Những kết luận mới của luận án: Qua nghiên cứu 85 bệnh nhân ung thư trực tràng trung bình, thấp được điều trị xạ trị bằng máy gia tốc tuyến tính với liều 50,4 Gy kết hợp Capecitabine trước mổ cho kết quả: - 100% bệnh nhân đáp ứng cơ năng sau hóa xạ trị - 3,5% bệnh nhân đáp ứng hoàn toàn, 81,2% đáp ứng một phần, 15,3% - Thời gian sống thêm toàn bộ 5 năm đạt 81,2%, trung bình là 59,9±1,72 tháng - Thời gian sống thêm không bệnh 5 năm đạt 74,1%, trung bình 52,3 ± 2,14 tháng. Tác dụng không mong muốn Độc tính trên hệ hệ huyết học ở mức độ nhẹ: 6,7% bệnh nhân sau điều trị có tiểu cầu độ 1, 6,9% bệnh nhân có bạch cầu hạt độ 1. Tỷ lệ 3,4% bệnh nhân tăng Creatinin độ 1 và 11,5% bệnh nhân tăng AST sau điều trị). 72,9% bệnh nhân bị loét da vùng tia độ I và 5,9% độ II, 92,9% bệnh nhân đau rát tầng sinh môn độ I; 3% đau rát độ II. 3,5% viêm bàng quang độ I. 37,6% bệnh nhân thấy buôn nôn độ I; 8,2% bệnh nhân có triệu chứng nôn ở mức độ nhẹ. 81,2% bệnh nhân bị tiêu chảy mức độ nhẹ. 35,3% bệnh nhân bị viêm ruột non độ I; 27,1% viêm niêm mạc ống hậu môn độ I; 5,9% bệnh nhân có hội chứng bàn tay chân độ I; 4,7% bệnh nhân loét bậu môn – trực tràng; 3,5% viêm miệng độ I. Xạ trị bằng máy gia tốc tuyến tính liều 50,4 Gy kết hợp Capecitabine trước mổ là phương pháp điều trị có hiệu quả cho bệnh ung thư trực tràng thấp tiến triển tại chỗ giúp cải thiện triệu chứng cơ năng, hạ thấp giai đoạn bệnh, tăng tỷ lệ phẫu thuật triệt căn và phẫu thuật bảo tồn cơ thắt hậu môn.
MINISTRY OF EDUCATION MINISTRY OF HEALTH AND TRAINING HANOI MEDICAL UNIVERSITY VO QUOC HUNG RESEARCH ON TREATMENT OF LOW RECTAL CANCER, AVERAGE PROGRESSION OF THE SPOT BY ACCELERATED PREOPERATIVE RADIOTHERAPY COMBINED WITH CAPECITABINE Speciality: CANCER Code: 9720108 THE DOCTORAL DISSERTATION SUMMARY HÀ NỘI - 2022 THE THESIS IS COMPLETED IN HANOI UNIVERSITY Supervisors: A.Prof Bui Cong Toan Reviewer 1: Dr Bui Vinh Quang Reviewer 2: A.Prof Pham Duc Huan Reviewer 3: A.Prof Pham Cam Phuong The thesis will be defended before the School-level Thesis Assessment Council at Hanoi Medical University At day month year The thesis can be found at: - Hanoi Medical University Library - National Library LIST OF SCIENTIFIC WORKS PUBLISHED RELATED TO THE THESIS Evaluate the results of treatment of rectal cancer at low, medium advanced stage in place by accelerated radiation therapy combined with capecitabine at K hospital from 2013-2019 Journal of Practical Medicine (1118) No 11/2019 pp 287-291 Clinical and subclinical characteristics of patients with low and average rectal cancer at K hospital from 2013-2019 Journal of Practical Medicine No 3/2020 p 30-34 QUESTION Rectal cancer is one of the most common cancers in our country and around the world The incidence of colorectal cancer (of which more than 50% is rectal cancer) in the world is increasing According to GLOBOCAN 2018 The International Agency for Research on Cancer estimates that there will be about 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 In which, colorectal cancer has a high rate the incidence rate was 9.2%, and the mortality rate was 6.1%1 In developed countries, colorectal cancer ranks second among cancers in both sexes, after lung cancer in men and breast cancer in women In France, there are about 34,500 new cases of colorectal cancer every year and about 16,800 deaths The disease occupies the first place among all types of cancer In Vietnam, colorectal cancer is among the most common cancers, ranking 5th among cancers Treatment of colorectal cancer is a multimodal treatment, in which surgery plays the main role Advances in multimodal treatment including combination chemotherapy and adjuvant radiation have helped prolong survival and reduce local recurrence In our country, the regimen has been applied for many years However, the previous combination regimen often used a continuous 5FU infusion line, causing difficulties in the treatment process, patients often had discomfort when continuously infusion of drugs even during radiation therapy The old methods of radiation therapy also bring many unwanted effects as well as side effects With the progress in recent years in the field of oncology: taking capecitabine orally makes it easier for patients to just take the drug, more comfortable, easier to use Especially, advances in radiation therapy when applying accelerated radiotherapy in treatment help further improve the effectiveness of preoperative chemotherapy and radiotherapy for patients with low and medium rectal cancer That's why we conducted the topic: Study on the treatment of low-grade, medium-stage rectal cancer in the local area with preoperative accelerated radiation therapy in combination with Capecitabine With goals: Evaluation of the results of accelerated radiation therapy combined with capecitabine before surgery on patients with low-grade, moderate-stage locally advanced rectal cancer at K hospital from September 2013 to November 2019 Describe some undesirable effects of preoperative accelerated radiation therapy combined with capecitabine in patients with low rectal cancer, moderate stage of local progression at K hospital from September /2013 11/2019 NEW CONTRIBUTIONS OF THE THESIS Rate of patients responding to treatment: 81.2% of patients had partial response, 3.5% had complete response and 15.3% had no response Overall, 5-year survival was 81.2% 5-year disease-free survival was 74.1% The study also showed several factors related to the response of treatment methods, the histopathological type of warts responded better than the infiltrative type, the poorly differentiated type responded better than the differentiated type, and the stage of the disease Especially increasing the dose to the initial tumor area increases the rate of radical treatment, thereby reducing the local recurrence rate, increasing the patient's survival time The study also found that increasing radiation dose to the U area did not increase the side effects of radiation therapy on organs and organs, both acutely and late Through the research results, it is applied to consider a combination regimen with capecitabine and high-dose radiation therapy for patients in the inoperable stage, especially those tumors that have invaded surrounding tissues and have lymph nodes +) STRUCTURE OF THE THESIS Thesis consists of 114 pages Problem statement pages, documentary overview 36 pages, research objects and methods 17 pages, research results 24 pages, discussion 32 pages, conclusion pages In the thesis, there are 33 tables, charts, 11 figures, and illustrations The thesis uses 98 references, including 29 Vietnamese documents, the rest are English and French documents, including 45 new documents within the past 10 years CHAPTER DOCUMENTARY OVERVIEW 1.1 Rectal surgery The rectum is the last segment of the colon that connects with the sigmoid colon from the 3rd sacral vertebra to the anus Consists of parts: The rectal ball is located in the small pelvis, 12-15 cm long with the function of storing stool, the anal canal is located in the perineum, narrow and short: 2-3 cm has the function of holding and removing stools 1.2 Epidemiology and Pathophysiology of Rectal Cancer 1.2.1 Situation of colorectal cancer 1.2.1.1 In the world In developed countries, colorectal cancer is one of the most common cancers, ranking second among cancers (in men after lung cancer and in women after breast cancer) 1.2.1.2 Vietnam Cervical cancer ranks 5th among all types of cancer In Hanoi, the incidence of colorectal cancer is 4.7/100,000 people, while in Ho Chi Minh City, this rate is 6.8/100,000 people 1.2.2 Pathogenesis and risk factors for colorectal cancer 1.2.2.1 Nutritional factors 1.2.2.2 Precancerous lesions 1.2.2.3 Genetic factors 1.3 Histological characteristics of rectal cancer 1.3.1 Histopathological classification - Adenocarcinoma: - Squamous cell carcinoma - Carcinoid tumors: Prefer silver salts, dislike silver salts and mixed tumors - Non-epithelial neoplasms: Smooth muscle sarcomas, fibroids, neuromas - Malignant lymphoma 1.3.2 Natural progression of rectal cancer - Invasion in the rectal wall: - Invasive access: - Invasion by lymphatic route: - Metastasis by blood: 1.3.3 Degree of differentiation Broders' classification of differentiation: + Grade 1: > 75% differentiated cells + Grade 2: 50 – 75% differentiated cells + Grade 3: 25 – 50% differentiated cells + Grade 4: < 25% differentiated cells 1.3.4 Classification of rectal cancer stages according to histology TNM classification According to AJCC staging (8th edition 2018) Primary T- U32 TX The primary tumor cannot be assessed T0 No evidence of primary tumor Carcinoma Tis in situ: Invasion of the stroma T1 Tumor invades submucosa T2 Tumor invades muscle layer T3 Tumor invades the lower layer or into non-peritoneal or perirectal tissues Tumor T4 directly invades other structural and/or visceral peritoneal organs T4a penetrates directly into the surface of the visceral peritoneum T4b Tumor invades directly into other organs or structures N – Regional lymph nodes NX Can't assess regional lymph nodes N0 No regional lymph node metastasis N1 Metastasis in to regional lymph nodes N1a Metastasis to regional lymph node N1b Metastasis to 2–3 regional lymph nodes N1c No regional lymph nodes were positive, but tumor cells were present in the mesentery, or perirectal/rectal tissue M - Distant metastasis M0 No distant metastasis M1 Distant metastasis M1a Localized metastasis in an organ (liver, lung, ovary, extra-regional lymph node(s)) without the peritoneum, M1b Metastasis in multiple organs M1c Metastasis to the peritoneum with or without organ involvement 1.4 Clinical characteristics, practical cancer of rectal cancer 1.4.1 Clinical Manifestations - Physical symptoms: + Rectal bleeding: + Disturbances of intestinal circulation + Change stool mold + Some colorectal cancer patients come to the clinic because of complications of the tumor such as semi-obstruction, intestinal obstruction, perforation causing peritonitis - Systemic symptoms: + Anemia: + Skinny 1.4.2 Rectal examination Manual rectal examination is the classic method of assessing cancer invasion by determining the extent of tumor mobility relative to the rectal wall and surrounding tissues 1.4.3 Endoscopic 1.4.4 Diagnostic imaging methods 1.4.4.1 Conventional X-ray 1.4.4.2 Computed tomography (CT scan) 1.4.4.3 Magnetic resonance imaging (MRI): Breast cancer is one of the indications for high-force magnetic resonance imaging (from 01 Tesla or more) of the subframe to detect and evaluate the tumor stage and regional lymph nodes High-force magnetic MRI machines can very effectively evaluate the wall of the digestive tract, especially the TT lesions Classification of invasiveness on MRI according to Franco includes stages 89 T1 T2 T3 T4 Invasion of mucosa and submucosa Invasion of sphincter and longitudinal muscle Invasion of surrounding fat tissue Invasion into surrounding organs Imaging of lymph nodes on MRI: + Dimensions over mm + Damage with heterogeneous signal + Round or oval shape 90 1.4.4.4 Endorectal ultrasonography (EUS) When rectal cancer is present, the endorectal ultrasound image is usually a tumor or a hypoechoic mass, sometimes non-homonymous, disrupting the normal structure of the rectal wall or invasive depending on the stage paragraph 95.96 1.4.4.5 PET-CT (Positron Emission Tomography -CT) 1.4.5 Other tests 1.4.5.1 CEA test 1.4.5.2 Test for potential blood in the stool 1.4.5.3 Tests Complete blood count, blood chemistry, blood group to evaluate bilan and side effects of treatment 1.4.5.4 Scintigraphy with specific monoclonal antibodies is being studied for the diagnosis of recurrent and metastatic colorectal cancer 1.4.5.5 KRAS gene mutation test Mutations in codon 12 or 13 of KRAS are strongly associated with failure to respond to anti-EGFR antibody treatment in patients with metastatic colorectal carcinoma.42 1.5 The treatments 1.5.1 Surgical treatment of rectal cancer 1.5.2 Radiation therapy for rectal cancer 1.5.4 Chemical treatment: Chemicals used in the study: FU: Xeloda: Main active ingredient: Capecitabine, a cytostatic drug, 150mg and 500mg tablets, route of administration: Oral 1.6 Some research in the country and international on precautional chemicals and release in contact cancer 1.6.1 Some studies on radiation therapy for rectal cancer in Vietnam Author Doan Huu Nghi, through 529 patients treated for colorectal cancer at K hospital in the period 1975-1983 and 1984-1992, showed that: Preoperative radiotherapy has the effect of reducing pain (71.1%), reducing the feeling of straining and pain reduction in the number of bloody stools (63.5%) was obvious in the majority of cases24 Pham Cam Phuong Researched 87 patients with locally advanced low rectal cancer who received accelerated radiation therapy with dose of 46 Gy combined with Capecitabine before surgery at the Nuclear Medicine and Oncology Center of Bach Mai Hospital and the Department of Cancer Radiotherapy Hospital K from 6/2009-12/2012 showed that: 100% of patients had a functional response after chemotherapy and radiotherapy, 46.0% of patients lowered the disease stage, 90.8% of patients achieved a response after treatment, 9.2% of patients had a complete response, 79.3% of patients had surgery, of which 67.8% of patients had radical surgery; 12.6% of patients had anal sphincter-conserving surgery 46 1.6.2 Some studies on preoperative chemoradiotherapy in rectal cancer in the world Kim JC et al studied on 95 patients with advanced stage low rectal cancer who received preoperative chemotherapy and radiotherapy with a dose of 46Gy in the whole pelvis and 4Gy in addition to tumor lesions Capecitabine was used daily at a dose of 1650mg/m2 Surgery was performed to weeks later followed by cycles of capecitabine (2500 mg/m 2/day for 14 days followed by cycles of capecitabine) followed by a 14-day stage reduction rate of 71% (56/79) on endorectal ultrasonography and there were 76% (71/94) histopathological response In a total of 54 patients with tumors about 5cm from the anal margin, 40 patients (74%) preserved anal sphincter 48 According to Kim JS and colleagues, 45 patients with stage T3, T4 or N+ cancer were treated with preoperative chemotherapy and radiation 45Gy radiotherapy to the pelvis, followed by radiation therapy adding 5.4 Gy to the primary tumor Chemotherapy used concurrently with radiation therapy: oral cycles of capecitabine (1650mg/m2/day) and leucovorin 20mg/m2/day for 14 days, cycle of 21 days 48 De Bruin AF, Nuyttens JJ and colleagues studied 80 patients with locally advanced stage cancer who were treated with preoperative chemotherapy and radiotherapy Radiation therapy with a total dose of 50 Gy to the pelvic region Chemotherapy given concurrently with oral capecitabine on days of radiotherapy results: Lowered tumor and lymph node staging in 67 patients (84%) Corvu R, Pastrone I et al: Preoperative radiotherapy alone or in combination with chemotherapy helps to lower tumor stage and increase the rate of anal sphincterotomy, thereby improving survival time and quality survival 49 Valentini V, Coco C, Rizzo G and colleagues studied 100 patients with stage T4 and M0 cervical cancer who were treated with preoperative chemotherapy and radiotherapy The results showed that 78 patients had radical surgery, the rate of postoperative sphincteric preservation subject is 57% 33 12 - Tumor size: Before treatment, most of the patients had large tumor size >3/4 of intestinal lumen: 83.9% After treatment, this rate decreased to 14.3% The proportion of patients with tumor size 1/2-3/4 of the intestinal lumen before treatment also decreased from 12.9% to 3.6% after treatment - Invasive nature: Before treatment, 67.7% of patients had tumors invading other structures and organs, the rate after treatment was only 7.2% Tumors invading other organs before treatment changed to invasive in the muscle layer, accounting for 60.7% after treatment - Lymph nodes: The proportion of patients with lymph nodes decreased from 67.7% before treatment to 28.6% after treatment After treatment, no patient appeared to have metastases Endoscopic characteristics before and after treatment: Before treatment, 85 patients were found to have tumors After treatment, there were patients with no visible tumor In terms of tumor morphology: Warts decreased from 19.3% before chemotherapy to 1.2% Ulcer and ulcerative forms also decreased after chemotherapy and radiotherapy from 32.5% and 75.9% respectively before intervention to 2.4% and 6.0% after treatment This difference is statistically significant Regarding tumor size: The proportion of patients with tumor size >3/4 circumference decreased from 74.7% to only 19.3% after treatment The proportion of patients with tumor size accounting for 1/2 to 3/4 of the intestinal lumen also decreased from 21.7% to 8.4% after chemotherapy and radiotherapy These differences are all statistically significant Response rate after treatment - There were 84.7% of patients responding to treatment, of which 3.5% had a complete response, 81.2% of patients had a partial response and 15.3% had no response response 3.2.3 Rate of surgical methods Among 85 patients participating in the study, after chemotherapy and radiotherapy, there were 19 patients with sphincter-preserving radical surgery, accounting for 22.4%, 53 patients with radical sphincter destruction surgery, accounting for 62.4% and 13 patients with symptomatic surgery accounted for 15.2% 3.2.4 Change of markers before and after treatment There were 70 out of 85 patients who had a CEA marker test, the CEA index decreased from 10.9 ± 17.82 mmol/l before treatment to 4.1 ± 5.68 mmol/l after treatment This difference is statistically significant with p0.05 3.3.5 Other Unwanted effects - The most severe effect of accelerated radiation therapy is skin ulceration in the irradiated area In our study, up to 72.9% of patients had skin ulcers of grade and 5.9% of grade - 92.9% of patients with grade perineal pain; 3% pain grade 3.3.6 Late complications after accelerated radiotherapy in combination with capecitabine Late systemic and gastrointestinal complications after accelerated radiotherapy combined with capecitabine were also mild The most common complications were: 35.3% of patients with grade small bowel inflammation; 27.1% grade anal mucositis; 5.9% of patients have hand and foot syndrome grade 1; 4.7% of patients with anorectal ulcer; 3.5% grade stomatitis CHAPTER DISCUSSION 4.1 Some characteristics of the study group of patients 1.1.1 Age and gender In the study group of patients, the average age: 57.5 ± 10.4 years old; Minimum age 27; The oldest age was 79 Most of the patients were over 40 years old (92.0%) The disease is more common in men than women In terms of sex, men (70.1%) are times higher than women (34.5%) This is consistent with many studies by domestic and foreign authors Rectal cancer is mainly seen in people over 40 years of age and is more common in men than women The author Vo Van Xuan (2012) when studying on 56 colorectal cancer patients who received accelerated radiation therapy to increase the preoperative dose, showed that the proportion of patients with the disease aged over 40 years old was 96.4%, the average age was 60.7 years; Male/female ratio: 1.33/1 50 Author Pham Cam Phuong, when studying on 87 patients with moderate and low rectal cancer who received chemotherapy + radiation before surgery at K Hospital, showed that the majority patients over 40 years old (92.0%) The disease is more common in men than in women; Male/female ratio: 1.3/1 46 Author Joshua DI Ellenhorn (2006) research shows that the disease occurs mainly in people over 40 years old, more men than women, male/female ratio: 16 1.7 /151 According to author Thomas J George (2010); the disease occurs mainly in people over 50 years old, more men than women 38 4.1.2 Reason for hospitalize Cancer patients often come to the hospital for examination when there are unusual symptoms, causing discomfort and affecting life In this study, 95.4% of the patients who came to the examination and treatment for colorectal cancer were due to bloody mucus in the stools, the remaining cases were caused by intestinal circulation disorders 87.4%, stool changes 82.8 %… Our study is consistent with the study of other authors: According to the study of author Pham Cam Phuong, 90.9% of patients who come to the examination and treatment for colorectal cancer are due to bloody mucus in the stool 46 According to Hoang Minh Thang noted, the main reason for admission was bloody stools, accounting for 83% of the case52 4.1.3 Time from first symptom until hospitalize The mean time from onset of suspected symptoms to hospital admission was 5.8 ± 4.0 months According to Vo Van Xuan, the time to detect the disease ≤ months is 48.2% Patients come to the doctor in the first months when there are unusual symptoms 46 4.1.4 Surgery to make artificial anus on tumor before treatment In our study, patients underwent colostomy surgery before treatment These patients were treated with HXT, then assessed their response and performed a second surgery Among these patients, 20% had sphincterconserving radical surgery and 80% had muscle-destructive radical surgery tighten Pham Cam Phuong's study also gave similar results Among 10 patients undergoing colostomy before treatment, patients (60%) had surgery to remove tumors46, this is one of the factors indicating the success of the treatment method Preoperative HXT aims to shrink the tumor size to make surgery easier 4.1.5 Histopathological characteristics before treatment In this study, 100% of patients had histopathology of adenocarcinoma of which mainly moderately differentiated adenocarcinoma (77.0%), the results were consistent with other domestic and foreign authors Author Vo Van Xuan (2012) found that: adenocarcinoma accounted for 83.9% 50 Author Pham Cam Phuong's research showed that prostate cancer accounted for 89.6% 46 According to the author's research Pham Quoc Dat (2002), the proportion of prostate cancer accounts for 87.5% 39 4.2 Response after treatment 4.2.1 Functional response after treatment: 17 Symptoms of bloody stools and bowel movements many times a day mainly gradually decreased and then ended in the second week of treatment This difference was statistically significant with P3/4 of the bowel circumference, 12.9% of the size of the tumor is from 1/2 -3/4 of the bowel circumference 93.5% of patients MRI with invasive tumor In which, most of the invasion is to other structures and organs, 29% is in the subserosal layer 21/31 patients had lymph node images 18 Table 3.11 shows about tumor size: Before treatment, most of the patients had large tumor size >3/4 of the intestinal lumen, accounting for 83.9% After treatment, this rate decreased to 14.3% The proportion of patients with tumor size from 1/2-3/4 of the intestinal lumen before treatment also decreased from 12.9% to 3.6% after treatment About invasion: Before treatment, most patients had invasive tumor (96.8%) After treatment, this rate was 71.4% Invasive nature: Before treatment, 67.7% of patients had tumors invading other structures and organs, the rate after treatment was only 7.2% Tumors invading other organs before treatment changed to invasive in the muscle layer, accounting for 60.7% after treatment Lymph nodes: The proportion of patients with lymph nodes also decreased from 67.7% before treatment to 28.6% after treatment After treatment, no patient appeared to have metastases According to a study by Nguyen Hoang Minh, "Study of 96 rectal cancer patients who received 1.5 Tesla magnetic resonance imaging and radical surgery, rectal resection and lymph node dissection at K Hospital from October 2009 to April 2012", the rate of lymph node metastasis was 46.9% The number of metastatic lymph nodes and the rate of metastasis to the base of the vascular base gradually increased with the level of cancer invasion according to the circumference of the rectal lumen Magnetic resonance imaging helps to correctly diagnose 83.9% of metastatic lymph nodes with size < - 10 mm and 93.9% of metastatic nodes with size > 10 mm 53 According to Pham Cam Phuong: The rate of stage reduction is 44 ,4% after treatment Especially after treatment, 13.0% of patients on subframe magnetic resonance imaging have reduced to stage or no abnormalities were detected 46 By comparing tumor and lymph node lesions on 1.5 Tesla subframe magnetic resonance imaging, it is possible to objectively assess the response rate after treatment Author Sun Ys Fau – Li et al., when studying on 97 colorectal cancer patients who were treated with HXT before surgery and evaluated the stage before and after treatment with 1.5 Tesla MRI, they showed the appropriateness in the diagnosis of stage T and histopathology was 73.2%55 4.2.3 Assessment of response through changes in CEA concentration In our study, 70 out of 85 patients tested for CEA markers, and the CEA index decreased from 10.9 ± 17.82 mmol/l before treatment to 4.1 ± 5.68 mmol /l after treatment This difference is statistically significant with p 5ng/ml in this study was higher than that of author Nguyen Cong Hoang 57 However, the proportion of patients with CEA > 5ng/ml was similar to that of 19 author Pham Cam Phuong but low 46 than author Hoang Manh Thang because author Hoang Manh Thang's study also selected patients with distant metastases58 This also partly represents a low response rate after treatment For patients with high pretreatment CEA levels, response can be assessed through the change in CEA levels before and after treatment Author Kim, J Y et al showed that: measuring the CEA levels after treatment help predict survival time and follow up after treatment for patients with stage III colorectal cancer In patients with pretreatment CEA levels > ng/ml; If this concentration decreases exponentially after treatment (from 0.9 to 1.0), the 5-year survival time and the 5-year disease-free survival time are 62.3% and 58.6%, respectively In the group with the concentration decreasing almost like an exponential function (from 0.5 to 0.9), the 5-year survival time and the 5-year disease-free survival time were 48.1% and 52.7%, respectively Author Park, YA (2006) when univariate analysis showed that pretreatment CEA concentration > 5ng/ml was associated with poorer response to treatment than group with CEA concentration ≤ 5ng/ml61 Authors Koca D Fau et al (2012) studied on 221 patients with stage II, III colorectal cancer, showing that high CEA concentration after surgery is a bad prognostic factor of the disease 60 The authors around the world have shown that to assess the response after treatment can be based on the CEA concentration before and after treatment, in patients with high blood CEA concentration, this value of CEA concentration can prognostic significance and monitoring of treatment effectiveness 53,54,58,61,6668 4.2.4 Assessment of response based on the proportion of patients undergoing surgery In our study in Table 3.14, it shows that out of 85 patients participating in the study, after chemotherapy and radiation, 19 patients had radical surgery to preserve the sphincter, accounting for 22.4%, 53 patients had surgery radical sphincter destruction accounted for 62.4% and 13 patients with symptomatic surgery accounted for 15.2% The rate of radical surgery in our study is higher than that of Pham Cam Phuong (67.8%)46 Because all the patients participating in our study had surgery after chemotherapy + Preoperative radiotherapy, after 45Gy radiation therapy, we boost the dose to the initial tumor volume (CTV) to 50.4 Gy with the aim of increasing the maximum dose to the tumor and at the same time reducing the maximum dose to healthy tissues On the other hand, the patients in the study group all had a large tumor size (T3-T4), the tumor had invaded the serosa and surrounding tissues According to Pham Cam Phuong's study, only 79.3% of patients underwent surgery to explain this, the author said that these patients had a total radiation dose of 46 Gy without boosting the dose to U, on 20 the other hand, after treatment Treatment showed that the disease responded well, the functional symptoms improved a lot, the patient was afraid of having to wear an artificial anus, so he refused surgery In the study of Vo Van Xuan (2012) the rate of Miles surgery was 48.2%; Hartmann 10.7%; Conservative surgery: 23.2%; Exploratory surgery to make colostomy: 17.9% 69 Our study is also consistent with other authors in the world: Elwanis M (2009): 9.3% of patients achieved a complete response, 74.4% of patients had a low stage 46.5% of patients had anal sphincter-conserving surgery 35 Author Kim JC (2005): 98% of patients had radical surgery after chemotherapy and radiation 74% of patients preserved anal sphincter 12% of patients have no cancer cells after surgery 48 Author De Bruin AF et al (2008) studied 60 patients with locally advanced breast cancer who were treated with preoperative HXT XT with a total dose of 50Gy into the pelvic region in combination with oral capecitabine in the days of radiotherapy Surgery is performed 6-10 weeks after the end of HXT Results 19 patients underwent rectal perineal resection, 25 patients underwent lower rectal tumor resection, and 16 patients underwent Hartmann surgery 17 The majority of clinical trials in the world on preoperative HXT in colorectal cancer have shown a reduction in local recurrence rate (50-70%) and an improvement in survival time (about 10%) compared with other methods previous treatment Therefore, in recent years, the trend of preoperative HXT is increasingly being expanded and considered as a standard treatment for cervical cancer stage T3, T4 72 4.2.5 Assessment of response through histopathology after surgery In our study: patients (3.5%) had a complete response, and no cancer cells were found on their specimens, 69 patients (81.2%) had a partial response, only 13 patients had a partial response patients (15.2%) did not respond For patients with partial response, we performed immunohistochemical staining and further evaluation of some histopathological indicators of these 69 patients, 85.1% had ulceration of the epithelial layer; 79.3% had degenerative changes in the intestinal wall; 75.9% of patients have coagulation degeneration cells; 71.3% of patients had fibrotic changes; 54.0% of patients had reactive epithelial changes at the site; 41.4% Lympodegenerative changes in metastatic nodes This proves that there is a marked change in tumor cells and lymph nodes after treatment The author Huebner et al (2012) conducted a study on 237 patients with stage I, II, III breast cancer who were treated with HXT and then underwent surgery and found that the tumor regression level was 0.05 This rate is also similar to the study of 22 Pham Cam Phuong: Before treatment, 4.5% of patients had high blood creatinine levels, after treatment the number of patients with grade I elevation of creatinine decreased to 3, 4% Before treatment, 5.7% of patients had grade I AST elevation; After treatment, the proportion of patients with grade I AST elevation increased to 9.2%; There were no patients with increased AST grade II, IV; 2.3% of patients increased AST grade III 46 When applying systemic chemotherapy, clinicians need to monitor liver and kidney toxicity If the toxicity is severe, it is necessary to stop treatment, reduce the dose and use diuretics and liver drugs In fact, in daily treatment, we give patients extra electrolytes, vitamins, drugs to protect liver cells, guide the patient to a diet, enough rest and the right way to help reduce the effects side effects of radiotherapy and chemotherapy, increasing the proportion of patients completing the full treatment regimen The combination of chemoradiotherapy - preoperative chemotherapy to improve the treatment effectiveness of locally advanced low rectal cancer has few undesirable effects and is tolerable by patients, with high safety 4.3.3 Other unwanted effects The most severe effect of accelerated radiation therapy is skin ulceration in the irradiated area In our study, up to 73.6% of patients had skin ulcers in grade I and 5.7% in grade II 93.1% perineal pain grade I and II, 3% burning pain grade II 36.8% of patients had grade I nausea, 8.0% of patients had mild symptoms of vomiting 81.6% of patients had mild diarrhea 59.8% of patients felt abdominal pain at level I Only 3.4% of painful urination was at level I Assessing this side effect, we found that all patients in the study group were in stage I Inoperable segments T3, T4, low or medium rectal position, there are cases where the tumor is close to the anal margin, the radiation field must ensure the coverage factor when the U volume is exhausted, the radiation dose is high (50.4 Gy) and the invasive tumor area, the perineal area always has many potential risk factors for ulceration On the other hand, the rectum located in the subframe adjacent to many organs such as: bladder, small intestine, prostate, seminal vesicles (in men), uterus, vagina, ovaries (in women), all of these organs located in a narrow cavity, sometimes a virtual space such as the vagina and bladder, so during radiation therapy it is inevitable that these organs must be subjected to a certain dose of radiation Currently, with the equipment of many modern radiotherapy machines (Multiple energy levels, munti leaves ) allows the application of many modern radiotherapy techniques such as: IMRT, VMART to help increase the dose of radiation tumor and reduce the dose to healthy organs and organs According to the author Adalsteinn Gunnlaugsson (2007) if radiation dose to the small intestine > 15Gy, there is a relationship between grade II diarrhea 23 and irradiated small intestine volume Radiotherapy doses of 1.8 Gy or Gy/day were not associated with grade II diarrhea 72 Author Corvo R et al (2003): when conducting a study with Capecitabine during radiation therapy at a dose of 850mg/m2 twice a day Severe hand foot syndrome occurred in patients (15%), this is also the most common complication; Severe diarrhea is uncommon, leukopenia is mild and reversible The study showed that the response rate after HXT was 31% and helped to increase the rate of anal sphincter preservation 49 The study by author de Las Heras M Fau - Arias et al (2013) showed that 32.8% of patients with grade I, II diarrhea and 5.1% of patients had grade I, II skin lesions There are 6.9% of patients with grade III diarrhea No toxicity grade IV 34 The study showed that the unwanted effects of the regimen were at an acceptable level, with little impact on the treatment process and the patient's daily life 4.4 Increased lifetime 4.4.1 Total survival time in years Within the first years after the end of treatment, there were 16 deaths, the 5-year overall survival time reached 81.2% The mean overall survival time was 59.9±1.72 months Through the study "Evaluating the results of preoperative chemoradiotherapy in invasive rectal cancer" by the authors Nguyen Van Hieu, Le Van Quang, Bui Cong Toan, Le Quoc Tuan The results showed that: The rate of total response on histopathology was 90.3%, complete response was 6.5%, rate of radical surgery was 80.7%, of which 12.9% had conservative surgery sphincter retention The 3-year disease-free survival time was 78.1% The side effects on the hematology system are grade I, II; Other side effects are less common The authors concluded, preoperative chemoradiotherapy had a high response rate, improved the rate of radical surgery and anal sphincterpreserving surgery The method of concurrent chemoradiotherapy is safe, low toxicity, side effects at low level 80 The study of Chu QD et al in 2016 showed that the 5-year overall survival time for stage IIIA was 73.5%, stage IIIB, C was 51.1% (P