Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art

Liver functional failure is one of the leading causes of cancer-related death. Primary liver tumors grow up mainly in the liver, and thus happens for liver metastases deriving from other organs having a lower burden of disease at the primary site. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion (HAI) of chemotherapy takes place. In literature, HAI chemotherapy was applied for the treatment of advanced hepatobiliary cancers with encouraging results. Different chemotherapeutic agents were used such as Oxaliplatin, Cisplatin, Gemcitabine, Floxuridine, 5-Fluorouracil, Epirubicin, individually or in combination. However, the efficacy of this treatment strategy remains controversial. Therefore, this review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers.

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Percutaneous Implantation of a Microcatheter-Port System for Hepatic Arterial Infusion Chemotherapy of Unresectable Liver Tumors: Technical Feasibility, Functionality, and Complications

Diagnostics ◽

10.3390/diagnostics11030399 ◽

2021 ◽

Vol 11 (3) ◽

pp. 399

Author(s):

Olivier Chevallier ◽

Ségolène Mvouama ◽

Julie Pellegrinelli ◽

Kévin Guillen ◽

Sylvain Manfredi ◽

...

Keyword(s):

Hepatic Artery ◽

Liver Tumors ◽

Hepatic Arterial Infusion ◽

Catheter Placement ◽

Port Catheter ◽

Liver Malignancies ◽

Arterial Infusion ◽

Side Hole ◽

Catheter Migration ◽

Catheter Implantation

To evaluate the feasibility and safety of percutaneously implanted arterial port catheter systems for hepatic arterial infusion of chemotherapy (HAI) in patients with unresectable liver malignancies. From October 2010 to August 2018, arterial port catheters for HAI were percutaneously implanted in 43 patients with unresectable liver malignancies. Three different catheter placement techniques were compared: a conventional end-hole catheter placed in the common hepatic artery (technique 1, n = 16), a side-hole catheter with the tip fixed in the gastroduodenal artery (technique 2, n = 18), and a long-tapered side-hole catheter with the tip inserted distally in a segmental hepatic artery (technique 3, n = 6). Catheter implantation was successful in 40 (93%) of the 43 patients. Complications related to catheter placement were observed in 10 (23%) patients; 5 (83%) of the 6 major complications were resolved, as well as all 4 minor complications. Catheter migration and occlusion occurred in 9 (22.5%) patients. Catheter migration was more frequent with technique 1 (n = 6) than with technique 2 (n = 1), although the difference was not significant (p = 0.066). Percutaneous arterial port catheter implantation for HAI is highly feasible and carries a low risk of complications.

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Eight years after introducing liver resection at the Oncology Institute of Vojvodina

Archive of oncology ◽

10.2298/aoo1304101m ◽

2013 ◽

Vol 21 (3-4) ◽

pp. 101-104

Author(s):

Ivan Majdevac ◽

Nikola Budisin ◽

Milan Ranisavljevic ◽

Dejan Lukic ◽

Imre Lovas ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Resection ◽

Liver Tumors ◽

Liver Parenchyma ◽

Malignant Neoplasms ◽

Chemotherapy Treatment ◽

Primary Liver Tumors ◽

Cancer Metastases ◽

Colorectal Cancer Metastases ◽

Medical Histories

Background: Hepatectomies are mostly performed for the treatment of hepatic benign or malignant neoplasms, intrahepatic gallstones, or parasitic cysts of the liver. The most common malignant neoplasms of the liver are metastases from colorectal cancer. Anatomic liver resection involves two or more hepatic segments, while non-anatomic liver resection involves resection of the metastases with a margin of uninvolved tissue. The aim of this manuscript was to show results of hepatectomies performed at the Oncology Institute of Vojvodina. Methods: We performed 133 liver resections from January 1997 to December 2013. Clinical and histopathological data were obtained from operative protocols, histopathological reports, and patients? medical histories. Results: We did 80 metastasectomies, 51 segmentectomies, and 18 radiofrequent ablations (RFA). Average number of colorectal cancer metastases was 1.67 per patient. We also made 10 left hepatectomies. In all cases, we made non-anatomic resections. Conclusion: Decision about anatomic versus non-anatomic resections for colorectal metastasis and primary liver tumors should be made before surgical exploration. Preservation of liver parenchyma is important with respect to liver failure and postoperative chemotherapy treatment.

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Identification of the Response-Related Biomarker of Bimonthly Hepatic Arterial Infusion Chemotherapy

Journal of Clinical Medicine ◽

10.3390/jcm10040629 ◽

2021 ◽

Vol 10 (4) ◽

pp. 629

Author(s):

Kei Moriya ◽

Tadashi Namisaki ◽

Hiroaki Takaya ◽

Kosuke Kaji ◽

Hideto Kawaratani ◽

...

Keyword(s):

Hepatic Arterial Infusion ◽

Progression Free Survival ◽

Serum Levels ◽

Hepatic Arterial Infusion Chemotherapy ◽

Advanced Hepatocellular Carcinoma ◽

Arterial Infusion ◽

Term Survival ◽

Arterial Infusion Chemotherapy ◽

Infusion Chemotherapy ◽

Molecularly Targeted Agents

Despite the availability of molecularly targeted agents for advanced hepatocellular carcinoma (aHCC), these are limited to compensated cirrhotic patients, and concerns about decreased hepatic functional reserve (HFR) and unknown adverse events, which may affect long-term survival, remain unaddressed. In this study, we enrolled 96 aHCC patients treated with bimonthly hepatic arterial infusion chemotherapy (B-HAIC) with cisplatin or sorafenib monotherapy (oral sorafenib 400 mg twice daily) not only to demonstrate its efficacy and significance but also to indicate preferable candidates by setting a response-related biomarker. Differences in treatment had no significant effect on overall survival (OS). The response rate in patients treated with B-HAIC was relatively higher than those treated with sorafenib. HFR was well maintained over the treatment course with B-HAIC, while it was significantly impaired with sorafenib. By employing multivariate analysis, we found negative trends between progression-free survival (PFS) periods and serum levels of alpha fetoprotein as well as des-gamma-carboxy prothrombin (DCP). In addition, a logistic regression analysis of the relationship between serum DCP levels and PFS periods over 420 days (14 months) showed that the PFS periods of patients with higher DCP was significantly shorter than those of patients with lower DCP (p = 0.02). Subsequently, the present study demonstrated the efficacy and safety of B-HAIC and identified a predictor of unpreferable patients. Based on these results, B-HAIC might be an alternative treatment after the implementation of new molecularly targeted therapies.

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Horizons of development of immunotherapy for malignant liver tumors

Experimental and Clinical Gastroenterology ◽

10.31146/1682-8658-ecg-191-7-81-89 ◽

2021 ◽

pp. 81-89

Author(s):

V. E. Mukhin ◽

Yu. S. Konstantinova ◽

R. R. Gimadiev ◽

N. V. Mazurchik

Keyword(s):

Liver Tumors ◽

Surgical Excision ◽

Malignant Neoplasms ◽

Therapeutic Approaches ◽

Liver Malignancies ◽

Primary Liver Tumors ◽

Malignant Liver Tumors ◽

Malignant Liver ◽

Methods Of Treatment ◽

New Strategies

Primary liver tumors are one of the most common types of malignant neoplasms. Surgical excision is still the most effective treatment in the early stages of the disease, however in most cases early diagnosis is difficult. Moreover, even if the treatment is carried out according to a radical program, the risk of relapse remains extremely high. In this regard, the search for new strategies for the treatment of liver malignancies that differ from traditional methods of treatment is not terminated. One of such promising approaches is immunotherapy. The present review is devoted to the current understanding of the mechanisms of action and the available clinical experience in the use of immunotherapy approaches in the treatment of liver malignancies. Combining different types of immunotherapy or combining immunotherapy with traditional therapeutic approaches can facilitate a synergistic effect and contribute to the development of personalized medicine.

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Phase II trial of hepatic arterial infusion of fluorouracil and recombinant human interferon alfa-2b for liver metastases of colorectal cancer refractory to systemic fluorouracil and leucovorin.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.4.1432 ◽

1997 ◽

Vol 15 (4) ◽

pp. 1432-1438 ◽

Cited By ~ 22

Author(s):

Y Z Patt ◽

A Hoque ◽

R Lozano ◽

R Pozdur ◽

J Chase ◽

...

Keyword(s):

Liver Metastases ◽

Response Rate ◽

Liver Tumors ◽

Hepatic Arterial Infusion ◽

Interferon Alfa ◽

Survival Duration ◽

Common Side Effect ◽

Human Interferon ◽

Arterial Infusion ◽

Median Response

PURPOSE To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). PATIENTS AND METHODS Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. RESULTS There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. CONCLUSION HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.

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Increased incidence of adverse events after concomitant hepatic arterial infusion plus systemic chemotherapy and bevacizumab for colorectal cancer with liver metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.591 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 591-591

Author(s):

S. Sadahiro ◽

T. Suzuki ◽

Y. Maeda ◽

A. Tanaka ◽

K. Okada ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Adverse Events ◽

Phase I ◽

Systemic Chemotherapy ◽

Response Rate ◽

Hepatic Arterial Infusion ◽

Progression Free Survival ◽

Arterial Infusion ◽

Grade 3

591 Background: FOLFOX+bevacizumab (BEV) is the standard systemic chemotherapy for metastatic colorectal cancer (CRC). We investigated the combination of FOLFOX4 and hepatic arterial infusion (HAI) in patients who had isolated liver metastasis from CRC. We also compared efficacy and safety between this combination therapy and its concomitant use with BEV. Methods: Twenty-five patients entered a phase I/II trial of HAI (5-FU 250 mg/d, leucovorin 25 mg/d; d1-7, q2w) combined with FOLFOX4. Fourteen other patients with a similar background received HAI + FOLFOX4 combined with BEV and the two regimens were compared. Results: In the phase I/II study, the recommended doses for FOLFOX were as follows: L-OHP, 85 mg/m2; l-LV, 100 mg/m2; 5-FU (bolus), 400 mg/m2; and 5-FU (infusion), 600 mg/m2. Sixteen patients who received this regimen showed a response rate of 93.8% (2 CR and 13 PR), a median progression-free survival of 323 days, and a one-year survival rate of 93.7%. In the subsequent phase II trial of HAI + FOLFOX4 with BEV, 14 patients were enrolled and the response rate was 78.6% (2 CR and 9 PR). The outcome was inferior when BEV was used concomitantly. The median numbers of doses were 10 (range: 1-27) for FOLFOX4 and 9 (1-27) for HAI without BEV, whereas the corresponding numbers with BEV were 8 (1-12) and 2 (0-9), respectively. There was a marked decrease in the number of HAI procedures when BEV was used. Thrombosis occurred in 8 patients who received concomitant BEV, which was the most common reason for cessation of HAI. Other adverse events (≥Grade 3) were neutropenia (n=7; 43.8%) and thrombocytopenia (n=2; 12.5%) without BEV or neutropenia (n=7; 43.8%) and diarrhea (n=1; 7.1%) with BEV, and no marked difference was seen between the two regimens. Both regimens were well tolerated. Severe neuropathy was only observed in 1 patient (6.3%; Grade 3) who received concomitant BEV. Conclusions: In the present study, HAI + FOLFOX combined with BEV caused thrombosis and disturbance of wound healing, thereby increasing the incidence of complications and making it difficult to continue treatment. These findings suggest that BEV should not be administered with HAI therapy. No significant financial relationships to disclose.

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Identification of new liver tumor biomarkers using proteomics.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e21091 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e21091-e21091

Author(s):

Peter J. Maimonis ◽

Yoh Zen ◽

David J. Britton ◽

Andrew Brand ◽

Malcolm Ward ◽

...

Keyword(s):

Liver Tumor ◽

Liver Tumors ◽

Early Stage ◽

Normal Liver ◽

Liver Parenchyma ◽

Tissue Type ◽

P Value ◽

Tumor Biomarkers ◽

Formalin Fixed Paraffin Embedded ◽

New Biomarkers

e21091 Background: It is crucial to identify new biomarkers that help diagnose cancers at an early stage and contribute to the development of new anti-cancer drugs. Here, we identify new liver tumor biomarkers using proteomics. Methods: We evaluated 9 types of liver tissue from 55 patients: normal liver parenchyma (n=7), hepatocellular carcinoma (HCC) (n=7), normal bile duct (n=6), peripheral cholangiocarcinoma (CC) (n=7), hilar CC (n=7), CC associated with primary sclerosing cholangitis (PSC) (n=7), metastatic colorectal cancer (n=7), and mixed HCC/CC after trans-arterial chemoembolization (n=7; areas of HCC and areas of CC separately examined). Protein extracted from microdissected, formalin-fixed paraffin-embedded tissue (0.15 mm3 in total) was reduced, alkylated and digested with trypsin in a stacking gel. Peptides were analyzed using nano-liquid chromatography-Mass spectrometry. The raw data were searched using Mascot. Normalized spectral counts for each protein among each tissue type were compared. For each comparison, an unrelated t-test was computed to obtain the p value. q values (adjusted p values) were computed using a direct False Discovery Rate approach (q < 0.05 considered statistically significant). Results: The mean number of proteins identified per sample was 762 +/- 119 S.D, resulting in a total of 2643 proteins identified. Numbers of proteins with significantly different expression levels among different tissue types are shown below. Some of these proteins are being reported here for the first time in the context of liver carcinogenesis. Conclusions: This study revealed proteins that are significantly over/underexpressed in particular types of liver tumors. Clinically useful new biomarkers may be present among these proteins and are now undergoing validation using immunohistochemisty. [Table: see text]

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Management of Focal Nodular Hyperplasia and Hepatocellular Adenoma

Swiss Surgery ◽

10.1024/1023-9332.5.3.122 ◽

1999 ◽

Vol 5 (3) ◽

pp. 122-125 ◽

Cited By ~ 13

Author(s):

Mentha ◽

Rubbia-Brandt ◽

Howarth ◽

Majno ◽

Morel ◽

...

Keyword(s):

Young Women ◽

Focal Nodular Hyperplasia ◽

Liver Tumors ◽

Imaging Techniques ◽

Young Patients ◽

Hepatocellular Adenoma ◽

Normal Liver ◽

Liver Parenchyma ◽

Diagnostic Error ◽

Nodular Hyperplasia

Hepatocellular adenoma and focal nodular hyperplasia are two benign hepatic tumors which are mainly detected in healthy young women. Hepatocellular adenoma is an indication for surgery due to the risk of haemorrhage and malignant transformation. By contrast, focal nodular hyperplasia should be managed conservatively. However, precise diagnosis of these benign liver tumors remains difficult and sometimes impossible, despite new imaging techniques. Because of the risk of diagnostic error, resection or large biopsies of presumed liver tumors should be performed in young women (and a fortiori in men and older patients in whom focal nodular hyperplasia is less prevalent) when the diagnosis of focal nodular hyperplasia is not firmly established. The risk of liver surgery in young patients with normal liver parenchyma is, in the opinion of the authors, lower than the risk of a mistaken diagnosis.

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Stereotactic body radiotherapy (SBRT) in combination with surgery for primary and metastatic liver tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.347 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 347-347

Author(s):

Erik Lappinen ◽

Ngoc Thai ◽

Kusum Tom ◽

Akhtar Khan ◽

Ellen Day ◽

...

Keyword(s):

Liver Tumors ◽

Hepatic Metastases ◽

Normal Liver ◽

Liver Parenchyma ◽

Metastatic Lesion ◽

Hepatic Lesions ◽

Unresectable Metastasis ◽

Metastatic Liver Tumors ◽

Metastatic Liver

347 Background: Evaluate the feasibility, safety, and efficacy of SBRT in combination with surgery for primary and metastatic liver tumors. Methods: 12 patients completed hepatectomy and SBRT for either hepatocellular carcinoma (HCC) (3) or metastases from colorectal (4), neuroendocrine (2), uterine (2), or sarcoma (1) primary. All patients with metastases completed chemotherapy. Most patients (7) had resection of their operable metastases, total of 19, and gold fiducials placed in the unresectable lesions, total of 9, to facilitate definitive adjuvant SBRT. One patient with an unresectable metastasis received preoperative SBRT. Two patients with HCC had SBRT as a bridge to liver transplant. Two patients had salvage SBRT for recurrence after surgery. All patients completed 4D-CT for ITV definition and SPECT/CT to define functional normal liver parenchyma volume (NLV). MV-fluoro was performed to confirm tumor/fiducial respiratory motion within the PTV. Results: All patients successfully completed a combination of hepatectomy and SBRT. Seventeen hepatic lesions (≤ 2/patient) were treated with SBRT with a mean PTV 186.0 cc (15.1-803.5). The mean dose was 49.3 Gy (39-60) prescribed to the PTV in 5-6 fractions. With median follow-up of 9.2 months (2.8-15.3) there was no RILD > Grade 1 observed. The most common toxicity was Grade ≤ 2 fatigue. Nine patients had reduced SPECT-NLV vs. calculated NLV by a mean of 487.5 cc (p = 0.0004). In 6 of these, the SPECT-NLV vs. the CT-NLV was reduced by a mean of 253.9 cc (44.6 - 1076.2) reflecting the importance of SPECT functional imaging for SBRT planning. Postoperative morbidity was ≤ Grade 1. All surgical margins were negative. Three patients developed intrahepatic failures post SBRT. However, on follow-up imaging no in-field failures have occurred. Conclusions: The combination of liver SBRT with hepatic resection is safe and effective. It can be used preoperatively to increase resectability or to salvage surgical failures. We also report on the combination of limited hepatectomy for peripheral (including bilobar) hepatic metastases with planned SBRT to unresectable metastatic lesion(s). SBRT planning with SPECT/CT allows identification and preservation of the NLV.

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