Nghiên cứu các đặc điểm lâm sàng, cận lâm sàng, đột biến gen braf và kết quả điều trị ung thư tuyến giáp biệt ttta

INTRODUCTION Thyroid cancer accounts for 3% of malignancies and accounts for less than 0.4% of cancer deaths globally According to GLOBOCAN, data show that the annual incidence of the disease increases by about 2% As of 2020, thyroid cancer is the 5th most common cancer in women For differentiated thyroid cancer, the main treatment methods include: surgery, radioactive iodine therapy and TSH suppressed therapy For the majority of patients with differentiated thyroid cancer, the above-mentioned treatments are highly effective and the 5-year survival rate is about 83-98% The concept of radioactive iodine refractory differentiated thyroid cancer has been introduced in recent years for differentiated thyroid cancer patients with recurrent, metastatic disease which have not responded to 131I therapy The criteria for defining radioactive iodine refractory have been presented in the 2015 Guidelines for Diagnosis and Treatment of Differentiated Thyroid Cancer of the American Thyroid Association According to studies, about 5-15% of patients became radioactive iodine refractory and the prognosis of these patients is very poor, the survival time of patients with radioactive iodine refractory with distant metastases is about 2.5-3.5 years The ability to absorb radioactive iodine of thyroid cancer cells is the centre of patients’ treatment and monitor Several gene mutations that play an important role in the pathogenesis of thyroid cancer have been discovered, of which the most interesting is the BRAF V600E gene mutation Studies have shown an association between the BRAF V600E mutation and the histopathology of papillary thyroid cancer with invasive features, increased risk of recurrence, loss of radioactive iodine capture and treatment failure Diagnosis and treatment of differentiated thyroid cancer patients with metastatic, recurrent, and radioactive iodine refractory are currently still challenging for clinical practice In this case, local treatments such as surgery, external radiation therapy and targeted therapy are often indicated In Vietnam, up to now, there have not been many studies on radioactive iodine refractory differentiated thyroid cancer We research the topic with objectives: Comment on some clinical, subclinical characteristics and BRAF V600E mutations in operable radioactive iodine refractory differentiated thyroid cancer patients Evaluation of the treatment results of the study subjects The urgency of the thesis Differentiated thyroid cancer (DTC) is the most common disease of the endocrine system and is on the rise globally Thanks to advances in thyroid surgery and the treatment of 131I diseases, the prognosis is good However, there are - 15% cases of disease that recur, metastasize and not respond to radioactive iodine treatment with poor prognosis There is no standard treatment for this group of patients With lesions in the cervical lymphnodes metastatic or thyroid bed, surgery is the first choice because it is possible for eradication if the lesion could be completely removed Mutations in the BRAF V600E gene are associated with pathogenesis, disease progression and open the way to targeted therapy with tyrosine kinase inhibitors It is necessary to learn about the clinical and laboratory characteristics and identify the BRAF V600E mutation in the group of patients with RAI refractory differentiated thyroid cancer At the same time, evaluate the treatment response on the group of patients with indications for surgery so that clinicians and nuclear medicine doctors can choose appropriate therapy, monitor, manage treatment indications and better prognosis of patients New contributions of the thesis - The thesis has contributed to providing information on clinical and subclinical characteristics of the group of patients with RAI refractory differentiated thyroid cancer, in which a high serum Tg level after 131I treatment will suggest cases of radioactive iodine refractory Imaging tests such as ultrasound, CT, PET/CT will be valuable in determining the location and number of recurrent, metastatic lesions The rate of BRAF V600E mutation is very high (76.2%) in this group of patients, however, we have not found an association between the BRAF V600E gene mutation and the clinical and histological characteristics of these patients with RAI refractory differentiated thyroid cancer - The study contributed to the surgical results of recurrent/metastatic in with RAI refractory DTC patients After surgery, the rate of excellent, indetermiate and biochemical incomplete response was quite high, only 18.8% have structural incomplete response After surgery for recurrence/metastasis, the patient continued to be treated with TSH suppression or TSH suppression + 131I or TSH suppression + external radiation therapy Response assessment showed a mean progression-free survival (PFS) of 45.37 ± 2.42 months, median of 53.83 months Independent prognostic factors for progression-free survival includes: age over 45 years, postoperative response and postoperative unstimulated Tg reduction Thesis layout The thesis consists of 133 pages: pages of introduction, 33 pages of overview, 15 pages of research subjects and methods, 37 pages of results, 44 pages of discussion, pages of conclusion; includes 38 tables, 15 charts, diagrams, figures and 164 references in Vietnamese and English CHAPTER 1: OVERVIEW 1.1 Radioiodine refractory differentiated thyroid cancer For more than 50 years, radioactive iodine has been used to treat differentiated thyroid cancer after total thyroidectomy and neck lymph node dissection The treatmeant is very effective in lesions that uptake radioactive iodine well Considerable effectiveness are often seen in young, highly differentiated, papillary thyroid cancer patients In these patients, radioactive iodine produced a good response to the lesions leading to stable disease and prolonged survival However, radioiodine therapy is often less effective in elderly patients who have large residual tumor volumes and poorly differentiation These cases often less radioactive iodine uptake and the effectiveness of 131I treatment is not high Furthermore, repeated treatment with RAI will lead to a decrease in the effectiveness of the treatment because the tumor lesions will gradually lose their ability to uptake radioactive iodine For the majority of patients with DTC, the above-mentioned treatments are highly effective, and the 5-year survival rate is about 83-98% in patients under 80 years of age The follicular cells of thyroid absorb radioactive iodine and the beta rays of 131I will kill the remaining cancer cells at the tumor site after surgery, so radioactive iodine treatment is the adjuvant treatment therapy after surgery However, about 5-15% of patients are resistant to 131I and the prognosis of these patients is quite poor The 5-year survival rate in patients with RAI-R differentiated thyroid cancer is 66% and the 10year survival rate is about 10% Studies show that the survival time of patients with RAI-R differentiated thyroid cancer with distant metastases is about 2.5-3.5 years on average The clinically accepted definition of RAI refractory is a nonradioactive uptake malignant lesions on scintigraphy following treatment with a dose of 131I greater than 30 mCi or after several diagnostic scintigraphy The American Thyroid Association (ATA) issued a standard for radioactive iodine refractory in 2015 giudeline, which includes the following four criteria: (1) the malignant/ metastatic tissue does not ever concentrate RAI (no uptake outside the thyroid bed at the first therapetic whole body scan), (2) the tumor tissue lose the ability to concentrate RAI after previous evident of RAI-avid disease, (3) RAI is concentrated in some lesions but not in others, and (4) metastatic disease progress despite significant concentrate of RAI 1.2 Mutation in the BRAF V600E gene in radioactive iodine refractory differentiated thyroid carcinoma The BRAF (B-type Raf kinase) gene is located on chromosome 7, with a coding region containing 18 exons, 2478 bp in size, and codes for a protein of 766 amino acids with a molecular weight of 84436 Daltons A mutation at the T1799A position on the BRAF gene sequence increases kinase enzyme activity and activates the MAPK signaling pathway, which plays a role in cell proliferation, differentiation, tumorigenesis and leads to progression of thyroid cancer The activation of the BRAF V600E gene in thyroid cancer was first reported in 2003, and the BRAF V600E mutation plays an important role not only in thyroid cancer occurrence but also in promoting invasion and progression Studies also point to the role of the BRAF V600E mutation in reducing NIS gene expression, which is crucial in thyroid hormone synthesis, making cells less sensitive to radioactive iodine and responsible for the mechanism of RAI refractory in differentiated thyroid cancer 1.3 Treatment of RAI refractory differentiated thyroid cancer In clinical practice, the decision of treatment intervention; How to treat patients with RAI refractory differentiated thyroid cancer is a matter of careful consideration In the face of a patient with RAI refractory recurrent/metastatic lesions we need to consider the following factors: - Location of lesions: recurrence in the thyroid bed, cervical lymph nodes or metastatic lesions: lungs, bones, brain - Size of lesions: lesions less than 1cm, especially with cervical lymph nodes can be closely monitored without intervention - Level of lesion progression: lesions that have progressed (assessed by RECIST criteria) within 6-14 months after the most recent therapeutic dose of 131I are considered for intervention measures - Potentially invasive, causing symptoms that affect the patient's life: recurrent lesions in the thyroid bed if not treated early can lead to invasion, tracheal compression, life-threatening Large lesions in the brain, lungs, mediastinal ganglia and metastatic lesions in the spinal cord are also potential sites of compression, requiring early intervention Possible treatment measures for patients with RAI refractory differentiated thyroid cancer: close follow-up of the patient (TSH suppressed therapy), surgical removal of recurrent/metastatic lesions, continued radioactive iodine treatment, external beam radio therapy, locally treatments (percutaneous ethanol injection, radiofrequency ablation, embolization ), chemotherapy or targeted therapy with tyrosine kinase inhibitors (TKIs) CHAPTER 2: RESEARCH SUBJECTS AND METHODS 2.1 Research subjects 123 patients were diagnosed with papillary or follicular differentiated thyroid cancer by histopathological results after undergoing total thyroidectomy and neck dissection All patients were treated with 131I and were found to be RAI refractory * Inclusion criteria - Patients who had total thyroidectomy and neck dissection and received 131I treatment for differentiated thyroid cancer were included in the study - Patients were evaluated RAI refractory based on the 2015 ATA guideline criteria - Patients with recurrent or metastatic lesions, surgical removal was performed and they were followed up and treated according to guidelines - All patients had complete clinical and histopathological information available - Patients with no other cancers and severe chronic diseases - Over 18 years old - Only patients who agreed to participate in the study were included *Exclusion criteria - Patients whose histopathological classification of thyroid cancer is not papillary or follicular carcinoma - Patients with differentiated thyroid cancer who have not undergone surgery or received 131I treatment - Patients under 18 years old - Patients not have a detailed record of the necessary information - Patient did not agree to participate in the study 2.2 Research Methods - Study design: descriptive study with longitudinal follow-up - Study duration: from January 01, 2015 to December 31, 2020 - Sample size: calculated using the formula for estimating a sample size for prevalence 𝑵 = 𝒁𝟐 𝟏−𝜶⁄𝟐 𝒑(𝟏 − 𝒑) 𝒅𝟐 According to Chiapponi C.(2021), the PFS prevalence of RAI-R patients was 6 % In the present study, p = 0.666 n: study sample size 𝛼 (level of significance): 0.05 𝑍 (1-α/2): alpha level’s z-score, with  = 0.05, 𝑍 (1-α/2) = 1,962 for the confident interval of 95% d: margin of error, in the present study, d = 0.1 Using the formula, the minimum number of patients needed to be recruited for the study was: n = 86 patients In this stydy, n = 123 patients 2.3 Step of study - Patients’ history can be taken and clinical examination, collect information about: + Age, gender + Time of surgery for total thyroidectomy, surgical method, tumor status, regional lymph node status recorded during initial surgery + Time from diagnosis of thyroid cancer to the time of RAI refractory + Number of treatments 131I, total treatment cummulated dose + Quantitative test of serum Tg and anti-Tg before 131I treatment and at the time of diagnosis of RAI refractory + Results of posttherapy whole body scan with 131I + Record the results: neck ultrasound, abdominal ultrasound, CT scan, PET/CT scan to assess metastasis + Assess the number and size of lesions on imaging tests + Staging according to the American Joint Committee on Cancer 2010 (AJCC7) - Patients will undergo surgery to remove recurrent lesions, cervical lymph nodes, or metastases at locations that can be surgically intervened - Information about surgical location, surgical method, and information about lesions recorded during surgery - Postoperative specimens will be tested for histophathology and classified into histopathological variants and malignancy grades according to WHO 2017 standards at the Department of Pathology - Samples with recurrence or metastasis will be tested for BRAF V600E gene mutations using Real-time PCR technique at the Department of Molecular Biology, Military Hospital 108 - Using classification of response to the therapy criteria according to the 2015 ATA guideline - After evaluating the surgical results, the patient's next treatment method will be decided by the Thyroid Cancer Tumor Board based on the surgical process, the assessment of the postoperative response, and the patient's progress: Hormone therapy for patients with excellent response, indeterminate response, incomplete biochemical response External radiation therapy for patients with incomplete structural response, during surgery, the surgeon described the lesion as invading surrounding tissues and not being able to completely remove the lesion Administer 131I in patients with RAI avid lesions (carefully consider in patients with a total dose exceeding 600mCi) or empiric dose in patients with negative diagnostic scans, high serum Tg - Evaluation of the rate and overall survival (OS) and progression-free survival (PFS) - Overall survival (OS) and progression-free (PFS) rates at 12 months, 24 months, 36 months, 48 months, 60 months - Disease progression-free survival rate by several factors: age, gender, postoperative response, stimulated Tg, unstimulated Tg after surgery, BRAF V600E mutation, histopathological variant, total dose 131 I accumulated, distant metastasis at the time of RAI refractory - Analysis of prognostic value of prognostic factors and multivariate analysis included factors: age, gender, clinical response, Tg response after surgery, BRAF V600E mutation, histopathological variation, distant metastasis 2.3 Data processing: using statistical software SPSS 20.0 Evaluation: p < 0.05: the difference is statistically significant p > 0.05: the difference is not statistically significant 2.4 Research ethics: The study was approved by the Ethics Committee of Hanoi Medical University CHAPTER 3: RESEARCH RESULTS 3.1 Clinical, laboratory and BRAF V600E mutations in study patients 3.1.1 Clinical features - Patients with RAI refractory differentiated thyroid cancer had an average age of 47.2 ±14.6 year The proportion of patients < 45 and 45≥ years old was similar at both the time of diagnosis of primary tumor and RAI refractory, the female/male ratio was 3.9/1 - Characteristics of tumors, cervical lymph nodes and metastases at the time of diagnosis of thyroid cancer: 32.5% of patients had tumors evaluated in surgery as T3-4; the percentage of capsular invasion was 28.4%, 21.9% had extrathyroidal invasion Most patients (60.2%) had lymph node metastasis, 2.4% had distant metastasis 55.3% of patients in stage I; 26.8% of patients in stage IV; high risk of recurrence was seen in 82.9% of patients - The average number of 131I treatments before being diagnosed RAI refractory was 2.76 ± 1.3; 78.9% of patients were treated from to times; 2.4% of patients were treated with 131I more than times The cumulated therapeutic dose of 131I before RAI-R was 358.6 mCi The majority of patients (70.8%) received a cumulative dose of