therapy was found to improve prognosis [21]. However, there is no consensus on
the usefulness of HAIC in HCC with hepatic vein invasion.
6. HCC refractory to TACEThe outcomes of TACE-refractory patients following
propensity score matching were significantly better withsorafenib treatment than with HAIC with a port system[28]. In another report, a TACE-refractory status was
identified as a contributing factor to OS (HR = 1.6, 95%
CI = 1.09–2.4, p = 0.04) [29]. These results indicate that
HAIC may not be suitable for TACE-refractory patients.
7. Patients with poor liver function
HAIC with a port system can be safely performed withmodest efficacy in patients with Child–Pugh B liver func-tion, but the ORR and OS are insufficient in patients witha Child–Pugh score of 9 [24, 30]. Furthermore, HAIC
with a port system will occasionally improve liver function from Child–Pugh B to Child–Pugh A when a response occurs [30].
8. Progression after systemic chemotherapyWith the advancement of systemic chemotherapy for
HCC in recent years, multiple systemic chemotherapeutic regimens have become available [15–17, 31–33].
Therefore, in cases of first-line therapy failure, if the patient still has Child–Pugh A liver function, another chemotherapeutic agent is indicated as a second-line therapy[18].
However, if liver function deteriorates to Child–
Pugh B, systemic chemotherapy is not applicable. In
such a case, HAIC may be the better treatment candidate in patients with Child–Pugh B. For example, relatively positive outcomes have been reported for HAIC
with a port system after sorafenib, with an ORR of
29.6% and an OS of 7.6 months [34]. HAIC may evenbe tolerated in patients with Child–Pugh B liver function as a later-line therapy. However, no therapeutic effects of HAIC have been reported except after sorafenib
therapy.
9. Patients with extrahepatic lesions
Extrahepatic lesions were not identified as an independent prognostic factor for OS following HAIC [7], andthe presence or absence of extrahepatic lesions did not
impact the prognosis in patients with portal vein invasion(median OS: 8 months for extrahepatic spread [EHS] [−]vs. 5 months for EHS [+], p = 0.201) [11], suggesting that
HAIC affects survival, even in the presence of extrahepatic lesions. However, HAIC is generally ineffective
against extrahepatic lesions, the presence of which was
identified as a significant factor related to disease progression (HR = 1.748, 95% CI = 1.153–2.646, p = 0.008)
and shorter OS (EHS [−] vs. [+]; HR = 0.543, 95% CI =0.356–0.829, p = 0.0046) [20]. These results indicate thatthe use of HAIC should be given careful consideration inpatients with extrahepatic lesions.
10.Etiology of liver disease
Several studies reported that the effects of HAIC witha port system were relatively better in patients with hepatitis C-related HCC (hepatitis C [+] vs. hepatitis C [−]:
odds ratio = 16.886, p = 0.010; hepatitis C [+] vs. hepatitis
C [−]: odds ratio = 2.436, p = 0.005) [9, 12]; however,other studies did not observe a significant difference,
which indicates the lack of a consensus.

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Chemotherapy with a Port System

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411

Interferon-α and 5-fluorouracil combination therapy (IFN/5FU)
IFNα (sc)5MU

IFNα (sc)

5MU

Day 1 Day 2 Day 3

Fluorouracil (ia) 300 mg/body/day
5 days continuous

Day 4

Day 5

PEG-Interferon-α and 5-fluorouracil combination therapy (PEG-IFN/5FU)
Day 6 Day 7

Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14

sc: subcutaneous infusion, ia: intra-arterial infusion

Low-dose cisplatin and 5-fluorouracil (Low-dose FP)
Day 1 Day 2 Day 3
CDDP (ia)
10 mg/body(30min)Fluorouracil (ia) 250 mg/body(3–5hours)
CDDP (ia)

10 mg/body(30min)Fluorouracil (ia) 250 mg/body(3–5hours)
CDDP (ia)

10 mg/body(30min)Fluorouracil (ia) 250 mg/body(3–5hours)
CDDP (ia)

10 mg/body(30min)Fluorouracil (ia) 250 mg/body(3–5hours)

90 μg/body

PEG-IFNα (sc)

90 μg/body

Day 1 Day 2 Day 3

Fluorouracil (ia) 300 mg/body/day
5 days continuous

Day 4

Day 5

Day 6 Day 7

Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14

Fluorouracil (ia) 250 mg/body(3–5 hours)

Fluorouracil (ia) 250 mg/body(3–5 hours)a

PEG-IFNα (sc)

Day 4

Day 5

Day 6 Day 7

Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14

Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21b

Low-dose cisplatin and 5-fluorouracil (SILIUS regimen)
Day 1 Day 2 Day 3 Day 4
CDDP (ia)
20 mg/m2(15 min)

Day 5

Day 6 Day 7

Fluorouracil (ia) 330 mg/m2/day(5 days continuous)

CDDP (ia)

20 mg/m2(15 min)Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14

Fluorouracil (ia) 330 mg/m2/day(5 days continuous)
CDDP

Day 15 Day 16 Day 17 Day 18 Day 19 Day 20 Day 21

Fluorouracil
Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28

CDDP

Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28

Fluorouracil
CDDP: cisplatin, ia: intra-arterial infusioncd

CDDP: cisplatin, ia: intra-arterial infusion
In the SILIUS study, this regimen was administeredwith sorafenib in the dose of 800 mg daily

New FP regimen on admission

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Lipiodol – CDDP CDDP 50 mg/bodysuspension (ia) Lipiodol 5–10 mL
Fluorouracil (ia) 250 mg/bodyFluorouracil (ia) 1,250 mg/m2(5 days continuous)
Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14
Lipiodol – CDDP CDDP 50 mg/bodysuspension (ia) Lipiodol 5–10 mL
Fluorouracil (ia) 250 mg/bodyFluorouracil (ia) 1,250 mg/m2(5 days continuous)

CDDP: cisplatin, ia: intra-arterial infusion

New FP regimen on out-patient department
Day 1
Lipiodol – CDDP CDDP 20–35 mg andsuspension
Lipiodol 2–5 mL/bodyFluorouracil (ia) 500–1,000 mg/body
1,250 mg/m2(5 days continuous)

Day 15

Day 29eEvery two weeks

Fig. 2. a IFN/5FU. b PEG-IFN/5FU. c Low-dose cisplatin and 5-fluorouracil (Low-dose FP). d Low-dose cisplatin and 5-fluorouracil (SILIUS regimen). e New FP regimen. IFN/5FU, interferon-alpha and 5-fluorouracil com-bination therapy; PEG-IFN/5FU, PEG-interferon-alpha and 5-fluorouracil combination therapy.

11.Tumor markers
Some studies reported that alpha-fetoprotein and protein induced by vitamin K absence II (also known as desγ-carboxyprothrombin) were related to OS [11, 12], butother studies found no association with OS [8, 9, 14, 15,
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20]. In addition, alpha-fetoprotein and protein inducedby vitamin K absence II were not found to be related to
ORR [12, 14]. Therefore, it is not necessary to consider
tumor marker levels for HAIC.

Ueshima et al.

3. What Regimens Should Be Used in HAIC with aPort System for HCC?

Recommendation
Regimens that use FP are recommended (strong recommendation, level of evidence C).
Commentary
A wide variety of HAIC regimens have been reported,
including the use of single drugs or combination regimens such as doxorubicin, epirubicin, mitomycin C,
5-fluorouracil, zinostatin stimalamer, cisplatin, miriplatin, and oxaliplatin. Generally, 5-fluorouracil-based regimens such as low-dose FP are used. Moreover, the effectiveness of the FOLFOX regimen using oxaliplatin, 5-fluorouracil, and leucovorin has recently been demonstrated.
The currently used regimens for HCC are described in thefollowing sections.
Combined Interferon and Intra-Arterial
5-Fluorouracil
This therapy consists of systemic interferon and intraarterial 5-fluorouracil (Fig. 2a, b). Previous studies on
combined interferon and intra-arterial 5-fluorouracil reported ORRs of 24.6%–73% and OS times of 6.9–14.7
months [35–44]. A retrospective study that comparedcombined interferon and intra-arterial 5-fluorouracil toa historical control observed a significant improvementin survival (1-year survival: 34% vs. 15%; 2-year survival:
18% vs. 5%, p < 0.01) [38].
A phase II trial on the effect of adding cisplatin to combined interferon and 5-fluorouracil observed a significant
improvement in ORR and PFS versus interferon and5-fluorouracil alone (ORR: 45.6% vs. 24.6%, p = 0.030;
PFS: 6.5 months vs. 3.3 months, p = 0.0048) [41]. However, a phase II trial that compared combined interferonand 5-fluorouracil with the best salvage therapy (intraarterial cisplatin or low-dose FP) did not produce a superior ORR (ORR: 26.7% vs. 25.8%) [42].
Low-Dose FP Therapy (Fig. 2c, d)
Low-dose FP therapy consists of low-dose cisplatinand continuous intra-arterial 5-fluorouracil. Previous
studies on cisplatin (including high dose of cisplatin) plus
5-fruorouracil HAIC with a port system reported ORRs
of 20%–71% and median OS times of 7.3–15.9 months[27, 44–53].
A propensity score analysis of patients with HCC registered to a nationwide database managed by the Liver
Cancer Study Group of Japan found that low-dose FP
Guidelines for Hepatic Arterial Infusion
Chemotherapy with a Port Systemtherapy was associated with a better prognosis than best
supportive care (HR = 0.60, p < 0.0001), and low-dose FP
therapy was also associated with a good prognosis in patients with four or more nodules or portal vein invasion[53]. A propensity score analysis comparing sorafeniband HAIC (mainly low-dose FP therapy) did not find significant differences in PFS or OS [19].
A retrospective study observed a better ORR with lowdose FP therapy than with sorafenib (30.9% vs. 4.8%) but
no significant difference in OS [29]. However, after adjusting for portal vein invasion, OS was significantly longer in the low-dose FP group than in the sorafenib group(14 months vs. 7 months, p = 0.005).
A retrospective study that focused on portal vein invasion and refractoriness to TACE observed significantly
better median OS with low-dose FP therapy than withsorafenib among non-TACE-refractory patients withportal vein invasion (13 months vs. 6 months). By contrast, among TACE-refractory patients without portal
vein invasion, OS was significantly worse in the low-dose
FP group than in the sorafenib group (8 months vs. 20
months) [29].
A retrospective trial comparing sorafenib and lowdose FP therapy in patients with portal vein invasion observed significantly better prognoses in the low-dose FP
group than in the sorafenib group (OS: 309 days vs. 120days) [27]. A phase III RCT to verify the additional effectof HAIC with a port system using low-dose FP (SILIUS
trial) found a significant improvement in PFS (5.3 months
vs. 3.5 months, p = 0.004) but not in OS (11.8 months vs.
11.5 months, p = 0.955). However, a sub-analysis suggested an additional effect of low-dose FP therapy among patients with main portal vein invasion (OS: 11.4 months vs.
6.5 months, p = 0.050) [25].
New FP Therapy (Fig. 2e)
The new FP therapy was conceived by Nagamatsu etal. [20]. This regimen consists of an arterial injection of
powdered cisplatin with lipiodol followed by continuous
intra-arterial 5-fluorouracil. Nakano and Niizeki conducted a nonrandomized prospective study of sorafenib
and new FP therapy [54]. Twenty patients with HCC withno extrahepatic spread and macroscopic vascular invasion were treated with sorafenib, and 44 were treated with
the new FP therapy. OS was significantly lower in the new
FP group than in the sorafenib group (25 months vs. 13
months, p = 0.0131). The ORR of the new FP group was
also significantly longer than that of the sorafenib group(71% vs. 10%).

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Table 1. Results of HAIC with a port system for HCC
Regimenn

ORR, %

TTP,
monthsCombined systemic interferon and continuous intra-arterial 5-fluorouracil
5FU+interferon-α1173
ND
5FU+interferon-α
55
43.6
ND
5FU+interferon-α
28
57.1
ND
5FU+interferon-α
116
52
ND
5FU+interferon-α
31
29
5.8
5FU+interferon-α
102
39.2
ND
5FU+interferon-α
57
24.6
ND
5FU+interferon-α
34
26.7
ND
5FU+Pegylated-interferon-α
55
44
ND
Low-dose FP therapy
CDDP+5FU
31
71
ND
CDDP+5FU
48
48
ND
CDDP+5FU
15
20
ND
CDDP+5FU
52
38.5
4.1
CDDP+5FU
71
35
ND
CDDP+5FU
476
40.5
ND
CDDP+5FU
32
31.3
ND
38
8
ND
*CDDP+5FU
41
22
7*CDDP+5FU
97
27.8
ND
*CDDP+5FU
New FP therapy
5FU+CDDP+Lipiodol
51
86.3
–
5FU+CDDP+Lipiodol
52
75–
5FU+CDDP+Lipiodol
44
71–
Combined sorafenib and low-dose FP therapy
5FU+CDDP+Sorafenib
102
36
5.3

PFS,
monthsOS,monthsAuthorYear

Ref. No

ND
5.2
ND
ND
ND
2
3.3
3.5
12.5

–
11.8
–
6.9
7.5
9
10.5
8.4
14.7

Sakon M
Ota H
Enjoji M
Obi S
Uka K
Nagano H
Yamashita T
Monden M
Wu J

2002
2005
2005
2006
2007
2011
2011
2012
2015

[33]
[35]
[34]
[36]
[37]
[38]
[39]
[40]
[41]

ND
ND
ND
ND
ND
ND
ND
ND
ND
6

–
10.2
7.3
15.9
10.2
13.9
309 days6
12
9.5

Okuda K
Ando E
Yamasaki T
Ueshima K
Niizeki T
Nouso K
Moriguchi M
Cheong JY
Park JY
Kim BK

1999
2002
2005
2010
2012
2013
2017
2005
2007
2011

[43]
[44]
[46]
[48]
[50]
[51]
[25]
[45]
[47]
[49]

8
8.6
9.5

33
27
30.4

Nagamatsu H 2010
Nagamatsu H 2016
Nakano M
2017

[18]
[58]
[52]

4.8

11.8

Kudo M[23]

2018

ORR, objective response rate; TTP, time to response; PFS, progression-free survival; OS, overall survival; 5FU, 5-fluorouracil; CDDP,
cisplatin. * High dose cisplatin+5FU.

OthersA phase I/II trial of combination 5-fluorouracil + mitoxantrone + cisplatin therapy for advanced HCC reported an ORR of 25%, PFS of 7.0 months, and OS of 11.3
months. Regarding grade 3/4 adverse events, 39% of patients exhibited neutropenia, 36% exhibited leukocytopenia, and 22% exhibited elevated AST [55].
A retrospective study that compared HAIC with a portsystem using FOLFOX to sorafenib found that HAIC significantly improved patient prognosis (PFS: 7.1 months
vs. 3.3 months, p < 0.001; OS: 14.5 months vs. 7.0 months,
p < 0.001) [56]. A phase II trial comparing HAIC using
mFOLFOX to TACE observed significant improvementsin the HAIC group (disease control rate: 83.8% vs. 52.5%,
p = 0.004; PFS: 5.87 months vs. 3.6 months, p = 0.015) andsignificantly fewer grade 3/4 adverse events (12 vs. 27,
p = 0.007) [57].

414Liver Cancer 2022;11:407–425
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A phase II trial of combined sorafenib and HAIC using
FOLFOX for patients with portal vein invasion reported
an ORR of 40%, a disease control rate of 77.1%, a PFS of
6.7 months, and an OS of 13.2 months [58]. A phase III
study found that sorafenib combined with HAIC using
FOLFOX resulted in better OS than sorafenib alone inpatients with portal vein invasion; however, femoral artery puncture and catheterization were performed every
cycle, and a port system was not used in the trial [22].
4. What Are the Therapeutic Outcomes of HAIC witha Port System for HCC?

Statements
The therapeutic outcomes of HAIC with a port systemvary depending on the regimen. Its local therapeutic effect is relatively high. With the commonly used low-dose
Ueshima et al.

FP therapy, the response rates range from 24.5% to 71%[27, 45, 46, 48, 50, 52, 53]. However, HAIC with a portsystem has produced little evidence of a survival benefit.
Commentary
The regimens used in HAIC with a port system for
HCC are (1) combined interferon and intra-arterial 5-fluorouracil, (2) low-dose FP therapy, (3) new-FP therapy,and (4) combined sorafenib and low-dose FP therapy.
The results of each treatment are summarized in Table 1.
1. Combined systemic interferon and continuous intraarterial 5-fluorouracil
Combination therapy with systemic interferon and intra-arterial 5-fluorouracil has been reported since 2002
[35–38, 40–43, 59], and the published studies examined
8–116 patients with portal vein invasion rates of 25%–
100%. The ORRs ranged from 24.6% to 73%, and OS
ranged from 6.9 to 14.7 months.
Obi et al. [38] reported the results of 116 patients withadvanced HCC and portal vein invasion. The ORR was
52%, and OS was 6.9 months, which were better than theoutcomes of untreated historical controls [38]. Yamashita et al. [41] reported an RCT comparing systemic interferon and continuous intra-arterial 5-fluorouracil withand without cisplatin in 114 patients with advanced HCC
and a portal vein invasion rate of 27.5%. Systemic interferon and continuous intra-arterial FP produced a significantly higher ORR of 45.6% and OS of 17.6 months
than systemic interferon and continuous intra-arterial
5-fluorouracil without cisplatin (ORR = 24.6%, OS = 10.5
months) [41].
2. Low-dose FP therapy
Low-dose FP therapy has been reported since 1999
[27, 45, 46, 48, 50, 52, 53], and studies have examined
31–114 patients with portal vein invasion rates of 26.4%–
100%. The ORRs ranged 20%–71%, and OS ranged 7.3–
15.9 months.
Niizeki et al. [52] conducted a retrospective analysis of
71 patients with advanced HCC and portal vein invasion
and reported an ORR of 35% and an OS of 10.2 months.
However, these studies were retrospective cohort studies
as opposed to RCTs. The evidence level for this therapy istherefore not high [52].
3. New FP therapy
Three studies have reported new FP therapy [20, 54,60]. Nakano et al. [54] conducted a nonrandomized prospective study that compared sorafenib with new FP therapy [54]. Twenty patients with HCC and vascular invasion but without distant metastasis received sorafenib,
whereas 44 patients received new FP therapy. The median
Guidelines for Hepatic Arterial Infusion
Chemotherapy with a Port SystemOS was 13.2 months with sorafenib, versus 30.4 months
with new FP therapy. The new FP therapy produced asignificant improvement in OS (p = 0.013) and a significant antitumor effect. The ORR was 10% with sorafenib,vs. 71% with the new FP therapy.
4. Combined sorafenib and low-dose FP therapy
Kudo et al. [25] conducted an RCT comparing
sorafenib alone with sorafenib plus HAIC with a port system using a low-dose FP regimen for the treatment ofadvanced HCC, mainly including patients with portal
vein invasion. Sorafenib combined with low-dose FP
therapy was administered to 102 patients, and sorafenib
alone was administered to 103 patients. The ORR for the
combination therapy was 36%, versus 18% for sorafenib
alone, with the difference being significant. However, theOS rates in the combination and monotherapy groups
were 11.8 and 11.5 months, respectively, with no significant difference observed.
A sub-analysis performed in this trial revealed thatmedian OS in patients with main portal vein invasion was
11.4 months in those treated with sorafenib combinedwith low-dose FP therapy, versus 6.5 months (4.5–8.4) inthose treated with sorafenib monotherapy (HR = 0.493,
95% CI = 0.240–1.014, p = 0.050). These results suggestthat sorafenib combined with low-dose FP therapy might
improve OS in patients with HCC and main portal veininvasion in comparison with sorafenib monotherapy.
5. What Therapies Can Be Combined with HAIC witha Port System for HCC?

Recommendations
Molecular targeted agents can be combined with
HAIC with a port system (weak recommendation, levelof evidence C).
Commentary
HAIC with a port system is widely used in patientswith advanced HCC and bilobar multiple tumors or portal vein invasion. Molecular targeted therapy is also often
selected in such cases [15–17, 31–33]. HAIC has a strong
ability to shrink tumors; however, its survival benefit has
not been confirmed. By contrast, sorafenib has been
proven to extend survival, but its response rate is low.
Kudo et al. [25] conducted a phase III trial comparing
sorafenib monotherapy with sorafenib plus low-dose FP
combination therapy to verify the effect of HAIC on survival. OS was 11.5 months (95% CI = 8.2–14.8) in thesorafenib monotherapy group, versus 11.8 months (95%
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415

ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; RCT, randomized controlled trial; FOLFOX, oxaliplatin, fluorouracil, andleucovorin; CDDP, cisplatin; Low dose FP, low dose cisplatin and 5-fluorouracil; TTP, time to progression.

Ikeda M 2021 [60]
–
17.2
–
6.3
–
45.7
36
Without a port system
36
Single arm II

Lenvatinib+HAIC CDDP

Ikeda M 2016 [59]HR = 0.60
p = 0.031
10.6
8.7
HR = 0.78
p = 0.212 TTP
3.1
2.8
p = 0.09
21.7
7.3
66
42
Without a port system
CDDP
66
42
II
RCT

Sorafenib+HAIC
Sorafenib

HR = 1.009 Kudo M 2018 [23]p = 0.955
11.8
11.5
HR = 0.753
p = 0.051
p = 0.003 4.8
3.5
36
18
102
103
Low dose FP With a port system
102
103
III
RCT

Sorafenib+HAIC
Sorafenib

2018 [56]
He M
–
13.2
–
6.7
–
40
35
Without a port system
Sorafenib＋HAIC FOLFOX
35
Single arm II

2019 [20]
III
RCT

125
122

Sorafenib＋HAIC FOLFOX
Sorafenib

Without a port system

125
122

40.8
2.46

p < 0.001 7.03
2.6

HR = 0.33
p < 0.001

13.37
7.13

HR = 0.35
p < 0.001

He M

Year Ref No.
AuthorOS,monthsPFS, months
ORR,%nPort system
Regimen of
HAIC
Arm
n
Phase
DesignTable 2. Results of HAIC in combination with molecular targeted agent for HCC

416

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CI = 9.1–14.5) in the sorafenib plus low-dose FP combination therapy group (HR = 1.009, 95% CI = 0.743–1.371,
p = 0.955). The safety of the combination therapy wasconfirmed. In a sub-analysis of patients with portal veininvasion, OS was 6.5 months (95% CI = 4.5–8.4) in thesorafenib monotherapy group, versus 11.4 months (95%CI = 7.0–15.9) in the sorafenib + low-dose FP combination therapy group, with the difference approaching significance (HR = 0.493, 95% CI = 0.240–1.014, p = 0.050),
suggesting that HAIC has an additional effect on OS inpatients with major portal vein invasion. Because conducting a large phase III trial on such a small patientgroup is unrealistic, it will be difficult to verify the additional effect of HAIC in patients with major portal veininvasion. Nevertheless, the use of this therapy appears to
be feasible in clinical practice, and combination therapy
with sorafenib and HAIC may be a safe and effective
treatment option for patients with HCC and major portal
vein invasion.
In addition, Ikeda et al. [61] reported that HAIC using
cisplatin without a port system combined with sorafenib
produced favorable OS versus sorafenib alone. The median survival times in the sorafenib alone and CDDP withsorafenib arms were 8.7 and 10.6 months, respectively(HR = 0.60, 95% CI = 0.38–0.96, p = 0.031) [61].
It was recently reported that HAIC using the FOLFOX
regimen without a port system in combination withsorafenib produced a survival benefit in patients with
HCC and major portal vein invasion [22, 57, 58]. Median
OS was 13.37 months in the HAIC with sorafenib groupversus 7.13 months in the sorafenib group (HR = 0.35,
95% CI = 0.26–0.48, p < 0.001). HAIC using the FOLFOX
regimen combined with sorafenib was linked to longer
PFS (7.03 months vs. 2.6 months) and a higher response
rate (40.8% vs. 2.46%, p < 0.001) than sorafenib alone[22].
Ikeda et al. [62] presented at ESMO2021 that HAIC
using cisplatin without a port system combined with lenvatinib produced a favorable objective response and OS.
The ORRs according to modified RECIST and RECIST
v1.1 were 64.7% and 45.7%, respectively. In addition, themedian PFS and OS were 6.3 and 17.2 months, respectively [62]. Therefore, lenvatinib may be a good candidate
drug for combination use with HAIC. The results of
HAIC in combination with molecular targeted agents are
summarized in Table 2.
All of the currently available regimens for HCC haveanti-VEGF activity. Inhibition of VEGF induces vascular
normalization and improves vascular permeability,
thereby reducing intratumoral interstitial pressure, imUeshima et al.

proving drug delivery, and possibly enhancing the effectof HAIC [63, 64]. Therefore, all agents with anti-VEGF
activity can be good candidates for combined use of
HAIC. Conversely, the cytotoxic effect of HAIC can induce increased neoantigen production. Therefore, HAIC
in combination with an immune checkpoint inhibitorcontaining regimen such as atezolizumab plus bevacizumab might represent a promising treatment that activates the immune system.
6. What Are the Indications of HAIC with a Port
System for Liver Metastases?

Recommendation
The indications for HAIC with a port system for thetreatment of liver metastases are as follows: (1) the presence of liver metastases affecting the prognosis; (2) disease refractory to systemic chemotherapy (or not indicated); and (3) systemic chemotherapy not sufficiently
effective against liver metastases that affect the prognosis(weak recommendation, level of evidence D).
Commentary
In HAIC with a port system, the presence or absenceof extrahepatic lesions affects the prognosis [65–67].
HAIC may be performed when intrahepatic lesions are
believed to have a greater impact on prognosis than extrahepatic lesions, when lesions are refractory to systemic chemotherapy, when lesions are not indicated for systemic chemotherapy, and when systemic chemotherapy
is not sufficiently effective against a liver metastasis that
affects the prognosis.
HAIC is sometimes considered in combination withsystemic chemotherapy. HAIC was not found to be usefulfor preventing liver metastasis after resection, particularly in patients with colorectal cancer [68], whereas it was
useful for reducing the risk of liver metastasis, although it
did not improve OS [69]. HAIC has sometimes been performed in patients who were resistant to systemic chemotherapy, although its efficacy remains unclear [70–72].
7. What Regimens Should Be Used in HAIC with aPort System for Metastatic Liver Cancer?

Recommendations
For liver metastases of colorectal cancer, weekly highdose 5-fluorouracil therapy or combined weekly highdose 5-fluorouracil therapy and systemic irinotecan is
Guidelines for Hepatic Arterial Infusion
Chemotherapy with a Port Systemrecommended (strong recommendation, level of evidence C). There are insufficient data to provide recommendations for other cancers (very weak recommendation, level of evidence D).
Commentary
Most studies on HAIC with a port system for liver metastases were concerned with liver metastases of primarycolorectal cancer. However, some studies investigated liver metastases from primary gastric, breast, pancreatic,
and biliary tract cancers (including gallbladder cancer
and cancer of the ampulla of Vater).
Outside Japan, 5-fluorodeoxyuridine (FUDR) is often
used for liver metastases of primary colorectal cancer [66,73], although there are several reports from Japan on
weekly high-dose 5-fluorouracil therapy or other 5-fluorouracil regimens. In a phase I/II trial of weekly high-dose
5-fluorouracil therapy, the ORR was 78%, and the median
OS was 25.8 months (extrahepatic lesion no vs. yes: 25.9
months vs. 17.3 months) [65]. A retrospective study using
the same regimen found similar results. A phase I/II trialof a combination regimen featuring weekly high-dose
5-fluorouracil and systemic irinotecan recorded an ORR
of 72% and a median OS of 49.8 months [74]. Other studies used irinotecan or oxaliplatin as part of the arterial
infusions [75, 76].
Regimens for liver metastases of gastric cancer are
based on 5-fluorouracil (intra-arterial 5-fluorouracil
only [77], 5-fluorouracil + epirubicin + mitomycin C[FEM regimen] [78], and 5-fluorouracil + cisplatin [FPtherapy] [79]). The regimen for liver metastases of breast
cancer is the FEM regimen [80]. Regimens for liver metastases of pancreatic cancer are intra-arterial 5-fluorouracil combined with systemic gemcitabine [81] and intra-arterial gemcitabine combined with systemic chemotherapy [82].
8. What Are the Therapeutic Outcomes of HAIC witha Port System for Liver Metastases?

Statements
The therapeutic outcomes of HAIC with a port system
for liver metastases, which depend on the primary cancer
or treatment regimen, are consistent local control effects
in the liver with fewer systemic side effects than observed
for systemic chemotherapy. If intrahepatic metastatic lesions affect the prognosis, HAIC with a port system may
be considered.

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417

Table 3. Results of HAIC with a port system for metastatic liver cancer
Primary lesion

RegimenN

ORR, %

DCR, % TTP, monthOS, month Author

Year

Ref. No.

Colon cancer

5FU+LV ia
FUDR ia
5-FU+LV iv

57
54
57

45
43.2
19.7

ND
ND
ND

9.2
5.9
6.6

18.7
12.7
17.6

Lorenz M

2000

[71]

Colon cancer

FUDR ia
5FU+LV iv

68
67

47
24

64
45

5.3
6.8

24.4
20.0

Kemeny N

1992

[97]

Colon cancer

5FU ia5FU ia10 (Phase1) 80
32 (Phase2) 78

100
97

ND
ND

ND
25.8

Arai Y

1997[63]

Colon cancer

5FU ia + CPT-11 iv

25

72

ND

ND

49.8

Arai Y

2012[72]

Colon cancer

CPT-11 ia

12

33

58

ND

ND

Fiorentini G

2003

[73]

Colon cancer

L-OHP ia+FU/LV iv

28

64

75

27 (PFS)

27

Ducreux M

2005

[74]

Gastric cancer

5FU ia

18

83.3

ND

ND

19.2

Ojima H

2007

[75]

Gastric cancer

5FU+Epi-ADM+MMC ia

63

55.6

88.9

ND

10.5

Kumada T

1999

[76]

Gastric cancer

CDDP+5FU ia

7

–

ND

ND

16.5

Yamakado

2005

[77]

Breast cancer

5FU+ADM+MMC ia/5FU+Epi-ADM ia

56

81

ND

ND

12.5

Arai Y

1994[78]

Pancreatic cancer

5FU ia + GEM iv

9

44.4

88.9

ND

14.1

Hashimoto A

2012

[79]

Pancreatic cancer

GEM ia + 5FU ia
GEM ia +S1 po

5
2

60
50

100
50

ND

22.4

Tajima H

2013

[80]

ORR, objective response rate; DCR, disease control rate; TTP, time to response; PFS, progression-free survival; OS, overall survival; ia, intra-arterial; iv, intravenous
infusion; po, per os; ND, no data; 5FU, 5-fluorouracil; LV, leucovorin; FUDR, fluorodeoxyuridine; CPT-11, irinotecan; L-OHP, oxaliplatin; Epi-ADM, epirubicin; MMC,
mitomycin-C; ADM, Adriamycin; GEM, gemcitabine; S-1, tegafur/gimeracil/oteracil potassium.

Commentary
The results of HAIC with a port system for metastatic
liver cancer are summarized in Table 3. Kemeny et al. [66]conducted an RCT comparing HAIC with a port systemusing FUDR with systemic 5-fluorouracil + leucovorin
for liver metastases of colorectal cancer. HAIC with a portsystem using FUDR produced better ORR (47% vs. 24%)
and OS (24.4 months vs. 20 months) [66].
Phase II trials of weekly high-dose 5-fluorouracil therapy in Japan reported ORRs of 52%–83% and OS times of
18.6–26 months [65, 83, 84]. No global randomized trials
have compared HAIC to FOLFOX and FOLFIRI, which
are the current standard therapies. In Japan, phase I/II
trials of the combination of HAIC plus intra-arterial
5-fluorouracil and systemic chemotherapy with intravenous irinotecan reported ORRs of 72%–86.4%, OS of 49.8
months, and PFS of 11.2 months [74, 85]. In a retrospective study, patients who were refractory to FOLFOX andFOLFIRI and who were administered intra-arterial 5-fluorouracil exhibited an ORR of 18.2%, an OS of 6.7 months,
and a PFS of 2.8 months [71].

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A phase II trial of intra-arterial FEM for hepatic metastases of gastric cancer reported an ORR of 55.6% anda median OS of 10.5 months [78]. A study that administered an FEM regimen to patients refractory to S1 reported an ORR of 42.9% and an OS of 12.7 months [86].
In a study of HAIC for hepatic metastases of breast
cancer, an FEM regimen had an ORR of 81% [80]. A recent study on HAIC that used therapeutic regimens suchas mitomycin/5-fluorouracil in patients that were refractory to systemic chemotherapy reported an ORR of 20%
and an OS of 12 months [87].
Intra-arterial 5-fluorouracil had an ORR of 44.4% in
patients with hepatic metastases of pancreatic cancer[81]. As described previously, the response rate varies depending on the type of carcinoma and regimen, but a highresponse rate is generally achieved. A limitation of HAIC
with a port system is that the survival benefit has not been
proven for patients who receive this treatment despite its
high response rate. Liver metastasis should be regarded asa phenotype of systemic disease, and systemic chemotherapy should be given as the first-line treatment. However, if standard systemic chemotherapy is not indicatedUeshima et al.

or the patient is refractory, HAIC with a port system may
be considered to avoid liver failure caused by tumor occupying the liver.
9. What Are the Complications and Treatments of
HAIC with a Port System?

Statements
The complications of HAIC with a port system are categorized into those caused by the implanted catheter andport system and those caused by the injected drugs [88].
If complications caused by the implanted system are observed, removing and/or replacing the catheter system isnecessary. If damage to the hepatic artery or gastrointestinal mucosa is caused by cytotoxic antitumor agents, cessation of the drug is necessary, and the port system should
be checked immediately by angiography or CT angiography.
Commentary
Complications caused by the port system include migration of the indwelling catheter, catheter occlusion because of thrombus formation, catheter kinking, catheterassociated bloodstream infections, fibrin sheath formation, the port turning inside-out, and stenosis, occlusion,or pseudoaneurysm of the blood vessel in which the catheter is inserted [89–93]. In most cases, invasive treatments such as removing or replacing the catheter system
are necessary.
Migration of the indwelling catheter may cause mucosal injury to the stomach and/or intestine when cytotoxic antitumor agents are injected. Slight migration of
the catheter is acceptable if there is no drug spillage toorgans outside the liver. If symptoms are caused by migration of the indwelling catheter, invasive treatments
such as removing or replacing the catheter system arenecessary.
Catheter occlusion attributable to thrombus formation or kinking may prevent the catheter from injecting
the agent. When injection is difficult, the port systemshould be checked, and if occlusion or kinking of thecatheter is suspected, the catheter should be replaced.
Mixing heparin with an anticancer drug solution may
prevent thrombotic obstruction of the catheter. Catheterassociated bloodstream infections may cause sepsis. Antibiotic therapy alone cannot cure this sepsis, and removal of the port system is needed.
Fibrin sheath formation may cause dysfunction of theport system or infection with the formation of biofilms.
Guidelines for Hepatic Arterial Infusion
Chemotherapy with a Port System

Angiography via the port system will lead to arterial stenosis around the catheter side hole; however, conventional angiography may reveal that the hepatic artery is patent. Fibrin sheath formation can be resolved by replacing
the catheter [91].
The implanted port is often turned inside-out. If thishappens, needle puncture will be difficult, and repositioning is needed.
Stenosis and occlusion of the blood vessel in which thecatheter is inserted may also cause dysfunction of the portsystem. For stenosis or occlusion of the common or proper hepatic artery, placing a metallic stent into the occluded artery may be useful.
Although relatively rare, complications such as cerebral infarctions have been reported when a catheter isplaced via the subclavian artery. Ischemic change in thevertebral artery region can cause symptoms of cerebral
infarction, but the symptoms are often not severe. In suchcases, HAIC can be continued with conservative therapy
including an antiplatelet agent.
Cytotoxic antitumor agents can cause vascular damage to the hepatic artery and damage the hepatic parenchyma or biliary system. Additionally, gastrointestinal ulcers can be caused by the leakage of cytotoxic antitumor
agents into the digestive tract. The systemic circulation ofcytotoxic antitumor agents can cause additional symptoms such as digestive organ symptoms and myelosuppression [65, 71, 80, 94–99]. Patients with a history ofbiliary reconstruction have a higher risk of hepatic abscess or biliary fistula.
Vascular damage to the hepatic artery caused by cytotoxic antitumor agents can be prevented by mixing hydrocortisone or other steroids with intra-arterial agents[100]. Symptoms of gastrointestinal ulcers caused byleakage into the digestive tract can be improved by histamine H2 receptor antagonists or proton pump inhibitors;
however, if clear signs of blood flow to the digestive tract
are observed on angiography via the port system, altering
blood flow by coiling the artery causing the symptoms
may be needed [101].
10. What Is the Appropriate Method for Implanting
the Catheter and Port System?

Recommendation
The tip fixation method of percutaneous placement
using an antithrombotic-coated catheter with a side holeis recommended (strong recommendation, level of evidence C).
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419

Peripheral hepatic artery fixation

Gastroduodenal artery (GDA) fixation

Implanted catheter

LHA
LGA

RGA
RHA
PHA

LHA

RHA
PHA

CA
SPA

CA
SPA

CHA

CHA
Coil

LGA

RGA

Side hole

CoilSide hole

Implanted catheter
GDA

a

GDA

b

Fig. 3. a GDA fixation. b Peripheral hepatic artery fixation.

Commentary
Percutaneous placement of the port system using IVR
technology is less invasive than surgical placement. The
patency rate of the hepatic artery and the frequency ofcatheter migration following percutaneous placementcompare favorably with those of surgical placement [102].
The tip fixation method for percutaneous placement using an antithrombotic-coated catheter with a side hole isrecommended [90, 103].
An approach via the subclavian artery or inferior epigastric artery is preferred for inserting the catheter because these approaches do not pass through any joints
and they are useful for preventing catheter migration[103]. The femoral artery approach is simple and widelyused [104].
Gastroduodenal artery (GDA) fixation, in which the
tip of the catheter is inserted into the GDA and is fixed using a metal coil, is the most commonly used method [90](Fig. 3a). Peripheral hepatic artery fixation, in which the
tip of the catheter is inserted into the peripheral branch of
the hepatic artery and the side hole is placed in the proper
hepatic artery, is another useful method [105] (Fig. 3b). In
420

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every method, the right gastric artery and GDA should beembolized by a metallic coil to avoid mucosal injury or
pancreatitis from the cytotoxic antitumor agents.
11. How Should an Implanted Catheter and Port
System Be Managed after Placement?

Recommendation
1. When puncturing the port percutaneously, the skinshould be disinfected using >0.5% chlorhexidine–alcohol (strong recommendation, level of evidence B).
2. A non-coring needle should be used to puncture theport (strong recommendation, level of evidence C).
3. After administering a drug via the implanted catheterand port system, heparin or a similar agent should be
provided to prevent occlusion of the system (strong
recommendation, level of evidence C).
4. Regular flow checks, i.e., CT angiography via the portsystem, are recommended to assess drug distribution
from the port system (strong recommendation, levelof evidence C).
Ueshima et al.

Commentary
1. When puncturing the port subcutaneously, the skinshould be disinfected using >0.5% chlorhexidine–alcohol.
Use >0.5% chlorhexidine–alcohol (used for skin disinfection in central vein catheters, in peripheral artery
catheters, and when changing dressings) to disinfectthe skin at the site of vascular access to the device. If
chlorhexidine is not available, use povidone-iodine
and 70% alcohol [106].
2. A non-coring needle should be used to puncture theport subcutaneously.
To prevent coring and hollowing out of the silicone
septum, a non-coring needle (also called a Huber needle) should be used [107]. Package inserts for port systems state the number of punctures for which a noncoring needle can be used.
3. After administering a drug via the port system, flushing with an anticoagulant should be performed to prevent occlusion of the system.
Because the port system communicates directly with ablood vessel, the port and catheter can be filled withthe anticoagulant heparin (heparin sodium 1,000
units/1 mL, depending on the volume of the port andcatheter) [90], or the system can be flushed with a heparin saline solution [108] to prevent occlusion of thesystem due to backflow of blood.
4. Regular flow checks, i.e., angiography or CT angiography via the port system, are recommended to assess
drug distribution from the implanted catheter andport system.
The distribution of drugs administered by the port system can be assessed by observing the distribution of acontrast agent injected via the port [109, 110]. The process of confirming the patency of the system and hepatic
artery and checking the contrast agent distribution iscalled a flow check, and it is often conducted by combining digital subtraction angiography with CT angiography. If a flow check finds abnormal drug distribution inside or outside the liver, the blood flow should be adjusted as needed to make the drug distribution appropriate[103].
12. For Which Clinical Condition Should HAIC with aPort System Be Suspended or Discontinued?

sion of the hepatic artery. HAIC can also be suspended
after a complete response is maintained for a certain
length of time (strong recommendation, level of evidenceD).
Commentary
Generally, chemotherapy should be discontinued on
disease progression. HAIC with a port system is often indicated for patients with relatively advanced primary or
metastatic liver cancer. If other systemic chemotherapeutic options are available, a change of therapy should beconsidered even though mild disease progression may occur.
Therapy cannot be continued in patients with hepatic
artery occlusion. Additionally, HAIC should be discontinued in patients with severe stenosis of the hepatic artery, which is likely to cause other complications [103,111]. When image findings reveal a complete response,
suspension of HAIC should be considered after continuing therapy for a certain period.
Long-term therapy has a risk of hepatic artery occlusion, whereas premature suspension of treatment can result in tumor regrowth [112]. In colorectal cancer, many
patients who exhibit a complete response to systemic
chemotherapy on imaging also exhibit viable cells on
pathological analysis. Although it can be difficult to decide how long to continue therapy, there is a general consensus that therapy can be suspended after approximately 6 months of gradually extended treatment intervals[112, 113].
Conclusions

HAIC with a port system plays an important role incontrolling intrahepatic tumors even though systemic
chemotherapy remains the mainstream treatment for
many cancers. In pathological conditions in which intrahepatic tumors affect the prognosis, HAIC with aport system has a weaker systemic effect from the viewpoint of side effects; it maximizes the local control effect, and it potentially improves the prognosis. This
guideline summarizes the evidence and consensus forhepatic artery infusion reservoir therapy in Japan, and
it is expected to contribute to the field of clinical practice.

Recommendations
HAIC with a port system should be suspended when
there is disease progression or severe stenosis or occluGuidelines for Hepatic Arterial Infusion
Chemotherapy with a Port System

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421

Acknowledgments
We greatly acknowledge the support of Prof. Norihiro Kokudo(the former chairman of the Committee of Clinical Practice Guidelines for Hepatocellular Carcinoma) and Prof. Tetsuo Takehara(president of the JSH). We also thank Joe Barber Jr., PhD, from
Edanz (https://jp.edanz.com/ac) for editing a draft of the manuscript.

Conflict of Interest Statement
Kazuomi Ueshima received honoraria and consulting or advisory fees from Bayer AG, Eisai Co. Ltd., Merck Sharp & Dohme,
Eli Lilly and Company, Chugai Pharmaceutical Co., Ltd., Takeda
Pharmaceutical Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co.,
Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., and Kowa Co., Ltd. and consulting or advisory fees from Eisai Co., Ltd., Eli Lilly and Company,
Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co.,
Ltd., and Pfizer Inc. Atsushi Komemushi, Takeshi Aramaki, Hideki Iwamoto, Shuntaro Obi, Yozo Sato, Toshihiro Tanaka, Kiyoshi
Matsueda, Hiroya Saito, Miyuki Sone, and Yoshitaka Inaba haveno relevant conflicts of interest to disclose. Michihisa Moriguchi
received honoraria from Bayer, Eisai, Eli Lilly, and Chugai andconsulting or advisory fees from Bayer, Eli Lilly, and Chugai.
Takuji Yamagami received a research grant from Guerbet Japan,
Nihon Medi-Physics, Eisai, Fujifilm Toyama Chemical Co. Ltd.,GE Healthcare, Boston Scientific, and Fuji Pharma Co., Ltd. Masatoshi Kudo received honoraria and consulting or advisory feesfrom Bayer AG and Eisai Co., Ltd.; honoraria from Bayer AG, Bristol Myers Squibb, EA Pharma Co., Ltd., Eisai Co., Ltd., and Merck
Sharp & Dohme; and research funding from Bayer AG, Daiichi

Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Merck Sharp& Dohme, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., and Taiho Pharmaceutical. Yasuaki Arai received honoraria from Merit Medical
Systems, Cosmotec, Fuji Pharma, Canon Medical Systems, Canon
Medical Systems Asia Pte. Ltd., Canon Medical Systems Malaysia
Sdn. Bhd., Sumitomo Bakelite, Boston Scientific Japan, Boston Scientific Corporation, Japan Lifeline, AstraZeneca plc, Guerbet Japan, Guerbet Asia Pacific, Kyorin Pharmaceutical, Daiichi SankyoCo., Ltd., and Eisai Co., Ltd. Masatoshi Kudo is the Editor-in-Chiefof Liver Cancer, and Kazuomi Ueshima is an Editorial Board Member of Liver Cancer.

Funding Sources
This article was funded with support from the Japanese Societyof Implantable Port Assisted Treatment.

Author Contributions
Concepts: Kazuomi Ueshima and Atsushi Komemushi. Manuscript preparation: Kazuomi Ueshima, Atsushi Komemushi,
Takeshi Aramaki, Hideki Iwamoto, Shuntaro Obi, Yozo Sato,
Toshihiro Tanaka, Kiyoshi Matsueda, Michihisa Moriguchi, Hiroya Saito, Miyuki Sone, Takuji Yamagami, and Yoshitaka Inaba.
Manuscript editing: Kazuomi Ueshima, Atsushi Komemushi,
Takeshi Aramaki, Hideki Iwamoto, Shuntaro Obi, Yozo Sato,
Toshihiro Tanaka, Kiyoshi Matsueda, Michihisa Moriguchi, Hiroya Saito, Miyuki Sone, Takuji Yamagami, and Yoshitaka Inaba.
Manuscript review and approval: Masatoshi Kudo, Yasuaki Arai,
and Yoshitaka Inaba.

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