Đánh giá kết quả điều trị ung thư dạ dày giai đoạn muộn bằng phác đồ TCX TT TIENG ANH

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY NGUYEN TRONG HIEU EVALUATION OF THE RESULTS OF TREATMENT OF LATE STAGE GASTRIC CANCER IN USING TCX REGIMEN THE DOCTORAL DISSERTATION SUMMARY HANOI– 2021 MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY NGUYEN TRONG HIEU EVALUATION OF THE RESULTS OF TREATMENT OF LATE STAGE GASTRIC CANCER IN USING TCX REGIMEN Specialist: Oncology No: 62720149 THE DOCTORAL DISSERTATION SUMMARY HANOI– 2021 THIS RESEARCH IS PRESENTED AT HANOI MEDICAL UNIVERSITY Doctoral advisor: Assoc Prof Dr Tran Dang Khoa Prof Dr Tran Thang 1st Opponent: 2nd Opponent: 3rd Opponent: The dissertation is defended before the Committee of Hanoi Medical University At : on / / For further detail of the dissertation, please search at: - The national library - The library of Hanoi Medical University NEW CONTRIBUTION OF THE THESIS TCX regimen showed significant improvement in symptoms, progression-free survival and overall survival The adverse effects of TCX regimens were lower than those of other triple regimens in terms of both frequency and severity of symptoms Therefore, physicians can consider the effectiveness and safety of the regimen for clinical use STRUCTURE OF THE THESIS The thesis has 133 pages, including: introduction and research objectives (2 pages), overview (43 pages), participants and methods (23 pages), research results (22 pages), discussion (40 pages), conclusion (2 pages) and recommendations (1 page) The thesis has 30 tables, charts, 16 images, 239 references, of which 39 are Vietnamese and 200 are in English INTRODUCTION Gastric cancer is a common cancer in the world as it is in Vietnam In Vietnam, gastric cancer ranks fourth in incidence and 3rd in mortality Most patients were admitted at their late stage, thus, chemotherapy played the most important role in improving symptoms and prolonging their survival times A number of studies had investigated the effect of Paclitaxel in the combination with Platinum and Capecitabin (TCX) in the treatment of late stage gastric cancer, in which the results were promising Besides, this regimen was better tolerance with less frequent, less severe, better controlled toxicity which allowed patients to complete more chemotherapy cycles, thus, it seems to be a more appropriate regimen for Vietnamese patients in general and patients at their late stage with poor performance status in particular Up until now, no studies have been conducted to investigate the effect and toxicity of the TCX regimen in the treatment of late stage gastric cancer The aim of this study was to evaluate: The treatment outcomes and associating factors of TCX regimen in late stage gastric patients in Hanoi Oncology Hospital from 2016 to 2019 The toxicity of TCX regimen in the above participants CHAPTER BACKGROUND 1.1 OVERVIEW OF GASTRIC CANCER Gastric cancer is a malignancy of the gastrointestinal tract Late stage gastric cancer includes cases where the disease is locally advanced and invasive, no longer capable of radical surgery; cases with distant metastases; or cases that have undergone radical surgery but have local recurrence or metastasis The disease is common in men, aged 50 to 70 years, and is developing in East Asia, South America and Eastern Europe The cause of gastric cancer is currently unknown The pathogenesis of the disease is a complex process caused by many factors It is a combination of factors originating from the environment with genetic and genetic modifications 1.2 DIAGNOSIS 1.2.1 Signs and symptoms Common symptoms are: abdominal pain, bloating, indigestion, nausea, vomiting, loss of appetite, weight loss, possibly bloody vomiting, black stools due to gastrointestinal bleeding Signs of metastasis are sometimes the first manifestations Symptoms may include palpable abdominal tumor, hepatomegaly with liver metastases, jaundice when tumor invades biliary tract causing biliary obstruction, ascites, left supraclavicular lymph nodes, and periumbilical lymph nodes 1.2.2 Blood tests and images study Endoscopy with biopsy: is the most important tool in the diagnosis of gastric cancer, both to evaluate the macroscopic features of the tumor and to biopsy the suspected lesion for pathology Endoscopic ultrasound: is an important tool in determining the extent of tumor invasion; metastasis to surrounding lymph nodes/organs, abdominal cavity Tumor markers: mainly help in prognosis and follow-up after treatment such as CEA, CA19-9 and CA 72-4 Pathology: the gold standard for definitive diagnosis, and histopathological classification helps in treatment and prognosis Molecular Biology: Levels of HER2; The expression of PDL1/dMMR has therapeutic significance CT, MRI, PET-CT, chest X-ray, abdominal ultrasound, laparoscopy, bone scan, etc are necessary to evaluate metastasis 1.2.3 Staging diagnosis Currently, the staging diagnosis is applied based on the TNM classification scale according to AJCC 2017 1.3 TREATMENT 1.3.1 The principles of treatment Combination of methods: surgery, radiotherapy, chemotherapy and biological treatment The treatment depends on the stage of the disease, the purpose of treatment and the condition of patient 1.3.2 Treatment options Surgery: Curative surgery is the method of choice in the early stage or in the advanced stage, in which the tumor is still localized and has not metastasized In the late stages, surgery is valuable in symptomatic treatment Radiation: Radiotherapy alone is mainly symptomatic treatment Radiation therapy can also combined with chemotherapy in adjuvant and neo-adjuvant therapy Chemotherapy and radiotherapy combination: the local gastric cancer cannot be surgically removed or the patient's condition does not allow for surgery; or in case of positive surgical margin Neo-adjuvant chemotherapy: Reduce disease stage, increase the possibility of curative surgery, reduce preoperative micrometastasis, reduce local recurrence rate and distant metastasis, improve theoverall survival and the sensitivity to chemicals Adjuvant chemotherapy: eliminate remaining cancer cells, reduce the risk of recurrence, improve survival time 1.3.3 Treatment options for late stage gastric cancer 1.3.3.1 The role of chemotherapy Results from many clinical trials showed that patients with advanced gastric cancer which unable to undergo curative surgery but can tolerate chemotherapy will experience small but clear benefits in terms of survival time and quality of life; compared to palliative care alone Patients with a KPS score of 60 or higher or an ECOG score of or less may be indicated for chemotherapy 1.3.3.2 Chemotherapy regimens -Mono regimen: Fluoropyrimidine (5-FU, UFT, S-1), Taxane, Irinotecan, Anthracycline -Doublet regimen: fluoropyrimidine and cisplatin, fluoropyrimidine and oxaliplatin, paclitaxel in combination with cisplatin/carboplatin, docetaxel with cisplatin Trastuzumab is also recommended along with chemotherapy in cases where there is evidence of Her2-neu overexpression -Tripplet regimen: In general, clinical trials have emphasized the effectiveness of CF, ECF and DCF regimens in the first-line treatment of advanced and metastatic gastric cancer -Biological treatment: Targeted factor is EGFR/VEGF -Immunotherapy: Pembrolizumab; Nivolumab; Avelumab 1.3.4 Progression and prognosis -Progression: Gastric cancer after treatment can progress, recur and metastasize The disease may recur locally, regionally or systemically -Prognosis: generally have a poor prognosis Prognostic factors are categorized into three groups: factors related to disease stage, factors related to the patient, and factors related to treatment 1.4 OVERVIEW OF TCX REGIMEN 1.4.1 The original of TCX regimen The DCF regimen is approved as one of the standard combination in the treatment of late stage gastric cancer However, the undesirable effects of this regimen are relatively obvious, so its use in clinical practice is limited As a result, DCF regimen had been modified in several ways including the use of variable dose docetaxel with cisplatin in combination with oral capecitabine (DCX regimen) With the emergence of many new generation anti-cancer drugs and the expectation of increasing treatment response rates as well as minimizing treatment toxicity, treatment regimens have been partially revised Carboplatin is the next generation of cisplatin that has the obvious advantage of reducing unwanted effects compared to cisplatin, especially on the kidney functions Paclitaxel belongs to the same group and has a similar mechanism of action with Docetaxel Data of various studies showed that paclitaxel is an effect treatment of choice in patients with advanced gastric cancer with a low incidence of adverse events when used as monotherapy Therefore, in order to ameliorate the adverse effects of triple therapy, the combination of capecitabine, carboplatin and paclitaxel (TCX regimen) is proposed There had been a number of studies applying this regimen in patients with esophageal and gastric cancer with promising results 1.4.2 Component drugs of the regimen - Paclitaxel: A drug that inhibits the decay of the microtubule reticulum of the chromatin, it stimulates the assembly of microtubule dimers into the microtubule and stabilizes the microtubule network by preventing untwisting In addition, paclitaxel causes the abnormal formation of clusters or clusters of microretinal networks during the cell cycle Indications: Gastric cancer and some other cancers Contraindications: hypersensitivity to paclitaxel; Neutrophils are severely reduced Undesirable effects: nausea, vomiting, hair loss, mucositis, hypersensitivity reactions, sensory disturbances, diarrhea, musculoskeletal pain, decreased leukocyte, platelets, and erythrocyte - Carboplatin: a drug that binds to DNA molecules via alkyl bonds, thereby inhibiting the synthesis through replication or cleavage of DNA molecules, inhibiting the synthesis of DNA and proteins of the cell Indications: gastric cancer, gastroesophageal cancer Contraindications: hypersensitivity to cisplatin and platinum-containing compounds, severe neutropenia, renal failure; pregnant and lactating women Undesirable effects: bone marrow suppression, nausea, vomiting, hair loss, mucositis, increased blood creatinine, increased liver enzymes, peripheral neuropathy - Capecitabine: is a fluoropyrimidine carbamate derivative prepared for oral administration that is tumor-activated and tumorselective cytotoxic The drug is indicated for advanced cases of gastric and colorectal cancer, breast cancer Contraindicated in patients with hypersensitivity to capecitabine or other fluoropyrimidine derivatives; patients with severe renal failure; patients with dihydropyrimidine dehydrogenase deficiency Side effects: dry mouth, abdominal bloating, diarrhea, some neurological and cerebellar abnormalities, marrow failure, skin and subcutaneous tissue abnormalities, liver failure and cholestatic hepatitis CHAPTER PARTICIPANTS AND METHODS 2.1 PARTICIPANTS Patients diagnosed with late stage gastric cancer which unable to undergo curative surgery at Hanoi Oncology Hospital from January 2016 to December 2019 2.1.1 Inclusion criteria -ECOG performance status ≤ -Evidence of gastric carcinoma in pathology -Patients of late stage gastric cancer who were no longer able to undergo curative surgery according to the criteria of NCCN 2011 and the Japan Association of Gastric Cancer -Patients of late stage gastric cancer who had underwent palliative surgery but the gross lesions still remain 2.1.2 Exclusion criteria -Patients diagnosed with late stage gastric cancer who were candidates for curative surgery -Patients treated with TCX regimen of less than cycles -Patients with history of prior chemotherapy treatment -Patients with a second cancer -Patients with cardiovascular diseases -Patients with hematological, hepatic, and renal function were not within normal range that may allow for chemotherapy 2.2 TCX regimen Doses and Time of administration Administration Paclitaxel Anzatax 175mg/m², IV Day Carboplatin Bocartin AUC Day Capecitabine Xalvobin 850 mg/m² BID Day to Day 14 - At least cycles were required, maximum cycles, each cycles were 21 days apart - Carboplatin dose were calculated with AUC = 5, based on the following formula: Drug Brand name Dose (mg) = AUC x [ ( ) ( ) + 25] 2.3 TIME AND LOCATION - Time: From January 2016 to December 2019 - Location: Hanoi Oncology Hospital 2.4 METHODS 2.4.1 Study design: prospective clinical trial 2.4.2 Sample size: were calculated according to the formula n = ( ) ( ) Trong đó: Z: confidence coefficient, Z1 - /2 =1,96, α = 0,05 p: response rate to DCX regimen in patients with late stage gastric cancer according to recent studies with p = 0.72 ε = 0,105 According to the above formula, we had calculated a sample size of 70,2; which were round up to a number of 71 participants 2.4.3 Data collection - Information was collected through pre-designed research medical records - Methods of information collection: Clinical examination, written inquiry and phone calls 2.4.4 Research process - Participants selected in this study were treated with TCX regimen for at least cycles, maximum cycles, each cycle was 21 days apart - The clinical data were evaluated at baseline; before each treatment cycle and at the end of treatment Follow up after treatment was conducted every months 11 Table 3.3 Baseline ECOG performance status (n = 71) ECOG PS n % 8,5 44 62,0 21 29,5 71 100 Total 1,21 0,58 Mean ( SD) Most participants in this study had the performance status of point, with the rate of 62,0%; The mean PS point of the participants was 1,21 0,58 Table 3.4 Histopathology of the participants Histopathology features Maglinancy Histopathology type n % grade Moderately differentiated Low 31 43,7 adenocarcinoma 23 32,4 Low differentiated adenocarcinoma High Squamous cell carcinoma 17 23,9 Total 71 100 Moderately differentiated adenocarcinoma accounted for the highest rate of 43.7% Low malignancy accounted for 43.7% and high malignancy was 56.3% Table 3.5 Staging characteristics of the participants (n = 71) Stage n % 20 28,2 T3 20 28,2 T T4a 31 43,6 T4b 10 14,1 N1 23 32,4 N N2 38 53,5 N3 18 25,4 M0 M 53 74,6 M1 71 100 Total 71,8% of the participants were in T4 stage; 53,3% were in N3 stage Most of the participants were in M1 stage with the rate of 74,6% 12 3.1.2 Treatment results and associated factors 3.1.2.1 Treatment response  Objective response Table 3.6 Response rate with chemotherapy Response rate n % Total Complete response 2,8 53,5 Response Partial response 36 50,7 Stable disease 28 39,5 Not 46,5 response Progressive disease 7,0 The rate of patients who responded to treatment was 53,5%; in which the percentage of patients with complete response accounted for 2,8% The disease was stable and progressed in 39,5% and 7% of cases, respectively  Factors associated with respone rate Table 3.7 Multivariate and univariate analysis of factors associated with response rate Factor Age Gender ECOG PS T N M Peritoneal metastatic Hepatic metastatic Histology ≤ 60 > 60 Male Female 0-1 T3 T4 N12 N3 M0 M1 No Yes No Yes Low maglinancy High maglinancy Univariate % p 52,2 0,477 56 51,9 0,431 57,9 56 0,349 47,6 75 0,021 45,1 81,8 < 0,001 28,9 66,7 0,154 49,1 75,7 < 0,001 29,4 57,8 0,242 46,2 100 13,2 < 0,001 Multivariate OR p 0,69 (0,05 - 9,88) 0,79 3,27 (0,15 - 70,74) 0,45 0,89 (0,06 - 13,15) 0,55 (0,02 - 16,34) 0,93 0,73 3,31 (1,24 - 8,85) 0,017 0,41 (0,03 - 4,84) 0,41 13,7 (1,25 - 90,91) 0,043 1,23 (0,09 - 15,41) 0,872 201,86 (10,55 3861) < 0,001 13 Univariate analysis results showed that low T-N stage, no distant metastasis, no peritoneal metastasis and low malignancy histology were the factors related to treatment response Multivariable regression analysis model showed that the factors without peritoneal metastasis, low N stage and low histopathological malignancy were the factors related to treatment response in study subjects with the OR of 11,2; 2,71 and 201,86; respectively The association was statistically significant with p < 0,05 3.12.2 Survival outcomes Figure 3.1 Progression free survival Figure 3.2 Overall survival The estimated mean progression-free survival (PFS) was 6,6 ± 0,5 months (95% CI: 5,7 – 7,5 months) Estimated progression-free survival rate at months, year, and years was 55,1%; 28,5% and 17,5%; respectively The estimated mean overall survival (OS) was 17,9 ± 1,5 months (95% CI: 14,9 – 20,8 months) Overall survival rate at year and years was 67,8% and 31,8%, respectively Table 3.8 Univariate and multivariate COX regression models of factors related to progression-free survival time (PFS) Factor Age Gender ≤ 60 > 60 Male Female Univariate Median p (95%CI) 5,9 (4,3 - 7,4) 0,128 8,3 (5,1 - 11,5) 5,6 (3,6 - 7,6) 0,367 7,1 (4,7 - 9,4) Multivariate HR (95%CI) P 0,72 (0,39 - 1,31) 0,29 2,48 (1,08 - 5,69) 0,03 14 ECOG PS T N M Peritoneal metastatic Hepatic metastatic Histology 0-1 T3 T4 N12 N3 M0 M1 No Yes No Yes Low maglinancy High maglinancy 6,8 (4,1 - 9,5) 6,5 (5,2 - 7,8) 7,0 (3,6 - 10,4) 6,6 (5,2 - 7,9) 10,5 (2,5 - 18,5) 5,8 (4,5 - 7,0) 5,6 (0 - 16,4) 6,6 (5,8 - 7,4) 7,0 (3,9 - 10,1) 6,5 (5,6 - 7,4) 6,6 (5,2 - 7,9) 6,6 (3,6 - 9,6) Yes 10,7 (5,4 - 16,0) No 4,8 (4,0 - 5,9) Respond to treatment 0,114 0,914 0,004 0,097 0,413 0,632 10,7 (5,1 - 16,3) 1,61 (0,88 - 2,95) 0,12 1,26 (0,62 - 2,58) 0,53 1,06 (0,84 - 1,32) 0,65 2,36 (0,88 - 6,38) 0,09 2,78 (1,25 - 6,19) 0,01 1,09 (0,59 - 2,04) 0,77 1,27 (0,41 - 3,92) 0,67 < 0,0001 5,3 (3,7 - 6,8) < 0,0001 6,19 (2,83 - 13,55) < 0,0001 Univariate analysis results showed that low N stage, response to treatment and low grade of malignancy were factors associated with potentially prolonging progression-free survival Meanwhile, Cox multivariable regression analysis model showed that gender female, no peritoneal metastasis, response to treatment were factors related to the ability to prolong progression free survival time; with the HR of 2,48; 2,78 and 6,19 The association was statistically significant with p < 0,05 Table 3.9 Univariate and multivariate COX regression models of factors related to overall survival time (OS) Factor Age Gender ECOG PS T N M ≤ 60 > 60 Male Female 0-1 T3 T4 N12 N3 M0 Univariate Median (95%CI) 17,7 (11,3 - 24,0) 18,1 (12,8 - 23,4) 17,4 (12,6 - 22,7) 18,8 (16,9 - 20,6) 18,8 (11,9 - 25,6) 17,4 (10,2 - 24,6) 23,7 (8,6 - 38,8) 17,9 (14,9 - 20,8) 30,9 (10,9 - 50,8) 14,2 (10,0 - 17,4) 19,3 (8,1 - 30,5) p 0,414 0,706 0,099 0,572 0,001 0,126 Multivariate Median (95%CI) p 0,76 (0,40 - 1,44) 0,402 1,04 (0,51 - 2,13) 2,18 (1,14 - 4,16) 0,91 0,019 0,97 (0,42 - 2,38) 0,998 1,19 (0,91 - 1,57) 0,188 2,25 (0,84 - 6,05) 0,107 15 Peritoneal metastatic Hepatic metastatic Histology Respond to treatment M1 No Yes No Yes Low maglinancy High maglinancy Yes No 16,6 (12,9 - 20,4) 17,7 (9,9 - 25,5) 17,9 (14,9 - 20,8) 15,1 (10,5 - 19,8) 19,3 (16,4 - 22,2) 0,540 0,632 30,9 (21,4 - 40,3) 5,19 (1,93 - 13,99) 0,001 0,55 (0,26 - 1,20) 0,135 3,35 (1,14 - 9,84) 0,028 2,58 (2,86 - 7.37) 0,048 0,000 12,6 (8,7 - 16,5) 26,8 (18,5 - 35,1) 10,4 (14,9 - 20,8) 0,000 Univariate analysis results showed that stage N 1-2, low grade of malignancy, and response to treatment were factors associated with potentially prolonged overall survival Cox multivariate regression analysis model showed that the factors of good performance status, no peritoneal metastasis, low grade of malignancy and response to treatment were factors related to the likelihood of extended overall survival with the HR of 2,18; 5,19; 3,35 and 2,58; respectively The correlation was statistically significant with p < 0,05 3.2 TREATMENT TOXICITY 3.2.1 Clinical toxicity Table 3.10 Clinical toxicity Grade ( n= 71) (%) Toxicity 3-4 Total Nausea/Vomitting 53,5 16,9 4,2 74,6 Diarrhea 14,1 4,2 1,4 19,7 Hand-foot syndrom 25,3 2,8 5,6 33,8 Peripheral neuropathy 32,4 8,5 7,0 47,9 Vomiting was the most common clinical toxicity with the rate of 74,6% The clinical toxicities were mainly encountered in mild and moderate severity 3.2.2 Hepatic and renal toxicity Table 3.11 Hepatic and renal toxicity Grade ( n= 71) (%) Toxicity 3-4 Total SGOT 35,2 9,9 2,8 47,9 SGPT 25,4 7,0 1,4 33,8 Ure 11,3 5,6 16,9 Creatinin 9,9 5,6 15,5 16 No participant in this study had hepatic and renal toxicity of grade The hepatic and renal toxicities were mainly encountered in mild and moderate severity 3.2.3 Hematological toxicities Table 3.12 Hematological toxicities Grade ( n= 71) (%) Toxicity 3-4 Total Anemia 57,7 18,3 4,2 80,2 Leukopenia 23,9 7,0 4,2 35,1 Neutropenia 36,6 2,8 11,3 50,7 Thrombocytopenia 11,3 0 11,3 Anemia and neutropenia were the most common toxicities with the prevalence of 80,2% and 50,7%, respectively, of which encountered severity were mainly mild (grades 1, 2) Only grade - agranulocytosis has a relative occurrence rate of 11.3% 3.2.4 The impact of the toxicities on the course of treatment Table 3.13 The impact of the toxicities on the course of treatment Treatment delay Number of treatment delay Due to anemia Due to thrombocytopenia Due to leukopenia Due to neutropenic fever Due to liver enzyme elevation Cycle Cycle Cycle Cycle Cycle Cycle 1 3 2 0 1 1 Of the 401 chemotherapy cycles, the number of discontinuations due to hemoglobin was highest and mainly in the early cycles The average number of days of discontinuation due to elevated liver enzymes is often prolonged due to long-term treatment of liver enzyme lowering CHAPTER DISCUSSION 4.1 TREATMENT RESULTS 4.1.1 Baseline characteristics 4.1.1.1 Age and gender The results of our study in Table 3.1 are quite similar to other studies, consistent with epidemiology of gastric cancer Most cancers, 17 especially those of epithelial origin, have an increased incidence with age Over time, negative exposures to multiple cancer risk factors are increasing, and also lead to cumulative accumulations over time of a variety of pathological changes at the molecular biological level The male/female ratio of the subjects in our study was 2.7/1 One possible explanation for this is probably the protective effect of the hormone estrogen in reducing the risk of stomach cancer in women Other causes such as dietary differences and other risk exposures such as alcohol consumption and smoking may also contribute to the increased incidence of gastric cancer in men Increasing conception rates and delaying menopause reduce the risk of stomach cancer, while antiestrogens such as tamoxifen increase this risk After menopause, the incidence of stomach cancer in women follows a pattern similar to that in men, but with a lag of about 10 to 15 years 4.1.1.2 Clinical signs and symptoms The most common symptoms in gastric cancer are epigastric pain, weight loss, vomiting, early satiety and anorexia In the early stage, symptoms of gastric cancer are often very vague and non-specific According to many studies conducted in gastric cancer patients, epigastric pain is always the most common symptom, accounting for over 75% to 100% In the early stage, when the disease has almost no symptom, the diagnosis is often difficult, but the treatment is favorable and the cure rate is high On the contrary, when the patient has clear clinical manifestations, it means that the disease is at a late stage, easier to diagnose, but less likely to have a chance of curative treatment, with high recurrence rate and low curative rate From the above fact, we realize that in order to prevent and treat gastric cancer well, it is necessary to take preventive measures as well as detect gastric cancer at an early stage, by developing a screening strategy in the community 4.1.1.3 ECOG performance status In this study, due to the high risk of toxicity of the tripplet chemotherapy regimen, we only included cases in good condition with PS index from – in order to ensure the compliance with cycles of chemotherapy This is completely consistent with the other large studies that have been conducted in the world in patients with advanced cancer in general 18 In this study, participants with PS = accounted for a higher proportion than other studies, mainly because our study focused on late stage cases with local or metastatic progression The condition of participants who have received curative treatment before is often worse than that of participants with metastatic disease who have not been treated in the first place However, we also only select patients with relatively good condition, who were qualified for chemotherapy 4.1.1.4 Histopathology All of the participants in our study were diagnosed at their late stage, with recurrence/metastasis status, thus, often associated high grade maglinancy pathology such as low-grade differentiated adenocarcinoma or squamous cell carcinomas This was different from the histopathological studies of early gastric cancer, with the highly differentiated adenocarcinomat often accounted for the highest percentage The histopathology plays an important role in the prognosis of gastric cancer, in which the squamous cells and the poorly differentiated carcinoma have high invasive and metastatic potential, thus lead to high risk of recurrence 4.1.2 Treatment results 4.1.2.1 Treatment response  Overall response rate Based on the results of various studies using different chemotherapy regimens on patients with advanced gastric cancer, we recognize that the TCX regimen had a higher response rate than all of the mono chemotherapy and most dual-drug chemotherapy regimens The results of our study also show that the response rate of the TCX regimen was higher than that of the other tripplet chemotherapy regimens commonly indicated in advanced gastric cancer patients that is no longer viable for surgery However, our study is a single-center study, the sample size is relatively small compared to other studies, and there is no clear separation between the physicians who conducted the intervention and the one who evaluated the treatment results via clinical imaging studies, so the results of treatment response were not entirely accurate due to subjective bias Pathological response was still the gold standard to assess the response to treatment, however, in this study, all of the participants were at their late stage and the goal of treatment is palliative chemotherapy rather curative chemotherapy, so we were forced to limit the assessment of response to clinical imaging tools 19  Factors associated with response rate Univariate analysis results showed that low T-N stage, no distant metastasis, no peritoneal metastasis and low malignancy histology were the factors related to treatment response Multivariable regression analysis model showed that the factors without peritoneal metastasis, low N stage and low histopathological malignancy were the factors related to treatment response in study subjects with the OR of 11,2; 2,71 and 201,86; respectively The association was statistically significant with p < 0,05 When compared with other studies, we found that there is no consensus on the factors that predict the responsive of patients with advanced gastric cancer to chemotherapy Most of the current data were focused on analyzing the significance of immunohistological markers in therapeutic response to biologic agents, while clinical predictors are often investigated in the analysis of primary outcomes such as diseasefree survival, progression-free survival and overall survival time Hopefully in the future, the results of large clinical trials will provide enough data for predicting the prognosis of response to chemotherapy, because this is also an important information to help clinicians make informed decisions in order to choose the most appropriate treatment regimen for the patient 4.1.2.2 Survival times  Progression free survival and overall survival The consideration of choosing a chemotherapy regimen for each patient plays a decisive role in the quality of treatment For cancer patients, especially those with advanced stage cancer, survival time is extremely important and should be considered with top priority For the same reason, progression-free survival and overall survival are consistently considered primary endpoints in most clinical studies evaluating the effects of the regimens in cancer patients Compared with monotherapy regimens, our study results showed the superiority of TCX regimen in improving progression-free survival/overall survival This is in agreement with the argument that has been demonstrated in multiple meta-analyses that multidrug therapy is superior to monotherapy in improving survival in patients with end-stage cancer, with the expectation that the combination of multiple drugs with different mechanisms of inhibiting/eliminating cancer cells would help 20 increase the effectiveness of tumor removal, thus increase the response rate of the treatment, improve quality of life and thereby increase patient’s survival times However, the increase in toxicity of combination multi-chemotherapy regimens compared with monotherapy regimens was also demonstrated in many large studies, escpecially severe life-threatening conditions such as severe leukopenia, anemia, thrombocytopenia, liver and kidney failure These factors also need to be considered when a multi-chemotherapy regimen is indicated to patients with late stage cancer, who usueally are in poor performance status and may have multiple comorbidities  Factors associated with progression free survival and overall survival time Gender: The results of our study showed that female is a good prognostic factor for progression-free survival with HR: 2,48; 95%CI: 1,08 – 5,69; p = 0,03 One possible explanation for this is probably the protective effect of the hormone estrogen in reducing the risk of cancer progression in women Performance status: Our findings were similar to other research results around the world On the multivariate Cox regression model, PS index - was one of the predictors of prolonging the overall survival time with HR: 2,48; 95%CI: 1,26-4, and p=0,01 Clearly, patients in good condition were more tolerable to chemotherapy, less likely to had to stop treatment, had a better response to treatment, and therefore had a longer survival after treatment Pathology type: There are many studies on the prognosis and treatment response of late gastric cancer in histopathologically malignant types such as squamous cell, low-grade or undifferentiated adenocarcinoma In general, the prognosis is usually poor In Piesen's report, when analyzing the median survival time in gastric cancer inoperable participants, the author noted that squamous cell carcinoma was a poor prognostic factor The median survival time was statistically significantly lower compared with other histopathological types (5 months versus months) In studies focusing on the chemosensitivity of gastric ring cell carcinoma group, these studies show that the chemosensitive level of gastric ring cell carcinoma has characteristics that are different from other types of adenocarcinoma According to the study of Rougier et al., the combination of 5-FU and cisplatin in the 21 treatment of advanced gastric cancer, when analyzing the level of response among histopathological types, the response to chemotherapy of Ring cell carcinoma is inferior to other histopathology However, there are reports showing the effectiveness of taxanes against this particular histopathology In a few reports of docetaxel treatment in metastatic gastric cancer, the combination with 5-FU and oxaliplatin (DOF) gave better results with squamous cell carcinoma more than 65% and no worse than other histopathological formsA study conducted from 2008 to 2015 on 3090 gastric cancer patients in China also showed that the low-grade or undifferentiated adenocarcinoma, along with squamous cell carcinoma were poor prognostic factors for overall survival Our study also showed that patients with low malignancy histopathology such as moderately differentiated adenocarcinoma are factors related to the prolongation of bot disease-free survival and overall survival time (p < 0.05) Peritoneal metastatis: In our study, the absence of peritoneal metastasis was a predictor of the prolongation of both progression-free survival and overall survival Peritoneal metastasis, along with liver metastasis, is one of the most common sites of metastasis in advanced gastric cancer Many other studies have also shown a poor prognosis if these metastases are present, mainly due to a very poor response to treatment This is also similar to our study, when the multivariate regression model and univariate analysis both showed that having peritoneal metastasis is a poor prognostic factor for treatment response Treatment response: In our study, treatment response was a positive prognostic factor for both progression-free survival and overall survival Theoretically, response to treatment results in tumor shrinkage, improvement in disease status, and in turn, improved patient survival However, in fact, the survival rate depends on many other factors such as the physical condition, treatment tolerance, co-morbidities ; and therefore, disease response rates are rarely the primary outcome instead of survival indicators 4.2 TOXICITY AND THE SAFETY OF THE REGIMEN 4.2.1 Clinical toxicity Vomiting was a common adverse effect, however, most cases were only mild and occurring in the first cycles at the beginning of treatment and tending to decrease in the following cycles Our results showed a higher rate of this toxicity than those of monotherapy studies, but only equivalent to or lower than those of the other triple 22 chemotherapy regimens This difference can be explained that other authors used cisplatin instead of carboplatin, and some authors used intravenous 5-FU instead of oral capecitabine in our protocol On the other hand, the dose of Capecitabine we used was lower to limit the gastrointestinal adverse effects In addition, another reason for this lower rate was that we actively administered Ondansetron and Dexamethasone and Diphenylhydramine just before each chemotherapy cycle as recommended in the latest guidelines to prevent nausea and vomiting from occurring when receiving chemotherapy, especially the platinum group Diarrhea and hand-foot syndrome are relatively common adverse effect of Capecitabine use In this study, we used Capecitabine at a dose of 850 mg/m²/time x times/day, within 14 days from the start of the treatment cycle, while Capecitabine were used at a higher and longer dose in other studies This may be a possible reason why the proportion of patients with diarrhea and hand-foot syndrome in our study was lower than that of other studies and in most of the cases, these adverse effects only encounted in mild degree A meta-analysis based on the results of 95 studies showed that peripheral neuropathy was one of the most common adverse effects in patients treated with chemotherapy, especially with the platinum group This can explain why TCX, as well as most other platinum-containing regimens, showed higher rates of peripheral neuropathy than other non platinum containing regimes 4.2.2 Hematological toxicities Our results showed that anemia was a very common toxicity; however, most of them are at mild degree (57,7%) In order to clarify the advantages of the adverse effects on erythrocytes of TCX regimen compared to other regimens, there should be a randomized clinical trial designed to compare between two groups of patients with similar clinical characteristics, or further subgroup analyzes are needed to match the homology between groups of patients in different studies On the other hand, we also observed cases of anemia due to bleeding from the tumor, due to a good response to chemotherapy, only after 1-2 cycles, the bleeding stopped and the patient recovered quickly without any additional processing Compared with other chemotherapy regimens, it can be seen that TCX is a relatively safe regimen in terms of causing leukopenia and 23 neutropenia, especially when compared with other standard multichemotherapy regimens in the treatment of advanced gastric cancer However, this is still a risk factor for complications during chemotherapy such as respiratory infections, urinary tract infections, digestive tract infections and it should be closely monitored for timely treatment, so that the patient does not have to interrupt treatment 4.2.3 Hepatic and renal toxicities The results of our study showed that there was a low rate of hepatic and renal toxicity, no case of severe liver or kidney failure had been observe during the course of treatment Similar to other studies, life-threatening adverse events in liver and kidney functions, or the termination of chemotherapy, or dose reduction due to hepatic and renal toxicities were very rare In one study, Capecitabine even showed safety when used in cancer patients with severe renal failure who were indicated for dialysis CONCLUSION Through a study of 71 patients with late stage gastric cancer treated with TCX regimen at Hanoi Oncology Hospital from January 2016 to December 2019, we drew some conclusions as follows: Treatment results and associated factors - The overall response rate was 53,5%, of which 2,8% was complete response; 50,7% was partial response - The symptoms were improved between before and after treatment with a statistically significant difference (p < 0,05) - Not having peritoneal metastasis, low N stage and low maglinancy hispathology were the factors associated with treatment response, with OR of 13,7; 3,31 and 201,86 respectively, with p < 0,05 - The estimated mean progression-free survival was 6,6 months (95% CI 5,7–7,5 months) The estimated progression-free survival rate at months, year and years was 55,1%; 28,5%; 17,5% - Gender female, not having peritoneal metastasis and response to treatment were the factors associated with prolonging the progression free time, with HR = 2,48; 2,78 and 6,19; respectively (p < 0,05) - The estimated overall survival time was 17,9 monts (95% CI 14,9 – 20,8 months) The estimated overall survival rate at year and years was 67,8%; 31,8%; respectively 24 - Good performance status, no peritoneal metastases, low malignancy pathology type and response to treatment were the factors asoociated with prolonging overall survival with HR of 2,18; 5,19; 3,35 and 2,58; respectively (p < 0.05) Toxicity and the safety of TCX regimen - Clinical toxicities included: vomiting was 74,6% (grade 3-4 was 4,2%); diarrhea was 19,7% (grade 3-4 was 1,4%), hand foot syndrome was 33,8% (grade 3-4 was 5,6%), peripheral neuropathy was 47,9% (grade 3-4 was 7,0%) - Hematological toxicities included: anemia (80,2%, grade 3-4 was 4,2%); leukopenia (35,1%, grade 3-4 was 4,2%); thrombocytopenia (11,3%), neutropenia (50,7%, grade - was 11,3%) - Hepatic toxicities included: elevated liver enzyme SGOT was 47,9% (grade was 2.8%), elevated SGPT liver enzyme was 33,8% (grade was 1,4%) No elevation of liver enzymes at grade was observed - Renal toxicity rate were 16,9%, no grade 3-4 toxicity was observed RECOMMENDATONS The TCX regimen was proved to be effective and safe in patients with late stage gastric cancer The regimen can be applied in hospitals and medical facilities with oncology department There should be studies on combining TCX regimen with supportive measures during the course of treatment to minimize the toxicities of the regimen 25 LIST OF PUBLISHED RESEARCH RELATED TO THIS DISSERTATION Nguyen Trong Hieu, Tran Thang (2019) Evaluation of treatment response of TCX regimen in late stage gastric cancer at Hanoi Oncology Hospital and some related factors Journal of practical medicine 1(1088): 38 – 43 Nguyen Trong Hieu, Tran Thang (2021) Evaluation of safety and some side effects of treatment of late stage gastric cancer with TCX regimen at Hanoi Oncology Hospital Journal of chinical medicine (121): 108 – 115 Nguyen Trong Hieu, Tran Thang (2021) Evaluation of results of treatment of late stage gastric cancer with TCX regimen at Hanoi Oncology Hospital from 2016 to 2019 Journal of clinical medicine (120): 115 – 125 ... Capecitabin (TCX) in the treatment of late stage gastric cancer, in which the results were promising Besides, this regimen was better tolerance with less frequent, less severe, better controlled... University NEW CONTRIBUTION OF THE THESIS TCX regimen showed significant improvement in symptoms, progression-free survival and overall survival The adverse effects of TCX regimens were lower than those... effect and toxicity of the TCX regimen in the treatment of late stage gastric cancer The aim of this study was to evaluate: The treatment outcomes and associating factors of TCX regimen in late stage