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THÔNG TIN TÓM TẮT NHỮNG KẾT LUẬN MỚI CỦA LUẬN ÁN TIẾN SĨ Tên đề tài: “Đánh giá kết quả hoá xạ trị đồng thời ung thư phổi tế bào nhỏ giai đoạn khu trú phác đồ cisplatin-etoposide tại Bệnh viện K” Mã số: 9720108; Chuyên ngành: Ung thư Nghiên cứu sinh: Hoàng Trọng Tùng Người hướng dẫn: PGS.TS Bùi Công Toàn Cơ sở đào tạo: Bộ môn Ung thư, trường Đại học Y Hà Nội Những kết luận mới của luận án: 1. Ung thư phổi tế bào nhỏ là bệnh lý có mức độ ác tính cao, tiên lượng xấu, với sự tiến triển nhanh, di căn xa sớm nếu không được chẩn đoán và điều trị kịp thời. Khi bệnh ở giai đoạn khu trú, phác đồ điều trị hóa xạ trị đồng thời có kết quả cao hơn, tuy nhiên tác dụng không mong muốn gặp phải cũng cao hơn, chính vì vậy trước kia rất khó áp dụng. Với sự phát triển của các kĩ thuật xạ trị tiên tiến cùng với các phác đồ hóa chất mới, việc kiểm soát tác dụng không mong muốn cũng được cải thiện hơn. Phác đồ mới được áp dụng trong thực hành lâm sàng tại nước ta trong những năm gần đây. Đây là nghiên cứu đầu tiên tại Việt Nam nghiên cứu về hiệu quả phác đồ hóa xạ trị đồng thời đối với ung thư phổi tế bào nhỏ giai đoạn khu trú. 2. Kết quả từ nghiên cứu cho thấy: Đáp ứng điều trị cao với tỷ lệ đáp ứng toàn bộ là 95,3%, trong đó đáp ứng hoàn toàn đạt 54,6%. 40,7% đạt đáp ứng một phần trong đó trong đó đa phần có mức giảm trên 60% thể tích khối u so với ban đầu. Đáp ứng cao hơn ở nhóm BN có chỉ số toàn trạng tốt PS=0 Thời gian sống thêm bệnh không tiến triển đạt được rất khả quan, trung bình: 14,4 ± 1,3 tháng. Thời gian sống thêm toàn bộ trung bình đạt được rất đáng khích lệ: 23,2 ± 1,6 tháng. Phân tích đa biến các yếu tố ảnh hưởng đến sống thêm không tiến triển bệnh là giai đoạn bệnh sớm, đáp ứng điều trị và điều trị đủ 4 chu kì hóa chất. Các yếu tố ảnh hưởng đến sống thêm toàn bộ là giai đoạn bệnh, mức độ di căn hạch, đáp ứng điều trị và điều trị đủ 4 chu kì hóa trị Tác dụng không mong muốn của phác đồ hóa-xạ trị đồng thời có thể kiểm soát tốt. Hay gặp nhất là tác dụng không mong muốn trên hệ tạo huyết: Giảm bạch cầu độ III và IV là 31,1%. Hạ tiểu cầu độ III-IV gặp 7,8%. Tác dụng không mong muốn trên gan, thận ít gặp, chỉ gặp độ I và II. Các tác dụng phụ liên quan đến xạ trị vùng ngực như viêm phổi, viêm thực quản chỉ gặp ở mức độ nhẹ, không gặp độ III,
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY HOANG TRONG TUNG EFFICACY OF CONCURRENT CHEMORADIATION LIMITTED STAGE SMALL CELL LUNG CANCER WITH CISPLATIN-ETOPOSIDE REGIMEN AT K HOSPITAL Specialty: Oncology Code: 9720108 SUMMARY OF PhD THESIS IN MEDICINET HA NOI - 2022 THE STUDY IS COMPLETED AT HA NOI MEDICAL UNIVERSITY Mentor: Assoc.Prof Bui Cong Toan Opponent 1: Assoc.Prof.Pham Cam Phuong Opponent 2: Assoc.Prof.Nghiem Thi Minh Chau Opponent 3: Assoc.Prof Phan Thu Phuong The thesis will be presented committee of Ha Noi medical university at o’clock, Date / /2022 The thesis could be found in: National Library Library of Hanoi Medical University INTRODUCTION Lung cancer is a malignancy and the most common cause of cancer death globally According to statistics of the International Organization for Research on Cancer (GLOBOCAN 2020), there are an estimated 2.2 million new cancer cases, accounting for 11.4% of all cancer patients and 1.79 million deaths , which accounts for 18% of all cancer deaths overall In Vietnam, cancer registry program in 2020 shows that lung cancer has a high morbidity and mortality rate in both sexes According to the classification of the World Health Organization (WHO), lung cancer is divided into two main groups based on histopathological characteristics: non-small cell lung cancer, accounting for 85-90% and small cell lung cancer These two histopathological forms are fundamentally different in terms of treatment modality and prognosis Smal cell lung cancer has different characteristics compared to other groups with high malignancy, poor prognosis, rapid growth, early distant metastasis if not diagnosed and treated promptly In clinical practice, SCLC is divided into stages: the localized stage and the extended-stage, in which the localized stage accounts for 1/3 of the patients with SCLC at the time of diagnosis In terms of disease treatment, in the past, due to limited technical issue as well as understanding of the biological nature of the disease, the treatment of limited-stage small cell lung cancer was usually applied sequentialy Nowaday, the principle of multimodal treatment by combining treatment methods, they are combined at each stage, each time to give best results Concurent chemoradiation is a radical treatment method for patients with limited-stage small cell lung cancer The regimen has been applied in many countries such as Japan, Canada, the US, Europe and has proven effective in helping to increase the response rate, decrease recurrence rate, and prolong overal survival In Vietnam, concurrent chemoradiotherapy regimens for limiteded-stage SCLC have been applied in the past few years, but no studies have reported the effectiveness of the regimen Therefore, we conducted this study with two objectives: Objectives: Primary objective: Describe some characteristics of limited-stage small cell lung cancer treated with concurent chemoradiation at Hospital K Secondary objectives: To evaluate efficacy of concurent chemoradiation with Cisplatin-Etoposide regimen These new findings of the thesis: Small cell lung cancer is a disease with high malignancy, poor prognosis, with rapid progression, early distant metastasis if not diagnosed and treated promptly When the disease is at a localized stage, the chemotherapy and radiotherapy regimen at the same time helps to improve the treatment efficiency and prolong the survival time However, the undesirable effects encountered are also higher That is why it was difficult to apply before With the development of more advanced radiotherapy techniques and new chemotherapy regimens, the control of undesirable effects has also improved New regimens have been applied in clinical practice in our country in recent years This is the first study in Vietnam to study the effectiveness of concurrent chemoradiotherapy regimens for limitted-stage small cell lung cancer Results from the study showed that: The response to treatment was high with the overall response rate of 95.3%, of which the complete response reached 54.6% 40.7% achieved a partial response in which most had a reduction of more than 60% of tumor volume compared to baseline The response was higher in the group of patients with good condition index PS=0; Age, weight loss, NSE/Pro GRP levels, radiation dose, or number of cycles of chemotherapy did not differ in complete response rates The progression-free survival was very satisfactory, on average: 14.4 ± 1.3 months The average overall survival achieved was very encouraging: 23.2 ± 1.6 months Multivariate analysis of factors affecting progressionfree survival was early stage, response to treatment and full cycles of chemotherapy Factors affecting overall survival are stage of disease, lymph node metastasis, response to treatment and complete cycles of chemotherapy Undesirable effects of concurrent chemoradiotherapy regimens can be well controlled The most common undesirable effect on the hematopoietic system: Grade III and IV leukopenia is 31.1% Thrombocytopenia grade III-IV was found in 7.8% Undesirable effects on the liver and kidneys are rare, only grade I and II Side effects related to thoracic radiotherapy such as pneumonia and esophagitis were only mild, no grade III, IV Structure of thesis: This thesis is composed of 128 pages (excluding appendices and references): Introduction (2 pages), Chapter 1: Overview (40 pages), Chapter 2: Material and method (13 pages); Chapter 3: Results (35 page); Chapter 4: Discussion (35 pages); Conclusions (2 pages); Recommendations (1 page) There are 39 tables, 21 charts and pictures References: 91 references (Vietnamese and English documents) Appendices consists of patients list, studying profile, letter CHAPTER 1: OVERVIEW 1.1 Epidemiology Lung cancer is a malignancy and the most common cause of cancer death globally According to statistics of the International Organization for Research on Cancer (GLOBOCAN 2020), there are an estimated 2.2 million new cancer cases, accounting for 11.4% of all cancer patients and 1.79 million deaths , which accounts for 18% of all cancer deaths overall In Vietnam, the results of recording cancer in the population also show that the incidence of TTP increases gradually over time and the mortality rate increases gradually over time and especially in both sexes According to GLOBOCAN in 2018, Vietnam had 21,865 new cancer patients and 19,559 deaths After only years, according to GLOBOCAN's report in 2020, the number of new cases has increased to 26,262 cases and 23,797 deaths from lung cancer According to the classification of the World Health Organization (WHO), cancer is divided into main groups based on histopathological characteristics: non-small cell lung cancer (NSCLC) accounting for 85-90% and small cell lung cancer 1.2 Screening and early diagnosis: people at high risk such as smokers and over 40 years old 1.3 Definitive diagnosis 1.3.1 Clinical manifestation - The early stages are often discovered incidentally (about 5-10%) The advanced stage of HCC usually develops in the large bronchi, grows rapidly, has high malignancy, and has a variety of clinical manifestations: cough (may be dry cough or sometimes bloody sputum), chest pain, shortness of breath, pneumonia More severe progression: superior vena cava compression, esophageal compression, nerve compression, pleural effusion, pericardial effusion, paraneoplastic syndrome 1.3.2 Work-up: Routine chest X-ray, Computed tomography, Magnetic resonance imaging, Scanning, PET-CT, Diagnostic ultrasound, Bronchoscopy, Thoracoscopy and mediastinoscopy, Methods Diagnostic method for histopathology Sampling by percutaneous thoracic aspiration biopsy under CT guidance Transbronchial aspiration biopsy, Cytological diagnosis, Histopathological diagnosis, Tumor markers 1.4 Diagnosis stage 1.4.1 VALSG staging classification Small cell lung cancer has a very early risk of distant metastasis, even at the time of diagnosis Up to now, people still use the VALSG (Veterans' Administration Lung Study Group) stage classification, which divides them into two main stages: the limitted stage and the extended stage • Limitted stage is defined when disease is limited to a field of radiation therapy, usually assessed to be limited to 1/2 of the thorax and regional nodes, including mediastinal and ipsilateral supraclavicular nodes • The extended stage is defined as disease beyond the limits of the upper regions, including pleural effusion, pericardial malignancy, or hematogenous metastases 1.4.2 TNM staging classification Compared with the VALSG classification, the localized stage NSCLC evaluated at stages I-III can be treated with chemoradiotherapy simultaneously, excluding cases of T3-T4 because the tumor invades too wide the irradiation field or has a large irradiation field satellite tumor lesions Invasive stage is evaluated at stage IV or T3-T4 when lesions cannot be covered in irradiation field 1.5 Differential diagnosis: NSCLC, neuroendocrine tumor, hamartoma 1.6 Prognostic factors: female, age 40 mL/min according to the Cockcroft-Gault formula - Volunteer to participate in research and have complete records * Exclude criteria - Mixed histopathology of small cell lung cancer and non-small cell lung cancer - Patients with malignant pleural effusion or malignant pericardial effusion - Patients stage I – T1N0M0 - Patients who have been treated surgically, R2 or N2 cut-outs are treated for IBD - The patient received chemotherapy for cycles before receiving radiation therapy - Previous history of thoracic and mediastinal radiation therapy - Symptomatic heart failure at the time of diagnosis or other cardiovascular diseases: left ventricular dyskinesia, myocardial infarction - Have other serious acute and chronic diseases: liver failure, kidney failure, or allergy to the ingredients of the drug Or have a history of organ transplantation - Patients with a combination of other cancers except: basal cell skin cancer, or cervical cancer in situ within the last years - Pregnant or lactating women - Known allergy or hypersensitivity to any ingredient or excipient of the drug used in the study regimen 2.2 Method 2.2.1 Design of study: Uncontrolled clinical trial 2.2.2 Sample size: Formulation: n Z (21 / 2) p.(1 p) ( p. ) Applying the above formula, the calculated sample size is 60 In this study we have 64 patients 2.2.3 Procedure - Clinical information, preclinical tests before treatment - Concurrent chemoradiotherapy treatment process: Radiation therapy is carried out simultaneously with chemotherapy and continued with full dose treatment in the next cycles of the regimen Radiation therapy: Start at the first cycle of chemotherapy and continue radiation therapy until the full dose Total radiation dose is 60 Gy, divided dose Gy/day, days/week The volume of radiotherapy included lung tumor + ipsilateral hilar nodes and mediastinum + bilateral supraclavicular nodes Chemotherapy: Etoposide – Cisplatin (EP) regimen Cycle weeks x cycles The first cycles will be done with radiation therapy Cycle Ngày Cisplatin Etoposide Radiation Cycle Ngày Cisplatin Etoposide Radiation Cycle Ngày Cisplatin Etoposide Radiation Cycle Ngày Cisplatin Etoposide Radiation Week Week Week 3 7 Week Week Week 3 7 Week Week Week 3 7 Week Week Week 3 7 10 CHAPTER 3: RESULT 3.1 CLINICAL CHARACTERISTICS Table 3.1: Patient characteristics Characteristics Age Giới Smoking history n 10 25 26 61 56 < 40 41 - 50 51 – 60 61 – 70 > 70 Male Female No Yes % 1,6 15,6 39,1 40,6 3,1 95,3 4,7 12,5 87,5 Comment: Under 40 years old is rare (1.6%), male is seen mainly with 95.3% of cases, the proportion of patients with a history of smoking is high (87.5%) Table 3.2: Clinical symptoms Clinical symptoms Respiratory symptoms Symptoms and syndromes due to compression and invasion in the thoracic cavity Systemic symptoms n=64 % Cough Dyspne Blood cough Chest pain 37 19 57,8 3,1 1,6 29,7 Hoarseness 3,1 Fatigue anorexia weight loss 25 26 22 35 29 42 22 39,1 40,6 34,4 0,0 56,3 43,7 65,6 34,4 Paraneoplastic syndrome Performance status Ưeight loss ECOG = ECOG = weight loss under 5% weight loss over 5% Comment: Dry cough is the most common symptom, accounting for 57.8% Other common non-specific systemic symptoms were fatigue (39.1%), anorexia (40.6%) and weight loss 34.4% In this study, we did not encounter any case of paraneoplastic syndrome Performance status (PS) ECOG = accounted for 56.3% and ECOG = 11 accounted for 43.7% 34.4% of patients had weight loss over 5% before treatment Table 3.3: Work-up Chest CT scan (n=64) n % < 5cm 31 48,4 5-7 cm 24 37,5 Tumor size > 7cm 14,1 Invading the Yes 44 68,9 surrounding 20 31,1 No organization Bronchoscopy (n=64) n % Convexity with superficial 99 87,6 ulceration Image Tumor ulcers 14 12,4 Infiltration 0 Tumor Markers n % Normal 28 43,7 NSE Elevated (>20 ng/ml) 36 56,3 Normal 16 25,0 Pro-GRP Elevated (>50 ng/ml) 48 75,0 Comment: The average tumor size before treatment was quite large 11.3 ± 2.3 cm, most of which had necrosis in the tumor (85.1%) Histopathology of rhabdoid cells accounted for the majority (68.6%), mitotic index was high > 5/50 microfield (51.1%) Table 3.4: Disease stage Disease stage n=64 % Tumor stage – T Node stage – N Disease stage T1 T2 T3 T4 N1 N2 N3 Giai đoạn II Giai đoạn IIIA Giai đoạn IIIB 11 37 45 13 36 23 14,1 17,2 57,8 10,9 9,4 70,3 13,8 7,8 56,3 35,9 Comment: Stage III accounts for 92.2%; stage IIIA accounted for the highest 56.3% Stage II accounts for only 7.8% 12 Tumor in stage T3 accounted for the highest rate with 57.8% Node N2 accounts for a high rate with 70.3% 3.2 TREATMENT RESULTS 3.2.1 Response to treatment * Response rate Table 3.5 Response rate Response Completed Response Partial Response Stable disease Progression disease Total Số BN (n=64) 35 26 64 Tỷ lệ (%) 54,6 40,7 3,1 1,6 100 % tumor shinked Comment: The rate of complete response was 95.3%, in which the complete response reached 35/64 patients, accounting for 54.6% Partial response rate 40.7% 100 90 80 70 60 50 40 30 20 10 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 Progressed disease Stable disease Partial reponse Completed response Figure 3.1 The extent of tumor size reduction compared to before treatment 13 * Relating response to a number of factors Table 3.6 Relating response to a number of factors < 50 ≥ 50 Yes Completed response (45,5) 30 (56,6) 12 (54,5) No 24(57,1) Factos Age Weight loss more than 5% PS = PS = Elevated NSE Normal 60Gy Radiatin dose < 60 Gy cycle No.chem otherapy < cycle Total PS 22 (61,1) 13 (46,4) 18 (50) 17 (60,7) 32 (57,1) (37,5) 31 (53,4) (66,7) 35 (54,7) Non-completed Total P response (55,5) 11 (100%) > 0,05 23 (43,4) 53 (100%) 10 (45,5) 22 (100%) > 0,05 18 (42,9) 42 (100%) 14 (30,9) 15 (53,6) 18 (50) 11 (39,3) 24 (42,9) (62,5) 27 (46,6) (33,3) 29 (45,3) 36 (100%) < 0,05 28 (100%) 36 (100%) > 0,05 28 (100%) 56 (100%) > 0,05 (100%) 58 (100%) > 0,05 (100%) 64 (100%) Comment: The group of patients with PS = had a higher complete response rate than the group of patients with PS = The difference was statistically significant with p 50 PS = PS = Stage II Stage IIIA Stage IIIB N1-2 N3 Completed response Non-completed response ≥ 60 Gy < 60 Gy cycle < cycle Harard ratio (HR) 1,354 1,215 1,665 2,522 1,219 1,925 1,378 1,592 Confidence interval (95% CI) 0,547 – 1,933 0,854 – 1,413 1,060 – 2,614 1,675 – 3,798 0,852 – 1,860 1,311 – 2,826 0,925 – 1,852 1,110 – 1,915 p 0,486 0,711 0,001 0,071 0,001 0,064 0,026 Comment: Disease stage, response to treatment and full cycles of chemotherapy are independent prognostic factors affecting the patient's ASD in multivariable analysis (p 50 PS = PS = Stage II Stage IIIA Stage IIIB N1-2 N3 Harard ratio (HR) 1,144 1,725 1,857 2,972 2,171 Confidence interval (95% CI) 0,905 - 1,399 0,961 - 3,095 p 0,511 0,068 1,110 – 3,107 2,405 - 6,562 0,001 1,233 – 3,823 0,007 16 Completed response 0,018 Non-completed response 2,086 1,3345 – 3,236 ≥ 60 Gy Radiatin dose 0,844 < 60 Gy 1,054 0,625 – 1,777 cycle No.chemotherapy 0,04 < cycle 1,709 1,510 – 2,985 Comment: Disease stage, degree of lymph node metastasis, response to treatment and complete cycles of chemotherapy are independent prognostic factors affecting patient's TB disease in multivariable analysis (p