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.Tóm tắt luận án Tiếng Anh

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 MEDICINE T

HA NOI - 2022

THE STUDY IS COMPLETED AT

HA NOI MEDICAL UNIVERSITY

Mentor:

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:

1 National Library

2 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 2 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

withCisplatin-Etoposide regimen

These new findings of the thesis:

1 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

2 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 progression-free survival was early stage, response to treatment and full 4 cycles of chemotherapy Factors affecting overall survival are stage of disease, lymph node metastasis, response to treatment and complete 4 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 7 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 2 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 2 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

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 1 irradiation field

1.5 Differential diagnosis: NSCLC, neuroendocrine tumor, hamartoma 1.6 Prognostic factors: female, age <70 years, normal LDH quantification, stage 1

1.7 Treatment

1.7.1 The principles of treatment

Simultaneous chemotherapy and radiotherapy plays the most important role Prophylactic brain radiation for controlled cases Surgery is only of little value in some cases, after surgery adjuvant chemotherapy is required

1.7.2 Methods of treatment

1.7.3 Limitted stage: concurrent chemotherapy and radiotherapy is the

standard treatment method, widely applied in countries around the world

1.8 Research in the world and in Vietnam on concurrent chemo-radio therapy for limitted-stage small cell lung cancer

1.8.1 International study

Currently, concurrent chemoradiotherapy with Etoposide/Cisplatin (EP) regimen, in which radiation therapy is carried out concurrently with chemotherapy in cycles 1 and 2, is the standard regimen in the treatment of small cell lung cancer localization phase

To date, 8 clinical trials and 2 meta-analytical studies have been performed to determine the timing of chest radiotherapy with chemotherapy for locally advanced small cell lung cancer In which, 2 studies with the most complete design and clearest results include:

Phase III clinical trial study was conducted in Japan, randomized to compare the effectiveness of concurrent chemoradiotherapy and alternate chemoradiotherapy in the focal stage In this study, all patients received 45Gy radiation therapy with 1.5Gy fraction x 2 times/day, chemotherapy using Etoposide-Cisplatin regimen x 4 cycles The first group received concurrent chemoradiotherapy starting from day 1 with EP chemotherapy every 4 weeks The second group received rotation therapy, radiation therapy was conducted after the end of 4 cycles of EP chemotherapy every 3 weeks The study results showed that the average survival time of the group receiving chemotherapy and radiation therapy was higher than that of the group receiving alternating chemotherapy and radiation, 27 months compared to 20 months

A second clinical trial was conducted in Canada to compare earlier or later concurrent chemoradiotherapy being more effective In this study, radiotherapy was administered in fractions of 3Gy/day with a total dose of 45Gy for 15 days Chemotherapy is carried out early at the 3rd or 15th week The study results show that the group receiving chemotherapy and radiation therapy earlier at the same time has a higher survival result with a median survival of 21 months compared with 16 months of late treatment group, the difference is significant with p=0.008 Two meta-analytical studies demonstrating the role of early radiotherapy in the first cycle of chemotherapy include: First, the meta-analytical study of Fried et al (2004) with more than 1500 patients showed that , radiotherapy early in cycle 1 or 2 of chemotherapy improves survival compared with radiation therapy later or radiotherapy alternately after the end

of chemotherapy The 2nd pooled study was a source-based analysis

The accompanying chemotherapy regimens for the localized phase, chemoradiotherapy and EP chemotherapy are still considered and standard regimens

With the EP chemotherapy regimen, the toxicity causing esophagitis, respiratory toxicity and hematological toxicity was higher Standard dose and dose fractionation for concurrent chemotherapy and radiotherapy for localized small cell lung cancer is still a hot issue and is under extensive research Small cell lung cancer is very sensitive to radiation, which suggests that high-dose radiotherapy in a short time will be more effective and less toxic to healthy tissues

The first study was performed from 1989 to 1992 with 417 patients randomly assigned to receive intermittent high-dose concurrent chemoradiotherapy compared with standard daily-dose radiotherapy in patients with locally advanced TCC In this study, all patients received chemotherapy with EP x 4 cycles and radiation therapy was started right from the 1st cycle of chemotherapy One group received daily radiotherapy at 1.8Gy for a total dose

of 45Gy for 5 weeks The second group received radiation therapy twice a day,

divided dose 1.5Gy total dose 45Gy for 3 weeks Respondents received prophylactic brain radiotherapy in both groups The results showed that the overall survival time in the group receiving radiation therapy twice a day was higher than that in the group receiving radiation therapy daily, the 5-year overall survival rate was 26% compared with 16% The recurrence rate was also lower in the twice-daily radiotherapy group, 36% versus 52% Toxicity was observed at a higher rate in the twice-daily radiotherapy group with grade III esophagitis rate of 26% compared with 11% in the once-daily radiotherapy group However, late toxicity or irreversible toxicity was similar in both groups This study gave a better 5-year overall survival than previous studies Therefore, concurrent chemoradiotherapy for localized small-small TTN is also more applicable

1.8.2 Vietnamese study

The standard regimen for treatment of localized small cell lung cancer

is concurrent chemoradiotherapy, and has been applied in countries around the world since the early years of the 20th century, but in our country, the treatment also has many limitations Therefore, previous studies on the treatment of localized small cell lung cancer were mainly combined treatment, often with alternate chemotherapy and radiotherapy, with limited treatment results From 2000-2010, at K hospital, there were a few studies on alternating chemotherapy and radiotherapy with CAV or EP chemotherapy regimens and thoracic radiotherapy, the response rate obtained was still limited with CAV or

EP chemotherapy regimens 64.7% In 2008, Vo Van Xuan, Nguyen Ba Duc and CS reported the results of treatment with CAV and EP regimens in combination with radiotherapy for 57 patients, showing that EP regimen has good survival results at 2 years than the CAV regimen was 43.5% and 8.82%, respectively Dang Thanh Hong et al (2004) reported the results of treatment of

107 patients with localized cancer with chemotherapy and radiotherapy, showing that the 2-year survival rate is 15%

From 2010 to present, thanks to the advancement in radiation therapy, with 3D radiotherapy machine or IMRT Simultaneously with supportive drugs during treatment, the basic concurrent chemoradiotherapy regimen has been applied in clinical practice However, the reports are only small, clinical case studies, there are not enough studies to evaluate the results of concurrent chemotherapy and radiotherapy for small cell lung cancer

CHAPTER 2: MATERIAL AND METHOD

2.1 Patients

The patient with confirmed diagnosis of limitted-stage SCLC was treated with chemotherapy and radiotherapy concurrently with the Etoposide - Cisplatin regimen at K hospital from January 2015 to December 2020

* Selection criteria

- Diagnosis: small cell lung cancer with limitted stage according to VALSG staging guidelines (the disease is within the limits of being covered by a radical irradiation field)

- Histopathological results: small cell carcinoma - according to histopathological classification WHO - 2015

- Age ≥ 18

- Be treated concurrent chemoradiation with Etoposide-Cisplatin regimen Radiation therapy should be started at the same time as chemotherapy

- Good general condition (PS ECOG 0 - 2 according to WHO scale)

- Organ and bone marrow function within limits allowing concurrent chemotherapy and radiotherapy: Hemoglobin ≥ 9.0 g/dL; quantity of information report ≥ 1.5 G/L; platelet count ≥ 100 G/L; Serum total bilirubin ≤ 1.5 times upper limit of normal, AST/ALT ≤ 2.5 times upper limit of normal; glomerular filtration rate > 40 mL/min according to the Cockcroft-Gault formula

- Volunteer to participate in research and have complete records

- 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 5 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:

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

Etoposide

Radiation

Ngày 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Cisplatin

Etoposide

Radiation

Ngày 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Cisplatin

Etoposide

Radiation

Ngày 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Cisplatin

Etoposide

Radiation

2 2

) 2 / 1 (

).(

)1.(





p

p p Z



- Radiotherapy procedure:

All patients participating in the study will be treated on a 3D-CRT linear accelerator with an energy level of 15Mv according to a radiotherapy procedure that includes the following steps:

Step 1: Record image data – Simulated CT scan

Step 2: Radiotherapy planning system

Step 3: Determine the treatment volumes

Step 4: Total dose and fractionation of radiation therapy

Step 5: Plan your radiotherapy

Step 6: Create shielding blocks

Step 7: Simulate test

Step 8: Radiate and monitor treatment

Step 9: Adjust your radiotherapy plan

2.2.4 Evaluation of treatment results and undesiable effects:

- Assessment of response according to RECIST 1.1: response rate, related to response with a number of factors

- Non-progressive survival time, total survival time

- Univariate and multivariate analysis to find out related factors affecting survival

- Some undesirable effects according to NCI's toxicity assessment criteria version 4.0

2.3 Data analysis

The information was collected through medical record

- Data were input on a database and analyzed by software SPSS, v 16.0

- Using χ2, test – student, log rank to evaluate differences between the groups

- P - values of less than 0.05 were considered significant

Survival time using Kaplan-Meier method Univariate analysis: Use the Log-rank test to compare survival curves between groups Multivariate analysis: Using Cox regression model with 95% confidence level (p = 0.05).- Study results are displayed in figures, charts, percentage (%), medium ± standard deviation

CHAPTER 3: RESULT 3.1 CLINICAL CHARACTERISTICS

Table 3.1: Patient characteristics

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

compression and invasion

in the thoracic cavity

Ưeight loss weight loss under 5% 42 65,6

weight loss over 5% 22 34,4

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 = 0 accounted for 56.3% and ECOG = 1

accounted for 43.7% 34.4% of patients had weight loss over 5% before treatment

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

Comment: Stage III accounts for 92.2%; stage IIIA accounted for the

highest 56.3% Stage II accounts for only 7.8%