Nghiên cứu kết quả điều trị và một số yếu tố tiên lượng ung thư biểu mô nội mạc tử cung giai đoạn I,II tiếng anh

1 MINISTRY OF EDUCATIONMINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY TRAN GIANG CHAU TREATMENT OUTCOME AND PROGNOSTIC FACTORS IN STAGE I, II ENDOMETRIAL CANCER MEDICAL DORTORAL THESIS HA NOI – 2020 The study was completed at: HANOI MEDICAL UNIVERSITY The scientific instructor: Assoc Prof Dr Bui Dieu Assoc Prof Dr Nguyen Van Tuyen Reviewer 1: Prof.Dr Tran Thi Phuong Mai Reviewer 2: Prof.Dr Le Chinh Dai Reviewer 3: Prof.Dr Pham Cam Phuong The dissertation will be defended in front of the University Thesis Evaluation CouncilMeeting at: Hanoi Medical University At: …… hour …… day …… month …… 2020 THESIS CAN BE LEARNED AT LIBRARY The National Library Library of Hanoi Medical University Central Medical Information Library INTRODUCTION OF THESIS Introduction In Vietnam, endometrial cancer ranks the second in gynaecological malignancies, after cervical cancer Treatments of endometrial cancer include surgery, radiation, chemotherapy, and hormonal therapy Surgical treatment is the most important components which is often applied to the majority of patients In general, endometrial cancer has a relatively good prognosis with the 5-year overall survival rate between 70-80% To achieve a good result, fully identify prognosis factors, from which appropriate treatment regimens and strategies are introduced, are the key issue leading a better outcome for patients We have conducted this study with two goals: Summary of results of treatment of endometrial carcinoma stage I, II Identify some prognostic factors of endometrial cancer Necessary of thesis Endometrial cancer is the most common gynecological cancer in developed countries In the US, endometrial cancer accounts for 6% of all cancers in women In 2018, worldwide, an estimated 380,000 new cases of endometrial cancer were diagnosed Each year, there are more than four thousand new cases and more than one thousand deaths, and it ranks 11th in the incidence of all cancers In the last years, the incidence of this gynecological malignancy tends to increase in Vietnam In our country, we have made a number of publications on this topic, but data on survival outcomes are lacking and a full appreciation of the prognostic factors of work is still in progress New contribution of thesis Results on 186 patients of endometrial cancer stage I and II underwent surgery, with or without adjuvant treatment based on the standard guideline have shown the mortality rate was 15.1%, the recurrence rate was 8.1%, metastasis rate is 16.7% DFS for years was 74.6% years OS was 79.9% The study has demonstrated a clear association of many factors with prognosis Non-endometrioid endometrial carcinoma has a 4.1fold higher risk of death Highgrade has 4.9 times higher mortality risk than intermediate and lơ grade The group of ER(-) PR (-) has 24 times higher mortality risk than ER (+) PR (+ ), lymph node metastases are 11.9 times more likely to die without lymph node metastases At the same time, multivariate analysis showed that histopathology, PR receptor, lymph node metastasis are independent prognostic factors in endometrial cancer Identifying prognostic factors during treatment is extremely important to help improve the effectiveness of treatment Structure of thesis The thesis consists of 115 pages and chapters: introduction - pages; chapter 1: 33 pages; chapter 2: 18 pages, chapter 3: 28 pages, chapter 4: 30 pages; conclusion and further research directions: pages; new contributions: page.In the thesis, there are 36 tables, 16 charts, pictures, diagram, 118 references (12 documents in Vietnamese, 106 documents in English) In the thesis summary, we present only some of the main contents Chapter 1: REVIEW 1.1 Pathogenesis and lymph node metastasis in endometrial cancer 1.1.1 Pathogenesis of endometrial cancer Currently, endometrial carcinoma is divided into two types, estrogendependent and non-estrogenic The type of estrogen dependence accounts for 75% - 85%, usually in young people, or at menopause with a history of use estrogen without progesterone The non-estrogenic type occurs in women who not use estrogen 1.1.2.Cancer spread lines in endometrial cancer Direct invasion is the predominant pathway of disease Spread through the fallopian tubes on both sides Lymphatic spread allows the transport of tumor cellsto the iliac lymph nodes and paraaortic lymph nodes Vaginal metastasis is less common Blood metastases to the lungs, liver, brain, and bones, but with a low incidence 1.2 Diagnosis and classification stage of endometrial cancer 1.2.1 Clinical features of endometrial carcinoma Clinical examination: whether the uterus is enlarged, or not, to detect late invasive cervical or vaginal fornix Place a speculum that shows blood or fluid through the cervix 1.2.2 Paraclinical featuresof endometrial carcinoma - Ultrasound and magnetic resonance imaging help to assess the degree of uterine muscle invasion relatively accurately - Pathology help identify histologic types and tumor grade: classification of WHO 2014 The most frequent type of endometrial cancer Clear-cell carcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, and serous adenocarcinoma are less common Histological classification of endometrial cancer according to WHO (2003) has three grade of differentiation: well differentiated, moderately differentiated, poorly differentiated 1.2.3 Staging endometrial cancer According to the International Federation of Gynecology and Obstetrics (FIGO) and the TNM classification according to WHO Currently, the classification of TNM 2017 and FIGO 2014 has been updated 1.3 Treatment of endometrial cancer and review of the literature Surgery is the main treatment in endometrial cancer Modern surgical approachs such as laparoscopic surgery and robotic surgery are being applied at multiple institutions Radiation therapy is the second most effective method of treating this disease Chemotherapy and hormone treatment is applied in the context of relapse or metastasis 1.3.1 Surgical management Surgery is often the main treatment for endometrial cancer and consists of a hysterectomy, often along with a salpingo-oophorectomy, and removal of lymph nodes In some cases, pelvic washings are done, the omentum is removed, and/or peritoneal biopsies are done If the cancer has spread throughout the pelvis and abdomen, a debulking procedure (removing as much cancer as possible) may be done Pelvic lymphadenectomy and paraaortic lymphadenectomyis part of a comprehensive staging which provide additional information for prognosis and indications for adjuvanttherapy According to GOG data: paraaortic lymhp nodes are more likely positive when: - Many positive pelvic lymph nodes - Adnexal involvement - Stage II, III and the tumor invade over 1/3 of the muscle layer 1.3.2 Radiotherapy in the management of endometrial cancer In some cases, patients have exclusive radiation therapy Most indications of radiation therapy in endometrial cancer are in adjuvant therapy after surgery Some radiotherapy techniques may be used: brachytherapy, whole pelvis radiotherapy or both 1.3.3 Chemotherapy, hormone therapy and targeted therapy in endometrial cancer There are a lot of mono or multi chemotherapy formulas Common chemical such as Doxorubicin, Platinum (Cisplatin or Cathoplatin) with Paclitaxel (Taxol) The response rate to progestin varies by stage, 20.5% at early stage, 1.4% at advanced stage When ER and PR are positive, the response rate is 70% When ER and PR are negative, the response rate is only 5% - 15% Absence of absence of ER, PR receptors expression associated with advanced stages has a a poor responseto hormone therapy Unlike progestins, Tamoxifen seems to work well for patients with poorly differentiated histology, hormone receptor positive, and has not been previously treated with any hormone therapy Some notes on hormone therapy in patients with endometrial cancer: - Patients with advanced or recurrent disease often have poor treatment response and may be related to ER and PR status - Highly differentiated cancer: high response rate - PR level drops significantly at advanced stage - Progestins for oral administration and intrauterine placement are suitable for patients with early stages with high differentiation 1.4 Prognosis factor Prognostic factors in endometrial cancer include age, stage, histologic subtype, stage, histologic grade, lymphovascular space invasion, depth of myometrial invasion, lymph node metastasis, level of nodal involvement 1.4.1 Age Many studies have documented age as an independent prognostic factor Younger endometrial cancer patients have a better prognosis than older people The authors also noted an increased risk of recurrence in elderly patients 1.4.2 Histologic subtype About 10% of histopathologies that are not endometrioid endometrial cancer, are at high risk of recurrence and distant metastases In contrast, type I endometrial carcinoma have a better prognosis 1.4.3 Histologic grade High grade is associated with an increased risk of recurrence and a reduction in overall survival High grade tumor are often associated with deep myometrial invasion, cervical involvement, and lymph node metastasis 1.4.4 Depth of myometrial invasion It has been noted that the lymphatic network in 1/2 outside the muscular layer is abundant that when cancer invades to this layer, it increases the risk of spreading out of the uterus The association between deep myometrial invasion and spread beyond the uterus and lymph node metastasis has been confirmed 1.4.5 Lymph node metastasis Lymph node metastasis (LNM) is one of the most important prognostic factors in endometrial cancer Patients with lymph node metastasis are times more likely to relapse than patients without lymph node metastasis The 5-year overall survival for patients with pelvic lymph node metastases was 54%, while this rate was 90% for patients without pelvic lymph node metastasis.Therefore, the complete lymphadenectomy is valuable in evaluating prognosis 1.4.6 Hormone receptors Reports on the prognostic value of hormone receptor status on endometrial cancer have been published since the 1980s Estrogen and progesterone receptor positivity are independent prognostic factors with a significantly improved disease-free survival Hormone therapy including progestins, aromatase inhibitors and selective estrogen receptor modulators are attractive first-line therapies for young patients wanting fertility-sparing options and supplemental therapies for patients with advanced disease since they lack adverse toxicities A few published cases report successful response in treating young patients with early-stage type I disease; however, the median progression-free survival in patients with recurrent or advanced disease are minimal at 1–3.7 months Hormone receptor status is still an important molecular prognostic factor and hormonal therapy should always be considered as supplemental and palliative targeted therapy 1.4.7 Tumor size If the size of tumor is less than 2cm, the 5-year overall survival rate is 98%, if the size of tumor is more than 4cm, the 5-year overall survival rate decreases to 84%, if the tumor occupying the entier endometrial cavity, the 5year overall survival rate is only 64 % Many studies have demonstrated a relationship between tumor size and the depth of myometrial invasion and lymph node metastasis 1.4.8 Some other factors In addition to the above factors, there are many other factors closely related to endometrial cancer The lack of manifestation of beta-catelamin is a predictor of poor prognosis, whereas PTEN deficiency is a good predictor of prognosis at an early stage The P53 gene often has a poor prognosis, which is seen in a later stage Chapter 2: SUBJECT AND METHOD 2.1 Subject Patients with stage I and II endometrial carcinoma were treated at K hospital from 1/2010 to 10/2016 2.1.1 Inclusion criteria 10 The patient was diagnosed with endometrial carcinoma, confirmed by histopathology Allpatientsunderwenthysterectomy,bilateralsalpingo- oophorectomy,andregionalnodaldissection 2.1.2 Exclusion criteria Patients with severe comorbid conditions, patients were not eligible to participate in the study, grave lack of data 2.2 Methods 2.2.1 Type of method: Aprospective,non-randomizedstudy 2.2.2 Sample Applying the formula for calculating sample sizes for prospective descriptive studies, the minimum number of patients needed for the study was184 patients Our study involved 186 patients 2.2.3 Sampling method Convenience sampling 2.2.4 Research facilities Existing medical examination and treatment equipment of K hospital 2.2.5 Conducting study Selection of patients according to criteria 2.2.5.1 Patient characteristics - Interrogation: age, reproductive history, reason for visiting the doctor - Examination: assessment of local and systemic lesions Local: assessment of uterine size, tumor size, invasive lesions Endometrial biopsy for histopathological diagnosis to evaluate histopathology and histology Systemic: evaluation of peripheral lymph node status, abdominal fluid, metastases to other organs - Staging: classification of disease stage according to FIGO 2009 and TNM 2010 12 + Metastasis: a new occurrence of diseases in organs other than the uterus after treatment Recognize organ metastases and treatment + Disease free survival Calculate from time of surgery to recurrence or metastasis (months) + Overall survival Calculate from time of surgery to death (months) + The time scales: progression free survivaland overall survivalis divided in levels: 2cm and invasive tumors ≤ 1/2 muscle layer account for the same great proportion: 60.8% The size of the tumor that occupies the entire uterus has the lowest rate: 12.9% 3.1.3 Histologic type Endometrioid type accounts for the highest rate of 86%, only case of mucinous adenocarcinoma, the remaining cases histopathology accounts for a low rate 3.1.4 Histologic grade Proportion of well differentciated and poorly differentciated: 43% and 22,1%, respectively 3.1.5 Hormone receptors status ER (+) PR (+) group accounted for 59.7%, ER (-) PR (-) group accounted for 26.9% 3.1.6 Lymph node status 14 The rate of lymph node metastasis is 9.1% (17/186) In which, there are patients have paraaortique lymph node metastasis, patients have bilateral pelvic node metastasis 3.1.7 Classification stage Stage IA accounts for the highest proportion (51.6%), stages IB and II are nearly equivalent 3.2 Evaluate the results of treatment of endometrial cancer 3.2.1 Treatment regimen Exclusive surgery accounted for 44.6% Surgery followed by adjuvant radiotherapy: 51.1%, surgery followed by adjuvant chemoradiotherapy accounts for 4.3% 3.2.2 Death report There are 28/186 deaths, accounting for 15.1% Of which the main cause is metastases in 26/28 cases (17 cases of distant metastasis, cases of local metastases), only 2/28 cases of death due to aging 3.2.3 Recurrence The recurrence rate was 8.1%, of which the paraaortique lymph node recurrence accounted for the highest rate (53.3%) In in 15 (6.7%) cases, there was a recurrence of peripheral lymphadenopathy.40% are pelvic relapse 3.2.4 Metastasis There are 31/186 metastases accounting for 16.7%, of which peritoneal metastases (45.2%), followed by liver metastases (32.3%),brain metastases (6.4%) 3.2.5 Long-term results 3.2.5.1 Disease free survival 5y-DFS was 74,6% 3.2.5.2 Overall suvival 15 5y-OS was79.9% 3.3 Assessment of prognosis factors for endometrial cancer 3.3.1 Age The mortality rate of the group> 50 years old is significantly higher than the group ≤ 50 (p = 0.048) The rates of relapse and metastases differ between the two age groups are not statistically significant 3.3.2 Tumor size 3.3.2.1 Mortality, recurrence and metastasis according to tumor size Mortality rates in the tumor-sized group accounting for the entire uterus were the highest (8/24 cases) Mortality rates were significantly different among tumor size groups (p = 0.005) 3.3.2.2 Disease free survival, overall suvival according to tumor size The group of patients with invasive tumor of the entire uterus has the worst long-term outcome,this difference is statistically significant (p 1/2 of muscle layer are higher than the group with the depth of invasion ≤ 1/2 of the muscular layer, and this group is at risk mortality was 4.1 times higher (OR = 4.1; 95% CI (1.7-9.6)), the risk of recurrence was 3.4 times higher (OR = 3.4; 95% CI ( 1,1-10,4)), the risk of metastasis is 2.5 times higher than the invasive group ≤ 1/2 muscle layer (OR = 2.5; 95% CI (1,1-5,5))3.3.3.2 3.3.3.2 Disease free survival, overall suvival according to tumor sizeaccording to depth of invasion Disease free survival, overall suvival of the group with the depth of invasion> 1/2 of muscle layer was inferior than the group with the depth of invasion ≤ 1/2 of muscle layer with statistical significance (p