ABBREVIATIONS NHOG : National hospital of Obstetrics and Gynecology UA : Uterine artery EDV : End diastolic velocity FIGO : International Federation of Gynecology and Obstetrics MTX : me
Trang 1ABBREVIATIONS
NHOG : National hospital of Obstetrics and Gynecology
UA : Uterine artery
EDV : End diastolic velocity
FIGO : International Federation of Gynecology and Obstetrics
MTX : methotrexat
PI : Pulsatility index
PSV : Peak systolic velocity
GTN : Gestational trophoblastic neoplasia
PROPOSAL
Gestational trophoblastic neoplasia (GTN) is a group of pathology caused by malignant neoplasia or high potential malignant of trophoblast In 1956, Li et al successfully treated GTN by Methotrexate (MTX) and opened a new era in the treatment of GTN In
2002, International Federation of Gynecology and Obstetrics (FIGO) established a revised classification system as well as a risk factor scoring system for GTN Low-risk patients are recommended to treat with single-agent chemotherapy, such as MTX Switching chemotherapy regimen due to MTX resistance will unnecessarily lengthen the overall duration of chemotherapy, cause considerable psychological distress to patients and slow down the recovery of their normal procreation ability
Neo-angiogenesis, the formation of new blood vessels, is a critical step in tumorogenesis Neo-angiogenesis is associated with increased tumor growth, acquisition
of metastatic potential and drug resistance Doppler ultrasonography is considered an appropriate non-invasive test to assess tumor vascularity and vascular characteristics of the main artery supply in GTN (uterine artery) Therefore, we carried out this research
with the aim to “Evaluate the value of uterine artery Doppler ultrasound and prognostic factors to predict methotrexate resistance in low-risk gestational trophoblastic neoplasia” with the following objectives:
1 Describe characteristics of uterine artery doppler ultrasound and prognostic factors in GTN patient treated by Methotrexat
2 Evaluate the effectiveness of uterine artery doppler ultrasound combined with related factor to predict MTX resistance in low-risk GTN patients
Trang 2STRUCTURE OF THESIS
The thesis has 135 pages, 4 chapters, 43 tables and 12 graphs
Introduction: 02 pages
Chapter 1: Overview: 36 pages
Chapter 2: Research Subjects and Methods: 22 pages
Chapter 3: Results: 29 pages
Chapter 4: Discussion: 42 pages
Conclusions: 02 pages Recommendations: 01page
144 reference documents
Annexes: pictures, data collection forms, patient lists
NEW CONCLUSIONS OF THE THESIS
1 This is the first study in Vietnam on the role of functional Doppler ultrasound
to describe the hemodynamic difference between MTX resistance and response groups of uterine preserving gestational trophoblastic neoplasia patients
2 The study found that hemodynamic characteristics of uterine artery is a new
factor contributing to the prognosis of MTX resistance chemotherapy The most appropriate cut-off point of the uterine artery pulsatility index (UAPI) to predict MTX resistance is at the value of 1.2
3 On univariate analysis, those GTN patients with UAPI ≤1.2 had an increment
of the odds ratio for MTX-R to 2.42 times, compared to patients with UAPI >1.2 On multivariate analysis, the data reported that the UAPI was the only significant independent predictor of MTX-R
4 The criteria of UAPI ≤ 1.2 corresponded 1-2 point of FIGO score when assessing MTX-R risk Taken together, FIGO scoring system combined with a UAPI
≤ 1.2 would allow better early identication the group should have the first regimen as the combination chemotherapy
5 Our study may help to make a more precise selection of GTN patients who need to be upgraded in treatment, so that they are less affected by empirical factors
Trang 3CHAPTER 1: OVERVIEW 1.1 Form of gestational trophoblastic neoplasia
1.1.1 Invasive mole (IV)
IM is usually a complete mole and rarely a partial mole which invades the myometrium (15%)
1.1.2 Choriocarcinoma (CC)
CC is composed predominantly of cells resembling villous cytotrophoblast and syncytiotrophoblast but, unlike in moles, no chorionic villi are present The tumour invades vessels and metastasizes aggressively, usually being fatal without treatment
1.1.3 Placental site trophoblastic tumor (PSTT)
This is a rare gestational trophoblastic neoplasm, representing 0·2% of gestational trophoblastic disease It is believed to be the malignant counterpart
of non-villous implantation site intermediate trophoblast, which infiltrates the placental site in normal pregnancy
1.1.4 Epithelioid trophoblastic tumour (ETT)
ETT is probably a variant of PSTT in which trophoblastic differentiation more closely resembles the ‘vacuolated’ trophoblast often seen in the chorion of late pregnancy
1.2 Pharmacokinetics of Methotrexat
Methotrexat is an anti-cancer chemotherapy drug and classified as an
antimetabolite Chemical formula: C 20 H 22 N 8 O 5
Hình 1.1 Chemical formula of Methotrexat
Absorption, distribution, metabolism, and excretion: Transport of MTX across
the capillary and cell membranes of the liver, kidney, and skin is rapid, so that equilibrium ratios of tissue to plasma concentrations (plasma concentrations > 1 µM) are established on a time scale consistent with plasma flow limitation This ratio is also established quickly in muscle, although transport across muscle cells is absent MTX also undergoes hydroxylation by liver aldehyde oxidase to form 7-hydroxymethotrexate, a metabolite with a long half-life of 24 h in humans MTX is
Trang 4cleared from the body through both biliary and urinary routes
1.3 8-day methotrexate regimen
The regime using 1 mg/kg IM on days 1, 3, 5, and 7 with IM folinic acid rescue on days 2, 4, 6, and 8; repeated every 14 days Remission rate of 8-day regime MTX/FA is
74 - 90% For convenient, some country using fixed dose 50 mg MTX at day 1,3,5,7 alternating folinic acid rescue via oral or IM route In NHOG, we use fixed dose by suitability with the economy and the status of Vietnamese women
1.4 Factors associated with MTX resistance in low-risk GTN
- Population kinetic modelling of patients' hCG
- FIGO prognostic scores
1.5 Uterine artery pulsatility index (UAPI), repeatability and reproducibility
Doppler ultrasound
Pulsatility index (PI) was calculated with formula PI = S-D/m
S : Peak systolic velocity, D: end-diastolic velocity, m: mean velocity
Repeatability and reproducibility of PI is high
1.6 Neo-angiogenesis study in GTN
Neo-angiogenesis, the formation of new blood vessels, is a critical step in tumourogenesis Neo-angiogenesis is associated with increased tumour growth, acquisition of metastatic potential, drug resistance and poor prognosis in a number of solid tumours such as breast, lung and ovarian cancer In 2011, Shih I.M published the study of vasculogenic mimicry in GTN, and show that GTN is a rare human tumor that could form new blood vessel by tumor cell to perfuse of rapidly growing tumors
1.7 Uterine artery (UA) Doppler ultrasound in GTN
1.7.1 UA Doppler ultrasound in follow-up treatment
Assessing the characteristics and evolution of vascular Doppler indices in tumor or culture source is a valuable information portal Characteristic in vascular Doppler ultrasound in GTN patients is high blood velocity and low impedance
Trang 51.7.2 UA Doppler ultrasound in evaluating and prognostic
Carter and Tepper used Doppler ultrasound to monitor the treatment of GTN patients and found that UA Doppler ultrasound is a non-invasive, useful exploration method to diagnose and treat GTN patients UAPI is closely related to treatment prognosis and βhCG levels
1.7.3 UA Doppler ultrasound in predicting MTX resistance
Long (1990) studied the value of UA Doppler in 38 GTN patients with 26 nonpregnant women and 23 normal pregnant women The author found that UAPI in GTN patients were lower than non-pregnant women (1.37 ± 0.73 compared to 3.25 ± 0.83, p <0.05) Pregnant women often have lower PI than GTN group (1.00 ± 0.32 compared to 1.37 ± 0.73, p <0.05) but the signals in uterine muscle are not diffuse and are not intense elevation like the GTN group The author found that uterine circulation
in GTN patients had characteristics that suggested low impedance in the blood vessels and suggested that UA Doppler may be significant in the initial evaluation of GTN patients before chemotherapy
In 1992, Long studied the hemodynamic of UA using Doppler ultrasound, which measured the UAPI in 40 GTN patients before starting chemotherapy and longitudinal monitoring until treatment was stopped The author found that patients with PI ≤ 1.1 were significantly more resistant to chemicals than patients with PI> 1.1 (p <0.04) The author also found that PI was not related to metastatic ability of cultured cells and symptoms of vaginal bleeding, moreover, 5/8 patients could avoid improper treatment
if used in combination Doppler ultrasound results with prognostic transcripts to select chemotherapy regimens for these patients The author concludes: assessing the UAPI before chemotherapy for GTN patients helps to predict who will be resistant to chemotherapy
Also in 1994, Hsieh studied the correlation between the value of coronary doppler and chemotherapy in 23 GTN patients compared with control group of 55 non-pregnant women and 15 patients after uncomplicated abortion Measuring PSV and RI before each chemotherapy session, the author found that the uterine artery PSV of GTN patients were higher than the non-pregnant group (57.5 ± 20.4 cm/s compared to 28.3 ± 3.41 cm/s, p <0.0001) and the group after uncomplicated abortion (57.5 ± 20.4 cm/s
Trang 6compared to 26.8 ± 3.08 cm/s, p<0.0001) This is a proof of the theoretical basis for the formation of dynamic venous connection (shunt) in GTN patients
Agarwal studied from 1994 to 1999 and found that the UAPI in Doppler ultrasound is a non-invasive method of evaluation for tumor perfusion in the GTN patient A low UAPI is a manifestation of increased shunt, a manifestation of abnormal new angiogenesis, a characteristic of GTN masses In a study of 164 GTN patients, Agarwal found that PI ≤ 1.0 was an independent prognostic factor for MTX resistance and when combined with Charing Cross Hospital (CXH) prognostic score improved predictability MTX resistance These findings suggest that UAPI may be a useful exploration to incorporate prognostic scoring systems that help identify patients who are resistant to MTX early and need to be treated with EMA-CO
At the present time, nearly all GTN patients are cured with chemotherapy, but incorporating a UAPI into the FIGO scoring system will help in selecting earlier and more accurate patients who need combined chemotherapy The main purpose is to increase the effectiveness of treatment, reduce the total duration of treatment, reduce psychological stress, reduce toxicity of chemicals and soon return fertility to GTN patients who still want to give birth Many authors such as Agarwal, Long, Sita Lumsden said that it would be helpful to supplement the UAPI with the FIGO risk scoring system It will be more objective and valuable when the UAPI is studied in a multicenter, if it is proven to be an effective and valuable exploration method at GTN treatment centers
To date, in Vietnam, there has not been any study to use Doppler ultrasound to predict the MTX resistance of low-risk GTN patients Therefore, we conducted this study to evaluate the effectiveness of Doppler ultrasound combined with related factors
to predict the resistance to MTX and choose the appropriate regimen to treat the disease
CHAPTER 2: RESEARCH SUBJECTS AND METHODS 2.1 Time and site of research
At the NHOG from 01/2015 to 09/2017
2.2 Research subjects
The patient was diagnosed as a low-risk GTN according to the FIGO 2002 classification, preserving uterus and treated with MTX
Trang 72.2.1 Selection criteria
Patients participating in the study must satisfy the following conditions:
- GTN patients with a score of 0 to 6, were classified as low-risk according to FIGO prognostic score in 2002
- Having diagnosis of GTN post-molar: a history of molar is diagnosed and treated at the NHOG or other hospital and one of the following criteria:
+ GTN may be diagnosed when the plateau of hCGlasts for 4 measurements over a period of 3 weeks or longer, that is days 1,7,14,21
+ GTN may be diagnosed when there is a rise of hCG on three consecutive weekly measurements, over a period of two weeks or longer, days 1,7,14
+ GTN is diagnosed if there is histologic diagnosis of choriocarcinoma
+ GTN is diagnosed when the hCG level remains elevated for 6 months or more
- GTN after miscarriage, abortion, postpartum and ectopic pregnancy
- Patients with liver, kidney and hematological function within normal limits
- Patients who voluntarily participate in the study and are treated at the NHOG until they are discharged or finished treatment because they are no longer capable of specific treatment
- The patient agrees to use contraception methods during treatment
2.2.2 Exclusion criteria
Patients who have any one among the following issues will be
excluded from the study:
- Not a GTN patient
- GTN but did not receive treatment at the hospital, gave up treatment or circumstances did not allow treatment and monitored until the end of the course
- GTN needs radiation therapy
- Having a history of other cancers being treated
- Allergy to MTX
- Not following the treatment regimen
- Incomplete or missing ultrasound results
Trang 8Table 2.1 Prognostic Scoring System 2002 by FIGO for GTN
Antecedent pregnancy mole abortion term
Interval months from index
pregnancy (month) < 4 4 - 6 7 - 12 > 12 Pretreatment serum hCG < 103 103 - 104 104 - 105 > 105 Largest tumour size
Site of metastases lung spleen,
kidney
intestinal
Gastro-liver, brain
Descriptive prospective study
2.3.2 Research sample size: is calculated using the following formula
2
2 ) 2 / α 1
d
q p Z
d: relative bias, chosen d = 0,06
α: Statistical significance level, chosen α = 0,05
Z from z table at α = 0,05, so taken Z = 1,96
Thus, the number of research subjects is at least 198 We selected 204 low-risk GTN patients
2.3.3 Research facilities
2.3.3.1 Drugs used in research
Trang 9Drugs used in research: Methotrexat 50mg / 5ml of Ebewe, licensed VN3-63-15 according to No 413 of the Drug Administration of 2015
2.3.3.2 Research ultrasound machine
GE's Voluson 730 ultrasound is used to conduct research data collection and UA Doppler measurement The device is equipped with a 3.5 MHz abdominal ultrasound probe It has pulse Doppler, Color Doppler and Power enhanced Doppler
2.3.3.3 Person performing ultrasound research
Doppler ultrasound is performed by a diagnostic imaging doctor or gynecologist who has a gynecological ultrasound certificate Doctors conducting ultrasound research are well-informed and know the procedure of abdominal gynecological ultrasound and bilateral uterine artery Doppler ultrasound
- Chest radiography to detect lung metastases
- General abdominal ultrasound to detect metastases in the liver and kidney
- Brain CT or MRI scan to detect brain metastases when clinically suggestive
- Hematological test:
+ Blood count test: Number of red blood cells, quantification of Hemoglobin
+ The number of white blood cells, neutrophils
+ Blood biochemistry: assessment of liver function and kidney function
2.4.1.6 Conseling patients participating in the study
- Patients who satisfy the selection criteria, desire and able to participate in the study will sign a consent form to participate in research
2.4.2 Steps to conduct research
Step 1: Pelvic ultrasound and UAPI Doppler measurement once for patients before
Trang 10- The patient was then used alternately MTX / FA regimen
Step 2: Implement the chemotherapy monotherapy regimen
- GTN patients will be given 50mgMTX, deep intramuscular injection on 1,3,5,7 days with 5mg FA intramuscular injection on 2,4,6,8 days
- Repeat regimen every 14 days
- Monitor the response to MTX by quantifying βhCG concentration before each course
of MTX/FA
- Before each course of treatment, patients were assessed red blood cells, white blood cells, platelets, liver, kidney function, and undesirable effects
- Monitor response to MTX chemotherapy
- Patients who are resistant to MTX will be swiched to treat with combined chemotherapy regimen EMACO, EMAEP
- Patients are treated until βhCG <5 IU/l
- After negative βhCG, patient were sent to outpatient monitoring (<5 IU / l) 3 consecutive times, 1 week apart, it will be considered as a cured
2.5 Method of evaluating results
2.5.1 Criteria of MTX cured
After treatment with MTX monotherapy, the patient achieves:
- Serum βhCG <5 I /L serum for 3 consecutive weeks
- Complete assessed when serum βhCG levels returned to normal (<5 IU/l)
+ Normal liver and kidney function
+ Normal blood formula
+ There is no sign of myelosuppression or leukopenia
+ No new metastase appear
+ No more metastase lesions in the lung on chest X-ray film
+ The myometrial invasion at the uterus often disappears In some cases, sclerosis may disappear after a few months
+ Normal abdominal ultrasound
2.5.2 Criteria of chemotherapy resistance
After each cycle of chemotherapy treatment (MTX, EMACO, EMAEP), the patient presents with:
- βhCG increases, does not decrease or decrease less than 10% after 2 weeks
- New metastatic need to be changed to chemotherapy regimen
- Patients on a regimen due to chemical side effects (mouth ulcers or allergies) are not considered chemotherapy resistant
2.5.3 Follow up after treatment
After the end of treatment, serum βhCG levels are monitored weekly for the first 4 weeks, then every 2 weeks for up to 3 months, followed by monthly for the first year, then every 3 months on second year and every 6 months to 1 year until the end of life
2.6 Ethics in research
- The research is for scientific purposes only, and is approved by the Ethics council of biomedical research, NHOG
- The participation of women in this research is completely voluntary
- All information about participants or information from medical records is kept confidential
Trang 112.7 Collect, enter and process data
The data are processed on computers by the method of medical statistics under the Stata program
CHAPTER 3: RESEARCH RESULTS 3.1 Characteristics and treatment results of patients of LR-GTN
Place of residence: patients living in rural and mountainous areas account for a high proportion (62.8%)
Number of living children: most patients have no children or only 1 child (84.3%)
History of abortion: The proportion of patients without a history of abortion accounts for
a high proportion (56.4%)
3.1.1 Treatment results of patients of LR-GTN
- The rate of response to MTX chemotherapy is quite high, accounting for 72.55%
- 27.45% of patients were resistant to MTX and had to switch regimens
3.1.2 Treatments after MTX resistance
Table 3.1 Treatments after MTX resistance
(min-max)
Duration(day) (min-max)
Rate (%)
EMACO (N=31) 4,0 ± 2,3
(1 - 9)
151,8 ± 76,7 (66 - 428) 55,4 Combined
+ chemo
EMACO (N=18) 2,9 ± 1,8
(1 - 4)
124,2 ± 46,8 (56 - 213) 28,5 EMACO+
EMAEP (N=5)
3,4 ± 2,3 (1 - 7) 3,6 ± 1,8 (1 - 6)
208,0 ± 63,9 (128 - 265) 12,5
- The group of patients who received surgery and EMACO treatment accounted for the majority
3.1.3 Results of treatment of patients of LR-GTN
- The total cured rate of LR-GTN patients was 99.5%
- 1 patient was not cured in the study
3.2 Characteristics of prognostic factors in GTN patients
- Age: on average, 26.3 years old (16-39 years old)
- Index pregnancy: Majority is molar 81.4%
Trang 12- Latent time: Most are <4 months, the average is 2.1 months
- History of MTX treatment: Only 3 cases GTN relapse, accounting for 1.5%
- Distribution of metastase location and stage: Most have no metastases and in stage 1
of FIGO, accounting for 95.6%
- Number of metastase: a few patients have ≥ 1 metastase, 4.4%
- Largest tumor size: The majority of patients without tumors, accounting for 66.7% Among 68 patients with tumors (including uterine, lung metastatic and vaginal metastases), the most common group of tumor size was 3-4 cm, accounting for 17.2% The largest size of an average tumor is 3.4 ± 1.1 cm (1.3 - 6.9 cm)
3.2.1 βhCG pretreatment of GTN patients
Bảng 3.2 Nồng độ βhCG trước điều trị của bệnh nhân UNBN NCT
- The majority of patients have pre-treatment hCG levels <1000 IU / l
3.3.2 Distribution of FIGO score of GTN patients
Figure 3.2 Distribution of FIGO score of GTN patients
- Distribution of FIGO score of GTN patients irregular, focused on groups with low FIGO scores of 0 - 3 points
3.3 Characteristics of uterine artery Doppler of GTN patients
3.4.1 Features of bilateral doppler ultrasound at uterin artery
Table 3.2 Features of bilateral doppler ultrasound at uterin artery
