MINISTRY OF EDUCATION MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY LE THANH TRUNG EVALUATION OF THE RESULTS OF GASTRIC CANCER TREATMENT IN THE ENDERLY WITH COMBINED SURGERY WITH EOX REGIMENT Specializa[.]
MINISTRY OF EDUCATION MINISTRY OF HEALTH HANOI MEDICAL UNIVERSITY LE THANH TRUNG EVALUATION OF THE RESULTS OF GASTRIC CANCER TREATMENT IN THE ENDERLY WITH COMBINED SURGERY WITH EOX REGIMENT Specialization : Oncology Code : 9720108 SUMMARY OF MEDICAL DOCTORAL THESIS HA NOI – 2023 THE STUDY WAS COMPLETED AT HANOI MEDICAL UNIVERSITY The scientific instructor: Assoc Prof Dr DOAN HUU NGHI Reviewer 1: PGS.TS Nghiem Thi Minh Chau Reviewer 2: PGS.TS Tran Bao Long Reviewer 3: PGS.TS Pham Cam Phuong The dissertation will be defended in front of the University Thesis Evaluation CouncilMeeting at: Hanoi Medical University at: day 2023 Thesis can be learned at library The National Library Library of Hanoi Medical University LIST OF PUBLISHED ARTICLES RELATED TO THE STUDY Le Thanh Trung, Doan Huu Nghi (2021), Evaluation of early results of gastric cancer surgery in the elderly, Journal of Medicine and Pharmacy, April 18, 2021, 186-191 Le Thanh Trung, Doan Huu Nghi (2021), Evaluation of some undesirable effects of EOX regimen in the treatment of stomach cancer in the elderly, Vietnam Medical Journal, May 2/ 2021, 65-69 Le Thanh Trung, Doan Huu Nghi (2021), Evaluation of gastric cancer survival time in the elderly after surgery in combination with EOX regimen, Vietnam Medical Journal, June 1st/ 2021, 78-82 INTRODUCTION Urgency of the topic Gastric cancer is a common malignancy According to the statistics of Globocan 2020, breast cancer is the 5th disease among 10 cancers, one of the main causes of death related to malignancies (after only common cancer and liver cancer) In Vietnam, colorectal cancer ranks 4th out of 10 common cancers (in both sexes), with 17906 new cases, 14615 deaths with an incidence rate of 24.64 per 100 000 population Along with the advancement of Medicine and the improvement of living conditions, the average life expectancy of people increases, increasing the number of elderly people In 2017, the elderly in Vietnam reached the threshold of 11% of the population, accounting for about 10.6 million people and is expected to reach 17.5% in 2030 (about 18.6 million people) and 28% in 2050 (about 32 million people), Vietnamese life expectancy in 2021 is 73.7 years old Therefore, the number of people aged 60 and older with gastric cancer has also increased In Vietnam so far, there have been many studies on the treatment of gastric cancer, but no in-depth research on the treatment of gastric cancer in the elderly Therefore, we conducted the topic "Evaluating the results of gastric cancer treatment in the elderly by surgery with combination chemotherapy with EOX protocol" Research objective Comment on clinical and paraclinical characteristics of elderly gastric cancer patients Evaluate the results of surgical treatment and chemotherapy with EOX regimen in this group of patients New contributions of the thesis The study helps to determine the clinical and subclinical characteristics of elderly patients with gastric cancer At the same time, it is assessed that surgery in the elderly is safe, there are no complications during surgery The operative time was shorter than many authors, an average of 152.2 ± 39.8 minutes There was no difference in the survival time of the group that used full courses of chemotherapy and the group that did not use cycles of EOX chemotherapy with p=0.8194 Adjuvant chemotherapy with EOX regimen 71.3% of chemotherapy cycles were reduced in dose, so there were few grade 3, side effects Overall survival time of years, years, years of the first study group are 85.6%, 59.7% and 46.7% respectively The mean overall survival was 49.7±1.8 months Cumulative disease-free survival time of 3, 4, and years was 63.5%, respectively; 45.8%; 35.6% The mean disease-free survival time was 44.4±2.1 months Patients with anemia had a mean survival time of 35.76±2.5 months, which was statistically significantly lower than that of the non-anemic group, which was 53.8±1.6 months with p=0.001 Patients with concomitant cardiovascular disease had a mean survival time of 37.45±3.5 months, which was lower than the mean survival time of the group without comorbid cardiovascular disease (51.8±1,8 months), (p= 0.03) Thesis structure The thesis is presented in 128 pages (excluding references and appendices) Thesis is divided into: - Ask questions: pages - Chapter 1: Overview of the document 49 pages - Chapter 2: Research subjects and methods 14 pages - Chapter 3: Research results 32 pages - Chapter 4: Discussion 30 pages - Conclusion: pages The thesis includes 46 tables, 13 charts, and 132 references Appendices include research works, references, some illustrations, research sheets, list of patients CHAPTER OVERVIEW 1.1 Epidemiology, risk factors for gastric cancer Stomach cancer is a common disease in the world as well as in Vietnam According to Globocal 2020, gastric cancer is the 5th most common cancer in the world with an incidence rate of 23.17 per 100 000 population, making it one of the three most common causes of cancerrelated death worldwide world, after lung cancer and liver cancer Our country is located in an area with a high incidence, according to Globocan 2020, gastric cancer ranks fourth after liver and lung cancer in both sexes with 17906 new cases, 14615 deaths, the incidence rate is 24.64 per 100 000 people 1.2 Diagnosing stomach cancer Definitive diagnosis: based on clinical and paraclinical tests such as contrast X-ray, abdominal ultrasound, endoscopic ultrasound, endoscopic biopsy for pathology, CT Scan, PET/CT In which, endoscopy and biopsies for pathology have decisive diagnostic value Diagnosis of staging according to AJCC 2017 1.3 Stomach cancer treatment Multimodal treatment includes surgery, chemotherapy, radiotherapy and immunotherapy When the disease is in the regional stage, surgery is the main treatment method, chemotherapy is an adjuvant treatment 1.4 Some factors affect treatment in the elderly Elderly people have aging and functional decline in many organs and have many comorbidities The elderly group has a higher risk of complications and perioperative mortality than younger people This rate can be reduced with good preoperative preparation, limited emergency surgery, application of minimally invasive surgical techniques, close monitoring during and after surgery for timely adjustment CHAPTER MATERIALS AND METHODS 2.1 Subjects Including 57 patients diagnosed with gastric cancer stage IIA-IIIC Surgical treatment combined with EOX regimen At hospital K and hospital E from January 2009 to December 2019 2.1.1 Inclusion criteria Histopathology type of carcinoma Age 60 was treated with radical gastrectomy, D2 lymphadenectomy Received chemotherapy with EOX regimen Full record keeping 2.1.2 Exclusion criteria Patients with co-morbid systemic diseases such as diabetes mellitus, uncontrolled hypertension Had chemoradiotherapy before surgery Surgery does not guarantee cure The case had another cancer 2.2 Methods 2.2.1 Type of method Retrospective non-controlled clinical intervention study with medical records 2.2.2 Sample The sample size is calculated by the formula describing a ratio: 𝑝(1 − 𝑝) 𝑛 = 𝑍1− /2 (𝑑)2 In there: n: study sample size α=0.05 Z1-α/2 = Zα/2 = 1,96 p is the overall survival after years According to the study of Vu Quang Toan et al (2016), the overall 5-year survival rate was 48.1%, so we chose p=0.48 d: allowable error, estimated d=0.15 The result of sample size calculation is n = 42 patients In this study, 57 patients met the inclusion criteria for the study CHAPTER RESULTS During the period from January 2009 to December 2019, there were 57 gastric cancer patients treated with EOX chemotherapy combined surgery at Hospital K and E hospital The results were as follows: 3.1 Clinical and paraclinical features 3.1.1 Age and sex characteristics Most of the patients in the study were male, accounting for 75.4%, female was 24.6%, the ratio was approximately 3/1 The mean age of men was 63.7±3.1 years, of women was 62.8±2.8, the overall mean of the study was 63.7±3.4 The highest is 72 years old for men and 69 years old for women 3.1.2 Comorbidities Table 3.1 Comorbidities Quantity Ratio Comorbidities (n=57) % 7,0 Arthritis Musculoskeletal 7,0 osteoporosis diseases 8,8 disc disease 14 Cataract 10,5 Diabetes 12,3 Kidney or urinary tract disease 12,3 Digestive diseases 5,26 Hepatobiliary disease 5,26 Respiratory disease 11 19,3 Heart-related diseaes Elderly people often have chronic diseases, in which the common diseases are bone and joint diseases, kidney disease, diabetes and gastrointestinal tract - Musculoskeletal diseases: arthritis 7%; osteoporosis 7%; disc disease 8.8% - Cataract 14% - Diabetes 10.5% - Kidney or urinary tract disease 12.3% - Digestive diseases 12.3% - Hepatobiliary disease 5.26% - Respiratory disease 5.26% - There are patients with high blood pressure and patients with abnormalities in the electrocardiogram: atrioventricular dysfunction - In the study, there were no patients with angina pectoris, myocardial infarction; cerebrovascular disease and tuberculosis 3.1.3 Clinical symptoms Table 3.2 Clinical symptoms Symptoms Skinny Difficulty swallowing Full stomach Nausea, vomiting Vomiting blood, black stools Anemia syndrome Self palpation of abdominal tumor Quantity (n=57) 26 02 40 11 05 16 04 Ratio % 45,6 3,5 70,2 19,3 8,8 28,1 07 - Symptoms of abdominal pain Most patients present with abdominal pain with the rate of 96.5% The main characteristic of dull pain is 98.2% Pain in the epigastrium 98.2% - The most common systemic symptom is weight loss 45.6% - Anemia syndrome 28.1% - There were patients presenting with gastrointestinal bleeding, accounting for 8.8% 3.1.4 Preoperative blood test - The rate of anemia (Hemoglobin < 10g/dL) is 21.1% - There were patients with hypoproteinemia (12.3%) and 15 patients with hypoalbuminemia (26.3%) 3.1.5 Tumor markers before surgery - There were 13 patients (22.8%) with increased CEA concentration > 5ng/ml - CA 19-9 and CA 72-4 increased slightly, only patients increased CA 19-9 (8.8%) and 11 patients increased CA 72-4 (19.3%) 3.1.6 gastroscopy - Patients with tumor lesions in the antrum accounted for the highest rate with 56.1% - Tumor size from 1-3 cm accounts for mainly 49.1% - The results of the macroscopic description on endoscopy showed that the ulcer type accounted for the highest rate (77.19%), the wart form and the infiltrated form were less common 3.1.7 Preoperative ultrasound The detection rate of lesions in the stomach and/or regional lymph nodes on ultrasound was 52.6% There were patients with signs of wall thickening with abdominal lymph nodes (7%) There were 27 patients (47.4%) with no lesions detected on preoperative ultrasound 3.1.8 Preoperative computed tomography scan - Most tumors were detected in antrum (59.6%) and small curvature (22.8%) - Signs of gastric wall thickening on CT scan were noted in all patients (100%) and signs of loss of layer structure were common (93%) - CT scan detected abdominal lymph nodes in 26/57 cases (1.8%) - CT scan detected invasive tumor in 5/57 cases (8.8%) 3.2 Results of surgical treatment 3.2.1 Surgery time - The average surgery time was 152.4±39.8 (minutes), the lowest 100 minutes, the highest 360 minutes - Surgery time from 2h-2.5h accounted for 43.9% 3.2.2 Surgical method Patients are mainly used methods of gastric bypass surgery - Partial gastrectomy 91.2% - Removal of the entire stomach 8.8% 3.2.3 Complications and complications after surgery There are 100% cases without complications during surgery Only case (1.8%) had complications of intestinal obstruction after surgery 3.2.4 Number of days in hospital after surgery - Most of the patients were hospitalized for more than 07 days with the rate of 91.2% - Patients were hospitalized for less than 07 days with the rate of 8.8% 3.2.5 Pathological results after surgery - Most patients have tumor size T3 and T4a with the rate of 42.1% - No lymph nodes account for 29.8%; N1 lymph nodes account for 49.1%; N2 accounts for 10.5%; N3 accounts for 10.6% - Patients are mainly stage IIB with 33.3%, IIIA with 31.6% - Histopathological results showed Mainly adenocarcinomas with low differentiation accounted for 10 - The cumulative survival time of years is 85.6%, years is 59.7%, years is 46.7% - The mean overall survival time was 49.7 ± 1.8 months - Cumulative disease-free survival time of years is 63.5%, years is 45.8%, years is 35.6% - The mean disease-free survival time was 44.4 ± 2.1 months - The difference in overall and disease-free survival time of the group using enough and not enough cycles of chemotherapy was not statistically significant with p = 0.8194 3.4.2 Some factors related to survival time Relation of survival time with anemia 0.00 0.25 0.50 0.75 1.00 Song them lien quan den thieu mau 20 40 60 analysis time thieumau = thieumau = p=0.001 Chart 3.2 The Kaplan-Meier diagram depicts the relationship between survival time and anemia Patients with anemia had a median survival time of 35.76 ± 2.5 months, which was lower than that of the non-anemic group of 53.8 ± 1.6 months The difference was statistically significant with p 5ng/ml; CA 19-9 and CA 72-4 increased slightly, only patients increased CA 19-9 (8.8%) and 11 patients increased CA 72-4 (19.3%) 4.1.5 Endoscopy Macroscopic picture of gastric lesions before surgery is observed directly through gastroscopy The results of the study showed that 24 cases 14 of ulceration accounted for 42.1%, wart ulceration was 35.1%, wart form was 12.3%, infiltrative form was not encountered Many studies on gastric cancer have been carried out in our country, the results of macroscopic images of gastric lesions still have some differences According to Trinh Hong Son's research, ulcers accounted for 80.2% of cases 4.1.6 Abdominal ultrasound In our study, 57 patients were evaluated by ultrasound before surgery, the detection rate of lesions in the stomach and/or regional lymph nodes on ultrasound was 52.6% There were patients with signs of wall thickening with abdominal lymph nodes (7%) There were 27 patients (47.4%) with no lesions detected on preoperative ultrasound Thus, our ultrasound results are also consistent with many domestic and foreign studies 4.1.7 Result of CT scan In our study, signs of gastric wall thickening on CT scan images were recorded in all patients (100%) and signs of loss of layer structure were common (93%) CT scan detected abdominal lymph nodes in 26/57 cases (45.6%) CT scan detected invasive tumor in 5/57 cases (8.8%) 4.2 Surgery results 4.2.1 Surgery time The shortest operative time was 100 minutes, and the longest was 360 minutes in total gastrectomy, the mean operative time was 152.4±39.8 (minutes) This result is shorter than the author Nguyen Lam Hoa 175.46 ± 35.62 minutes In Le Manh Ha's study, the average time of the D2 lymph node dissection group was 215 ± 47.4 minutes, for the D3 lymph node dissection group it was 245 ± 44.5 minutes, the difference was statistically significant, but the treatment time was statistically significant The mean value after surgery between the groups was not significantly different (p > 0.05) Table 4.1 Comparison of surgery time in some studies Surgical time D2 Study year n (minutes) Trinh Hong Son 2001 306 228,3 ± 56,1 Le Manh Ha 2007 119 215 ± 47,4 Nguyen Lam Hoa 2008 197 175,46 ± 35,62 Nguyen Quang Đo 2017 53 232,08 ± 14,61 This study 2021 57 152,4 ± 39,8 15 4.2.2 Surgical method In 57 cases of gastric cancer that we studied, 52 cases were indicated for partial gastrectomy, accounting for 91.2% There were patients indicated for total gastrectomy, accounting for 8.8% Compared with other authors, our total gastrectomy rate is lower: Trinh Hong Son (2001) is 17.97%, possibly because some patients after total gastrectomy are in poor health and have not been able to so were included in our study 4.2.3 Complications, complications and blood transfusion in surgery In our study, there were no complications during surgery There is a patient with intestinal obstruction after surgery is a 62-year-old male patient, 12 days after surgery, he has severe abdominal pain, nausea, bowel obstruction, unprepared abdominal imaging has images of water and gas levels The patient was diagnosed with intestinal obstruction after surgery and medical treatment for 10 days was unsuccessful The patient was re-operated on the 22nd postoperative day, the cause of intestinal obstruction was caused by a loop of intestine sticking to the incision, flexing the angle After surgery, the patient stabilized, recovered well and was discharged after 07 days Author Nguyen Cuong Thinh said that radical surgery in gastric cancer is a major surgery with a complication rate of about 3.99% Fistula anastomosis, acute pancreatitis after surgery are the most common complications and are fatal complications for patients The results of the study by Do Trong Quyet and Trinh Hong Son showed that the postoperative complication rates were 5.7% and 8.6% and there was no mortality after surgery Thus, through the above results, it is shown that radical gastrectomy due to cancer in the elderly is a safe surgery Complications and mortality from surgery can be completely limited by perfecting surgical techniques, preparing patients well for surgery, and resuscitating patients after surgery 4.2.4 Number of days in hospital Our study results recorded that 91.2% of patients had a hospital stay of more than 07 days Only 8.8% of patients were hospitalized for less than days because in our study they were 60 years old or older, weak in health and had many comorbidities Depending on the patient's condition, stage of disease, surgical technique, qualifications and 16 experience of the surgeon, equipment and instruments of the medical facility, post-operative resuscitation system as well as post-operative care will affect the length of hospital stay after surgery 4.2.5 Pathological results after surgery (TNM classification according to AJCC 2017) In our study, stage IIB accounted for the highest rate with 33.3%, followed by IIIA 31.6%, IIA 21.1%, only 7% patients with stage IIIB and IIIC Some studies of the same authors also showed similar results: Osti et al (2012) studied 55 patients with concurrent chemoradioradiation after surgery and showed that stage IB 13%, II 29%, IIIA 24%, IIIB 9%, IV 25%; Zilberstein et al (2004) studied 100 patients with stage IA 25%, IB 11%, II 18%, IIIA 16%, IIIB 19%, IV 10%; Sasako et al (2011) studied on 1034 patients showed that stage IIA accounted for 52.03%, stage IIIA 30.75%; IIIB 10.25% and stage IV 6.96% Thus, most of the studies at home and abroad show clinical results mainly from stage II to stage IV, which is consistent with our research results In our study, the most common ductal carcinoma accounted for 73.7%, ring cell carcinoma accounted for 26.3% According to Vu Hai, the tubular glands account for 76.0%, the ring glands 10.0%, the mucous glands 6.0% and the undifferentiated types make up 4.0% The results of studies showing that in cancerous tumors, mainly ductal adenocarcinoma is also consistent with the results in our study Gastric adenocarcinoma is divided into levels of differentiation based on gland formation and cellular abnormalities This differentiation is applicable to ductal adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma; and ring cell adenocarcinoma is always poorly differentiated in nature In our research results, the high differentiation rate accounted for 1.8%, the moderately differentiated type accounted for 35.1%, the poorly differentiated type accounted for 36.8% Vu Hong Thang et al studied on 85 patients, showing that the well-differentiated type accounted for 15.6%, the moderatelydifferentiated type accounted for 40.0%, the poorly differentiated type accounted for 28.9% and the undifferentiated type accounted for 15 ,5% Sasako (2011) studied on 1034 patients, the results showed that the differentiated form accounted for 40.91%, the undifferentiated form accounted for 58.8%, the difference in the rate of different types of 17 differentiation between the two study groups according to them I may be due to the difference in sample size 4.3 Results of adjuvant chemotherapy after surgery 4.3.1 Dose In the study, 28.7% of the cycles were treated with the maximum dose (100%) Because elderly patients are less healthy and have many comorbidities, the rate of full-dose treatment is lower Vu Quang Toan had 48.4% full treatment with the maximum dose (100%) Cunningham (2006) in the REAL-2 study also found that 42% of the patients on the EOX regimen had at least cycle of adjusting the dose of drug in the regimen 4.3.2 Unwanted effects Undesirable effects on hematology - Anemia† Overall, after cycles of chemotherapy, hemoglobin toxicity accounted for 38.6% of cases However, mainly at mild level 1: 28.9% and is 9.6% There were no cases of toxicity grade 3, Therefore, after receiving hemoglobin infusion, the patient recovered quickly, was able to continue chemotherapy, did not affect the treatment much treat Dang Hoang An (2015) adjuvant treatment with concurrent chemoradiotherapy and EOX chemotherapy in Hue was mainly grade anemia with 40.5% Cunningham (2006) in the REAL-2 study found anemia in 64.2% of patients treated with EOX regimen, of which grade 3-4 anemia was 8.6% - Leukopenia The seed BC line was most affected over cycles of chemotherapy However, mainly at mild level, including grade is 15.85% and grade is 9.9% There is a small rate of grade and agranulocytosis (2.6%) but after using drugs to stimulate the concentration of granules, it is stable Dang Hoang An (2015) encountered mainly grade leukopenia, 59.5% Cunningham (2006) had very common leukopenia with the rate of 62.9%, of which grade 34 accounted for 27.6% But granulocytopenia, on the contrary, only accounts for a very small rate of 9.8%, of which grade 3-4 is also very low, 7.8% Barreto (2014) also found the regimen to be safe to use, only experiencing about 14% of general grade 3-4 toxicity on the hematopoietic system - Platelet The effect of causing thrombocytopenia in the study group of ... STUDY Le Thanh Trung, Doan Huu Nghi (2021), Evaluation of early results of gastric cancer surgery in the elderly, Journal of Medicine and Pharmacy, April 18, 2021, 186-191 Le Thanh Trung, Doan Huu... treatment of stomach cancer in the elderly, Vietnam Medical Journal, May 2/ 2021, 65-69 Le Thanh Trung, Doan Huu Nghi (2021), Evaluation of gastric cancer survival time in the elderly after surgery... regimen 3.4.1 Extra life time 0.50 0.25 0.00 Ti le % 0.75 1.00 Song them toan bo 20 thoi gian (tháng) 40 60 Chart 3.1 Kaplan - Meier diagram depicting overall survival time 10 - The cumulative