Nghiên cứu giá trị doppler động mạch tử cung và một số yếu tố liên quan tiên lượng kháng methotrexat ở bệnh nhân u nguyên bào nuôi nguy cơ thấp tt tiếng anh

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: Describe characteristics of uterine artery doppler ultrasound and prognostic factors in GTN patient treated by Methotrexat 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, 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 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 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 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 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 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 > 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 cleared from the body through both biliary and urinary routes 1.3 8-day methotrexate regimen The regime using mg/kg IM on days 1, 3, 5, and 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 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 3.4.5 Relationship between latent time and MTX resistance The group with latency period ≥ months had higher rate of MTX resistance than the other group, but the difference was not statistically significant, p> 0.05 3.4.6 Relationship between history of MTX treatment and MTX resistance GTN patients with a history of MTX treatment had a higher prevalence of MTX resistance, the difference was statistically significant, with p = 0.02 3.4.7 Relationship between metastases and MTX resistance Patients with lung or vaginal metastases had a higher rate of MTT resistance than the non-metastatic group, but the difference was not significant, with p> 0.05 15 3.4.8 Relationship between metastatic site and MTX resistance Patients with to metastatic nodules had a higher prevalence of MTX resistance than those without metastases, but the difference was not significant, p> 0.05 3.4.9 Relationship between βhCG pre treatment and MTX resistance Table 3.6 Relationship between βhCG pre treatment and MTX resistance βhCG pre treatment (IU/l) MTX resistance No OR Yes (95% CI) n % n % < 10.000 (n = 151) 116 76,8 35 23,2 2,17 ≥ 10.000 (n = 53) 32 60,4 21 39,6 (1,11 - 4,24) p 0,02 The group with βhCG concentration pre treatment ≥ 10,000 IU/l had the risk of MTX resistance increased by 2.17 times compared to the group with βhCG 240 cm3 had higher MTX resistance rate than the other group, but the difference was not statistically significant, p> 0.05 3.4.11 Relationship between luteal cyst and MTX resistance The group with luteal cyst had a lower prevalence of MTX resistance than the other group, but the difference was not statistically significant, p> 0.05 3.4.12 Relationship between largest tumor size and MTX resistance Table 3.7 Relationship between largest tumor size and MTX resistance (n = 68) MTX resistance OR No Yes p (95% CI) n % n % < (n = 57) 42 73,7 15 26,3 4,90 0,03 ≥ (n = 11) 36,4 63,6 (1,25 – 19,14) The size of the tumor group ≥ cm had the risk of MTX resistance increased 4.9 times Largest tumor size (cm) compared to the size group 1,2 ≤ 1,2 OR 95% CI p 5,89 1,44 – 24,13 0,014 0,45 – 4,99 0,507 βhCG pretreatment (IU/l) < 10.000 ≥ 10.000 1,50 Largest tumour size (cm) 1.2 Resistance rate to MTX FIGO score FIGO alone n Resis FIGO + PI > 1,2 % n Resis % 18 ≥0 204 56 27,45 148 33 22,30 ≥1 154 50 32,47 99 27 27,27 ≥2 96 35 36,46 49 14 28,57 ≥3 53 22 41,51 22 22,73 ≥4 20 10 50,00 25,00 ≥5 42,86 0,00 - When using FIGO score alone, the rate of MTX resistance tends to increase with FIGO score - In the same FIGO score group, patients with UAPI> 1.2 had a lower MTX resistance rate than those using FIGO alone 3.6.2 The significance of FIGO score when combining UAPI ≤ 1.2 Table 3.9 Significance of FIGO score when combining UAPI ≤ 1.2 Resistance rate to MTX FIGO score FIGO + PI ≤ 1,2 FIGO alone n Resis % n Resis % ≥0 204 56 27,45 56 23 41,07 ≥1 154 50 32,47 55 23 41,82 ≥2 96 35 36,46 46 21 45,65 ≥3 53 22 41,51 31 17 54,84 ≥4 20 10 50,00 12 66,67 ≥5 42,86 3 100,00 - The MTX resistance tends to increase when using FIGO score combining UAPI ≤ 1.2 - In the same FIGO score group, patients with UAPI ≤ 1.2 had a higher MTX resistance rate than those using FIGO alone 3.6.3 FIGO score < group combined threshold 1.2 UAPI (n = 151) Table 3.13 FIGO score < group combined threshold 1.2 UAPI UAPI > 1,2 (n = 126) ≤ 1,2 (n =25) MTX resistance No Yes n % n % 98 77,8 28 22,2 19 76,0 24,0 OR (95% CI) p 1,105 (0,40 – 3,03) 0,846 19 - With FIGO score of - 2, the prevalence of MTX resistance in the group with UAPI ≤ 1.2 is not much higher than that of the group having UAPI > 1.2 and the difference is not statistically significant,p> 0,05 3.6.4 FIGO score ≥ group combined threshold 1.2 UAPI (n = 53) Table 3.14 FIGO score ≥ group combined threshold 1.2 UAPI MTX resistance UAPI No Yes OR (95% CI) n % n % > 1,2 (n = 22) 17 77,3 22,7 4,129 ≤ 1,2 (n = 31) 14 45,2 17 54,8 (1,22 – 14,02) p 0,019 - With FIGO score of - 6, the prevalence of MTX resistance in the group with UAPI ≤ 1.2 is higher than that in the group with UAPI > 1.2 (54.8% compared to 22.7%) and the difference is significant, p < 0.05 CHAPTER 4: DISCUSSION 4.1 Discuss the object and research method The study subjects of 204 patients diagnosed with GTN were carefully selected according to FIGO diagnostic criteria to help reduce random errors in sample selection 4.2 Discuss the factors related to prognosis of MTX resistance Age: results showed that there were no statistically significant differences in MTX resistance among age groups, similar to the authors Gueye, Phan Chi Thanh and Nguyen Quang Bac Index pregnancy: our study has not found an increase of MTX resistance after abortion or stillbirth Type of molar: Analysis of 166 GTN post molar found that the rate of MTX resistance post complet molar or partial molar was not significantly different This result is consistent with the comments of authors such as Hemida, Gilani and Growdon Latent time: We also found no association between latency time and MTX resistance rate History of MTX treatment: we found that a recurrent GTN patient who had a history of MTX treatment was all resistant to the MTT chemotherapy this time and was significantly different from the group without a history of MTX treatment 20 Location and number of metastase: Our study is due to the small number of metastase and metastases in less prognostic organs (lung or vagina), so as author Roberts did not see relationship between the number of metastase and the rate of MTX resistance The βhCG pretreatment: The higher the βhCG pretreatment, the higher the resistance to MTX chemotherapy Our study was similar to that of domestic and foreign authors, showing that βhCG before treatment is valuable for predicting the risk of chemotherapy resistance Uterine volume: we found that different uterine volume groups had no different rates of antiretroviral therapy Luteal cyst: is not a significant predictor of MTX resistance Largest tumor size is a factor associated with prognosis of MTX resistance in GTN patients FIGO score: The greater the FIGO score is, the lower the likelihood of successful treatment with MTX chemotherapy But we agree with other authors on the review of FIGO's prognostic scoring system as necessary to be able to select first-line chemotherapy more effectively, along with which prognostic factors need to be identified to improve treatment outcomes and reduce anxiety for patients and families 4.3 Features of UA Doppler ultrasound of GTN patients The GTN originates in the uterus, which is a typical tumor with vascular neoplasia and hyperplasia In this study, all patients underwent pelvic Doppler ultrasound to assess uterine volume and blood flow through the uterin artery and thus calculate indices such as PI, RI, S/D A low PI indicates that there is a new angiogenesis associated with a arterio-venous shunt in the GTN and is considered a poor prognostic factor Therefore, in this study we assessed whether UAPI, an indirect method of neovascularization, were a predictor of MTX resistance in GTN patients When conducting the study, we kept the Doppler spectra results of bilateral UA of the GTN patients Based on PI index, there are groups: low PI and high PI Table 3.3 shows that there are significant differences between PSV and EDV of UA The higher EDV on the lower PI side exhibits lower impedance probably as a result of the increase in arterio-venous shunt associated with angiogenesis in GTN Thus, in GTN patients, the impedance of UA is not the same and taking low-impedance PI to find out the meaning of predicting the resistance of MTX chemotherapy is reasonable Therefore we retain the lower UAPI as represented by will correspond to the maximum variation 21 of uterine circulation compared to normal Similar to Hsieh, our study also found that there is an increase in PSV in GTN patients Our GTN patients showed an increase in PSV of UA at the time of diagnosis (mean PSV was 63.0 ± 27.9 cm / s), possibly due to an increase in blood flow to the uterus to nourish trophoblastic neoplasms 4.4 Characteristics of Doppler ultrasound GTN patients resistant and response to MTX 4.4.1 PSV of GTN patients resistant and response to MTX Patients who are resistant to MTT chemotherapy have a higher level of PSV than patients who are not resistant to MTX chemotherapy A higher PSV in chemotherapy resistant patients showed a higher and stronger need for blood supply to neoplastic trophoblast in this group 4.4.2 EDV of GTN patients resistant and response to MTX In GTN patients, Doppler ultrasound showed an increase in EDV (which exhibits lower impedance) as a result of increased arterio-venous shunt, new angiogenesis and vascular structure due to the nature of the trophoblastic cells (replace endothelial vascular, expansion, diameter increase and detorsion) Long proposed two hypotheses to explain the association between low impedance of UA and chemotherapy resistance during treatment First, the low impedance at the uterine artery is a result of arterio-venous shunt Arterio-venous shunt will reduce tumor perfusion Decreased tumor perfusion leads to a decreased chemotherapy concentration in the tumor organization and a decrease in the effectiveness of the chemotherapy (due to a shortcut from the artery to a vein without distribution to the tumor organization) and consequently resistance to chemotherapy Secondly, chemotherapy resistance can occur due to the nature of the type of cell that causes the tumor GTN is derived from cytotrophoblast that are very sensitive to chemotherapy, but interstitial cytotrophoblasts are less sensitive to chemicals Our study found that the patients who were resistant to chemotherapy were more likely to show an increase in EDV This review is in line with the research of authors such as Long, Argawal and Sita ‐ Lumsden 4.4.3 UAPI characteristics of GTN patients resistant and response to MTX Based on the ROC curve of UAPI and sequential analysis, we saw that the UAPI cut point by 1.2 appears to statistically predict the prognosis of MTX chemotherapy in both univariate and multivariate regression models (Table 3.9, 3.10) 22 The results in Table 3.9 showed that, in all patients (FIGO score from to 6), the group with UAPI ≤ 1.2 had a significant higher rate of MTX resistance than those with UAPI > 1.2 (41.1% compared to 23.3%) Hemodynamic characteristics of uterine artery is a new factor contributing to the prognosis of MTX resistance When the UAPI ≤ 1.2 increases the risk of MTX resistance by 2.63 times compared to the group with UAPI > 1.2 4.5 Discuss the significance of the UAPI combined with FIGO score to predict MTX resistance Hemodynamic characteristics of the UA expressed in PI values are also an independent prognostic factor with FIGO score on risk of chemotherapy resistance When using the FIGO prognostic score in combination with the UAPI ≤ 1.2, the results showed that the rate of MTX resistance increased compared to when using FIGO alone The rate of MTX resistance was 41.07% in patients with FIGO scores ≥ to 100% of MTX resistance in patients with FIGO scores ≥ 5(Table 3.12) When using FIGO prognostic scores in combination with UAPI > 1,2 showed a lower risk of chemoresistance than using FIGO alone (Table 3.11) Thus, in the same FIGO prognosis group, GTN patients with will be at higher risk of MTX resistance if UAPI ≤ 1.2 and risk of MTX resistance is lower if UAPI > 1.2 We found that the criteria of UAPI ≤ 1.2 is equivalent to 1-2 FIGO points when evaluating the rate of chemotherapy resistance of MTX in table 3.12 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% FIGO≥0 FIGO≥1 FIGO đơn FIGO≥2 FIGO≥3 FIGO + PI >1,2 FIGO≥4 FIGO≥5 FIGO + PI ≤1,2 Figure 4.3 MTX resistance rate when using FIGO alone and when combined with the UAPI threshold of 1.2 We pay special attention to the significance of the UAPI ≤ 1,2 in high prognostic groups When FIGO ≥ 4, if combined with UAPI ≤ 1.2, 66.67% of patients will be resistant to MTX (Table 3.12) The question is if the probability of failure is higher 23 than the probability of success, whether we should continue treatment with MTX or should start with combined chemotherapy Although the data is not very large, the significance of the PI ≤ 1.2 threshold is also more evident when combining FIGO ≥ points indicating that 100% of patients are resistant to MTX Thus, the cut-off point of the UAPI is 1.2 with prognostic significance both above and below the threshold 4.6 Discuss when to use UAPI Our study shows that the rate of resistance to MTX in the FIGO group ≥ is 50% Table 3.14 shows that the threshold of UAPI at 1.2 with the discriminant value of MTX resistance in FIGO score group from to (54,8% compared to 22,7%) Table 3.13 also shows that, at this threshold, the value of the MTX resistance rate in the FIGO score group from to is not significant We believe that the GTN is a disease affected by many factors and the UAPI is a new factor contributing to the prognosis of the disease, the more expressive this factor is when the FIGO score increases We recommend Doppler ultrasound to evaluate the pulse index for GTN patients with FIGO score ≥ before treatment, since patients in this group have a UAPI ≤ 1.2, the resistance to MTX up to 54.8% (Table 3.12) CONCLUSION Study of 204 GTN patients treated at the Department of Gynecology oncologic from January 2015 to September 2017 draws the following conclusions: Characteristics of UA doppler ultrasound and prognostic factors in GTN patient treated by MTX - Describe prognostic factors in LR-GTN patients The average age was 26.3 ± 5.1 years, index pregnancy was mainly molar and the average latent period was 2.1 months Patients with a history of MTX treatment accounted for only 1.5% Most patients have no metastases and are in stage according to FIGO The mean βhCG pretreatment was 11,667.2 ± 25,773.5 IU / l, median was 1.622,1 IU/l, most of GTN patients had βhCG < 1000IU/l The distribution of FIGO prognosis scores is non-standard, concentrated in groups with low scores from to points - Description of uterine artery doppler in GTN patients + The average PSV is 63.0 ± 27.9 cm/s, median is 55,65 cm/s + The average EDV is 15.1 ± 19.1 cm/s, median is 7,48 cm/s + Comparing the low PI side and the high PI side, the median difference between PSV, EDV, PI, RI, S / D has statistically significant differences, p 1.2 Based on the multivariate regression, UAPI ≤ 1.2 is the only independent prognostic factor for MTX resistance - Meaning combining UAPI with FIGO score to predict MTX resistance + Combination of FIGO score and UAPI ≤ 1.2 allow better detect the risk of MTX resistance in GTN patients + UAPI ≤ 1.2 equivalent to 1-2 points FIGO RECOMMENDATIONS From the research results of this thesis, I would like to make some recommendations as follows: - Doppler ultrasound should be used to evaluate the PI for LR-GTN patients with FIGO score ≥ because these patients have UAPI ≤ 1.2, the ability of MTX resistance is up to 54.84% - Further research is needed on the resistance of MTX chemotherapy to patients with FIGO score of 5-6 points and treatment considerations, because in our study, when combined with UAPI ≤ 1.2 the resistance of MTX chemotherapy of this group is 100%  ... 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 1.7.2 UA Doppler ultrasound in evaluating... 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