Tóm Tắt (Anh) Đánh Giá Kết Quả Kỹ Thuật Nút Tĩnh Mạch Cửa Và Tĩnh Mạch Gan Trước Phẫu Thuật Cắt Gan.pdf

Results of increasing the future liver remnant volume after portal and hepatic vein embolization in hepatocellular carcinoma.. However, because it often occurs in patients with chronic l

HANOI MEDICAL UNIVERSITY

ABSTRACT OF DOCTORAL THESIS

HA NOI - 2024

HANOI MEDICAL UNIVERSITY

Supervisors:

Supervisor 1: Associate professor Le Thanh Dung

Supervisor 2: Professor Pham Minh Thong

Reviewer 1: Associate professor Nguyen Quoc Dung

Reviewer 2: Associate professor Tran Bao Long

Reviewer 3: Associate professor Nguyen Cong Long

The thesis will be present in front of board of university examiner and reviewer lever at 14h00 on October 23rd 2024

This thesis can be found at:

National Library:

National Medical Informatics Library

Library of Hanoi Medical University

RELATED TO THE DISSERTATION

1 Than Van Sy, Le Thanh Dung, Bui Van Giang, Nguyen

Quang Nghia, Ninh Viet Khai, Cao Manh Thau, Pham Gia Anh, Trinh Hong Son, Nguyen Minh Duc Safety and efficacy of liver venous deprivation following transarterial chemoembolization before major hepatectomy for

hepatocellular carcinoma Therapeutics and Clinical Risk Management 2023;19:425-433 (SCIE, Scopus Q1)

2 Than Van Sy, Le Thanh Dung, Cao Manh Thau, Phạm Gia

Anh, Nguyen Quang Nghia, Ninh Viet Khai, Tran Ha Phuong, Nguyen Hai Nam, Tran Dinh Tho, Trinh Hong Son, Bui Van Giang, Trinh Ha Chau, Vu Đang Luu, Pham Minh Thong Results of increasing the future liver remnant volume after portal and hepatic vein embolization in

hepatocellular carcinoma Journal of Medical Research

2023;170(9): 195-204

3 Than Van Sy, Le Thanh Dung, Pham Minh Thong

Comparing the results of simultaneous portal and hepatic vein embolization using a trans-jugular approach with a

transhepatic approach Vietnam Medical Journal 2024;

535(1B): 298-304

INTRODUCTION

According to statistics from the Global Cancer Observatory in

2022, hepatocellular carcinoma (HCC) ranks second in incidence and is the leading cause of death among cancers in Vietnam Liver resection is the preferred radical treatment option if resection is possible However, because it often occurs in patients with chronic liver disease (chronic hepatitis, fibrosis, and cirrhosis), the risk of liver failure after surgery to treat HCC remains a major problem, especially after major liver resection, which is mainly due to insufficient future liver remnants (FLR) Portal vein embolization (PVE) has been widely applied worldwide to increase FLR volume for several decades However, this method requires a relatively long waiting time for surgery, usually after

4 - 8 weeks, and up to 30% of patients could not receive surgery after PVE due to insufficient liver volume or tumor progression Some other techniques to increase the effectiveness of liver hypertrophy have been applied, such as Embolization of the right portal vein and segment IV, Associating liver partition and portal vein ligation for staged hepatectomy - ALPPS, Additional hepatic vein embolization after a few weeks of PVE Each method has advantages and disadvantages but cannot wholly replace PVE

Recently, to overcome the disadvantages of the above methods, the simultaneous portal vein and hepatic vein embolization (also named liver venous deprivation - LVD) has been applied and has gradually become a good alternative to PVE However, the available data mainly applies to the group of liver metastatic colon cancer and cholangiocarcinoma Data on the application of this method to patients with HCC are few and scattered, especially for patients with severe liver fibrosis and cirrhosis In Vietnam, there are currently only a few single reports with a few patients receiving LVD to cause liver hypertrophy

before surgery Therefore, we conducted the study: "Evaluating the

results of portal and hepatic vein embolization before hepatectomy"

with two objectives:

1 Describe the clinical, paraclinical, and imaging characteristics of hepatocellular carcinoma patients with preoperative portal vein and hepatic vein embolization

2 Evaluate the safety and results of increasing liver volume of the portal vein and hepatic vein embolization technique before major hepatectomy

1 THE NEED OF THESIS IMPLEMENTATION

In 2022, hepatocellular carcinoma (HCC) ranked as the sixth most commonly diagnosed cancer and the third most common cause of cancer death globally In Vietnam, HCC ranks second in incidence and

is the leading cause of death among cancers The number of new cases and deaths due to HCC each year is approximately equal, showing that the burden of this disease is still substantial Surgical excision is the preferred radical treatment option if resection is possible However, because it often occurs in patients with chronic liver disease (chronic hepatitis, fibrosis, and cirrhosis), the risk of posthepatectomy liver failure is a long-standing concern in HCC treatment

There have been many studies reporting on the safety and effectiveness of LVD for liver hypertrophy in subjects with liver metastasis of colon cancer and cholangiocarcinoma Data on the application of this method to patients with HCC are few and scattered, especially for patients with advanced liver fibrosis and cirrhosis Therefore, applying LVD to preoperative liver hypertrophy in HCC patients is a new topic with scientifically meaningful, and practical value

2 NOVEL CONTRIBUTIONS OF THE THESIS

The results of this study show that portal and hepatic vein embolization is a safe and well-tolerated technique to increase future liver remnant volume in patients with hepatocellular carcinoma Post-procedure major complications occurred in 1 patient (accounting for 1.6%)

Portal vein and hepatic vein embolization obtained an excellent liver hypertrophy rate (54.5% after 3 weeks), and the FLR/sTLV increased from 32.5% to 48.4% (p < 0.001) 90.2% of patients with initially small FLR obtained sufficient target future liver remnant volume for hepatectomy after 3 weeks 1 out of 61 patients had disease progression while waiting for surgery (1.6%)

The liver hypertrophy rate when using the transjugular approach compared to the transhepatic approach was not statistically significant (58.3% versus 52.6%, p = 0.260)

In cases of insufficient liver hypertrophy for surgery after portal vein and hepatic vein embolization, additional transarterial chemoembolization not only helped to control the tumor but also provided a more significant increase in future liver remnant volume than

in those without additional transarterial chemoembolization (p < 0.05)

The hypertrophy rate is significantly lower in the liver fibrosis F3-F4 group than in the F1-F2 group (46.8% versus 62.6%, p = 0.015)

3 THESIS OUTLINE

The thesis consists of 135 pages, including 2 pages of introduction, 35 pages of literature review, 21 pages of materials and methods, 35 pages of results, 39 pages of discussion, 2 pages of conclusions, and 1 page of recommendation It also has 27 tables, 18 figures, 18 charts, and 163 references (Vietnamese: 8, English: 155)

The PhD student published 03 original articles in prestigious medical journals, of which 1 was published in an international journal (SCIE, Scopus)

Chapter 1: OVERVIEW 1.1 Literature review in the world

LVD was a modification from the PVE by adding hepatic vein embolization in the same procedure after the portal vein embolization to accelerate FLR hypertrophy, thereby increasing the rate of patients obtaining surgery Combining portal and hepatic vein embolization is thought to cause more damage to the embolized lobe than PVE alone, reducing residual portal flow and the effect of the hepatic arterial buffer response, thereby increasing the regeneration of the FLR

In 2003, Masato Nagino et al reported the first simultaneous portal and hepatic vein embolization in a 61-year-old female patient with

a cholangiocarcinoma of segment I that invaded all three main hepatic veins In this case, because the patient has an accessory right hepatic vein with average size, the purpose of embolization of the right hepatic vein was to help redirect blood flow to the accessory right hepatic vein when surgically removing all three main hepatic veins An extended left hepatectomy was performed 21 days later The patient lived another 15 months after surgery before dying from tumor recurrence

In 2009, Shin Hwang et al reported the effectiveness of additional liver vein embolization in 12 patients with limited liver hypertrophy at two weeks after PVE Although this approach was a safe and effective solution in improving liver hypertrophy compared to the PVE group, this method required two times of intervention and a long waiting time Later, the concept of simultaneous portal and hepatic vein embolization (LVD) has recently emerged to reduce the waiting time for surgery and improve the effectiveness of liver hypertrophy

In 2016, Boris Guiu et al reported the first series of 7 patients undergoing LVD (using a transhepatic approach) to induce preoperative liver hypertrophy The patients were well tolerated, there were no complications, and 6 out of 7 patients were eligible for surgery after three weeks

Subsequently, many studies compared the safety and effectiveness of the LVD and PVE alone, showing equivalent safety between the two methods The liver hypertrophy rate was significantly higher in the LVD group, and the waiting time for surgery was shortened

Gianluca Cassese et al (2023) compared short- and mid-term outcomes in 33 patients with colon cancer liver metastases who underwent LVD (n = 17) and PVE (n = 16) before major hepatectomy The results showed that LVD had similar short- and medium-term outcomes but achieved better liver hypertrophy than PVE

Many studies have shown no difference in the complication rate between LVD and PVE Only some mild complications have been reported for LVD, including mild to moderate post-procedure pain and, fever and post-embolization syndrome No liver necrosis was noted

1.2 Literature review in Vietnam

In 2009, Trinh Hong Son et al reported the first PVE in Vietnam in a patient scheduled for right hepatectomy due to liver metastases after pancreaticoduodenectomy but having a small initial FLR volume This patient significantly increased FLR after embolization from 207 mL (0.4% of body weight) to 490 mL (0.94% of body weight) However, due to the long waiting time for liver hypertrophy (12 months), the patient had a tumor recurrence at the anastomosis, so he could not undergo liver resection surgery

After that, there were some studies from Le Thanh Dung et

al, Trinh Hong Son et al., with many patients and changes in applied techniques It brings about improvements in liver hypertrophy effects

Le Thanh Dung's (2018) study on 82 patients undergoing PVE showed that the average FLR increased from 367.9 mL (before intervention) to 613.2 mL (after intervention) Among them, 73 patients (accounting for 89%) had post-intervention FLR greater than 40% of the total standard liver volume However, only 53/82 cases (accounting for 64.6%) underwent liver resection; the remaining 20 cases could not undergo surgery due to tumor progression or other contraindications appearing during the waiting time for surgery

In 2021, Le Thanh Dung et al reported the first series of LVD

in Vietnam, comparing the liver hypertrophy rate between the first 4 cases of LVD and 11 cases of PVE The results showed that LVD had statistically significantly higher hypertrophy and kinetic growth rates than PVE (118% vs 32%, p = 0.024, and 38 %/week vs 5 %/week, p = 0.01)

Chapter 2: MATERIALS AND METHODS

− General health status WHO 0 or 1

− Child-Pugh A liver function

− Patients whose biological parameters are:

o Platelets ≥ 100 000/mL (acceptable after platelet

− Contraindications or not suitable for major hepatectomy:

o General health status WHO ≥ 2

o Poor liver function (Child-Pugh B/C, decompensated cirrhosis)

o Multifocal liver tumor, which is distributed in two lobes and cannot be resected

o Tumor in the vein

o Extrahepatic metastases and cannot be resected

− Contraindications of the procedure and surgery:

o Serious non-stabilized disease, active uncontrolled infection or other serious underlying disorder likely to prevent the patient from receiving the treatment

o Treatment with anticoagulants (heparin or AVK) that cannot be interrupted for 48h, or treatment with anti-platelets that cannot be interrupted for 5 days for aspirin or clopidogrel

− Contraindicated for CT scan and MRI with drug injection

− Pregnant or breastfeeding

− Do not agree to participate in research and treatment methods

2.2 Methodology

2.2.1 Methodology

Non-controlled clinical trial study

2.2.2 Estimated patient number

The sample size is calculated based on the sample size formula for before-after study Estimated sampling was 61 patients

2.3 Intervention description

2.3.1 Liver venous deprivation

− LVD procedure is performed at least a few days after TACE when clinical and laboratory signs do not suggest liver failure or complications after TACE

− The LVD is divided into 2 parts:

• PVE: The right portal vein and its branches were occluded in all cases

The portal vein branches of segments I/IV can also be embolized if segment I/IV is scheduled to be resected

− Step 1: Ultrasound evaluates the portal system and chooses the

appropriate access

− Step 2: Disinfect the abdominal wall area

− Step 3: Local anesthesia at the puncture site with 1% Lidocaine

− Step 4: The peripheral branch of the right portal vein is accessed

using a using 16G Angiocath needle

− Step 5: A 5F sheath is inserted and portography is performed by a

5F catheter into the main portal trunk

− Step 6: The portal vessels supplying the future resected liver will

be embolized using a mixture of cyanoacrylate and lipiodol (ratio 3–5/1) If segment IV is scheduled to be resected, PVE of portal vein branches of segment IV is allowed

− Step 7: Tract embolization of portal vein access is performed using

the mixture used for PVE

− Technical success of PVE is defined by a complete occlusion of portal branches feeding the future resected liver segments

• Hepatic vein embolization: This procedure is performed immediately

after PVE Hepatic vein access is used either via the transjugular or transhepatic approaches The transhepatic approach is preferred if an acoustic window is available through the liver parenchyma (not obscured by the tumor)

Transhepatic approach:

− Step 1: Right hepatic vein as well as accessory right hepatic vein(s)

(when present) are accessed using a 16G Angiocath needle under ultrasound guidance

− Step 2: The 7-8F sheath is placed into the hepatic vein

− Step 3: Deploying an Amplatzer Vascular Plug II (50-100%

oversizing) at least 20 mm before the origin of the hepatic vein

− Step 4: Embolization of distal venous branches and tract

embolization are conducted using a mixture of cyanoacrylate and lipiodol (ratio 3–5/1)

Transjugular approach:

− Step 1: An 8F sheath is placed into the right internal jugular vein

toward the hepatic vein that needs embolization

− Step 2: Embolizing the hepatic vein with a type II parachute of

appropriate size (50 - 100% oversizing)

− Step 3: Venography of the inferior vena cava, slightly compress the

site of the jugular route

2.3.2 Post-procedure follow-up

− Technical success is defined as complete occlusion of the portal vein, and complete occlusion of the right hepatic vein (and right hepatic vein accessory according to the intervention plan)

− On the first day after embolization, the vital signs are pulse, temperature, blood pressure, and urine, abdominal conditions, pain, fever, and post-embolic syndrome (pain, fever, vomiting, nausea, etc.)

− The second day after embolization:

o Doppler ultrasound of the portal vein system, liver function tests, coagulation, and complete Blood Count

− Supplement multivitamins for at least 3 -5 days after intervention

− Volumetry after LVD:

o Measure liver volume on CT scan at 3 weeks after LVD If the liver volume has not increased enough after 3 weeks, CT will be repeated within 2 - 4 weeks to evaluate liver volume

o While waiting for surgery, additional TACE can be performed if the tumor still has hypervascularity on the CT scan

2.4 Statistical analysis

Data analysis: Data were collected and processed using Microsoft Excel

version 16.66.1 and SPSS 23.0 software (SPSS Inc., Chicago, IL, USA)

Data analysis:

− Qualitative variables: described by frequency, percentage

− Quantitative variables: Before conducting analysis, the assumption

of normality is checked by the Kolmogorov-Smirnov test when the sample size is greater than 50 or the Shapiro-Wilk test when the sample size is less than 50, at a significance level of 0.05

− Non-normal distribution variables are described by median (interquartile range (IQR), [min – max] Comparison of median values

of two independent groups was performed via the Mann–Whitney U test Comparison of median values before and after treatment of quantitative variables was performed via the Wilcoxon test

The difference is statistically significant at any test when with p < 0.05

Chapter 3: RESULTS

From January 2021 to December 2023, 61 HCC patients scheduled for major hepatectomy but with small initial FLR volume underwent LVD to induce liver hypertrophy

3.1 Clinical, paraclinical, imaging characteristics

Abdominal pain, fatigue, and right shoulder pain are the most common symptoms, accounting for 29.5%, 13.2% and 11.4% respectively 10/62 (16.4%) patients had HCC detected through routine examination

The patients were in good physical condition 50 patients were in the ASA grade I group (accounting for 82.0%), 8 patients were in the ASA grade II group, and 2 patients were in the ASA grade III group According to the WHO classification, 60/61 patients had performance status grade 0

Most patients received 1 TACE before LVD (N = 41, 67.2%) 40/61 (65.6%) of the patients underwent LVD within 1 week after the last TACE

3.1.2 Paraclinical and imaging characteristics before intervention

Regarding pre-procedure tests, the number of patients with AST and ALT higher than the upper normal limits accounted for 68.9% and 60.7%, respectively Four cases had total bilirubin concentrations higher than normal, accounting for 6.6% All patients had pre-procedural prothrombin ratios within normal limits Three cases had platelets in the range of 103 - 132 G/L, and one case had thrombocytosis (672 G/L) The patients in the study had good liver function and belonged to the Child-Pugh A group, of which 59 cases had Child-Pugh A scores of

5 (96.7%), and only 2 cases had Child-Pugh A scores 6 points 55.7% of patients were in the ALBI grade 1 group (N = 34), and the remaining patients were in the ALBI grade 2 group (N = 27, accounting for 44.3%) Median MELD and MELD-Na scores were 7 points and 11 points, respectively

Table 3.8 Tumor markers Tumor markers N (%) Median; IQR; [min – max]

Comment: Serum AFP testing was performed in 61 patients, of

which 46 cases showed increased AFP (accounting for 75.4%) Meanwhile, all 9 patients tested for PIVKA-II had results higher than the upper normal limit (median 4043.0 mAU/mL)

The majority (96.8%) of patients had ≤ 3 tumors Most cases had tumors localized in the right liver parenchyma (N = 57, accounting for 91.9%), and 5 cases had tumors from the right liver invading segment IV, accounting for 8.1%

The median TLV before LVD was 1187.7 mL, the median sTLV was 1513.8 mL, and the FLR volume before intervention was 398.7 mL, accounting for 33.8% TLV, 32.5% sTLV, and 0.7% body weight

3.2 Safety and results of liver hypertrophy after LVD

3.2.1 Technical safety

When performing LVD, all patients had access to the TMC via ipsilateral (right) access Most cases had the right cranial nerve branch node, except for 1 case that had the right cranial nerve branch and the lower segment IV branch For hepatic veins, the approach through the liver parenchyma is preferred (N = 48, accounting for 78.7%) The median LVD intervention time of the group accessing the hepatic vein through the liver parenchyma was statistically significantly shorter than the group accessing the internal carotid vein (47.0 minutes vs 61.0 minutes, p < 0.001)

Table 3.14 The material used in LVD

Comment: In this study, most patients received PVE with glue

alone (N = 56, 90.2%) Combined glue and plug were the most common material used in HVE (N = 48, accounting for 78.7%), using plug alone only for cases accessed through the transjugular route (N = 13, accounting for 21.3%)

After LVD, at 1-day post-LVD, increasing serum AST, ALT, and bilirubin levels and decreased prothrombin were observed (p < 0.001) These tests returned approximately to pre-intervention values when assessed three weeks after LVD

Post-embolization pain occurred in all cases, in which the majority of cases present with mild or moderate pain (VAS ≤ 6 points); Severe pain (VAS 7 - 10 points) was found in 13 cases, accounting for 21.4% Complications after LVD occurred with low frequency and are mostly mild grade The rate of major complications was low (1.6%) 1 case of transient liver failure (grade A according to ISGLS) and recovered after 7 days

3.2.2 Results of liver venous deprivation

Table 3.17 Change in liver volume before and 3 weeks after LVD

FLR/TLV, % 33.8; 8.2;

[20.2 – 39.9]

47.5; 10.6 [34.6 – 66.5] < 0,001

FLR/sTLV, % 32.5; 8.3;

[20.6 – 39.6]

48.4; 10.9 [34.8 – 74.4] < 0,001

FLR/BW, % 0.7; 0.19;

[0.44 – 0.81]

1,06; 0,29 [0.76 – 1.61] < 0,001