ABBREVIATIONS AJCC American Joint Committee on Cancer ASCO American Society of Clinical Oncology CTV Clinical Target Volume CR Completed Respon EBRT External Beam Radiation Therapy FIGO Fédération Internationale de Gynécologie et d'Obstétrique GTV Gross Tumor Volume HDR High Dose Rate HPV Human Papilloma Virus IHC Immunohistochemistry IV Irradiated Volume LDR Low Dose Rate PR Partial Respon PTV Planning Target Volume TV Treatment Volume UICC Union for International Cancer ControL WHO World Health Organization 1 INTRODUCTION 1. Scientific aims Cervical cancer is one of the most common cancers in women. It is the first leading cause of death in women in the world. In 2008, there are 529 800 new cases of cervical cancer worldwide (accounting for 9% of total newly cancer patients) and an estimated 275.100 women die of this disease (8% of total cancer deaths). According to a cancer registry in Hanoi from 1998 to 2007 in Vietnam, there are 2.093 new cases of cervical cancer, accounted for 7.3% of total cancers in women, with age-standardized incidence rate of 6.8 / 100.000. Although the screening program of cervical cancer has been deployed but the rate of inoperable stage (IIB, III) cervical cancer is still account for over 50% of new cases. For early stages, cervical cancer has high cure rate with surgery or radiation therapy alone, or a combination of the two methods. However, patients in the later stages as IIB, III have low response rate and high relapse rate, this has promoted new studies to find the effective treatments, and one of the regimens mentioned that chemotherapy in concurrent with radiation. The roles of chemotherapy in combined with radiation therapy aims to increase the sensitivity of tumors to radiotherapy and kill the metastatic lesions. A series of prospective trials have shown that cisplatin in combined with radiation have high response rate and survivals than radiation alone have. Patients with stage IIB-IIIB cervical cancer, radiation therapy is external beam pelvic radiation in combined with brachytherapy. Both low-dose rate (with Radium 226, cesium 137) and high-dose rate (with Ir-192) brachytherapy are currently being used. Recently, high-dose rate brachytherapy is preferred for higher efficiency, higher safety and shorter duration of treatment. High-dose rate brachythepary has been applied in K hospital since 8/2008 but no reports of results, which is why we conduct research “Evaluating the results of high-dose rate brachytherapy in combined with external beam radiation therapy and cisplatin in the treatment of stage IIB-IIIB cervical cancer”. 2. Objectives 2.1. To evaluate the results of high-dose rate brachytherapy in combined with external beam radiation therapy and cisplatin in the treatments of stage IIB-IIIB cervical cancer. 2.2. To assess the toxicity of high-dose rate brachytherapy in combined with external beam radiation therapy and cisplatin in the treatments of stage IIB-IIIB cervical cancer. 3. The contributions of the thesis Confirmed the role and effectiveness of HDR brachytherapy in combined with EBRT and cisplatin in the treament of stage IIb-IIIb cervical cancer. 2 Overall response rate was 90.5%, complete response rate was 73.2%. The 1 year, 2 years, 3 years and 4 years overall survival rates were respectively 97.8%, 90.7%, 80% and 40.4%. Average survival time of the patients was 42.1 ± 1.2 (months). The 4-year overall survival rate of the response patients were higher than the not response patients were (42.0% compared with 14.9%), p <0.01. The 4-year overall survival rate of anemia patients were lower than those who were not anemia (14.5% compared with 47.5%), p <0.01. The local recurrence rate was 8.2%. The metastasis rate was 16.6% which is the most common location of lung metastases (5%). To assess the hematological toxicities, the hepatic and renal toxicities of the regimen. Leukopenia, neutropenia, anemia are the most common toxicity, higher rates in the last cycles of chemotherapy. Evaluating the late toxicities of the gastrointestinal tract and the urinary tract showed that gastrointestinal complications were 74.4%, bleeding proctitis accounted for the highest percentage (40.8%), followed by diarrhea (31.2%), rectovaginal fistula (0.6%), intestinal necrosis (0.6%). Urinary complications were 10.1%, including dysuria (5.7%), irritation during urination (3.8%), hematuria (0.6%). The rate of late complications in the first year was 69.3%, the second year was 14.0%, the third year was 1.2%, no patients had the late toxicities in the fourth year. Average time of post-treatment late toxicities was 7.9 ± 5.5 months. 4. The structure of the thesis The thesis consists of 108 pages, with 4 main chapters: Introduction 2 pages , Chapter 1 (Overview) 35 pages 35, Chapter 2 (Patients and Methods) 17 pages, Chapter 3 (results) 24 pages, Chapter 4 (discussion) 27 pages, Conclusion and recommendation 3 pages. The thesis has 28 tables, 6 pictures and photos and 15 diagrams, 128 references (102 Vietnamese and 26 English). CHAPTER 1: OVERVIEW 1.1. The burden of cervical cancer 1.2. Anatomy and histology of the cervix 1.3. Risk factors 1.4. Pathogenesis of cervical cancer 1.5. Screening 1.6. Diagnostic workup 1.6.1. Carcinoma in situ 1.6.2. Invasive cervical cancer 1.6.2.1. Signs and symptoms 3 1.6.2.2. Tests 1.6.3. Staging AJCC Tumor- Node- Metastases (TNM) and International Federation of Gynecology and Obstetrics (FIGO) Surgical Staging Systems for Carcinoma of the Uterine Cervix TNM FIGO T(Tumor ) T 2B II B Tumor with parametrial invasion T 3 III Tumor extends to pelvic wall and/or involves lower third of the vagina and/or causes of hydronephrosis or nonfunctioning kidney T 3A III A Tumor involves lower third of the vagina, no extension to pelvic wall T 3B III B Tumor extends to pelvic wall and/or causes of hydronephrosis or nonfunctioning kidney N (Regional lymph node): Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis M (Distant Metastasis) M0 No distant metastasis M1 Distant metastasis Stage T N M IIB T2b N0 M0 III T3 N0 M0 IIIA T3a N0 M0 IIIB T3b Any N M0 T1-3 N1 M0 AJCC (2010). Cancer staging manual, seventh edition. 1.7. Treatment of cervical cancer 1.7.1. The treatment of carcinoma in situ 1.7.2. The treatment of stage IA 1.7.3. The treatment of stage IB-IIA 4 1.7.4. The treatment of stage IIB-III Chemoradiation - Single- agent weekly Cisplatin with the dosage of 40 mg/m 2 in 5 weeks. - A typical regimen of EBRT is 50 Gy, followed by 50 Gy to point A with brachytherapy for a total dose of 65 Gy to point A. 1.7.5. The treatment of stage IV 1.7.6. Improvements in the treatment of cervical cancer 1.7.6.1. Accelerated radiation therapy 1.7.6.2. Brachytherapy in the treatment of cervical cancer - Low-dose rate brachytherapy - High-dose rate brachytherapy 1.7.6.3. Chemoradiation 1.7.6.4. Best supportive care 1.8. Cisplatin drug informations 1.9. Common toxicities of the regimen 1.10. Previous studies Foreign studies: Lorvidhaya et al [74] studied of 1992 cervical cancer patients were treated with high dose rate brachytherapy, the 5 years relapse-free suvival of stage IB, IIA, IIB, IIIA, IIIB, IVA, IVB were respectively 79.5%, 70%, 59.4%, 46.1%, 32.3%, 27.8% and 23.1%. Research by JC Kim et al [64] on 135 stage IIIA-IIIB cervical cancer patients were treated with chemoradiation, the 5 years overall survival rate was 37.5%. In results announced by Toita T et al [115] in 40 stage IIB-IIIB cervical cancer patients, the 3 years overall survival was 79%. Teshima et al [112] published results of treatment of 430 patients (171 patients LDR, HDR 259 patients) in combined with external beam radiation therapy, the grade 2 and 3 pelvic toxicity rates of HDR were higher than those of LDR (10% vs. 4%, p = 0.002). In the study by Arai et al [29] on 147 stage I patients, 256 stage II patients, 515 stage III patients, 104 stage IV patients showed grade 3 and 4 toxicity rate in the rectum was 4.1%, in the bladder was 1.2%, in the small intestine was 1.1%. Author Nakato T et al [83] did the study in 210 stage IIIB cervical cancer patients, the results showed the rate of late toxicities in HDR and LDR groups were respectively 6% and 10%. Vietnamese studies: Bui Dieu studied on 226 stage IB-IIA cervical cancer patients at Hospital K from 1992 to 2003, the 5-year overall survival rates of the Caesium 137 brachytherapy group and Radium 226 brachytherapy group were respectively 65.5% and 50.8%. The study by Nguyen Van Tuyen on 331 patients with stage IB-II cervical cancer treated with surgery in combined with radiotherapy in 5 from 1999 to 2002, the recurrence rate after 5 years was 11.7%, metastasis rate was 15.0%, the 5-year overall survival rate was 76.4% , the 5-years disease-free survival rate was 74.3%. The results from study of Thi Tuyet Anh Cung et al on 45 patients with stage IIB-IIIB cervical cancer treated with chemoradiation showed the response rate was 88.9%. Chapter 2: PATIENTS AND METHODS 2.1. Patients 157 patients with stage IIB-IIIB cervical cancer were treated with cisplatin in combined with high-dose rate brachytherapy and external beam radiation therapy from 8/2008 to 8/2011 at K hospital. 2.1.1. Patient criteria - The patients with stage IIB - IIIB cervical cancer according to TNM and FIGO classification are eligible for this study. - Histopathology was carcinoma of the cervix - No prior chemotherapy or radiotherapy - The patients must have a performance status of 0, 1 and 2 ECOG score (Eastern Cooperative Oncology Group). - Blood counts are in the normal range (granulocytes> 2000/ml, platelets> 100.000/ml, Hb> 9g/dl). - Total serum bilirubin < 1.5 mg/dL and SGOT, SGPT <2.5 x normal. - Serum creatinine <1.5 x normal and serum ure < 10,9 mmol/l. - Patients who do not suffer from other acute and chronic severe diseases. - Patients have reliable follow-up information. 2.1.2. Exclusion criteria of patients. - The patients have PS of 3-4 according to ECOG score. - The patients are not in stage IIB-IIIB. - Patients who dropped out during treatment. - Patients have abnormal bone marrow functions or hepatic failure or renal failure. - Patients who are pregnant, breast-feeding. - Patients have other sever diseases (cardiovascular, psychiatric disorders, other cancers ). 2.2. Methods 2.2.1. Research design: Randomized un-controlled clinical trial. All eligible patients were enrolled the trial. 2.2.2. Sample size 6 The sample size was calculated by the formula: n = 2 2/1 α − Ζ 2 )1( d PP − 2.2.3. Steps 2.2.3.1. Clinical and test characteristics before treatment • The clinical features: + Age, sex, time from first symptoms on admission (in months), the symptoms: abnormal vaginal bleeding, back pain + Clinical examination: To evaluate tumor location, size, shape (warts, sores, infection ), and bleeding, extensive surrounding tissue • Laboratory tests + Complete blood count + Blood chemistries + SCC-Ag serum for monitoring during and after treatment. • Radiologic tests + All patients underwent MRI to evaluate the spread of the tumor. + CT sim plan radiation therapy. + Abdominal ultrasound: assessment of other organs, abdominal lymph nodes. + Chest X-ray: detecting metastatic lung lesions. Chest- CT if required for better disease evaluation. + Bone- scan: detecting metastatic bone lesions. • Histopathology: Histopathological classification according to WHO. • Confirmed diagnosis is based on clinical and histopathology. • Staging of the disease is based on clinical and MRI. 2.2.3.2. Treatment plan • Intravenous cisplatin - Cisplatin 40 mg/m 2 IV weekly x 5 weeks in concurrent with EBRT - Cisplatin does not use in the day of brachytherapy. - External radiation is started 2-2.5 hours after cisplatin injection. Administration: - Before the drug infusion: 1.5-2 liters Glucose 5% or 0.9% Natriclorid IV - Cisplatin is diluted with 500 mL 0.09 percent sodium chloride for injection. Patients were given Manitol 10-20% (100 ml for 20 mg cisplatin/m2). Fluid administration should be adequate to establish a urine flow of at least 100 mL/hour for two hours prior to and two hours after cisplatin administration. 7 - Other drugs: Odansetron x 8 mg, Depersolon x 30 mg IV before cisplatin injection and 200ml 0.9% Natriclorid, Odansetron x 8 mg IV after cisplatin injection to prevent side effects. Patients were assessed for their general condition, symptoms, complete blood count, live function and kidney function tests prior to each treatment cycle. If neutrophils <2.0 x 10 9 /l or platelets <100 x 10 9 /l or the other grade 2-3 toxicities (except anemia), chemotherapy should be delayed until recovering. • External beam radiation therapy - Posture patients: + Lie on your back. + Two hand on her chest. - CT simulation confirmed adequate coverage of the iliac lymph nodes. The caudad extent of disease can be determined by inserting radiopaque markers in the cervix or at the lowest extent of vaginal disease. Potential internal organ motion must be taken into account, particularly in the design of lateral treatment fields. - Anterior- posterior pelvic radiation fields + Body in the 0 position. + The upper limit: S1-S2 or L4-L5. + The lower limit: including vaginal and orifice of ureter with stage II, III. + The lateral limits: Head of the femur. The body turns 180 degrees. - Lateral pelvic radiation fields. + Body turns 90 degrees to the left or 270 degrees to the right. + The goal is increasing the pelvic lymph nodes dosage and decreasing surface dosage. + The front limit: pubic bone. + The behind limit: sacrum bone. + The lower and upper limits are the same as interior- posterior fields. Dose and fractionation: + Fractionation of 1,8-2 Gy/ day, 5 days/ week. + Total dose: 50 Gy + Increase dose 10 Gy for patients with large lesions in pelvic lymph nodes parameter. • High- dose rate brachytherapy - Prepare the patient: + Patients enema before treatment. + Used prophylactic antibiotics. 8 + Injection premedication before 10-15 minutes. + Foley bladder sonde during treatment. - Brachytherapy is usually delivered using afterloading applicators that are placed in the uterine cavity and vagina. Vaginal packing is used to hold the tandem and colpostats in place and to maximize the distance between the sources and the bladder and rectum. Radiographs should be obtained at the time of insertion to verify accurate placement, and the system should be repositioned if positioning can be improved. - Radioactive sources: Iridum use 192 (HDR) - Paracentral doses are most frequently expressed at a single point, usually designated Point A. This reference point has been calculated in a number of different ways. The most accepted definition of Point A is a point 2 cm lateral to the cervical collar and 2 cm above the top of the colpostats, measured at their intersection with the tandem midpoint on the lateral radiograph. - The time and dose of radiation therapy: a treatment period is 8-30 minutes, 4-6 times, once a week, every 5-7 Gy in fractionation. Total dose of 60-65 at point A. Depending on the size of the primary tumor, stage of disease, response to radiotherapy of the tumor that total radiation dose can be changed to achieve optimal efficiency. 2.3 Monitoring and evaluation criteria A. Outcomes ∗ Response criteria: Imaging modalities for response evaluation should be MRI. According to RECITS: Complete response; Partial response, Stable disease, Progressive disease. ∗ Definition of outcomes - Getting information of the patients by routine examination, mails or phone numbers. - On study criteria: The day start the treatment - Off study criteria: + Death. + Lost to follow-up. + Withdrawal of consent for any further data submission. - Reviewing the 1-year, 2-year, 3-year and 4-year overall survivals. - Recurrent events: New lesions appear at ≥ 6 months after treatment. Confirmed recurrence by clinical examination, imaging, cytology and histopathology (if possible). - Metastasis events: metastasis diagnosis based on clinical examination, diagnostic imaging, cytology and histopathology (if possible). - Status of patients: Alive, death, healthy, recurrence or metastasis. 9 - The overall disease-free survival was defined as the time from randomization until loco regional recurrence, metastasis, or death by any cause. B. Common toxicities ∗ Hematological toxicities, hepatic toxicities and renal toxicities Common Toxicity Criteria for Anticancer Drugs (WHO) Adverse Event Grade 0 Grade I GradeII GradeIII Grade IV Leukocytes (x 10 3 ) ≥ 4 3 - 3,9 2 - 2,9 1-1,9 < 1 Neutrophils (x 10 3 ) ≥ 2 1,5 - 1,9 1 - 1,4 0,5-0,9 < 0,5 Hemoglobin (g/L) ≥ 125 100-24,9 80- 99,9 65-79,9 < 65 Platelets (x 10 3 ) 150-450 75 - 149 50- 74,9 25-49,9 < 25 SGOT and/or SGPT ≤ 40 40,1-100 100,1-200 200,1-800 ≥ 800,1 Creatinin (mmol/L) ≤ 120 120,1-180 180,1-360 360,1-720 ≥ 720,1 ∗ Late complications: the urinary and gastrointestinal systems 2.4. Data collection and statistics 2.4.1. Collecting data based on the available medical records 2.4.2. Data processing ∗ The information is encoded and processed by SPSS 16.0 software. ∗ The statistical algorithms: description, comparative tests ∗ Analysis of survival: Using Kaplan-Meier estimator to estimate survival. CHAPTER 3: RESULTS 3.1. Patient characteristics Staging characteristic Stage Patients % 10 [...]... stage IIIA According to Cung Thi Tuyet Anh, 45 patients were treated with concurrent chemotherapy and HDR brachytherapy, the stage IIB rate was 55.6% and the stage IIIB rate was 44.4% 18 Table 4.1.1 Staging characteristics of patients Researcher n Stage StageIII IIB A Le Phuc Thinh (2005) 999 66,96% Ngo Thi Tinh (2005) 243 52,8% 2,6% Nguyen Ba Duc et al (2005) 30 20% Cung Thi Tuyet Anh (2007) 45 55,6%... our study similar to Le Phuc Thinh’s study about staging rates, however, differ from the results of Ngo Thi Tinh, Cung Thi Tuyet Anh 4.2 Results Response rates Numbe r of patients Duenas-Gonzalez 2005 Zarbá 2003 80 36 Watanabe 2006 25 Nguyen Ba Duc 2004 30 Tran Tu Quy 2005 Cung Thi Tuyet Anh 2007 46 45 Nguyen Tien Quang 2012 157 Stage IB2-IIB IIBIVA IIBIVA IIBIIIB IB-IIIB IIBIIIB IIBIIIB Overall respons... 76 84,4 17,4 4,4 90,5 73,2 17,3 Table 4.2.1 Response rates Zarba (2003) dis the study on 36 patients with stage IIB-IVA cervical cancer, the overall response rate was 97.1% (88.8% CR, 8.3% PR) Cung Thi Tuyet Anh (2007) did the study on 45 cases of stage IIB-IIIB cervical cancer, the response rate was 88.9% The research of Watanabe (2006) showed overall response rates of stage IIB-IVA patients were 96%... local-recurrence rates was 27%, followed by peritoneum (14%), liver (4%), lung (17%), bone (3%) Bui Dieu did the study in the patients were treated with Radium 266 and Caesium 137 brachytherapy, the recurrence rates were 6.2% and 4.4%, the metastatic rates were 23% and 15.9%, the most common organ was pelvic lymph nodes in, followed by lung and supraclavicular lymph nodes 4.3 Toxicities and complications... result of our study was similar to results of Gillian Thomas Local-recurrence and metastases In our study, there were 26 metastatic patients accounted for 16.6% The more common metastatic organs were lung metastases 5%, supraclavicular lymph nodes metastases (3.8% ), mediastinal lymph nodes metastases (2.6%), peritonial metastases (2.6%), liver metastases (1.3%), bone metastases (1.3%) There were 13... freedom 1; P < 0,01 Table 3.2.2.4 Overall survival according to anemia status 14 Local- recurrences and metastases Organs 2 1,3 Supraclavicular metastases Mediastinal lymph nodes Peritoneal metastases Lung metastases Bone metastases Local recurrance and 6 4 4 8 2 13 3,8 2,6 2,6 5 1,3 8,2 39 Local-recurrence Tỷ lệ (%) Liver metastases Metastasis n 24,8 pelvic Total Table 3.2.2.5 Local- recurrences and... was higher than patients with anemia (47.5% compared with 14.5%), p . Intravenous cisplatin - Cisplatin 40 mg/m 2 IV weekly x 5 weeks in concurrent with EBRT - Cisplatin does not use in the day of brachytherapy. - External radiation is started 2-2.5 hours after cisplatin. hours after cisplatin administration. 7 - Other drugs: Odansetron x 8 mg, Depersolon x 30 mg IV before cisplatin injection and 200ml 0.9% Natriclorid, Odansetron x 8 mg IV after cisplatin injection. therapy and cisplatin in the treatments of stage IIB-IIIB cervical cancer. 2.2. To assess the toxicity of high-dose rate brachytherapy in combined with external beam radiation therapy and cisplatin