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MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY ********** DANG TRUNG THANH SUBCLINICAL VALUES IN PROGNOSIS AND MONITORING OF TREATMENT FOR HEPATOCELLUL

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH

HANOI MEDICAL UNIVERSITY

**********

DANG TRUNG THANH

SUBCLINICAL VALUES IN PROGNOSIS AND

MONITORING OF TREATMENT FOR HEPATOCELLULAR

CARCINOMA WITH TRANSARTERIAL

CHEMOEMBOLIZATION COMBINED WITH

RADIOFREQUENCY ABLATION

Major : Gastroenterology Code : 62.72.01.43

ABSTRACT OF DOCTORAL DISSERTATION

HANOI - 2020

BACH MAI HOSPITAL AND HANOI MEDICAL UNIVERSITY HOSPITAL

Supervisor: Assoc Prof Tran Ngoc Anh

Reviewer 1: Tran Viet Tu, M.D, Ph.D

Reviewer 2: Le Chinh Dai, M.D, Ph.D

Reviewer 3: Vu Truong Khanh, M.D

The dissertation is going to be defended in front of the doctoral thesis evaluation committee at Hanoi Medical University

The thesis can be found at:

Vietnamese National Library

Library of Hanoi Medical University

INTRODUCTION

Hepatocellular carcinoma (HCC) is the 3rd most severe malignancy in terms of mortality in all cancers with approximately 787,200 deaths per year Vietnam is one of the countries with the highest HCC incidence with over 10,000 new cases each year Multidisciplinary treatment of HCC has been gaining attention in recent years, including transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) To study the effectiveness of combination therapy, clinicians also combine imaging diagnosis to monitor treatment efficacy, along with the use

of tumor markers, which also play an important role in diagnosing, evaluating treatment results and monitoring the recurrence of HCC

In Vietnam, a new set including three markers of AFP, L3 and PIVKA-II was put into use in the diagnosis and evaluation of HCC treatment results To data, very little study in Vietnam reported

AFP-on the role of these 3 markers, especially the use of GALAD and BALAD models in HCC diagnosis and evaluation Hence, this study was conducted with the aims of:

1 To evaluate diagnostic values of AFP, AFP-L3, PIVKA II and GALAD in HCC

2 To evaluate the values of AFP- L3, PIVKA-II and BALAD in the prognosis and monitoring of treatment outcomes of HCC with transarterial chemoembolization combined with radiofrequency ablation

IMPORTANCE OF DOCTORAL DISSERTATION

Investigation of the value of AFP, AFP-L3 and PIVKA II markers in HCC patients This study identified cut-off threshold values of AFP, AFP-L3 and PIVKA II markers, GALAD scale for HCC diagnosis Evaluate the values of AFP, AFP-L3 and PIVKA-II, BALAD scale was in prognosis and monitor the effectiveness of treatment of liver tumors by combining transarterial chemoembolization (TACE) with radiofrequency ablation (RFA) We also initially determined the values of AFP-L3, PIVKA II, BALAD, GALAD scores in estimating the life expectancy and treatment response of HCC patients Thereby, the assessment of the response of treatment was according to the Japan Hepatobiliary Association, in Fwhich the proportion of patients responding to treatment was 68.9%

FINDINGS OF DOCTORAL DISSERTATION

We examined important values of AFP, AFP-L3, and PIVKA

II in hepatocellular carcinoma (HCC) To explore cut-off points of AFP, AFP-L3, PIVKA-II, and GALAD in the diagnosis of HCC To evaluate the values of AFP- L3, PIVKA-II and BALAD in the prognosis and monitoring of treatment outcomes of HCC with transarterial chemoembolization combined with radiofrequency ablation The life expectancy of patients with HCC was estimated based on the values of AFP-L3, PIVKA-II, BALAD, and GALAD The proportion of patients responding to treatment was 68.9% according to the Japan Society of Hepatology

THESIS STRUCTURE

The thesis consists of 140 pages including 02-page introduction, page overview, 25-page methods, 37-page results, 36-page discussion, 02-page conclusions, and 01-page recommendation The thesis has 52 tables, 25 illustrations, 9 figures There are 182 references, of which 17 are Vietnamese

37-Chapter 1 OVERVIEW 1.1 Diagnosis and treatment of HCC

1.1.1 Diagnostic criteria of HCC

- American Gallbladder Association

- European Hepatobiliary Association

- Asian and Pacific Liver Association

- Japanese Gallbladder Association

- Diagnostic criteria for HCC according to the Ministry of Health of Vietnam

1.1.2 Diagnostic criteria of liver hemangioma

Hepatic hemangiomas are divided into two main types: cavernous hemangioma and capillary hemangioma, in which most Hepatic hemangiomas are cavernous hemangioma

1.2 Treatment methods of HCC

1.2.1 Liver resection/ liver transplantation

Liver resection is the optimal choice for cases of AF, with good liver function even on cirrhosis (Stage T1-3, N0, M0) The

widely accepted criteria for liver transplantation is that Child C cirrhosis has 1 liver tumor less than 5cm or has up to 3 tumors with a size of less than 3cm each and has no invasive vascular invasion or extrahepatic metastases (Milan criteria)

1.2.2 Destroy the tumor on the spot

Methods to destroy the tumor on the spot include: absolute alcohol injection, high frequency (RFA), and microwave heating

1.2.3 Cut off the tumor blood supply

The tumor does not cut or many 2 lobes There may be small portal venous thrombosis Overall score (PS) = 0-2 Child Pugh A, B

No distant metastasis

1.3 Subclinical methods used in the diagnosis and monitoring of patients with primary HCC

1.3.1 Image diagnostic methods

Ultrasound, CT - scanner, computerized tomography (CT) scan / magnetic resonance imaging (MRI) play the important role in the diagnosis and monitoring of disease status

1.4 The values of AFP-L3, PIVKA II and GALAD model in monitoring treatment of primary HCC

1.4.1 The effectiveness of HCC treatments combines RFA and TACE

TACE in conjunction with RFA TACE is a local destruction therapy by obstructing the blood vessels that feed the tumor and providing local chemotherapy TACE can reduce the cooling effect

of large vessels adjacent to the UTBMTBG, resulting in a significant increase in the excision region TACE may also be effective in treating small undetected metastases adjacent to the primary tumor

1.4.2 The values of AFP-L3, PIVKA II and GALAD model

Pathogenesis of HCC complex is influenced by many factors, besides the markers being studied in phase 1 and phase 2 Another approach scientists are taking is to combine existing cancer markers

in the GALAD or BALAD model to provide better diagnostic and follow-up values

Chapter 2 METHODS 2.1 Research objects

2.1.1 Location and time

The study was conducted at the Center for Nuclear Medicine and Oncology at Bach Mai Hospital and Hanoi Medical University Hospital from June 2016 to September 2019

2.1.2 Patients

The patients were diagnosed with HCC and hepatic

hemangiomas

Wallis test were applied; For qualitative variables we used fisher’s exact test The difference was considered to be statistically significant with p <0.05

2.4.5 Ethics

All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki Hanoi Medical University Institutional Review Board Committee approved the study protocol Informed consents were obtained from all individual participants included in the study

Chapter 3 RESULTS 3.1 GENERAL CHARACTERISTICS

3.1.1 Age

Table 3.1 Number patients according to age

Age groups HCC (n=90)

Hepatic hemangiomas

The average age of HCC group in the study is 61.9 ± 9.9 years There was a difference in the average age of HCC and hepatic hemangiomas (p <0.05)

Table 3.2 Gender characteristics

Hepatic hemangiomas

Table 3.1 Risk factors

The percentage of hepatitis B accounts for the highest with 67.5%

Table 3.3 Tumor characteristics

Table 3.4 Values of AFP, AFP-L3, PIVKA II and GALAD

between HCC and hepatic hemangioma

HCC (n=90)

Hepatic hemangiomas (n=90)

p

AFP (ng/ml) 40,3(1,5 – 78165) 2,4(0,1 – 120) <0,001* AFP-L3 (%) 22,7(0,5 – 93,6) 0,5(0,1 – 31,1) <0,001* PIVKAII

(mAU/ml) 530,8(12,5 – 47499) 19(10 – 370) <0,001* GALAD 2,9(-3,4 – 13,3) -4,5(-8,7 – 2,3)) <0,001*

* Mann – Whitney test

The average concentration of AFP was 40.3 (1.5 - 78165), AFP-L3 was 22.7 (0.5 - 93.6), PIVKA II was 530.8 (12.5 - 47499), GALAD was 2.9 (-3.4 - 13.3)

3.2.1 Correlation between tumor size and AFP-L3, PIVKA II and GALAD values

The mean value of AFP-L3 (29.13%), PIVKA-II (378 mAu / ml) in HCC patients with tumor size <2 cm was significantly lower than that of HCC with size > 5cm AFP –L3 (32, 2%); PIVKA-II (1212 mAu / ml) (p <0.05) There was a positive correlation between tumor size and AFP-L3, PIVKA II concentration values and GALAD score

3.2.2 The calues of AFP, AFP-L3, PIVKA II and GALAD in the diagnosis

Figure 3.2 Characteristic ROC curves of AFP, AFP-L3, PIVKA II,

GALAD in the diagnosis of HCC

AFP-L3 ratio has: J = max (Se + Sp) - 1 = 0.666 The optimal cutting value is 10.0% AFP ratio has: J = max (Se + Sp) - 1 = 0.311 The optimal shear value is 12.6 (ng / ml) PIVKA II ratio has: J = max (Se + Sp) - 1 = 0.556 The optimal shear value is 42.5 (mAU / ml) GALAD ratio has: J = max (Se + Sp) - 1 = 0.822 The optimal cutoff value is -1.90

Table 3.5 HCC diagnostic value of AFP, AFP-L3, PIVKA II and

The area under the ROC curve of the individual markers and when combined all have good diagnostic values for patients with TBoma (over 0.8) The highest diagnostic value is based on the GALAD score The lowest diagnostic value is based on AFP

Figure 3.3 Characteristic ROC curves of AFP-L3, PIVKA II, GALAD in the diagnosis of AFP with AFP <20ng / ml

AFP-L3 ratio had: J = max (Se + Sp) - 1 = 0.664 The optimal cutting value was 10.0% PIVKA-II ratio had: J = max (Se + Sp) - 1 = 0.533 The optimal shear value was 25 (mAU / ml) GALAD ratio had: J = max (Se + Sp) - 1 = 0.868 The optimal shear value was -2.27

Table 3.6 Diagnostic values for AFP - L3 and PIVKA-II, GALAD

in AFP group <20ng / ml

Cut-off Sensi

tivity

Specifi city

Positive predictive value

Negative predictio

0,795 (0,703 – 0,887)

0,980 (0,955 – 1,000)

The cut-off point of value of AFP-L3 value was 10% The cut-off point of PIVKA II value was 25 mAU / m and the cut-off of the GALAD value was -2.27

3.3 VALUES OF AFP-L3, PIVKA II, BALAD, AND GALAD IN MORNITORING OF TREATMENT OUTCOME OF HCC WITH TACE COMBINED WITH RFA

No patients died within 3 months and 6 months At the end

of the study, the number of patients died was 20/90, accounting for 22.2%

Table 3.8 Value makers at the time of follow-up treatment

AFP ng/ml 85,4(1,6 – 121000) 40,5(1,5 – 26366) <0,001* AFP-L3 (%) 12,9(0,5 – 69,5) 8,4(0,5 – 89,7) <0,001* PIVKA II

(mAU/ml) 479,0(6,5 – 43000) 154,5(2,8 – 14242) <0,001* GALAD 2,8(-2,8 – 13,9) 1,7(-3,2 – 10,0) <0,001* BALAD 1,8(-1,9 – 2419,9) 0,6(-3,9 – 527,9) <0,001*

*Sign test

After treatment, there were significant differences at 3 months and 6 months after treatment for the diagnostic marker values AFP, AFP-L3, PIVKA II, GALAD, and BALAD (p <0.001)

Table 3.9 Classification of BALAD values at the time of

monitoring after treatment

BALAD Discharge After 3 months After 6 months

After treatment, BALAD level classification did not differ significantly at time of discharge, after 3 months and after 6 months

Table 3.10 mResist classification after 3 months and 6 months of

*McNemar test

After treatment, there was a significant difference after 3

months and after 6 months in the partial response group (p <0.05)

Figure 3.4 The proportion of patients who responded to treatment

according to the Japan Hepatobiliary Society

According to the classification of the Japan Hepatobiliary Society, 62 patients with HCC responded to treatment (68.9%)

Figure 3.5 Overall survival rates over time

After 600 days, the cumulative survival rate was 68%

Table 3.11 Average additional survival time according to AFP-L3

The patient group with AFP-L3 value <10%, the highest

survival time was 708.1 days

Table 3.12 Average survival time according to PIVKA II

(95% CI)

The patients with PIVKA II value ≤40, the highest survival time was 723.5 days

Table 3.13 Average survival time according to BALAD

threshold of -0.36, the group with the GALAD score <-0.36 had the highest extra time

Table 3.15 Extra time in the treatment response group according to

the classification of the Japan Hepatobiliary Society

In our study, the majority of patients in the HCC group were over 50 years old (90.0%) Meanwhile, the patients in liver hemangioma group were mostly under 50 years old (54.4%) In terms

of gender, the study found that the proportion of male patients in the HCC group (91.1%) was significantly higher than that of the male patients in the group of liver tumors (37.8%) In general, the rate of HCC was higher for males than for females This result was similar

to previous studies of Tran Van Huy and Vu Manh Duy

The most common symptom patients were pain in the right upper quadrant pain (48.9%), in addition to other non-specific symptoms such as fatigue (33.3%), anorexia (32.2%) and up to

14.4% of patients with digestive disorders Compared to the study of

Vu Van Khien, the study had similarities

In terms of physical symptoms, 40.0% of patients had enlarged spleen, 34.4% of patients had enlarged liver and only 1.1%

of patients had jaundice The patients in the study of Vuong Thu Ha had similar physical symptoms as in our study, mainly hepatomegaly, splenomegaly By stage of Child Pugh cirrhosis, the majority of patients were at Child Pugh A stage (81.1%) 10.0% of patients were

in Child Pugh B phase and 3.3% were in Child Pugh C Among 33 patients in the study of Vuong Thu Ha, most was stage Chil-pugh A (97%), while stage B was only one patient (3%)

4.2 DIAGNOSTIC VALUES OF AFP, AFP-L3, PIVKA II AND GALAD IN PRIMARY HCC

1,768,6, which were significantly higher than the control group of benign liver diseases

In our study, there was also a statistically significant difference between the average concentration of tumor markers by the stage of HCC - Barcenola classification (stage O and A - early stage) and late stage (stage B, C, D according to Barcenola classification) except AFP imprint (pAFP = 0,50; pAFP-L3< 0,001; pPIVKA

II < 0,001) This result was similar to the research results of Marrero

et al, Park et al

4.2.2 The value and cut-off threshold of the markers in the

diagnosis

At the AFP cut-off point was 12.6%, the sensitivity and specificity for diagnosis of HCC were 66.7% and 64.4%, respectively At the AFP-L3 cut-off point of 10.0%, the sensitivity and specificity for diagnosing HCC was at 83.3% At the cut-off point of PIVKA II was 42.5%, the sensitivity and specificity for diagnosis of HCC were 85.6% and 70.0%, respectively This result showed that the use of AFP-L3 and PIVKA II was valuable in disease diagnosis The results were similar to the studies of Sang Joon Park et al When conducting a direct comparison of the usefulness of AFP, AFP-L3 and PIVKA-II both individually and in combination in HCC diagnosis

We also looked at HCC diagnostic values of AFP-L3, PIVKA-II and GALAD scores in patients with AFP levels <20 ng /

mL The highest diagnostic value for PIVKA-II markers, with the area under the AUROC curve in diagnosing patients with HCC was