Nội dung

1 ABBREVIATIONS NHOG : National hospital of Obstetrics and Gynecology UA : Uterine artery EDV : End diastolic velocity FIGO : International Federation of Gynecology and Obstetrics MTX : methotrexat LR : low-risk 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. 2 STRUCTURE 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. 3 CHAPTER 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: C20H22N8O5. NH2 N CH2 CH3 O N C N NH2 NH CH COOH CH2 CH2 N N COOH 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 4 cleared 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 - Pretreatment βhCG - Hysterectomy - Metastase - Neo-angiogenesis - Histopathology is choriocarcinoma - 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 5 1.7.2. 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 6 compared 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. 7 2.2.1. 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. 8 Table 2.1. Prognostic Scoring System 2002 by FIGO for GTN Scores Prognostic factors 0 1 Age (years) < 40 ≥ 40 Antecedent pregnancy mole abortion term <4 4-6 7 - 12 > 12 < 103 103 - 104 104 - 105 > 105 3-4 ≥5 spleen, Gastro- liver, kidney intestinal brain 1-4 5-8 >8 Interval months from index pregnancy (month) Pretreatment serum hCG Largest tumour size (including uterus) Site of metastases lung Number of metastases Previous failed chemotherapy 2 single drug 4 ≥ 2 drugs 2.3. Research methods 2.3.1. Research design: Descriptive prospective study 2.3.2. Research sample size: is calculated using the following formula n= Z (21 α / 2) .p.q d2 n: number of patients p: resistance rate to MTX chemotherapy (following the study of Phan Chí Thành (2012) resistance rate is 24,5%), so p = 0,245. q = 1- p. 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 9 Drugs 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 obstetriciangynecologist 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. 2.4. Research steps 2.4.1. The process of enrolling patients in the study 2.4.1.1. Identify GTN patients - Collect patients with GTN diagnosed who are treated at the GIO meeting the selection criteria. - GTN patients who are admitted to hospital are assessed prognosis according to FIGO 2002. 2.4.1.2. Full physical examination 2.4.1.3. Antecedent question 2.4.1.4. Gynecological examination 2.4.1.5. Paraclinical tests - 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 starting MTX treatment. - The patient have ultrasound done when bladder half full to measure uterine volume, uterine myometrial invasion size , then UAPI Doppler ultrasound on both sides. - UAPI index retained for analysis is a lower index (reflecting maximum variation compared to normal values). - The original Doppler ultrasound results will be retained for inclusion in the study. 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.