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BỘ GIÁO DỤC VÀ ĐÀO TẠO BỘ Y TẾ TRƯỜNG I HC Y H NI NGUYN VIT H ĐáNH GIá KếT Quả ĐIềU TRị UNG THƯ PHổI KHÔNG Tế BàO NHỏ GIAI ĐOạN IIIB-IV BằNG PHáC Đồ PEMETREXED Và CISPLATIN T¹I BƯNH VIƯN K Chun ngành : Ung thư : 9720108 TÓM TẮT LUẬN ÁN TIẾN SĨ Y HỌC HÀ NỘI – 2022 Cơng trình hồn thành tại: TRƯỜNG ĐẠI HỌC Y HÀ NỘI Hướng dẫn khoa học: PGS.TS Nguyễn Tuyết Mai Phản biện 1: Phản biện 2: Phản biện 3: Luận án bảo vệ trước Hội đồng chấm luận án cấp trường Họp tại: Trường Đại học Y Hà Nội Vào hồi ngày tháng năm 2022 Có thể tìm hiểu luận án tại: - Thư viện Qu c gia - Thư viện Trường Đại học Y Hà Nội DANH MỤC CƠNG TRÌNH NGHIÊN CỨU CỦA TÁC GIẢ ĐÃ CƠNG BỐ CĨ LIÊN QUAN ĐẾN ĐỀ TÀI LUẬN ÁN Nguyễn Việt Hà, Nguyễn Tuyết Mai Kết điều trị ung thư phổi không tế bào nhỏ giai đoạn IIIB –IV phác đồ Pemetrexed –Cisplatin Tạp chí Y học Việt Nam, s 01 năm 2021: 264-268 Nguyễn Việt Hà, Nguyễn Tuyết Ung thư phổi không tế bào nhỏ - Lâm sàng chẩn đốn hình ảnh Tạp chí Y Dược học s 21 năm 2021: 113-117 INTRODUCTION OF THESIS Background: Lung cancer (LC) is one of the most common cancers and the leading cause of cancer death in the world.Lung cancer is classified into two main groups as non-small cell lung cancer (NSCLC) accounts for 80-85% and small cell lung cancer.Treatment of non-small cell lung cancer depends on the stage of the disease.In the late stage, distant metastasis recurrence is mainly systemic treatment with chemotherapy , targeted agents Chemotherapy regimens that have been recommended for the first-line treatment of non-operative non-small cell lung cancer include cisplatin or carboplatin in combination with one of the drugs such as docetaxel, paclitaxel, gemcitabine, vinorelbine Early in the 21st decade pemetrexed has been included in the treatment of pleural mesothelioma and advanced NSCLC Pemetrexed has been shown to have an advantage in survival for patients with advanced NSC metastases are widespread.Analysis shows superior efficacy of pemetrexed in patients with no squamous cell and Asian patients with favorable safety data compared with other standard treatment options The drug is indicated for the treatment of non-small cell lung cancer in many countries around the world including In Vietnam, there have been a number of studies by the authors in Vietnam on the effectiveness and undesirable effects of this regimen, but the studies are still small Stemming from that clinical practice, we carried out the project "Evaluating the results of treatment for stage IIIB-IV non-small cell lung cancer with Pemetrexed and Cisplatin regimens at K Hospital" with two objectives pepper: + Objective 1: To evaluate the results of treatment of stage IIIB-IV non-small cell lung cancer with Pemetrexed regimen combined with Cisplatin at K Hospital from November 2014 to October 2019 and some related factors related to treatment outcomes in this group of patients + Objective 2: Review some unwanted side effects of PemetrexedCisplatin regimen in the above group of patients 2.Urgency of the themes Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death Lung cancer has a poor prognosis, with a 5-year survival rate of 17.8% About 40% of patients with non-small cell lung cancer when found to have distant metastases, this stage is mainly treated with chemotherapy, targeted drugs, and immunotherapy For patients without the leading mutation, chemotherapy is a treatment with proven benefits, but the unwanted effects of chemotherapy compromise treatment outcomes Pemetrexed has been shown to have an advantage in survival and fewer side effects than other chemicals Currently, the regimen is still the preferred choice to treat patients with advanced non-squamous NSCLC in Vietnam New contributions of the thesis: This is a study on the results of treatment of stage IIIB and IV nonsmall cell lung cancer with Pemetrexed and Cisplatin regimens, evaluating the promising treatment results of the regimen with an entity response of 39.4 %, the disease control rate is 78.8% The average survival time of the NR is 7.23 months The overall median survival was 13.27 months The 1year survival rate is 41.5%; years is 7.3% The study also analyzed the relationship between the rate of response to treatment with a number of factors: physical condition, disease stage, smoking status Analyze the relationship between overall survival time, NR survival and the following factors: overall status, functional response, physical response The study reported side effects that were mostly mild and did not disrupt treatment Analyze the relationship between hemoglobin status and treatment response and overall survival time The composition of the thesis: The thesis consists of 120 pages, of which: Introduction (2 pages), Chapter 1: Overview (32 pages), Chapter 2: Research objects and methods (14 pages), Chapter 3: Research results ( 36 pages), chapter 4: Discussion (33 pages), conclusion (2 pages), recommendations (1 page) In the thesis there are 41 tables, 26 charts, 08 figures, 01 diagram The thesis has 166 reference documents, including 36 Vietnamese documents, 130 English documents, mainly in recent years CHAPTER OVERVIEW 1.1 EPIDEMIOLOGICAL SITUATION AND RISK FACTORS 1.1.1 Epidemiological situation 1.1.2 Rík factors 1.2 DIAGNOSE 1.2.1 Clinical 1.2.2 Subclinical 1.2.2.1 Image analysation 1.2.2.2 Histopathological diagnosis Methods of taking specimens for histopathological diagnosis Flexible bronchoscopy, Endoscopic ultrasound, CT-guided transthoracic biopsy, Virtual bronchoscopy with multi-probe CT, Diagnostic laparoscopic surgery, Mediastinoscopy, Cytological and histopathological examination Histopathological classification according to WHO 2015: squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, large cell carcinoma, small cell carcinoma 1.2.2.3 Diagnostic molecular biology 1.2.2.4 Other biomarkers and tests 1.2.2.5 Diagnosis of non-small cell lung cancer Table 2.1.Staging: Stages in NSCLC T/M T1 T1a ( ≤ 2cm ) T1b ( > 2cm - ≤ 3cm) T2 T2a ( > 3cm - ≤ 5cm) T2b (> 5cm - ≤ 7cm) T3 >7cm T3 T3(Intrusion) T3 (same lobe nodule) T4 (invade) T4 T4 (same side) M1a M1a(TDMP) M1a(opposite side) M1b N0 Ia Ia Ib IIa IIb IIb IIb IIIa IIIa IV IV IV N1 IIa IIa IIa IIb IIIa IIIa IIIa IIIa IIIa IV IV IV N2 IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIb IIIb IV IV IV N3 IIIb IIIb IIIb IIIb IIIb IIIb IIIb IIIb IIIb IV IV IV 1.3 TREATMENT OF NSCLC The main treatment methods are surgery, radiation therapy, and systemic treatments including chemotherapy, targeted therapy, immunotherapy Indications for treatment of NSCLC mainly depend on the stage of the disease Stage I: Surgery (possibly adjuvant chemotherapy) Stage II: Surgery - adjuvant chemotherapy Stage III : IIIA : Surgery - chemotherapy - radiotherapy IIIB: Synchronous chemoradiotherapy Chemotherapy or radiotherapy alone Stage IV: systemic treatment including chemotherapy, targeted therapy, immunotherap 1.4 CHEMICALS TREATMENT NSCLC ADVANCED STAGE 1.4.1 Overview of late stage chemotherapy For NSCLC at stage IIIB and IV with widespread metastatic lesions that are no longer operable, the choice of treatment depends on the stage of the disease, the patient's physical condition, and the molecular biology diagnosis Stage IIIB no longer requires surgery, the trend of treatment is concurrent chemoradiotherapy, then additional chemotherapy In cases where there is no indication for combination therapy, chemotherapy or radiation therapy is effective in relieving symptoms Stage IV with localized metastatic lesions consider the possibility of surgical removal of metastatic lesions combined with lung tumor surgery followed by systemic chemotherapy or chemotherapy first, then surgery For diffuse chemical lesions alone, anti-compression, anti-pain and targeted therapy Currently, histology and genetic mutation status are recommended predictors that may allow selection of therapeutic approach for patients with advanced NSCLC For lung adenocarcinoma, up to 64% have found that the cause of cancer is mutations, these mutations have targeted drugs for each type, bringing many positive results The remaining mutations and the cases of unknown mutations make the choice of first-line treatment still chemotherapy for the stage of widespread metastasis Pemetrexed is an anti-metabolite folate derivative that inhibits folate-dependent metabolic pathways that are essential for cell replication For patients with non-small cell lung cancer Late-stage or metastatic squamous cell carcinoma with nonsquamous cell histology, with unknown mutation status pemetrexed has been shown to be firstline (in combination with cisplatin) or as replacement therapy (in combination with cisplatin) alone two) because the drug has a multitargeted anti-cancer mechanism, so it has higher potency and a broader spectrum of anti-tumor activity when compared with other antimetabolites Side effects of pemetrexed were significantly lower than with other anticancer drugs when vitamin B12 and folic acid were supplemented during treatment CHAPTER OBJECTS AND METHODOLOGY 2.1 RESEARCH OBJECTS The study was conducted on 94 patients diagnosed with stage IIIB IV non-small cell lung cancer treated with chemotherapy regimen Pemetrexed - Cisplatin 2.1.1 Criteria for selecting patients - Patients over 18 years old, diagnosed with non-small cell lung cancer, stage IIIb or stage IV (According to the 2009 IASLC classification) - Overall health index PS = 0-1 according to the ECOG scale - EGFR mutation test negative - There are target lesions to assess response according to RECIST criteria - Bone marrow, liver, and kidney function within limits allowed for chemotherapy - No serious acute or chronic diseases in recent times - Treatment with pemetrexed - cisplatin step and treatment with a minimum of chemotherapy courses - Voluntarily participate in research and sign a volunteer agreement - Have a complete record of information 2.1.1 Criteria for selecting research objects - Patient does not meet the above selection criteria - Patients with stage IV lung cancer with brain metastases - Do not have other cancers at the same time - The patient is allergic to one of the ingredients of the drug - Pregnant or lactating women - There is no follow-up information after treatment 2.2 METHODOLOGY 2.2.1 Research design Study type: longitudinal follow-up clinical intervention study - Research period: from November 2014 to October 2019 - Research location: Department of Internal Medicine - Central K Hospital - Estimated study sample size: A Simon's two-stage minimax phase II design was used to determine the minimum sample size for statistical significance: Determined by the formula: n = Z2(1-α/2) x In there: n : Sample size needed for the study α: Stati tical ignificance level, choo e α = 0.05 (corre ponding to 95% confidence) Z (1-α/2) : The Z value obtained from the Z table corre pond to the elected α value (u ually the confidence coefficient Z is 95%, respectively Z1-α/2 = 1.96 and α = 0.05) p: One-year survival rate after treatment with Pemetrexed - cisplatin regimen in the treatment of NSCLC with extensive metastases (p = 0.409) [111] ε : Relative deviation range We choo e ε = 0.3 Applying the above sample size calculation formula, we calculate the theoretical ample ize a n ≈ 62 patient In fact, we collected 94 patients who met the inclusion criteria and did not violate the exclusion criteria from participating in the study 2.2.2 The method of data collection - Design of clinical samples with the objectives of the project 2.2.3 Study progress 2.2.3.1 Clinical and paraclinical examination before treatment Clinical and laboratory assessment before starting the treatment regimen, before each chemotherapy cycle and monitoring after treatment Clinical examination: All patients in the study had a detailed clinical examination of local symptoms, exploiting functional and systemic symptoms Assess the patient's general condition before treatment based on the ECOG score (PS) In this study, patients with PS index -1 at the time of treatment were selected Record the following information: •General feature + Age, gender + Date of admission, date of metastasis recurrence, location of metastasis recurrence + Date of death History of internal medicine •Clinical feature : Exi ting clinical ymptom , PS tatu index Clinical Examination: Diagnostic imaging and tests Record the following information: •Image analysation: + Results of tumor assessment on normal X-ray, CT, MRI, PET - CT Determine size, location of tumor and lymph nodes, identify metastatic lesions + Image of lesions through endoscopy: warts, infiltrates, bronchial narrowing, congestion + Results of bone scan, SPECT lung • Hi topathological diagno i : adenocarcinoma, large cell carcinoma •Te t re ult : blood biochemi try, blood count, electrocardiogram, respiratory function measurement, tumor marker test, EGFR mutation test 2.2.3.2 Chemical treatment Eligible patients will be included in the study and receive chemotherapy according to the following regimen: Pemetrexed – Cisplatin - Pemetrexed 500 mg/m2 IV infusion on day - Cisplatin 75 mg/m2 intravenous infusion on day Supplementation of folic acid and Vitamin B12 during treatment 10 3.2.1.3 Mechanical response of the studied patient Patients with functional response had the highest improvement rate (58.5%), patients with stable functional response, bad had the rate of 25.5%, 16.0%, respectively 3.2.1.4 Some factors affecting response to treatment Table 3.2 Some factors affecting response to treatment Response to treatment Factor Age PS Gender Stage Smoke Histopathology Respond Not Respond < 60 27 (40,9%) 39 (59,1%) ≥60 10 (35,7 %) 18 (64,3%) PS0 26 (56,5%) 20(43,5%) PS1 11 (22,9%) 37 (71,1%) Mal 28 (36,8 %) 40 (63,2%) Femal (50 %) (50 %) IIIA (50%) (50%) IV 36 (39,1%) 56 (60,9%) Yes 22 (32,4%) 46(67,6%) No 15(57,7%) 11 (42,3%) Adenocarcinoma 36(39,6%) 55(64,4%) 1(33,3%) 2(66,7%) p 0,41 0,002 0,42 0,03 0,03 Large cell carcinoma 0.66 Comment: The rate of treatment response is related to the following factors: physical condition, stage, smoking, this difference is statistically significant, with p0.05 11 3.2.2 Progression-free survival 3.2.2.1 Progression-free survival time Chart 3.1 Progression-free survival time of study patients Comment: Median progression-free survival was 6.09 months, maximum 24 months 3.2.2.2 Progression-free survival with a number of related factors * Progression - free survival according to condition The progression-free survival time was higher in the group of patients with PS0 status than in the PS1 group, the difference was statistically significant with p