1 ABBREVIATIONS AJCC American Joint Commitee on Cancer BN Patient BTV Biological target volume CLVT Computed Tomography GĐ Stage GTV Gross tumor volume HT Chemotherapy HXT Chemoradiotherapy HMMD Immunohistochemistry HMNT Ostomy IGRT Image guided radiation therapy IMRT Intensity modulated radiation therapy IQR Interquartile range M Metastasis MBH Pathology MRI Magnetic resonance imaging N Lymph nodes NCCN National Comprehensive Cancer Network PET/CT Positron emission tomography/computed tomography PT Surgical RHM Anal margin SUV max Standardized Uptake Value maximum T Tumor cTNM clinical TNM pTNM pathological TNM TRG Tumor regression grade TT Rectum XT Radiation UTBM Adenocarcinoma UTĐTT Colorectal cancer UTTT Rectal cancer WHO World Health Organization INTRODUCTION 1. Scientific aims 2 Colorectal cancer is one of the common cancers in our country and around the world. The incidence of this cancer is increasing. In developed countries, colorectal cancer ranks the second most common cancer, after lung cancer in men and breast cancer in women. In France, each year there are about 34,500 cases of colorectal cancer and approximately 16,800 deaths. In the United States, there is about 41,000 new cases every year, 6-13% of new patients with stage T4 disease. Approximately 5-30% of these patients will have recurrence. In Vietnam, colorectal cancer is among common cancers and ranks sixth in all cancers, with the incidence of 9.2/100,000 population and the mortality rate of 5.0/100,000 population. Currently, almost rectal cancer patients present with late- stage disease, and the lesions have invaded the surrounding tissues. Due to this, the rate of radical and anal preserving surgery is low, particularly when the tumor has invaded in the sacrum (T4). Therefore, survival and quality of life is not high. In recent years, locally advanced rectal cancer patients have been treated by preoperative radiotherapy. But there are still cases resistant to radiation (Vo Van Xuan: The rate of complete response after preoperative radiotherapy: 8.9%). The proportion of palliative care patients with ostomy was high (according to Vo Quoc Hung: 21.5%). In the world today, the treatment of rectal cancer is progressing and changing. Many authors are researching new techniques, medications and coordinating methods in order to improve the efficiency of treatment and quality of life. One of these is preoperative radiochemotherapy. There have been some studies using capecitabine plus preoperative radiotherapy (45 to 50.4 Gy) for locally advanced rectal cancer patients. These studies showed positive results: down-stage, increased the rate of anal sphincter-preserving surgery (Elwanis et al, 2009: down- stage after radiochemotherapy was 74.4%) In Vietnam until now there have been no studies about this issue, specifically assessing the effectiveness of preoperative radiochemotherapy for locally advanced rectal cancer patients (T3, T4). Therefore, we are undertaking this study: "Evaluating the effects of preoperative radiochemotherapy with Capecitabine in low locally advanced rectal cancer" 2. Objectives 2.1. Evaluating the effectiveness of preoperative radiochemotherapy with Capecitabine in low locally advanced rectal cancer 2.2. Assessing the side effects of this regime 3. The contributions of the thesis - Confirmed the role and effectiveness of Capecitabine combined with preoperative radiotherapy in low locally advanced rectal cancer. The functional response: 100%; response rate 90.8%; complete response: 9.2%; the down-stage: 46.0%. The tumor volume expended to rectal circumference was decreased after treatment. Before treatment: 52.9% of patients with tumors expanded entire circumference and this dropped 16.1% after treatment. 2.3% of patients tumors had a complete response after treatment. 40.0% of patients fell over 10,000 mm3 tumor volume on 1.5Tesla magnetic 3 resonance image. 40.2% of patients had before treatment CEA levels > 5ng/ml, of these patients 91.4% had reduced levels of CEA after treatment. 79.3% of patients were operated, in which 67.8% had radical surgery and 12.6% underwent anal sphincter-preserving surgery. 9.2% of patients had recurrence or metastasis and 11.5% of patients died in the follow-up of 36 months. - Assessed the haematological, hepatic and renal toxicities of this regimen: preoperative radiation plus Capecitabine in low locally advanced rectal cancer: low toxicities, mostly grade 1 and 2. - Evaluated the gastrointestinal, urinary tract and skin complications of this regimen. The majority of patients had undesirable effects with low rates at grade 1 and 2 (nausea, vomiting, stomatitis, diarrhea): 23.0%, 20.7%, 1.1%; 5.7%, respectively, 39.1% of patients had red inflamed skin in the radiated area, 12.6% had ulcers in irradiated skin, 32.2% of patients had cystitis and 24.1% of patients had pain in the anus. 4. The structure of the thesis The thesis consists of 121 pages, with 4 main chapters: Introduction 2 pages, Chapter 1 (Overview) 32 pages, Chapter 2 (Patients and Methods) 18 pages, Chapter 3 (results) 33 pages, Chapter 4 (discussion) 32 pages, Conclusion and recommendation 3 pages. The thesis has 39 tables, 23 pictures, 12 diagrams, 126 references (30 Vietnamese, 95 English and 1 French). CHAPTER 1: OVERVIEW 1.1. Anatomy of rectum 1.2. Diagnostic workup 1.2.1. Signs and symptoms 1.2.2. Tests 1.2.3. Staging: according to AJCC: American Joint Committee on Cancer 2010 1.3. Treatment of rectal cancer 1.3.1. Surgery in rectal cancer 1.3.2. Radiation therapy in rectal cancer Preoperative radiation: helps reduce the size of the tumor, contributes to making surgery easier, increases the rate of radical and anal sphincter-preserving surgery. Some studies showed that preoperative radiotherapy reduces the 50% risk of local recurrence which significantly increases survival. Preoperative radiotherapy doses of 45Gy-50.4Gy in 5 weeks are being studied, becoming a more and more popular trend in reseach. Preoperative radiotherapy is indicated for locally advanced rectal cancer (stage T3, T4) 1.3.3. Chemotherapy in rectal cancer Radiochemotherapy: Recent researches shows that 5FU is an attractive radiosensitizer. Radiochemotherapy is indicated for locally advanced rectal cancer (stage T3, T4), N(-/+). So far, many studies about preoperative radiochemotherapy 4 for rectal cancer found the positive results included down-stage, reduced local recurrence and increased survival. Chemotherapy options and doses for concomitant chemotherapy during radiation: 1. 5FU 325-350mg/m 2 + Leucovorin 20mg/m 2 IV, bolus, d1-5, week 1 and 5 2. 5FU 400mg/m 2 + Leucovorin 100mg/m 2 IV, bolus, d1,2,11,12,21,22 3. 5FU 1000mg/m 2 IV, bolus, d1-5, week 1 and 5 4. 5FU 250mg/m 2 IV continuous infusion on days 1-14 and 22-35 and Oxaliplatin 50mg/m 2 IV d1,8,22,29 5. 5FU 225mg/m 2 continuous infusion 5 days per week, together with radiotherapy 6. Capecitabine 800-825mg/m 2 , bid po continuously, 5-7 days per week, together with radiotherapy 7. UFT 300-350mg/m 2 /day and Leucovorin 22,5-90mg/day po continuously, 5- 7 days per week, together with radiotherapy 1.4. Chemotherapy drug information used in research 1.5. Previous studies about preoperative radiochemotherapy in rectal cancer 1.5.1. Foreign studies: Kim JS et al (2002): Primary tumor and node downstaging occurred in 63% and 90% of patients, respectively. The overall downstaging rate, including both primary tumor and nodes, was 84%. A pathologic complete response was achieved in 31% of patients. Twenty-one patients had tumors located initially 5 cm or less from the anal verge; among the 18 treated with surgery, 72% received sphincter- preserving surgery. No Grade 3 or 4 hematologic toxicities developed. Other Grade 3 toxicities were as follows: hand-foot syndrome (7%), fatigue (4%), diarrhea (4%), and radiation dermatitis (2%). Kim JC et al (2005): Downstaging rate was 71% (56/79) on endorectal ultrasonography, and it was 76% (71/94) on pathology finding. No tumor cell was observed in the specimens of 11 patients (12%). 40 patients (74%) underwent sphincter-preserving procedures. Grade 3 toxicities were rare (diarrhea in 3% and neutropenia in 1%). Elwanis et al (2009): Preoperative chemoradiation resulted in a complete pathologic response in 4 patients (9.3%) and an overall downstaging in 32 patients (74.4%). Sphincter sparing surgical procedures were done in 20 out of 43 patients (46.5%). Toxicity was moderate and required no treatment interruption. Grade II anemia occurred in 4 patients (9.3%), leukopenia in 2 patients (4.7%) and radiation dermatitis in 4 patients (9.3%) respectively. Valentini V. et al (2009): 100 patients were included. R0 resection was performed in 78 patients. R0 resection rate was greater in females (93% vs 67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability to perform a sphincter-saving procedure was 57%, greater in middle rectal location. 1.5.2. Vietnamese studies: In Vietnam, radiation for rectal cancer was applied from the 1980s, only using preoperative Cobalt radiotherapy with doses of 36Gy. Since 2000, linear accelerators have been installed in Vietnam and have been used to treat rectal cancer. Đoàn Hữu Nghị (1994): preoperative radiotherapy is effective in reducing 5 pain (71.1%), decreased sensation tenesmus and reduce the number patients of bloody diarrhea (63.5%) in majority of cases. Author Pham Quoc Dat (2002): the average survival following preoperative radiation therapy was 70 months, after radiotherapy before and after surgery was 46.5 months and using radiotherapy postoperatively was 36 months. Vo Quoc Hung (2004) reviewed some of the clinical features and histology and evaluated the response of preoperative radiotherapy in rectal cancer at Hospital K with doses of 36Gy and 45Gy. This showed that 100% patients had improved functional symptoms, 41.0% patients had reduced tumor size ≥ 50%, 51.8% patients had tumor change from fixed to mobile after radiotherapy. Complications of preoperative radiotherapy include: perineal pain 83.9%, cystitis 33.9%, 16.9% digestive disorders, ulcers and cirrhosis on the irradiated area 8.9% and 7.1% intestinal adhesion. The rate of radical surgery was 78.5%, in which 21.4% had conservation surgery. Radiation therapy with a dose of 45Gy was better than 36Gy. Author Vo Van Xuan (2012) studied 56 rectal cancer patients treated by preoperative hyperfractionated radiation showed the complete response rate was 8.9%, partial response rate was 73.2%; entire response rate was 82.1%. Miles surgery was 48.2%, 10.7% Hartmann surgery, sphincter-preserving surgery: 23.2%; ostomies surgery: 17.9%. The studies of foreign authors showed that preoperative radiochemotherapy (Capecitabine + Radiation) for locally advanced rectal cancer patients had good results and increased the rate of radical and sphincter-preserving surgery. The response rate of radiochemotherapy is better than radiotherapy alone, less toxicity. In Vietnam, the T3, T4 stage rectal cancer patients were treated by preoperative radiation therapy but the results were not high. To update the new treatments to be similar to new regimens in the world, we undertook this study to evaluate the effectiveness of preoperative radiochemotherapy for locally advanced rectal cancer patients. Chapter 2: PATIENTS AND METHODS 2.1. Patients 87 patients with stage 3, 4 low rectal cancer treated by preoperative radiochemotherapy at The Center of Nuclear Medicine and Oncology, Bach Mai Hospital and Department of Radiation 4, K Hospital from 6/2009 to 12/2012 2.1.1. Patient criteria: - Patients diagnosed with low rectal cancer (tumors located ≤ 6 cm from the anal margin): it was histopathological adenocarcinoma, ring cell carcinoma, mucinous carcinoma, tumor was fixed or limited mobile, with or without lymph node metastasis, no distant metastasis. - Age ≤ 85; The patients must have Karnofsky > 60% or 1 - 2 ECOG score (Eastern Cooperative Oncology Group) - Good function of bone marrow, kidney and liver - Patients who do not suffer from other acute and chronic severe diseases. 2.1.2. Exclusion criteria of patients: - Patients diagnosed: + High, middle rectal cancer (tumors located > 6cm from the anal margin) 6 + Tumor was mobile (stage 1,2 according to Y.Mason) + Distant metastasis - Anal cancer: squamous cell carcinoma developed from skin and anal mucosa of external anus, inguinal lymph node metastasis. - Age > 85; The patients have Karnofsky ≤ 60% or 3-4 ECOG score 2.2. Methods: 2.2.1. Research design: The method was clinical intervention study without control p p Zn . 1 2 2 )2/1( ε α − = − The sample size was calculated by the formula: 2.2.2. Steps Patients who had the criteria will be selected in the study. Patient’ medical records were made in the standard form. Data collection selected by medical research form 2.2.2.1. Clinical and test characteristics before treatment: * Clinical characteristics * Subclinical characteristics + Colonoscopy + Pelvic MRI + Tests to evaluate the state of distant metastasis + CBC tests + Blood biochemical tests + Histology tests 2.2.2.2. Treatment plan: - All low rectal cancer patients with criteria received preoperative concurrent chemoradiotherapy: Chemotherapy: Oral Capecitabine (Xeloda) 825mg/m2 twice daily on radiotherapy days (5days/week), drug manufactured by Hoffmann-La Roche Radiation: • Radiotherapy technique: using a linear accelerator with three-dimensional technique (3D conformal) • Energy: 6 MeV and 15 MeV • Using CT simulation for planning treatment • Patients posture: prone, straight legs, two hands over head, fasting before radiotherapy. • The volume of radiation: tumor and lymph nodes and around the rectum location where tumor spreads • Beam: three or four beams • Using lead for shielding normal tissues (dose of radiation on the tumor and lymph nodes is maximal but the healthy surrounding organs is minimal) • Dose Radiation: Total dose: 46Gy/25 fractions, 200cGy/day, 5 days/week 2.2.2.3. Assess the effects of research + Subjective response: Evaluate response based on the functional symptoms, 7 patient’s answere on questions about: bloody diarrhea, frequency of defecation, tenesmus feeling, before and after treatment, compared on each with other of patients + Objective response: * Criteria for evaluation the response treatment after preoperative radiotherapy based on RECIST (Response Evaluation Criteria in Solid tumors): • Complete Response: Disappearance of all target lesions • Partial Response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter • Stable Disease: Neither sufficient shrinkage to qualify for Partial Response nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum longest diameter since the treatment started • Progressive Disease: At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions * Criteria for evaluation of tumor response: + Evaluate Response based on rectal examination before and after treatment: * Evaluate response based on compared tumor size and mobility * Based on compared the tumor volume with rectal circumference before and after treatment * Based on the down- stage according to Y. Mason classification + Assessing Response based on pelvic 1.5 Tesla MRI before and after treatment: * Evaluate response based on compared pelvic MRI before and after treatment on each patient: rate of down-stage * Evaluate response based on compared tumor volume before and after treatment on each patient with tumors were cubic form. Assessed by pelvic 1.5 Tesla MRI: the formula of tumor volume used: Volume = length × width × height × 0.52 • The change of tumor volume on MRI: tumor volume before treatment - tumor volume after treatment • The percentage of tumor reduced volume after treatment: = (tumor volume before treatment - tumor volume after treatment) x100/the tumor volume before treatment • Compared the value of tumor volume before and after treatment with Paired- Samples T Test * Assess tumor stage and lymph nodes before and after treatment by pelvic 1.5 Tesla MRI with TNM classification of AJCC 2010 + Assess Response by comparing CEA levels before and after treatment: * Assess based on compared CEA before and after treatment in each patient with CEA pre-treatment levels > 5ng/ml: • Assess by CEA before and after treatment: CEA level before treatment - CEA level after treatment • The average percentage of decreased CEA levels after treatment: (CEA 8 before treatment-after treatment)x100/CEA before treatment • Compare CEA levels before and after treatment: by Paired-Samples T Test + Assess Response based on the rate of surgery: * After radiation treatment, patients were evaluated response, noted side effects. Surgery was usually done after 3 weeks of radiation therapy. * Evaluate the rate of radical, anal sphincter-preserving surgery, after chemoradiotherapy and assessing tumor and lymph nodes stage after surgery (pT, pN) according to the TNM classification of AJCC 2010 + Assess Response based on histopathology after surgery: - Assess the rate of cell degeneration - Assess tumor regression grade (TRG) by Dworak et al: + TRG 0: No regression: Fibrosis was completely absent + TRG 1: Minor regression: Dominant tumor mass with obvious fibrosis in 25% or less of the tumor mass + TRG 2: Moderate regression: Dominant tumor mass with obvious fibrosis in 26% to 50% of the tumor mass + TRG 3: Good regression: Dominant fibrosis outgrowing the tumor mass; more than 50% tumor regression + TRG 4: Total regression: No viable tumor cells; only fibrotic mass - Evaluate the fibrosis around the tumor - Assess of mucosal tank - The phenomenon of fatty macrophage - The phenomenon of hemoglobin macrophages - The phenomenon epithelial regenerated reaction - The phenomenon slipped and ulcerated epithelium - The phenomenon of degenerative intestinal wall Divided the patients into two groups: Response: include complete response and partial response No response: include stable disease and progressive disease * Review the relationship between response with some factors such as age, sex, stage of disease, histological type, pretreatment CEA levels * Review the relationship between the tumor regression with some factors such as age, sex, stage of disease, histological type, pretreatment CEA levels + In case of progressive disease after radiochemotherapy, patients treated by radiation and chemotherapy or ostomies surgery 2.2.2.4. Assess the side effects (toxicities): according to WHO Common Toxicity Criteria for Anticancer Drugs and the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE) of National Cancer Institute 2009 2.3. STASTICS * The information is encoded and processed by SPSS 16.0 software * The statistical algorithms: description, comparative tests CHAPTER 3: RESULTS 9 3.2. Evaluate Response: 3.2.1. Functional response: Table 3.1. The rate of post-treatment functional response Functional response n % The percentage of response, patients identified (all symptoms) < 50% 12 13,8 ≥ 50% 75 86,2 Total 87 100 3.2.2. Evaluate Response based on rectal examination and rectoscopy before and after treatment: Figu re 3.1. The tumor volume with rectal circumference (RCC) 10 Figure 3.2. Changing stage after treatment 3.2.3. Assessing Response based on pelvic 1.5Tesla MRI: Table 3.2. Changing the tumor volume before and after treatment on MRI Changing the tumor volume before and after treatment (mm3) n % Increased 2 5,7 Decreased 0-1000 0 0 Decreased 1001-5000 8 22,9 Decreased 5001-10000 11 31,4 Decreased 10001-20000 6 17,1 Decreased > 20000 8 22,9 Total 35 100 The percent of average tumor volume decreased after treatment: 78,9 ± 17,3% [...]... 0 67 77,0 Nausea 1 18 20,7 2 2 2,3 0 69 79,3 Vomiting 1 16 18,4 2 2 2,3 0 86 98,9 Stomatitis 1 1 1,1 0 82 94,3 Diarrhoea 1 4 4,6 2 1 1,1 Total 87 100 Bảng 3.12 Hand foot syndrome Grade n % 15 No symptom Grade 1 Grade 2, 3 Total 84 3 0 87 96,6 3,4 0 100 Bảng 3.13 Side effects of radiation therapy on the gastrointestinal tract Grade 1 Grade 2 n % n % Anorectal mucositis 11 12,6 0 0 Anorectal ulcer Small... Total 7 15 0 0 8,0 17,2 0 0 Side effects Grade 3, 4,5 0 4 4,6 0 0 0 0 0 0 87 patients 0 0 0 0 Bảng 3.14 Side effects of radiation therapy on genital-urinary tract Side effects Cystitis noninfective Vaginal inflammation Total Grade 1 Grade 2 n % n % 20 23,0 8 9,2 7/38 female 18,4 0 0 87 patients Grade 3, 4, 5 0 0 Bảng 3.15 Side effects of radiation therapy on the skin Side effects Pelvic pain Skin ulceration... (40/87) patients were down-stage for both stages 3 and 4 The rate of tumor stage 4 reduced into stage 3 was 61.5%, higher than Vo Quoc Hung (2004): 51.8% It may be the reason that we combined chemoradiation therapy for advanced rectal cancer patients but Vo Quoc Hung have used radiation therapy alone Soumarova R et al (2010): They acquired data of 78 patients from 1 January 2005 to 31 December 2007... after treatment this percentage rose to 73.6% Author Vo Quoc Hung studying radiation therapy for rectal cancer patients also found the effectiveness CEA levels decreased after treatment: 46.2% patients have had CEA ≥ 5ng/ml before radiotherapy reduced to 29.5% after treatment Our study had the ratio of CEA > 5ng/ml is higher than Vo Quoc Hung but lower than Tran Bang Thong: 44.7% of his patients with... treatment this syndrome also gradually decreased Author Corvo R et al (2003): the study using capecitabine during radiotherapy (825 mg/m2/day through a bid administration) Severe hand-foot syndrome occurred in 7-15% of patients, representing the most commonly observed toxicity It is noteworthy that severe diarrhea with capecitabine during radiotherapy was not common Leukopenia frequently occurred but was... conformal radiation therapy are applied, improving dose at 46Gy and desired effect can be accepted Comparing with the study of authors Vo Quoc Hung, Pham Quoc Dat: the ratio of cystitis and painful anus, skin ulcers in treated area in this study was lower In the Vo Quoc Hung's research (2004), the complications of preoperative radiotherapy included: hot and perineal pain 83.9%, cystitis 33.9%, 16.9% digestive... of our study on 87 patients with low locally advanced rectal cancer treated by preoperative capecitabine and radiotherapy at the Center of Nuclear Medicine and Oncology, Bach Mai Hospital and Department of 4th Radiation, K Hospital from 6/2009-12/2012 show: 1 Effective treatment: Radiation therapy combined capecitabine before surgery was effective for low locally advanced rectal cancer, improved functional... treatments helped the patients to improve on specific symptoms specially with anxiety and discomfort symptoms such as bloody diarrhea, tenesmus, abdominal pain, weight loss This is appropriate with Vo Quoc Hung (2004): 100% patients improved functional symptoms Tumor volume compared with rectal circumference decreased after treatment: specially 2.3% patients with non-palpable tumors Prior treatment, there... countries the rate of surgery is lower In Vo Van Xuan’ study (2012) the Miles’ surgery rate was 48.2%, 10.7% Hartmann, anal sphincter conservation: 23.2%; ostomies: 17.9% According to the research by Vo Quoc Hung (2004): the rate of radical surgery 78.5% in which 21.4% conservation surgery It was explained by the proportion of surgical patients in this study were not high (20.7%), many patients had improved... from 6/2000 to 11/2001 informed the recurrence rate and metastasis after 5 years was 50% The author clarified that the success reason was the higher applied radiation dose (46Gy) and it combined with capecitabine, after operation patients also continued to treat by chemotherapy, so the rate of recurrence and metastasis were more improved The resuls of this study showed that a preoperative radiotherapy . radiochemotherapy with Capecitabine in low locally advanced rectal cancer" 2. Objectives 2.1. Evaluating the effectiveness of preoperative radiochemotherapy with Capecitabine in low locally. 1,1 Diarrhoea 0 82 94,3 1 4 4,6 2 1 1,1 Total 87 100 Bảng 3.12. Hand foot syndrome Grade n % 15 No symptom 84 96,6 Grade 1 3 3,4 Grade 2, 3 0 0 Total 87 100 Bảng 3.13. Side effects of radiation therapy. patients Bảng 3.15. Side effects of radiation therapy on the skin Side effects Grade 1 Grade 2 Grade 3, 4,5 n % n % Pelvic pain 11 12,6 10 11,5 0 Skin ulceration 7 8,0 4 4,6 0 Total 87 patients Bảng